WO2005049602A1 - Agents antibacteriens a la quinolone - Google Patents

Agents antibacteriens a la quinolone Download PDF

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Publication number
WO2005049602A1
WO2005049602A1 PCT/IB2004/003666 IB2004003666W WO2005049602A1 WO 2005049602 A1 WO2005049602 A1 WO 2005049602A1 IB 2004003666 W IB2004003666 W IB 2004003666W WO 2005049602 A1 WO2005049602 A1 WO 2005049602A1
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Prior art keywords
methyl
cyclopropyl
oxo
dihydro
carboxylic acid
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PCT/IB2004/003666
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English (en)
Inventor
Edmund Lee Ellsworth
Clarke Bentley Taylor
Sean Timothy Murphy
Mark Ryan Rauckhorst
Jeremy Tyson Starr
Kim Marie Hutchings
Chris Limberakis
Denton Wade Hoyer
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Warner-Lambert Company Llc
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Publication of WO2005049602A1 publication Critical patent/WO2005049602A1/fr

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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
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to compounds bearing a quinolone core structure which exhibit antibacterial activity, methods for their preparation, as well as pharmaceutically acceptable compositions comprising such compounds.
  • Antibacterial resistance is a global clinical and public health problem that has emerged with alarming rapidity in recent years. Resistance is a problem in the community as well as in health care settings, where transmission of bacteria is greatly amplified. Because multiple drug resistance is a growing problem, physicians are now confronted with infections for which there is no effective therapy. The morbidity, mortality, and financial costs of such infections pose an increasing burden for health care systems worldwide. As a result, alternative and improved agents are needed for the treatment of bacterial infections, particularly for the treatment of infections caused by resistant strains of bacteria.
  • X is N or C, provided that when X is N, R 5 is absent at that position;
  • Rj is (Ci-Qdalkyl, halo(C 1 -C 6 )alky], (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, heterocyclic, aryl, heteroaryl; and CH 2 (C 3 -C 6 )cycloalkyl;
  • R 2 is OH
  • R 2e and R 2e' are each independently H or (C 1 -C 6 )alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and X] and Y] are each independently NH or O;
  • R 3 , R 4 , and R 5 are each independently H, OH, halo, NRyR z , wherein R y and R 2 are each independently H or (Q- C 6 )alkyl,
  • R ⁇ and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO 2 , or NR X , wherein R x is H or (C 1 -C 6 )alkyl; and
  • R' ( R", R'", and R"" are each independently H, (Q-Q alkyl, -OCQ-QOalkyl, haloCd-C ⁇ alkyl, aryl,or heteroaryl;
  • R' is not -O(C 1 -C 6 )alkyl, and wherein "- ⁇ " indicates the point of attachment;
  • R c and R d are each independently H, (C 1 -C 6 )alkylnitrile
  • R 2a R2a' — (CR 2a R2a')g-0 QR 2b f wherein g is an integer from to 10j Q is as defined above, and R 2a and R 2a > are each independently H or (C 1 -C 6 )alkyl, or taken together with the carbons to which they are attached form a 3, 4, 5, or 6-membered substituted or unsubstituted ring, and R 2 is ( -C ⁇ alkyl, aryl, or heteroaryl,
  • TMTM indicates the point of attachment
  • p is 0 or 1
  • R 2c is H
  • R2a, R2b, and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH) 2 , OPO(O(C ⁇ -
  • R 2 d and R 2e are each independently H, (Ci-C ⁇ alkyl, or (C3-
  • R 2f and R 2 f are each independently H, (C ⁇ -Cg)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a 3, 4, 5, or 6 membered substituted or unsubstituted ring, and R 2g is (C 1 -C 6 )alkyl,
  • R e and R f are each independently H, C C ⁇ alkyl, haloalkyl, halo, or R e and R f taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring;
  • R g and R h are each independently H, alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring.;
  • R j and R k are each independently H, (C 1 -C 6 )alkyl, haloalkyl, (d-C 6 )alkyl-
  • X is N or C, provided that when X is N, R 5 is absent at that position;
  • Rj is (CrQ alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, heterocyclic, aryl, heteroaryl; and CH 2 (C 3 -C 6 )cycloalkyl;
  • R 2 is OH
  • R 2a is as defined above, n is an integer of from 2 to 10, Y is OH or NR 2c R2d, wherein R 2c and R 2c j are each independently H, (C 1 -C 6 )alkyl, or (C 3 -C 6 )cycloalkyl, or
  • TMTM indicates the point of attachment
  • 2a is as defined above
  • R 2e and R 2e - are each independently H or (d-C 6 )alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring
  • e is an integer of from 1 to 10
  • p is an integer of from 2 to 10
  • Xi and Yi are each independently NH or O
  • R 3 , R 4 , and R 5 are each independently H, halo
  • R y and R z are each independently H or ( - ) alkyl, ( -Q alkyl, halo(C C 6 )alkyl, O(C 1 -C 6 )alkyl, O(C r C 6 )haloalkyl, nitrile;
  • Ri and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO 2 , or NR X , wherein R x is H or (C C 6 )alkyl; and
  • z is O, 1, or 2;
  • R' is H
  • R c is H, (C 1 -C 6 )alkylnitrile
  • R 2b is (C 1 -C 6 )alkyl, aryl, or heteroaryl
  • R2a 5 R2b > and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH) 2 , OPO(O(C!- C6»2, or NR 2d R 2e , wherein R 2d and R 2e are each independently H, (C ⁇ -C6)alkyl, or (C3-
  • R 2 f and R 2 f are each independently H, (Cj-C6)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a
  • R 2g is
  • R e and Rf are each independently H, -C ⁇ alkyl, haloalkyl, halo, or R e and R f taken together with the carbon to which they are attached form a
  • R g and Rh are each independently H, C t -C ⁇ alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring.
  • X is N or C, provided that when X is N, R 5 is absent at that position;
  • Ri is (CrC 6 )alkyl, halo(C 1 -C 6 )alkyl,
  • R 2 is OH, OBF 2
  • R 2a is as defined above, n is an integer of from 2 to 10
  • Y is OH or NR 2c R 2 d, wherein R 2c and R 2 d are each independently H, (C 1 -C 6 )alkyl, or (C 3 -C6)cycloalkyl, or
  • R 2e and R 2e - are each independently H or ( -C ⁇ alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and X 1 and Y] are each independently NH or O;
  • R 3 , R , and R 5 are each independently H, halo,
  • R y and R z are each independently H or ( -C ⁇ ) alkyl
  • R x and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO 2 , or NR X , wherein R x is H or (C ⁇ -C 6 )al yl; and
  • z is O, l, or 2;
  • R' is H
  • R a and R b are each independently H, (C 1 -C 6 )alkyl, ( -C ⁇ alkoxy, haloC -
  • Rc is H
  • R 2c is H
  • R2 a> 2 b> and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH) 2 , OPO(O(C ⁇ -
  • R 2d and R 2e are each independently H, (C ⁇ -C6)alkyl, or (C3-
  • R 2 f and R 2f are each independently H, (C ⁇ -C6)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a 3, 4, 5, or 6 membered substituted or unsubstituted ring, and R2 g is
  • R e and R f are each independently H, Ci-C 6 alkyl, haloalkyl, halo, or R e and R f taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring;
  • R g and R h are each independently H, -C ⁇ alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring;
  • R j and R k are each independently H, (C ⁇ -C6)alkyl, haloalkyl, (C 1 -C 6 )alkyl-
  • the invention is also directed to a compound of formula IV:
  • X is N or C, provided that when X is N, R 5 is absent at that position;
  • R t is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, heterocyclic, aryl, heteroaryl; and CH 2 (C 3 -C 6 )cycloalkyl;
  • R 2 is OH, OBF 2
  • R 2e and R 2e - are each independently H or (C 1 -C 6 )alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and X ⁇ and
  • Y] are each independently NH or O;
  • R 3 , R 4 , and R 5 are each independently H, halo,
  • R y and R z are each independently H or ( - C 6 )alkyl
  • Ri and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO 2 , or NR X , wherein R x is H or (d-C ⁇ alkyl; and
  • z 0, 1, or 2;
  • R a and R b are each independently H, ( -C ⁇ alkyl, (C 1 -C 6 )alkoxy, haloC - C 6 )alkyl, halo, or R a and R b taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring;
  • R' is H, halo
  • R c and R d are each independently H
  • R 2b is (C 1 -C 6 )alkyl, aryl, or heteroaryl
  • TM ⁇ indicates the point of attachment
  • p is 0 or 1
  • R 2c is H, (C 1 -C 6 )alkyl
  • R 2a , R 2b , and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH) 2 , OPO(O(C ⁇ -
  • R 2d and R 2e are each independently H, (C; ⁇ -C(j)alkyl, or (C3-
  • R 2g is
  • R e and R f are each independently H, C C 6 alkyl, haloalkyl, halo, or R e and R f taken together with the carbon to which they are attached form a
  • X is N or C, provided that when X is N, R 5 is absent at that position;
  • Rj is (Q-Q alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, heterocyclic, aryl, heteroaryl; and CH 2 (C 3 -C 6 )cycloalkyl; R 2 is OH,
  • OCd-C ⁇ alkyl O(C 3 -C 6 )cycloalkyl, O 0-(CHR 2a ) m -0 Q R 2b 5 wherein m is an integer from 1 to 10, Q is O or NH or N(C 1 -C 6 )alkyl or is absent, and R 2a is H or (C 1 -C 6 )alkyl and R 2b is aryl, or heteroaryl, 0-(CHR 2a ) n -Y ⁇ wherein R 2a is as defined above, n is an integer of from 2 to 10, Y is OH or NR 2o R 2 d, wherein R c and R 2 d are each independently H, (C 1 -C 6 )alkyl, or (C 3 -C 6 )cycloalkyl, or NR 2a , wherein R 2a is as defined above,
  • R 2e and R 2e > are each independently H or ( -C ⁇ alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and X ⁇ and Yi are each independently NH or O;
  • R 3 , R_ ⁇ , and R 5 are each independently H, halo,
  • R y and R z are each independently H or ( - C 6 )alkyl, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, O(C ⁇ -C 6 )haloalkyl, nitrile; R ⁇ and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- pr 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO 2 , or NR X , wherein R x is H or (C 1 -C 6 )alkyl; and
  • q is 0, 1, 2, or 3 and z is 0, 1, or 2;
  • R b is H, ( -C ⁇ alkyl, haloCd-C ⁇ alkyl, halo, or R a and R b taken together with the carbon to which they are attached form a 3,4,5 or 6- membered substituted or unsubstituted ring;
  • R', R", R'", and R" are each independently H, (d-C 6 ) alkyl, -O(C C 6 )alkyl, haloCQ-C f alkyl, aryl, or heteroaryl;
  • R c and R d are each independently H, (C 1 -C 6 )alkylnitrile
  • R 2b is (C ⁇ -C 6 )alkyl, aryl, or heteroaryl
  • R 2c is H, (C ⁇ -C 6 )alkyl, O(C ⁇ -C 6 )alkyl, (C3-C7)cycloalkyl, aryl, heterocyclo, heteroaryl, or
  • R 2a , R 2b , and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH) 2 , OPO(O(C!-
  • R 2d and R 2e are each independently H, (C ⁇ -C6)alkyl, or (C3-
  • R 2f and R 2f are each independently H, (C ⁇ -C6)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a 3, 4, 5, or 6 membered substituted or unsubstituted ring, and R 2g is
  • R e and R f are each independently H, Q-C ⁇ alkyl, haloalkyl, halo, or R e and
  • R f taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring
  • R g and R h are each independently H, CrC 6 alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring
  • R f taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring
  • R g and R h are each independently H, CrC 6 alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring
  • R f taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring
  • R g and R h are each independently H, CrC 6 alkyl, haloalky
  • R j and R are each independently H, (Q-C ⁇ alkyl, haloalkyl, (C 1 -C 6 )alkyl-
  • a pharmaceutical formulation comprising a compound of one of formula I, ⁇ , HI, IV, V, or VI admixed with a pharmaceutically acceptable diluent, carrier, or excipient.
  • What is also provided is a method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of formula I, ⁇ , HI, IV, V, or VI.
  • alkyl refers to a linear or branched hydrocarbon of from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • the alkyl group can also be substituted with one or more of the substituents selected from lower (C ⁇ -C( ) )alkoxy, (Cj-C ⁇ thioalkoxy, halogen, aryl, heteroaryl, oxo, thio, -OH, -SH, -F, -CF ,- OCF 3 , -NO 2 , -CO 2 H, -CO 2 (C ⁇ -C 6 )alkyl, or — O,
  • (C 3 -C 6 )cycloalkyl means a hydrocarbon ring containing from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Where possible, the cycloalkyl group may contain double bonds, for example, 3-cyclohexen-l-yl.
  • the cycloalkyl ring may be unsubstituted or substituted by one or more substituents selected from alkyl, alkoxy, thioalkoxy, hydroxy, thiol, halogen, for yl, carboxyl, -CO2(Ci -C ⁇ alkyl, -CO(C ⁇ -C6)alkyl, aryl, heteroaryl, wherein alkyl, aryl, and heteroaryl are as defined herein, or as indicated above for alkyl.
  • substituents selected from alkyl, alkoxy, thioalkoxy, hydroxy, thiol, halogen, for yl, carboxyl, -CO2(Ci -C ⁇ alkyl, -CO(C ⁇ -C6)alkyl, aryl, heteroaryl, wherein alkyl, aryl, and heteroaryl are as defined herein, or as indicated above for alkyl.
  • substituted cycloalkyl groups include fluorocycl
  • halo includes chlorine, fluorine, bromine, and iodine.
  • haloalkyl means a (Cj-C ⁇ lkyl group substituted with one or more halo.
  • aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms, and being unsubstituted or substituted with one or more of the substituent groups recited above for alkyl groups including, halogen, nitro, cyano
  • Examples include, but are not limited to phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- methoxyphenyl, 3-methoxy ⁇ henyl, 4-methoxyphenyl, 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 3-chloro-2-methylphenyl, 3- chloro-4-methylphenyl, 4-chloro-2-methylphenyl, 4-chloro-3-methylphenyl, 5- chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4- dichlorophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, naphthyl, 4-thionaphthyl, tetralinyl, anthracinyl, phenanthreny
  • heteroaryl means an aromatic cyclic or polycyclic ring system having from 1 to 4 heteroatoms selected from N, O, and S.
  • Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5- imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5- 1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2- pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-
  • heteroaryl groups may be unsubstituted or substituted by 1 to 3 substituents selected from those described above for alkyl, alkenyl, and alkynyl, for example, cyanothienyl and formylpyrrolyl.
  • Preferred aromatic fused heterocyclic rings of from 8 to 10 atoms include but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7- benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7- benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
  • Heteroaryl also includes 2- and 3- aminomethylfuran, 2- and 3- aminomethylthiophene and the like.
  • heterocyclic means a monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring systems.
  • Monocyclic heterocyclic rings contain from about 3 to 12 ring atoms, with from 1 to 5 heteroatoms selected from N, O, and S, and preferably from 3 to 7 member atoms, in the ring.
  • Bicyclic heterocyclics contain from about 5 to about 17 ring atoms, preferably from 5 to 12 ring atoms.
  • Bicyclic heterocyclic rings may be fused, spiro, or bridged ring systems.
  • heterocyclic groups include cyclic ethers (oxiranes) such as ethyleneoxide, tetrahydrofuran, dioxane, and substituted cyclic ethers, wherein the substituents are those described above for the alkyl and cycloalkyl groups.
  • Typical substituted cyclic ethers include propyleneoxide, phenyloxirane (styrene oxide), cis-2-butene-oxide (2,3-dimethyloxirane), 3-chlorotetrahydrofuran, 2,6-dimethyl- 1,4-dioxane, and the like.
  • Heterocycles containing nitrogen are groups such as pyrrolidine, piperidine, piperazine, tetrahydrotriazine, tetrahydropyrazole, and substituted groups such as 3-aminopyrrolidine, 4-methylpiperazin-l-yl, and the like.
  • Typical sulfur containing heterocycles include tetrahydrothiophene, dihydro- l,3-dithiol-2-yl, and hexahydrothiophen-4-yl and substituted groups such as aminomethyl thiophene.
  • heterocycles include dihydro- oxathiol-4-yl, dihydro-lH-isoindole, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydro- oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
  • heterocycles containing sulfur the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothiophene.
  • protecting groups may have been used to allow synthetic manipulation of one functional group in the presence of other functional groups.
  • the appropriate use and choice of protecting groups is well-known by one skilled in the art. It is also to be understood that such groups not only serve to protect chemically reactive sites, but also to enhance solubility or otherwise change physical properties.
  • a good general reference for protecting group preparation and deprotection is Greene, Theodora, Protective Groups in Organic Synthesis; Wiley: New York, USA, 1991 and later editions.
  • invention compounds characterized by the presence of a protecting group as disclosed and described in Greene are also to be considered invention compounds.
  • ⁇ When a bond is represented by a line such as " ⁇ " this is meant to represent that the bond is the point of attachment between two molecular subunits.
  • patient means all mammals, including humans. Other examples of patients include cows, dogs, cats, goats, sheep, pigs, and rabbits.
  • a “therapeutically effective amount” is an amount of a compound of the present invention that, when administered to a patient, provides the desired effect; i.e., lessening in the severity of the symptoms associated with .a bacterial infection. It will be appreciated by those skilled in the art that compounds of the invention having one or more chiral centers may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
  • the present invention encompasses any racemic, optically-active, polymorphic, geometric, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine activity or cytotoxicity using the standard tests described herein, or using other similar tests which are well known in the art. Certain compounds of the invention are also useful as intermediates for preparing other compounds of the invention. Thus, a compound wherein R 2 is BF 2 , can be hydrolyzed to form another compound of the invention wherein R 2 is H.
  • pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinates suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzensoulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge, S.M. et. al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1-19).
  • the acid addition salt of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine,
  • N-methylgluc amine N-methylgluc amine
  • procaine see, for example, Berge S.M., supra., 1977.
  • the base addition salts of said acidic compounds are prepared by contacting the free acid orm with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • a “prodrug” is an inactive derivative of a drug molecule that requires a chemical or an enzymatic biotransformation in order to release the active parent drug in the body.
  • a specific value for X is C or N.
  • a specific value for R] is (C ⁇ -
  • a specifc value for R 3 is H or NH .
  • a specific value for R is H or halo.
  • a specific value for R5 is halo, methyl, trifluoromethyl, methoxy, fluoromethoxy, difluoro ethoxy, or trifluoromethoxy when X is C.
  • a specific value for X is C or N.
  • a specific value for ⁇ is cyclopropyl or fluorocyclopropyl.
  • a specific value for R 3 is H or NH 2 .
  • a specific value for R 4 is H or F.
  • a specific value for X is C or N.
  • a specific value for R 5 is halo, methyl, or methoxy.
  • R l3 R 3 , and R5 are as provided in the following structures, wherein R 2 is OH, OBF 2 , or O(C ⁇ -C 6 )alkyl,
  • A is or 2. Specifically, z is 0, 1, 2, when q is 2 or 3; alternatively, z is 1 or 2 when q is 0, 1, 2, or 3.
  • R', R", R'", and R"" each independently can be H, (Q- C 6 )alkyl, -O(C 1 -C 6 )alkyl, halo(C 1 -Ce)alkyl, aryl,or heteroaryl. More specifically, R', R", R 1 ", and R”" are each independently H, fluoro, methyl, ethyl, flouromethyl, fluoroethyl, phenyl, benzyl, or methoxy.
  • B is R f R e R - R W
  • R' is not -O(C ⁇ -C 6 )alkyl.
  • R c and R each independently can be H, (C 1 -C 6 )alkylnitrile,
  • R c and R each independently are H, methyl, or ethyl.
  • R e and R f each independently can be H, -C ⁇ alkyl, haloalkyl, halo, or R e and R f taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring. More specifically, R e and R f each independently are H, methyl, or ethyl.
  • R g and Rh each independently can be H, Ci-C 6 alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring. More specifically, R g and R h each independently are H, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl, isoxazolyl, carboxymethyl, carboxyethyl, or O )
  • R j and R k each independently can be H, ( -C ⁇ alkyl, haloalkyl, (d-C 6 )alkyl-NR c R d , (C 1 -C 6 )alkyl-OR c , aryl, heteroaryl, heterocycle,
  • R d O (C-i -C 6 )alkyl Z— R d ⁇ wherein z is 0 or j ⁇ or Rj and Rk tB ⁇ sa together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring. More specifically, Rj and R k each independently are H, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl,
  • B can or
  • B can have any of the following structures:
  • R is CH 2 CH 2 CN.
  • R is CH 2 CN.
  • R is CH 2 CH 2 CN. Also given the description of A and B, encompasses any of the following structures r
  • R c is H or (C 1 -C 6 )alkyl and R is CH 2 CN.
  • compounds of the present invention are characterized by a quinolone core, covalently bound to a C-7 sidechain , 0 r .
  • the invention compounds can be prepared via coupling of a suitably C-7 substituted quinolone core, wherein X 2 is halo, triflate, or a similar reactive group known to the skilled artisan, and an appropriately substituted azetidine, pyrollidine, piperidine.
  • the first part describes the synthesis of the requisite quinolone core precursors.
  • the second part describes the synthesis of the requisite C-7 sidechain precursors.
  • 3-(l- tert-butoxycarbonylamino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidine-l-carboxylic acid tert-butyl ester was prepared from 3-formyl-pyrrolidine-l -carboxylic acid tert-butyl ester by the addition of lithiated isopropylcyanide to the intermediate a- amidoalkyl sulfone.
  • the compound was prepared as provided in WO 96/39407.
  • cyclopenta[c]pyrrol-3a-ylmethyl)-carbamic acid tert-butyl ester Alternatively, if the reduction of the ester moiety in 2-benzyl-hexahydro- cyclopenta[c]pyrrole-3a-carboxylic acid methyl ester is stopped at the aldehyde oxidation state (for example, by employing DIBALH as the reducinig agent), a reductive amination using ammonium formate or a primary alkyl amine such as methyl or ethyl amine can be employed to provide the aminated product. Reductive amination conditions and reagents are readily known to the skilled artisan.
  • Coupling of the sidechain precursor to the quinolone core precursor to provide the compounds of the present invention or precursors to compounds of the present invetnion can occur from either the core precursor as the free acid, alkyl ester, or borate ester, as depicted in Scheme II.
  • a molar excess of the side chain precursor is combined with the quinolone core in a polar solvent such as acetonitrile.
  • a molar excess of an amine base such as triethylamine is added, and the reaction mixture is heated to about 80 °C.
  • the reaction mixtures becomps homogenous.
  • the mixture is heated for sufficient time to drive the raction to completion, typically from about 3 to about 12 hours.
  • the mixture is then worked up according to procedures widely uused by the skilled artisan to provide a compound of the invention.
  • the quinolone core, sidechain, and triethylamine are combined in a solvent such as acetonitrile.
  • the resulting reaction mixture is heated to 80 °C and stirred for 12 hours, is heated to about 80 °C.
  • the reaction mixtures becomes homogenous.
  • the mixture is heated for sufficient time to drive the raction to completion, typically from about 3 to about 12 hours.
  • the mixture is then worked up according to procedures widely uused by the skilled artisan to provide a compound of the invention.
  • the requisite borate ester is typically prepared from the free acid upon reaction with BF 3 according to conditions available to the skilled artisan.
  • the borate ester is typically combined with the side chain in a solvent such as acetonitrile and treated with an amine base such as triethylamine.
  • a solvent such as acetonitrile
  • an amine base such as triethylamine.
  • the resulting reaction mixture is typically stirred at room temperature for sufficient time to drive the reaction to completion, typically from about 24 to about 96 hours.
  • the mixture is then worked up according to procedures widely used by the skilled artisan (i.e., deprotection of the borate ester in ethanol in the presence of triethylamine) to provide a compound of the invention.
  • Coupling of the sidechain precursors to the quinolone core precursors may give rise to invention compounds.
  • post-coupling transformations may be necessary to give rise to invention compounds.
  • Typical post-coupling transformation include deprotection of protected amines to provide invention compounds of formula TJ, as depicted in Scheme IH. Deprotection, as well as reaction with acrylonitrile or the like, gives rise to invention compounds of formulas III and IV.
  • the present invention also provides pharmaceutical compositions which comprise a bioactive invention compound or a salt such or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.
  • the compositions include those in a form adapted for oral, topical or parenteral use and can be used for the treatment of bacterial infection in mammals including humans.
  • the compounds, such as antibiotic compounds, also referred to herein as antimicrobial compounds, according to the invention can be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other bioactive agents such as antibiotics. Such methods are known in the art and are not described in detail herein.
  • the composition can be formulated for administration by any route known in the art, such as subdermal, by-inhalation, oral, topical or parenteral.
  • the compositions may be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention can be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also.contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present, for example, from about 1% up to about 98% of the formulation. For example, they may form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods will known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anesthetic preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain, for example, from about 0.1% by weight, e.g., from about 10-60% by weight, of the active material, depending on the method of administration.
  • each unit will contain, for example, from about 50-500 mg of the active ingredient.
  • the dosage as employed for adult human treatment will range, for example, from about 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to about 1.5 to 50 mg/kg per day.
  • the dosage is, for example, from about 5 to 20 mg/kg per day.
  • the invention compounds can be screened to identify bioactive molecules with different biological activities using methods available in the art.
  • the bioactive molecules for example, can possess activity against a cellular target, including but not limited to enzymes and receptors, or a microorganism.
  • a target cellular ligand or microorganism is one that is known or believed to be of importance in the etiology or progression of a disease.
  • diseases states for which compounds can be screened for biological activity include, but are not limited to, inflammation, infection, hypertension, central nervous system disorders, and cardiovascular disorders.
  • the invention provides methods of treating or preventing a bacterial infection in a subject, such as a human or other animal subject, comprising administering an effective amount of an invention compound as disclosed herein to the subject.
  • an "infectious disorder” is any disorder characterized by the presence of a microbial infection, such as bacterial infections.
  • infectious disorders include, for example central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients.
  • the compounds and compositions comprising the compounds can be administered by routes such as topically, locally or systemically.
  • Systemic application includes any method of introducing the compound into the tissues of the body, e.g., intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oral administration.
  • the specific dosage of antimicrobial to be administered, as well as the duration of treatment, may be adjusted as needed.
  • the compounds of the invention may be used for the treatment or prevention of infectious disorders caused by a variety of bacterial organisms.
  • Gram positive and Gram negative aerobic and anaerobic bacteria including Staphylococci, for example S. aureus; Enterococci, for example E. faecalis; Streptococci, for example S. pneumoniae; Haemophilus, for example H. influenza; Moraxella, for example M. catarrhalis; and Escherichia, for example E. coli.
  • Other examples include Mycobacteria, for example M. tuberculosis; intercellular microbes, for example Chlamydia and Rickettsiae; and Mycoplasma, for example M. pneumoniae.
  • the ability of a compound of the invention to inhibit bacterial growth, demonstrate in vivo activity, and enhanced pharmacokinetics are, demonstrated using pharmacological models that are well known to the art, for example, using models such as the tests described below.
  • Test A Antibacterial Assays
  • the compounds of the present invention were tested against an assortment of Gram-negative and Gram-positive organisms using standard microtitration techniques (Cohen et. al., Antimicrob., 1985;28:766; Heifetz, et. al., Antimicrob., 1974;6:124). The results of the evaluation are shown in Tables IA and B.
  • N-(l-Benzhydryl-3-ethyl-azetidin-3-ylmethyl)-2,2,2-trifluoro-acetamide (3.67 g) was hydrogenated (Pd/C in 100 mL MeOH) with one equivalent of HCl overnight to give 2.40 g, (100 % yield) of the title compound which was used without purification.
  • Ammonium acetate (6.00 g, 77.8 mmol) was added to a mixture of 1-(1- benzhydryl-azetidin-3-yl)-propan-l-one (2.59 g, 9.27 mmol) and 4 angstrom molecular sieves (2.60 g) in methanol (80 mL). The mixture was cooled to 0 °C, and sodium cyanoborohydride (1.17 g, 18.5 mmol) was added in several portions.
  • NN-Dibenzylacrylamide (79.5 g, 0.317 mol) and ⁇ -(methoxymethyl)- ⁇ - (trimethylsilylmethyl)- ⁇ -methylbenzylmine (103 g, 0.412 mol) were dissolved in CH 2 C1 2 (1500 mL) and cooled to 0 °C.
  • Trifluoroacetic acid solution 1.0 M in CH 2 C1 2 , 27 mL was added over a period of 20 minutes and the resulting reaction mixture was stirred at room temperature overnight. The mixture was washed with aqueous NaHCO 3 , brine, dried over Na 2 SO 4 and concentrated. The residue was purified by flash chromatography (heptane-EtOAc-Et 3 N/10:2:0.1) to furnish 97.7 g of the title compound (77% yield) as a mixture of two diasteromers.
  • EtMgBr ethylmagnesium bromide
  • EtMgBr (3.0 M in ether, 150 mL, 0.450 mol) was added followed by the rapid addition of Ti(OzPr) 4 (54.6 g, 55.6 mL, 0.192 mol) in THF (150 mL). The resulting mixture was stirred at room temperature for 1.0 hour before it was quenched with aqueous ammonium chloride (3000 mL) and water (800 mL). The mixture was filtered through Celite, rinsed with ether. The organic layer was separated. The aqueous layer was made basic (pH ⁇ 8.5) with aqueous NaOH and extracted with ether.
  • the phthalimide (5.00g, 14.9 mmol) was taken up in isopropyl alcohol and charged with hydrazine hydrate (7.04g, 149 mmol). The resulting solution was heated to 60 °C. After 1 hour a colorless precipitate had formed. The reaction was diluted with isopropyl alcohol and filtered. The filter cake was washed with isopropyl alcohol and the combined filtrates were concentrated to give an off white oily solid.
  • reaction was then quenched with saturated aqueous ammonium chloride (NE C1) and extracted twice with CH 2 C1 2 .
  • the organic phase was washed with saturated aqueous NaHCO 3 , then dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • Diastereomer B (2.1 g) was separated by chiral HPLC using a ChiralPak AD column eluted with a methanol/ethanol gradient to give 0.87 g of isomer Bl (41%) and 0.53 g of isomer B2 (25%).
  • the solid was further purified via preparatory high performance liquid reverse phase chromatography eluting with a gradient of water (0.1% formic acid): acetonitrile (0.1% formic acid) (95:5 to 50:50) to afford a yellow residue.
  • the residue was dissolved in a minimum amount of water and lyophilized to deliver 19 mg (20%) of the title compound as a yellow solid.
  • the compound was approximately 75% parent and 25% formate salt by 1H NMR.
  • LC/MS (APCI) 427.2; HPLC purity 100%.
  • the invention compound, lactose, and com starch (for mix) are blended to uniformity.
  • the corn starch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste.
  • the paste is used to granulate the mixed powders.
  • the wet granules are passed through a No. 8 hand screen and dried at 80°C.
  • the dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet.
  • Such tablets can be administered to a human from one to four times a day for treatment of pathogenic bacterial infections.
  • Sorbitol Solution (70 % N.F.) 40 mL
  • the sorbitol solution is added to 40 mL of distilled water, and the invention compound is dissolved therein.
  • the saccharin, sodium benzoate, flavor, and dye are added and dissolved.
  • the volume is adjusted to 100 mL with distilled water.
  • Each milliliter of syrup contains 4 mg of invention compound.

Abstract

L'invention concerne des composés de formule (I) s'utilisant dans une grande variété d'applications, et notamment comme agents antibactériens.
PCT/IB2004/003666 2003-11-18 2004-11-05 Agents antibacteriens a la quinolone WO2005049602A1 (fr)

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US10435403B2 (en) 2015-06-09 2019-10-08 Bayer Pharma Aktiengesellschaft Positive allosteric modulators of muscarinic M2 receptor

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US8106072B2 (en) 2003-09-10 2012-01-31 Kyorin Pharmaceutical Co., Ltd. 7- (4-substituted-3-cyclopropylaminomethyl-1-pyrrolidinyl) quinolonecarboxylic acid derivative
WO2007019344A1 (fr) 2005-08-04 2007-02-15 Sirtris Pharmaceuticals, Inc. Dérivés d’imidazo [2,1-b] thiayole en tant que modulateurs de sirtuine
WO2007019416A1 (fr) 2005-08-04 2007-02-15 Sirtris Pharmaceuticals, Inc. Dérivés de benzimidazole en tant que modulateur du sirtuin
EP2468752A1 (fr) 2005-08-04 2012-06-27 Sirtris Pharmaceuticals, Inc. Dérivés de thiazolopyridine comme modulateurs de sirtuine
WO2007019345A1 (fr) 2005-08-04 2007-02-15 Sirtris Pharmaceuticals, Inc. Dérivés de l’imidazopyridine en tant qu’agents modulant la sirtuine
EP2388263A1 (fr) 2005-08-04 2011-11-23 Sirtris Pharmaceuticals, Inc. Dérivés d'imidazo[2,1-b]thiazole comme modulateurs de sirtuin
WO2007019417A1 (fr) 2005-08-04 2007-02-15 Sirtris Pharmaceuticals, Inc. Dérivés d’oxazolopyridine comme modulateurs du sirtuin
AU2007339692B2 (en) * 2007-01-05 2012-01-19 Daiichi Sankyo Company, Limited Fused substituted aminopyrrolidine derivative
CN101622240A (zh) * 2007-01-05 2010-01-06 第一三共株式会社 稠合取代氨基吡咯烷衍生物
TWI409068B (zh) * 2007-01-05 2013-09-21 Daiichi Sankyo Co Ltd 稠合經取代之胺基吡咯啶衍生物
CN101622240B (zh) * 2007-01-05 2014-07-23 第一三共株式会社 稠合取代氨基吡咯烷衍生物
WO2008082009A3 (fr) * 2007-01-05 2008-12-11 Daiichi Sankyo Co Ltd Dérivé d'aminopyrrolidine substitué lié par fusion
RU2443698C2 (ru) * 2007-01-05 2012-02-27 Дайити Санкио Компани, Лимитед Конденсированное замещенное производное аминопирролидина
US8618094B2 (en) 2007-01-05 2013-12-31 Daiichi Sankyo Company, Limited Fused substituted aminopyrrolidine derivative
US8222407B2 (en) 2007-05-24 2012-07-17 Kyorin Pharmaceutical Co., Ltd. Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position
EP2050754A1 (fr) * 2007-08-01 2009-04-22 Wacker Chemie AG Procédé de fabrication d'alkyle-méthoxyméthyle-triméthylsilanylméthylamines
US7847117B2 (en) 2007-08-01 2010-12-07 Wacker Chemie Ag Process for preparing alkyl(methoxymethyl)trimethylsilanylmethylamines
WO2009145286A1 (fr) 2008-05-30 2009-12-03 武田薬品工業株式会社 Composé hétérocyclique
WO2010090290A1 (fr) 2009-02-06 2010-08-12 日本新薬株式会社 Dérivé d'aminopyrazine et médicament correspondant
US10227314B2 (en) 2012-07-25 2019-03-12 Sova Pharmaceuticals, Inc. Cystathionine-gamma-lyase (CSE) inhibitors
US9771339B2 (en) 2012-07-25 2017-09-26 Sova Pharmaceuticals, Inc. Cystathionine-γ-lyase (CSE) inhibitors
TWI606040B (zh) * 2012-07-25 2017-11-21 索法製藥股份有限公司 胱硫醚－γ－解離酶（ＣＳＥ）抑制劑（二）
EP2877458A4 (fr) * 2012-07-25 2016-08-10 Sova Pharmaceuticals Inc Inhibiteurs de la cystathionine-y-gamma-lyase (cse)
AU2018200635B2 (en) * 2012-07-25 2019-07-04 Sova Pharmaceuticals, Inc. Cystathionine-y-gamma-lyase (CSE) inhibitors
US10435403B2 (en) 2015-06-09 2019-10-08 Bayer Pharma Aktiengesellschaft Positive allosteric modulators of muscarinic M2 receptor
WO2018011017A1 (fr) 2016-07-11 2018-01-18 Bayer Pharma Aktiengesellschaft Amides de l'acide 1-pyridyl-naphthyridin-3-carboxylique substitués en position 7, et leur utilisation
CN109689654A (zh) * 2016-07-11 2019-04-26 拜耳医药股份有限公司 7-取代的1-吡啶基-萘啶-3-甲酰胺类及其用途
US10519154B2 (en) 2016-07-11 2019-12-31 Bayer Pharma Aktiengesellschaft 7-substituted 1-pyridyl-naphthyridine-3-carboxylic acid amides and use thereof
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AR046638A1 (es) 2005-12-14
PE20050582A1 (es) 2005-08-25
NL1027545A1 (nl) 2005-05-23

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