WO2006034491A2 - Composes a base de quinoleine et de quinazoline a substitution phenylique pour le traitement du diabete - Google Patents

Composes a base de quinoleine et de quinazoline a substitution phenylique pour le traitement du diabete Download PDF

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WO2006034491A2
WO2006034491A2 PCT/US2005/034367 US2005034367W WO2006034491A2 WO 2006034491 A2 WO2006034491 A2 WO 2006034491A2 US 2005034367 W US2005034367 W US 2005034367W WO 2006034491 A2 WO2006034491 A2 WO 2006034491A2
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cycloalkyl
inhibitors
optionally substituted
mmol
diabetes
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PCT/US2005/034367
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WO2006034491A3 (fr
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David Cantin
Steven Magnuson
David Gunn
William Bullock
Jennifer Burke
Wenlang Fu
Ellalahewage Sathyajith Kumarasinghe
Sidney X. Liang
Jason Newcom
Herbert Ogutu
Philip Wickens
Zhonghua Zhang
Donald Bierer
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Bayer Pharmaceuticals Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D401/10—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 aromatic rings
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the invention relates to 2-phenyl-substituted quinoline and quinazoline compounds, pharmaceutical compositions, and methods for treating diabetes and related disorders.
  • Type 1 diabetes or insulin dependent diabetes mellitus (IDDM) arises when patients lack insulin-producing ⁇ -cells in their pancreatic glands.
  • IDDM insulin dependent diabetes mellitus
  • Type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM)
  • IIDDM insulin dependent diabetes mellitus
  • the current treatment for type 1 diabetic patients is the injection of insulin, while the majority of type 2 diabetic patients are treated with agents that stimulate ⁇ -cell function or with agents that enhance the tissue sensitivity of the patients towards insulin.
  • the drugs presently used to treat type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, metformin, and insulin.
  • Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose.
  • the drawbacks of insulin treatment include, for example, the need for drug injection, the potential for hypoglycemia, and weight gain.
  • cAMP cyclic adenosine monophosphate
  • Metabolism of glucose promotes the closure of ATP-dependent K + channels, which leads to cell depolarization and subsequent opening of Ca ++ channels. This in turn results in the exocytosis of insulin granules.
  • cAMP is a major regulator of glucose-stimulated insulin secretion.
  • the effect of cAMP is, however, glucose- dependent, that is, cAMP has little if any effects on insulin secretion at low glucose concentrations (Weinhaus, et al., Diabetes 47:1426-1435, 1998).
  • the effects of cAMP on insulin secretion are thought to be mediated by a protein kinase A pathway.
  • Endogenous secretagogues utilize the cAMP system to regulate insulin secretion in a glucose-dependent fashion ( Komatsu, et al., Diabetes 46:1928-1938, 1997).
  • Examples of such endogenous secretagogues include pituitary adenylate cyclase activating peptide (PACAP), vasoactive intestinal polypeptide (VIP), and glucagon-like peptide-1 (GLP-1).
  • PACAP pituitary adenylate cyclase activating peptide
  • VIP vasoactive intestinal polypeptide
  • GLP-1 glucagon-like peptide-1
  • new therapies to treat diabetes are needed.
  • new treatments to maintain normal (glucose-dependent) insulin secretion are needed.
  • Such new drugs should have the following characteristics: 1) dependency on glucose for promoting insulin secretion, that is, compounds that stimulate insulin secretion only in the presence of elevated blood glucose and therefore, low probability for hypoglycemia; 2) low primary and secondary failure rates; and 3) preservation of islet cell function.
  • Phosphodiesterases are a family of cAMP and/or cGMP-hydrolyzing enzymes that cleave 3',5'-cyclic nucleotide monophosphates to 5'-nucleotide monophosphates. PDEs are known to be involved in the regulation of the cAMP system.
  • PDE1 OA is a phosphodiesterase that hydrolyses cAMP and cGMP with K m values of approximately 0.1-7 ⁇ M (Fujishige, et al., J.
  • cGMP and cAMP are important second messengers that are involved in the regulation of vascular smooth muscle tone.
  • the PDE10 family comprises enzymes that are responsible for the degradation of cAMP and cGMP in various tissues (Fujishige, et al., J. Biol. Chem. 274:18438- 18445, 1999).
  • guanylate cyclases leads to increased intracellular cGMP levels and induces vasodilation.
  • GPCRs G protein-coupled receptors
  • adenylate cyclases generation of intracellular cAMP
  • vasodilation 3',5'-cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of 3',5'-cyclic nucleotides to their respective nucleoside 5'- monophosphates.
  • PDE10A likely plays a role in the cardiovascular system.
  • the compounds of the present invention may be used to inhibit PDE1 OA activity and thus, may be used to treat diseases and/or disorders such as diabetes, cardiovascular disorders, or PDE10A-related diseases and/or disorders.
  • the present invention relates to 2-phenyl-substituted quinoline and quinazoline compounds useful for the treatment of diabetes, including type 1 and type 2 diabetes. Additional methods of the invention include treatment of disorders related to diabetes, such as Syndrome X, impaired glucose tolerance, and impaired fasting glucose.
  • the present invention also relates to methods of treating gestational diabetes, maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), and associated diabetic dyslipidemia and other diabetic complications, as well as hyperglycemia, hyperinsulinemia, dyslipidemia, hypertriglyceridemia, and insulin resistance.
  • the invention further relates to methods of stimulating insulin release from pancreatic cells in a mammal by administering an effective amount of a compound of the present invention.
  • This method of insulin release may be in response to an elevation of the concentration of glucose in the blood of a mammal.
  • the compounds of the present invention may also be administered in conjunction with other diabetes therapies, such as alpha-glucosidase inhibitors (e.g., acarbose), insulin sensitizers (e.g., thiazolidinediones), compounds that reduce hepatic glucose output (e.g., metformin), insulin secretagogues (e.g., sulfonylureas), ⁇ -3 agonists, and insulin.
  • the compounds of the present invention may be administered in conjunction with one or more weight reduction agents, such as orlistat, sibutramine, ⁇ -3 agonist, or CB-1 antagonist.
  • the compounds of the present invention may be administered in combination with an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, or an antihypertensive drug.
  • the compounds may be administered for the treatment of dementia or urogenital tract disorders.
  • Urogenital tract disorders include, but are not limited to, incontinence, stress incontinence, benign prostatic hyperplasia, erectile dysfunction, female sexual dysfunction, and hypertrophy of prostate.
  • compounds of the present invention may be administered for the treatment of cardiovascular disorders, such as hypertension, ischemic heart disease, myocardial infarction, stable and unstable angina, peripheral occlusive disease, and ischemic stroke.
  • the invention provides 2-phenyI-substituted quinoline and quinazoline compounds of Formula (I)
  • X is a group selected from
  • Y is CR 7 or N
  • R 1 is:
  • R 3 is:
  • R 4 and R 4 which may be the same or different, are:
  • R 5 is:
  • R 6 is:
  • R 7 is:
  • aryl, heteroaryl, and heterocyclyl being optionally substituted at any available position by up to 3 independently selected R 8 groups, and optionally fused to a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclyl or heteroaryl ring containing up to 3 additional heteroatoms selected from N, O, and S, wherein said fused ring may be optionally substituted at any available position by up to 3 independently selected R 8 groups;
  • R is selected from hydroxy
  • C 6 )alkoxy or a mono or bicyclic ring radical selected from the group consisting of: a) a phenyl optionally fused to a 5- or 6-membered cycloalkyl or a 5- or 6- membered saturated or partially unsaturated heterocyclic ring containing up to 3 heteroatoms selected from N, O, and S, b) a 5- or 6-membered heterocyclic ring radical containing up to 4 heteroatoms selected from N, O, or S, optionally fused to a 5- or 6-membered cycloalkyl, and c) a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from up to 3 heteroatoms selected from N, O, and S, said mono or bicyclic ring radical being optionally substituted with up to 3 independently selected R 9 groups;
  • R 9 is:
  • the invention also provides 2-phenyl-substituted quinoline and quinazoline compounds of Formula (II)
  • X is a group selected from
  • R 1 is:
  • R 2 is:
  • R 3 is:
  • R 4 and R 4' which may be the same or different, are:
  • R 4 and R 4' can join to form a saturated (C 3 -C 6 )-cycloalkyl or a (C 3 - C 6 )heterocyclyl ring optionally substituted with:
  • R 5 is:
  • R 6 is:
  • R 8 is:
  • C 6 )alkoxy or a mono or bicyclic ring radical selected from the group consisting of: a) a phenyl optionally fused to a 5- or 6-membered cycloalkyl, or a 5- or 6- membered saturated or partially unsaturated heterocyclic ring containing up to 3 heteroatoms selected from N, O, and S, b) a 5- or 6-membered heterocyclic ring radical containing up to 4 heteroatoms selected from N, O, or S, optionally fused to a 5- or 6-membered cycloalkyl, and c) a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from up to 3 heteroatoms selected from N, O, and S, said mono or bicyclic ring radical being optionally substituted with up to 3 independently selected R 9 groups;
  • R 9 is:
  • R 10 is halo
  • Prefixes such as (C 1 -C 6 ) are used to indicate the respective number of carbon atoms, for example, in this case, 1 to 6 carbons.
  • halo means F, Cl, Br, or I.
  • (C 1 -C 6 )alkyl means a straight or branched saturated hydrocarbon carbon chain of from 1 to about 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, isopropyl, sec-butyl, 2-methylpentyl, n-hexyl, and the like.
  • (C 2 -C 6 )alkenyl means a straight or branched unsaturated hydrocarbon carbon chain of from 2 to about 6 carbon atoms. Examples of such groups include, but are not limited to, vinyl, allyl, isopropenyl, 2-butenyl, 3-ethyl-2-butenyl, 4-hexenyl, and the like.
  • (C 1 -C 6 )haloalkyl means a (C 1 -C 6 )alkyl group substituted by 1 to 3 halogen atoms or fluorine up to the periluoro level. Examples of such groups include, but are not limited to, trifluoromethyl, tetrafluoroethyl, 1 ,2-dichloropropyl, 5-bromopentyl, 6-iodohexyl, and the like.
  • (C 3 -C 6 )cycloalkyl or "(C 3 -C 8 )cycloalkyl” means a saturated carbocyclic ring system of from 3 to about 6 carbon atoms or from 3 to about 8 carbon atoms, respectively.
  • Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, and the like.
  • 5- to 6-membered cycloalkly means a saturated or patially unsaturated carbocyclic ring system of 5 or 6 carbon atoms, respectively.
  • groups include, but are not limited to, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.
  • (C 1 -C 6 )BCyI means a (C 1 -C 6 )alkyl group attached at the carbonyl carbon atom.
  • the radical is attached to the rest of the molecule at the carbonyl bearing carbon atom. Examples of such groups include, but are not limited to, acetyl, propionyl, n-butanoyl, 2-methylpentantoyl, and the like.
  • thioaryl means an aryl group attached to a sulfur atom.
  • the S atom is the point of attachment of the thioaryl substituent to the rest of the molecule.
  • the term also includes the different oxidation states of sulfur (e.g., -SO-, -SO 2 -). Examples of such groups include, but are not limited to, thiophenyi, phenyl sulfoxide, phenyl sulfone, and the like.
  • (C 1 -C 6 )alkoxy means a linear or branched saturated carbon group having from 1 to about 6 C atoms, said carbon group being attached to an O atom.
  • the O atom is the point of attachment of the alkoxy substituent to the rest of the molecule.
  • Such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
  • (CVC 6 )thioalkyl means a linear or branched saturated carbon group having from 1 to about 6 C atoms, said carbon group being attached to an S atom.
  • the S atom is the point of attachment of the thioalkyl substituent to the rest of the molecule.
  • the term also includes the different oxidation states of sulfur (e.g., -SO-, -SO 2 -).
  • Such groups include, but are not limited to, methylthio, propylthio, hexylthio, ethylsulfoxide, methyl sulfone, and the like.
  • (C 1 -C 6 )haloalkoxy means a (C 1 -C 6 )alkoxy group further substituted on C with 1 to 3 halogen atoms or fluorine up to the perfluoro level.
  • groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloroethoxy, 3- chloropropoxy, 1-fluoro-2,2,-dichloroethoxy, and the like.
  • (C 3 -C 6 )cycloalkoxy means a (C 3 -C 6 )cycloalkyl group attached to an O atom.
  • the O atom is the point of attachment of the cycloalkoxy group with the rest of the molecule.
  • examples of such groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • phenoxy means an aryl group attached to an O atom.
  • the O atom is the point of attachment of the phenoxy group to the rest of the molecule.
  • aryl represents a mono- to bicyclic carbocyclic radical, which is aromatic at least in one ring, having generally 6 to 10 carbon atoms, illustratively representing phenyl and naphthyl.
  • heteroaryl represents an mono- or bicyclic radical, having generally 5 to 10 ring atoms from which up to 4 atoms may be selected from the group consisting of N, O, and S, which is aromatic at least in one ring.
  • the mono- or bicyclic radical can be attached to the rest of the molecule via a ring carbon atom or a ring nitrogen atom. If the radical represents a bicyclic, wherein one ring is aromatic and the other one is not, it can be attached at either ring.
  • Illustrative examples are thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuryl, benzimidazolyl, benzothiophenyl, benzooxazolyl, benzothiaolyl, quinolinyi, isoquinolinyl, 1 ,3-benzodioxinyl, 1 ,4- benzodioxinyl, or benzodioxolyl.
  • heterocyclyl represents a mono- or bicyclic nonaromatic (saturated or partially saturated) radical having generally 3 to 10 ring atoms from which up to 3 atoms may be selected from the group consisting of N, O, and S.
  • the radical can be attached via a ring carbon atom or a ring nitrogen atom.
  • Illustrative examples are tetrahydrofuran-2-yl, pyrrolidin-2-yl, tetrahydropyridyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, piperazinyl, thiomorpholinyl, morpholinyl, perhydroazepinyl, dihydropyrano, pyrazolinyl, imidazolinyi, or dihydrofuryl,
  • the heteroaryl or heterocyclyl group When the heteroaryl or heterocyclyl group is attached to the rest of the molecule as a substituent, it becomes a radical.
  • the point of attachment of the radical may be from any available C or N atom of the ring to the rest of the molecule.
  • Also included in the compounds of the present invention are (a) the stereoisomers thereof, (b) the pharmaceutically-acceptable salts thereof, (c) the tautomers thereof, (d) the protected acids and the conjugate acids thereof, and (e) the prodrugs thereof.
  • stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers may be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the inhibitors described above.
  • Pharmaceutically-acceptable salts of the compounds of the present invention include salts commonly used to form alkali metal salts or form addition salts of free acids or free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • organic and sulfonic classes of organic acids includes, but are not limited to, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, ⁇ /-hydroxybutyric, salicylic, galactaric, and galacturonic acid, and combinations thereof.
  • Tautomers of the compounds of the invention are encompassed by the present invention.
  • a carbonyl includes its hydroxy tautomer.
  • the protected acids include, but are not limited to, esters, hydroxyamino derivatives, amides, and sulfonamides.
  • the present invention includes the prodrugs and salts of the prodrugs. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability, and release time (see, e.g., "Pharmaceutical Dosage Form and Drug Delivery Systems” (Sixth Edition), Ed. Ansel, et al., Williams & Wilkins (1995), which is hereby incorporated by reference). Commonly used prodrugs are designed to take advantage of the major drug biotransformation reactions, and are also to be considered within the scope of the invention.
  • Major drug biotransformation reactions include ⁇ /-dealkylation, O- dealkylation, aliphatic hydroxylation, aromatic hydroxylation, /V-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation, and acetylation (see, e.g., Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), Ed. Molinoff, et al., McGraw-Hill (1996), which is hereby incorporated by reference).
  • the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to routine, conventional chemical methods. The following preparative methods are presented to aid the reader in the synthesis of the compounds of the present invention.
  • primary amides (VII) are prepared from acids of Formula (Vl) by conversion to the acid chloride using a chlorinating agent such as SOCI 2 , followed by exposure to ammonia. Subsequent reduction of the nitro group to the amine of Formula (VIII) is achieved through the use of a catalyst (e.g., Pd/C, Pd(OH) 2 ) under an atmosphere of hydrogen. Condensation of intermediate of Formula (VIIl) with aldehydes of Formula (IX) in the presence of sodium hydrogen sulfite in a polar solvent such as ⁇ /, ⁇ /-dimethylacetamide affords quinazolones of Formula (X).
  • a catalyst e.g., Pd/C, Pd(OH) 2
  • Intermediate (XVIIb) can be prepared by the reaction of a substituted isatoic anhydride of Formula (XVIII) or a ⁇ /-hydroxysuccinimide ester of Formula (XIX) with a cyanoacetophenone of Formula (XX), together with a strong base such as sodium hydride.
  • intermediate (XXVI) is prepared by the reaction of a substituted isatoic anhydride of Formula (XVIII) with a cyanoacetate of Formula (XXV), together with a strong base such as sodium hydride. Conversion to a 2,4-dichlorosubstituted intermediate of Formula (XXVII) can be achieved by action of a chlorinating agent such as POCI 3 . Nucleophilic addition of the compound of Formula (III) in the presence of base provides the quinoline intermediate of Formula (XXVIII). Subsequent Suzuki coupling reaction with a boronic acid of Formula (XIII) or Formula (XIV) gives the compound of Formula (Ig) or Formula (Ih). Optional hydrolysis of Formula (Ig), for example, using aqueous sodium hydroxide, gives the corresponding acid compound of Formula (Ih).
  • Reaction Scheme 8 may be prepared as illustrated in Reaction Schemes 8-15 below, beginning with Reaction Scheme 8 which illustrates the preparation of common intermediates of Formula (XXXV) and Formula (XXXVII). [069] Reaction Scheme 8
  • Reaction Scheme 9 illustrates the preparation of compounds of Formulae (U) and (Im) in
  • the compound of Formula (XXXVlI) is esterified, for example, by reaction with MeI and a base, to provide the ester intermediate of Formula (XXXVIII).
  • This compound is then reduced to the primary alcohol (XXXIXa) with a suitable reducing agent such as DIBAL.
  • the alcohol can then be oxidized to the aldehyde of Formula (XL) under selective oxidizing conditions such as a Swern oxidation [DMSO, oxalyl chloride, and triethyl amine], and this intermediate can be used to prepare an alcohol of Formula (XXXIXb) by Grignard reaction with the reagent of Formula (XLI).
  • Either alcohol (XXXIXa) or (XXXIXb) may then be O-aikylated in base with an 2-halo ester of Formula (XXXII), to prepare the compound of Formula (U). Hydrolysis of (U) in aqueous base provides the corresponding carboxylic acid compound of Formula (Im).
  • the intermediate carboxylic acid of Formula (XXXV) is esterified to the corresponding ester of Formula (XLIII), then reduced to the primary alcohol of Formula (XLIVa) with a selective reducing agent such as DIBAL.
  • Oxidation of (XLIVa) to the aldehyde of Formula (XLV) is accomplished with a selective oxidation, for example, under Swern conditions [DMSO, oxalyl chloride, and triethyl amine].
  • the aldehyde is then allowed to react with a Grignard reagent of Formula (XLI) to provide the alcohol of Formula (XLIVb), where R 4 is alkyl.
  • the carboxylic acid intermediate of Formula (XXXV) is coupled with an amino acid derivative of Formula (Ll) in the presence of a coupling agent such as EDCI.
  • the product, intermediate of Formula (LII) may then be subjected to Suzuki coupling conditions using a boronic acid of Formula (XIII) or Formula (XIV) to give the compound of Formula (Ir) where R 3 is alkyl.
  • Hydrolysis of Formula (Ir) using aqueous base such as sodium hydroxide gives the acid compound of Formula (Is) where R 3 is H.
  • an alcohol intermediate of Formula (XLIV), described in Reaction Scheme 10 is converted to the corresponding chloro compound of Formula (XLVII).
  • This intermediate may be ⁇ /-alkylated with the amino acid derivative of Formula (Lib) or Formula (LIc), optionally in the presence of a base, to give the intermediate of Formula (LIII).
  • Suzuki coupling with the boronic acid derivative of Formula (XIII) or Formula (XIV) gives the compound of Formula (It) where R 3 is alkyl
  • hydrolysis of Formula (It) with aqueous base gives the compound of Formula (Iu) where R 3 is H.
  • a 4-halobenzoate of Formula (LlV) is transformed to the corresponding ketone of Formula (LV) using acetonitrile or dimethyl sulfone in THF in the presence of a strong base [e.g., NaH (rt to reflux), LiHMDS (-78 °C to rt)].
  • a strong base e.g., NaH (rt to reflux), LiHMDS (-78 °C to rt)
  • Suzuki coupling with the boronic acid derivative of Formula (XIII) or Formula (XIV) gives the compound of Formula (XX).
  • the steps can be reversed where Suzuki coupling of halobenzoates of Formula (LIV) with boronic acid derivatives of Formula (XIII) or Formula (XIV) gives the compound of Formula (LVI).
  • isatoic anhydrides of Formula (XVIII) can be obtained through oxidation of the isatins of Formula (XXXIII), for example, using peroxides such as H 2 O 2 or m- chloroperbenzoic acid.
  • isatoic anhydrides of Formula (XVIII) can be accessed from amino acids of Formula (LVII) using phosgene in the presence of a base such as Et 3 N.
  • n-hydroxysuccinimide esters of Formula (XlX) can be obtained by reaction of an amino benzoic acid of Formula (LVII) and reacting with n-hydroxysuccinimide under peptide-coupling conditions such as EDCI in DMF.
  • Celite ® brand of diatomaceous earth filtering agent registered trader of Celite Corporation cone concentrated d doublet dd doublet of doublet ddd doublet of doublet of doublet
  • Electron impact mass spectra were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 ⁇ M coating; 30 m x 0.25 mm). The ion source was maintained at 250°C and spectra were scanned from 50-800 amu at 2 sec per scan.
  • LC-MS High pressure liquid chromatography-electrospray mass spectra
  • LC-MS High pressure liquid chromatography-electrospray mass spectra
  • a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization.
  • Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source.
  • the eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA.
  • ELSD Electrode L i ght Scattering Detector
  • the eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA.
  • Gradient elution from 10% to 90% B over 3.5 minutes at a flow rate of 1.5 mL/min was used with an initial hold of 0.5 minutes and a final hold at 90% B of 0.5 minutes. Total run time was 4.8 minutes. An extra switching valve was used for column switching and regeneration.
  • Agilent 1100 HPLC system The Agilent 1100 HPLC system was equipped with an Agilent
  • the HPLC column used was a Waters Sunfire (2.1 x 30 mm, 3.5 uM).
  • the eluents were A: water with 0.1 Formic acid and B: acetonitrile with 0.1% Formic acid. Gradient elution from 10% B to 90% B over 3.0 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 2.0 minutes and a final hold at 95% B of 1.0 minutes. Total run time was 8.0 minutes.
  • the reaction was heated (85°C) for 16 h and then cooled to rt.
  • the mixture was concentrated to dryness and then the residue was dissolved in methanol and acetonitrile.
  • This suspension was filtered through a C8 reverse phase extraction cartridge and the filtrate was concentrated to dryness.
  • the residue was purified by preparative HPLC using a gradient elution from 10% to 100% acetonitrile in water to obtain 90 mg (58%) of the desired product.
  • amino benzamides can be prepared using the method described below.
  • the mixture was concentrated to dryness and the residue was dissolved in a mixture of methanol and DMSO.
  • the residue was purified by HPLC using a gradient elution from 10% to 90% acetonitrile in water to obtain 95 mg (43%) of the desired product.
  • the solid was added to phosphorous oxychloride (5 mL, 53.6 mmol), and the mixture was heated to reflux for 3 h. After cooling to rt, the reaction was quenched with ice and then the solution was adjusted to pH 7 using aqueous sodium hydroxide solution (1 N). The aqueous layer was extracted with dichloromethane (3 X 10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel flash chromatography to obtain 1.55 g (27%) of the desired product.
  • the solution was concentrated to dryness, and the residue was purified by silica gel flash chromatography using a gradient elution from 20% to 100% ethyl acetate in hexanes followed by 0-10% methanol in dichloromethane to obtain 680 mg (46%) of the desired product.
  • the reaction was heated (85°C) for 16 h and then cooled to rt.
  • the mixture was concentrated to dryness and the residue was dissolved in a mixture of methanol and acetonitrile. This solution was filtered through a C8 reverse phase extraction cartridge and the filtrated was concentrated to dryness.
  • the residue was purified by preparative HPLC using a gradient elution from 10% to 100% acetonitrile in water to obtain 100 mg (91%) of the desired product.
  • Example 93 was obtained as a solid (10 g, 70%) after drying under mechanical vacuum at 40°C.
  • 1 H NMR 400 MHz, DMSO-Of 6 ) 12.95 (s, 1 H), 7.86 (m, 2H), 7.75 (m, 5H); ES-MS m/z 343.2 [M+H] + , LCMS RT (min) 2.74.
  • Example 94 Preparation of 2-(4-bromophenyl)-6-fluoro-4-chloroquinoline-3-carbonitrile
  • the reaction mixture was heated at 150°C for 12 min in a microwave reactor and then was cooled to rt. The mixture was then filtered. The filtrate was diluted with 2 mL DMSO then was purified by preparative HPLC using a gradient elution from 10% to 100% acetonitrile in water with 0.1% TFA as modifier to obtain 4.8 mg (9.4%) of the desired product.
  • the mixture was filtered and the filtrate concentrated to dryness under reduced pressure.
  • the residue was purified by preparative HPLC (eluent: 10 to 100% acetonitrile in water [0.1 % TFA]).
  • the fraction containing desired product was concentrated under reduced pressure and the pH of the resulting aqueous solution was adjusted to ⁇ 5.
  • the aqueous mixture was then extracted with ethyl acetate and the combined organic phases were dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to give 15 mg of the desired product.
  • the organic solution was washed successively with K 2 CO 3 (10% aqueous solution), NH 4 CI (10% aqueous solution), and water, and the organic phase was dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure.
  • the residue was triturated with diethyl ether and dried under vacuum to give 1.2 g desired product. Additional amounts of Example 193 were recovered from the filtrate, which was concentrated under reduced pressure.
  • the residue was dissolved recrystallized from hexanes/ethyl acetate (50 ml_, 1 :1 mixture). The solid was collected by filtration and then dried under mechanical vacuum to give 900 mg of desired product.
  • the reaction mixture was filtered and the filtrate concentrated to dryness under reduced pressure.
  • the residue was purified by preparative HPLC (eluent: 10 to 100% acetonitrile in water [0.1 % TFA]).
  • the fractions containing desired product were concentrated under reduced pressure, and the pH of the resulting aqueous solution was adjusted to ⁇ 5.
  • the aqueous mixture was then washed with ethyl acetate, and the solid from resulting aqueous suspension was collected by filtration. The solid was washed with water and then dried under mechanical vacuum at 40°C to give 23 mg of the desired product.
  • Example 199 (1.1 g) as a solid, which was used in the next step without further purification.
  • Example 200 (470 mg) as a solid that was used in the next step without further purification.
  • Example 201
  • the mixture was concentrated to dryness and the residue was dissolved in a mixture of DMSO and MeOH.
  • the crude mixture was purified by HPLC using a gradient elution from 10% to 90% acetonitrile in H 2 O to obtain 44 mg (40%) of the desired product.
  • Examples 221 and 222 were prepared using the procedures of Example 208 and 209, respectively.
  • the starting materials ethyl N-[2-(4-bromo-2-methylphenyl)-3-cyanoquinolin-4-yl]-beta- alaninate, was prepared using the methods described for the preparation of Examples 93-95.
  • Example 289 were recovered after concentration of the filtrate under reduced pressure and purification of the residue by silica gel flash chromatography (10 to 50% ethyl acetate in hexane) to give an additional 300 mg of Example 289.
  • the reaction was stirred at rt and then diluted with water (80 mL).
  • the product was extracted with ethyl acetate (3 x 20 mL) and then the combined organic extracts were washed with brine, dried with sodium sulfate, and evaporated under reduced pressure.
  • the residue was purified by silica gel chromatography using 25% ethyl acetate/hexanes to afford 273 mg (45%) of desired product.
  • the mixture was diluted with ethyl acetate (50 mL) and then successively washed with water (50 mL) and 1 N aqueous sodium hydroxide solution (30 mL), dried over sodium sulfate, and concentrated to dryness.
  • the residue was purified by HPLC using a gradient of 25-75% acetonitrile in water to afford 167 mg (34%) of the desired product.

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Abstract

La présente invention a trait à des composés à base de quinoléine et de quinazoline à substitution phénylique en position 2, à des compositions pharmaceutiques, et à des procédés pour le traitement du diabète et de troubles associés.
PCT/US2005/034367 2004-09-23 2005-09-23 Composes a base de quinoleine et de quinazoline a substitution phenylique pour le traitement du diabete WO2006034491A2 (fr)

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WO2012069856A1 (fr) * 2010-11-26 2012-05-31 Liverpool School Of Tropical Medicine Composés antipaludiques
JP2012513464A (ja) * 2008-12-23 2012-06-14 ザ トラスティーズ オブ コロンビア ユニヴァーシティ イン ザ シティ オブ ニューヨーク ホスホジエステラーゼ阻害剤及びその使用
WO2012112946A1 (fr) 2011-02-18 2012-08-23 Allergan, Inc. Dérivés de 6,7-dialkoxy-3-isoquinolinol substitués en tant qu'inhibiteurs de la phosphodiestérase 10 (pde10a)
EP2624695A1 (fr) * 2010-10-08 2013-08-14 N30 Pharmaceuticals, Inc. Nouveaux composés quinoléine substitués en tant qu'inhibiteurs de s-nitrosoglutathione réductase
WO2014071044A1 (fr) 2012-11-01 2014-05-08 Allergan, Inc. Dérivés de 6,7-dialcoxy-3-isoquinoline substitués à titre d'inhibiteurs de phosphodiestérase 10 (pde10a)
CN103787966A (zh) * 2012-11-05 2014-05-14 清华大学 一种化合物及其在制备抗寄生虫病药物中的应用
WO2014142322A1 (fr) 2013-03-15 2014-09-18 第一三共株式会社 Dérivé du benzothiophène
US9012646B2 (en) 2010-12-16 2015-04-21 Nivalis Therapeutics, Inc. Substituted bicyclic aromatic compounds as S-nitrosoglutathione reductase inhibitors
US9200016B2 (en) 2013-12-05 2015-12-01 Allergan, Inc. Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
AU2015224464B2 (en) * 2010-10-08 2016-12-15 Laurel Therapeutics Ltd Novel substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors
US10399946B2 (en) 2015-09-10 2019-09-03 Laurel Therapeutics Ltd. Solid forms of an S-Nitrosoglutathione reductase inhibitor
EP3445170A4 (fr) * 2016-04-18 2019-11-20 New York University Composés de quinoléine utilisés en tant que modulateurs de l'activité de rage et leurs utilisations
WO2022192760A1 (fr) * 2021-03-12 2022-09-15 Accro Bioscience (Hk) Limited Composés hétéroaryle utilisés en tant qu'inhibiteurs de la kinase rip2, composition et application de ceux-ci

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US5304554A (en) * 1990-04-27 1994-04-19 Emory University 4-[(alkyl or dialkyl)amino]quinolines and their method of preparation
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JP2012513464A (ja) * 2008-12-23 2012-06-14 ザ トラスティーズ オブ コロンビア ユニヴァーシティ イン ザ シティ オブ ニューヨーク ホスホジエステラーゼ阻害剤及びその使用
EP2624695A4 (fr) * 2010-10-08 2014-07-30 N30 Pharmaceuticals Inc Nouveaux composés quinoléine substitués en tant qu'inhibiteurs de s-nitrosoglutathione réductase
US9433618B2 (en) 2010-10-08 2016-09-06 Nivalis Therapeutics, Inc. Substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors
EP2624695A1 (fr) * 2010-10-08 2013-08-14 N30 Pharmaceuticals, Inc. Nouveaux composés quinoléine substitués en tant qu'inhibiteurs de s-nitrosoglutathione réductase
JP2013542937A (ja) * 2010-10-08 2013-11-28 エヌ３０ ファーマシューティカルズ，インコーポレイテッド Ｓ−ニトロソグルタチオン還元酵素阻害薬としての新規置換キノリン化合物
AU2015224464B2 (en) * 2010-10-08 2016-12-15 Laurel Therapeutics Ltd Novel substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors
RU2599144C2 (ru) * 2010-10-08 2016-10-10 Нивалис Терапьютикс,Инк. Новые замещенные хинолиновые соединения как ингибиторы s-нитрозоглутатион-редуктазы
US9856219B2 (en) 2010-10-08 2018-01-02 Nivalis Therapeutics, Inc. Substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors
US9315462B2 (en) 2010-10-08 2016-04-19 Nivalis Therapeutics, Inc. Substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors
EP2977050A1 (fr) * 2010-10-08 2016-01-27 Nivalis Therapeutics, Inc. Nouveaux composés quinoléine substitués comme inhibiteurs de la s-nitrosoglutathione réductase
US9139528B2 (en) 2010-10-08 2015-09-22 Nivalis Therapeutics, Inc. Substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors
AU2011311920B2 (en) * 2010-10-08 2015-06-11 Laurel Therapeutics Ltd Novel substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors
WO2012069856A1 (fr) * 2010-11-26 2012-05-31 Liverpool School Of Tropical Medicine Composés antipaludiques
US9012646B2 (en) 2010-12-16 2015-04-21 Nivalis Therapeutics, Inc. Substituted bicyclic aromatic compounds as S-nitrosoglutathione reductase inhibitors
US9364481B2 (en) 2010-12-16 2016-06-14 Nivalis Therapeutics, Inc. Substituted bicyclic aromatic compounds as S-nitrosoglutathione reductase inhibitors
US9221810B2 (en) 2010-12-16 2015-12-29 Nivalis Therapeutics, Inc. Substituted bicyclic aromatic compounds as S-nitrosoglutathione reductase inhibitors
US8772316B2 (en) 2011-02-18 2014-07-08 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE10A)
WO2012112946A1 (fr) 2011-02-18 2012-08-23 Allergan, Inc. Dérivés de 6,7-dialkoxy-3-isoquinolinol substitués en tant qu'inhibiteurs de la phosphodiestérase 10 (pde10a)
US9670181B2 (en) 2011-02-18 2017-06-06 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
WO2014071044A1 (fr) 2012-11-01 2014-05-08 Allergan, Inc. Dérivés de 6,7-dialcoxy-3-isoquinoline substitués à titre d'inhibiteurs de phosphodiestérase 10 (pde10a)
CN103787966A (zh) * 2012-11-05 2014-05-14 清华大学 一种化合物及其在制备抗寄生虫病药物中的应用
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US9464076B2 (en) 2013-03-15 2016-10-11 Daiichi Sankyo Company, Limited Benzothiophene derivative
WO2014142322A1 (fr) 2013-03-15 2014-09-18 第一三共株式会社 Dérivé du benzothiophène
US9200016B2 (en) 2013-12-05 2015-12-01 Allergan, Inc. Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US9902710B2 (en) 2013-12-05 2018-02-27 Exonhit Therapeutics, Sa Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US10399946B2 (en) 2015-09-10 2019-09-03 Laurel Therapeutics Ltd. Solid forms of an S-Nitrosoglutathione reductase inhibitor
EP3445170A4 (fr) * 2016-04-18 2019-11-20 New York University Composés de quinoléine utilisés en tant que modulateurs de l'activité de rage et leurs utilisations
US11192859B2 (en) 2016-04-18 2021-12-07 New York University Quinoline compounds as modulators of RAGE activity and uses thereof
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