WO2012111995A1 - Dérivés d'oxime formant agonistes du récepteur gpr119 - Google Patents

Dérivés d'oxime formant agonistes du récepteur gpr119 Download PDF

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WO2012111995A1
WO2012111995A1 PCT/KR2012/001185 KR2012001185W WO2012111995A1 WO 2012111995 A1 WO2012111995 A1 WO 2012111995A1 KR 2012001185 W KR2012001185 W KR 2012001185W WO 2012111995 A1 WO2012111995 A1 WO 2012111995A1
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phenyl
piperidin
difluoro
cyclohexyl
yloxyimino
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PCT/KR2012/001185
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English (en)
Inventor
Young Kwan Kim
Hyun Woo Joo
Myoung Yeol KIM
Heui Sul Park
Tae Hee Lee
Hyo Shin Kwak
Dong Sup Shim
Eun Sil Choi
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Lg Life Sciences Ltd.
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Publication of WO2012111995A1 publication Critical patent/WO2012111995A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • 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
    • C07D401/12—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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    • 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
    • C07D401/14—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 three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel oxime derivatives as GPR119 agonists, a method for preparing the same, a pharmaceutical composition comprising the same and use thereof.
  • a GPR119 agonist means a compound which can be effectively used for preventing or treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis by stimulating the secretion of insulin in the pancreas and promoting GLP-1 and GIP formation in the gastrointestinal tract.
  • Diabetes is divided into two types ⁇ i.e., insulin-dependent type 1 diabetes and insulin-independent (insulin-resistant) type 2 diabetes which is found in 90% or more of diabetic patients.
  • sulfonlyureas act directly on the pancreas to secret insulin
  • metformin has the mechanism of action of preventing glucolysis in the liver.
  • Sulfonylureas have problems of decreasing the function of the pancreas and incurring hypoglycemia due to excessive secretion of insulin, and metformin causes gastroenteric disorders or renal toxicity.
  • Glitazones also have side effects of weight gain, serious heart failure, etc.
  • incretin-related drugs such as DPPIV inhibitors or Exenatide
  • DPPIV inhibitors which have recently entered the market
  • DPPIV inhibitors have a marginal effect
  • Galvus has a side effect of skin toxicity
  • Exenatide has a disadvantage in that it must be given by means of injection.
  • GPR119 agonists which are noted for possible treatment of type 2 diabetes, are known to have antidiabetic effects caused by the actions of (1) stimulating the secretion of insulin in the pancreas and (2) increasing incretin hormone in intestinal cells.
  • GPR119 agonists show antidiabetic effects by acting directly on ⁇ -cells in the pancreas to stimulate GSIS and acting on intestinal cells to stimulate the secretion of incretin hormones, GLP-1, GIP and PYY.
  • GLP-1 is known to act on ⁇ -cells in the pancreas to stimulate the secretion of insulin, and also to have an effect of various antidiabetics, anti-obesity, and prevention and treatment of osteoporosis, including a decrease of glucagon secretion after meals, a decrease of gastrointestinal activity, appetite loss, weight loss and proliferation of ⁇ -cells in the pancreas.
  • GPR119 agonists, which stimulate the secretion of incretin hormones are also expected to have the effects of incretin hormones.
  • GPR119 agonists are actively in progress.
  • patentability is mainly established in the center bridge structure binding left and right substituents and determining the orientation of the whole structure.
  • GPR119 agonist compounds having aromatic substituents are disclosed in WO 2007/003964, WO 2008/109702, WO 2008/076243 and WO 2008/085316.
  • the object of the present invention is to provide oxime derivatives as GPR119 agonists.
  • Another object of the present invention is to provide a method for preparing the oxime derivatives.
  • Still another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis which comprises as active components the oxime derivatives, and a method for preparing the composition.
  • a still further object of the present invention is to provide a method for preventing and treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis which use the oxime derivatives as active components.
  • the present invention provides oxime derivatives of Formula 1, or pharmaceutically acceptable salts or isomers thereof:
  • RA represents a partially or fully saturated 4- to 7-membered cycloalkyl
  • RB represents a partially or fully saturated 4- to 7-membered heterocycle, or a [5.5], [5.6], [5.7], [6.6] or [6.7] fused ring system consisting of two rings,
  • R1 and R2 represent independently hydrogen, halogen or alkyl
  • n an integer of 0 to 10 in each ring
  • A represents nitrogen or carbon
  • D represents carbon, nitrogen, oxygen or sulfur
  • R3, R4 and R5 are independently hydrogen or halogen, or represent in each case optionally substituted aryl, arylalkyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl or amine,
  • R3, R4 and R5 are connected together to form optionally substituted 3- to 7-membered cycloalkyl or heterocycle, or to form optionally substituted 5- or 6-membered aryl or heteroaryl,
  • E, F, G, H and I represent independently carbon, nitrogen, oxygen or sulfur to form 6-membered aryl or heteroaryl, or form optionally benzo-fused 5-membered aryl or heteroaryl excluding one of E, F, G, H and I,
  • n an integer of 0 to 5
  • R6 is hydrogen or halogen; or represents optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl or heteroarylalkyl; or represents hydroxy or amine optionally substituted by 1 or 2 alkyl or aryl, wherein two substituents of amine are connected together to form 3- to 7-membered heterocyclyl,
  • J represents optionally substituted C 1 -C 4 -alkylene or sulfonyl
  • R7 is hydrogen or halogen, or represents optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, and
  • Ar represents optionally substituted aryl or heteroaryl.
  • the compounds of Formula 1 according to the present invention can form pharmaceutically acceptable salts, which include acid-addition salts which are formed from inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid; organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicylic acid; or sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, which form non-toxic acid-addition salts including pharmaceutically acceptable anion.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid
  • organic acids such as tart
  • the pharmaceutically acceptable carboxylic acid salts include the salts with alkali metal or alkali earth metal such as lithium, sodium, potassium, calcium and magnesium; salts with amino acid such as lysine, arginine and guanidine; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine.
  • alkali metal or alkali earth metal such as lithium, sodium, potassium, calcium and magnesium
  • salts with amino acid such as lysine, arginine and guanidine
  • organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine.
  • the compounds of Formula 1 according to the present invention can be converted into their salts by conventional methods.
  • the compounds of Formula 1 according to the present invention can have an asymmetric carbon center and asymmetric axis or plane, they can exist as E- or Z-isomer, R- or S-isomer, racemic mixtures or diastereoisomer mixtures and each diastereoisomer, all of which are within the scope of the present invention.
  • the term “the compounds of Formula 1” is used to mean all the compounds of Formula 1, including the pharmaceutically acceptable salts and isomers thereof.
  • Halogen or halo means fluoride (F), chlorine (Cl), bromine (Br) or iodine (I).
  • Alkyl means straight or branched hydrocarbons which can include single bond, double bond or triple bond.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, acetylene, vinyl, trifluoromethyl and the like.
  • Cycloalkyl means partially or fully saturated single or fused ring hydrocarbons and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and the like.
  • Aryl means aromatic hydrocarbons and includes, but is not limited to, phenyl, naphthyl and the like.
  • Heteroaryl means aromatic hydrocarbons which form a single or fused ring including at least one hetero atom selected from N, O and S.
  • heteroaryl include, but are not limited to, pyridinyl, pyrimidinyl, pyridazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, thiophenyl, benzthiazole, benzimidazole, 1,2,3,4-tetrahydroisoquinolyl, thiazolopyridyl and the like.
  • Heterocyclyl means partially or fully saturated hydrocarbons which form a single or fused ring including at least one hetero atom selected from N, O and S.
  • heterocyclyl include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, imidazolinyl, piperazinyl, tetrahydrofuran, tetrahydrothiofuran and the like.
  • Arylalkyl and heteroarylalkyl mean groups which are formed by the combination of the above-mentioned aryl with alkyl and heteroaryl with alkyl. Examples include, but are not limited to, benzyl, thiophene methyl, pyrimidine methyl and the like.
  • alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl and heteroarylalkyl may be substituted by at least one group selected from the following groups: alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, oxo, cyano, halo, nitro, -OR, -OC(O)R, -OC(O)OR, SR, -S(O)R, -S(O) 2 R, -C(O)R, -C(O)OR, -C(S)R, -C(O)NRR, -NR 2 , -NRCHO, -NRC(O)R, -NRC(O)NRR, -C(S)NRR, -NRC(S)R, -NRC(S)NRR, -NRC(S)NRR
  • Preferable compounds of Formula 1 according to the present invention used as GPR119 agonists are those wherein A is nitrogen.
  • n, R3, R4, R5, R6 and R7 are as defined above.
  • K, L, M, Q and T represent independently carbon or nitrogen and form phenyl or 6-membered heteroaryl, or represent, when one of K, L, M, Q and T does not exist, 5-membered heteroaryl to which oxygen, nitrogen or sulfur may be added as a ring atom,
  • n an integer of 1 to 5
  • R8 is independently hydrogen, halogen, cyano or nitro, or represents in each case optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, amine, hydroxyl, acetylene or vinyl, or is selected from the following groups:
  • U is selected from carbon, nitrogen, oxygen, phosphorus and sulfur
  • n independently 1 or 2
  • n 1
  • n 0,
  • R9 represents hydrogen or optionally substituted hydroxyl, amine, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and
  • V represents carbon, nitrogen, oxygen or sulfur.
  • R10, R11 and R12 are independently hydrogen, halogen or carbamoyl, or represent optionally substituted hydroxyl, alkyl, amine, cycloalkyl, heterocyclyl, aryl or heteroaryl, or two groups selected from R10, R11 and R12 may be connected to form a ring, and
  • Especially preferable compounds are those wherein Ar is selected from the following groups:
  • n an integer of 1 to 5
  • R8 is nitro, or represents optionally substituted hydroxyl, alkyl, acetylene, amine, heteroaryl or heterocyclyl, or is selected from the following groups:
  • n, R9, R10, R11 and R12 are as defined above.
  • RA is selected from the following groups:
  • RB is selected from the following groups:
  • R1 and R2 represent independently hydrogen or C 1 -C 6 -alkyl
  • n in each ring an integer of 0 to 9
  • A represents nitrogen
  • n an integer of 0 to 5
  • R3, R4 and R5 are independently hydrogen or halogen, or represent C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 6 -alkyl, C 5 -C 10 -aryl, C 5 -C 10 -aryl-C 1 -C 6 -alkyl, heterocyclyl or heterocyclyl-C 1 -C 6 -alkyl (wherein, heterocyclyl is a partially or fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom); or R4 and R5 are connected to form C 3 -C 10 -cycloalkyl, or a partially of fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom; wherein each radical in the definition of R3, R4 and R5 can be optionally substituted by
  • R6 represents hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 10 -cycloalkyl, C 1 -C 6 -alkoxy, C 5 -C 10 -aryl or di(C 1 -C 6 -alkyl)amine, and n represents 0 or 1,
  • R7 is hydrogen or halogen, or represents C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, C 5 -C 10 -aryl, or 5- or 6-membered heteroaryl including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom, wherein each radical in the definition of R7 can be optionally substituted by at least one selected from halogen, hydroxyl, amine, oxo, carboxy, C 1 -C 6 -alkoxycarbonyl and C 1 -C 6 -alkyl,
  • Ar is selected from the following groups:
  • n 1 or 2
  • R8 is nitro or hydroxy-C 1 -C 6 -alkyl, or represents amine optionally 1- or 2- substituted by C 1 -C 6 -alkylsulfonyl, partially or fully saturated 5- or 6-membered heterocyclyl which includes 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and is optionally substituted by oxo, or 5- or 6-membered heteroaryl which includes 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom, or is selected from the following groups:
  • n 1 or 2
  • R9 represents amino, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamine, di(C 1 -C 6 -alkyl)amine, C 3 -C 10 -cycloalkylamine, C 5 -C 10 -arylamine, C 5 -C 10 -aryl-C 1 -C 6 -alkylamine, heterocyclyl or heterocyclyl-C 1 -C 6 -alkylamine (wherein, heterocyclyl is a partially or fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom), wherein each radical in the definition of R9 is optionally substituted by at least one selected from halogen, hydroxyl, amine,
  • R10, R11 and R12 represent independently hydrogen, hydroxyl, halogen, carbamoyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 6 -alkyl, C 5 -C 10 -aryl, C 1 -C 6 -alkylamine, di(C 1 -C 6 -alkyl)amine, C 3 -C 10 -cycloalkylamine, C 5 -C 10 -arylamine or C 5 -C 10 -aryl-C 1 -C 6 -alkylamine, or represent heterocyclyl, heterocyclyl-C 1 -C 6 -
  • Representative compounds of Formula 1 according to the present invention include, but are not limited to, the following compounds:
  • butane-1-sulfonic acid (4- ⁇ 4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -2,5-difluoro-phenyl)-amide;
  • the present invention also provides a method for preparing the compounds of Formula 1.
  • the method for preparing the compounds of Formula 1 is explained based on exemplary reactions in order to illustrate the present invention.
  • a person skilled in the art could prepare the compounds of Formula 1 by various methods based on the structure of Formula 1, and such methods should be interpreted to be within the scope of the present invention. That is, the compounds of Formula 1 may be prepared by the methods described herein or by combining various methods disclosed in the prior art, which should be interpreted to be within the scope of the present invention. Accordingly, a method for preparing the compounds of Formula 1 is not limited to the following methods.
  • RA, RB, Ar, A, B, R1, R2 and n are as described above,
  • X represents a leaving group, preferably halogen, methanesulfonate (-OMs) and the like.
  • reaction scheme 1 will be explained in detail.
  • Compound 4 is obtained by the reaction of Compound 2 with Compound 3 in the presence of a conventional base or an organometallic catalyst.
  • Compound 5 is obtained by a conventional reduction and deprotection reaction from Compound 4.
  • Compound 7 can be obtained from Compound 6 by the Mitsunobu reaction with N-hydroxyphthalimide.
  • Compound 8 is then obtained by reacting Compound 7 with a conventional amine deprotecting agent such as hydrazine or alkyl hydrazine.
  • the compound of Formula 1 is obtained by a conventional condensation reaction of the intermediates of Compounds 5 and 8.
  • the compounds of Formula 1 according to the present invention can be prepared by the following reaction.
  • RA, RB, Ar, A, B, R1, R2, n and X are as described above.
  • Compound 5 is reacted with hydroxylamine to yield oxime compound 5-1, and Mitsunobu reaction is then carried out with Compound 6 to yield Compound 1.
  • Compound 1 can be obtained by the reaction of oxime compound 5-1 with the intermediate compound 6-1 which is substituted by the leaving group X.
  • Exemplary bases include, but are not limited to, metallic base such as sodium hydride (NaH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (Cs 2 CO 3 ), sodium carbonate (Na 2 CO 3 ) and potassium carbonate (K 2 CO 3 ), and organic base such as diisopropylethylamine, triethylamine and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).
  • metallic base such as sodium hydride (NaH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (Cs 2 CO 3 ), sodium carbonate (Na 2 CO 3 ) and potassium carbonate (K 2 CO 3
  • organic base such as diisopropylethylamine, triethylamine and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).
  • Preferable solvents include, but are not limited to, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, methanol, ethanol, water, 1,2-dichloroethane, dimethylsulfoxide, ethylether, methyl tert-butylether, methylene chloride, chloroform and mixtures thereof.
  • the compounds of Formula 1 obtained by the above methods can be separated or purified from the reaction products by conventional methods such as recrystallization, ionospheresis, silica gel column chromatography or ion-exchange chromatography.
  • the compounds according to the present invention can be prepared by a variety of methods, which should be interpreted to be within the scope of the present invention.
  • the compounds of Formula 1 according to the present invention have the effect of GPR119 agonists. Accordingly, the present invention provides a pharmaceutical composition as GPR119 agonists comprising the compounds of Formula 1, pharmaceutically acceptable salts or isomers thereof as an active component.
  • Exemplary diseases which can be prevented or treated by the pharmaceutical composition according to the present invention as GPR119 agonists include, but are not limited to, diabetes, complications of diabetes, obesity, dyslipidemia, osteoporosis and the like.
  • the pharmaceutical composition of the present invention can be used to prevent or treat type 1 or type 2 diabetes, especially preferable to prevent or treat type 2 diabetes.
  • the present invention provides a composition for lowering blood glucose level comprising an effective amount of a compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof and a pharmaceutically acceptable carrier.
  • the present invention provides a method for preparing the composition for preventing or treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis which comprises the step of mixing the compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof as an active component and a pharmaceutically acceptable carrier.
  • the “pharmaceutical composition” or the “composition for lowering blood glucose level” can include carriers, diluents, excipients or combinations thereof, in addition to the active component of the present invention. Accordingly, the pharmaceutical composition can include pharmaceutically acceptable carriers, diluents, excipients or combinations thereof as necessary.
  • the pharmaceutical composition facilitates the administration of compounds into the body. Various methods for administering the compounds include, but are not limited to, oral, injection, aerosol, parenteral and local administration.
  • carriers mean compounds that facilitate the addition of compounds into the cell or tissue.
  • dimethylsulfoxide is a conventional carrier facilitating the administration of compounds into the living cell or tissue.
  • diluents mean compounds that not only stabilize a biologically active form but are also diluted in solvent dissolving the compounds. Dissolved salts in buffer are used as diluents in this field.
  • a conventionally used buffer is a phosphate buffer saline copying salt form in body fluid. Since buffer solution can control the pH of the solution at low concentration, buffer diluents hardly modify the biological activity of compounds.
  • pharmaceutically acceptable means such property that does not impair the biological activity and physical property of compounds.
  • the compounds according to the present invention can be formulated as various pharmaceutically administered dosage forms.
  • an active component specifically, the compound of Formula 1 ⁇ , a pharmaceutically acceptable salt or isomer thereof is mixed with selected pharmaceutically acceptable carriers considering the dosage form to be prepared.
  • the pharmaceutical composition of the present invention can be formulated as injections, oral preparations and the like, as needed.
  • the compounds of the present invention can be formulated by conventional methods using known pharmaceutical carriers and excipients, and inserted into a unit or multi-unit containers.
  • the formulations may be solution, suspension or emulsion in oil or aqueous solvent and include conventional dispersing agents, suspending agents or stabilizing agents.
  • the compounds may be, for example, dry powder form which is dissolved in sterilized pyrogen-free water before use.
  • the compounds of the present invention can be formulated into suppositories by using a conventional suppository base such as cocoa butter or other glycerides.
  • Solid forms for oral administration include capsules, tablets, pills, powders and granules. Capsules and tablets are preferred. Tablets and pills are preferably enteric-coated.
  • Solid forms are manufactured by mixing the compounds of the present invention with at least one carrier selected from inert diluents such as sucrose, lactose or starch, lubricants such as magnesium stearate, disintegrating agents, binders and the like.
  • carrier selected from inert diluents such as sucrose, lactose or starch, lubricants such as magnesium stearate, disintegrating agents, binders and the like.
  • the compounds according to the present invention can be administered in combination with other drugs ⁇ for example, other antidiabetics, as required.
  • the dose of the compounds according to the present invention is determined by a physician’s prescription considering the patient’s body weight, age and disease condition.
  • a typical dose for adults is in the range of about 0.3 to 500 mg per day according to the frequency and intensity of administration.
  • a typical daily dose of intramuscular or intravenous administration for adults is in the range of about 1 to 300 mg per day which can be administered in divided unit dosage. Some patients need a higher daily dose.
  • the present invention also provides a method for preventing or treating diseases by using an effective amount of the compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof as an active component of GPR119 agonists.
  • Representative diseases to be treated by GPR119 agonists include, but are not limited to, metabolic disorders such as the above-mentioned diabetes, complications of diabetes, obesity, dyslipidemia, osteoporosis and the like.
  • treatment is used to mean deterring, delaying or ameliorating the progress of diseases in a subject exhibiting symptoms of diseases.
  • prevention is used to mean deterring, delaying or ameliorating the sign of diseases in a subject at risk of exhibiting symptoms of diseases, even if he or she does not exhibit the symptoms.
  • the oxime derivatives of Formula 1 according to the present invention stimulate the secretion of insulin in the pancreas and promote GLP-1, PYY and GIP formation in the gastrointestinal tract, and can accordingly be effectively used for preventing or treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis.
  • M means molar concentration
  • N means normal concentration
  • the mixture was made vacuous by using a vacuum pump and purged with nitrogen. Under nitrogen gas, the mixture was refluxed at 80 °C for 16 hours. The reaction was terminated by adding water, filtered with celite, and washed with ethyl acetate, water and saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography using 4:1 mixture solution of hexane and ethyl acetate to obtain the title compound (21.1 g, 85% yield).
  • Triphenylphosphine (4.17 g, 17.97 mmol) was dissolved in tetrahydrofuran (150 mL) and cooled to 0 °C. N,N-diisopropylazodicarboxylate (3 mL) was added dropwise and 4-hydroxy-piperidin-1-carboxylic acid tert-butyl ester (3 g, 14.9 mmol) was added thereto and the mixture was stirred for 30 minutes. Hydroxyphthalimide (2.46 g, 15.12 mmol) was added and the mixture was stirred at room temperature for 16 hours.
  • the reaction mixture was distilled under reduced pressure to remove the solvent, and purified by column chromatography using 5:5:1 mixture solution of hexane, methylene chloride and ethyl acetate to obtain 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (3.11 g, 60% yield).
  • the obtained compound (3.11 g, 8.97 mmol) was dissolved in methylene chloride (50 mL) and cooled to 0 °C. Methylhydrazine (0.53 g, 11.67 mmol) was added and the mixture was stirred at room temperature for 16 hours.
  • the reaction mixture was cooled to 0 °C and filtered under reduced pressure with methylene chloride to obtain the title compound (1.8 g, 92% yield).
  • the filtrate was distilled under reduced pressure, extracted with ethyl acetate, and washed with water and saturated aqueous solution of sodium chloride.
  • the organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure and purified by column chromatography using 4:1 ⁇ 1:1 mixture solution of hexane and ethyl acetate to obtain the title compound (80 mg, 88% yield).
  • Tetrahydrofuran (7.3 mL) was added to 4-[4-(1,4-dioxaspiro[4,5]decan-8-yloxyimino)cyclohexyl]-2,5-difluoroaniline (0.2 g, 0.5 mmol) obtained in Preparation Example 67 and cooled to 0 oC.
  • 6N HCl aqueous solution (1.5 mL) was added dropwise slowly and the mixture was stirred at room temperature. After confirming a completion of the reaction by TLC, sodium bicarbonate aqueous solution was used to adjust to pH 7, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the title compound (0.18 g, 99% yield).
  • Example 1 4-(4- ⁇ 2,5-difluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl ⁇ -cyclohexylideneaminooxy)-piperidine-1-carboxylic acid tert-butyl ester
  • 3-hydroxyazetidine hydrochloride (9.3 mg, 0.0857 mmol) and triethylamine (78 mg, 0.58 mmol) were added sequentially and stirred at room temperature for 10 minutes. Water was added to terminate the reaction, and then the mixture was washed with methylene chloride, water and saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, distilled under reduced pressure and then separated by Prep-TLC using 1:1 mixture solution of methylene chloride and ethyl acetate to obtain the title compound (20 mg, 50% yield).
  • Example 8 4-[4-(2,5-difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester
  • sodium borohydride (492 mg, 13.01 mmol) was added and dissolved into water at 0 oC, and stirred at room temperature for 3 hours. 1N hydrochloride aqueous solution was added thereto to terminate the reaction, and then the mixture was washed with ethyl acetate, water and saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, distilled under reduced pressure and then separated by column chromatography using 2:1 mixture solution of hexane and ethyl acetate to obtain the title compound (90 mg, 84% yield).
  • Example 10 4-[4-(2,5-difluoro-4-methoxycarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester
  • Example 13 4-[4-(2,5-difluoro-4- ⁇ [(3-hydroxy-azetidine-1-carbonyl)-amino]-methyl ⁇ -phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester
  • Example 16 4- ⁇ 4-[2,5-difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy ⁇ -piperidine-1-carboxylic acid isopropyl ester
  • Example 17 4-(4- ⁇ 2,5-difluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl ⁇ -cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
  • Example 18 4-(4- ⁇ 4-[3-(2,3-dihydroxy-propyl)-ureido]-2,5-difluoro-phenyl ⁇ -cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
  • Example 19 4-[4-(4-methanesulfonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester
  • Example 20 4-(4- ⁇ 4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl ⁇ -cyclohexylideneaminooxy)-piperidine-1-carboxylic acid tert-butyl ester
  • Example 21 4-(4- ⁇ 4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl ⁇ -cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
  • reaction mixture was distilled under reduced pressure to remove the solvent and then separated by Prep-TLC to obtain N-(2,5-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-N-(methanesulfonyl)methanesulfonamide (18.3 mg, 67% yield).
  • Example 35 3-hydroxy-azetidine-1-carboxylic acid (3-fluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-amide
  • Example 36 1-(2,5-difluoro-4- ⁇ 4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-methoxy-ethyl)-urea
  • Example 40 ⁇ 2,5-difluoro-4-[4-(1-thiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl ⁇ -carbamic acid methyl ester
  • Example 39 A byproduct produced in Example 39 was purified to obtain the title compound (4.2 mg, 7% yield).
  • Example 42 ⁇ 4-[4-(1- benzothiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-2,5- difluoro-phenyl ⁇ -carbamic acid methyl ester
  • Example 45 1-(2,5-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(3-hydroxy -2,2-dimethyl-propyl)-urea
  • Example 46 1-(2,5-difluoro-4- ⁇ 4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(3-hydroxy -2,2-dimethyl-propyl)-urea
  • Example 48 3-hydroxy-azetidine-1-carboxylic acid (2,6-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-amide
  • Example 50 4-[4-(2,5-difluoro-4-guanidinocarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester
  • Example 54 (4- ⁇ 4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -2,5-difluoro-phenyl)-urea
  • Example 56 3-hydroxy-azetidine-1-carboxylic acid ⁇ 2,5-difluoro-4-[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yloxyimino)-cyclohexyl]-phenyl ⁇ -amide
  • Example 57 1-(4- ⁇ 4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -2,5-difluoro-phenyl)-3-(2-hydroxy-propyl)-urea
  • Example 58 1-(4- ⁇ 4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea
  • Example 59 1-(2,5-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-ethoxy-ethyl)-urea
  • Example 60 1-(4- ⁇ 4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea
  • Example 61 1-(2,5-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-[2-(2-hydroxy-ethoxy)-ethyl]-urea
  • Example 62 ⁇ 2,5-difluoro-4-[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yloxyimino)-cyclohexyl]-phenyl ⁇ -urea
  • Example 65 1-(2,3-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-hydroxy-propyl)-urea
  • Example 66 3-(4- ⁇ 4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -2,5-difluoro-phenyl)-1,1-dimethyl-urea
  • Example 69 1-(2,6-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-methoxy-ethyl)-urea
  • Example 70 1-(2,5-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea
  • Example 72 1-(2,5-difluoro-4- ⁇ 4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(3-hydroxy-propyl)-urea
  • Example 73 3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4- ⁇ 4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-amide
  • Example 74 1-(2,6-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-hydroxy-ethyl)-urea
  • Example 75 1-(2,6-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(3-hydroxy-propyl)-urea
  • Example 76 1-(2,6-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-hydroxy-propyl)-urea

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Abstract

La présente invention concerne des dérivés d'oxime, un procédé pour leur préparation, une composition pharmaceutique les comprenant et leur utilisation. Les dérivés d'oxime selon la présente invention agissent comme des agonistes du récepteur GPR119 pour stimuler la sécrétion d'insuline et favoriser la formation de GLP-1 pour prévenir ou traiter le diabète de type 2, les complications du diabète, l'obésité, la dyslipidémie ou l'ostéoporose.
PCT/KR2012/001185 2011-02-17 2012-02-16 Dérivés d'oxime formant agonistes du récepteur gpr119 WO2012111995A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains

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CN106632302A (zh) * 2016-12-15 2017-05-10 苏州汉德创宏生化科技有限公司 1‑(噻唑‑2‑基)哌啶‑4‑醇的合成方法

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WO2004069852A1 (fr) * 2003-02-04 2004-08-19 Syngenta Participations Ag Avermectines substituees dans les positions 4'' et 4' ayant des proprietes pesticides
US20070173495A1 (en) * 2006-01-20 2007-07-26 Anandan Palani Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia
US20090312338A1 (en) * 2008-06-10 2009-12-17 Abbott Laboratories Novel Tricyclic Compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004069852A1 (fr) * 2003-02-04 2004-08-19 Syngenta Participations Ag Avermectines substituees dans les positions 4'' et 4' ayant des proprietes pesticides
US20070173495A1 (en) * 2006-01-20 2007-07-26 Anandan Palani Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia
US20090312338A1 (en) * 2008-06-10 2009-12-17 Abbott Laboratories Novel Tricyclic Compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains

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