WO2004058727A1 - 3,5-dihydro-4-h-imidazol-4-ones substitues utilises dans le traitement de l'obesite - Google Patents

3,5-dihydro-4-h-imidazol-4-ones substitues utilises dans le traitement de l'obesite Download PDF

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WO2004058727A1
WO2004058727A1 PCT/US2003/040843 US0340843W WO2004058727A1 WO 2004058727 A1 WO2004058727 A1 WO 2004058727A1 US 0340843 W US0340843 W US 0340843W WO 2004058727 A1 WO2004058727 A1 WO 2004058727A1
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alkyl
optionally substituted
alkoxy
halo
compound
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PCT/US2003/040843
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Yuanwei Chen
Stephen James O'connor
David Gunn
Jason Newcom
Jianqing Chen
Lin Yi
Hai-Jun Zhang
Laszlo Matyas Hunyadi
Reina Natero
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Bayer Pharmaceuticals Corporation
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Priority to AU2003299791A priority Critical patent/AU2003299791A1/en
Publication of WO2004058727A1 publication Critical patent/WO2004058727A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/68—Halogen 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
    • C07D401/06—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
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention relates to substituted 3,5-dihydro-4/J-imidazol-4-ones compounds which are useful in the treatment of obesity and obesity-related disorders, and as weight-loss and weight- control agents.
  • Obesity which is defined as an excess of body fat relative to lean body mass, is a well- established risk factor for a number of potentially life-threatening diseases such as atherosclerosis, hypertension, diabetes, stroke, pulmonary embolism, sleep apnea, and cancer. Furthermore, it complicates numerous chronic conditions such as respiratory diseases, osteoarthritis, osteoporosis, gall bladder disease, and dyslipidemias. The complexity of this problem is best reflected in the fact that death rates escalate with increasing body weight. More than 50% of all-cause mortality is attributable to obesity-related conditions once the body mass index (BMI) exceeds 30 kg/m 2 , as seen in 35 million Americans (Lee, JAMA 268:2045-2049, 1992).
  • BMI body mass index
  • Obesity has also been treated by administering specific agents, for example, anorectic agents, to obese subjects.
  • anorectic agents such as dextroamphetamine, the combination of the non-amphetamine drugs phentermine and fenfluramine (Phen-Fen), and dexferjfluramine (Redux) alone, are associated with serious side effects.
  • Indigestible materials such as olestra (OLEAN ® , mineral oil or neopentyl esters, U.S. Patent No. 2,962,419) have been proposed as substitutes for dietary fat.
  • Garcinia acid and derivatives thereof have been described as treating obesity by interfering with fatty acid synthesis.
  • Swellable crosslinked vinyl pyridine resins have been described as appetite suppressants via the mechanism of providing non-nutritive bulk (see, e.g., U.S. Patent No. 2,923,662).
  • the invention pertains to substituted 3,5-dihydro-47J-imidaz-5-one compounds of Formula (la) and pharmaceutical salts and esters thereof.
  • the invention pertains to a compound of Formula (la)
  • R 1 and R 2 are independently selected from (C C 6 )alkyl, thienyl, pyridyl optionally substituted with halo, CN, (C ⁇ -C 6 )alkyl, or (C ⁇ -C 6 )haloalkoxy, and phenyl optionally substituted with halo, CN, (C ⁇ -C 6 )alkyl, (C ⁇ -C 6 )alkoxy,
  • R 1 and R 2 are each (C ⁇ -C 6 )alkyl, they can be taken together with the carbon atom to which they are attached to form a saturated 5- or 6-membered carbocyclic ring;
  • n 0 or 1
  • R 3 is independently selected from H,
  • X is represents a linker selected from a bond, and a (C r C 5 )alkyl chain optionally substituted with F, OH, alkoxy, C0 2 R 5 , C(0)R 6 , oxo, or C(0)NHR 7 ;
  • R 4 is selected from
  • a 4-6-membered saturated heterocyclic ring selected from
  • R' is H or (C r C 6 )alkyl
  • R 6 is (C 3 -C 8 )cycloalkyl or (d-C 6 )alkyl optionally substituted by phenyl;
  • R' is H or (C 1 -C 6 )alkyl
  • R 8 and R 9 are independently selected from H, phenyl optionally substituted with CN, (C ⁇ -C 6 )alkyl, halo, (C ⁇ -C 6 )alkoxy, COR 6 ,
  • R 10 is selected from H
  • R u is selected from H, pyrimidyl, (C C 6 )alkyl, and pyridyl optionally substituted with CN, (C ⁇ -C 6 )alkyl, halo, (C ⁇ -C 6 )alkoxy, COR 6 ,
  • (C ⁇ -C 6 )haloalkyl, orNR 8 R 9 and phenyl optionally substituted with CN, (C ⁇ -C 6 )alkyl, halo, (C ⁇ -C 6 )alkoxy, COR 6 , (C ⁇ -C 6 )haloalkyl, or NR 8 R 9 ;
  • R 12 is independently selected from H, and (C C 6 )alkyl; R 13 is selected from H,
  • R 14 is selected from
  • R 15 is selected from
  • (C ⁇ -C ⁇ )alkyl optionally substituted with one group selected from phenyl, OH, halo, and
  • (C ⁇ -C 6 )alkoxy pyridyl optionally substituted on C with up to two groups selected from CN, CONHR 6 , CO 2 R 5 , (C C 6 )alkoxy, halo, OH, and (C C 6 )alkyl, and optionally substituted on N by oxo, naphthyl, benzodioxol-5 -yl, l,2,4-oxadiazol-5-yl optionally substituted with pyridyl, phenyl, or (C ⁇ -C 6 )alkyl optionally substituted with (C 1 -C 6 )alkoxy.
  • R 16 is selected from H
  • R 17 is selected from H
  • R 18 is selected from H, halo, CN, (C C 6 )alkyl, (C r C 6 )alkoxy, or (C r C 6 )haloalkyl;
  • R 19 is H, (C C 6 )alkyl, or phenyl
  • R 20 is selected from H
  • C0 2 (C ! -C 6 )alkyl optionally substituted with phenyl(C0 2 -benzyl), S0 2 CH 3 , and phenyl;
  • the invention also pertains to a compound of Formula (lb)
  • R 24 and R 25 are independently selected from (C C 6 )alkyl, thienyl, pyridyl optionally substituted with halo, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl,
  • W is (CH 2 ) p ;
  • R 27 and R 2 are independently selected from H, phenyl optionally substituted with CN, (C ⁇ -C 6 )alkyl, halo, (C ⁇ -C 6 )alkoxy, CO(C ⁇ -C 6 )alkyl,
  • (C r C 6 )haloalkyl NH 2 , N[(C C 6 )alkyl] 2 , or NH(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, and (C ⁇ -C 6 )alkyl optionally substituted with halo, phenyl, (Q-C ⁇ ⁇ lkoxy or OH;
  • R 29 is H, halo, CN, (C C 6 )alkyl, (C C 6 )alkoxy, or (C C 6 )haloalkyl;
  • halo means F, Cl, Br, or I.
  • (C ⁇ -C 6 ) alkyl means a straight or branched saturated hydrocarbon carbon chain of from 1 to about 6 carbon atoms, respectively. Examples of such groups include methyl, ethyl, isopropyl, sec-butyl, 2-methylpentyl, n-hexyl, and the like.
  • (C C 6 )haloalkyl means a Ci-C ⁇ alkyl group substituted by 1 to 3 halogen atoms or fluorine up to the perfluoro level. Examples of such groups include trifluoromethyl, tetrafluoroethyl, 1,2-dichloro ⁇ ropyl, 5-bromopentyl, 6-iodohexyl, and the like.
  • (C 3 -C 8 )cycloalkyl means a saturated carbocyclic ring system of from 3 to about 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • (C C 6 )acyl means a Cj-C ⁇ 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 acetyl, propionyl, n-butanoyl, 2-methylpentantoyl, and the like.
  • (C 1 -C 6 )alkoxy mean a linear or branched saturated carbon group having from 1 to about 6 C atoms, respectively, and 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, «-propoxy, isopropoxy, and the like.
  • (C ⁇ -C 6 )haloalkoxy means a C C 6 alkoxy group further substituted on C with 1 to 3 halogen atoms or fluorine up to the perfluoro level.
  • any moiety when any moiety is described as being substituted, it can have one or more of the indicated substituents that can be located at any available position on the moiety.
  • each term shall be defined independently of any other substituent so that, accordingly, the substituents can be the same or different.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • analog of a compound refers to a compound having a substantial structural similarity to a particular compound and having essentially the same biological activity as the compound.
  • derivatives of a compound or of a small molecule refers to a compound which can be derived, for example, by chemical synthesis, from the original compound.
  • a derivative of a compound has certain structural similarities with the compound.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991).
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87.
  • the term "hydrocarbon” is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom.
  • the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted.
  • Representative salts of the compounds of Formulae (la) and (lb) include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts andN-methyl-D-glucamine.
  • basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl, and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, lau
  • the esters in the present invention are non-toxic, pharmaceutically acceptable ester derivatives of the alcohols of Formulae (la) and (lb). This includes ester derivatives prepared from acetic, benzoic, mandelic, stearic, lactic, salicylic, hydroxynaphthoic, glucoheptonic, and gluconic acid.
  • the alcohol compounds of Formulae (la) and (lb) may be esterified by a variety of conventional procedures including reacting the appropriate anhydride, carboxylic acid, or acid chloride with the alcohol group of the respective Formulae (la) or (lb) compound.
  • anhydride is reacted with the alcohol in the presence of an acylation catalyst such as 1,8- bis[dimethylamino]naphthalene or DMAP (NN-dimethylaminopyridine).
  • an acylation catalyst such as 1,8- bis[dimethylamino]naphthalene or DMAP (NN-dimethylaminopyridine).
  • An appropriate carboxylic acid may be reacted with the alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, l-[3-dimethylan ⁇ inopropyl]-3-ethylcarbodiimide or other water soluble dehydrating agents which are used to drive the reaction by the removal of water, and optionally, an acylation catalyst.
  • Esterification may also be reached using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and optionally, pyridine, or in the presence of N,N- carbonyldiimidazole with pyridine.
  • Reaction of an acid chloride with the alcohol may be carried out with an acylation catalyst such as DMAP or pyridine.
  • an acylation catalyst such as DMAP or pyridine.
  • Sensitive or reactive groups on the compound of Formulae (la) and (lb) may need to be protected during any of the above methods for forming esters, and protecting groups may be added and removed by conventional methods well known in the art.
  • the compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R,S) configuration, preferably in the (R)- or (S)- configuration, whichever is most active.
  • Formulae (la) and (lb) compounds may be prepared by standard techniques known in the art and by known processes analogous thereto.
  • seven such standard methods may be used, the selection of which may be based, among other considerations, upon the availability of the required individual starting materials. These seven methods are illustrated in Reaction Schemes 1, 2, 3, 5, 8, 9, and 10 below.
  • Additional compounds of Formulae (la) and (lb) may be prepared from other Formulae (la) and (lb) compounds by elaboration of functional groups present.
  • elaboration includes, but is not limited to, hydrolysis, reduction, oxidation, alkylation, acylation, esterification, amidation, and dehydration reactives.
  • Such transformations may in some instances require the use of protecting groups by the methods disclosed in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999), and incorporated herein by reference. Such methods would be initiated after synthesis of the desired compound or at another place in the synthetic route that would be readily apparent to one skilled in the art.
  • each variable may be any moiety within that variable's definition
  • Reaction Scheme 1 wherein an appropriate diketone (III) is allowed to react with the appropriate amidine (IV) (commercially available or prepared by Reaction Scheme 5) to provide cyclic intermediate (II).
  • This cyclization step is typically carried out in a base at rt to 150°C, and in an aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile, acetone, dioxane, or an alcohol such as ethanol, isopropanol, n- propanol, n-butanol, iso-butanol, and t-butanol.
  • the base is typically one of the following base such as Cs 2 C0 3 , K 2 C0 3 , Na 2 C0 3 , K 3 P0 , Na 3 P0 , NaOH, KOH, NaH, or a sodium or potassium alkoxide.
  • the intermediate (II) may then be converted into compounds of Formula (la) by alternative routes.
  • the first route is alkylation of (II) under basic conditions with an appropriate alkylation reagent and represented by the Formula LG-X-R 4 .
  • (ID can be reacted with alkyl dihalide to provide intermediate (V), which is reacted with HR 4 under basic conditions to provide (la).
  • intermediate (II) is allowed to react with an alcohol containing a leaving group (i.e., LG-X-OH) to produce intermediate (VI), which is converted to a mesylate or tosylate, and allowed to further react with HR to provide compound (la).
  • LG-X-OH a leaving group
  • a fluoro containing compound with Formula (Id) can be prepared from (Ic) by reaction of a fluorinating agent such as DAST in a solvent such as toluene or benzene (Reaction Scheme 3).
  • the intermediate (II) may also be prepared by an alternative route as shown in Reaction Scheme 4.
  • (lie) can be prepared from (XIID, prepared according to Reaction Scheme 1, and an amine, R 8 R 9 NH, as shown in Reaction Scheme 7.
  • the compound of Formula (If), where R 10 is a (C ⁇ -C 6 )alkyl substituted with substituted piperidine or substituted pyrrolidine can be prepared by the route shown in Reaction Scheme 8.
  • the amino acid (XTV) either commercially available or prepared by the standard methods, is reacted with an acyl chloride or an anhydride to provide an oxazolone (XV).
  • Imidazolone (XVT) is obtained by treatment of (XV) with aminopiperidine. The protecting group is removed and alkylated with an alkylation agent to provide (If).
  • Reaction Scheme 9 describes the preparation of compounds of Formula (la) in which R is
  • R is (C ⁇ -C 6 )alkyl substituted by pyridyl of phenyl, or more generally represented as Formula (XVITD in which one of Z 1 , Z 2 , and Z 3 is either a carbon or nitrogen atom; p and q are 0 or 1; and o is 0, 1, 2, 3, 4, or 5.
  • XVITD N- alkylation of Intermediate (ID under basic conditions provides intermediate (XVII), which is converted to compound (XVLTD by reductive animation or alkylation reactions.
  • PG and PG' indicates a suitable protecting group such as BOC, added and removed as needed to facilitate the synthesis, according to standard methods known in the art.
  • R 10 is (C r C 6 )alkyl substituted by phenyl or pyridyl
  • LG Cl, Br, I, OMs, or OTs
  • Piperidines (Al) are commercially available or can be prepared according to one of the many procedures described in the literature. Some can be prepared by the reactions described below.
  • Piperidine substituents e.g, R 15 groups which are aromatic such as phenyl or pyridyl, are introduced by Suzuki coupling, followed by hydrogenation and deprotection to provide (Al).
  • (Al) can also be prepared by the borane (XXV), which is prepared from bis(pinacolato)diboron (XXII), under standard Suzuki coupling conditions followed by hydrogenation.
  • (Al) can also be prepared by the reaction of Grignard reagent or Lithium reagent with ketone (XXIID, followed by dehydration, catalytic hydrogenation.
  • LG Cl, Br, I, OMs, or OTs
  • (Al) can be prepared according to Reaction Scheme 12. Pyridine (XXVID can be coupled with boronic acid under Suzuki coupling conditions to provide an aryl pyridine (XXVIID, which can be reduced by a reducing agent such as NaBIL, and the protecting group can be removed to provide the piperidine (Al).
  • a reducing agent such as NaBIL
  • LG Cl, Br, I, OMs, or OTs
  • the piperidine of Formula (A2) in which R 8 and R 9 are H or a lower alkyl group as described above can be prepared according to Reaction Scheme 13.
  • a heteroketoester (XXX) is converted to an enol ether (XXXI), which can be coupled with a aryl boronic acid (in which aryl is phenyl or pyridyl) to provide a compound of Formula (XXXID.
  • Reduction and hydrolysis, followed by coupling with a primary or secondary amine provides a compound of Formula (XXXV).
  • deprotection provides the intermediate of Formula (A2).
  • the carbonyl group of Formula (XXXIID can be also reduced to the alcohol of Formula (XXXVI), and finally deprotection provides the intermediate of Formula (A3).
  • Piperidines of structure (A4) in which R 15 is and R 18 is as defined above can be prepared according to Reaction Scheme 14.
  • the compound of Formula (XXXVID can be obtained under reductive amination conditions and then reacted with an acyl chloride to provide the compound of Formula (XXXVIIl).
  • Deprotection of (XXXVIIl) provides intermediate (A4).
  • Piperidines of Formula (A5) in which R 15 is optionally substituted pyrimidyl, can be prepared by Reaction Scheme 15.
  • condensation of a malonate with a carboxylic acid (XXXIX) provides ⁇ -ketone esters of Formula (XL) which is then treated with an amidine and deprotected to provide (A5).
  • R ? 21 ⁇ _ H, (C C 6 )alkyl, phenyl or pyridyl
  • Piperidine (A6) in which R 15 is substituted oxadiazolyl (i.e., R 22 is a alkyl group or aryl) can be prepared according to Reaction Scheme 16.
  • the acid of Formula (XXXLX) is coupled with a hydrazide to provide an oxadiazole of Formula (XLID, which is deprotected to give (A6).
  • (A7) may also be prepared from (XXXLX) in similar fashion.
  • Piperidines of Formula (A8) in which Z 1 is either carbon or nitrogen, and R 23 is as defined below, can be prepared as described in Reaction Scheme 17.
  • the compound of Formula (XLIV) is treated with a aromatic halide in basic conditions to provide the compound of Formula (XLV), which is then hydrolyzed, decarboxylated, and deprotected to provide (A8).
  • Ester of Formula (XLV) may also be reduced with an reducing agent such as LiAUL,, to provide (XLVID, which is cyclized under basic conditions and deprotection to provide the compound of Formula (A9).
  • R 23 CN, CONHR 6 , C0 2 R 5 , (C C 6 )alkoxy, halo, OH, or (C-rCeJaikyl, [071]
  • the piperidine of Formula (AlO) can be prepared as shown in Reaction Scheme 18.
  • ketophenol (XLLX) is allowed to react with a ketone piperidine (XXIID to give a pyranone of Formula (L); and deprotection of (L) gives (AlO).
  • R 25 halo, C0 2 R 5 , NHCOR 6 , CONR 8 R 9 , (C 1 -C 6 )alkyl, (C C 6 )alkoxy, NH 2 , N0 2 , CN, and CF 3
  • Celite ® diatomaceous earth filter agent ® Celite Corp.
  • HPLC-electrospray mass spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro C18 2.0 mm x 23 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95%> B over 4 minutes was used on the HPLC. Buffer A was 98% water, 2% acetonitrile, and 0.02% TFA; and Buffer B was 98% acetonitrile, 2% water, and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source.
  • Proton ('H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me 4 Si ( ⁇ 0.00) or residual protonated solvent (CHC1 3 ⁇ 7.26; MeOH ⁇ 3.30; DMSO ⁇ 2.49) as standard.
  • Carbon ( 13 C) ⁇ MR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 ⁇ 77.0; d 3 -MeOD; ⁇ 49.0; d 6 -DMSO ⁇ 39.5) as standard.
  • Step 1 Preparation of l-(3-chloropropyl -4-r4-(trifluoromethvDphenyllpiperidine
  • K 2 C0 3 9.1 g, 65.4 mmol
  • 4 - (4- trifluorophethyl-phenyl)-piperidine 3 g, 13.1 mmol
  • CH 3 CN 50 mL
  • 3- bromopropanol (1.36 mL, 15.0 mmol) were added to the solids.
  • the reaction was allowed to stir at 23°C for 16 h.
  • the reaction mixture was filtered through a plug of Celite ® and concentrated in vacuo.
  • the resulting yellow/orange oil solidified over 2 h under high vacuum to provide l-(3- hydroxy)-4-[4-(trifluoromethyl)phenyl]piperidine, which was used directly in the next without further purification.
  • Step 3 Preparation of 5.5-bis(4-fluorophenvD-2-methyl-3-(3-(4-r4-(trifluoromethvD phenyll - 1 -piperidinyl ⁇ propyD-3 ,5 -dihvdro-4H-imidazol-4-one
  • Step 1 Preparation of 5.5-Diphenyl-2-thiophen-2-yl-3,5-dihydro-imidazol-4-one
  • benzil 2 g, 10 mmol, 1 equiv
  • 2-amidinothiophene 1 g, 8 mmol, 0.8 equiv
  • the tube was sealed and heated to 100°C for 3 h with magnetic stirring.
  • the resulting solution was concentrated in vacuo.
  • Step 3 Preparation of 5.5-Diphenyl-3-[3-(4-phenyl-piperidin-l-yl)-propyl1-2-thiophen-2- yl-3.5 -dihvdro-imidazol-4-one
  • Step 1 Preparation of 3-(3-bromobutyl -5.5-bis(4-fluorophenyl -2-methyl-3.5-dihydro-4/J- imidazol-4-one
  • Step 3 Preparation of HCl salt of (SV5.5-bis(4-fluorophenvD-3-f3-r4-(4-fluorophenyl -l- piperidinyl1butyl ⁇ -2-methyl-3,5-dihydro-4iJ " -imidazol-4-one
  • Step 2 Preparation of (- -5-ethyl-5-(4-fluorophenvD-2-methyl-3-(3- ⁇ 4-[3-(acetamino phenyl]-l-piperdmyl ⁇ propyD-3 -dmydro-4H-imidazol-4-one
  • N-[3-(4-piperidinyl)phenyl]acetamide (0.08 g, 0.32 mmol) was dissolved in anhyd DMF (3 mL) followed by the dropwise addition of triethylamine (0.14 g, 0.81 mmol).
  • 3-(3-Bromopropyl)-5- ethyl-5-(4-fluorophenyl)-2-methyl-3,5-dmydro-47J-imidazol-4-one from Step 1 (0.11 g, 0.32 mmol) was then added to the reaction which was then heated to 80°C for 18 h. The reaction was quenched with water and extracted with ethyl acetate (2 x 30 mL).
  • Step 2 Preparation of 5.5-bis(4-fluorophenyl)-3- ⁇ 3-[4-(4-fluorophenyl)-l-piperidinyll-2- hyQ ⁇ oxypropyl ⁇ -2-memyl-3,5- ⁇ vdro-4H-imidazol-4-one
  • (+) and (-) enantiomers (+)-5-ethyl-5-(4-fluorophenyD-2-methyl-3.5-dihvdro- 4 Z " -imidazol-4-one and (-)-5-ethyl-5-(4-fluorophenyl)-2-methyl-3.5-dihydro-4H-imidazol-4-one
  • (+)- and (-)- enantiomers of 5-ethyl-5-(4-fluorophenyl)-2-methyl-3,5-dihydro-4H-imidazol-4- one were separated by chiral HPLC; Column: Chiracel OD, 20 x 250 mm; Mobile Phase, hexane/ isopropanol w/ 0.1% TEA; Flow Rate, 15 mL/min.; Detector (UV), 250 mn.
  • Step 3 Preparation of 5.5-bis(4-fluorophenvD-2-(3-f4-(4-fluorophenvD-l- piperidinyl1propyl ⁇ -3.5-dihvdro-4H-imidazol-4-one
  • Step 3 Preparation of 3-( ⁇ l-[3-(1.3-benzodioxol-5-yl)-2-methylpropyl1-4- piperidinyl ⁇ methyl -5,5-bis(4-fluorophenyl ' )-2-methyl-3.5-dihydro-4H-imidazol-4-one
  • Step 1 Preparation of ethyl 3-[4.4-bis(4-fluorophenvD-2-methyl-5-oxo-4.5-dihvdro-lH- imidazol- 1 -yllpropanate
  • Step 3 Preparation of 5.5-bis(4-fluorophenvD-2-methyl-3-(3-oxo-3-(4- 4- (trifluoromethyl phenyll - 1 -piperidinyl ⁇ propyD-3 ,5 -dihvdro-4H-imidazol-4-one
  • Step 1 Preparation of tert-butyl 4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ -3,6-dihydro-l(2H)- pyridinecarboxylate n-Butyl lithium (17.33 mL, 27.73 mmol, 1.6 M in hexanes) was added to a solution of diisopropyl amine (3.89 mL, 27.73 mmol) in 6.5 mL of dry THF at -60°C and stirred for 20 minutes while warming to - 30°C. The solution was cooled to -60°C, and a white precipitate formed (LDA). THF (18 mL) was added and the reaction was cooled to -72°C.
  • LDA white precipitate formed
  • Pd(OH) 2 (0.02 g, 0.14 mmol) was added into a flask, flushed with argon, and wet with ethanol (4 mL).
  • the catalyst was filtered through Celite ® , and the reaction was evaporated to dryness.
  • Step 1 Preparation of ethyl l- ⁇ 3-[4.4-bis(4-fl.uorophenvD-2-methyl-5-oxo-4.5-dihvdro-lH- imidazol- 1 -yllpropyl ⁇ -4-piperidinecarboxylate
  • Step 3 Preparation of ethyl 3-(l- ⁇ 3-[4.4-bis(4-fluorophenyl -2-methyl-5-oxo-4.5-dihydro- lif-imidazol-l-yl]propyl ⁇ -4-piperidinyD-3-oxopropanoate
  • Step 2 Step 3 [173] Step 1.
  • Step 2 Step 2
  • Step 3 Step 1
  • Step 2 Step 3
  • Step 1 Preparation of ethyl l-benzyl-4-[2-fluoro-4-(trifluoiOmethyl phenyl]-4- piperidinecarboxylate
  • N-benzylpiperidine-4-carboxylic acid ethyl ester (6.1 g, 24.7 mmol) in 100 mL THF at -78°C was added LDA (14.2 mL of 2M in THF, 28.4 mmol) over 15 minutes.
  • LDA 14.2 mL of 2M in THF, 28.4 mmol
  • the solution was stkred at -78°C for another 15 minutes, followed by addition of a solution of 3,4- difluorobenzotrifluoride (4.5 g, 24.7mmol) in 20 mL THF over 15 minutes.
  • N-Boc-piperidine-4-carboxylic acid ethyl ester 2.0 g, 8.3 mmol
  • LDA 5.0 mL of 2M in THF, 10 mmol
  • the solution was sti ⁇ ed at -78°C for another 15 minutes, followed by addition of a solution of l-fluoro-3- nitrobenzene (1.2 g, 8.2 mmol) in 20 mL THF over 15 minutes.
  • the starting materials (490 mg, 1 mmol), prepared in the same way as Example 29 and Example 30, were dissolved in 15 mL 2M ammonia in MeOH in a sealed tube. The mixture was heated at 90°C for 2 days. The solvent was then removed by evaporation to give crude product.

Abstract

L'invention concerne des composés 3,5-dihydro-4-H-imidazol-4-ones utilisés dans le traitement de l'obésité et des troubles associés à l'obésité, et en tant qu'agents d'amaigrissement et de contrôle du poids. L'invention concerne également des méthodes de synthèse de ces composés, des compositions pharmaceutiques contenant ces composés, et des méthodes d'utilisation de ces compositions pour induire une perte de poids et traiter l'obésité et les troubles associés à l'obésité.
PCT/US2003/040843 2002-12-20 2003-12-19 3,5-dihydro-4-h-imidazol-4-ones substitues utilises dans le traitement de l'obesite WO2004058727A1 (fr)

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Publication number Priority date Publication date Assignee Title
EP1622878A2 (fr) * 2003-05-15 2006-02-08 Cytokinetics, Inc. Composes, compositions et procedes
WO2006069788A1 (fr) * 2004-12-30 2006-07-06 Novartis Ag Composes organiques
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US7105544B2 (en) 2001-07-05 2006-09-12 Synaptic Pharmaceutical Corporation Substituted alkyl amido piperidines
WO2006128562A1 (fr) * 2005-06-02 2006-12-07 Merck Patent Gmbh Utilisation de derives de chromone
WO2007038271A1 (fr) * 2005-09-26 2007-04-05 Wyeth Composes d'amino-5-[4-(difluoromethoxy) phenyl]-5-phenylimidazolone utilises comme inhibiteurs de la beta-secretase (bace)
WO2007067504A2 (fr) 2005-12-05 2007-06-14 Incyte Corporation Composes lactames et procedes d'utilisation de ceux-ci
GB2435828A (en) * 2006-03-09 2007-09-12 Del Dr Esteve S A Spain Lab Use of substituted phenyl-piperazine compounds for treatment of food related disorders
GB2435829A (en) * 2006-03-09 2007-09-12 Del Dr Esteve S A Spain Lab Pyrimidinyl-2-piperazine compounds for use in disorders related to food intake
US7279486B2 (en) 2004-03-29 2007-10-09 Pfizer Inc. Alpha aryl or heteroaryl methyl beta piperidino propanoic acid compounds as ORL1-receptor antagonists
WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
US7417047B2 (en) 2005-06-30 2008-08-26 Wyeth Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation
US7482349B2 (en) 2004-06-16 2009-01-27 Wyeth Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2009050201A2 (fr) * 2007-10-16 2009-04-23 Novartis Ag Composés organiques
US7563796B2 (en) 2005-01-14 2009-07-21 Wyeth Diphenylimidazopyrimidines as inhibitors of β-secretase
US7582667B2 (en) 2006-02-24 2009-09-01 Wyeth Dihydrospiro[dibenzo[a,d][7]annulene-5,4′-imidazol] compounds for the inhibition of beta-secretase
WO2010003624A2 (fr) 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
US7700606B2 (en) 2006-08-17 2010-04-20 Wyeth Llc Imidazole amines as inhibitors of β-secretase
US7723368B2 (en) 2007-03-23 2010-05-25 Wyeth Llc Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of beta-secretase
US7732457B2 (en) 2005-02-01 2010-06-08 Wyeth Llc Amino-pyridines as inhibitors of β-secretase
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
US7763609B2 (en) 2003-12-15 2010-07-27 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
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US7776874B2 (en) 2004-05-07 2010-08-17 Incyte Corporation Amido compounds and their use as pharmaceuticals
US7825244B2 (en) 2005-06-10 2010-11-02 Janssen Pharmaceutica Nv Intermediates useful in the synthesis of alkylquinoline and alkylquinazoline kinase modulators, and related methods of synthesis
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
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US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
US8071768B2 (en) 2005-06-10 2011-12-06 Janssen Pharmaceutica, N.V. Alkylquinoline and alkylquinazoline kinase modulators
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
US8093389B2 (en) 2007-01-12 2012-01-10 Merck Sharp & Dohme Corp. Substituted spirochromanone derivatives
US8093254B2 (en) 2006-12-12 2012-01-10 Schering Corporation Aspartyl protease inhibitors
US8138197B2 (en) 2007-01-12 2012-03-20 Msd K.K. Spirochromanon derivatives
US8178513B2 (en) 2003-12-15 2012-05-15 Schering Corporation Heterocyclic aspartyl protease inhibitors
WO2012120050A1 (fr) 2011-03-08 2012-09-13 Sanofi Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, médicaments contenant ces composés et leur utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
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US8278318B2 (en) 2007-06-21 2012-10-02 Incyte Corporation Spirocycles as inhibitors of 11-beta hydroxyl steroid dehydrogenase type 1
US8288417B2 (en) 2004-06-24 2012-10-16 Incyte Corporation N-substituted piperidines and their use as pharmaceuticals
US8362248B2 (en) 2005-01-10 2013-01-29 Arena Pharmaceuticals, Inc. Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto
US8410119B2 (en) 2003-07-14 2013-04-02 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
WO2014039769A1 (fr) * 2012-09-07 2014-03-13 Janssen Pharmaceutica Nv Dérivés d'imidazoline—5-one utiles en tant qu'inhibiteurs de l'acide gras synthase (fasn) pour le traitement du cancer
CN104177298A (zh) * 2014-09-18 2014-12-03 湘潭大学 4,4-二取代-4,5-二氢-1h–咪唑-5-酮、衍生物及其合成方法
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
WO2015037716A1 (fr) 2013-09-12 2015-03-19 住友化学株式会社 Composé hétérocyclique saturé contenant de l'azote
US20150166529A1 (en) * 2013-12-17 2015-06-18 Janssen Pharmaceutica, Nv Imidazolin-5-one derivative useful as fasn inhibitors for the treatment of cancer
CN105272919A (zh) * 2015-11-12 2016-01-27 中国科学院过程工程研究所 一种从肉苁蓉低聚糖浆中制备尿囊素的方法
WO2017049321A1 (fr) 2015-09-17 2017-03-23 Miller Marvin J Composés hétérocycliques contenant de la benzylamine et compositions utiles contre une infection mycobactérienne
US9840491B2 (en) 2015-02-05 2017-12-12 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US9902728B2 (en) 2014-12-30 2018-02-27 Forma Therapeutics, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US9932351B2 (en) 2015-02-05 2018-04-03 Forma Therapeutics, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9938300B2 (en) 2015-02-05 2018-04-10 Forma Therapeutics, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10000495B2 (en) 2014-12-30 2018-06-19 Forma Therapeutics, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
WO2019170543A1 (fr) 2018-03-07 2019-09-12 Bayer Aktiengesellschaft Identification et utilisation d'inhibiteurs d'erk5
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022108A1 (fr) * 1996-11-20 1998-05-28 Merck & Co., Inc. Imidazoles a substitution triaryle et leurs procedes d'utilisation
US6043366A (en) * 1997-12-05 2000-03-28 Hoffman-La Roche Inc. 1,3,8,-triaza spiro (4,5)decan-4-on derivatives
WO2003037332A1 (fr) * 2001-10-12 2003-05-08 Bayer Pharmaceuticals Corporation Heterocycles utiles pour le traitement de l'obesite
WO2003040107A1 (fr) * 2001-09-24 2003-05-15 Bayer Pharmaceuticals Corporation Preparation et utilisation de derives d'imidazole dans le traitement de l'obesite

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022108A1 (fr) * 1996-11-20 1998-05-28 Merck & Co., Inc. Imidazoles a substitution triaryle et leurs procedes d'utilisation
US6043366A (en) * 1997-12-05 2000-03-28 Hoffman-La Roche Inc. 1,3,8,-triaza spiro (4,5)decan-4-on derivatives
WO2003040107A1 (fr) * 2001-09-24 2003-05-15 Bayer Pharmaceuticals Corporation Preparation et utilisation de derives d'imidazole dans le traitement de l'obesite
WO2003037332A1 (fr) * 2001-10-12 2003-05-08 Bayer Pharmaceuticals Corporation Heterocycles utiles pour le traitement de l'obesite

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US7105544B2 (en) 2001-07-05 2006-09-12 Synaptic Pharmaceutical Corporation Substituted alkyl amido piperidines
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
EP1622878A4 (fr) * 2003-05-15 2008-04-09 Cytokinetics Inc Composes, compositions et procedes
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US8410119B2 (en) 2003-07-14 2013-04-02 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US7763609B2 (en) 2003-12-15 2010-07-27 Schering Corporation Heterocyclic aspartyl protease inhibitors
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US8937093B2 (en) 2003-12-15 2015-01-20 Merck Sharp & Dohme Corp. Heterocyclic aspartyl protease inhibitors
US7279486B2 (en) 2004-03-29 2007-10-09 Pfizer Inc. Alpha aryl or heteroaryl methyl beta piperidino propanoic acid compounds as ORL1-receptor antagonists
US8058288B2 (en) 2004-05-07 2011-11-15 Incyte Corporation Amido compounds and their use as pharmaceuticals
US9670154B2 (en) 2004-05-07 2017-06-06 Incyte Holdings Corporation Amido compounds and their use as pharmaceuticals
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US7700602B2 (en) 2004-06-16 2010-04-20 Wyeth Llc Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase
US7482349B2 (en) 2004-06-16 2009-01-27 Wyeth Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase
US8288417B2 (en) 2004-06-24 2012-10-16 Incyte Corporation N-substituted piperidines and their use as pharmaceuticals
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
EP2289510A1 (fr) * 2004-09-20 2011-03-02 Xenon Pharmaceuticals Inc. Dérivés hétérocycliques pour le traitement des maladies induites par des enzymes stearoyl-coa desaturase
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
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WO2006034315A3 (fr) * 2004-09-20 2006-07-27 Xenon Pharmaceuticals Inc Derives heterocycliques et utilisation de ceux-ci comme agents therapeutiques
US8178559B2 (en) 2004-12-30 2012-05-15 Novartis Ag Organic compounds
US8084450B2 (en) 2004-12-30 2011-12-27 Novartis Ag Organic compounds
WO2006069788A1 (fr) * 2004-12-30 2006-07-06 Novartis Ag Composes organiques
US8362248B2 (en) 2005-01-10 2013-01-29 Arena Pharmaceuticals, Inc. Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto
US7563796B2 (en) 2005-01-14 2009-07-21 Wyeth Diphenylimidazopyrimidines as inhibitors of β-secretase
US7732457B2 (en) 2005-02-01 2010-06-08 Wyeth Llc Amino-pyridines as inhibitors of β-secretase
WO2006128562A1 (fr) * 2005-06-02 2006-12-07 Merck Patent Gmbh Utilisation de derives de chromone
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
US7825244B2 (en) 2005-06-10 2010-11-02 Janssen Pharmaceutica Nv Intermediates useful in the synthesis of alkylquinoline and alkylquinazoline kinase modulators, and related methods of synthesis
US8071768B2 (en) 2005-06-10 2011-12-06 Janssen Pharmaceutica, N.V. Alkylquinoline and alkylquinazoline kinase modulators
US7417047B2 (en) 2005-06-30 2008-08-26 Wyeth Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation
US7705030B2 (en) 2005-06-30 2010-04-27 Wyeth Llc Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation
WO2007038271A1 (fr) * 2005-09-26 2007-04-05 Wyeth Composes d'amino-5-[4-(difluoromethoxy) phenyl]-5-phenylimidazolone utilises comme inhibiteurs de la beta-secretase (bace)
US7423158B2 (en) 2005-09-26 2008-09-09 Wyeth Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of β-secretase
EP2256107A1 (fr) * 2005-09-26 2010-12-01 Wyeth LLC Composés d'amino-5-[4-(difluorométhoxy)phényl]-5- phénylimidazolone comme inhibiteurs de la bêta-sécrétase (BACE)
WO2007067504A3 (fr) * 2005-12-05 2007-11-08 Incyte Corp Composes lactames et procedes d'utilisation de ceux-ci
JP2009518408A (ja) * 2005-12-05 2009-05-07 インサイト・コーポレイション ラクタム化合物およびそれを用いる方法
WO2007067504A2 (fr) 2005-12-05 2007-06-14 Incyte Corporation Composes lactames et procedes d'utilisation de ceux-ci
US8193207B2 (en) 2005-12-05 2012-06-05 Incyte Corporation Lactam compounds and methods of using the same
US7582667B2 (en) 2006-02-24 2009-09-01 Wyeth Dihydrospiro[dibenzo[a,d][7]annulene-5,4′-imidazol] compounds for the inhibition of beta-secretase
GB2435829A (en) * 2006-03-09 2007-09-12 Del Dr Esteve S A Spain Lab Pyrimidinyl-2-piperazine compounds for use in disorders related to food intake
GB2435828A (en) * 2006-03-09 2007-09-12 Del Dr Esteve S A Spain Lab Use of substituted phenyl-piperazine compounds for treatment of food related disorders
WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
US7700606B2 (en) 2006-08-17 2010-04-20 Wyeth Llc Imidazole amines as inhibitors of β-secretase
US8093254B2 (en) 2006-12-12 2012-01-10 Schering Corporation Aspartyl protease inhibitors
US8138197B2 (en) 2007-01-12 2012-03-20 Msd K.K. Spirochromanon derivatives
US8093389B2 (en) 2007-01-12 2012-01-10 Merck Sharp & Dohme Corp. Substituted spirochromanone derivatives
US7723368B2 (en) 2007-03-23 2010-05-25 Wyeth Llc Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of beta-secretase
US9006260B2 (en) 2007-06-21 2015-04-14 Incyte Corporation Spirocycles as inhibitors of 11-beta hydroxyl steroid dehydrogenase type 1
US8278318B2 (en) 2007-06-21 2012-10-02 Incyte Corporation Spirocycles as inhibitors of 11-beta hydroxyl steroid dehydrogenase type 1
US9873698B2 (en) 2007-06-21 2018-01-23 Incyte Holdings Corporation Spirocycles as inhibitors of 11-beta hydroxyl steroid dehydrogenase type 1
US9371323B2 (en) 2007-06-21 2016-06-21 Incyte Holdings Corporation Spirocycles as inhibitors of 11-beta hydroxyl steroid dehydrogenase type 1
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
US7786155B2 (en) 2007-10-16 2010-08-31 Novartis Ag Organic compounds
WO2009050201A3 (fr) * 2007-10-16 2009-08-13 Novartis Ag Composés organiques
WO2009050201A2 (fr) * 2007-10-16 2009-04-23 Novartis Ag Composés organiques
WO2010003624A2 (fr) 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
WO2012120058A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des groupes benzyle ou hétérométhylène, leur procédé de production, leur utilisation comme médicament ainsi que produits pharmaceutiques les contenant et leur utilisation
WO2012120051A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés benzyl-oxathiazine substitués avec adamantane ou noradamantane, médicaments contenant ces composés et leur utilisation
WO2012120050A1 (fr) 2011-03-08 2012-09-13 Sanofi Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, médicaments contenant ces composés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120057A1 (fr) 2011-03-08 2012-09-13 Sanofi Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, agent pharmaceutique contenant ces composés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
US10077261B2 (en) 2012-09-07 2018-09-18 Janssen Pharmaceutica Nv Imidazolin-5-one derivative useful as FASN inhibitors for the treatment of cancer
US20150099730A1 (en) * 2012-09-07 2015-04-09 Janssen Pharmaceutica, Nv Imidazolin-5-one derivative useful as fasn inhibitors for the treatment of cancer
US20160002219A1 (en) * 2012-09-07 2016-01-07 Janssen Pharmaceutica Nv Imidazolin-5-one derivative useful as fasn inhibitors for the treatment of cancer
WO2014039769A1 (fr) * 2012-09-07 2014-03-13 Janssen Pharmaceutica Nv Dérivés d'imidazoline—5-one utiles en tant qu'inhibiteurs de l'acide gras synthase (fasn) pour le traitement du cancer
JP2015527397A (ja) * 2012-09-07 2015-09-17 ヤンセン ファーマシューティカ エヌ．ベー． がん治療用の脂肪酸合成酵素（ｆａｓｎ）阻害剤として有用なイミダゾリン−５−オン誘導体
WO2015037716A1 (fr) 2013-09-12 2015-03-19 住友化学株式会社 Composé hétérocyclique saturé contenant de l'azote
JP2016540812A (ja) * 2013-12-17 2016-12-28 ヤンセン ファーマシューティカ エヌ．ベー． 癌の治療用のｆａｓｎ阻害剤として有用なイミダゾリン−５−オン誘導体
US20150166529A1 (en) * 2013-12-17 2015-06-18 Janssen Pharmaceutica, Nv Imidazolin-5-one derivative useful as fasn inhibitors for the treatment of cancer
US9718813B2 (en) 2013-12-17 2017-08-01 Janssen Pharmaceutica Nv Imidazolin-5-one derivative useful as FASN inhibitors for the treatment of cancer
WO2015095011A1 (fr) * 2013-12-17 2015-06-25 Janssen Pharmaceutica Nv Dérivé d'imidazoline-5-one utile en tant qu'inhibiteur de fas pour le traitement du cancer
CN104177298A (zh) * 2014-09-18 2014-12-03 湘潭大学 4,4-二取代-4,5-二氢-1h–咪唑-5-酮、衍生物及其合成方法
US10981915B2 (en) 2014-12-30 2021-04-20 Valo Early Discovery, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US9902728B2 (en) 2014-12-30 2018-02-27 Forma Therapeutics, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US10934299B2 (en) 2014-12-30 2021-03-02 Valo Early Discovery, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US11795171B2 (en) 2014-12-30 2023-10-24 Valo Health, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US10000495B2 (en) 2014-12-30 2018-06-19 Forma Therapeutics, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US10351571B2 (en) 2014-12-30 2019-07-16 Forma Therapeutics, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US10377760B2 (en) 2014-12-30 2019-08-13 Forma Therapeutics, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US10377773B2 (en) 2015-02-05 2019-08-13 Forma Therapeutics, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9938300B2 (en) 2015-02-05 2018-04-10 Forma Therapeutics, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US11739071B2 (en) 2015-02-05 2023-08-29 Valo Health, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10508098B2 (en) 2015-02-05 2019-12-17 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10513508B2 (en) 2015-02-05 2019-12-24 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10513507B2 (en) 2015-02-05 2019-12-24 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10519128B2 (en) 2015-02-05 2019-12-31 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10519130B2 (en) 2015-02-05 2019-12-31 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10519127B2 (en) 2015-02-05 2019-12-31 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10519129B2 (en) 2015-02-05 2019-12-31 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10836741B2 (en) 2015-02-05 2020-11-17 Valo Early Discovery, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10377767B2 (en) 2015-02-05 2019-08-13 Forma Therapeutics, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10906916B2 (en) 2015-02-05 2021-02-02 Valo Early Discovery, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10927130B2 (en) 2015-02-05 2021-02-23 Valo Early Discovery, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9932351B2 (en) 2015-02-05 2018-04-03 Forma Therapeutics, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9840491B2 (en) 2015-02-05 2017-12-12 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
WO2017049321A1 (fr) 2015-09-17 2017-03-23 Miller Marvin J Composés hétérocycliques contenant de la benzylamine et compositions utiles contre une infection mycobactérienne
CN105272919A (zh) * 2015-11-12 2016-01-27 中国科学院过程工程研究所 一种从肉苁蓉低聚糖浆中制备尿囊素的方法
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
WO2019170543A1 (fr) 2018-03-07 2019-09-12 Bayer Aktiengesellschaft Identification et utilisation d'inhibiteurs d'erk5

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