WO2006098342A1 - Composes de la piperazinyle - Google Patents

Composes de la piperazinyle Download PDF

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Publication number
WO2006098342A1
WO2006098342A1 PCT/JP2006/305064 JP2006305064W WO2006098342A1 WO 2006098342 A1 WO2006098342 A1 WO 2006098342A1 JP 2006305064 W JP2006305064 W JP 2006305064W WO 2006098342 A1 WO2006098342 A1 WO 2006098342A1
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optionally substituted
lower alkyl
compound
aryl
group
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Tadashi Terasaka
Kazuya Fujita
Hirofumi Yamamoto
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Astellas Pharma Inc
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Astellas Pharma Inc
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Priority claimed from AU2005901293A external-priority patent/AU2005901293A0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • 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
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D403/10—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 carbon chain containing aromatic rings
    • 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
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings 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
    • C07D413/02—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
    • C07D413/10—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 linked by a carbon chain containing aromatic 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to the compound and pharmaceutically acceptable salt thereof which inhibit dipeptidyl peptidase-IV (DPP-IV) .
  • this invention relates to medicament or pharmaceutical composition
  • medicament or pharmaceutical composition comprising the above-mentioned compound or pharmaceutically acceptable salt thereof as an active ingredient, a method for treatment and/or prevention of the disease mediated by DPP-IV, use of the above compound, and the like.
  • DPP-IV has various physiological functions in living body, especially has the action which inactivates Glucagon-1 i ke peptide-1 (GLP-I) by cleaving the N-terminal dipeptide (His-Ala) and decomposes some cytokines. That is, the resultant peptide is the receptor antagonist of GLP-I and totally reduces the activity of GLP-I.
  • GLP-I has very important role in glucose metabolism.
  • GLP-I (1) intensifies the secretion of insulin, (2) stimulates expression of genes which' are indispensable for the secretion of insulin, (3) stimulates proliferation of ⁇ -cell, (4) suppresses secretion of glucagon, (5) suppresses the function involving secretion and motility of digestive organs (especially, peristalsis), and (6) suppresses appetite. That is, GLP-I restricts food ingestion, postpones the process of digestion and absorption, and raises the use of the glucose in blood.
  • the inhibitor of DPP-IV can maintain the activity of GLP-I, so it is expected as a medicine to treat and prevent various diseases, especially type 2 diabetes mellitus (T2DM) .
  • T2DM type 2 diabetes mellitus
  • this invention relates to DPP-IV inhibitor. More particularly, this invention relates to DPP-IV inhibitor useful for treating or preventing conditions mediated by DPP-IV, more particularly useful for treating or preventing altered glucose tolerance, glucosuria, hyperlipidemia , metabolic acidosis, diabetes mellitus (type 1 and type 2) , diabetic neuropathy, nephropathy, and secondary diseases in mammals caused by diabetes mellitus. That is, one object of this invention is to provide new compound and pharmaceutically acceptable salt thereof, of which activity to inhibit DPP-IV is remarkably improved against known compounds, preferably having a good oral activity and a high safety profile .
  • Another object of this invention is to provide a medicament and pharmaceutical composition containing the compound or pharmaceutically acceptable salt thereof as an active ingredient.
  • a further object of this invention is to provide an inhibitor of DPP-IV and a method for inhibiting DPP-IV comprising administering an effective amount of the compound' or pharmaceutically acceptable salt thereof.
  • a further object of this invention is to provide a use of the compound and pharmaceutically acceptable salt thereof as medicaments.
  • a further object of this invention is to provide the compound and pharmaceutically acceptable salt thereof which are useful for the manufacture of medicaments for treating or preventing conditions mediated by DPP-IV inhibition, more particularly useful for treating or preventing altered glucose tolerance, glucosuria, hyper1 ipidemia , metabolic acidosis, diabetes mellitus (type 1 and type 2), diabetic neuropathy, diabetic nephropathy, and secondary diseases in mammals caused by diabetes mellitus, especially T2DM.
  • a further object of this invention is to provide the commercial package comprising the pharmaceutical composition containing the new compound.
  • the present invention is directed to the following compound of the formula (I) or pharmaceutically acceptable salt thereof.
  • Ar is aryl or heteroaryl, optionally substituted;
  • R 1 is acy1 ;
  • each R 2 is independently selected from the group consisting of H and lower alkyl;
  • each R 3 is independently selected from the group consisting of H and lower alkyl;
  • each R 4 is independently selected from the group consisting of H and lower alkyl.
  • aryl means an aromatic hydrocarbon group, such as phenyl, naphthyl, indenyl, biphenyl, and the like, and it is preferably ( C6-C10 ) aryl , more preferably phenyl.
  • cycloalkyl includes a cycloalkyl group having 3 to 10 carbon atoms, that may be crosslinked, preferably a cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl group.
  • heterocycle includes a saturated or unsaturated 4- to 8-membered heterocyclic group which has 1 to 4 hetero atoms selected from N, S and O, and which may be a monocyclic ring, or may form a bicyclic or tricyclic fused ring by being fused with heterocycle ( s ), aryl(s) or cycloal ky1 ( s ) .
  • the "saturated heterocyclic group” means preferably 5- to 7-membered heterocyclic group and may fuse with cycloalkyl (s).
  • the “saturated heterocyclic group” may include pyrrol idiny1 , imida zol idiny1 , t et rahydro furany1 , piperidinyl, tet rahydro-2H- pyranyl,' tetrahydro-2H-thiopyranyl, piperadinyl, morpholinyl, thiomorphol iny1 , azepanyl and dia zepanyl .
  • the "unsaturated heterocyclic group” includes heteroaryl and partially saturated heteroaryl.
  • the "partially saturated heteroaryl” includes pyrrolinyl, imida zol iny1 , pyrazolinyl, dihydrothia zoly1 , dihydroi sothia zoly1 ,- dihydrooxa zoly1 , dihydroisoxazolyl, dihydrothiadiazolyl, dihydrooxadiazolyl , dihydrofuranyl , pyranyl, dihydropyranyl, dihydrothiopyranyl, tet rahydroa zepiny1 , dihydroa zepiny1 , azepinyl, diazepinyl, 3 , 4 -dihydro-2H- 1 , 4 -benzoxadiny1 , 3, 4-dihydro-2H-l, 4-benzothiadinyl,
  • heteroaryl means preferably 5- or 6-membered or condensed aromatic heterocyclic group which contains at least one hetero atom such as nitrogen, oxygen and sulfur atom.
  • the "heteroaryl” may include 5-membered heteroaryl group such as pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, i sothia zoly1 , thiadiazol, or the like; 6-membered heteroaryl group such as pyridinyl , pyrazinyl, pyrimidinyl, pyridazinyl, or the like; and condensed heteroaryl group such as indolyl, isoindolyl, indazolyl, purinyl, quinolyl, isoquin ⁇ lyl, benzopyrroly1 , benzoimida zoly1
  • the "lower alkyl” means a straight or branched chain aliphatic hydrocarbon, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like. It is preferably
  • (C1-C4 ) alkyl more preferably ( C1-C2 ) al kyl , most preferably methyl.
  • lower alkoxy means a straight or branched chain aliphatic hydrocarbon oxy group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, hexoxy, and the like. It is preferably (C1-C4 ) alkoxy, more preferably (C1-C2 ) alkoxy , most preferably methoxy.
  • the "halogen” may include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, more preferably a fluorine atom or a chlorine atom, most preferably a fluorine atom.
  • halogenated lower alkyl means the above lower alkyl substituted by halogen atom(s), such as fluoromethyl , chloromethy1 , di fluoromethy1 , dichloromethyl , dibromomethy1 , t ri.fluoromethyl , t richloromethy1 , fluoroethyl, chloroethy1 , 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl , . fluoropropy1 , fluorobutyl, fL-uorohexyl, and the like. It is preferably halogenated ( C 1 -C 4 ) al kyl , more pre ferably halogenated
  • (C1-C2 ) alkyl more preferably fluorinated ( C1-C4 ) al kyl , more preferably fluorinated ( Cl -C2 ) al kyl , most preferably t ri f luoromet hy1.
  • aryl- (lower alkyl) means the “lower alkyl” group mentioned above substituted by the aryl group, and includes benzyl, 1 -phenylethy1 , 2 -phenyIethy1 , 3 -phenylpropy1 , 4 -phenylbut y1 , 1 -naphthylmethy1 , 2-naphthylmethyl, 2-(l-naphthyl)ethyl,
  • heterocycle- ( lower alkyl) means the “lower alkyl” group mentioned above substituted by the heterocyclic group. It is preferably het erocycle- ( C 1 -C4 ) al ky1 , more preferably heterocycle- (C1-C2 ) alkyl , more preferably heterocycle -methyl .
  • aryl- (lower alkoxy) means the “lower alkoxy” group mentioned above substituted by the aryl group, and includes benzyloxy, 1 -phenyIethoxy , 2 -phenyIethoxy , 3 -phenylpropoxy , 4 -phenylbut oxy , 1-naphthylmethoxy, 2-naphthylmethoxy,
  • heteroaryl- ( lower alkoxy) means the "lower alkoxy” group mentioned above substituted by the heteroaryl group. It is preferably heteroaryl -( C 1 -C4 ) al koxy , more preferably heteroaryl- ( C1-C2 ) alkoxy , more preferably heteroaryl-methoxy.
  • the " (lower alkoxy) -carbonyl” means carbonyl group substituted by the above mentioned lower alkoxy group, and includes methoxycarbony1 , ethoxycarbonyl , propoxycarbony1 , i sopropoxycarbonyl , but oxycarbonyl , i sobutoxycarbonyl , t -but oxycarbony1 , pent oxycarbony1 , hexoxycarbonyl , and the like. It is preferably
  • substituted in the definition of Compound (I) is not limited, it means general substituent.
  • the "substituent” can be preferably selected from the group cons i st ing of lower al kyl , lower alkoxy, halogen, hydroxy, cyano, nitro, amino, carbamoyl, aminosul fony1 , carboxy, (lower alkoxy) -carbonyl, R 6 -S-, R 6 -S(O)-, R 6 -SO 2 -, R 6 -SO 2 NH-, R 6 -CONH-, R 6 -CONHSO 2 -, R 6 -SO 2 NHCO-, lower alkyl substitutedby 1 to 3 of R 7 , heteroaryl, and oxo; wherein R 6 is lower alkyl, halogenated lower alkyl, or phenyl optionally substituted with halogen, lower alkyl or halogenated lower alkyl; R 7 is
  • the number of substituent may be two or more if possible, preferably up to 5, more preferably up to
  • substituents may be identical or different to each other.
  • substituents may be the same or different to each other.
  • the Compound (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or dias tereoi somers . This invention includes both mixtures and separate individual isomers.
  • the compounds of the formula (I) may also exist in tautomeric forms and this invention includes both mixtures and separate individual tautomers.
  • the Compound (I) and their salts may be in a form of a solvate such as hydrate, which is included within the scope of the present invention. Also included in the scope of this invention are radiolabel led derivatives of Compound (I) which are suitable for biological studies.
  • the prodrug of the Compound (I) is included, which prodrug i s capable of undergoing metabolic conversion to Compound (I) following administration in body.
  • metabolites of Compound (I) are included, which metabolites may be therapeutically active in the treatment of the targeted medical condition.
  • Suitable salts of the compounds (I) are pharmaceutically acceptable conventional non-toxic salts and include an organic acid sal t (e.g., acetate, maleate, tartrate, methanesul fonate , benzene sul fonate , formate, toluenesulfonate , t rif luoroacet ate , or the like), an inorganic acid salt (e.g., hydrochloride, hydrobromide , sulfate, phosphate, or the like), a salt with an amino acid (e.g., aspartate, glutamate, or the like), or the like.
  • an organic acid sal t e.g., acetate, maleate, tartrate, methanesul fonate , benzene sul fonate , formate, toluenesulfonate , t rif luoroacet ate , or the like
  • the compound (I) may preferably include Compound (Ia) as following:
  • Ar is aryl or heteroaryl, optionally substituted; each R 2 is independently selected from the group consisting of H and lower alkyl; each R 3 is independently selected from the group consisting of H and lower alkyl; each R 4 is independently selected from the group consisting of H and lower alkyl;
  • R 5 is lower alkyl, halogenated lower alkyl, aryl optionally substituted, heterocycle optionally substituted, cycloalkyl optionally substituted, aryl-0 optionally substituted, he t er ocycle-0 optionally substituted, aryl- (lower alkyl) optionally substituted o n t he a r y 1 , heterocycle- ( lower alkyl) optionally substituted on the heterocycle, aryl- (lower alkoxy) optionally substituted on the aryl, or heterocycle- ( lower alkoxy) optionally substituted on the heterocycle;
  • the compound (I) may more preferably include
  • Ar is aryl or heteroaryl, optionally substituted; each R 2 is independently selected from the group consisting of H and lower alkyl; each R 3 is independently selected from the group consisting of H and lower alkyl; each R 4 is independently selected from the group consisting of H and lower alkyl; R 5 is lower alkyl, halogenated lower alkyl, aryl optionally substituted, heterocycle optionally substituted, cycloalkyl optionally substituted, aryl-0 optionally substituted, het erocycle-0 optionally substituted, aryl- (lower alkyl) optionally substituted on the ary1 , he terocycle- ( lower alkyl) optionally substituted on the heterocycle, aryl- (lower alkoxy) optionally substituted on the aryl, or he terocycle- ( lower alkoxy) optionally substituted on the heterocycle; the same applies hereinafter.]
  • Ar is aryl optionally substituted
  • Ar is phenyl optionally substituted
  • the substituent (s) of Ar is selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, cyano, nitro, amino, carbamoyl, aminosul fony1 and carboxy;
  • the substituent(s) of Ar is halogen;
  • thesubstituent(s) of Ar is selected from the group consisting of a fluorine atom and a chlorine atom;
  • the subs t i tuent ( s ) of Ar is a fluorine atom
  • R 5 i s selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, cyano, nitro, amino, carbamoyl, aminosul fonyl , carboxy, (lower alkoxy) -carbonyl, R 6 -S-, R 6 -S(O)-, R 6 -SO 2 -, R 6 -SO 2 NH-, R 6 -CONH-, R 6 -CONHSO 2 -, R 6 -SO 2 NHCO-, lower alkyl substituted by 1 to 3 of R 7 , heteroaryl, and oxo ; wherein R 6 is lower alkyl, halogenated lower alkyl, or phenyl optionally substituted with halogen, lower alkyl or halogenated lower alkyl; R 7 is hydroxy, lower alkoxy, carboxy, (lower al koxy ) -carbon
  • R 2 is H
  • R 2 is (C1-C4 ) alkyl
  • R 2 is (C1-C2 ) alkyl
  • R 3 is H; (24) R 3 is (C1-C4 ) alkyl; (25) R 3 is (C1-C2 ) alkyl;
  • R 4 is H
  • R 4 is (C1-C4) alkyl
  • R 4 is (C1-C2 ) alkyl .
  • the combination of any two or more of (1) to (28) is more preferable.
  • the Compound (I) is preferably selected from:
  • the Compound (I) of the present invention can be prepared according to the following Process A to C.
  • an appropriate protective group namely a group readily convertible to the functional group, at the stage of a raw material or intermediate.
  • the protective group can be eliminated, if necessary, to obtain the desired compound.
  • Examples of such a functional group include an amino group, hydroxyl group, carboxyl group and the like.
  • Protective groups thereof are, for example, those described in Protective Groups in Organic Synthesis, the third edition (T. W. Green and P. G. M. Wuts, eds., JOHN WILLY & SONS, INC. (the contents of which are hereby incorporated by reference) ) . These may be appropriately used depending on the reaction conditions. For introducing and eliminating such protective groups, the methods described in the reference can be suitably applied.
  • R 2a is a protective group, such as (lower alkoxy)- carbony1 , and when R 2 is lower alkyl, R 2a is lower alkyl or a protective group; the same applies hereinafter.
  • condensating agent employable in this process is not particularly limited so long as it accelerates forming amide bond and may include carbodiimide compounds such as dicyclohexy1- carbodiimide (DCC), di i sopropylcarbodi imide (DIPCI), 1 -ethyl- 3- (3' -dimethylaminopropyl) carbodiimide
  • DCC dicyclohexy1- carbodiimide
  • DIPCI di i sopropylcarbodi imide
  • additive is generally used.
  • the additive employable in this process is not particularly limited so long as it can mainly make the carboxyl groups of Compound (-III) active or suppress the racemi zat ion , and may include 1 -hydroxybenzot ria zole (HOBt), 3, 4-dihydro-3-hydroxy-4-oxo-l, 2 , 3-benzotriazine
  • HOOBt l-hydroxy-7-azabenzotriazole
  • the solvent employable in this process is not particularly limited so long as it is inactive in this reaction and may include amides such as dimethy1 formamide (DMF) and dimethylacet amide (DMA); aromatic hydrocarbons such as benzene, toluene; ethers such as tetrahydrofuran (THF), 1,4-dioxane; halogenated hydrocarbons such as dichloromethane , chloroform .
  • amides such as dimethy1 formamide (DMF) and dimethylacet amide (DMA)
  • aromatic hydrocarbons such as benzene, toluene
  • ethers such as tetrahydrofuran (THF), 1,4-dioxane
  • halogenated hydrocarbons such as dichloromethane , chloroform .
  • This process is generally carried out by adding
  • the reaction time after the adding depends on the starting material, the solvent, or the like, and it is usually from lhr to 24hrs.
  • the mixture is quenched with water, and extracted with organic solvent insoluble with water such as ethyl acetate, chloroform, or the like.
  • organic layer is washed by water such as hydrochloric acid, saturated aqueous NaHC ⁇ 3, brine, or the like.
  • the washed organic layer is dried over anhydrous magnesium sulfate or sodium sulfate, and evaporated in vacuo.
  • the target compound is purified by the conventional method such as silica gel chromatography to obtain Compound (I) .
  • Compound (I) can also be synthesized by following Process B.
  • Process B
  • L is OH or a leaving group; the same applies hereinafter.
  • Compound (IV) such as carboxylic acid compound with piperazinyl compound (V) in the presence of catalyst in solvent.
  • Compounds (IV) may be purchased if it is commercial , or synthesized according to general methods obvious to the person skilled in the organic chemistry from commercial compounds, since the structure of Compound
  • a base an inorganic base such as potassium carbonate, sodium hydroxide, or the like, or an organic base such as t riethylamine
  • TAA di i sopropyIethylamine , pyridine, or the like
  • each acyl group can be easily cleaved as protective group of amino group.
  • Process C is the process for removing of acyl group from amino group of piperazinyl moiety.
  • Compound (1-2) can be synthesized by Process A mentioned above.
  • Process C can be carried out according to the method described in the aforementioned "Protective Groups in Organic Synthesis", the third edition. Above processes, all starting materials and product compounds may be salts. The compounds of above processes can be converted to salt according to a conventional method.
  • the pharmaceutical composition of the invention which contains as effective components one type or two or more types of the compound of the invention, can be prepared according to a method usually used by using pharmaceutical carriers, excipients and the like for general use in this field. Administration thereof may be either oral via tablets, pills, capsules, granules, powders, liquids, and the like or parenteral dosing via injections such as intravenous injections, int ramus cular inj ect ions , andthelike, external agent s such as ointment s , plasters, creams, jellies, cataplasm, sprays, lotions, eyedrops, eye ointment s , andthelike, suppositories, inhalation agents, and the like.
  • injections such as intravenous injections, int ramus cular inj ect ions , andthelike, external agent s such as ointment s , plasters, creams, jellies, cataplasm, spray
  • the solid composition for oral administration tablets,' powders, granules and the like are used.
  • one or more active substances are mixed with at leas t one inert excipient , forexample, lactose, mannitol, glucose, hydroxypropy1 cellulose, microcrys t a 11 ine cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate, or the like.
  • the composition may contain inert additives such as lubricants, e.g., magnesium stearate, or the like; disintegrators, e.g., sodium carboxymethy1 starch, or the like; and dissolution auxiliary agents.
  • the tablets or pills may be coated with sugar coating or stomach- soluble or enteric coating.
  • liquid composition for oral administration examples include pharmaceutically acceptable emulsions, liquids, suspensions, syrups, elixirs, or the like, in which inert solvents for general use such as purified water, ethanol, or the like can be incorporated.
  • inert solvents for general use such as purified water, ethanol, or the like can be incorporated.
  • the composition may further contain auxiliary agents such as solubilizing agents, moistening agents and suspending agents; sweetening agents; flavoring agents; aromatic agents and preservatives.
  • Examples of the injections for parenteral administration include sterile aqueous or non-aqueous liquids, suspensions and emulsions.
  • the aqueous solvents include, for example, distilled water for injections and physiological saline.
  • the non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (under trade name) and the like.
  • Such compositions may further contain isotonic agents, preservatives, moistening agents, emulsifying agents, dispersing agents, stabilizers and dissolution auxiliary agents. These are sterilized by filtering through bacteria -retaining filters, by incorporating sterilizing agents, or by irradiation. Alternatively, these may be produced into a sterile solid composition and then dissolved or suspended in sterile water or sterile solvents for injections prior to use.
  • an average single dose of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the Compound (I) may be effective for treating the above-mentioned diseases .
  • amounts between 0.01 mg/body and about 1, 000 mg/body may be administered per day. The dose is administered once or in- separate portions.
  • Triethylamine (0.44 mL ) was added to a suspension of hyd ' roxyl amine hydrochloride (250 mg) in dimethy1 sul foxide (DMSO, 5.0 mL ) .
  • DMSO dimethy1 sul foxide
  • An insoluble material was filtered off and washed with THF.
  • the Filtrate was concentrated in vacuo to remove THF, and t-Butyl [ (2R) -4- [4- (4-cyanobenzoyl) -1-piperazinyl] - 1- (2, 4, 5-tri fluorophenyl) -4-oxobutyl] carbamate (250 mg) was added to the DMSO solution.
  • reaction mixture was diluted with water and extracted with ethyl acetate.
  • aqueous solution was added 1 mol/L NaOH aqueous solution and extracted with ethyl acetate (3 x 30 mL ) .
  • the combined organic solution was washed with brine and dried over magnesium sulfate.
  • Reference compounds Ref . A and Ref . B are disclosed in WO 03/000181, Example 12 and 45, respectively.
  • the compound (I) or pharmaceutically acceptable salt thereof is useful for treating or preventing disease mediated by DPP-IV, more particularly useful for treating or preventing altered glucose tolerance, glucosuria, hyper lipidemia , metabolic acidosis, diabetes mellitus (type 1 and type 2), diabetic neuropathy, nephropathy, and secondary diseases in mammals caused by diabetes mellitus.
  • the compound (I) or pharmaceutically acceptable salt thereof is useful for treating or preventing autoimmune disease, arthritis, rejection of transplanted organs, systemic lupus erythematosus

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé de formule (I) ou un de ses sels pharmaceutiquement acceptables : [où Ar est un aryle ou un héréroaryle, éventuellement substitué ; R1 est un acyle ; R2 est H ou un alkyle inférieur ; R3 est H ou un groupement analogue ; R4 est H ou un groupement analogue] ayant une action d’inhibition de l’activité de la DPP-IV. Ce composé est donc utile dans le traitement ou la prévention de maladies liées à la DPP-IV, comme le diabète mellitus de type 2.
PCT/JP2006/305064 2005-03-16 2006-03-08 Composes de la piperazinyle Ceased WO2006098342A1 (fr)

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AU2005901293A AU2005901293A0 (en) 2005-03-16 Piperazinyl Compounds
AU2005901293 2005-03-16

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WO2010114291A3 (fr) * 2009-03-30 2011-01-20 동아제약 주식회사 Procédé amélioré d'élaboration d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2010114292A3 (fr) * 2009-03-30 2011-01-20 동아제약 주식회사 Procédé amélioré de fabrication d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
US8673920B2 (en) 2009-05-06 2014-03-18 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
AU2013200419B2 (en) * 2009-03-30 2014-04-17 Dong-A Pharmaceutical Co., Ltd. Improved method for preparing dipeptidyl peptidase-IV inhibitor and intermediate
US8952166B2 (en) 2012-07-26 2015-02-10 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US8999990B2 (en) 2011-10-25 2015-04-07 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US8999991B2 (en) 2011-10-25 2015-04-07 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9056859B2 (en) 2010-10-29 2015-06-16 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9062070B2 (en) 2011-08-19 2015-06-23 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9073882B2 (en) 2010-10-27 2015-07-07 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9108947B2 (en) 2011-10-31 2015-08-18 Merck Sharp & Dohme Corp. Inhibitors of the Renal Outer Medullary Potassium channel
US9139585B2 (en) 2011-10-31 2015-09-22 Merck Sharp & Dohme Corp. Inhibitors of the Renal Outer Medullary Potassium channel
US9206199B2 (en) 2011-12-16 2015-12-08 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9493474B2 (en) 2011-10-31 2016-11-15 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9527830B2 (en) 2011-09-16 2016-12-27 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9573961B2 (en) 2012-12-19 2017-02-21 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9604998B2 (en) 2013-02-18 2017-03-28 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
WO2017061957A1 (fr) * 2015-10-09 2017-04-13 Agency For Science, Technology And Research Composés destinés au traitement du cancer et épigénétique
US9751881B2 (en) 2013-07-31 2017-09-05 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9765074B2 (en) 2013-03-15 2017-09-19 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9777002B2 (en) 2012-11-29 2017-10-03 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
CN109721555A (zh) * 2019-01-04 2019-05-07 广东东阳光药业有限公司 酰化哌嗪类化合物及其用途

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WO2004043940A1 (fr) * 2002-11-07 2004-05-27 Merck & Co., Inc. Derives de phenylalanine utilises comme inhibiteurs de la dipeptidyl peptidase dans le traitement ou la prevention du diabete
EP1541143A1 (fr) * 2003-12-09 2005-06-15 Graffinity Pharmaceuticals Aktiengesellschaft Inhibiteurs de dpp-iv
EP1598341A1 (fr) * 2004-05-21 2005-11-23 Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft Inhibiteurs de DPP-IV

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WO2004043940A1 (fr) * 2002-11-07 2004-05-27 Merck & Co., Inc. Derives de phenylalanine utilises comme inhibiteurs de la dipeptidyl peptidase dans le traitement ou la prevention du diabete
EP1541143A1 (fr) * 2003-12-09 2005-06-15 Graffinity Pharmaceuticals Aktiengesellschaft Inhibiteurs de dpp-iv
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RU2498976C9 (ru) * 2009-03-30 2014-02-27 Донг-А Фармасьютикал. Ко., Лтд Усовершенствованный способ получения ингибитора дипептидилпептидазы-iv и промежуточного соединения
AU2013200419B2 (en) * 2009-03-30 2014-04-17 Dong-A Pharmaceutical Co., Ltd. Improved method for preparing dipeptidyl peptidase-IV inhibitor and intermediate
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KR101152899B1 (ko) 2009-03-30 2012-06-05 동아제약주식회사 디펩티딜 펩티다아제-ⅳ 저해제 및 중간체의 개량된 제조방법
KR101152898B1 (ko) 2009-03-30 2012-06-05 동아제약주식회사 디펩티딜 펩티다아제-ⅳ 저해제 및 중간체의 개량된 제조방법
AU2010232085B2 (en) * 2009-03-30 2013-02-21 Dong-A Pharmaceutical. Co., Ltd Improved method for preparing dipeptidyl peptidase-IV inhibitor and intermediate
US8598347B2 (en) 2009-03-30 2013-12-03 Dong-A Pharmaceutical. Co., Ltd Method for manufacturing dipeptidyl peptidase-IV inhibitor and intermediate
WO2010114292A3 (fr) * 2009-03-30 2011-01-20 동아제약 주식회사 Procédé amélioré de fabrication d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2010114291A3 (fr) * 2009-03-30 2011-01-20 동아제약 주식회사 Procédé amélioré d'élaboration d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
US9249109B2 (en) 2009-03-30 2016-02-02 Dong-A Pharmaceutical Co., Ltd. Method for preparing dipeptidyl peptidase-IV inhibitor and intermediate
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