WO2005073186A1 - Dérivés de pyrrolidine - Google Patents

Dérivés de pyrrolidine Download PDF

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Publication number
WO2005073186A1
WO2005073186A1 PCT/JP2005/000999 JP2005000999W WO2005073186A1 WO 2005073186 A1 WO2005073186 A1 WO 2005073186A1 JP 2005000999 W JP2005000999 W JP 2005000999W WO 2005073186 A1 WO2005073186 A1 WO 2005073186A1
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Prior art keywords
pyrrolidine
compound
reference example
carbonyl
nmr
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PCT/JP2005/000999
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English (en)
Japanese (ja)
Inventor
Hisao Nakai
Takashi Kondo
Susumu Yamamoto
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Ono Pharmaceutical Co., Ltd.
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Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Publication of WO2005073186A1 publication Critical patent/WO2005073186A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • 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

Definitions

  • the present invention relates to a pyrrolidine derivative.
  • Dipeptidyl peptidase IV (also referred to as DPP4, DPP-IV, DP4, or DPPIV; hereinafter abbreviated as DPP4) is derived from a dipeptide Xaa_Pro from a peptide chain having proline or alanine at the second position from the N-terminus.
  • DPP4 Dipeptidyl peptidase IV
  • Xaa_Pro dipeptide chain having proline or alanine
  • GLP-1 As physiological actions of GLP-1, not only an action of promoting secretion of insulin from the knee but also an action of prolonging the gastric emptying time and an action of suppressing eating are known. In fact, attempts have been made to treat non-insulin-dependent diabetes mellitus (type 2 diabetes) by continuously administering GLP-1 subcutaneously. However, GLP-1 is metabolized in vivo in minutes. Among them, especially DPP4 Metabolism is important, and DPP4 rapidly cleaves GLP-1 to produce inactive GLP-1. Since this inactive GLP-1 antagonizes the GLP-1 receptor, the physiological action of GLP-1 may be further attenuated.
  • the method of suppressing the degradation of GLP-1 by inhibiting DPP4 is considered to be the best approach for enhancing the action of GLP-1.
  • DPP4 inhibition can enhance the action of GLP-1, enhance insulin secretion, and improve glucose metabolism, and is expected to be useful for the treatment of type 2 diabetes. It can also be expected as an anti-obesity drug with an antifeeding effect.
  • DPP4 is involved in the metabolism of neuropeptide Y, a neuropeptide, various cytokins, chemodynamics, activation of immunocompetent cells, adhesion of cancer cells to endothelium, etc. Is known to be. Through these actions, inhibition of DPP4 is considered to be useful for treating autoimmune diseases, cancer, HIV infection, infertility, anemia, thrombocytopenia, wounds, and the like.
  • DPP4 expression was found in dermal fibroblasts of patients with psoriasis, rheumatoid arthritis and lichen planus, and high DPP4 activity was found in patients with prostatic hypertrophy. Inhibition of DPP4 is also expected to be effective for skin diseases and prostatic hypertrophy.
  • hyperlipidemia syndrome X
  • diabetic complications hyperglycerinemia
  • arteriosclerosis impaired glucose tolerance
  • polycystic ovary syndrome growth disorders
  • arthritis transplant rejection
  • enteritis It is considered to be useful for treatment and / or prevention such as
  • Patent Document 1 WO 02/14271 pamphlet
  • Patent Document 2 International Publication No. 04/16587 pamphlet
  • the present inventors have conducted intensive studies to find a DPP4 inhibitor that exhibits an effect over a long period of time, and as a result, have found that the pyrrolidine derivative represented by the general formula (I) achieves the object.
  • the present invention has been completed.
  • the present compound suppresses the activity of DPP4 for a long time after administration, it is possible to reduce the number of doses per day, for example. Therefore, it is possible to maintain and improve the compliance and QOL of patients with diabetes (particularly type 2 diabetes, postprandial hyperglycemia, etc.).
  • R la , R lb , R le , R ld and R x each independently represent a hydrogen atom or a substituent, n represents 0 or an integer of 17; R represents hydrogen Represents an atom or a cyano group, and has the symbol [0021]
  • [0024] indicates that the head is connected to the other side of the paper (the arrangement of the strings). ), A salt thereof, a solvate thereof, a dioxide thereof or a prodrug thereof,
  • DPP4-mediated diseases include diabetes, obesity, autoimmune disease, cancer metastasis, HIV infection, skin disease, prostatic hypertrophy, hyperlipidemia, syndrome X, diabetic complications, hyperglycerinemia, arteriosclerosis
  • a drug comprising a combination of at least one selected from the group consisting of
  • R la , R lb , R lc , R ld and R x are each independently
  • (1) 1 one 5 by the R 2 may be substituted C1 one 8 hydrocarbon group
  • R la and R lb or R le and R ld represent ring C together with the carbon atoms to which they are attached.
  • I, or R la and R le together with the carbon atom to which they are attached, represent ring D (ring C and ring D may be further substituted by 115 R 3 ).
  • R 2 is (1) halogen atom, (2) nitro, (3) Shiano, (4) Okiso, (5) -OR 10, (e) -NR 1
  • a ring or a heterocyclic ring which may be substituted by (26) 1-5 R 3 ;
  • R 3 is (1) a halogen atom, nitro, cyano, oxo, one OR 10 , one NR “R 12 , one SR 10 , -SO
  • S ⁇ R 13 represents (26) a substituted or unsubstituted carbocyclic ring or (27) a substituted or unsubstituted heterocyclic ring.
  • R 1Q represents (1) a hydrogen atom, (2) a C18 hydrocarbon group which may have a substituent, (3) a group which has a substituent, Or (4) represents a heterocyclic ring having a substituent.
  • R 11 R 12 and R 14 are each independently (1) hydrogen atom, (2) may have a substituent C1 one 8 hydrocarbon group, have a (3) substituents which may be carbocyclic, (4) heterocyclic ring which may have a substituent group, (5) - ⁇ _013 ⁇ 4 13 or (6) -30 R 13.
  • R ′′ is (1) a C1-8 hydrocarbon group which may have a substituent, and (2) a group which has a substituent. And represents a carbocyclic ring or a (3) heterocyclic ring having a substituent.
  • C1-8 Anorekinore, C2-8 alkenyl or force represents a C2-8 alkynyl ,, R la and R l b or R le and R ld is together such connection C1- 8 alkylidene, alkenylidene or C
  • C1-8 alkyl represents, for example, methinole, ethyl, propyl, butyl, pentyl, hexinole, heptyl, octyl and isomers thereof.
  • C2-8 alkenyl represents, for example, ethyl, propenyl, butyr, pentyl, hexenyl, heptur, otatur and isomers thereof.
  • C2-8 alkynyl represents, for example, ethur, propiel, butchur, penthur, hexur, heptul, otatur and isomers thereof.
  • C1-8 alkylidene includes, for example, methylidene, ethylidene, propylidene, butylidene
  • C3-8 alkenylidene refers to, for example, propylidene, butenylidene, penteylidene, hexenylidene, heptenylidene, octenylidene and isomers thereof.
  • the C3-8 alkynylidene represents, for example, propynylidene, butylidene, pentylidene, hexylidene, heptinylidene, octylidene and isomers thereof.
  • the halogen atom represents, for example, fluorine, chlorine, bromine and iodine.
  • the “C3_15 monocyclic or polycyclic carbocycle” includes a C3-15 monocyclic or polycyclic carbon ring aryl, a carbocyclic ring partially or wholly saturated, a spiro bond, Polycyclic carbocycles and bridged polycyclic carbocycles, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclononane, Clodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclootatene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene,
  • R la, R lb, R le, R ld, R x or "heterocyclic in R 2 represents" 1 one five heterocyclic be substitution by R 3 '
  • the term “ring” refers to "a monocyclic or polycyclic heterocyclic ring containing 115 heteroatoms selected from a 3- to 15-membered oxygen atom, nitrogen atom and sulfur atom".
  • the "3- to 15-membered monocyclic or polycyclic heterocycle containing 5 to 15 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom” includes a 3 to 15-membered oxygen atom.
  • Examples of the monocyclic or polycyclic heterocyclic aryl containing 115 hetero atoms selected from a 3 to 15-membered oxygen atom, nitrogen atom and sulfur atom include pyrrole and imidazo. , Triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, chepin, oxazole, isoxoxazole, thiazole, isothiazole, flazane, oxaziazinole, Oxazine, oxaziazine, oxazepine, oxazinezepine, thiadiazonole, thiazine, thiadiazine, thiazepine, thiadiazepine, indonele, isoindole
  • Examples of partially or wholly saturated 3 to 15 membered monocyclic or polycyclic heterocyclic aryl containing one to five heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom include, for example, Aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, villazolidine, dihydric pyridine, tetrahydropyridine, piperidine, dihydrovirazine, tetrahydrovirazine, piperazine, dihydropyrimidine , Tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodazepine, t
  • ring c represents a carbocyclic or heterocyclic ring.
  • the carbocycle represented by ring C represents a C3-15 monocyclic or polycyclic carbocyclic aryl which may be partially or wholly saturated, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentane Hexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclootaten, cyclononene, cyclodecene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, cyclononadiene, cyclononadiene Decadiene, dihydronaphthalene, tetrahydronaphthalene, indene, indane, fluorene ring and the like can be mentioned.
  • the heterocyclic ring represented by ring C may be partially or completely saturated, and may be a monocyclic ring containing 115 hetero atoms selected from a 3 to 10-membered oxygen atom, a nitrogen atom and a sulfur atom.
  • ring D represented by R la and 11 ⁇ : together with the carbon atom to which it is bonded represents a carbocyclic or heterocyclic ring.
  • the carbocycle represented by ring D represents a C3-10 monocyclic or polycyclic carbocyclic aryl which may be partially or completely saturated, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentane Hexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclootaten, cyclononene, cyclodecene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, cyclononadiene, cyclononadiene Decadiene, benzene, naphthalene, indane ring and the like can be mentioned.
  • the heterocyclic ring represented by ring D may be partially or completely saturated, and contains 115 hetero atoms selected from 3-10 membered oxygen, nitrogen, and sulfur atoms
  • C1_8 hydrocarbon group in “C 1-8 hydrocarbon group optionally having substituent (s)” represented by R 1Q , R ′′, R 12 , R 13 and R 14 Represents a C 1-8 alkynole, a C 2-8 alkenyl or a C 2-8 alkynyl, which have the same meaning as described above.
  • the “substituent” in the “C 1-8 hydrocarbon group which may have a substituent” represented by R 1Q , R ′′, R 12 , R 13 and R 14 is: For example, hydroxyl group, C1-8 alkoxy, mono (C1-8 alkyl) amino, di (C1-8 alkyl) amino, C2-8 acyl, C1-8 alkoxycarbonyl, benzyloxycarbonyl, carboxy, halogen atom, nitro , Cyano, (C1-8 alkyl) sulfonylamino, C2-8 acylamino, phenyl, C3-8 cycloalkyl, pyridinole, and oxo.
  • R 3, R 10, R 11 R 12, R 13 and R m represents "good be substituted les, carbocycle” Les a and "substituent
  • the term “carbocycle” and “complex ring” in “may be a heterocycle” have the same meanings as the above “carbocycle” and “heterocycle”, respectively.
  • substituents in the term “heterocycle” include, for example, a C1-8 hydrocarbon group, a hydroxyl group, a C1-8 alkoxy, an amino (C1-8alkyl) amino, di (C1— 8alkyl) amino, C2-8acyl, C1-8alkoxycarbonyl, benzyloxycarbonyl, carboxy, mercapto, C1-8alkylthio, halogen atom, (C1-8alkyl) sulfonyl, (C1-8alkyl) sulfonyl 115 groups selected from amino, C2-8 acylamino, oxo, phenyl, C3-8 cycloalkyl, nitro, cyano and pyrid
  • the "C1-8 hydrocarbon group" in the "substituent” means C1-8 anolequinole, C2-8 alkenyl or C2-8 alkynyl, which have the same meanings as described above.
  • the Cl_8 alkoxy in the "substituent” means, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyl / reoxy, octyloxy and isomers thereof.
  • the term "mono (C1-8 alkyl) amino" in the "substituent” refers to an amino group substituted by one C1-8 alkyl group, and includes, for example, methinoleamino, ethylamino, propinoleamino, butinoleamino, pentylamino, Hexylamino, heptylamino, octylamino and its isomers.
  • di (C1-8 alkyl) amino in the "substituent” refers to an amino group substituted by two independent C1-8 alkyl groups, for example, dimethylamino, detinoleamino, dipropynoleamino, dibutylamino, dipentylamino. Mino, dihexylamino, diheptylamino, dioctylamino, methylpropylamino with ethylmethylamino, ethylpropylamino and isomers thereof.
  • the C2-8 acyl in the "substituent” means, for example, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, otatanyl and isomers thereof.
  • C1-8 alkoxycarbel in the "substituent” means, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycanolebonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl and isomers thereof. Represents the body.
  • the C18 alkylthio in the "substituent” means, for example, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio and isomers thereof.
  • (C1-8 alkyl) sulfonyl in the "substituent” includes, for example, methylsulfonyl, ethinolesnolehoninole, propinoresnolehoninole, butinolesnolehoninole, pentinolesnolehoninole , Hexylsulfonyl, heptylsulfonyl, octylsulfonyl and isomers thereof.
  • (C1-8 alkyl) sulfonylamino in the "substituent” refers to, for example, methylsulfonylamino, propylsulfonylamino, butylsulfonylamino, butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, etc. , Heptylsulfonylamino, Octylsulfonylamino and its isomers.
  • C2-8 acylamino in the "substituent” means, for example, acetylamino-propionylamino, butyrylamino, valerylamino, hexanoylamino, heptanoylamino, otatanylamino and isomers thereof.
  • C3-8 cycloalkyl in the "substituent” represents, for example, cyclopropyl, cycloptynole, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
  • the compound represented by the general formula (IA) and the compound represented by the general formula (IB) are also preferable, but the compound represented by the general formula (IA) is more preferable.
  • R lc is preferably (1) C 1-8 alkyl substituted by one to three of —CONI ⁇ R 12 or —COR 13 , (3) —COR 13 or (4) an optionally substituted carbocycle, more preferably one selected from (1) —C ⁇ NR ”R 12 and one C ⁇ R 13 group C1 one 4 alkyl substituted by the group, (2) - CONR "R 12, ( 3) 3 or (4) c which is substituted, substituted, or phenyl
  • a 1 2 is, for example, the following groups.
  • a heterocyclic ring which may have a substituent is preferable, and a heterocyclic force containing at least one nitrogen atom which may have a substituent is more preferable.
  • Preferred heterocycles include, for example, azetidine, pyrrolidine, piperidine, perhydroazepine, perhydroazosin, pyrrole, dihydropyrrole, dihydropyridine, tetrahydropyridine, dihydroazepine, tetrahydroazepine, piperazine, monoreforin, thiomorpholine Oxazolidine, thiazolidine, dihydroindole, dihydroisoindole, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, tetrahydrothiazolopyridine, tetrahydrotriazolopyrazine ring, etc., and these rings have substitution groups. May be.
  • phenyl group optionally having substituent (s) a phenyl group substituted by at least three hydroxyl groups is preferable.
  • Powerful phenyl groups are selected from alkyl, alkoxy, halogen atoms (fluorine, chlorine, bromine, iodine), mono (cialkyl) amino and di (alkyl) amino, in addition to the three hydroxyl groups. May be present as substituents.
  • R la Of R la , R lb , R le and R ", a combination in which R lb and R ld are hydrogen is preferable.
  • annalequinole, alkoxy, alkylthio, alkenyl, alkynyl, alkylene, alkylidene, alkenylidene and alkynylidene include straight and branched ones.
  • isomers in double bonds, rings and condensed rings (E, Z, cis, trans isomers), isomers due to the presence of asymmetric carbon (R, s, isomer, / 3 isomer, enantiomer, diastereomer), optical rotation Optical isomers (D, L, d, one, +,-), polar isomers (highly polar, less polar) by chromatographic separation, equilibrium compounds, and compounds in any proportion of these , Racemic mixtures are all included in the present invention.
  • [0093] indicates that the force, which is one of the connection to the front of the paper surface or the connection to the other side, is not determined.
  • optically active compound in the present invention is not only a 100% pure compound but also contains less than 50% of other optical isomers.
  • [0097] represents that the geometric isomer of the double bond is a mixture of an E-form and a Z-form at an arbitrary ratio.
  • ring G is a heterocyclic ring having at least one nitrogen atom among “heterocyclic rings which may have a substituent” in R ”(for example, azetidine, pyrrolidine, piperidine , Perhid Loazepine, perhydroazosin, pyrrole, dihydropyrrole, dihydropyridine, tetrahydropyridine, dihydroazepine, tetrahydroazepine, oxazolidin, thiazolidine, or tetrahydrotriazolopyrazine ring), and Ra has a “substituent in R 13 . May have the same meaning as the “substituent” in the “heterocycle”, t represents an integer of 0 or 115, and other symbols have the same meanings as described above. ), A compound represented by the general formula (IA—e)
  • orchid is a carbon atom in “a carbocycle optionally substituted by 1 to 5 R 3 ” and a “heterocycle optionally substituted by 1 to 5 R 3 ” in R le
  • the other symbols have the same meanings as described above for the ring and the heterocyclic ring, and a compound represented by the general formula (IA-h)
  • Salts of the compounds represented by formula (I) include all pharmacologically acceptable ones.
  • the pharmacologically acceptable salts are preferably those with low toxicity and water solubility.
  • Suitable salts include, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts (tetramethylammonium salt, tetrabutylammonium) Salts), organic amines (triethylamine, methinoleamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N-methyl-D -Gnorecamine, etc.), acid addition salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate
  • the N-year-old oxide form refers to any oxidized nitrogen atom contained in the compound represented by the general formula (I).
  • the salt of the compound of the present invention and the N-methoxide include a solvate or a solvate of an alkali (earth) metal salt, an ammonium salt, an organic amine salt, and an acid addition salt of the compound of the present invention. Things are also included.
  • the solvate is non-toxic and water-soluble. Suitable solvates include, for example, solvates such as water and alcohol solvents (such as ethanol).
  • the compound of the present invention can be converted to a pharmacologically acceptable salt, N-oxide or solvate by a known method.
  • the prodrug of the compound represented by the general formula (I) refers to a compound that is converted into a compound represented by the general formula (I) in a living body by a reaction with an enzyme, gastric acid, or the like.
  • a prodrug of the compound represented by the general formula (I) when the compound represented by the general formula (I) has an amino group, a compound in which the amino group is acylated, alkylated, or phosphorylated (for example, General formula (I )), The amino group of the compound represented by eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-1-yl) methoxycarbonylation, tetrahydrofurerylation, pyrrolyl Zylmethylation, bivaloyloxymethylation, acetoxymethylation, tert-butylated compound, etc.); when the compound represented by the general formula (I) has a hydroxy
  • the prodrug of the compound represented by the general formula (I) may be any of a hydrate and a non-hydrate.
  • the repeated oral glucose tolerance test in rats can be performed based on the single oral glucose tolerance test method described in Experimental Example 4 below.
  • the total oral glucose load was 3 times (the first oral glucose load was performed 30 minutes after oral administration of the compound of the present invention, the second oral glucose load was 6 hours after the first oral glucose load, and the third oral glucose load was 12 hours later.
  • An oral glucose load is performed.) Blood is collected immediately before oral administration of the compound of the present invention, after the first oral glucose load, and immediately before the remaining two oral glucose loads, and after oral glucose load. By this test, the hypoglycemic effect of the compound of the present invention can be measured.
  • the compound of the present invention represented by the general formula (I) a known method, for example, complexity Heng Shiv 'O ⁇ force nick' Tofunsufo 1 ⁇ menu 1 ⁇ Shonsu (and omprehensive Organic Transformations: A Guide to Functional Group Preparations ⁇
  • the second piece 3 ⁇ 4j (Richard C. Larock, John Wiley & Sons Inc, 1999) can be produced by appropriately improving the method described in, for example, the method shown below, or a combination of the methods shown in Examples.
  • the starting conjugate may be used as a salt, such as those described as the pharmaceutically acceptable salts of the above-mentioned general formula (I). Can be used.
  • a compound having the meaning S which may be protected when these have a carboxyl group, an amino group, a hydroxyl group and / or a mercapto group, and other symbols having the same meanings as described above)
  • a deprotection reaction of a protecting group for a nitrogen atom By subjecting the compound to a deprotection reaction of a protecting group for a nitrogen atom and, if necessary, to a deprotection reaction for a protecting group of another carboxyl group, an amino group, a hydroxyl group and / or a mercapto group.
  • Examples of the protecting group for the nitrogen atom include benzyloxycarbonyl, tert-butoxycanolebonyl, aryloxycarbonyl (Alloc), 1-methyl-1_ (4-biphenylinole) ethoxycarbonyl (Bpoc), trifluorocarbonyl Examples include roacetyl, 9_fluorenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl, benzyloxymethyl (BOM), and 2_ (trimethylsilinole) ethoxymethyl (SEM).
  • Examples of the carboxyl-protecting group include methyl, ethyl, aryl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl, tritinol, 2-cyclotrityl, and a structure thereof having a bond. And the like.
  • hydroxyl-protecting group examples include methyl, trityl, methoxymethinole (MOM), 1-ethoxyshethyl (EE), methoxyethoxymethyl (MEM group, 2-tetrahydroviranyl (THP), trimethylsilyl (TMS), Triethylsilyl (TES), tert-butyldimethylsilinole (TBD MS), tert-butyldiphenylsilinole (TBDPS), acetyl (Ac), bivaloyl, benzoyl, benzyl (Bn), p_methoxybenzyl, aryloxy Carbonyl (Alloc), 2,2,2-trichloromouth ethoxycarbonyl (Troc) and the like.
  • Examples of the protecting group for an amino group include the same as those described above for the protecting group for a nitrogen atom.
  • Examples of the mercapto group-protecting group include benzyl, methoxybenzyl, methoxymethinole (MOM), 2-tetrahydroviranyl (THP), diphenylmethyl, acetyl (Ac) and the like.
  • the protecting group for the carboxyl group, the hydroxyl group, the amino group and / or the mercapto group is not particularly limited as long as it is a group which can be easily and selectively eliminated in addition to the groups described above.
  • those described in T. W. ureene, Protective uroups in Organic Syntnesis, Wiley, New York, 1999 are used.
  • Deprotection reactions of a protecting group for a nitrogen atom and a protecting group for a carboxyl group, a hydroxyl group, an amino group and / or a mercapto group are well known, and include, for example,
  • the deprotection reaction by alkali hydrolysis is performed, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.), in the presence of an alkali metal hydroxide (sodium hydroxide, hydroxide hydroxide, lithium hydroxide, etc.), alkali hydroxide, or the like.
  • an alkali metal hydroxide sodium hydroxide, hydroxide hydroxide, lithium hydroxide, etc.
  • alkali hydroxide alkali hydroxide, or the like.
  • hydroxides of earth metals barium hydroxide, hydroxide, etc.
  • carbonates sodium carbonate, potassium carbonate, etc.
  • the deprotection reaction under acidic conditions is carried out, for example, by using an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, methanesulfonic acid, etc.) in an organic solvent (dichloromethane, clonor honolem, dioxane, ethyl acetate, anisol, etc.).
  • the reaction is performed at a temperature of 0-100 ° C in methylbenzenesulfonic acid or the like, or an inorganic acid (hydrochloric acid, sulfuric acid or the like) or a mixture thereof (hydrogen bromide Z acetic acid or the like).
  • the deprotection reaction by hydrogenolysis includes, for example, solvent (ether (tetrahydrofuran, dioxane, dimethoxyethane, getyl ether, etc.), alcohol (methanol, ethanol, etc.), benzene (benzene, etc.). , Toluene, etc.), ketones (acetone, methylethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof.
  • solvent ether (tetrahydrofuran, dioxane, dimethoxyethane, getyl ether, etc.), alcohol (methanol, ethanol, etc.), benzene (benzene, etc.). , Toluene, etc.), ketones (acetone, methylethyl ketone, etc.), nitriles (
  • the reaction is carried out at 0-200 ° C in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.), in a hydrogen atmosphere under normal pressure or pressure, or in the presence of ammonium formate.
  • a catalyst palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.
  • the deprotection reaction of the silyl group is carried out, for example, by using tetrabutylammonium fluoride in a water-miscible organic solvent (tetrahydrofuran, acetonitrile, etc.) at a temperature of 0 to 40 ° C. It is done in.
  • a water-miscible organic solvent tetrahydrofuran, acetonitrile, etc.
  • the deprotection reaction using a metal is carried out, for example, by reacting powdered zinc in an acidic solvent (acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixture thereof and an organic solvent such as tetrahydrofuran). In the presence, it is carried out at a temperature of 0-40 ° C, applying ultrasound if necessary.
  • an acidic solvent acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixture thereof and an organic solvent such as tetrahydrofuran.
  • the deprotection reaction using a metal complex can be performed, for example, by using a trapping reagent (hydrogen) in an organic solvent (dichloromethane, dimethyl honoleamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof.
  • a trapping reagent hydrogen
  • organic solvent dichloromethane, dimethyl honoleamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.
  • the intended compound of the present invention can be easily produced by properly using these deprotection reactions.
  • the amidation reaction is known, for example,
  • the method of using an acid halide is, for example, a method in which a carboxylic acid is converted into an acid halide (oxalyl chloride, thioyuric acid or the like) in an organic solvent (chloroform, dichloromethane, dimethyl ether, tetrahydrofuran or the like) or without solvent.
  • an organic solvent chloroform, dichloromethane, dimethyl ether, tetrahydrofuran or the like
  • Amide and an organic solvent in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.).
  • a base pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.
  • Black mouth The reaction is carried out at 0-40 ° C in form, dichloromethane, getyl ether, tetrahydrofur
  • the reaction can also be carried out by reacting the obtained acid halide with an amine in an organic solvent (dioxane, tetrahydrofuran, etc.) using an aqueous alkali solution (aqueous sodium bicarbonate or sodium hydroxide solution) at 0-40 ° C. .
  • an organic solvent dioxane, tetrahydrofuran, etc.
  • an aqueous alkali solution aqueous sodium bicarbonate or sodium hydroxide solution
  • a carboxylic acid is dissolved in an organic solvent (eg, chloroform, dichloromethane, dimethyl ether, tetrahydrofuran) or in the absence of a solvent in the presence of a base (pyridine, triethylamine, dimethyl).
  • an organic solvent eg, chloroform, dichloromethane, dimethyl ether, tetrahydrofuran
  • a base pyridine, triethylamine, dimethyl
  • a carboxylic acid and an amine derivative can be prepared by adding a carboxylic acid and an amine derivative in an organic solvent (e.g., chloroform, dichloromethane, dimethylformamide, getyl ether, tetrahydrofuran) or in the absence of a solvent.
  • an organic solvent e.g., chloroform, dichloromethane, dimethylformamide, getyl ether, tetrahydrofuran
  • All of the reactions (1), (2) and (3) are desirably carried out under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.
  • inert gas argon, nitrogen, etc.
  • R 11A and R 1 represent the same meaning as R 11 and R ", respectively. When these have a ropoxyl group, an amino group, a hydroxyl group and / or a mercapto group, they are protected, And w represents an integer of 0 or 115, and other symbols have the same meanings as described above.
  • amidation reaction can be carried out in the same manner as described above.
  • w represents an integer of 0 or 115, and other symbols represent the same meaning as described above.
  • amidation reaction can be carried out in the same manner as described above.
  • the compound represented by III-III) can be produced by the method represented by the following reaction scheme 11-S.
  • Boc represents tert-butoxycarbonyl
  • Me represents methyl
  • Et represents ethyl
  • tBu represents tert-butyl
  • Ts represents p-tonolenesulfonyl
  • Tf represents trifluoromethanesulfonyl
  • Bn represents benzyl
  • Z represents benzyloxycarbonyl
  • Q represents a protecting group such as methinole, ethyl, benzyl, tert-butyl
  • m represents 0 or 1.
  • R 3A has the same meaning as R 3 , but is protected when it represents an amino group, a carboxyl group, a hydroxyl group or a mercapto group.
  • R P represents a single bond at the base bonded to the pyrrolidine ring of R le is a double bond
  • R A ' is R la ' or Represents any of the groups of R lb
  • R B is to Table Wa any group of R le or R ".
  • All the reactions in each reaction scheme can be performed according to a known method.
  • the other starting materials and each reagent in the present invention can be produced according to a known force or a known method.
  • the compound represented by the general formula (IV) is known, and the compound represented by the general formula (III) can be produced from a known compound according to a known method.
  • a reaction product is produced by a conventional purification means, for example, distillation under normal pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, Alternatively, it can be purified by a method such as column chromatography or washing and recrystallization. Purification may be performed for each reaction or may be performed after completion of several reactions.
  • a conventional purification means for example, distillation under normal pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, Alternatively, it can be purified by a method such as column chromatography or washing and recrystallization. Purification may be performed for each reaction or may be performed after completion of several reactions.
  • the toxicity of the compound of the present invention represented by the general formula (I) is extremely low, and it is sufficiently safe for use as a medicament.
  • the compound of the present invention represented by the general formula (I) inhibits DPP4 to produce DPP4-mediated diseases such as diabetes (particularly type 2 diabetes, postprandial hyperglycemia, etc.), obesity, autoimmune disease, and cancer metastasis. , HIV infection, infertility, anemia, thrombocytopenia, wound, skin disease, prostatic hypertrophy, hyperlipidemia, syndrome X, diabetic complications, hyperglycerinemia, arteriosclerosis, impaired glucose tolerance, polycystic ovary syndrome , Growth disorders, arthritis, transplant rejection, enteritis, etc. and as a Z or prophylactic agent.
  • diabetes particularly type 2 diabetes, postprandial hyperglycemia, etc.
  • obesity autoimmune disease
  • cancer metastasis e.g., HIV infection, infertility, anemia, thrombocytopenia, wound, skin disease, prostatic hypertrophy, hyperlipidemia, syndrome X, diabetic complications, hyperglycerinemia, arteriosclerosis, impaired glucose tolerance, poly
  • the compound represented by the general formula (I), a salt thereof, an N-hydroxylated compound or a solvate, or a prodrug thereof may be abbreviated as a compound represented by the general formula (I) or the like) )) 1) complement and / or enhance the therapeutic and / or prophylactic effects of the compound, 2) improving the kinetics and / or absorption of the compound, reducing the dose,
  • the compound may be administered as a concomitant drug in combination with other drugs to reduce the side effects of the compound.
  • a concomitant drug of a compound represented by the general formula (I) and another drug may be administered in the form of a combination drug in which both components are combined in one formulation, or may be administered as separate formulations. You can also take the form to do.
  • the administration in the form of separate preparations includes simultaneous administration and administration with a time lag.
  • administration with a time lag may be performed by administering the compound represented by the general formula (I) first and then administering another drug later, or administering the other drug first and then administering the compound represented by the general formula (I).
  • the indicated compound or the like may be administered later, and the respective administration methods may be the same or different.
  • Diseases in which a therapeutic and / or prophylactic effect is exerted by the above concomitant drug are not particularly limited, and diseases that complement and / or enhance the therapeutic and / or prophylactic effect of the compound represented by the general formula (I) and the like. If so,
  • drugs for complementing and / or enhancing the action of the compound represented by the general formula (I) include, for example, sulfonylureas, biguanides, ⁇ -dalcosidase inhibitors, insulin Secretagogues, insulin sensitizers, insulin preparations, PPAR agonists ( ⁇ AR a agonist, PPAR ⁇ agonist, PPAR ⁇ + ⁇ agonist, etc.), ⁇ adrenergic receptor
  • Agonists aldose reductase inhibitors, DPP4 inhibitors and the like.
  • sulfonylurea drugs examples include acetohexamide, dalibenclamide, daliclazide, glicloviramide, chlorpropamide, tolazamide, tolptamide, glimepiride and the like.
  • biguanides examples include buformin hydrochloride, metformin hydrochloride and the like.
  • Examples of the heart darcosidase inhibitors include acarbose and voglibose.
  • insulin secretagogue examples include nateglinide, repaglinide and the like.
  • insulin sensitizer examples include ⁇ NO_5816, YM_440, JTT_501, and NN-2 344 and the like.
  • Examples of the PPAR agonist include pioglitazone, troglitazone, rosiglitazone and the like.
  • Examples of ⁇ -adrenergic receptor agonists include AJ9677, L750355, and CP33164.
  • aldose reductase inhibitor examples include epalrestat, fidarestat, zenarestat and the like.
  • DPP4 inhibitor listed are: LAF-237, MK_0431, BMS_477118, P93
  • HMG_CoA inhibitor examples include pravastatin, simpastatin, lovastatin, flupastatin, atorvastatin, rospastatin, pitapastatin and the like.
  • the dose varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually in the range of lng to lOOmg per adult, once to several times a day. Per parenteral dose per adult or adult, parenteral once or several times daily in the range of 0.1 to 10 mg, or intravenously in the range of 1 to 24 hours daily Is administered continuously.
  • the solid preparation for oral administration for oral administration includes tablets, pills, capsules, powders, granules and the like.
  • Capsules include hard capsules and soft capsules.
  • one or more active substances are used as they are, or excipients (ratatose, mannitol, gnorecose, microcrystalline cellulose, starch, etc.), binders (hydroxypropylcellulose, Polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrator (calcium glycolate, etc.), lubricant (magnesium stearate, etc.), stabilizer, solubilizer (glutamic acid, aspartic acid, etc.) It is mixed, formulated and used according to a conventional method.
  • a coating agent sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
  • capsules of absorbable substances such as gelatin.
  • Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like.
  • one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (eg, purified water, ethanol or a mixture thereof).
  • the liquid preparation may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffer and the like.
  • Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections that are dissolved or suspended in a solvent before use. Injectables are prepared by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • the solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol and the like, and combinations thereof are used.
  • the injection may contain a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer, a preservative, and the like. . these Is manufactured and prepared by sterilization or aseptic operation in the final step.
  • a sterile solid preparation for example, a lyophilized product, can be produced and dissolved in sterilized distilled water for injection or other solvents before use.
  • Dosage forms of external preparations for parenteral administration include, for example, ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, eye drops, Includes nasal drops and the like. These contain one or more active substances and are manufactured and prepared by known methods or commonly used formulations.
  • the ointment is produced by a known or commonly used formulation. For example, it is manufactured and prepared by grinding or melting one or more active substances in a base.
  • the ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (Such as beeswax, spermaceti, and ceresin), surfactants (such as polyoxyethylene alkyl ether phosphate), higher alcohols (such as cetanol, stearyl alcohol, and setstearyl alcohol), and silicone oils (such as dimethylpolysiloxane) ), Hydrocarbons (hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.
  • the gel is produced by a known or commonly used formulation. For example, it is produced and prepared by melting one or more active substances in a base.
  • the gel base is selected from known or commonly used ones. For example, lower alcohols (ethanol, isopropynole alcohol, etc.), gelling agents (carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, etc.), neutralizing agents (triethanolamine, diisopropanolamine, etc.),
  • surfactants polyethylene glycol monostearate, etc.
  • gums water, absorption enhancers, and anti-rash agents Let's do it. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • a cream is produced by a known or commonly used formulation. For example, it is produced and prepared by melting or emulsifying one or more active substances in a base.
  • the term base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers (polyoxyethylene alkyl ether) , Fatty acid esters, etc.), water, absorption enhancers, and rash preventives. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the poultice is produced by a known or commonly used formulation. For example, it is manufactured by melting one or more active substances in a base, forming a kneaded product, and spreading and applying the mixture on a support.
  • the compress base is selected from known or commonly used ones. For example, thickeners (polyatalinoleic acid, polybierpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, Calcium, magnesium, etc.), water, a dissolution aid, a tackifier, and an anti-rash agent. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the patch is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material and spreading and coating the support material on a support.
  • the base for the patch is selected from known or commonly used ones. For example, a mixture of one or more selected from a polymer base, oils and fats, higher fatty acids, tackifiers and anti-rash agents is used. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the liniment is produced by a known or commonly used formulation.
  • one or more active substances are dissolved, suspended or emulsified in one or more selected from water, alcohol (ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soap, emulsifier, suspending agent, etc. It is manufactured and prepared. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • Sprays, inhalants, sprays and nasal drops are generally used in addition to diluents.
  • Buffers which provide isotonicity with stabilizers such as sodium bisulfite may contain isotonic agents such as sodium chloride, sodium citrate or citric acid.
  • isotonic agents such as sodium chloride, sodium citrate or citric acid.
  • a nasal drop When a nasal drop is administered, it is generally sprayed quantitatively into the nasal cavity with a solution or powder containing the drug, using a special nasal dropper or nebulizer.
  • Eye drops for parenteral administration include eye drops, suspension-type eye drops, emulsion-type eye drops, dissolvable-type eye drops and eye ointments.
  • These eye drops are prepared and prepared according to a known method.
  • one or more active substances are used by dissolving, suspending or emulsifying in a solvent.
  • the solvent for the ophthalmic solution for example, sterilized purified water, physiological saline, other aqueous solvents or injectable non-aqueous agents (eg, vegetable oil) and the like and combinations thereof are used.
  • Eye drops include isotonic agents (sodium chloride, concentrated glycerin, etc.), buffering agents (sodium phosphate, sodium acetate, etc.), surfactants (polysorbate 80 (trade name), polyoxyl stearate 40, It contains, as necessary, a suitable additive such as a reoxyethylene hydrogenated castor oil, a stabilizer (sodium taenoate, sodium edetate, etc.), a preservative (benzanoleconidum chloride, paraben, etc.). Is also good. These are manufactured and prepared by a sterile operation method that is sterilized in the final process. In addition, a sterile solid preparation, for example, a lyophilized product, can be manufactured and dissolved in sterilized purified water or another solvent before use, and used.
  • a suitable additive such as a reoxyethylene hydrogenated castor oil, a stabilizer (sodium taenoate, sodium edetate, etc.),
  • Inhalants for parenteral administration include aerosols, powders for inhalation, and solutions for inhalation, and the solutions for inhalation are dissolved or suspended in water or another appropriate medium before use. May be used.
  • a preservative eg, Shizani Benzanoreconium, paraben
  • a coloring agent e.g, a coloring agent
  • a buffer e.g, sodium phosphate, sodium acetate
  • an isotonic agent Sodium chloride, concentrated glycerin, etc.
  • a thickener such as cariboxybul polymer
  • an absorption enhancer etc.
  • lubricants stearic acid and its salts, etc.
  • binders starch, etc.
  • Dextrin starch, etc.
  • excipients lactose, cellulose, etc.
  • coloring agents preservatives
  • preservatives benzanolone chloride, benzene, etc.
  • absorption promoters etc., as appropriate, and prepared.
  • a nebulizer (an atomizer, a nebulizer) is usually used to administer a liquid for inhalation, and an inhaler / administrator for powdered medicine is usually used to administer a powder for inhalation.
  • compositions for parenteral administration include suppositories for rectal administration and pessaries for vaginal administration, which contain one or more active substances and are prescribed in a conventional manner. Is included. The invention's effect
  • the compound of the present invention represented by the general formula (I) has DPP4 inhibitory activity and is therefore useful as a therapeutic and / or prophylactic agent for DPP4-mediated diseases.
  • the solvent in the kakkou indicated by the chromatographic separation and TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
  • NMR is a measured value of 1 H NMR, and the solvent in kakko
  • the compound name used in the present specification is generally a computer program for naming according to the rules of IUPAC, ACD / Name (registered trademark, manufactured by Advanced Chemistry Development Inc.) or ACD / Name batch ( (Registered trademark, manufactured by Advanced Chemistry Development Inc.) or according to the IUPAC nomenclature.
  • Participant example 2 l_tert_butyl 2_methyl (2S) _4_ “2-methoxy-3- (methoxymethoxy) phenyl ⁇ —2.5-dihydro-1H-pyrro-mono-1.2-dicarboxylate
  • Participant example 5 tert_butyl (2S.4R) _2_i “(2S) _2_cyanopyrrolidine-1-yl ⁇ carbonyl” _4_ “2-methoxy_3_ (methoxymethoxy) phenyl ⁇ rosin-1 1-carboxy Two In a solution of the compound (818 mg) prepared in Reference Example 4, (2S) -2-cyanopyrrolidine 4-methylbenzenebenzenesulfonate (689 mg) and 1-hydroxybenzotriazole monohydrate (289 mg) in dimethylformamide (6 ml).
  • Example 1 (2S) -li r (2S. 4R) _4_ (3-hydroxy-2,6-dimethoxyphenyl) pyrrolidine-2-yl ⁇ carbonyl ⁇ pyrrolidine_2_carboditrinole 4_methyl Benzenesulfonate ⁇
  • Example 1 (2S) _1 _ ⁇ “4_ (3-hydroxy_5_methylphenyl) pyrrolidine—2-yl ⁇ ⁇ carbinole ⁇ pyrrolidine-1_2-carboditrinole 4_methylbenzenesulfonate
  • Example 1 (4): (2S) _1 _ ⁇ “(2S.4R) _4_ (3-hydroxy-6-methoxy_2_methylphenyl) pyrrolidine-l-2-yl ⁇ carbonyl ⁇ pyrrolidine-l_2-carboditrinole 4_ Methylbenzene sulfonic acid salt
  • Example 1 (9): Methyl "3 _ ((3R.5S) _5 _ ⁇ " (2S) _2_cyanopyrrolidine-1-yl ⁇ ubonyl ⁇ pyrrolidine-3-yl) -2.4-dimethylphenyl ⁇ uylbamate 4_ methylbenzene sulfonic acid salt
  • Example 1 (10): N_ “3 _ ((3R.5S) _5 _ ⁇ “ (2S) _2_cyanopyrrolidine-1-yl ⁇ carbonyl ⁇ pyrrolidine-1-3-inole) _2,4-dimethylpheninole ⁇ Urea 4-methylbenzenesulfonate
  • Example 1 (12): 3 _ ((3R.5S) _5 _ ⁇ "(3S) _3_fluoropyrrolidine-1-yl carbo ⁇ pyrrolidine-3-inole) -2.4_dimethylphenol 4 _Methylbenzenesulfonic acid product '
  • Participant example 6 l_tert_butyl 2_methyl (2S) _4_ (1.3.5_trimethyl_1H-pyrazolone-4_yl) -1-2.5-dihydro-1H-pyrrole-1, 2-dicarboxy Rat
  • Example 2 (2S) -li r (2S. 4R) -4- (3.5_dimethylpyridine-1-41yl) pyrrolidin-1--2-yl ⁇ carbinole) pyrrolidine-1_ Carbonitrinolebis (4-methylbenzenesulfonate)
  • Triethylamine (3.5 ml), copper iodide (304 mg), bis (triphenylphosphine) dichloropalladium (II) (374 mg) and propargyl were added to a solution of the compound (200 g) produced in Reference Example 1 in tetrahydrofuran (11 ml). Alcohol (0.62 ml) was added and stirred at room temperature for 30 minutes. An aqueous solution of a saturated sodium chloride ammonium salt was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried, and concentrated. The residue was purified by column to give the title compound (1.37 g).
  • Reference Example 4 Reference Example 5 Using the compound prepared in Reference Example 8 in place of the compound prepared in Reference Example 3, (2S, 4S) _2_cyano_4_fluoropyrrolidine 4_methylbenzenesulfonate.) ⁇ A compound of the present invention having the following physical properties was obtained in the same manner as in the method shown in Example 1. .
  • Example 3 The following compound of the present invention was obtained in the same manner as in Example 3 using the corresponding compound instead of the compound produced in Example 2.
  • Example 3 (2S) _1 _ ⁇ “(2S.4S) _4_ (3-hydroxy-3-methylbutyl) pyrrolidine_2-yl ⁇ carbinole ⁇ pyrrolidine-1-carboditrinore 4-methylbenzenesulfone Acid salt
  • Example 4 (1): 3 _ ((3S, 5S) _5_ (2S, 4S) _2-cyanol 4_fluoropyrrolidine 1_inole ⁇ carbinole ⁇ pyrrolidine _3-inole) _N, N-dimethylpropanamide 4 Methylbenzene sulfonic acid salt
  • Reference Example 5 (Dimethyl instead of (2S) _2_cyanopyrrolidine 4-methylbenzenesulfonate) using the compound prepared in Reference Example 9 instead of the compound prepared in Reference Example 4. The amine was used. ) ⁇ Reference Example 4 ⁇ Reference Example 5 (2S, 4S) _2_Cyano _4_Fluoropyrrolidine 4_Methylbenzenesulfonate instead of ((2S) —2-Cyanopyrrolidine 4-methylbenzenesulfonate) ⁇
  • the compound of the present invention having the following physical properties was obtained in the same manner as in the method shown in Example 1.
  • Participant example 10 l_tert-butynole 2_methyl (2S) _4_ (7-hydroxyheptyl) —2.5_dihydro-1H-pyrromonol-1.2-2-dicanolevoxylate
  • potassium carbonate (310 mg) was added to a solution of the compound prepared in Reference Example 1 (422 mg) in a mixed solvent of N, N-dimethylformamide / water (7: 1) (6 ml) (310 mg) to prepare in advance.
  • Participant example 13 (4R) -4- ⁇ 2- (benzyloxy) _2_oxoethyl ⁇ _1_ (tert-butoxycarbonyl)-L-prolyl- L-prolinamide
  • step (b) To a solution of the compound prepared in step (a) (12.5 g) and benzyl bromide (4.5 ml) in N, N-dimethylformamide (70 ml) was added potassium carbonate (5.7 g), and the mixture was allowed to stand at room temperature. Stir for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by column to give the title compound (10 g). Participant example 14: tert-butyl (2S. 4R) _4_ “2_ (benzyloxy) _2_oxoethyl ⁇ —
  • Example 7 2 — ((3R.5S) _5 _ ⁇ “(2S) _2_cyanopyrrolidine-1-yl dicarbonyl ⁇ pyro J2 gin-3-inole) __N._N—gelase 4_methylbenzene Sulfonate [0227] [Formula 44]
  • Example 7 (2S) -li r (2S. 4R) -4- (2-oxo-2-piperidine-1-ylethyl) pyrrolidine-12-yl ⁇ carbinole ⁇ pyrrolidine-1 2 —Carbonitorinole 4-methylbenzenesulfonate ⁇
  • Example 7 (4): (2S) _1 _ “((2S, 41) _4_ ⁇ 2_“ 4_ (methylsulfonyl) pyrazine_1—yl ⁇ _2_2-oxoethylen ⁇ pyrrolidine_2_yl) carbonyl Lysine-2_carbonitorinole 4_methylbenzenesulfonate
  • Example 7 (2S) -l-( ⁇ (2S.41) _4_ “2_ (4_acetyl_1.4-diazepan-1_yl) _2_oxosetyl ⁇ pyrrolidine-2-yl ⁇ carbonyl ) Pyrrolidine_2_carbonitrile 4_methylbenzenesulfonate
  • Example 7 (9): 6_i4 _ “((3R.5S) _5_i“ (2S) _2_cyanopyrrolidine-l-yldicarbonyl ⁇ pyrrolidine_3_yl) acetyl, piperazine-l-yl ⁇ nicotino Nitrinolebis (4-methylbenzenesulfonic acid) salt
  • Example 7 (10): 4-r ((3R.5S) -5- (2S) -2-cyanopyrrolidine-l-yl ⁇ carbinole ⁇ pyrrolidine-l-yl) acetyl ⁇ _ ⁇ , ⁇ -dimethylpiperazine 1-11 Carboxamide 4 Methylbenzenesulfonate
  • Example 7 (11): Ethyl 4 _ "((3R.5S) _5_i” (2S) _2_cyanopyrrolidine-1-yl ⁇ carbonyl ⁇ pyrrolidine-1-3-yl) acetyl dipyrazine-1_carboxy LAT 4-Methylbenzenesulfonate
  • Example 7 N.N-dimethyl_2 _ ((3R.5S) _5_ (pyrrolidine-1-ylcarbonyl) pyrrolidine-1-3-yl diacetamide 4_methylbenzenesulfonate
  • Example 7 (13): 2 _ ((3R.5S) _5 _ ⁇ “(3S) _3_fluoropyrrolidine-1-yl ⁇ carbonyl” pyrrolidine-1-yl) _N.N-dimethylacetamide 4_ methylbenzene sulfonate
  • Example 7 (14): 2 _ ((3R, 5S) -5-ir (2S.4S) _2-cyano 4-fluoropyrrolidine 1-inole dicarbonyl ⁇ pyrrolidine_3-inole) -1-N, N-dimethylacetate Amide 4_methylbenzene sulfonic acid salt
  • Participant example 16 tert_butyl (2S. 4R) _4_ “(benzyloxy) carbonyl @amino 1 methyl) _2 _ ⁇ (2S) _2_cyanopyrrolidine-1-yl ⁇ carbonyl ⁇ pyrrolidine_1_carboxylate
  • the obtained solution was dropped into a reaction vessel heated to 90 ° C over 30 minutes, and the mixture was stirred for 1 hour.
  • the reaction mixture was fed with benzyl alcohol (2.8 ml) and pyridine (0.1 ml) and stirred at 100 ° C for 20 hours.
  • the reaction mixture was concentrated, and the residue was purified by column to give the title compound (1.07 g).
  • Participant example 17 tert_butyl (2S. 4R) _4 _ “(acetylamino) methyl_2_i” (2S) _2_ cyanopyrrolidine-1-yl ⁇ carbonyl ⁇ pyrrolidine-1-carboxylate
  • Reference Example 18 tert-butyl (2S, 4S) _2_i “(2S) _2_cyanopyrrolidine-1-ylcarbonyl ⁇ 1-141 ⁇ “ (methylsulfonyl) aminoaminomethyl ⁇ pyrrolidine-1-carboxylate Reference Example 17 To a solution of the compound prepared in (a) (304 mg) in dichloromethane (4.7 ml) was added triethylamine (0.39 ml), the mixture was cooled to 0 ° C, and mesyl chloride (0.11 ml) was added dropwise.
  • Triethylamine (0.39 ml) and mesyl chloride (0.11 ml) were added dropwise, and the mixture was stirred for 40 minutes.
  • the reaction mixture was added to a saturated aqueous solution of sodium hydrogen carbonate (o ° c).
  • the organic layer was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by column to give the title compound (283 mg).
  • Participant example 19 tert_butyl (2S.4R) _4 _ ((dimethylamino) carbonyl ⁇ amino ⁇ methylenol) —2_i “(2S) _2_cyanopyrrolidine—1-yl ⁇ carbonyl ⁇ pyrrolidine_1_carboxylate Reference Example 17 Triethylamine (0.72 ml) was added to a dichloromethane (5 ml) solution of the compound (334 mg) prepared in (a), and N, N-dimethylcarbamoyl chloride (0.19 ml) was added to the mixture at 0 ° C. Was added dropwise, and the mixture was stirred at room temperature for 1.5 hours.
  • N, N-dimethylcarbamoinolechloride (0.19 ml) was further added dropwise, and the mixture was further stirred for 1 hour.
  • the reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate (0 ° C), and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column to give the title compound (271 mg).
  • Participant example 20 Echinore “((3S.5S) _5 _ ⁇ “ (2S) _2_cyanopyrrolidine-1-yl ⁇ carbonyl ⁇ pyrrolidine-l-3-yl) methyl thiolbamate 4_methylbenzenesulfonic acid
  • Participant example 21 tert_butyl (2S. 41 _4 _ ⁇ "(5_cyanopyridine_2_yl) aminoamino ⁇ _2_i” (2S) _2_cyanopyrrolidine-1-yl ⁇ carbonyl ⁇ pyrrolidine_1_ Carboxy Silato
  • Example 8 Example 8 (4)
  • Example 8 N'-r ((3S.5S) _5— (2S) _2 cyanopyrrolidine 1-yl ⁇ carbinole ⁇ pyrrolidine-1-3-yl) methyl ⁇ _ ⁇ , ⁇ -dimethylperyl 4-methylbenzenesulfone Acid salt
  • Participant example 22 l_tert_butyl 2_methyl (2S) _4_ ⁇ 1 _ “(benzyloxy) carbonyl ⁇ — 1. 2.3.6 6-tetrahydropyridine-14-yl ⁇ —2.5-dihydro-1H —Pyrogenone 1.2 Dicanoleboxylate
  • Participant example 23 l_tert_butyl 2_methyl (2S. 4R) _4_i 1 — “(benzyloxy) carbonyl piperidine—4-yl ⁇ pyrrolidine—1,2-dicarboxylate
  • Example 9 (1): (2S) -li r (2S. 4R) _4_ (1_acetylpyperidine_4_yl) pyrrolidin-1--2-yl ⁇ carbinole) pyrrolidine-1 2_carboni Torinole 4_methylbenzenesulfonic acid product '
  • Example 9 (2S) -l-( ⁇ (2S.4R) -4- "l- (methylsulfonyl) piperidine 4-ynole-pyrrolidine-1-yl ⁇ carbonyl) pyrrolidine-1 2 Carbonitorinole 4 Methylbenzene sulfonate
  • Example 9 4-((3R.5S) _5 _ ⁇ “(2S) _2_cyanopyrrolidine-1-yl ⁇ carbonyl ⁇ pyrrolidine-1-3-yl) _N, N-dimethylpiperidine-1_ Carboxamide 4_methylbenzensnolefonate
  • Example 9 Ethyl 41-((3R, 5S) -5-i "(2S) -2-cyanopyrrolidine-1-yl” Rubonyl ⁇ pyrrolidine-1-3-inole) piperidine-1-1-carboxy Lat 4-methylbenzenesulfonate ⁇
  • Example 9 6_ “4 _ ((3R.5S) _5_i“ (2S) _2_cyanopyrrolidine-l-yldicarbonyl ⁇ pyrrolidine_3_yl) piperidine-l-yl ⁇ nicotinoni Trinole bis (4-methylbenzenesulfonic acid) salt
  • Reference Example 3 Reference Example 5 (in place of (2S) _2_cyanopyrrolidine 4_methylbenzenesulfonate) using the compound prepared in Reference Example 26 instead of the compound prepared in Reference Example 2.
  • L-prolinamide was used.
  • Reference Example 4 ⁇ Reference Example 13
  • Reference Example 14 ⁇ Reference Example 15 ⁇ Reference Example 5 ((2S) _2_cyanopyrrolidine 4_methylbenzenesulfonate
  • the procedure of Example 1 was repeated to give the compound of the present invention having the following physical data.
  • Reference Example 3 Reference Example 5 (L-Prolinamide was used instead of (2S) _2 cyanopyrrolidine 4-methylbenzenesulfonate) using the compound prepared in Reference Example 26 instead of the compound prepared in Reference Example 2.
  • Reference Example 4 Reference Example 13 ⁇ Reference Example 14 ⁇ Reference Example 15 ⁇ Reference Example 5 ((2S) _2_cyanopyrrolidine The corresponding amine was used in place of 4-methylbenzenesulfonate. )
  • the compound of the present invention was obtained in the same manner as in Example 1.
  • Example 11 (3S.5S) _5 _ ⁇ “(2S) _2_cyanopyrrolidine-1-yl ⁇ carbonyl ⁇ _N.N-dimethylpyrrolidine-1_3_carboxamide 4_methylbenzenesulfonate
  • Example 11 (2S) -li r (2S.4S) _4 -— (azetidine-1-ylcarbonyl) pyrrolidin-1-2-yl ⁇ carbinole) pyrrolidine-1 2_carbonitrinole 4_methylbenzene Sulfonic acid products'
  • Example 11 (10): (3S.5S) _5 _ ⁇ “(2S) _2_cyanopyrrolidine-1-yldicarbonyl ⁇ _N-Propylpyrrolidine-1-carboxamide 4-methylbenzenesulfonate
  • Participant example 28 l_tert-butynole 2-ethynole (2S) —4.4-diarylpyrrolidine—1.2-dica-noreboxylate
  • Participant example 30 4-benzyl l_tert_butyl 2-ethyl (2S.4S) _4_methyl_5-oxopyrrolidine 1.2.4. Tricarboxylate
  • lithium hexamethyldisilazide (1M tetrahydrofuran solution; 12 ml) was added dropwise at ⁇ 78 ° C. to a solution of the compound (4.28 g) prepared in Reference Example 29 in tetrahydrofuran (50 ml) at the same temperature.
  • Methyl iodide (0.75 ml) was added dropwise to the mixture, and the mixture was stirred at 0 ° C for 1 hour and at room temperature overnight.
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried, and concentrated. The residue was purified by column to give the title compound (0.9 g).
  • Reference Example 24 (b) Reference Example 5 ((2S) -cyanopyrrolidine 4 methylbenzenesulfonic acid, using the compound prepared in Reference Example 32 instead of the compound prepared in Reference Example 24 (a). (L) Prolinamide was used in place of the salt.) ⁇ Reference Example 27 (b) ⁇ The compound of the present invention was obtained in the same manner as in the method shown in Example 12.
  • Reference Example 24 (b) Reference Example 5 ((2S) _2_cyanopyrrolidine 4-methylbenzenesulfonic acid salt using the compound prepared in Reference Example 32 instead of the compound prepared in Reference Example 24 (a)) Was replaced with (L) _prolinamide.) ⁇ Reference Example 4 ⁇ Reference Example 5 (Dimethylamine was used instead of (2S) _2_cyanopyrrolidine 4_methylbenzenesulfonate) ⁇ Reference Example 1 4 ⁇ The compound of the present invention was obtained in the same manner as in the method shown in Example 1.
  • Example 16 (1) Example 16 (22)
  • Example 16 (1): (2S, 3R. 5S) -5-i "(2S) -2-cyanopyrrolidine-l-l- ⁇ carbyl ⁇ -lN, N. 2-trimethylpyrrolidine-l-carboxamide hydrochloride salt
  • Example 16 (3): (2S. 3R. 5S) -5-i “(2S, 4S) _2_cyano _4_fluoropyrrolidine- 1-yl ⁇ carbonyl ⁇ . N. 2_trimethylpyrrolidine _3_ Carboxamide hydrochloride
  • Example 16 (2S) _1 _ ⁇ “(2S, 4S.5S) _5_methyl_4 -— (piperidine-1-ylcarbonyl) pyrrolidine_2_ylcarbonyl ⁇ pyrrolidine_2_carboditrinole 4_methylbenzensulfone Acid salt
  • Example 16 (2S. 3S. 5S) _5_i “(2S) _2_cyanopyrrolidine-1-yl ⁇ carbino ⁇ _N_ethyl _N, 2-dimethylpyrrolidine _3_carboxamide 4_methylbenzene Sulfonic acid ⁇
  • Example 16 (10): (2S) _1 _ ⁇ “(2S.4S.5S) _4_ (azocan-1-ylcarbonyl) -5-methylpyrrolidine-2-yl ⁇ carbonyl ⁇ pyrrolidine_2_carbonitrinole 4 —Methinolevene zensulfonate
  • Example 16 (11): (2S) -li r (2S. 4S. 5S) _4_ (3,6-dihydropyridine_1 (2H) -ylcarbinole) _5-methylpyrrolidine-1-yl ⁇ carbinole ⁇ Pyrrolidine mono-2-carbino trinole 4-methylbenzenesulfonate
  • Example 16 (16): (2S) _1 _ “((2S, 4S.5S) _5_methyl_4 _ ⁇ “ 4- (methylsulfoninole) piperazine-1-1-yl ⁇ carbonyl ⁇ pyrrolidine-1-2-yl) carbonyl ⁇ Pyrrolidine 1-2-Carbonitorinole 4-methylbenzenesulfonate
  • Participant example 33 l_tert_butyl 2-ethynole (2S) —4.4_bis (2-hydroxyethyl) pyrrolidine-1-1.2-dicanoleboxylate
  • Triethylamine (2.8 ml) and methanesulfonyl chloride (0.8 ml) were added to a solution of the compound prepared in Reference Example 33 (609 mg) in dichloromethane (10 ml) at 0 ° C., and the mixture was stirred for 30 minutes.
  • a saturated aqueous solution of ammonium salt which was extracted with ethyl acetate.
  • the organic layer was washed with brine, dried and concentrated.
  • the residue was dissolved in N, N-dimethylformamide, potassium fluoride (532 mg) and benzylamine (lml) were added, and the mixture was stirred at 60 ° C for 6 hours.
  • the insolubles were removed by filtration, and the filtrate was concentrated.
  • the residue was dissolved in ethyl acetate, washed with saturated saline, dried and concentrated.
  • the residue was purified by column to give the title compound (324 mg).
  • Participant example 35 l_tert_butyl 2_methyl (2S.4R) _4_ (2-hydroxyethyl) pyrrolidine-li 2-dicarboxylate (a) using (2S) _N_ (tert_butoxycarbonyl) _4_oxopyrrolidine_2_carboxymethyl instead of 2-benzyl-11-tert-butyl (2S) -4-oxopyrrolidine- 1,1,2-dicarboxylate, Reference Example 12 ⁇ The procedure of Reference Example 3 was repeated to obtain [(3R, 5S) _1- (tert-butoxycarbonyl) -15_ (methoxycarbonyl) pyrrolidine-13-yl] acetic acid.
  • Reference Example 8 Reference Example 4 ⁇ Reference Example 5 ((2S) _2_cyanopyrrolidine 4_methylbenzenesulfonic acid, using the compound prepared in Reference Example 35 instead of the compound prepared in Reference Example 7 (Pyrrolidine was used in place of the salt.) ⁇ The same procedure as described in Example 1 was carried out to obtain the compound of the present invention having the following physical data.
  • Example 19 (1): (2 S, 4S) —4—Fluoro 1—ill 2 S. _4R) — 4— ⁇ 2—Hetoni mouth quichetil ⁇ Pyrrolidine 1-2-yl ⁇ carbonole ⁇ pyrrolidine 1-2-carboditrinole 4-methylbenzenesulfonate
  • Reference Example 8 Reference Example 4 ⁇ Reference Example 5 (in place of (2S) _2_cyanopyrrolidine 4_methylbenzenesulfonic acid salt) using the compound prepared in Reference Example 35 instead of the compound prepared in Reference Example 7. (2S, 4S) _2_cyano_4_fluoropyrrolidine 4_methylbenzenesulfonate was used.) ⁇ The same physical properties as those in Example 1 were obtained. The compound of the present invention was obtained.
  • Example 20 (2S. 3S. 5S) _5_i “(2S) _2_cyanopyrrolidine-1-yl ⁇ carbonyl ⁇ _2_methylpyrrolidine_3_carboxylic acid 4-methylbenzenesulfonate
  • Participant example 36 ⁇ 2 _ “(2S.3S.5S) _5_i“ (2S) _2— (aminocarbonyl) pyrrolidine_1_inole ⁇ carbinole ⁇ _l_ (tert_butoxycarbinole) one 2_methylpyrrolidine 3—Innole ⁇ —2 —Oxos
  • Participant example 37 tert_butyl (2S. 3R. 5S) _5 _ ⁇ "(2S) _2- (aminocarbonyl) pyrrolidin-1-yl ⁇ carbonyl ⁇ _3_ (2-methoxy-12-oxoxenotinole) -2_methyl Pyrrolidine_1_carboxylate
  • Example 21 2 _ ((2S, 3R.5S) _5—i “(2S) _2—cyanopyrrolidine-l-yl-carbo-norre ⁇ _2_methylpyrrolidine-l-yl) _ ⁇ , ⁇ -dimethylacetate Amide 4_methylbenzene sulfonate
  • Reference Example 4 Reference Example 5 (Dimethylamine was used in place of (2S) _2_cyanopyrrolidine 4_methylbenzenesulfonate instead of the compound prepared in Reference Example 3) ) ⁇ Reference Example 14 ⁇
  • the compound of the present invention having the following physical properties was obtained in the same manner as in the method shown in Example 1.
  • Reference Example 3 Reference Example 5 (in place of (2S) -2-cyanopyrrolidine 4-methylbenzensulfonate) using the compound prepared in Reference Example 26 or a corresponding compound instead of the compound prepared in Reference Example 2.
  • Reference Example 4 Reference Example 5 (The corresponding amine was used instead of (2S) _2-cyanopyrrolidine 4-methylbenzenesulfonate.)
  • Example 1 (4-methylbenzene Using sulfonic acid or hydrochloric acid.), The compound of the present invention was obtained.
  • Example 22 (3S.5S) -N.N_dimethyl-5_ (1_pyrrolidinylcarbonyl) -3-pipi'2zincarboxamide 4_methylbenzenesulfonate [0258] [Formula 59]
  • Example 22 (3R.5S) -N.N_dimethyl-5_ (1_pyrrolidinylcarbonyl) —3-piperidineLysincarboxamide 4 Methylbenzenesulfonate
  • Example 22 1-isobutylylyl 4-i “(3S, 5S) -5- (1-pyrrolidinylcarbonyl) -3_pyrrolidinyl ⁇ carbonyl ⁇ piperazine hydrochloride
  • Example 22 1-acetyl-4_i “(3S.5S) _5_ (1_pyrrolidinylcarbonyl) _3_pyrrolidinyl ⁇ carbonyl ⁇ pidazine hydrochloride
  • Example 22 N.N-dimethyl_3_oxo_3_ (4 _ ⁇ “(3S.5S) _5_ (1_pyrrolidinylcarbonyl) _3_pyrrolidinyl ⁇ carbonyl ⁇ _1-pidazuryl) propanamide hydrochloride
  • Example 22 (8): l- (3-methoxypropanoyl) -4- (3S, 5S) _5_ (1-pyrrolidinylcarbonyl) -1-3-pyrrolidinyl ⁇ carbonyl ⁇ piperazine hydrochloride
  • Example 22 (9): 1- (methoxyacetyl) -4- (3S, 5S) -5- (l-pyrrolidinylcarbonyl) -1_3-pyrrolidinyl ⁇ carbonyl ⁇ piperazine hydrochloride
  • Example 22 (12): 2_methyl_5 _ ⁇ “(35.5S) _5_ (1_pyrrolidinylcarbonyl) -3-pyrrolidinylcarbonyl ⁇ _4.5.6. 7-tetrahydro“ 1.3 ⁇ thiazolo ”4 , 5_c pyridine hydrochloride
  • Participant example 37 1- (1,1-dimethylethyl) 2-ethynole (2S.4R) _5_oxo_4— (phenylmethyl) oxy] methyl ⁇ pyrrolidine-1,2-dicarboxylate (compound C) and
  • lithium hexamethyldisilazane (( ⁇ ⁇ 0 ⁇ tetrahydrofuran solution, 22 mL) was added at _78 ° C at a temperature of 78 ° C with tetrahydrofuran (20 mL) / hexamethylphosphoric acid of 5-ethyl-oxo-L-prolinate (5.15 g).
  • a solution of triamide (5 mL) was added dropwise, and the mixture was stirred for 1 hour at the same temperature.
  • the reaction mixture was added to a solution of benzyloxymethyl chloride (5.5 mL) in tetrahydrofuran (10 mL) at _78 ° C under an argon atmosphere.
  • Participant example 41 (2R, 3S. 5S) _l_i “(l, 1-dimethylethyl) oxy ⁇ carbonyl ⁇ _5_“ (ethyloxy) carbonyl, _2_methylpyrrolidine-1__carboxylic acid
  • Example 25 (1): (2R.3R.5S) _5_i "(2S) _2_cyano_1_pyrrolidinyl ⁇ carbonyl ⁇ _N.N.2_trimethyl-3_pyrrolidinecarboxamide 4_methylbenzenesulfonate
  • Reference Example 37 Using the compound D prepared in Reference Example 37 in place of the compound C produced, Reference Example 38 ⁇ Reference Example 39 ⁇ Reference Example 40 ⁇ Reference Example 41 ⁇ Operating in the same manner as shown in Example 25, the following The compound of the present invention having physical properties was obtained.
  • Example 26 (1) Example 26 (4)
  • Reference Example 24 The compound prepared in Reference Example 32 was used in place of the compound prepared in (a), or the compound B prepared in Reference Example 31 was used and obtained in the same manner as in the method shown in Reference Example 32.
  • Reference Example 24 (b) Reference Example 5 ((2S)) using a compound ((2S, 4R, 5S) -41- (methoxycarbonyl) -15-methylpyrrolidine-12-potassium trifluoroacetate) The corresponding amine was used instead of _2_cyanopyrrolidine 4-methylbenzenesulfonate.) ⁇ Reference Example 4 ⁇ Reference Example 5 (instead of (2S) _2-cyanopyrrolidine 4_methylbenzenesulfonate) ⁇ A compound of the present invention was obtained in the same manner as in Example 1 (4-monomethylbenzenesulfonic acid or hydrochloric acid was used).
  • Example 26 (1): (2S. 3R. 5S) _5_i “(2R) _2_cyano_1_pyrrolidinyl ⁇ carbonyl ⁇ -N._NL 2_trimethyl-3_pyrrolidinecarboxamide 4-methylbenzenesulfonate [0266] [Formula 63]
  • the DPP4 activity inhibition experiment was performed according to the following method. DPP4 was roughly purified from human plasma by ammonium sulfate fractionation, weak anion exchange chromatography and gel filtration chromatography. A 60 ⁇ 1 / 1 / Gly-Pro-MC (glycylprolyl_7_amide_4_methyl_tamarin) aqueous solution (50 ⁇ l) serving as a substrate was mixed with the compound of the present invention (10 ⁇ l) and distilled water (20 ⁇ l). Next, a 0.5 mol / l Tris-HCl buffer (pH 7.4; 10 ⁇ l) and an enzyme solution (10 ⁇ l) were added to start the enzyme reaction.
  • the DPP4 activity inhibition rate (%) was determined by the following formula.
  • Inhibition rate (%) (1-V / V) x 100
  • the IC value was calculated according to the following equation after obtaining the slope (a) and intercept (b) of the regression line from the concentration of the compound of the present invention and the inhibition rate at two points sandwiching the inhibition rate of 50%.
  • the compound of the present invention inhibited DPP4-like activity.
  • the value of the compound of Example 1 (6) was 6.1 nM. Therefore, the compound of the present invention is useful as a therapeutic agent for type 2 diabetes. It is for.
  • Plasma containing DPP4 was prepared by centrifuging the blood of healthy volunteers or rats. In the enzymatic reaction, a 120 II mol / 1 Gly-Pro_MC aqueous solution (25 ⁇ 1) as a substrate, a compound of the present invention (10 ⁇ ) and distilled water (15 ⁇ ) are mixed, and then plasma (50 ⁇ 1) is mixed. In addition, it has begun. The change in the fluorescence intensity at 460 nm when excited at 355 nm using a fluorescent plate reader (Fmax; manufactured by Molecular Devices) was measured for 15 minutes, the initial velocity was calculated, and the plasma DPP4-like activity was determined.
  • Fmax fluorescent plate reader
  • the compound of the present invention was prepared as a 10 mmol / l DMS solution, diluted to 1 mmol / 1 with distilled water, and further diluted with a 10% DMS solution (final concentration: 10 ⁇ mol / l, 1% DMSO, 1% DMSO). From the reaction rate V in the presence of a solvent and the reaction rate V in the presence of the compound of the present invention, the DPP4-like activity inhibition rate (%) in plasma was determined by the following formula.
  • Inhibition rate (%) (1-V / V) x 100
  • the IC value was calculated according to the following equation after obtaining the slope (a) and intercept (b) of the regression line from the concentration of the compound of the present invention and the inhibition rate at two points sandwiching the inhibition rate of 50%.
  • the compound of the present invention inhibited DPP4-like activity in plasma.
  • the compound of Example 1 (6) had an IC value of 42 nM in human plasma and 58 nM in rat plasma. Therefore, the compound of the present invention is useful as a therapeutic agent for type 2 diabetes.
  • Experiment is f * DPP4 street cattle when rats were given ⁇ to beef cows.
  • Experiments SD rats (male, 5 weeks old) that had been fasted from the day before the test were used, and the compound of the present invention was 0.5% methylcellulose. It was dissolved in distilled aqueous solution and orally administered at a dose of lmg / kg.
  • Plasma 50 ⁇
  • 60 ⁇ mol / 1 Gly-Pro-MC 50 ⁇ l serving as a substrate were mixed, and the enzyme reaction was started.
  • Fluorescent plate The change in the fluorescence intensity at 460 nm when excited at 355 nm was measured for 15 minutes using a magnetic field (Fmax; manufactured by Molecular Devices), and the initial velocity was calculated to determine the DPP4-like activity.
  • Fmax magnetic field
  • the DPP4-like activity inhibition rate (%) was determined by the following formula.
  • Inhibition rate (%) (1— V / V) X 100
  • the compound of the present invention inhibits plasma DPP4-like activity for a long time.
  • the compound of Example 1 (6) showed 96% inhibition after 6 hours and 42% after 24 hours. Therefore, the compound of the present invention is useful as a persistent therapeutic drug for diabetes.
  • a sugar of lg / kg body weight was dissolved in water for injection in the Japanese Pharmacopoeia, and orally administered at a concentration of 5 ml / kg 30 minutes after administration of the compound of the present invention or a 0.5% aqueous solution of methylcellulose in distilled water.
  • blood was collected from the tail vein using capillaries treated with palin. The obtained blood was immediately centrifuged at 12,000 ⁇ m for 3 minutes at 4 ° C. Plasma was obtained and frozen on dry ice.
  • Blood glucose (mgZdl) was measured by taking 2.5 ⁇ L of plasma in a 96-well plate and using a blood glucose measurement kit: Diacolor GC TM (manufactured by Ono Pharmaceutical Co., Ltd.).
  • antibody-reactive insulin (IRI) in plasma was measured using an insulin measurement ELISA kit (manufactured by Morinaga Biochemical Laboratory).
  • the compound of the present invention suppressed an increase in blood glucose level and showed high insulin secretion promoting ability.
  • the compound of Example 1 (6) by oral administration of 0.1 mg / kg, increased insulin secretion 15 minutes after glucose load by 27% compared with the vehicle control group, and showed a 30% increase in blood glucose level 30 minutes after glucose load. The increase was suppressed by 40% compared to the vehicle control group. Therefore, the compound of the present invention is useful for treating type 2 diabetes. Useful as a therapeutic.
  • the present invention can be applied to the following pharmaceuticals.
  • the compound of the present invention represented by the general formula (I) has DPP4 inhibitory activity, it can be used for, for example, diabetes mellitus (particularly type 2 diabetes, postprandial hyperglycemia, etc.), obesity, autoimmune disease, cancer metastasis, HIV infection , Infertility, anemia, thrombocytopenia, wound, skin disease, prostatic hypertrophy, hyperlipidemia, syndrome X, diabetes complications, hyperglycerinemia, arteriosclerosis, impaired glucose tolerance, polycystic ovary syndrome, growth It is useful as a therapeutic and / or prophylactic agent for diseases such as disorders, arthritis, transplant rejection, and enteritis.
  • diabetes mellitus particularly type 2 diabetes, postprandial hyperglycemia, etc.
  • obesity autoimmune disease
  • cancer metastasis HIV infection
  • Infertility anemia
  • thrombocytopenia wound
  • skin disease skin disease
  • prostatic hypertrophy hyperlipidemia
  • syndrome X diabetes complications
  • hyperglycerinemia ar

Abstract

[PROBLÈMES] Fournir des composés présentant des activités d'inhibition de la dipeptidase DPP4 et étant utiles en tant qu'agents thérapeutiques et/ou préventifs pour des maladies dans lesquelles intervient la DPP4. [MOYENS POUR RÉSOUDRE LES PROBLÈMES] Des composés représentés par la formule générale (I), des sels, des solvates, ou des N-oxydes ou autres et des promédicaments de ceux-ci : la formule (I) (dans laquelle R représente de l'hydrogène ou un cyano, R1a, R1b, R1c, R1d et Rx représentent chacun de l'hydrogène ou un groupe substituant et où n est un nombre entier de 0 à 7). Les composés représentés par la formule générale (I) les sels, les solvates, ou les N-oxydes ou autres et des promédicaments de ceux-ci comportent des activités d'inhibition de la dipeptidase DPP4 et sont de ce fait utiles en tant qu'agents thérapeutiques et/ou préventifs pour les maladies dans lesquelles intervient la DPP4, par exemple des diabètes ( tels que l'hyperglycémie postprandiale et les diabètes de type II).
PCT/JP2005/000999 2004-01-29 2005-01-26 Dérivés de pyrrolidine WO2005073186A1 (fr)

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WO2006073167A1 (fr) * 2005-01-07 2006-07-13 Ono Pharmaceutical Co., Ltd. Derives de la pyrrolidine
WO2007072083A1 (fr) 2005-12-23 2007-06-28 Prosidion Limited Traitement du diabete de type 2 par combinaison d'un inhibiteur de dpiv a de la metformine ou de la thiazolidinedione
US7348346B2 (en) 2004-03-08 2008-03-25 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
TWI385171B (en) * 2009-03-13 2013-02-11 Pyrrolidine compounds
US8551524B2 (en) 2008-03-14 2013-10-08 Iycus, Llc Anti-diabetic combinations
WO2014206257A1 (fr) * 2013-06-26 2014-12-31 浙江九洲药业股份有限公司 Procédé de préparation de dérivés d'acide pyrrolidine-2-carboxylique
CN104447479A (zh) * 2015-01-13 2015-03-25 佛山市赛维斯医药科技有限公司 含金刚烷和酰胺类衍生物、其制备方法和用途
CN104447478A (zh) * 2015-01-13 2015-03-25 佛山市赛维斯医药科技有限公司 一种含腈基金刚烷和酰胺结构的衍生物、其制备方法和用途
CN104478778A (zh) * 2015-01-13 2015-04-01 佛山市赛维斯医药科技有限公司 金刚烷酰胺类衍生物、其制备方法和用途
CN104478777A (zh) * 2015-01-13 2015-04-01 佛山市赛维斯医药科技有限公司 一种含硝基金刚烷和酰胺结构的衍生物、其制备方法和用途
CN104496876A (zh) * 2015-01-13 2015-04-08 佛山市赛维斯医药科技有限公司 一种羟基金刚烷酰胺衍生物、其制备方法和用途
JP2016517412A (ja) * 2013-03-13 2016-06-16 フォーマ セラピューティクス，インコーポレイテッド Ｆａｓｎを阻害するための新規化合物および組成物
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US7348346B2 (en) 2004-03-08 2008-03-25 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US7671076B2 (en) 2004-03-08 2010-03-02 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
WO2006073167A1 (fr) * 2005-01-07 2006-07-13 Ono Pharmaceutical Co., Ltd. Derives de la pyrrolidine
WO2007072083A1 (fr) 2005-12-23 2007-06-28 Prosidion Limited Traitement du diabete de type 2 par combinaison d'un inhibiteur de dpiv a de la metformine ou de la thiazolidinedione
US8551524B2 (en) 2008-03-14 2013-10-08 Iycus, Llc Anti-diabetic combinations
TWI385171B (en) * 2009-03-13 2013-02-11 Pyrrolidine compounds
US10457655B2 (en) 2013-03-13 2019-10-29 Forma Therapeutics, Inc. Compounds and compositions for inhibition of FASN
US10472342B2 (en) 2013-03-13 2019-11-12 Forma Therapeutics, Inc. Compounds and compositions for inhibition of FASN
US10995078B2 (en) 2013-03-13 2021-05-04 Forma Therapeutics, Inc. Compounds and compositions for inhibition of FASN
US10800750B2 (en) 2013-03-13 2020-10-13 Forma Therapeutics, Inc. Compounds and compositions for inhibition of FASN
US10450286B2 (en) 2013-03-13 2019-10-22 Forma Therapeutics, Inc. Compounds and compositions for inhibition of FASN
US10399951B2 (en) 2013-03-13 2019-09-03 Forma Therapeutics, Inc. Compounds and compositions for inhibition of FASN
JP2016517412A (ja) * 2013-03-13 2016-06-16 フォーマ セラピューティクス，インコーポレイテッド Ｆａｓｎを阻害するための新規化合物および組成物
JP2019048833A (ja) * 2013-03-13 2019-03-28 フォーマ セラピューティクス，インコーポレイテッド Ｆａｓｎを阻害するための新規化合物および組成物
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WO2014206257A1 (fr) * 2013-06-26 2014-12-31 浙江九洲药业股份有限公司 Procédé de préparation de dérivés d'acide pyrrolidine-2-carboxylique
CN104478777B (zh) * 2015-01-13 2016-08-24 佛山市赛维斯医药科技有限公司 一种含硝基金刚烷和酰胺结构的衍生物、其制备方法和用途
CN104496876A (zh) * 2015-01-13 2015-04-08 佛山市赛维斯医药科技有限公司 一种羟基金刚烷酰胺衍生物、其制备方法和用途
CN104478777A (zh) * 2015-01-13 2015-04-01 佛山市赛维斯医药科技有限公司 一种含硝基金刚烷和酰胺结构的衍生物、其制备方法和用途
CN104447479A (zh) * 2015-01-13 2015-03-25 佛山市赛维斯医药科技有限公司 含金刚烷和酰胺类衍生物、其制备方法和用途
CN104478778A (zh) * 2015-01-13 2015-04-01 佛山市赛维斯医药科技有限公司 金刚烷酰胺类衍生物、其制备方法和用途
CN104447478A (zh) * 2015-01-13 2015-03-25 佛山市赛维斯医药科技有限公司 一种含腈基金刚烷和酰胺结构的衍生物、其制备方法和用途
US10875848B2 (en) 2018-10-10 2020-12-29 Forma Therapeutics, Inc. Inhibiting fatty acid synthase (FASN)
US11299484B2 (en) 2018-10-10 2022-04-12 Forma Therapeutics, Inc. Inhibiting fatty acid synthase (FASN)
US10793554B2 (en) 2018-10-29 2020-10-06 Forma Therapeutics, Inc. Solid forms of 4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
US11267805B2 (en) 2018-10-29 2022-03-08 Forma Therapeutics, Inc. Solid forms of (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl) piperazine-1-yl)(1-hydroxycyclopropyl)methanone

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