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WO2017135471A1 - INHIBITEUR DE L'INTÉGRINE α4β7 - Google Patents

INHIBITEUR DE L'INTÉGRINE α4β7 Download PDF

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Publication number
WO2017135471A1
WO2017135471A1 PCT/JP2017/004277 JP2017004277W WO2017135471A1 WO 2017135471 A1 WO2017135471 A1 WO 2017135471A1 JP 2017004277 W JP2017004277 W JP 2017004277W WO 2017135471 A1 WO2017135471 A1 WO 2017135471A1
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Prior art keywords
group
substituent
lower alkyl
alkyl group
pharmaceutically acceptable
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PCT/JP2017/004277
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English (en)
Japanese (ja)
Inventor
宗孝 徳増
昌嗣 野口
瑞季 川平
佳奈 岩▲崎▼
敦彦 早川
渉 宮永
友希 斎藤
唯 山浦
綾俊 安藤
敦 鶴田
美里 野口
Original Assignee
Ｅａファーマ株式会社
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Publication of WO2017135471A1 publication Critical patent/WO2017135471A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the present invention relates to a sulfonamide derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing these compounds as active ingredients.
  • the present invention relates to a compound useful as a therapeutic or prophylactic agent for inflammatory diseases in which an ⁇ 4 integrin-dependent adhesion process is involved in the disease state.
  • Patent Document 1 discloses a phenylalanine derivative represented by the following formula or a pharmaceutically acceptable salt thereof, and a typical compound thereof has the following chemical structure.
  • Patent Document 1 shows the results of VCAM inhibitory activity (VCAM-1 / ⁇ 4 ⁇ 1 binding assay) and (VCAM-1 / ⁇ 4 ⁇ 7 binding assay).
  • Patent Document 2 discloses a phenylalanine derivative represented by the following formula having a terminal R12 (R13) N—X1-group or a pharmaceutically acceptable salt thereof. This compound has been shown to have a higher VCAM-1 / ⁇ 4 ⁇ 1 integrin inhibitory activity in the presence of serum than the compound of Example 1 of Patent Document 1.
  • Patent Document 3 also discloses a compound having an ⁇ 4 integrin inhibitory action.
  • Patent Document 4 (WO2005 / 077915) describes a phenylalanine derivative having an ⁇ 4 integrin inhibitory action as represented by the following formula, but a 2,6-dichlorobenzoyl group or amino acid residue is present at the N-terminus of phenylalanine. A group is bound.
  • Patent Document 5 Japanese Patent Application Laid-Open No. 2003-321358 describes a phenylalanine derivative having an ⁇ 4 integrin inhibitory activity represented by the following formula. Are joined.
  • Patent Document 6 (WO01 / 56994) describes a phenylalanine derivative having an ⁇ 4 integrin inhibitory action represented by the following formula, and proline and the like are bonded to the N-terminus of phenylalanine.
  • Patent Document 7 (WO 2006/127584) describes a phenylalanine derivative having an ⁇ 4 integrin inhibitory action represented by the following formula, and a pyrimidine ring or the like is directly bonded to the N-terminus of phenylalanine.
  • Patent Document 8 (WO01 / 42215) describes a phenylalanine derivative having an ⁇ 4 integrin inhibitory action represented by the following formula, and the phenylalanine has an N-terminus such as a 2-chloro-6-methylbenzoyl group.
  • Patent Document 9 (WO2013 / 161904) describes a phenylalanine derivative having an ⁇ 4 ⁇ 7 integrin inhibitory action represented by the following formula. This document shows the results of a VCAM-1 / ⁇ 4 ⁇ 1 integrin binding inhibitory activity evaluation of a specific phenylalanine derivative and a MAdCAM-1 / ⁇ 4 ⁇ 7 integrin binding inhibitory activity evaluation test in the presence of serum. Has a low effect and is described as having a high effect on ⁇ 4 ⁇ 7 integrin.
  • Patent Document 10 (WO2015 / 064580) describes a phenylalanine derivative having an ⁇ 4 ⁇ 7 integrin inhibitory action represented by the following formula. This document also shows the results of VCAM-1 / ⁇ 4 ⁇ 1 integrin binding inhibitory activity evaluation of specific phenylalanine derivatives and MAdCAM-1 / ⁇ 4 ⁇ 7 integrin binding inhibitory activity evaluation test in the presence of serum. Has a low effect and is described as having a high effect on ⁇ 4 ⁇ 7 integrin.
  • An object of the present invention is to provide a novel compound having a chemical structural formula that has not been known so far and having an excellent ⁇ 4 integrin inhibitory action.
  • an object of the present invention is to provide a novel compound having an ⁇ 4 integrin inhibitory action with high selectivity, which has a low effect on ⁇ 4 ⁇ 1 and a high effect on ⁇ 4 ⁇ 7.
  • Another object of the present invention is to provide a compound having an excellent ⁇ 4 integrin inhibitory action that can be administered orally.
  • Another object of the present invention is to provide a compound having an ⁇ 4 integrin inhibitory activity excellent in safety.
  • Another object of the present invention is to provide a compound having a long-lasting ⁇ 4 integrin inhibitory activity.
  • Another object of the present invention is to provide a novel compound having an excellent ⁇ 4 integrin inhibitory action in human whole blood. Another object of the present invention is to provide a pharmaceutical composition containing the above novel compound and a pharmaceutically acceptable carrier. Another object of the present invention is to provide a medicament containing the novel compound. Another object of the present invention is to provide a therapeutic or prophylactic agent for inflammatory diseases in which an ⁇ 4 ⁇ 7 integrin-dependent adhesion process is involved in the disease state. Another object of the present invention is to provide an ⁇ 4 integrin inhibitor.
  • the present inventors examined the inhibitory activity of ⁇ 4 ⁇ 7 integrin in human whole blood for compounds having various structures. As a result, a sulfonamide derivative having a specific chemical structure having a heterocyclic group having an aminocarbonyl group as a substituent or a sulfonamide group to which a phenyl group is bonded or a pharmaceutically acceptable salt thereof is excellent in human whole blood. It was found to have ⁇ 4 ⁇ 7 integrin inhibitory activity.
  • a sulfonamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof (In the formula Represents a single bond or a double bond, R 1 and R 2 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, lower alkenyl group, a lower alkoxy group, a lower alkoxy-lower alkyl group, hydroxy group, or a hydroxy lower alkyl group, R 1 And R 2 are bonded to each other to form a benzene ring which may have a substituent, an alicyclic hydrocarbon having 4 to 7 carbon atoms which may have a substituent, or a heteroaryl ring which may have a substituent Or may form a heterocyclic ring which may have a substituent, R 3 represents a lower alkyl group, e, f, g, and h each independently represent C—H or a nitrogen
  • a heteroaryl ring or a hetero ring that may have a substituent is a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, an amino group, a lower alkylamino group, and
  • R 1 and R 2 each independently represent a hydrogen atom, a lower alkyl group, or a lower alkoxymethyl group, and R 1 and R 2 may be bonded to each other to have a substituent.
  • the alicyclic hydrocarbon of formula 4 to 7, a heteroaryl ring which may have a substituent, or a heterocycle which may have a substituent may be formed, and the substituent is a lower alkyl group
  • R 1 and R 2 are bonded to each other to have a cyclohexene which may have a substituent, pyridine which may have a substituent, dihydropyran which may have a substituent, or a substituent.
  • a tetrahydropyridine may be formed, and the substituent is selected from a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, an amino group, a lower alkylamino group, and a lower alkylamino lower alkyl group,
  • the sulfonamide derivative according to 1] or [2], or a pharmaceutically acceptable salt thereof is selected from a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, an amino group, a lower alkylamino group, and a lower alkylamino lower alkyl group.
  • D represents an benzene ring which may have a substituent, and the substituent is selected from a halogen atom, a lower alkyl group, a lower alkoxy group, and a hydroxy group. Or a pharmaceutically acceptable salt thereof.
  • R 4 and R 5 may each independently have a hydrogen atom, a lower alkyl group that may have a substituent, a lower alkenyl group that may have a substituent, or a substituent.
  • R 4 and R 5 may be bonded to form a heterocyclic group which may have a substituent, and the substituent is a lower alkyl group, a lower alkoxy group, or a hydroxy group.
  • R 4 and R 5 each independently represent a hydrogen atom, a lower alkyl group which may have a substituent, or a heterocyclic group which may have a substituent, wherein the substituent is , A halogen atom, a cyano group, a hydroxy group, a lower alkoxy group, a trifluoromethyl group, and a heterocyclic group, R 4 and R 5 may be bonded to each other to have a lower alkyl group as a substituent.
  • R 1 and R 2 each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a lower alkoxy lower alkyl group, and R 1 and R 2 are bonded to form a carbon number of 4 to 7 alicyclic hydrocarbons, heteroaryl rings, or heterocycles that may be substituted with lower alkyl groups
  • D represents a benzene ring or a heteroaryl ring which may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a hydroxy group
  • R 4 and R 5 are each independently Represents a hydrogen atom or a lower alkyl group which may have a substituent selected from the group consisting of a lower alkoxy group, a heterocyclic group, a
  • a novel compound having a chemical structural formula that has not been known so far and having an excellent ⁇ 4 integrin inhibitory action is provided.
  • the present invention also provides a compound having an excellent ⁇ 4 integrin inhibitory action that can be administered orally.
  • a compound having ⁇ 4 integrin inhibitory activity excellent in safety is also provided.
  • a compound having a long-lasting ⁇ 4 integrin inhibitory activity is also provided.
  • the present invention also provides a novel compound having an excellent ⁇ 4 integrin inhibitory action in human blood.
  • a pharmaceutical composition comprising the novel compound and a pharmaceutically acceptable carrier.
  • the pharmaceutical containing the said novel compound is also provided.
  • the present invention also provides a therapeutic or prophylactic agent for inflammatory diseases in which an ⁇ 4 ⁇ 7 integrin-dependent adhesion process is involved in the disease state.
  • an ⁇ 4 integrin inhibitor is also provided.
  • substituent means “substituted or unsubstituted”.
  • position and number of substituents are arbitrary and are not particularly limited. When substituted with two or more substituents, these substituents may be the same or different.
  • substituents include a halogen atom, a nitro group, a cyano group, a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkylthio group, a hydroxy lower alkyl group, a hydroxy lower alkenyl group, and a hydroxy lower group.
  • the term “lower” means a group having 1 to 6 carbon atoms
  • the “lower alkyl group” means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms.
  • the “lower alkenyl group” refers to a linear or branched alkenyl group having 2 to 6 carbon atoms including each isomer. Examples thereof include a vinyl group, an allyl group, a propenyl group, a butenyl group, a pentenyl group, and a hexenyl group, and a vinyl group, an allyl group, and a propenyl group are preferable.
  • the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and preferably a fluorine atom and a chlorine atom.
  • the “lower alkoxy group” refers to an alkoxy group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms.
  • methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentyloxy group, n-hexyloxy group isopropoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, cyclopropyloxy Group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group, and a methoxy group, an ethoxy group, and an n-propoxy group are preferable.
  • lower alkoxymethyl group refers to a methyl group that is mono-substituted or further substituted with the above-mentioned “lower alkoxy group”. Examples thereof include a methoxymethyl group, an ethoxymethyl group, an isopropoxymethyl group, a tert-butoxymethyl group, and the like, and a methoxymethyl group and an ethoxymethyl group are preferable.
  • hydroxy lower alkyl group refers to a lower alkyl group substituted with a hydroxyl group, and examples thereof include a hydroxymethyl group and a hydroxyethyl group, and a hydroxymethyl group is preferred.
  • lower alkylamino lower alkyl group refers to a lower alkyl group substituted with the above-mentioned “lower alkyl group” mono- or di-substituted amino group.
  • Examples include a methylaminomethyl group, an ethylaminomethyl group, a propylaminomethyl group, an isopropylaminomethyl group, a methylaminoethyl group, an ethylaminoethyl group, a dimethylaminomethyl group, and a methylethylaminomethyl group, preferably methyl An aminomethyl group, an ethylaminomethyl group, and a methylaminoethyl group;
  • the “alicyclic hydrocarbon” refers to a cyclic structure composed of carbon atoms and hydrogen atoms, and includes cycloalkanes that are all formed by single bonds and cycloalkenes that may contain double bonds.
  • cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclohexene and the like can be mentioned, and cyclohexane and cyclohexene are preferable.
  • heteroaryl ring refers to a 4- to 10-membered aromatic ring containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring atoms.
  • Heterocycle refers to a 4- to 10-membered monocyclic to bicyclic heterocycle containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring atoms.
  • any carbon atom which is a ring atom may be substituted with an oxo group, and a sulfur atom or a nitrogen atom may be oxidized to form an oxide. Further, it may be condensed with a benzene ring.
  • Heterocyclic group refers to a 4- to 10-membered monocyclic to bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring atoms. .
  • any carbon atom which is a ring atom may be substituted with an oxo group, and a sulfur atom or a nitrogen atom may be oxidized to form an oxide. Further, it may be condensed with a benzene ring.
  • the sulfonamide derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is preferably the following:
  • R 1 and R 2 are each independently preferably a hydrogen atom, a lower alkyl group or a lower alkoxymethyl group, more preferably a hydrogen atom or a lower alkyl group, a hydrogen atom or a methyl group. Is particularly preferred.
  • the ring formed by combining R 1 and R 2 is preferably pyridine, cyclohexene, dihydropyran and tetrahydropyridine, more preferably cyclohexene, dihydropyran and tetrahydropyridine, and dihydropyran.
  • R 3 is preferably a lower alkyl group, particularly preferably a methyl group.
  • e, f, g and h are preferably C—H 2 or a nitrogen atom, more preferably any one is a nitrogen atom, and particularly preferably e or f is a nitrogen atom. preferable.
  • B is preferably a hydroxy group or a lower alkoxy group, more preferably a hydroxy group, a methoxy group, an ethoxy group, an isopropoxy group, or a cyclohexyl group, and a hydroxy group, a methoxy group, an ethoxy group, or an isopropoxy group.
  • D is preferably a benzene ring which may have a substituent or a heteroaryl ring which may have a substituent, more preferably a benzene ring or a pyridine ring, and particularly preferably a benzene ring.
  • the substituent of D is preferably a halogen atom, a lower alkyl group, a lower alkoxy group or a hydroxy group, more preferably a fluorine atom, a methyl group, a methoxy group or a hydroxy group.
  • D when D represents a benzene ring or a pyridine ring, the substitution position of the aminosulfonyl group and aminocarbonyl group bonded to D is preferably the para position.
  • R 4 and R 5 are each independently a lower alkyl group which may have a substituent or a heterocyclic group which may have a substituent, preferably a methyl group or an ethyl group.
  • the substituents of R 4 and R 5 are preferably a methoxy group, a morpholino group, a trifluoromethyl group, a hydroxy group or a cyano group, and particularly preferably a morpholino group, a trifluoromethyl group or a cyano group.
  • the ring formed by combining R 4 and R 5 is preferably a heterocyclic ring which may have a substituent, and morpholine and piperazine are particularly preferable.
  • R 1 and R 2 each independently represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a lower alkoxy lower alkyl group, and R 1 and R 2 are bonded to form an alicyclic group having 4 to 7 carbon atoms.
  • D represents a benzene ring or a heteroaryl ring which may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a hydroxy group
  • R 4 and R 5 are each independently Represents a hydrogen atom or a lower alkyl group which may have a substituent selected from the group consisting of a lower alkoxy group, a heterocyclic group, a hydroxy group, a cyano group and a halogen atom, provided that R 4 and R 4 5 may be bonded to form a heterocyclic group which may be substituted with a lower alkyl group;
  • R 1 and R 2 each represent a lower alkyl group
  • D is a benzene ring having a substituent selected from the group consisting of a halogen atom
  • R 4 and R 5 are each independently Represents a hydrogen atom or a lower alkyl group which may have a substituent
  • the salt may be pharmaceutically acceptable, for example, for an acidic group such as a carboxyl group in the formula
  • Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, organic salts such as aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine and dicyclohexylamine Examples thereof include salts with amines and salts with basic amino acids such as arginine and lysine.
  • salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid
  • organic carboxylic acids such as acids and salts with organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid.
  • a method for forming a salt a compound of the general formula (I) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersing agent, or cation exchange or anion is performed based on other salt forms. It can also be obtained by ion exchange.
  • the compound of the present invention may also contain a solvate of the compound represented by the general formula (I), for example, a hydrate, an alcohol adduct and the like.
  • the compound of the present invention includes a prodrug form of the compound represented by formula (I).
  • the prodrug of the compound of the present invention is a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, enzymatically causes oxidation, reduction, hydrolysis, etc.
  • the prodrug of the compound represented by the general formula (I) are not limited to those exemplified in the compounds of Examples.
  • the prodrug may be a compound in which the amino group is acylated, alkylated or phosphorylated (eg, a compound represented by the general formula (I)
  • examples thereof include methylated, tert-butylated compounds, etc.
  • the prodrug includes acylated, alkylated, phosphorylated, borated.
  • the compound represented by the general formula (I) is acetylated, palmitoylated, propano
  • a compound having a carboxy group as a prodrug such as a compound having a carboxy group, and a pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compound, etc.
  • the prodrug includes a compound in which the carboxy group is esterified with a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms. These compounds are preferably represented by the formula (I) by a method known per se. ).
  • the prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. There may be.
  • the present invention includes all isotopes of the compounds represented by formula (I).
  • the isotope of the compound of the present invention is one in which at least one atom is substituted with an atom having the same atomic number (number of protons) and a different mass number (sum of the number of protons and neutrons).
  • Examples of isotopes contained in the present compound a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, include a chlorine atom, respectively, 2 H, 3 H, 13 C , 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, and the like.
  • unstable radioisotopes that emit radioactivity and emit neutrons are useful in tests of tissue distribution of drugs or compounds.
  • Stable isotopes can be used safely because they do not decay, their abundances are almost unchanged, and there is no radioactivity.
  • the isotope of the compound of the present invention can be converted according to a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope.
  • the compound represented by the general formula (I) or a salt thereof is administered as it is or as various pharmaceutical compositions.
  • a dosage form of such a pharmaceutical composition for example, it may be a tablet, powder, pill, granule, capsule, suppository, solution, sugar coating, devoted, or syrup, and a usual formulation aid.
  • tablets may contain phenylalanine derivatives, which are the active ingredients of the present invention, known auxiliary substances such as inert diluents such as lactose, calcium carbonate or calcium phosphate, binders such as gum arabic, corn starch or gelatin, alginic acid, corn starch or the like Gelatinized starch and other leavening agents, sweeteners such as sucrose, lactose and saccharin, flavoring agents such as peppermint, red mono oil and cherry, lubricants such as magnesium stearate, talc and carboxymethylcellulose, fats, waxes and semi-solids And liquid gelatin, soft gelatin capsules such as natural or hardened oils and excipients for suppositories, water, alcohol, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Obtained by.
  • inert diluents such as lactose, calcium carbonate or calcium phosphate
  • binders such as gum
  • An inhibitor comprising a compound represented by the general formula (I) or a salt thereof as an active ingredient can be used as a therapeutic or prophylactic agent for inflammatory diseases in which an ⁇ 4 integrin-dependent adhesion process is involved in the pathological state.
  • inflammatory diseases include, for example, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis, Sjogren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular disease, arteriosclerosis, relapse Examples include stenosis, tumor growth, tumor metastasis, transplant rejection, and / or human immunodeficiency virus infection (see Non-Patent Document 1).
  • the dose to be used for the above purpose is determined by the intended therapeutic effect, administration method, treatment period, age, weight, etc., but it is usually given orally as a daily dose for adults by the oral or parenteral route.
  • administration 1 ⁇ g to 5 g may be used, and in the case of parenteral administration, 0.01 ⁇ g to 1 g may be used.
  • an aminocarbonyl group is provided as a substituent of D.
  • excellent ⁇ 4 ⁇ 7 integrin inhibitory activity can be obtained in human whole blood.
  • the sulfonamide derivative of the present invention has a high concentration to the portal vein and the amount of exposure in the circulating blood increases, a stronger effect can be obtained. From this viewpoint, the ⁇ 4 ⁇ 7 integrin-dependent adhesion process is useful as a therapeutic or prophylactic agent for inflammatory diseases in which the disease state is involved.
  • the 2-position and 5-position of phenyl in the phenylalanine moiety are substituted with fluorine atoms.
  • the compound represented by the general formula (I) of the present invention includes, for example, an intermediate having a carboxyl group at the terminal represented by the general formula (MI) and an amino group at the terminal represented by the general formula (M-II). And an intermediate having an amidation reaction.
  • the amidation reaction is known, and examples thereof include (1) a method using a condensing agent and (2) a method using an acid halide.
  • a method using a condensing agent is, for example, a method in which a carboxylic acid and an amine or a salt thereof are mixed with, for example, dichloromethane, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF) or acetonitrile.
  • a solvent that does not adversely influence the reaction for example, in the presence or absence of a base such as pyridine, triethylamine or N, N-diisopropylethylamine, for example, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7
  • condensation aids such as azabenzotriazole (HOAt) or N-hydroxysuccinimide (HOSu), for example 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide (WSC) ), 1,3-dicyclohexylcarbodiimide (DCC)
  • DCC 1,3-dicyclohexylcarbodiimide
  • 7-azabenzotriazole-1-yl) -N, N, N ' is carried out by reacting with a condensing agent such as N'- tetramethyluronium hexafluorophosphate (HATU).
  • a condensing agent such as N'- t
  • the carboxylic acid is used in a solvent that does not adversely influence the reaction, such as dichloromethane, or in the absence or presence of a catalyst such as DMF in the absence of a solvent.
  • a solvent that does not adversely influence the reaction such as dichloromethane, or in the absence or presence of a catalyst.
  • an acid halide obtained by reacting with thionyl chloride, oxalyl chloride, thionyl bromide, etc., for example, dichloromethane, THF, etc., in a solvent that does not adversely affect this reaction, for example, pyridine, triethylamine, or
  • the reaction is carried out by reacting with an amine or a salt thereof in the presence of a base such as N, N-diisopropylethylamine.
  • the intermediate having a carboxyl group at the terminal represented by the general formula (MI) can be produced, for example, by the following method.
  • the production method of a representative compound among the intermediates having a carboxyl group at the terminal represented by the general formula (MI) which is the compound of the present invention is shown below.
  • D is a phenyl group that may have a substituent selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, and a halogen atom, or a pyridyl group.
  • the intermediate body (S8) which has a carboxyl group at the terminal is compoundable by using the method (manufacturing method A, B, and C) etc. which are described below, for example.
  • D 1 represents the above-described substituent represented by D, or a substituent that can be easily converted to D by an operation such as deprotection
  • R 21 represents, for example, a lower alkyl group or the like.
  • X 1 represents a halogen atom such as chlorine, bromine or iodine, or a leaving group such as trifluoromethanesulfonyloxy group.
  • the sulfonyl chloride derivative (S1) and the aniline derivative (S2) are reacted in a solvent that does not adversely affect the reaction such as dichloromethane, acetonitrile, THF, or DMF, for example, in the presence of a base such as pyridine or triethylamine.
  • a base such as pyridine or triethylamine.
  • the obtained sulfonamide derivative (S3) is obtained in the presence of a base such as triethylamine or N, N-diisopropylethylamine in a solvent that does not adversely affect the reaction such as DMF or N-methylpyrrolidone (NMP).
  • the aldehyde derivative (S4) can be synthesized by performing a coupling reaction in a carbon dioxide atmosphere using a metal catalyst such as 1,1′-bis (diphenylphosphinoferrocene) dichloropalladium (II).
  • the obtained aldehyde derivative (S4) can synthesize a carboxylic acid derivative (S5) by performing an oxidation reaction such as Pinnick oxidation.
  • a base such as triethylamine or N, N-diisopropylethylamine
  • a condensation aid such as HOBt, HOAt or HOSu, for example, WSC
  • a condensing agent such as DCC or HATU
  • the amide derivative (S7) is used in a solvent that does not adversely influence the reaction such as THF, 1,4-dioxane, methanol or ethanol, for example, using a base such as sodium hydroxide or lithium hydroxide.
  • the target carboxylic acid derivative (S8) can be produced by performing alkaline hydrolysis or acid hydrolysis using, for example, hydrochloric acid or trifluoroacetic acid.
  • D 1 represents the above-described substituent represented by D, or a substituent that can be easily converted to D by an operation such as deprotection
  • R 21 represents, for example, a lower alkyl group or the like.
  • the sulfonyl chloride derivative (S9) and the aniline derivative (S2) are reacted in a solvent that does not adversely affect the reaction such as dichloromethane, acetonitrile, THF, or DMF, for example, in the presence of a base such as pyridine or triethylamine.
  • a base such as pyridine or triethylamine.
  • the obtained sulfonamide derivative (S5) and amine derivative (S6) or a salt thereof in a solvent that does not adversely affect the reaction such as dichloromethane, THF, 1,4-dioxane, DMF or acetonitrile, for example,
  • a solvent such as dichloromethane, THF, 1,4-dioxane, DMF or acetonitrile
  • a base such as pyridine, triethylamine, or N, N-diisopropylethylamine
  • a condensation aid such as HOBt, HOAt or HOSu, for example WSC
  • a condensing agent such as DCC or HATU
  • the amide derivative (S7) is used in a solvent that does not adversely influence the reaction such as THF, 1,4-dioxane, methanol or ethanol, for example, using a base such as sodium hydroxide or lithium hydroxide.
  • the target carboxylic acid derivative (S8) can be produced by performing alkaline hydrolysis or acid hydrolysis using, for example, hydrochloric acid or trifluoroacetic acid.
  • D 1 represents the above-described substituent represented by D, or a substituent that can be easily converted to D by an operation such as deprotection
  • R 21 represents, for example, a lower alkyl group or the like.
  • the sulfonyl chloride derivative (S10) and the aniline derivative (S2) are reacted in a solvent that does not adversely influence the reaction such as dichloromethane, acetonitrile, THF, or DMF, for example, in the presence of a base such as pyridine or triethylamine.
  • a base such as pyridine or triethylamine.
  • the sulfonamide derivative (S7) is treated with a base such as sodium hydroxide or lithium hydroxide in a solvent that does not adversely affect the reaction such as THF, 1,4-dioxane, methanol or ethanol.
  • a base such as sodium hydroxide or lithium hydroxide
  • the target carboxylic acid derivative (S8) can be produced by carrying out the alkaline hydrolysis used or acid hydrolysis using, for example, hydrochloric acid or trifluoroacetic acid.
  • D is a phenyl group which may have a substituent selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group and a halogen atom, or a pyridyl group
  • the intermediate (S8) having a carboxyl group at the terminal where R 5 is a hydrogen atom can be synthesized by using, for example, the method described below (Production Method D).
  • D 1 represents the above-described substituent represented by D, or a substituent that can be easily converted to D by an operation such as deprotection
  • R 21 represents, for example, a lower alkyl group or the like.
  • X 1 represents a halogen atom such as chlorine, bromine or iodine, or a leaving group such as trifluoromethanesulfonyloxy group.
  • the halogenaryl derivative (S3) and the isocyanide reagent (S11) are mixed with, for example, a base such as cesium carbonate in a solvent that does not adversely affect the reaction such as DMSO, for example, in the presence or absence of water.
  • the tert-butylamide derivative (S12) can be synthesized by reacting in the presence using, for example, a metal catalyst such as bistriphenylphosphine dichloropalladium (II).
  • the obtained tert-butylamide derivative (S12) is used in a solvent that does not adversely influence the reaction such as THF, 1,4-dioxane, methanol or ethanol, for example, a base such as sodium hydroxide or lithium hydroxide.
  • the target carboxylic acid derivative (S8) can be produced by carrying out alkaline hydrolysis using, acid hydrolysis using, for example, hydrochloric acid or trifluoroacetic acid.
  • Each process can be synthesized by using generally replaceable reaction conditions, and should be selected in a timely manner according to the type of raw material compound.
  • the compound of the present invention obtained by the above method can be purified using techniques such as extraction, distillation, crystallization, column chromatography and the like usually used in organic synthesis.
  • the intermediate (S17) having an amino group at the terminal represented by the general formula (M-II), which is the compound of the present invention, may be produced by, for example, the following production methods (Production Methods E, F, and G). It can be synthesized by using.
  • Production Methods E, F, and G production methods
  • symbols in the formula are the same as defined in the formula (I).
  • R 31 is, for example, tert- butoxycarbonyl group, such as benzyloxycarbonyl group, for example, a substituent of the general amines which can removed by manipulation of deprotection such as, wherein X 3 is, for example, chlorine, bromine, represents a leaving group such as a halogen atom or for example, trifluoromethanesulfonyloxy group iodine, wherein B 1 represents, by operation of deprotection such, represents a readily converted can substituents B.
  • the halogenated aryl derivative (S13) and a borane derivative such as bis (pinacolato) diborane for example, in a solvent that does not adversely affect the reaction such as DMF, for example, in the presence of a base such as potassium acetate, for example,
  • a metal catalyst such as 1,1′-bis (diphenylphosphinoferrocene) dichloropalladium (II)
  • the corresponding boronic acid ester derivative is derived, and then the boronic acid obtained
  • the boronic ester is deprotected by treating the ester derivative with, for example, sodium periodate or ammonium acetate and water in a solvent that does not adversely affect the reaction, such as acetone.
  • the corresponding boronic acid derivative (S14) can be synthesized.
  • the obtained boronic acid derivative (S14) and uracil derivative (S15) are mixed with a solvent that does not adversely affect the reaction, such as dichloromethane, dimethyl sulfoxide (DMSO), or DMF, such as pyridine or triethylamine.
  • a solvent that does not adversely affect the reaction such as dichloromethane, dimethyl sulfoxide (DMSO), or DMF, such as pyridine or triethylamine.
  • the amino acid derivative (S16) can be synthesized by performing a coupling reaction using a metal catalyst such as copper (II) acetate or copper (II) trifluoromethanesulfonate in the presence of a base.
  • amino acid derivative (S16) is subjected to deprotection such as acid hydrolysis using hydrochloric acid or trifluoroacetic acid or hydrogenolysis to produce the target carboxylic acid derivative (S17). be able to.
  • R 31 is, for example, tert- butoxycarbonyl group, such as benzyloxycarbonyl group, for example, a substituent of the general amines which can removed by manipulation of deprotection such as, wherein R 32 and R 33 Each independently represents, for example, a lower alkyl group or a substituent of a general ester such as a benzene ring which may have a substituent, wherein B 1 is converted to B by an operation such as deprotection. Represents a substituent that can be easily converted.
  • the nitro derivative (S18) is, for example, a catalytic reduction reaction using a metal catalyst such as palladium carbon, palladium hydroxide, or Raney nickel in a solvent that does not adversely affect the reaction such as methanol, ethanol, or isopropyl alcohol.
  • a metal catalyst such as palladium carbon, palladium hydroxide, or Raney nickel in a solvent that does not adversely affect the reaction such as methanol, ethanol, or isopropyl alcohol.
  • the aniline derivative (S19) can be synthesized by reacting a metal such as zinc under acidic conditions (for example, hydrochloric acid, acetic acid, or ammonium chloride).
  • the obtained aniline derivative (S19) and carbamate derivative (S20) are mixed with triethylamine, pyridine, or diaza in a solvent that does not adversely affect the reaction, such as dichloromethane, 1,4-dioxane, THF, or DMF.
  • the amino acid derivative (S16) can be synthesized by reacting with a base such as bicycloundecene (DBU).
  • DBU bicycloundecene
  • the target carboxylic acid derivative (S17) is produced by deprotecting the amino acid derivative (S16) by, for example, acid hydrolysis using hydrochloric acid or trifluoroacetic acid or hydrogenolysis. Can do.
  • R 31 represents a general amine substituent which can be removed by an operation such as deprotection, for example, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, etc., wherein X 3 , X 4 and X 5 each independently represents, for example, a halogen atom such as chlorine, bromine, iodine or the like, or a leaving group such as trifluoromethanesulfonyloxy group, wherein B 1 represents B by the operation such as deprotection.
  • halogenated aryl derivative (S21) and the uracil derivative (S15) are mixed in a solvent that does not adversely influence the reaction, such as DMSO, NMP, or DMF, for example, triethylamine, N, N-diisopropylethylamine, DBU, or the like.
  • a solvent that does not adversely influence the reaction such as DMSO, NMP, or DMF, for example, triethylamine, N, N-diisopropylethylamine, DBU, or the like.
  • a compound (S22) is synthesized by performing a coupling reaction using a metal catalyst such as copper (I) iodide, copper (I) bromide, or copper (I) chloride. Can do.
  • the obtained compound (S22) and halide (S23) are treated with, for example, tris (di-acid) in the presence of zinc powder activated with, for example, iodine in a solvent that does not adversely affect the reaction such as DMF.
  • a metal catalyst such as benzylideneacetone
  • dipalladium (0) dipalladium (0)
  • a ligand commonly used in organic synthesis such as 2-dicyclohexyl-2 ′, 6′-dimethoxybiphenyl (SPhos).
  • amino acid derivative (S16) is subjected to deprotection such as acid hydrolysis using hydrochloric acid or trifluoroacetic acid or hydrogenolysis to produce the target carboxylic acid derivative (S17). be able to.
  • reaction solution was adjusted to about pH 6 with 2M hydrochloric acid, and extracted with ethyl acetate. After washing with saturated brine and drying over anhydrous magnesium sulfate, the residue was slurry washed with acetonitrile to give the title compound (0.56 g, quant.).
  • the compounds of [Synthesis Example 9], [Synthesis Example 10], [Synthesis Example 22], and [Synthesis Example 27] are methyl 4-amino-2, 5-difluoro in [Synthesis Example 1] (Step 1). It can be synthesized in the same manner as the compound of [Synthesis Example 1] by allowing 5-benzopyridin-2-sulfonyl chloride or 6-iodopyridine-3-sulfonyl chloride to act on -benzoate.
  • the compound of [Synthesis Example 21] can be synthesized in the same manner as the compound of [Synthesis Example 19] by using the compound of [Synthesis Example 18].
  • the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • the reaction solution was concentrated under reduced pressure, and water (20 ml) and ethyl acetate (30 ml) were added. Extraction was performed three times with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.64 g, 75%).
  • the reaction solution was concentrated under reduced pressure, and the residue was slurry washed with ethyl acetate.
  • the obtained solid was dissolved in dichloromethane (50 ml), and N, N-diisopropylethylamine (7.9 ml, 45 mmol) was added. Under ice-cooling, benzoyl chloride (5.3 g, 37 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction twice with dichloromethane. The organic layer was washed successively with 0.5M hydrochloric acid and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
  • the reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (50 ml). Potassium carbonate (4.5 g, 33 mmol) and methyl iodide (2.8 ml, 45 mmol) were sequentially added, and the mixture was stirred at room temperature for 12 hours. Water (30 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The title compound was obtained by filtering the solid (7.4 g, quant.).
  • the reaction solution was cooled to room temperature, and water (25 ml) and dichloromethane (25 ml) were added. After filtration through celite and extraction twice with dichloromethane, the organic layer was washed with a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound mixture (1: 1) (0.29 g).
  • This mixed solution was added to the previously prepared mixed solution, degassed and purged with argon three times, and then stirred at 60 ° C. for 18 hours.
  • the reaction solution was cooled to room temperature, and water (25 ml) and dichloromethane (25 ml) were added. After filtration through celite and extraction twice with dichloromethane, the organic layer was washed with a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.21 g).
  • Step 6 Synthesis of Methyl (2S) -2-amino-3- [6- (3-methyl-2,6-dioxo-pyrimidin-1-yl) -3-pyridine] propanoate
  • the compound (0.21 g, 0.52 mmol) obtained in (Step 5) was dissolved in 1,4-dioxane (2.0 ml) and methanol (1.0 ml).
  • 4M Hydrochloric acid / 1,4-dioxane solution (2.0 ml) was added, and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure to give the hydrochloride of the title compound (0.18 g, quant.).
  • MS (ESI) m / z 305 [M + H] + .
  • the compound of [Synthesis Example 33] can be synthesized in the same manner as the compound of [Synthesis Example 32] by using thymine in (Step 1) of [Synthesis Example 32].
  • the compound of [Synthesis Example 34] is the same as the compound of [Synthesis Example 31] by using 6- (ethoxymethyl) -1H-pyrimidine-2,4-dione in (Step 1) of [Synthesis Example 31]. It can synthesize
  • the residue was subjected to reverse phase HPLC using ODS as a filler, and eluted with a mixed solution of water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid.
  • the desired fraction was freeze-dried to obtain the trifluoroacetate salt of the title compound.
  • the reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added. Extraction was performed twice with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to reverse phase HPLC using ODS as a filler and purified in the same manner as in (Step 2) to obtain the trifluoroacetate salt of the title compound (0.40 g, 51%).
  • reaction solution was cooled to room temperature, filtered through celite, and concentrated under reduced pressure.
  • residue was subjected to reverse phase HPLC using ODS as a filler, and water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid.
  • the title compound was obtained by elution with a mixed solution and lyophilization of the desired fraction (0.26 g, 26%).
  • reaction solution was concentrated under reduced pressure, the residue was subjected to reverse phase HPLC using ODS as a filler, and eluted with a mixed solution of water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid. Lyophilization gave the title compound (0.20 g, 74%).
  • This mixed solution was added to the previously prepared mixed solution, degassed and purged with argon three times, and then stirred at 60 ° C. for 18 hours. After cooling the reaction solution to room temperature and concentrating under reduced pressure, the residue was subjected to reverse phase HPLC using ODS as a filler, and eluted with a mixed solution of water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid. The desired fraction was lyophilized to give the title compound (0.12 g, 45%).
  • Step 6 Methyl (2S) -2-amino-3- [6- (1-methyl-2,4-dioxo-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-3-yl) -3- pyridyl] propanoate
  • the compound obtained in (Step 5) (0.12 g, 0.26 mmol) was dissolved in 1,4-dioxane (1.0 ml) and methanol (1.0 ml).
  • the compound of [Synthesis Example 46] and [Synthesis Example 47] is obtained by using 6-methyluracil or 5,6-dimethyluracil in [Step 3] of [Synthesis Example 43]. It can be synthesized by a method similar to that of the compound.
  • This mixed solution was added to the previously prepared mixed solution, degassed and purged with argon three times, and then stirred at 60 ° C. for 15 hours.
  • the reaction solution was cooled to room temperature, and water (25 ml) and dichloromethane (25 ml) were added. After filtration through celite and extraction twice with dichloromethane, the organic layer was washed with a saturated aqueous sodium chloride solution. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (223 mg, 57.3%).
  • N, N-diisopropylamine (58 ⁇ l, 0.34 mmol) were sequentially added and stirred at room temperature for 5 hours. Concentrate under reduced pressure, subject the residue to reverse phase HPLC using ODS as a filler, elute with a mixed solution of water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid, and freeze-dry the desired fraction. This gave the title compound (47 mg, 67%).
  • the compound shown in Table 1 is any one selected from [Synthesis Example 1] to [Synthesis Example 27], any carboxylic acid intermediate, and [Synthesis Example 28] to [Synthesis Example 48]. Can be synthesized in the same manner as the compound of [Example 1].
  • reaction solution was allowed to reach room temperature. After cooling and concentration under reduced pressure, the residue was subjected to reverse phase HPLC using ODS as a filler, eluting with a mixed solution of water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid. Fractions were lyophilized to give the title compound (34 g, 91%).
  • the compound shown in Table 2 is a method similar to the compound of [Example 2] by using any sulfonamide derivative selected from A1 to A58 and the corresponding alcohol (isopropyl alcohol or cyclohexyl alcohol). Can be synthesized.
  • VCAM-1 / ⁇ 4 ⁇ 1 integrin binding inhibitory activity evaluation test Measures the ability of a test substance to inhibit binding of human T cell line Jurkat, which is known to express ⁇ 4 ⁇ 1 integrin, to VCAM-1 did.
  • buffer A carbonate buffer, pH 9.6
  • Block Ace Snow Brand Milk Products
  • Various concentrations of test substances diluted in binding buffer (DMEM containing 40 mM HEPES, 0.2% BSA and 4 mM MnCl 2 ) and Jurkat cells (2 ⁇ 10 6 cells / mL) were 100 ⁇ L each of VCAM-1 / Fc was added to the coated plate (5 ⁇ 10 5 cells / well) and incubated at 30 ° C. for 15-30 minutes. After binding the cells to the wells, unbound cells were removed by washing with PBS. Buffer C (PBS containing 1.5% Triton X-100) was added to the plate at 50 ⁇ L / well to lyse the bound Jurkat cells.
  • binding buffer containing 40 mM HEPES, 0.2% BSA and 4 mM MnCl 2
  • Jurkat cells 2 ⁇ 10 6 cells / mL
  • Test example 2 (2) MAdCAM-1 / ⁇ 4 ⁇ 7 integrin binding inhibitory activity evaluation test Ability of test substance to inhibit binding of human B cell line cell line RPMI-8866 known to express ⁇ 4 ⁇ 7 integrin to MAdCAM-1 was measured. 50 ⁇ L / well of a recombinant mouse MAdCAM-1 / Fc (R & D systems) solution (1 ⁇ g / mL) diluted with buffer A (carbonate buffer, pH 9.6) was added to a 96-well microtiter plate at 4 ° C. Incubated overnight. After washing once with PBS, Block Ace (Snow Brand Milk Products) was added at 150 ⁇ L / well and incubated at room temperature for 2 hours. After removal, washing was performed once with PBS.
  • buffer A carbonate buffer, pH 9.6
  • Test example 3 (3) MAdCAM-1 / ⁇ 4 ⁇ 7 integrin binding inhibitory activity evaluation test in the presence of serum (1) The ability of test substances to inhibit binding of human B cell line cell line RPMI-8866, known to express ⁇ 4 ⁇ 7 integrin, to MAdCAM-1 was determined. 50 ⁇ L / well of a recombinant mouse MAdCAM-1 / Fc (R & D systems) solution (1 ⁇ g / mL) diluted with buffer A (carbonate buffer, pH 9.6) was added to a 96-well microtiter plate at 4 ° C. Incubated overnight. After washing once with PBS, Block Ace (Snow Brand Milk Products) was added at 150 ⁇ L / well and incubated at room temperature for 2 hours.
  • buffer A carbonate buffer, pH 9.6
  • test substances and RPMI-8866 cells (2 ⁇ 10 6 cells / mL) diluted in binding buffer (DMEM containing 40 mM HEPES, 0.2% BSA and 4 mM MnCl 2 ) were added at 50% final concentration. 100 ⁇ L each was added to a plate coated with MAdCAM-1 / Fc to contain human serum (7.5 ⁇ 10 5 cells / well) and incubated at 30 ° C. for about 60 minutes. After binding the cells to the wells, unbound cells were removed by washing with PBS.
  • binding buffer DMEM containing 40 mM HEPES, 0.2% BSA and 4 mM MnCl 2
  • Buffer C PBS containing 1.5% Triton X-100 was added to the plate at 50 ⁇ L / well to lyse bound RPMI-8866 cells.
  • 30 ⁇ L of Substrate Buffer Promega, CytoTox 96 Non-Radioactive Cytotoxicity Assay
  • 30 ⁇ L of Stop Solution was added, and the absorbance at 490 nm was measured using a plate reader.
  • the absorbance obtained here was obtained by detecting the lactate dehydrogenase (LDH) activity eluted in the supernatant of each well, that is, the number of RPMI-8866 cells remaining on the plate after binding to MAdCAM-1. Is proportional to The test was performed in duplicate, and the cell binding rate at various concentrations when the absorbance of wells not containing the test substance was taken as 100% was determined, and the concentration IC 50 that caused 50% binding inhibition was calculated. The results obtained are summarized in Table 3.
  • LDH lactate dehydrogenase
  • the compound of the present invention has high selectivity such that the effect on ⁇ 4 ⁇ 1 is low and the effect on ⁇ 4 ⁇ 7 is high. .
  • the high selectivity for ⁇ 4 ⁇ 1 is low and the effect is high for ⁇ 4 ⁇ 7 reduces the effect on ⁇ 4 ⁇ 1 which suppresses the infiltration of lymphocytes around the whole body and is expressed specifically in the intestinal tract. Since the action on ⁇ 4 ⁇ 7 can be greatly suppressed, there is an advantage that the adaptive disease can be treated more efficiently.
  • Test example 4 (4) MAdCAM-1 / ⁇ 4 ⁇ 7 integrin binding inhibitory activity evaluation test in human whole blood The binding inhibitory activity of T cell ⁇ 4 ⁇ 7 integrin and MAdCAM-1 in human whole blood was measured by a test substance. Blood samples were obtained by donating blood from healthy volunteers. 4 mM MnCl2 solution and various test substance dilutions were added to human whole blood and incubated for 10 minutes. 10 ⁇ g / mL recombinant mouse MAdCAM-1 / Fc (R & D Systems) was added and incubated for a total volume of 50 ⁇ L for 30 minutes. 950 ⁇ L of Lyse / Fix (BD Biosciences) was added, and hemolysis and fixation were performed at 37 ° C.
  • Lyse / Fix BD Biosciences
  • PE Rat Anti-Mouse CD4 (BD Pharmigen) was added and incubated for 30 minutes or more. After washing with the medium, the ratio of the MAdCAM-1-positive cell ratio in the CD4-positive cells was measured using flow cytometry. Tests are based on the results of independent tests using 2 to 3 different blood samples. From wells containing no test substance, the absence of ligand is 100% inhibition and the presence of ligand is 0% inhibition. The inhibition rate of MAdCAM-1 binding was determined and the concentration IC 50 resulting in 50% binding inhibition was calculated.
  • Test Example 5 The mouse portal vein concentration of the test substance was measured and the oral absorbability was evaluated.
  • the test substance was dissolved or uniformly suspended in a 0.5% (w / v) aqueous solution of methylcellulose, and 3 compounds (3 mg / 10 mL / kg) were added to female mice (BALB / cAnNCrlCrlj, 7-9 weeks old) using a gastric tube. ) was orally administered in a cassette. 30 minutes after administration, the abdomen was opened under isoflurane anesthesia, and about 0.2 mL of blood was collected from the portal vein using a syringe treated with DDVP (esterase inhibitor) and heparin sodium, and stored on ice.
  • DDVP esterase inhibitor
  • the collected blood was centrifuged at 18,000 g ⁇ 3 minutes using a refrigerated centrifuge to obtain a plasma sample. After extracting the test substance with acetonitrile, the plasma concentration was quantified by LC / MS / MS. The plasma concentration was the sum of the test substance and its active metabolite. The calculated plasma concentrations are shown in Table 5.

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Abstract

L'invention concerne un composé ayant une excellente action d'inhibition de l'intégrine α4. Elle concerne également un dérivé de sulfonamide représenté par la formule générale (I) ou son sel pharmaceutiquement acceptable. (Dans cette formule, R1-R5, e-h, D, et B sont tels que définis dans la description.)
PCT/JP2017/004277 2016-02-05 2017-02-06 INHIBITEUR DE L'INTÉGRINE α4β7 WO2017135471A1 (fr)

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Cited By (10)

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WO2019147824A1 (fr) 2018-01-26 2019-08-01 Progenity, Inc. Traitement d'une maladie du tractus gastro-intestinal avec un inhibiteur de pde4
WO2019246455A1 (fr) 2018-06-20 2019-12-26 Progenity, Inc. Traitement d'une maladie du tractus gastro-intestinal par un inhibiteur de l'intégrine
TWI717080B (zh) * 2018-10-30 2021-01-21 美商基利科學股份有限公司 咪唑并吡啶衍生物
WO2021030438A1 (fr) * 2019-08-14 2021-02-18 Gilead Sciences, Inc. Composés pour l'inhibition de l'intégrine alpha 4 bêta 7
WO2021174024A1 (fr) 2020-02-28 2021-09-02 First Wave Bio, Inc. Méthodes de traitement de la colite auto-immune iatrogène
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
WO2023058645A1 (fr) * 2021-10-05 2023-04-13 Ｅａファーマ株式会社 Procédé de production d'un composé ou d'un sel pharmaceutiquement acceptable de celui-ci
WO2025059417A1 (fr) * 2023-09-15 2025-03-20 Morphic Therapeutic, Inc. Inhibition de l'intégrine α4β7 humaine

Citations (2)

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WO2013161904A1 (fr) * 2012-04-24 2013-10-31 味の素株式会社 Dérivé de sulfonamide et utilisation médicale associée
WO2015064580A1 (fr) * 2013-10-29 2015-05-07 味の素株式会社 Dérivé de sulfonamide et son utilisation médicinale

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WO2013161904A1 (fr) * 2012-04-24 2013-10-31 味の素株式会社 Dérivé de sulfonamide et utilisation médicale associée
WO2015064580A1 (fr) * 2013-10-29 2015-05-07 味の素株式会社 Dérivé de sulfonamide et son utilisation médicinale

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019147824A1 (fr) 2018-01-26 2019-08-01 Progenity, Inc. Traitement d'une maladie du tractus gastro-intestinal avec un inhibiteur de pde4
WO2019246455A1 (fr) 2018-06-20 2019-12-26 Progenity, Inc. Traitement d'une maladie du tractus gastro-intestinal par un inhibiteur de l'intégrine
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
TWI717080B (zh) * 2018-10-30 2021-01-21 美商基利科學股份有限公司 咪唑并吡啶衍生物
US12053462B2 (en) 2018-10-30 2024-08-06 Gilead Sciences, Inc. Quinoline derivatives
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
WO2021030438A1 (fr) * 2019-08-14 2021-02-18 Gilead Sciences, Inc. Composés pour l'inhibition de l'intégrine alpha 4 bêta 7
JP2022543465A (ja) * 2019-08-14 2022-10-12 ギリアード サイエンシーズ， インコーポレイテッド α４β７インテグリンの阻害のための化合物
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin
JP7491996B2 (ja) 2019-08-14 2024-05-28 ギリアード サイエンシーズ， インコーポレイテッド α４β７インテグリンの阻害のための化合物
WO2021174024A1 (fr) 2020-02-28 2021-09-02 First Wave Bio, Inc. Méthodes de traitement de la colite auto-immune iatrogène
WO2023058645A1 (fr) * 2021-10-05 2023-04-13 Ｅａファーマ株式会社 Procédé de production d'un composé ou d'un sel pharmaceutiquement acceptable de celui-ci
WO2025059417A1 (fr) * 2023-09-15 2025-03-20 Morphic Therapeutic, Inc. Inhibition de l'intégrine α4β7 humaine

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