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WO2006038594A1 - Inhibiteur de canal de calcium de type n - Google Patents

Inhibiteur de canal de calcium de type n Download PDF

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Publication number
WO2006038594A1
WO2006038594A1 PCT/JP2005/018306 JP2005018306W WO2006038594A1 WO 2006038594 A1 WO2006038594 A1 WO 2006038594A1 JP 2005018306 W JP2005018306 W JP 2005018306W WO 2006038594 A1 WO2006038594 A1 WO 2006038594A1
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WO
WIPO (PCT)
Prior art keywords
group
substituent
ring
general formula
ethyl
Prior art date
Application number
PCT/JP2005/018306
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English (en)
Japanese (ja)
Inventor
Tazumi Ohtani
Tohru Kambe
Kaoru Kobayashi
Hideyuki Takimizu
Yoko Ito
Original Assignee
Ono Pharmaceutical Co., Ltd.
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Filing date
Publication date
Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Publication of WO2006038594A1 publication Critical patent/WO2006038594A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to an N-type calcium channel inhibitor.
  • Voltage-gated calcium channels are opened by depolarization of the cell membrane and selectively allow extracellular calcium ions to flow according to an electrochemical gradient. Voltage-gated calcium channels are currently classified into N-type, L-type, P / Q-type, R-type, and T-type!
  • L-type and T-type calcium channels are present in a wide variety of tissues, it is known that L-type is particularly abundant in smooth muscle and cardiomyocytes.
  • N-type, PZQ-type and R-type calcium channels are mainly present in the nervous system and are involved in the release of various neurotransmitters.
  • This neurotransmitter is normally stored in a synaptic vesicle at the nerve terminal, but when the nerve action potential is transmitted through the presynaptic fiber through information transmission and reaches the nerve terminal, the voltage-dependent calcium channel is activated. It is beaten and calcium ions enter the nerve endings. From this, synaptic vesicles are synaptic Fusion to the anterior membrane releases neurotransmitters.
  • N-type calcium channel inhibitors are useful for various diseases caused by massive release of neurotransmitters. For example, cerebral infarction (J. Cereb. Blood Flow Metab., 17, 421- 429, 1997), transient cerebral ischemic attack, cerebrospinal disorder after heart surgery, spinal vascular disorder, stress hypertension (Science, 239, 57-61, 1988), neurosis, epilepsy, asthma (Neuroscience, 34) , 1, 243-25 0, 1990), frequent urination (Jpn. J.
  • N-type calcium channel inhibitors As N-type calcium channel inhibitors, ⁇ -conotoxin GVIA and ⁇ -conotoxin MVIIA isolated from potato shellfish venom are known.
  • the compound represented by the general formula (W) is a calcium receptor antagonist (for example, see Patent Document 1).
  • Y 1W represents a bond, Cl-4 alkyl, etc.
  • Y 2W represents Cl-4 alkyl or CF
  • Cyclobut may represent a pill
  • G W represents a bond or a CR 6W group
  • a W — B W represents CH CH, a bond
  • R 5W represents an optionally substituted phenol or naphthyl
  • R 7W represents hydrogen, OH, Cl-4 alkoxy
  • R 8W is hydrogen or Cl ⁇ 4
  • X 7 represents alkyl
  • R 7W and R 8W may together represent oxo
  • X w represents a benzene ring having a substituent.
  • R is hydrogen, Cl-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-Cl-4 alkyl or optionally substituted.
  • F 2 represents Cl to 4 alkyl
  • R 2Z is Cl to 6 alkyl, C 3 to 10 cycloalkyl, C 3 to 10 cycloalkyl—Cl to 4 alkyl, optionally substituted phenyl—Cl to 4 alkyl or — (CH) NR 5Z R 6Z (R 5Z and R 6Z are each hydrogen or C1
  • R 3Z and R 4Z are substituted with Cl-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl—Cl-4 alkyl, 3-6 alkyl, respectively! In any case, it may be a phenol or a substituted, or a fluorine Cl to 4 alkyl, or R 1Z and R 2Z , R 3Z and R 4Z , R 5Z and R 6Z are the nitrogen to which they are attached Together with the atoms may form a C4-7 carbocycle containing an oxygen atom or even a nitrogen atom which may be substituted by 1 to 3 methyl or ethyl groups. The carbocycle may be further condensed with an optionally substituted phenyl group. ).
  • Patent Document 1 Pamphlet of International Publication No. 98Z45255
  • Patent Document 2 Pamphlet of International Publication No. 01Z04087
  • ring Y represents a cyclic group which may further have a substituent
  • a and R each independently represent a hydrogen atom, a chain hydrocarbon group which may have a substituent or a substituted group.
  • B and D each independently represent a bond or a spacer having 1 to 6 atoms in the main chain
  • W represents an oxygen atom or a substituent.
  • X represents a force representing a bonder or a spacer having 1 to 8 atoms in the main chain, and a cyclic group which may have a substituent
  • Z may be a protected hydroxyl group, protected An amino group or a substituent which may be substituted, each represents a cyclic group, and A and R together have a substituent containing one or more nitrogen atoms. It may form a good heterocyclic ring.
  • W may have a substituent, and when it represents a nitrogen atom, W contains a nitrogen atom together with ring Y and its substituent. Form a polycyclic heterocycle optionally having substituents, or W contains a nitrogen atom together with X, has substituents! /, May!
  • W, X and Z may be taken together to form an optionally substituted heterocyclic ring containing one or more nitrogen atoms.
  • the substituents of R and ring Y may be combined to contain one or more nitrogen atoms, have a substituent, or may form a complex ring.
  • D is —SO— group or —SO NR 1C> 3 group (in which R 1C> 3 is a hydrogen atom or a substituent
  • X may have a bond or a substituent! / ⁇ may be Cl-6 alkylene or V may have a substituent, and may be a C3-10 carbocyclic group.
  • X may have a bond or a substituent! / ⁇ may be Cl-6 alkylene or V may have a substituent, and may be a C3-10 carbocyclic group.
  • ring Y 1 is an optionally substituted benzene, naphthalene, pyridine, pyrazine, thiazole, oxazole, pyrimidine or pyridazine ring, and D 1 is a SO-group.
  • alkylene or location substituent may have C3 ⁇ 10 carbocyclic group, W 1 represents a nitrogen atom which may have have a oxygen atom or a substituent, and other symbols [1], wherein Means the same. )
  • R 11 and R ′′ each independently represent a hydrogen atom or a protecting group for a nitrogen atom
  • R G , R w and R Y each independently represent a hydrogen atom or R 11C> represents a hydrogen atom or a substituent
  • m represents 0 or an integer of 1 to 5
  • n represents an integer of 2 to 6
  • p represents an integer of 0 or 1 to 5
  • S represents an integer of 1 to 4
  • each of ring Z 1 and ring Z 2 independently represents a heterocyclic ring containing one or more nitrogen atoms
  • ring X 1 may have a substituent.
  • Good C3 ⁇ : represents an LO carbocycle, and other symbols have the same meanings as described in the above [1].
  • ring A 1 represents a benzene or cyclohexane ring, and other symbols have the same meanings as described in [1 or 8] above
  • a compound thereof, a salt thereof or Solvates or prodrugs thereof
  • a pharmaceutical composition comprising a compound represented by the general formula (I) according to [1], a salt thereof, a solvate thereof, or a prodrug thereof,
  • composition according to [11] above which is a cocoon-type calcium channel inhibitor
  • Type IV calcium channel-mediated disease is pain, cerebral infarction, transient ischemic attack, cerebrospinal disorder after heart surgery, spinal vascular disorder, stress hypertension, neurosis, epilepsy, asthma, frequent
  • a method for the prevention and Z or treatment of N-type calcium channel mediated diseases in [19] the general formula (I) described in [1] above for producing a preventive and Z or therapeutic agent for N-type calcium channel mediated diseases Use of the indicated compounds, salts thereof, or solvates thereof or prodrugs thereof, and
  • the present invention relates to a method for producing a compound represented by the general formula (I).
  • Cyclic group in “having a substituent, which may have a substituent”, represented by A, R, X, and Z or Z Examples of these include carbocycle and heterocycle.
  • the carbocycle includes, for example, a C3-15 monocyclic or polycyclic aromatic carbocyclic ring, a carbocyclic ring partially or completely saturated, a spiro-bonded polycyclic carbocyclic ring, and Examples thereof include a bridged polycyclic carbocyclic ring.
  • Examples of the C3-15 monocyclic or polycyclic aromatic carbocyclic ring and a carbocyclic ring partially or completely saturated include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane.
  • Cyclononane Cyclodecane, Cycloundecane, Cyclododecane, Cyclotridecane, Cyclotetradecane, Cyclopentadecane, Cyclopentene, Cyclohexene, Cycloheptene, Cyclootaten, Cyclopentagen, Cyclohexagen, Cyclohexadiene, Cyclooctadene, Benzene, Pentalen Perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, heptalene, -Hydroheptalene, biphenylene, as-indacene, s-indacene, isanaphthylene, isanaphthene, fluorene, phenalene, phenylene
  • spiro-bonded polycyclic carbon ring and the bridged polycyclic carbocycle examples include, for example, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] undecane, bicyclo [2 2. 1.] Heptane, bicyclo [2. 2. 1] Hepter 2—Yen, Bicyclo [3. 1. 1] Heptane, Bicyclo [3. 1. 1] Hepter 2—Yen, Bicyclo [2. 2. 2] Octane, Bicyclo [2. 2. 2] Otter 2 —Nen, adamantane, and nonoredamantane ring.
  • heterocyclic ring examples include a 1 to 5 heteroatom selected from an oxygen atom, a nitrogen atom, and Z or a sulfur atom.
  • Ring Y represents “an optionally substituted cyclic group”
  • A, R, X and Z or Z examples of the “substituent” in the “cyclic group” may be, for example, (1) have a substituent, may be an alkyl group, and (2) have a substituent. ! /, Alkenyl group, (3) optionally substituted alkynyl group, (4) optionally substituted carbocyclic group, (5) substituted group (6) a hydroxyl group which may have a protecting group, (7) a mercapto group which may have a protecting group, and (8) a protecting group which may have a protecting group.
  • Butyl, C1 ⁇ such as nyl, hexyl, etc .: C0-15 carbocyclic group such as L0 alkyl or phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, piperidyl, pyrrolidyl, piperazyl, A carbonyl group bonded to a heterocyclic group such as furyl or phenyl), (30) a formyl group, (31) a protecting group !, or a Cl-6 alkyl group substituted with a hydroxyl group, (32 ) Has a protecting group!
  • alkyl group in “(1) an optionally substituted alkyl group” as the “substituent” include, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, Examples thereof include Cl-20 alkyl groups such as ntadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and icosyl groups.
  • alkyl group in “(2) may have a substituent! / Alkenyl group” as “substituent” include, for example, etule, probe, butyr, pentene -C2-20 alkenyl groups such as -l, hexyl, heptul, otatur and the like.
  • Alkyl group in “(3) Alkynyl group having a substituent!”
  • substituted is, for example, etul, propiel, butynyl, pentyl, hexyl And C2-20 alkyl groups such as rutile, heptul, octyl and the like.
  • alkyl group optionally having substituent (s) (2) “alkyl group optionally having substituent (s)” and (3) “having substituent (s)
  • substituent in the “optionally alkyl group” and (29) “optionally substituted acyl group” include, for example, a hydroxyl group, an oxo group, a mercapto group, an amino group, a carboxyl group, a nitro group, and a cyano group.
  • a carbocyclic group and a substituent may include a heterocyclic group, and 1 to 4 of these optional substituents may be substituted at substitutable positions.
  • the acyl group in the acyl group, the acylamino group, and the N acyl-N— (Cl-6 alkyl) amino group is the same as the above-mentioned “(29) Substituent! Represents meaning.
  • the carbocyclic group which may have a substituent and the heterocyclic group which may have a substituent are each described in the following “(4) carbocyclic group which may have a substituent”. , And “(5) have a substituent! / May be a heterocyclic group”.
  • the carbocyclic group in “(4) have a substituent! / May be a carbocyclic group” has the same meaning as the “carbocycle” represented by the above-mentioned ring Y and the like.
  • substituent of the carbocyclic group for example, a Cl to 6 alkyl group (methyl, ethyl, propyl, butyl, pentyl, hexyl group, etc.) which may be substituted with a hydroxyl group, a C2 to 6 alkene, and the like.
  • -Luyl group etul, probe, butur, pental, hexel, etc.
  • C2-6 alkyl group etul, probule, butur, pentyl, hexyl, etc.
  • hydroxyl group Cl- 6 alkoxy groups (methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.), mercapto groups, Cl-6 alkylthio groups (methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, etc.), amino groups, mono- Or DiCl-6 alkylamino group (methylamino-containing aminoamino, n-propylamino-containing isopropylamino-containing n-butylamino-containing isobutylamino-containing t ert-butylamino n-pentylami-containing isopentylami
  • heterocyclic group in “(5) have a substituent! / ⁇ may be! / ⁇ heterocyclic group” has the same meaning as the “heterocycle” represented by the ring Y and the like.
  • the substituent of the heterocyclic group has the same meaning as the substituent in the above-mentioned “(4) may have a substituent! / ⁇ carbocyclic group”.
  • alkyl group which has the same meaning as the above-mentioned “(3) Substituent! // Alkyl group” or a substituent.
  • a good carbocyclic group (having the same meaning as the above-mentioned “(4) optionally substituted carbocyclic group”), a heterocyclic group optionally having a substituent (above-mentioned “(5) substitution” It represents the same meaning as the “heterocyclic group optionally having a group”), an alkylsulfonyl group (for example, a Cl to 4 alkylsulfol group such as methylsulfol, ethylsulfol, etc.), an aromatic ring sulfo- Group (for example, C 6-10 aromatic sulfonyl group such as phenylsulfol, naphthylsulfol, etc.), acyl group (the above-mentioned (29) has a substituent!
  • Powerful rubamoyl group optionally having substituent (s)" as the substituent includes, for example, unsubstituted force rubamoyl group, N-mono-Cl-6 alkyl strength rubamoyl (for example, N-methyl) Rucarbamoyl, N-ethylcarbamoyl, N-propyl-powered rubamoyl, N-isopropyl-powered rubamoyl, N-butylcarbamoyl, etc., N, N di-Cl-6 alkylcarbamoyl (eg, N, N dimethylcarbamoyl, N, N jetty) And lucarbamoyl, N, N dipropyl-powered rubamoyl, N, N-dibutylcarbamoyl, etc.), piperidine 1-ylcarbol, pyrrolidine 1-ylcarbol and the like.
  • N-mono-Cl-6 alkyl strength rubamoyl for
  • the “(10) optionally substituted sulfamoyl group” as a substituent includes, for example, an unsubstituted sulfamoyl group, N-mono-Cl-6 alkylsulfamoyl (eg, N-methyl) Sulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N—isopropylsulfamoyl, N-butylsulfamoyl, etc.), N, N di-Cl to 67 ruylsulfamoyl (for example, N, And N, N-dimethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl group, etc.).
  • N-mono-Cl-6 alkylsulfamoyl eg, N-methyl
  • alkoxy carbo yl group in "(12) having a substituent! / May be an alkoxy carbo ol group" as a substituent include, for example, methoxy carbo ol, ethoxy carbo ol, Examples include Cl-6 alkoxycarbonyl groups such as propoxycarbol and tertbutoxycarbol groups, and examples of the substituent include the above-mentioned “(1) optionally substituted alkyl group” and the like. And the same as the “substituent”.
  • / ⁇ may have a mercapto group ”and“ (8) an amino group optionally having a protecting group ” "Means the same.
  • the "chain hydrocarbon group" in the “chain hydrocarbon group which may have a substituent” represented by A and Z or R includes an alkyl group, an alkenyl group, an alkynyl group, An alkylidene group, an alkenylidene group and an alkylidene group are included.
  • alkyl group, alkyl group, and alkyl group are each in the above-mentioned “substituent”.
  • alkyl group “alkyl group” and “alkyl group” in “-group” and “(3) having a substituent! /, But an alkyl group”. Represents.
  • alkylidene group examples include Cl-20 alkylidene groups such as methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene and the like.
  • alkenylidene group examples include C2-20 alkenylidene groups such as etulidene, probelidene, buteuridene, penterylidene, hexylidene and the like.
  • alkynylidene group examples include C3-20 alkylidene groups such as propynylidene, butynylidene, pentynylidene, hexylidene and the like.
  • substituted in the "having a substituent or a chain hydrocarbon group” represented by A and Z or R may be the above-mentioned "(1) having a substituent”. It represents the same meaning as “substituent” in “alkyl group” and the like.
  • the "spacer having 1 to 6 atoms in the main chain” represented by B and Z or D means an interval in which 1 to 6 atoms in the main chain are connected.
  • the “number of atoms in the main chain” is counted so that the atoms in the main chain are minimized.
  • the “spacer having 1 to 6 atoms in the main chain” for example, it may have 1 to 2 substituents —CH 2 —, which has 1 to 2 substituents. Even
  • Examples of the “spacer having 1 to 6 atoms in the main chain” represented by B and Z or D include CR 101 R 102 —, — NR 103 —, — C (O) —, — O One, One S, One SO, One SO —, One SO NR —, -NR SO One, One NR CO—
  • R 101 , R 102 and R 1 are each independently a hydrogen atom ,
  • An alkyl group which may have a substituent (which may have the same meaning as the above-mentioned “(1) substituent, an alkyl group”) or a substituent (the “(1) substituent This represents the same meaning as the “substituent” in the “alkyl group optionally having.” In the case where there are a plurality of the same symbols, they may be the same or different. ) And the like.
  • W represents "substituent nitrogen atom which may have a" specifically, -NR 110 - (the radical, R 11C> may have a hydrogen atom, a substituent Alkyl (represents the same meaning as the above-mentioned “(1) may have a substituent! / ⁇ alkyl group”) or a substituent (the above-mentioned “(1) has a substituent! /, May have It represents the same meaning as “substituent” in “alkyl group”.
  • the “optionally acidified sulfur atom” represented by W is S 1, 1 SO 2 or 1 SO— group
  • the “optionally substituted —CH— group” represented by W is specifically CRmR 112
  • R 111 and R 112 are each independently a hydrogen atom or a substituent (the same as the “substituent” in the above-mentioned “(1) alkyl group, which may have a substituent)”. Represents a group represented by).
  • the “optionally substituted —CH—O group” represented by W is specifically —CR 111
  • R 112 — O represents a group represented by the formula (wherein all symbols have the same meanings as described above).
  • Spacer having 1 to 8 atoms in the main chain represented by X means an interval in which 1 to 8 atoms in the main chain are connected.
  • the “number of atoms in the main chain” is counted so that the atoms in the main chain are minimized.
  • Examples of the “spacer having 1 to 8 atoms in the main chain” include CH— which may have 1 to 2 substituents, and 1 to 2 substituents.
  • the “position” in the above-mentioned “(1) optionally substituted alkyl group” is mentioned.
  • the meaning is the same as “substituent”.
  • Protected ! may be a hydroxyl group” and “protected, may be an amino group” represented by Z respectively represent the above-mentioned "hydroxy group which may have a protecting group” and It has the same meaning as “having a protecting group and may be an amino group”.
  • Heterocycle in “optionally substituted heterocycle containing one or more nitrogen atoms formed by A and R joined together” includes one nitrogen atom 5 to 15-membered monocyclic or polycyclic, optionally containing a nitrogen atom, an oxygen atom, and a sulfur atom, optionally containing one to three heteroatoms selected, partially or fully saturated
  • aromatic heterocycles such as pyrrole, imidazole, pyrazole, indole, isoindole, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, perhydroazepine, perhydroazocine, nohydroazocan, indoline, Dihydroisoindole, Dihydroquinoline, Tetrahydroquinoline, Perhydroquinoline, Dihydroisoquinoline, Tetrahydrin Oral isoquinoline, Tetrahydroisoquinoline, carbazole, and a ⁇ -carboline, etc.
  • Heterocycle in “heterocycle optionally having substituent (s) containing nitrogen atom formed by combining W and ring ⁇ ⁇ and its substituent together” is 8- to 15-membered Examples include polycyclic aromatic heterocycles which may be partially or fully saturated, such as indole, dihydroindole (indoline), isoindole, dihydroisoindole, perhydroisoindole, indazole, dihydroindazole.
  • Heterocycle in “having a substituent containing a nitrogen atom formed by W and X together, having a substituent! / ⁇ may be! / ⁇ a heterocycle” is 4 to: one of LO members Monocyclic or polycyclic heterocycles which may be partially or fully saturated, such as pyrrolidine, imidazolidine, piperidine, piperazine, azepine, perhydroazepine, 2,8-diazaspiro [4 5] Examples include decane and jazepan.
  • Heterocycle in “having one or more substituents containing one or more nitrogen atoms formed by W, X, and Z together! -4 to 15-membered monocyclic or polycyclic aromatic heterocycles partially or fully containing nitrogen atoms, such as azetidine, pyrrolidine, imidazolidine, piperidine , Piperazine, perhydroazepine, perhydrodiazepine, perhydroazocine, perhydrodiazocine, 2,8-diazaspiro [4.5] decane, and the like.
  • Heterocycle in "having a substituent containing one or more nitrogen atoms, which may be a heterocycle” formed by a substituent of R and ring Y taken together is, for example, ,
  • Substituent in “having a substituent containing one or more nitrogen atoms, which may be formed by a substituent of R and ring Y together” may be the above-mentioned “substituent” And may have the same meaning as the “substituent” in “V ⁇ cyclic group”.
  • Preferred embodiments in the present invention are as follows.
  • the “cyclic group” in the “cyclic group” represented by the ring Y is preferably an aromatic carbocycle or an aromatic heterocycle.
  • the aromatic carbocycle represented by ring Y is preferably benzene or naphthalene, and the aromatic heterocycle is preferably pyridine, pyrazine, furan, pyran, thiophene, quinoline, quinoxaline, quinazoline, isoquinoline, thiazole, oxazole, pipette Lysine or piperazine, pyrimidine, pyridazine. More preferably, ring Y is benzene, naphthalene, piperidine or piperazine.
  • the "substituent" in the "cyclic group optionally having substituent (s)" represented by ring Y is preferably Cl-4 alkyl (for example, methyl, ethyl, propyl, butyl), trifluoromethyl, Sheared halogen atoms (fluorine, chlorine, bromine, iodine), hydroxyl groups, Cl-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy), carboxyl,-(Cl-4 alkyl) OH (eg, hydroxymethyl, Hydroxyethyl, hydroxypropyl, hydroxybutyl, etc.), Cl-4 acylamino (eg, acetylamino substituted propanoylamino, etc.), Amylated Cl-4 aminoalkyl (aminomethyl, aminoethyl, etc.), nitro, mercapto, C1-4 Alkylthio (methylthio, ethylthio, propylthio
  • a and R are each preferably a hydrogen atom or a substituent, which may be a chain hydrocarbon group or a cyclic group which may have a substituent.
  • the cyclic group which may have a substituent is preferably a substituent, and may be a carbocycle or a substituent, and may be a heterocyclic ring.
  • the “chain hydrocarbon group” in the “chain hydrocarbon group having a substituent” represented by A and Z or R is preferably Cl-6 alkyl, C2-4 alkyl, C2 ⁇ 4-alkenyl and the like, more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, butenyl, butul and the like.
  • the "substituent" in “having a substituent, or a chain hydrocarbon group” represented by A and Z or R is preferably a carbocycle optionally having a substituent, substituted Heterocyclic ring optionally having a group, hydroxyl group, optionally having Cl-8 alkoxy (methoxy, ethoxy, propoxy, cyclopropylmethyloxy), halogen atom (fluorine, chlorine, bromine, iodine) 1), 5), phenoxy, benzyloxy, Cl-4alkoxycarbol (ethoxycarbo), cyan, carboxyca are also selected.
  • the carbocycle which is a substituent of the "optionally substituted chain hydrocarbon group" represented by A and Z or R is preferably partially or fully saturated C3 To: LO monocyclic or polycyclic aromatic carbocyclic ring, more preferably benzene, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like.
  • the heterocyclic ring which is a substituent of the “chain hydrocarbon group having a substituent” represented by A and Z or R is preferably selected from a nitrogen atom, an oxygen atom and a sulfur atom. May be partially or fully saturated containing three heteroatoms 5 to: a LO-membered bicyclic ring, more preferably thiophene, furan, piperidine, thiazole, oxazole, morpholine, thiomorpholine Etc.
  • the "cyclic group" in the "cyclic group” represented by A and Z or R is preferably partially or fully saturated.
  • Cyclic or bicyclic carbocycles and 5- to 10-membered monocyclic or bicyclic heterocycles which may be partially or fully saturated More preferably as a C3-10 monocyclic or bicyclic carbocycle which may be partially or fully saturated, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, benzene, naphthalene, indane More preferred are benzene and cyclohexane.
  • substituent in “having a substituent, which may be substituted,” represented by A and Z or R, preferably a halogen atom (chlorine, fluorine, bromine, iodine), Cl-6 Alkyl (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl and their isomers), C 2-6 alkanes (eg, etul, probe, butur, pentyl, hexyl) And isomers thereof), hydroxyl group, Cl-6 alkoxy (for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy), Cl-6 alkoxy carbocycle (for example, methoxycarbol, ethoxycarbol, Propoxycarbol, butoxycanoleboninole, pentinorexicanoleboninole, hexinorexicanoleboninole), fen
  • Cl-6 Alkyl eg
  • a "optionally substituted heterocyclic ring containing one or more nitrogen atoms" formed by A and R together is also preferred.
  • a heterocyclic ring containing 1 to 4 nitrogen atoms of LO member is preferred, and indoline, pyrrolidine, piperidine, pyrrole, indole, tetrahydroquinoline and tetrahydroisoquinoline are more preferred.
  • substituent in the “optionally substituted heterocycle containing one or more nitrogen atoms” formed by A and R together include, for example, Cl which may have a substituent.
  • 1-6 groups selected from -6 alkyl, Cl-6 alkoxy, hydroxyl, amino-containing mono (Cl-8 alkyl) ami-di (C1-6 alkyl) amino, carboxy, Cl-6 acyl, halogen atoms Is preferred. More preferred are methyl, ethyl, propyl, methoxy, ethoxy, propoxy, hydroxyl, amino-containing methylamino, ethylamino-containing dimethylamino-containing dimethylamino-containing carboxy, acetyl, fluoro, and black mouth.
  • B is preferably a bond, a nitrogen atom, an oxygen atom or a sulfur atom, and may be substituted, C1-6 alkylene (one carbon atom of the alkylene group is substituted with an oxygen atom or a sulfur atom) ), Carbon, C2-67 alkylene, C2-6 alkylene, more preferably a bond, Cl-4 alkylene.
  • Examples of the substituent in Cl-6 alkylene which may be substituted include a phenyl group.
  • D is preferably a bond, —SO—, —CO or —SO— NR 1G3 — (R 1G3 is water
  • O—NR 1C) 3 more preferably a SO— group.
  • All are preferable as W, but more preferably a nitrogen atom which may have a substituent, an oxygen atom, a sulfur atom which may be oxidized, or a substituent which may have —CH— Base
  • Nitrogen atom that may have (substituents include Cl-4 alkyl carb, Cl-47 alkyl, ferro (Cl-4 alkyl), Cl-4 alkoxy carboro (Cl-4 alkyl) And more preferably methyl, ethyl, propyl, isopropyl, acetyl, butanol, benzyl, phenethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl) or an oxygen atom.
  • X is preferably all, but more preferably a bond or a C 1-6 alkylene which may have a substituent (the substituent is preferably an oxo group, a hydroxyl group, etc.), and a substituent.
  • C3-10 carbocyclic group (cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, benzene, naphthalene, etc.) that may have (substituents such as Cl, methyl, ethyl, propyl, etc.) 6
  • halogen atoms such as alkyl, fluorine, chlorine, bromine, oxo, strong rubamoyl, carbole, etc.
  • more preferably a bond ethylene, propylene, butylene, pentylene, benzene ring, cyclohexane ring It is.
  • Z may have an amino group and a substituent which may be protected, and may be a heterocyclic ring or a protected group, and may be a hydroxyl group and substituted. Or a heterocyclic ring, more preferably a substituent, or a heterocyclic ring containing a nitrogen atom, and particularly preferably piperazine, piperidine, pyrrolidine. , Perhydroquinoline, perhydroazepine, perhydroisoquinoline, 8 azabicyclo [3.2.1] octane, indole, indoline, thiazolidine, perhydropyridazine.
  • amino group which may be protected include amino-containing ethylamino, jetylamino-containing phenethylamino, benzoylamino-containing benzylamido tert-butoxycarbonylamino-containing cyclohexylmethylamino and the like.
  • C1-6 alkyl carb optionally with 1-5 substituents Cl-6 alkoxy carbo, 1-5 1-6 substituents which may have one or more substituents Cl-6 alkyl carboyl, mono- (Cl-6 alkyl) ami-di (Cl-6-alkyl) ami-containing 1-5 substituents
  • Preferable ferrules Cl to 6 alkoxy carbonyl amino acids (Cl to 4 alkyl), OH, and the like.
  • the polycyclic heterocyclic ring optionally containing a nitrogen atom-containing polycyclic heterocyclic ring formed by combining W and ring Y and its substituent together, indole, indoline, tetrahydroquinoline, Tetrahydroisoquinoline, benzofuran, benzothiophene.
  • substituent include Cl-4 alkyl, hydroxyl group, Cl-4 alkoxy, and amide-containing mono (Cl-4 alkyl) amido-di (Cl-4 alkyl) amino group, and more preferably a hydroxyl group and methoxy. , Ethoxy, and dimethylamino.
  • W and X are formed together, containing a nitrogen atom, having a substituent!
  • Preferred examples of the heterocyclic ring include pyrrolidine, piperidine, piperazine, perhydroazepine, and diazepan.
  • Preferred substituents are Cl to 4 alkyl, hydroxyl, Cl to 4 alkoxy, and amino-containing mono (Cl to 4 alkyl) amino-containing di (Cl to 4 alkyl) amino groups, and more preferably hydroxyl, methoxy, Ethoxy, dimethylamino with amide.
  • the heterocyclic ring optionally having a substituent containing one or more nitrogen atoms formed by W, X, and Z together, piperidine, piperazine, pyrrolidine, imidazoli are preferable.
  • Preferred examples of the substituent include a hydroxyl group, Cl to 4 alkoxy, and an amino-containing mono (Cl to 4 alkyl) amino-containing di (Cl to 4 alkyl) amino group, and more preferably a hydroxyl group, methoxy, ethoxy, and amino-containing. Dimethylamino.
  • preferred compounds include, for example, the general formula (I—a—1)
  • n represents an integer of 2 to 8
  • R and R are each independently a hydrogen atom or Protecting group (in the group, the protecting group has the same meaning as the protecting group in “(8) protecting group! / May be an amino group” as the “substituent”)).
  • the other symbols have the same meaning as described above.
  • R w represents a hydrogen atom or a substituent of a cyclic group
  • m represents 0 or an integer of 1 to 5, and other symbols represent the same meaning as described above,
  • ring Y represents an optionally substituted benzene, naphthalene, pyridine, pyrazine, thiazole, oxazole, pyrimidine or pyridazine ring
  • D 1A represents a —SO— group
  • Z 1A represents an optionally protected amino group or nitrogen atom.
  • X 1A represents a bond, optionally substituted Cl-6 alkylene or optionally substituted C3-10 carbocyclic group
  • W 1A represents an oxygen atom Or represents a nitrogen atom which may have a substituent, and other symbols represent the same meaning as described above.
  • ring A represents a cyclic group which may have a substituent among A
  • R 11 and R 12 each independently represents a hydrogen atom or a protecting group (in which the protecting group is Represents the same meaning as the protecting group in “(8) Amino group optionally having protecting group” as “substituent”, and represents a hydrogen atom or A with “having a substituent! /, May! / Represents a substituent in the cyclic group, p represents 0 or an integer of 1 to 5, and the other symbols have the same meaning as described above.)
  • ring Z 1 represents a heterocyclic ring containing one or more nitrogen atoms
  • R w represents a hydrogen atom or a substituent
  • m represents 0 or an integer of 1 to 5, and the other symbols are as described above. Has the same meaning as To express. )
  • ring z 1 represents a heterocyclic ring containing one or more nitrogen atoms, and other symbols have the same meanings as described above,
  • ring z represents a heterocyclic ring containing 1 or more nitrogen atoms, and other symbols have the same meaning as described above
  • the ring represented by represents a heterocyclic ring containing two or more nitrogen atoms (imidazolidine, piperazine, perhydrodiazepine (diazepan), etc.), and other symbols have the same meaning as described above. ),
  • ring A represents a cyclic group which may have a substituent among A
  • R 11 and R 12 each independently represents a hydrogen atom or a protecting group (in which the protecting group is Represents the same meaning as the protecting group in “(8) Amino group optionally having protecting group” as “substituent”, and represents a hydrogen atom or A with “having a substituent! /, May! / Represents a substituent in the cyclic group, p represents 0 or an integer of 1 to 5, and the other symbols have the same meaning as described above.)
  • ring A 1 represents a benzene or cyclohexane ring, and other symbols have the same meaning as described above.
  • each of the ring Z 1 and the ring Z 2 is preferably piperazine, piperidine, pyrrolidine, perhydroquinoline, perhydroazepine, perhydro, which may have a substituent.
  • Ring X 1 is preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, benzene or the like which may have a substituent.
  • R A and R B represent R or A
  • Me is methyl
  • Et is ethyl
  • Pr is propyl
  • iPr is isopropyl
  • Bu is butyl
  • Ph is phenyl
  • Bn represents benzyl
  • other symbols have the same meanings as described above.
  • the compound of the present invention represented by the general formula (I) can be obtained by a known method, for example, compliant to the nicked Tofunspho. ) (Ricnard C. Larock, John Wiley & Sons Inc, 1999), etc., as appropriate, for example, can be produced according to the following methods, methods equivalent thereto, or methods shown in the examples. it can.
  • the raw material mixture may be used as a salt.
  • salts those described as pharmaceutically acceptable salts of general formula (I) can be used.
  • Z is protected and may be an amino group
  • D is a sulfol group or a carbo group
  • W 1P is an oxygen atom
  • a group adjacent to Z in X is a —CH— group or a carbo group.
  • D 1P represents a sulfonyl group or a carbo group, and represents an oxygen atom, a —NR 11 — group, a sulfur atom, or a CH 2 O group, and a group represented by “one X 1P — X 2P —”.
  • X 1P represents a bonder or a spacer having 1 to 7 atoms in the main chain
  • X 2P represents (i) —CH— group or (ii) carbo group
  • L represents a leaving group (for example, a halogen atom (bromine, iodine, chlorine, fluorine), methanesulfoxy group, benzenesulfooxy group, toluenesulfooxy group, etc.)
  • a ⁇ , B ⁇ , R ⁇ , D 1PA , ring Y AP , W 1PA and X 1PA have the same meanings as A, B, R, D 1P , ring Y, w lp and X 1P , respectively.
  • a hydroxyl group, an amino group or a mercapto group is contained, the compound is protected when it is required to be protected.
  • R 11AP and R 12AP represent the same meaning as R 11 and R 12 respectively, but are protected when protection is required). It can be produced by subjecting to a deprotection reaction of the protecting group if necessary.
  • the N-alkylated reaction is known, for example, in the presence or absence of a base (sodium hydride, triethylamine, dimethylaminopyridine, pyridine, potassium carbonate, cesium carbonate, sodium bicarbonate, etc.) It is carried out by reacting at 78 ° C to reflux temperature.
  • a base sodium hydride, triethylamine, dimethylaminopyridine, pyridine, potassium carbonate, cesium carbonate, sodium bicarbonate, etc.
  • This reaction is preferably carried out in the presence of an inert gas and under anhydrous conditions.
  • the deprotection reaction of a protective group for a carboxyl group, a hydroxyl group, an amino group, or a mercapto group is well known, for example, (1) alkaline hydrolysis, (2) deprotection reaction under acidic conditions, (3) deprotection reaction by hydrogenolysis, (4) silyl group deprotection reaction, (5) metal deprotection reaction, ( 6) Deprotection reaction using a metal complex.
  • the deprotection reaction by alkali hydrolysis is carried out, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.) in an alkali metal hydroxide (sodium hydroxide, sodium hydroxide, lithium hydroxide, lithium hydroxide). Etc.), alkaline earth metal hydroxides (barium hydroxide, potassium hydroxide, etc.), carbonates (sodium carbonate, potassium carbonate, etc.), aqueous solutions thereof or mixtures thereof, 0 to Performed at 40 ° C.
  • an organic solvent methanol, tetrahydrofuran, dioxane, etc.
  • alkali metal hydroxide sodium hydroxide, sodium hydroxide, lithium hydroxide, lithium hydroxide.
  • Etc. alkaline earth metal hydroxides
  • barium hydroxide, potassium hydroxide, etc. carbonates (sodium carbonate, potassium carbonate, etc.), aqueous solutions thereof or mixtures thereof, 0
  • the deprotection reaction under acid conditions is carried out, for example, by using an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid) in an organic solvent (dichloromethane, chloroform, formaldehyde, diethyl acetate, ethyl acetate, etc.). , P-tosylic acid, etc.), or inorganic acids (hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (hydrogen bromide, Z acetic acid, etc.) in the presence or absence of 2, 2, 2-trifluoroethanol, 0 Performed at ⁇ 100 ° C.
  • organic acid acetic acid, trifluoroacetic acid, methanesulfonic acid
  • organic solvent dichloromethane, chloroform, formaldehyde, diethyl acetate, ethyl acetate, etc.
  • P-tosylic acid, etc. P-tosylic acid, etc.
  • Deprotection reaction by hydrogenolysis includes, for example, a solvent (ether type (tetrahydrofuran, dioxane, dimethoxyethane, jetyl ether, tert-butyl methyl ether, etc.), alcohol type (methanol, ethanol, etc.) , Benzene (benzene, toluene, etc.), keton (acetone, methyl ethyl ketone, etc.), nitrile (acetonitrile, etc.), amide (dimethylformamide, etc.), water, ethyl acetate, acetic acid or their 2 In the presence of a catalyst (palladium-carbon, noradium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.), in a hydrogen atmosphere under normal pressure or under pressure, or in the presence of ammonium formate, Performed at 0-200 ° C.
  • a solvent ether type (tetrahydrofuran, dioxane,
  • the deprotection reaction of the silyl group is carried out, for example, at 0 to 40 ° C using tetraptyl ammonium fluoride in an organic solvent miscible with water (tetrahydrofuran, acetonitrile).
  • the deprotection reaction using a metal is carried out, for example, by the presence of powdered zinc in an acidic solvent (acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixture thereof with an organic solvent such as tetrahydrofuran). Currently, it is carried out at 0 to 40 ° C while applying ultrasonic waves if necessary.
  • an acidic solvent acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixture thereof with an organic solvent such as tetrahydrofuran.
  • the deprotection reaction using a metal complex is carried out, for example, with an organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof in a trap reagent (hydrogen Tryptyl tin, triethyl silane, dimedone, morpholine, jetylamine, pyrrolidine, etc.), organic acids (acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and Z or organic acid salts (sodium 2-ethylhexanoate, 2-ethyl) Metal complexes (tetrakistriphenylphosphine palladium (0), disodium bisbis (triphenylphosphine)) in the presence or absence of phosphine reagents (triphenylphosphine, etc.
  • an organic solvent
  • the deprotection reaction can be performed by a method described in, for example, T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
  • Examples of the protecting group for the carboxyl group include a methyl group, an ethyl group, an aryl group, a tert-butyl group, a trichlorodiethyl group, a benzyl (Bn) group, a phenacyl group, a p-methoxybenzyl group, a trityl group, 2 —A solid phase carrier to which a black mouth trityl group or a structure thereof is bound.
  • Examples of the protective group for the hydroxyl group include a methyl group, a trityl group, a methoxymethyl (MOM) group, a 1-ethoxyethyl (EE) group, a methoxyethoxymethyl (MEM) group, a 2-tetrahydrovinyl (THP) group, Trimethylsilyl (TMS) group, Triethylsilyl (TES) group, tert Butyldimethylsilyl (TBDMS) group, tert Butyldiphenylsilyl (TBDPS) group, Acetyl (Ac) group, Pivaloyl group, Benzyl group, Benzyl (Bn) group , P-methoxybenzyl group, allyloxycarbol (Alloc) group, 2,2,2-trichloroethoxy group (Troc) group, and the like.
  • Examples of the protecting group for the amino group include a benzyloxycarbonyl group, a tert-butoxycarbonyl group, an aryloxycarbol (Alloc) group, 1-methyl-1- (4-biphenol). Ethoxy) (Bpoc) group, trifluoroacetyl group, 9 fluormethoxymethoxy group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, 2 — (Trimethylsilyl) ethoxymethyl (SEM) group and the like can be mentioned.
  • Examples of the mercapto group-protecting group include a benzyl group, a methoxybenzyl group, a methoxymethyl (MOM) group, a 2-tetrahydrovinyl (THP) group, a diphenylmethyl group, and an acetyl (Ac) group.
  • the protecting group for the carboxyl group, hydroxyl group, amino group, or mercapto group is not particularly limited as long as it is a group that can be easily and selectively removed other than the above.
  • those described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999, etc. are used.
  • the desired compound of the present invention can be easily produced by using and separating these deprotection reactions.
  • the reductive amination reaction is known, for example, in a reducing agent (sodium cyanoborohydride, triacetoxyhydrogen) in an organic solvent (methanol, ethanol, dimethylformamide, dimethyl sulfoxide, dichloromethane, dichloroethane, acetonitrile, etc.).
  • a reducing agent sodium cyanoborohydride, triacetoxyhydrogen
  • organic solvent methanol, ethanol, dimethylformamide, dimethyl sulfoxide, dichloromethane, dichloroethane, acetonitrile, etc.
  • an organic solvent methanol, ethanol, dimethylformamide, dimethyl sulfoxide, dichloromethane, dichloroethane, acetonitrile, etc.
  • an organic solvent methanol, ethanol, dimethylformamide, dimethyl sulfoxide, dichloromethane, dichloroethane, acetonitrile, etc.
  • the deprotection reaction of the protecting group can be performed by the same method as described above.
  • amid ⁇ reaction is known, for example,
  • the carboxylic acid is used in an organic solvent (such as chloroform, dichloromethane, jetinoreethenole, tetrahydrofuran, dimethoxyethane, tert-butinoremethyl ether) or without solvent.
  • organic solvent such as chloroform, dichloromethane, jetinoreethenole, tetrahydrofuran, dimethoxyethane, tert-butinoremethyl ether
  • acid nitriding agents oxalyl chloride, thionyl chloride, etc.
  • the obtained acid chloride is used in an organic solvent (dioxane, tetrahydrofuran, dichloromethane, etc.) in a phase transfer catalyst (tetrabutylammonium chloride, triethylbenzylammonium chloride, tri-n-octylmethylammonium chloride, In the presence or absence of quaternary ammonium salts such as trimethyldecyl ammonium chloride, tetramethyl ammonium chloride, etc.
  • the reaction can also be carried out by reacting with amines at 0 to 40 ° C. using an aqueous alkali solution (such as aqueous sodium bicarbonate or sodium hydroxide solution).
  • a method using a mixed acid anhydride is, for example, a method in which a carboxylic acid is used in an organic solvent (such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, tert butyl methyl ether) or without a solvent in a base (pyridine , Triethylamine, dimethylamine, dimethylaminoviridine, diisopropylethylamine, etc., in the presence of acid halides (pivaloyl alkride, tosyl lipride, mesyl lipride, etc.), or acid derivatives (black ethyl formate,
  • the resulting mixed acid anhydride is reacted with an amine in an organic solvent (such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, tert-butyl methyl ether, etc.) at 0 to 40 ° C. The reaction is carried out at 0 to 40
  • a method using a condensing agent includes, for example, carboxylic acid and amine in an organic solvent (such as chloroform, formaldehyde, dichloromethane, dimethyl ether, tetrahydrofuran, tert-butyl methyl ether) or In a solvent, in the presence or absence of a base (pyridine, triethylamine, dimethylaminoline, dimethylaminopyridine, etc.), a condensing agent (1,3 dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [ 3— (Dimethylamino) propyl] carbodiimide (EDC), 1,1, -carbodiimidazole (CDI), 2—black mouth—1 methylpyridyl-mu-iodine, 1 propylphosphonic acid cyclic anhydride (1 propanephosphonic acid Cyclic anhydride, PPA), etc.) and 1-hydroxybenzotriazole (HO
  • the deprotection reaction of the protecting group can be performed by the same method as described above.
  • Z may have a substituent containing a nitrogen atom, D may be a heterocyclic ring, D may be a sulfonyl group or a carbo group, W is an oxygen atom, a single NR 11 group, a CH—O group or a sulfur atom, and one of the nitrogen atoms in the ring is bonded to X.
  • X is a compound in which the group adjacent to Z is —CH 2 or a carbonyl group
  • DAP is a force group having the same meaning as D, and when it contains a carboxyl group, a hydroxyl group, an amino group or a mercapto group, it should be protected if protection is required. It represents the same meaning as described above.
  • x AP and z AP are protected when a protection group is required when a carboxyl group, a hydroxyl group, an amino group or a mercapto group is contained in the force group having the same meaning as X and Z, respectively.
  • the compound represented by formula (1) can be produced by subjecting it to an ether reaction and, if necessary, subjecting it to a deprotection reaction of a protecting group.
  • the etherification reaction is known, for example, in an organic solvent (dichloromethane, jetyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, tert butyl methyl ether, etc.), an azo compound (jet dicarboxylate (DEAD), azodicarboxylate).
  • organic solvent dichloromethane, jetyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, tert butyl methyl ether, etc.
  • an azo compound jet dicarboxylate (DEAD), azodicarboxylate
  • Disopropyl acid 1,1 '-(azodicarbol) dipiperidine, 1,1'-azobis (N, N dimethylformamide) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer support)
  • 1,1'-azobis N, N dimethylformamide
  • phosphine compounds triphenylphosphine, tributylphosphine, trimethylphosphine, polymer support
  • the deprotection reaction of the protecting group can be performed by the same method as described above.
  • the compound represented by the general formula (1-3) is a compound represented by the general formula (II-6)
  • This reaction is known, for example, hydrogen in an organic solvent (acetone, acetonitrile, tetrahydrofuran, dimethoxyethane, dimethylformamide, dimethylacetamide, dimethylimidazolidinone, etc.) at 0 to 130 ° C.
  • organic solvent acetone, acetonitrile, tetrahydrofuran, dimethoxyethane, dimethylformamide, dimethylacetamide, dimethylimidazolidinone, etc.
  • Sodium hydride, lithium hydride, tert-butoxy potassium sodium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate, sodium hydroxide, etc. In the presence or absence of.
  • the deprotection reaction of the protecting group can be performed by the same method as described above.
  • reaction of the compound represented by the general formula (II 7) and the compound represented by the general formula (X-2) is publicly known.
  • an organic solvent toluene, N, N dimethylformamide, dimethylacetamide).
  • palladium reagent diacetyloxypalladium, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) Palladium ( ⁇ )) Phosphorus ligand reagent
  • BINAP ((S) — (—)-2,2, —Bis (diphf-ruphosphino) 1,1, -binaphthyl ((S) -BINAP) or (R) — (—) — 2, 2, bis (diphenyl-phosphit
  • the deprotection reaction of the protecting group can be performed by the same method as described above.
  • W is an optionally substituted CH—O group.
  • R 111AP and R 112AP independently represent the same meaning as R 111 and R 112 , respectively, but are protected when protection is required, and other symbols have the same meaning as described above.
  • the compound represented by the general formula (X-1) can be prepared by subjecting the compound to a reaction, followed by deprotecting the protecting group as necessary.
  • reaction of the compound represented by the general formula (II 8) and the compound represented by the general formula (X-1) is publicly known.
  • an organic solvent acetone, acetonitrile, tetrahydrofuran, dimethoxyethane, dimethylformamide, Dimethylacetamide, dimethylimidazolidinone, etc.
  • 0-1 At 30 ° C, in the presence or absence of a base (sodium hydride, lithium hydride, tert-butoxypotassium, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate, sodium hydroxide, etc.) ,It can be carried out.
  • the deprotection reaction of the protecting group can be performed by the same method as described above.
  • W is a carbon atom having a hydroxyl group as a substituent, and W, X, and Z together contain one or more nitrogen atoms
  • reaction of the compound represented by the general formula (II 6) and the compound represented by the general formula (X-4) is publicly known.
  • an organic solvent for example, tetrahydrofuran, jetyl ether, dimethoxyethane, dichloromethane, Base (tert butyl lithium, n butyl lithium, LDA (lithium dipropyl pyramide), isopropyl magnesium promide, metallic magnesium, metallic lithium, etc. at 78 ° C to 80 ° C in toluene, benzene, tert butyl methyl ether, etc. )
  • HMPA hexamethylphosphoramide
  • TMEDA tetramethylethylenediamine
  • the deprotection reaction of the protecting group can be performed by the same method as described above.
  • J and L 1 each independently represent a leaving group such as a halogen atom, a methanesulfoloxy group, a benzenesulfoloxy group, a toluenesulfoloxy group, and Q 1 is It represents a protecting group for a hydroxyl group, an amino group or a mercapto group, Q 2 represents a protecting group for a carboxyl group, and Q 3 represents a protecting group for a hydroxyl group.
  • L1A1H4 represents lithium aluminum hydride and DIBAH represents diisobutylaluminum hydride. Other symbols represent the same meaning as described above.
  • reaction involving heating can be performed using a water bath, an oil bath, a sand bath, or a microwave reactor, as will be apparent to those skilled in the art.
  • a polymer for example, polystyrene, Solid phase supported reagents supported on acrylamide, polypropylene, polyethylene glycol, etc.
  • a polymer for example, polystyrene, Solid phase supported reagents supported on acrylamide, polypropylene, polyethylene glycol, etc.
  • the reaction product is obtained by a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin. It can be purified by methods such as scavenger rosin, force ram chromatography, washing and recrystallization. Purification can be done for each reaction, and V, after several reactions have been completed.
  • a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin. It can be purified by methods such as scavenger rosin, force ram chromatography, washing and recrystallization. Purification can be done for each reaction, and V, after several reactions have been completed.
  • alkyl, alkyl, alkyl, alkoxy, alkylthio, alkylene, alkylene, alkylene, alkylidene, alkylkelidene and alkylidene groups are linear. And branched chains are included.
  • isomers (E, Z, cis, trans isomers) in double bonds, rings, fused rings, isomers due to the presence of asymmetric carbon (R, S isomer, a, ⁇ configuration, enantiomers, diastereomers),
  • Optically active isomers with optical activity (D, L, d, 1), tautomers, polar isomers by chromatographic separation (high polarity, low polarity), equilibrium compounds, rotamers, any of these
  • a mixture of proportions, a racemic mixture are all included in the present invention.
  • optically active compound in the present invention is not limited to a substantially pure compound, and may contain other optical isomers of less than 50%.
  • the salts of the compound represented by the general formula (I) include all pharmacologically acceptable salts.
  • the pharmacologically acceptable salt is preferably non-toxic and water-soluble.
  • Suitable salts of the compound represented by the general formula (I) include, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts (tetramethylammonium).
  • Suitable solvates of the compound represented by formula (I) include solvates such as water and alcohol solvents (ethanol and the like).
  • the solvate is preferably non-toxic and water-soluble.
  • the solvates of the compounds of the present invention also include solvates such as alkali (earth) metal salts, ammonium salts, organic amine salts and acid adduct salts of the compounds of the present invention.
  • the salts of the present invention that can be converted into the above-mentioned salts and the above-mentioned solvates by a known method include quaternary ammonium salts.
  • a quaternary ammonium salt is represented by the general formula (I). In this case, the nitrogen atom of the compound is quaternized with a group (R group is Cl to 8 alkyl group, Cl to 8 alkyl group substituted by a phenyl group).
  • Salts also include N-aged xoxide.
  • the compound of the present invention can be converted to N-oxide by any method.
  • N-oxide represents a compound of general formula (I) that has been oxidized by nitrogen atom force.
  • a prodrug of the compound represented by the general formula (I) 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 in a living body.
  • a prodrug of the compound represented by the general formula (I) for example, when the compound represented by the general formula (I) has an amino group, the amino group is acylated, alkylated, or phosphorylated.
  • Compound (for example, the amino group of the compound represented by the general formula (I) is converted to eicosanolation, alanylation, pentylaminocarbolation, (5-methyl-2-oxo-1,3-dioxolene-4-yl) methoxycarboxylation.
  • the compound represented by formula (I) has a hydroxyl group
  • the prodrug of the compound represented by the general formula (I) may be either a hydrate or a non-hydrate.
  • prodrugs of compounds represented by general formula (I) are described in Yodogawa Shoten, 1990, “Development of Drugs”, Vol. 7, “Molecular Design”, pages 163-198.
  • it may be changed to a compound represented by the general formula (I) under physiological conditions.
  • the compound represented by the general formula (I) may be labeled with an isotope (eg, 3 H, “C, 35 S, 1251, etc.).
  • the compound represented by the general formula (I), a salt thereof, a solvate thereof, or a prodrug thereof (hereinafter sometimes abbreviated as the compound of the present invention) has very low toxicity and is used as a medicine. Safe enough to do.
  • N-type calcium channel-mediated diseases such as pain (for example, acute pain, chronic pain, postoperative pain, cancer pain, neuralgia, infectious pain, etc.) Cerebral infarction, transient cerebral ischemic attack, cerebrospinal disorder after cardiac surgery, spinal vascular disorder, stress hypertension, neurosis, epilepsy, asthma, frequent urination, eye disease (eg glaucoma, diabetic retinopathy, It is useful as a preventive and Z or therapeutic agent for macular degeneration, retinal vascular occlusion, etc.
  • pain for example, acute pain, chronic pain, postoperative pain, cancer pain, neuralgia, infectious pain, etc.
  • Cerebral infarction transient cerebral ischemic attack
  • cerebrospinal disorder after cardiac surgery spinal vascular disorder
  • stress hypertension e.g., neurosis, epilepsy
  • asthma frequent urination
  • eye disease eg glaucoma, diabetic retinopathy, It is useful as a preventive and Z
  • the compound of the present invention comprises 1) supplementation and Z or enhancement of the prevention and Z or therapeutic effects of the compound of the present invention, 2) kinetics of the compound of the present invention 'improvement of absorption, dose reduction and Z or 3) the present invention To reduce compound side effects, combine with other drugs and administer as a concomitant drug.
  • the combination of the compound of the present invention and another drug may be administered in the form of a combination drug in which both components are mixed in one preparation, or may be in the form of separate preparations.
  • simultaneous administration and administration by time difference are included.
  • administration by time difference may be such that the compound of the present invention is administered first and the other drug may be administered later, or the other drug is administered first and the compound of the present invention is administered later.
  • Each administration method is the same or different.
  • the other drug may be a low molecular compound or a high molecular protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy, antibody, or vaccine. Etc.
  • the dosage of other drugs can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and other drugs It can be appropriately selected depending on the age and weight of the subject, administration method, administration time, target disease, symptom, combination and the like.
  • the other drug may be used in an amount of 0.01 to 100 parts by mass with respect to 1 part by mass of the compound of the present invention.
  • the other drugs may be administered by combining at least one selected from the following homogeneous groups and heterogeneous groups in an appropriate ratio.
  • Any disease that complements and enhances or enhances the preventive and Z or therapeutic effects of the compound of the present invention may be used.
  • drugs for complementing and enhancing or enhancing the effects of the compound of the present invention on pain include, for example, narcotic or non-narcotic analgesics, nonsteroidal anti-inflammatory drugs, antipyretic analgesics, antiepileptic drugs.
  • Drugs, antiarrhythmic drugs, antidepressants, anxiolytics, antipsychotics, corticosteroids, antihistamines, local anesthetics, NMDA antagonists, migraine treatments, painful diabetic neuropathy, calcium Examples include channel modulators and analgesics.
  • drugs for complementing and enhancing or enhancing the effects of the compound of the present invention on cerebral infarction include, for example, antiepileptic drugs, acetylcholinesterase inhibitors, neurotrophic factors, and aldose reductase inhibition.
  • Drugs antithrombotic drugs, oral anticoagulants, synthetic antithrombin drugs, antiplatelet drugs, thrombolytic drugs, factor Xa inhibitors, factor Vila inhibitors, cerebral circulation metabolism improvers, antioxidants, glycerin preparations, ⁇ -secretase inhibitors Drugs, ⁇ -amyloid protein aggregation inhibitor, brain function activator, dopamine receptor agonist, monoamine acid ⁇ enzyme ( ⁇ ) inhibitor, anticholinergic agent, COMT inhibitor, amyotrophic lateral sclerosis treatment Drugs, statins, antihyperlipidemics, fibrates, antiapoptotics, neurodevelopmental regeneration promoters, nonsteroidal anti-inflammatory drugs, steroids, Sex hormone or its derivatives, nicotine receptor modulator, ⁇ secretase inhibitor, amyloid vaccine, ⁇ - amyloidase , squalene synthetase inhibitor, therapeutic agent for abnormal behavior and epilepsy associated with dementia progression, antihypertensive, diabetes Therapeutic agents, antidepressants, anti
  • the other compounds for the prevention and sputum or therapeutic effect of frequent urination of the compounds of the present invention and sputum or enhancement include, for example, anticholinergic drugs, tricyclic antidepressants, a agonist, a antagonist, GABA agonist, antidiuretic, anti-androgen, luteinizing hormone, P2X antagonist, LPA, EP antagonist, capsaicin (resi-feratoxin), 5 ⁇ reda
  • Cutase inhibitor 5— ⁇ reuptake inhibitor, 5— ⁇ antagonist, ACh antagonist, Hpro
  • Examples of the therapeutic agent for painful diabetic neuropathy include mexiletine hydrochloride and the like.
  • analgesic adjuvants include bisphosphonates used for bone metastasis of cancer. For example, alendronate, risedronate, minodronate, incadronate, clodronate, chinoledronic acid, etidronate, innocronate, pyridronate, nomidronate, zoledronic acid, olpadronate, neridronate and the like.
  • Examples of calcium channel modulators include gabapentin, technotide, tregilobaline, and the like.
  • acetylcholinesterase inhibitor examples include donevezil hydrochloride, TAK-147, rivastigmine, galantamine and the like.
  • neurotrophic factor examples include ABS-205.
  • antithrombotic agents include t t, heparin, and the like.
  • an oral anticoagulant for example, phafarin and the like can be mentioned.
  • Examples of the synthetic antithrombin drug include gabexate mesylate, nafamostat mesylate, and argatroban.
  • antiplatelet drug examples include aspirin, dipyridamole, ticlovidin hydrochloride, beraprost sodium, cilostazol, ozadarel sodium and the like.
  • thrombolytic drug examples include urokinase, tisokinase, alteplase and the like.
  • drugs for improving cerebral circulation metabolism include idebenone, calcium hovantenate, amantadine hydrochloride, meclofenoxate hydrochloride, dihydroergotoxine mesylate, and pyritio hydrochloride.
  • idebenone calcium hovantenate
  • amantadine hydrochloride meclofenoxate hydrochloride
  • dihydroergotoxine mesylate dihydroergotoxine mesylate
  • pyritio hydrochloride examples include idebenone, calcium hovantenate, amantadine hydrochloride, meclofenoxate hydrochloride, dihydroergotoxine mesylate, and pyritio hydrochloride.
  • Xin ⁇ -aminobutyric acid, bifuemalan hydrochloride, lisuride maleate, indeloxazine hydrochloride, -sergoline, propentofylline and
  • anti-acid glaze examples include edaravone.
  • glycerin preparation examples include glycerol.
  • ⁇ -secretase inhibitors include 6- (4-biphenyl-methoxy) 2- [2—
  • ⁇ -amyloid protein aggregation inhibitory agents include, for example, PTI-00703, ALZHEMED (NC-531), ⁇ -368 (Special Tables Hei 11-514333), ⁇ -558 (Special Tables 2001-500852), SKF -74652 (Bioc hem. J., 340 (1) ⁇ , 283-289, 1999).
  • Examples of the brain function activator include arracetam and -sergoline.
  • Examples of the donomin receptor agonist include L-dopa, promocributin, pergolide, talipexol, pramipexole, strength belgolin, amantadine and the like.
  • Examples of monoamine oxidase (MAO) inhibitors include safradin, deplel, selegiline (selegiline), remasemide, riluzole and the like.
  • Anticholinergic agents include, for example, oxybutchunic hydrochloride, betanecol chloride, propiverine hydrochloride, propantheline bromide, odorous methylbenactidime, butylscopolamine bromide, alcohol Tolterodine Irate, Trospium Chloride, Z-338, UK-112166-04, KRP-197 (ONO-8025)
  • COMT inhibitor examples include entacapone and the like.
  • Examples of the therapeutic agent for amyotrophic lateral sclerosis include riluzole.
  • statins for treating hyperlipidemia include pravastatin sodium, atostastastatin, sympastatin, rospastatin and the like.
  • fibrate hyperlipidemia therapeutic agent examples include clofibrate.
  • apoptosis inhibitor examples include CPI-1189, IDN-6556, CEP-1347 and the like.
  • neuronal differentiation 'regeneration promoter examples include retepurinim, xalibroden (SR-5774 6-A), SB-216763, and the like.
  • Examples of the steroid drug include dexamethasone, hexestrol, cortisone acetate and the like.
  • sex hormones or derivatives thereof include progesterone, estradiol, estradiol benzoate and the like.
  • agonists include SL-251039, midodrine hydrochloride, ABT-866, etc.
  • antagonists include terazosin hydrochloride, bunazosin hydrochloride, urapidil, tamsucine hydrochloride, doxazosin mesylate, prazosin hydrochloride , Indolamine, naphthovir, alfuzosin hydrochloride and the like.
  • Examples of the 5 ⁇ -reductase inhibitor include finasteride and GI-998745.
  • Examples of 5- reuptake inhibitors include duloxetine hydrochloride and the like.
  • Examples of the 5- ⁇ antagonist include REC-15-3079 and the like.
  • Examples of the ACh antagonist include oxiputinin and the like.
  • H blocker examples include tecastemisole, levocabastine hydrochloride, istemizole, nortememisole, diphenhydramine, chlorfelamin maleate and the like.
  • potassium channel modulators include NS-4591, ABT-598, AZD-0947, NS-8, YM-934, ZD-6169, WAY-151616, A-278637, and the like.
  • Muscarin (M ⁇ agonists include, for example, albamerine maleate and fesoterodine.
  • muscarinic (M, M) antagonists examples include YM905, KRP-197, ONO-8025, Bami
  • norepinephrine reuptake inhibitor examples include S-didesmethylsibutramine and the like.
  • Neurocun (NK, NK, NK) antagonists include, for example, TAK-637, SSR-24060
  • Vasopressin V agonists include, for example, OPC-51803, WAY-141608, FE-106483
  • Examples of the ⁇ agonist include KUC-7483 and the like.
  • dopamine reuptake inhibitors examples include S-didesmethylsibutramine.
  • drugs that complement and / or enhance the prophylactic and / or acupuncture or therapeutic effects of the compounds of the present invention are not only those that have been found to date based on the mechanism described above, but will be used in the future. This includes what is found.
  • a pharmaceutical composition comprising the compound of the present invention or a concomitant agent of the compound of the present invention and another drug for the above purpose, it is usually administered systemically or locally in an oral or parenteral form.
  • the dosage, age, body weight, symptom, therapeutic effect, administration method, the processing time and the like usually, adult per capita, at a time, over date over times mosquitoes even several times in the range of 100 / ⁇ of 1,000,111 8 Orally administered, or parenterally once or several times a day in the range of 50 / zg to 500 mg per adult, or intravenously in the range of 1 to 24 hours per day It is administered continuously.
  • a pharmaceutical composition comprising the compound of the present invention or a combination agent of the compound of the present invention and another drug is administered, for example, a solid preparation for internal use for oral administration, a liquid preparation for internal use, and parenteral administration Used as injections, external preparations, suppositories, eye drops, inhalants and the like.
  • solid preparations for internal use for oral administration include tablets, pills, capsules, powders, and condyles.
  • capsules include node capsules and soft capsules.
  • one or more kinds of active substances are used as they are, or excipients (for example, latatose, mannitol, glucose, microcrystalline cellulose, starch, etc.), Binder (for example, hydroxypropyl cellulose, polyvinyl pyrrolidone, magnesium aluminate, etc.), disintegrant (for example, calcium calcium glycolate), lubricant (for example, magnesium stearate), stabilizer, dissolution It is mixed with an auxiliary agent (for example, dartamic acid, aspartic acid, etc.), etc., and is used after being formulated according to a conventional method.
  • excipients for example, latatose, mannitol, glucose, microcrystalline cellulose, starch, etc.
  • Binder for example, hydroxypropyl cellulose, polyvinyl pyrrolidone, magnesium aluminate, etc.
  • disintegrant for example, calcium calcium glycolate
  • lubricant for example, magnesium stearate
  • a coating agent for example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose phthalate, etc.
  • a coating agent for example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose phthalate, etc.
  • capsules of absorbable substances such as gelatin.
  • Liquid preparations for internal use for oral administration include, for example, pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like.
  • a solution one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (for example, purified water, ethanol or a mixture thereof).
  • this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
  • dosage forms for external use for parenteral administration include ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, aerosols, eye drops. And nasal drops. These contain one or more active substances and are prepared by known methods or commonly used formulations.
  • the ointment is produced by a known or commonly used formulation. For example, it is prepared by mixing or melting one or more active substances in a base. Ointment bases are known or The power that is normally used is selected. For example, higher fatty acid or higher fatty acid ester (for example, 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 (eg, beeswax, whale wax, ceresin, etc.), surfactants (eg, polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (eg, cetanol, stearyl alcohol, cetostearyl alcohol, etc.) , Silicone oil (for example, dimethylpolysiloxane), hydrocarbons (for example, hydrophilic petrolatum, white petrol, etc.
  • the gel is produced by a known or commonly used formulation. For example, it is prepared by melting one or more active substances in a base.
  • the gel base may be selected from known or commonly used forces.
  • lower alcohol eg, ethanol, isopropyl alcohol, etc.
  • gelling agent eg, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.
  • neutralizing agent eg, triethanolamine, Diisopropanolamine, etc.
  • surfactants eg, polyethylene glycol monostearate
  • gums water, absorption promoters, anti-rash agents
  • One or more types are used in combination.
  • it contains preservatives, antioxidants, and flavoring agents.
  • the cream is produced by a known or commonly used formulation. For example, it is prepared by melting or emulsifying one or more active substances in a base.
  • the cream base is selected from known or commonly used cream bases. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (eg, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (eg, 2-hexyldecanol, cetanol, etc.)
  • Emulsifiers for example, polyoxyethylene alkyl ethers, fatty acid esters, etc.
  • a mixture of one or more selected from water, absorption promoters and anti-rash agents is used.
  • the poultice 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 applying it as a kneaded product on a support.
  • the poultice base is selected from known or commonly used ones. For example, thickeners (eg, polyacrylic acid, polybulurpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (eg, urea, glycerin, propylene glycol, etc.), fillers (eg, kaolin, Zinc oxide, talc, calcium, magnesium, etc.), water, solubilizers, tackifiers and anti-rash agents are used in admixture. 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 and spreading and coating them on a support.
  • the base for patch is selected from known or commonly used ones. For example, one or more selected from polymer bases, oils and fats, higher fatty acids, tackifiers, and anti-rash agents can be used. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.
  • 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 (eg, ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soap, emulsifier, suspending agent, etc. Prepared. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • Sprays, inhalants, and sprays are buffers that provide isotonicity with stabilizers such as sodium bisulfite in addition to commonly used diluents, such as sodium chloride salt, sodium quenate, May contain isotonic agents such as citrate.
  • stabilizers such as sodium bisulfite
  • diluents such as sodium chloride salt, sodium quenate
  • isotonic agents such as citrate.
  • injections for parenteral administration include solutions, suspensions, emulsions, and solid injections used by dissolving or suspending in a solvent at the time of use.
  • An injection is used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • a solvent for example, distilled water for injection Saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used.
  • distilled water for injection Saline vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used.
  • the injection here is distilled water for injection Saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used. Furthermore, the injection here
  • Stabilizers eg, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.
  • suspending agents eg, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.
  • suspending agents eg, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.
  • suspending agents eg, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.
  • suspending agents eg.g, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.
  • suspending agents eg.g, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.
  • suspending agents eg.g, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.
  • suspending agents eg.g, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc
  • Eye drops for parenteral administration include ophthalmic solutions, suspension-type eye drops, emulsion-type eye drops, use-dissolving eye drops, and eye ointments.
  • Eye drops are produced according to known methods. For example, it is used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • a solvent for example, sterilized purified water, physiological saline, other aqueous solvents or non-aqueous preparations for injection (for example, vegetable oil) and the like, and combinations thereof are used.
  • Eye drops include isotonic agents (eg, sodium chloride, concentrated glycerin, etc.), buffering agents (eg, sodium phosphate, sodium acetate, etc.)
  • Surfactants eg, polysorbate 80 (trade name), polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil, etc.
  • stabilizers eg, sodium citrate, sodium edetate, etc.
  • preservatives eg, (Salmon benzalcoum, paraben, etc.
  • an aseptic solid preparation for example, a freeze-dried product, can be produced and used by dissolving in aseptic or aseptically purified water or other solvent before use.
  • Inhalants for parenteral administration include aerosols, inhalation powders or inhalation solutions, which are dissolved or suspended in water or other suitable medium at the time of use.
  • the form to use may be sufficient.
  • preservatives eg, salt benzalcoum, parabens, etc.
  • coloring agents e.g., coloring agents, buffering agents (eg, sodium phosphate, sodium acetate, etc.), isotonicity Agents (for example, sodium chloride salt, concentrated glycerin, etc.), thickeners (for example, cariboxybule polymer) Etc.), absorption accelerators and the like are appropriately selected as necessary.
  • lubricants eg, stearic acid and its salts
  • binders eg, starch, dextrin, etc.
  • excipients eg, lactose, cellulose, etc.
  • coloring It is prepared by appropriately selecting agents, preservatives (eg, salt benzalcoum, parabens, etc.), absorption promoters and the like as necessary.
  • a nebulizer for example, an atomizer, a nebulizer, etc.
  • an inhaler for powder medicine is usually used.
  • compositions for parenteral administration include suppositories for rectal administration and pessaries for intravaginal administration that contain one or more active substances and are prescribed by conventional methods.
  • the compound of the present invention has, for example, an inhibitory action on N-type calcium channels, N-type calcium channel-mediated diseases (for example, cerebral infarction, transient ischemic attack, cerebrospinal injury after cardiac surgery, It is useful as a preventive and Z or therapeutic agent for spinal vascular disorders, stress hypertension, neurosis, epilepsy, asthma, frequent urination, eye diseases, etc.).
  • N-type calcium channel-mediated diseases for example, cerebral infarction, transient ischemic attack, cerebrospinal injury after cardiac surgery, It is useful as a preventive and Z or therapeutic agent for spinal vascular disorders, stress hypertension, neurosis, epilepsy, asthma, frequent urination, eye diseases, etc.).
  • the compound of the present invention represented by the general formula (I) is useful as a preventive and Z or therapeutic agent for pain (for example, acute pain, chronic pain, postoperative pain, cancer pain, neuralgia, infectious pain, etc.). is there.
  • Chromatographic separation site, solvent in Katsuko shown in TLC indicates the elution solvent or developing solvent used, and the ratio indicates volume ratio.
  • the ammonia water used for TLC was 28% ammonia water.
  • Solvent Liquid A: 0.1% trifluoroacetic acid aqueous solution
  • Liquid B 0.1% trifluoroacetic acid acetonitrile solution.
  • Example 5 4— ⁇ 2— [3 (Jetylamino) 1 pyrrolidyl] ethoxy ⁇ N ethyl N-phenylbenzenesulfonamide 'dihydrochloride
  • Example 5 4- [2- (Jetylamino) ethoxy] —N ethyl N-phenol benzenesulfonamide hydrochloride
  • Example 5 4— ⁇ 2— [3 (Jetylamino) 1 pyrrolidyl] ethoxy ⁇ —N, N— Jetylbenzenesulfonamide. Dihydrochloride
  • Example 5 (10): 4- [2- (Jetylamino) ethoxy] -N, N Jetylbenzenesulfonamide 'hydrochloride
  • Example 5 N-Cyclohexyl 4 ⁇ 2— [3 (Jetylamino) 1 pyrrolidyl] ethoxy ⁇ -N-ethylbenzenesulfonamide dihydrochloride
  • Example 5 N-Cyclohexyl 4 [2 (Jetylamino) ethoxy] -N ethylbenzenesulfonamide hydrochloride
  • Example 5 (13): N— (4 ⁇ 2— [3 (Jetylamino) 1 pyrrolidyl-ethoxy] phenenole) N ethenorebenzenesulefonamide
  • ⁇ Bebebe ⁇ (/ ⁇ ⁇ /
  • VL 6VL '(HS' ⁇ ) TZ—W '( ⁇ ' s) 60 "Z '(HS' ⁇ ) ⁇ 0 ⁇ -86 ⁇ 9 '( ⁇ 2' ⁇ ) ⁇ 8 ⁇ 9 ' ⁇ ') 8 ⁇ ' ⁇ ') Z'f ' ⁇ ') OS'S Wl-ZZ'l '(HS S8'0 9-(OQD) H NH T
  • Example 5 Ethyl 1 [2- (4-— ⁇ [Butyl (phenyl) amino] sulfol ⁇ phenoxy) ethyl] -4-piperidinecarboxylate HPMC retention time: 3.68 min; MS (LC-
  • Example 5 N-butyl-4 [2- (4-methyl-1-piberidyl) ethoxy] -N phenol benzenesulfonamide HPMC retention time: 3.68 min; MS (LC-MS, ESI, Pos.
  • Example 5 4— [2— (1azepar-ethoxy) ethoxy] N-butyl-N-phenolbenzenesulfonamide HPMC retention time: 3.66 minutes; MS (LC-MS, ESI, Pos .20 V), 431 (
  • Example 5 N-butyl 4- (2-octahydro-2- (1H) -isoquinolinylethoxy) -N-phenolbenzenesulfonamide HPMC retention time: 3.81 min; MS (LC- MS, ESI, Pos. 20 V), 471 ( ⁇ + ⁇ ) +.
  • Example 5 tertbutyl 1 [2- (4 ⁇ [ptyl (phenyl) amino] sulfol ⁇ phenoxy) ethyl] -3 pyrrolidyl-carbamate HPMC retention time: 3.76 min; MS (L
  • Example 5 4— ⁇ 2— [4 (4-Bromophenol) -4-hydroxy-1-pivelyl] ethoxy ⁇ —N-butyl-N-phenolbenzenesulfonamide HPMC retention time:
  • Example 5 (44): ⁇ 2— [(4 &! ⁇ , 8aS) —octahydro 2 (1H) —isoquinolinyl] ethoxy ⁇ —N butyl N phenol benzenesulfonamide HPMC retention time: 3.82 Min
  • Example 5 (4— ⁇ 2— [(4 & 3, 8aS) —octahydro 2 (1H) isoquinolinyl] ethoxy ⁇ —N butyl N phenol benzenesulfonamide HPMC retention time: 3.80 minutes
  • Example 5 tert butyl (3S) — 1 [2— (4 ⁇ [(ptyl (phenol) amino] sulfur ⁇ phenoxy) ethyl] -3-pyrrolidylcarbamate HPMC retention Time: 3.74 min; (LC-MS, ESI, Pos. 20 V), 518 (M + H) +.
  • Example 5 (71): N-butyl-4 ⁇ 2- [4 (3-hydroxyphenol) 1-piveridyl] ethoxy ⁇ N phenolbenzenesulfonamide HPMC retention time: 3.70 min; MS ( L
  • Example 5 N-Butyl-4 ⁇ 2- [3 (Jetylamino) 1 pyrrolidyl-ethyl] ⁇ -N phenolbenzenesulfonamide HPMC retention time: 3.40 min; MS (LC-MS
  • Example 5 N-Butyl-4 ⁇ 2— [4 (2-oxo-2,3 dihydro-1H benzimidazole-1-yl) 1-piveridyl] ethoxy ⁇ -N-phenylbenzenesulfonamide HPMC retention time: 3.66 min; MS (LC-MS, ESI, Pos. 20 V), 549 (M + H) +.
  • Example 5 4 -— (2— ⁇ 4 [Bis (4 fluorophenyl) methyl] 1-piperage ⁇ ethoxy) —N-butyl-N-phenolbenzenesulfonamide HPMC retention time :
  • Example 5 N-butyl-4 ⁇ 2- [4 (3-methoxyphenol) 1-piperazine] ethoxy ⁇ -N phenolbenzenesulfonamide HPMC retention time: 3.78 minutes MS (
  • Example 5 N-butyl N-phenyl—4— (2— ⁇ 4— [(2E) —3 phenol 2
  • Example 5 (92):? ⁇ — Butyl? ⁇ -Fe-Lou 4 ⁇ 2 -— [4- (4-Pyridyl) -1-piperazyl] ethoxy ⁇ benzenesulfonamide HPMC retention time: 3.38 min; MS (LC-MS
  • Example 5 (94): N-butyl-4 [2— (4 oxo 1 felt 1, 3, 8 triaza spiro [4. 5] dec-8-yl) ethoxy] —N phenol Benzenesulfonamide HPMC retention time: 3.73 min; MS (LC-MS, ESI, Pos. 20 V), 563 (M + H) +.
  • Example 5 (95): N-butyl-N phenol 4— [2— (4-ferro 1-pivelidyl) ethoxy] benzenesulfonamide HPMC retention time: 3.84 min; MS (LC- MS, ESI, Pos. 20 V), 493 (M + H) +.
  • N, N-deethylchloroacetamide (57 mg) and cesium carbonate (328 mg) were added to a solution of N-ethyl N-phenyl-4-hydroxyphenylsulfonamide (70 mg) in N, N-dimethylformamide (0.5 ml).
  • the mixture was stirred at 80 ° C for 5 hours.
  • the reaction mixture was extracted by adding tert-butyl methyl ether and water.
  • the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated.
  • the residue was purified by silica gel column chromatography to give the compound of the present invention (78 mg) having the following physical data.
  • Example 7 N-ethyl-4-methoxy-N-phenolpenamide
  • N-ethyl-4-methoxy-N-phenolpenamide In an argon atmosphere, dissolve Nethylaline (lg) and Triethylamine (3.5 mL) in salt methylene (30 mL), stir in ice-cooling, add 4-methoxybenzoic acid chloride (2.1 g), stir for 30 minutes. did. Water was added to the reaction mixture to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated.
  • Example 8 4— ⁇ 2— [3 (Jetylamino) 1 pyrrolidyl-ethoxy] N ethyl-N-phenol pensamide
  • Example 7 Using the compound prepared in Example 7, the title compound having the following physical property values was obtained in the same manner as in the method shown in Example 3 ⁇ Example 4 ⁇ Example 5. Further, a hydrogen chloride methanol solution was added to the compound and then concentrated to obtain the corresponding dihydrochloride.
  • ⁇ Bebebe ⁇ (ci i / 1 ⁇ )-

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Abstract

L’invention concerne un inhibiteur de canal de calcium de type N contenant un composé ayant une activité inhibitrice de canal de calcium de type N et représenté par la formule générale (I): (où les symboles sont les mêmes que ceux définis dans la description), un sel de celui-ci, un solvate de l’un ou l’autre, ou un promédicament de n’importe lequel de ceux-ci. Compte tenu de son activité inhibitrice de canal de calcium de type N, le composé sert d’agent préventif et/ou thérapeutique pour des maladies auxquelles participe le canal de calcium de type N, comme des douleurs (par exemple une douleur aiguë, une douleur chronique, une douleur postopératoire, une douleur cancéreuse, une névralgie et une douleur infectieuse), une attaque cérébrale, une attaque ischémique cérébrale transitoire, une encéphalomyélopathie après une opération cardiaque, des troubles spinovasculaires, une hypertension, une névrose, une épilepsie, de l’asthme, une urination fréquente et des maladies oculaires.
PCT/JP2005/018306 2004-10-04 2005-10-03 Inhibiteur de canal de calcium de type n WO2006038594A1 (fr)

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