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WO2002092606A1 - Derives d'imidazolidine fusionnes, leur procede de preparation et d'utilisation - Google Patents

Derives d'imidazolidine fusionnes, leur procede de preparation et d'utilisation Download PDF

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Publication number
WO2002092606A1
WO2002092606A1 PCT/JP2002/004640 JP0204640W WO02092606A1 WO 2002092606 A1 WO2002092606 A1 WO 2002092606A1 JP 0204640 W JP0204640 W JP 0204640W WO 02092606 A1 WO02092606 A1 WO 02092606A1
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optionally substituted
group
hydrogen atom
hydrocarbon group
substituted hydrocarbon
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Japanese (ja)
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WO2002092606A8 (fr
Inventor
Yasunori Funabashi
Masayuki Takizawa
Shinji Morimoto
Kohei Notoya
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to a novel condensed imidazolidine derivative useful as a medicament such as an agent for treating a joint disease, a method for producing the same, or an agent therefor.
  • Osteoarthritis is a progressive disease with degeneration and destruction of articular cartilage caused by aging, obesity> mechanical stress, inflammation, etc., and mainly occurs in the knee and hip joints.
  • anti-inflammatory drugs and hyaluronic acid preparations have been used as therapeutic agents mainly for the purpose of pain relief [Bad Etz Chin- (Bird, HA :), Drugs & Aging, 12, 87-95, 1998, Lund, B., Scandinavian Journal Rhematology (Scandinavian J. Rheumatol.), Vol. 27, pp. 32-37, 1998, and Ando Inoue, Diagnosis and treatment of osteoarthritis, Medical Shoin, 94-99, 1994].
  • Cartilage is formed from chondrocytes and a cartilage matrix produced by chondrocytes.
  • the matrix components are proteodalican, which has hydration ability and gives flexibility and elasticity to cartilage, and type II, which forms a reticulated skeleton. It is roughly divided into collagen.
  • Cartilage destruction in osteoarthritis can be divided into two stages: proteodalican degradation followed by type II collagen degradation [Poole, AR], Takashi Fujisawa (translation), protein nucleic acid enzymes, 40, 520—531, 1995, Takei Doi et al., The Bone, 1, 293—297, 2000].
  • Hymen ialdisine a compound derived from a marine sponge, has been reported to inhibit proteoglycan degradation from articular cartilage [Alison, MB (Alison, MB), The Journal of Pharmaceutical Sciences and Ande The Journal of Pharmacology and Experimental Therapeutics, Vol. 290, pp. 587-593, 1999], and a derivative of hymenialdisine, debromohymenialdisine (DBH), Inhibition of matrix meta-oral proteinase (MMP) mRNA production in articular chondrocyte culture system [Vasios, G. Proceedings of 1999 American College of Rheumatology Announcer Meeting, poster session! (Poster Session D), No. 1123], Protective effect on articular cartilage in animal models [Huibregtse, ⁇ ⁇ , et al., Proceedings of 1999 American College of Rheumatology Annual Meeting ), Poster Session D, No. 1102].
  • MMP matrix meta
  • R 1 represents one (S) n —; 2 or one NR 3 R 4 , n represents an integer of 0 to 2
  • R 2 represents a hydrogen atom, an optionally substituted hydrocarbon group or substituted
  • R 3 and R 4 are the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or A nitrogen-containing heterocyclic ring formed together with a nitrogen atom
  • R 5 is a hydrogen atom, and an optionally substituted hydrocarbon
  • R 6 represents a hydrogen atom, a hydrocarbon group which may be substituted, a cyano group, an acyl group, a propyloxyl group which may be esterified or amidated, or a heterocyclic group which may be substituted;
  • R 7 is an optionally substituted hydroxyl group;
  • R 8 and R 9 are each a hydrogen atom or an optionally substituted hydrocarbon group (R 5 and R 6 , R 5 and R 8 or R 8 And R 9 may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring),
  • R 1 Is a hydrogen atom, -ZR 15 (Z is _S0 2 —, SO—, _C ⁇ NR 18 S ⁇ 2 — (R 18 is 6 alkyl), — CONR 19 — (R 19 is —6 alkyl R 15 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) or — P ( ⁇ ) R 16 R 17 (R 16 and R 17 Represents an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group), and R 11 represents a hydrogen atom or an optionally substituted hydrocarbon group ( R 1Q and R 11 may together form a nitrogen-containing heterocyclic ring which may be substituted), R 12 and R 13 are each a hydrogen atom or an optionally substituted hydrocarbon group, or Together with the nitrogen atom to which it is attached forms a nitrogen-containing heterocycle, R 14 is a hydrogen atom, Or a hydrocarbon group or ZR 15 (Z and R 15 have the same meanings as described
  • R 14 represents an optionally substituted hydrocarbon group or ZR 15 (Z and R 15 have the same meanings as described above).
  • the present invention has been completed based on these findings. That is, the present invention
  • R 1 represents one (S) n —R 2 or —NR 3 R 4 , n represents an integer of 0 to 2, R 2 represents a hydrogen atom, or a substituted or unsubstituted hydrocarbon group.
  • R 3 and R 4 may be the same or different and represent a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted or
  • R 5 represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, an esterified or amidated nitrogen-containing heterocyclic ring formed together with a nitrogen atom A xyl group or an optionally substituted heterocyclic group,
  • R 6 represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or a heterocyclic group which may be substituted
  • 7 is an optionally substituted hydroxyl group
  • R 8 and R 9 are each a hydrogen atom or an optionally substituted hydrocarbon group (R 5 and R 6 , R 5 and R 8 or R 8 R 9 may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring),
  • R 10 is a hydrogen atom
  • _ZR 15 ( ⁇ one S0 2 -, -SO-, - CONR 18 SO 2 - (R 18 represents a CI- 6 alkyl), one CONR 19 - (R 19 is ( Or 6 represents an alkyl) or —CO—
  • R 15 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) or — P (0)
  • R 16 R 17 R 16 and R 17 each represent an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group
  • R 11 represents a hydrogen atom or an optionally substituted hydrocarbon group.
  • a hydrogen group (R 1 ° and R 11 may be taken together to form a nitrogen-containing heterocyclic ring which may be substituted);
  • R 12 and R 13 each represent a hydrogen atom or a carbon atom which may be substituted; hydrogen group, or a connexion nitrogen-containing heterocyclic ring such together with the nitrogen atom to which they are attached,
  • R 14 is a hydrogen atom, Conversion are optionally substituted hydrocarbon group or also -.
  • Z 15 (Z and R 15 are as defined above) shows the proviso, R 5 is a hydrogen atom, XY is
  • R 14 represents an optionally substituted hydrocarbon group or ZR 15 (Z and R 15 have the same meanings as described above).
  • R 1 is (S) n _R 2 or _NR 3 R 4 , n is an integer of 0 to 2, R 2 is a hydrogen atom, an optionally substituted hydrocarbon group or a substituted R 3 and R 4 may be the same or different and represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or a nitrogen atom to which they are bonded.
  • R 5 is a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or a substituted heterocyclic ring.
  • a heterocyclic group which may be Is or
  • R 6 represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, an esterified or amidated propyloxyl group or an optionally substituted heterocyclic group.
  • R 7 is an optionally substituted hydroxyl group;
  • R 8 and R 9 are each a hydrogen atom or an optionally substituted hydrocarbon group (R 5 and R 6 , R 5 and R 8 Or R 8 and R 9 may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring),
  • R 1 () is a hydrogen atom or _ZR 15 (Z - S0 2 - or - a CO-
  • R 15 is a optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • R 11 represents a hydrogen atom or an optionally substituted hydrocarbon group
  • R 12 and R 13 represent a hydrogen atom or an optionally substituted hydrocarbon group, respectively
  • R 14 represents a hydrogen atom, an optionally substituted hydrocarbon group or one ZR 15 (Z and R 15 have the same meanings as described above)
  • R 5 is a hydrogen atom,
  • R 14 represents an optionally substituted hydrocarbon group or ZR 15 (Z and R 15 have the same meanings as described above). Or a salt thereof or a sulfoxide thereof;
  • R 5 is an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or an optionally substituted heterocyclic group.
  • R 5 is an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or an optionally substituted heterocyclic group.
  • R 6 is a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group
  • R 7 is an optionally substituted hydroxyl group or an optionally substituted heterocyclic group
  • R 7 is an optionally substituted hydroxyl group
  • R 8 and R 9 are each a hydrogen atom or a substituted
  • R 10 is a hydrogen atom, one ZR 15 (Z one S0 2 -, One SO-, One C_ ⁇ _NR 18 S_ ⁇ 2 one (R 18 is (: 6 represents an alkyl), - CONR 19 - (R 19 ⁇ - a indicates to) or single CO- 6 alkyl, R 15 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) or - P (O) R 16 R 17 (R 16 and R 17 each represent an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group), and R 11 represents a hydrogen atom or a substituted R 1 Q and R 11 may be taken together to form a nitrogen-containing compound ring which may be substituted, and R 12 and R 13 are each a hydrogen atom or (1) a hydrocarbon group which may be substituted, or a nitrogen-containing heterocyclic ring together with a nitrogen atom to which they are bonded].
  • R 1C1 represents a hydrogen atom or _ZR 15 (Z represents one S ⁇ 2 — or —C ⁇ one, and R 15 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. ), R 11 is a hydrogen atom or an optionally substituted hydrocarbon group, and R 12 and R 13 are each a hydrogen atom or an optionally substituted hydrocarbon group, or a nitrogen atom to which they are bonded. Together with a nitrogen-containing heterocycle].
  • R 1Q is — S ⁇ 2 R 15 (R 15 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and R 5 and R 6 are each substituted Or (8) a hydrocarbon group which may be substituted or an optionally substituted cyclic hydrocarbon or an optionally substituted heterocyclic ring which are formed together, and wherein R 11 is a hydrogen atom.
  • R 15 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • R 5 and R 6 are each substituted Or (8) a hydrocarbon group which may be substituted or an optionally substituted cyclic hydrocarbon or an optionally substituted heterocyclic ring which are formed together, and wherein R 11 is a hydrogen atom.
  • R 1 is one SR 2 (R 2 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group).
  • R 2 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group.
  • Compound; (11) The compound according to the above (10), wherein R 2 is an optionally substituted hydrocarbon group;
  • R 1 is one SR 2 (R 2 is an optionally substituted alkyl group having 1 to 8 carbon atoms, an alkenyl group optionally having 2 to 8 carbon atoms, A cycloalkyl group having 3 to 8 carbon atoms or an aralkyl group having 7 to 10 carbon atoms which may be substituted), wherein R 15 is an optionally substituted phenyl group, an optionally substituted benzyl group Or the optionally substituted phenyl group, the compound according to the above (9), wherein both R 5 and R 6 are methyl groups;
  • R 1G is —COR 15 (R 15 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and R 5 and R 6 are each substituted.
  • a hydrocarbon group which may be optionally substituted or an optionally substituted cyclic hydrocarbon or an optionally substituted heterocyclic ring which are formed together, wherein R 11 is a hydrogen atom;
  • a pharmaceutical composition comprising the compound (I) according to the above (1) or a salt thereof, a sulfoxide thereof or a prodrug thereof;
  • composition according to the above (30) which is an agent for preventing or treating a disease caused by cartilage destruction; (35) the pharmaceutical composition according to the above (30), which is a matrix meta-oral proteinase gene expression inhibitor;
  • a proteoglitin degradation inhibitor comprising a condensed imidazolidine derivative
  • a cartilage matrix degrading enzyme production inhibitor comprising a condensed imidazolidine derivative
  • a prophylactic / therapeutic agent for osteoarthritis comprising a condensed imidazolidine derivative
  • a method for preventing or treating osteoarthritis which comprises administering to a mammal an effective amount of the compound (II) or a salt thereof or a sulfoxide or a prodrug thereof according to (1);
  • (42) a method for preventing or treating a disease caused by cartilage destruction, which comprises administering an effective amount of the compound (I) or a salt thereof or a sulfoxide or a prodrug thereof according to the above (1) to a mammal;
  • [L is a leaving group, and R 5 and R 6 have the same meanings as described in the above (1)] or a salt thereof, and then subjected to a ring-forming reaction, and if desired, a hydrolysis reaction and a dehydration reaction.
  • General formula characterized by conducting a reaction, an alkylation reaction, a substitution reaction and / or an oxidation reaction.
  • R 1 represents — (S) n —R 2 or —NR 3 R 4 , n represents an integer of 0 to 2, R 2 represents a hydrogen atom, an optionally substituted hydrocarbon group or R 3 and R 4 are the same or different hydrogen atoms, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic group, A nitrogen-containing heterocyclic ring formed together with a nitrogen atom is shown.
  • Alkenyl group as the optionally substituted hydrocarbon group includes alkenyl groups having 2 to 20 carbon atoms (for example, vinyl, aryl, isoprobenyl, 1-probenyl, 1-butenyl, 2-butenyl, 3 -Butenyl, 1,3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2_methyl-2-propenyl 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-pentenyl, 2,4-pentenyl, 1,4-pentagenenyl, 1-methyl-1-butenyl, 2-methyl 1-butenyl, 3-methyl-1-butenyl, 1_methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl 3-butenyl, 3-methyl-3-butenyl, 1-ethyl-1
  • alkynyl group as the optionally substituted hydrocarbon group include an alkynyl group having 2 to 20 carbon atoms (eg, ethynyl, 1-propynyl, 2-propynyl,
  • Examples of the "reyl group” as the optionally substituted hydrocarbon group include an aryl group having 6 to 10 carbon atoms (eg, phenyl, 0-tolyl, m-tolyl, p-tolyl, 2-,
  • cycloalkyl group examples include cycloalkyl groups having 3 to 8 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.). ). These may further be condensed with an aryl group such as a phenyl group, and examples thereof include indanyl, benzocyclohexyl, benzocycloheptyl, and benzocyclooctyl. Of these, preferred are cyclohexyl, cycloheptyl, cyclohexyl, indanyl, benzocycloheptyl and the like.
  • This cycloalkyl group is bridged through a linear atom chain having 1 or 2 carbon atoms to form bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [ 3.2.1 octyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.23 nonyl, etc. (preferably a cyclo group having a bridge through a linear atom chain having 1 or 2 carbon atoms) Hexyl, and more preferably bicyclo [2.2.1] heptyl) may form a crosslinked cyclic hydrocarbon residue. It also forms an adamantyl group. May be formed.
  • cycloalkenyl group examples include a cycloalkenyl group having 3 to 8 carbon atoms (for example, 2-cyclopropenyl, 2-cyclobutenyl, 2-cyclopentenyl, 3-cyclopentenyl). Pentenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 4-cycloheptenyl; k 2-cyclooctenyl, 3-cyclooctenyl, 4-cyclooctenyl.
  • aryl group such as a phenyl group, for example, indenyl, benzocyclohexenyl, benzocycloheptenyl, benzocyclooctenyl and the like.
  • aryl group such as a phenyl group
  • indenyl benzocyclohexenyl
  • benzocycloheptenyl benzocyclooctenyl
  • benzocyclooctenyl and the like.
  • Hexenyl, 2-cycloheptenyl, cyclooctyl, indenyl and the like can be mentioned.
  • substituent of the “optionally substituted hydrocarbon group” for R 2 include (1) a nitro group, (2) an oxo group, and (3) a halogen atom (eg, fluorine, chlorine, bromine, (4) cyano group, (5) methylene group, (6) optionally substituted lower alkyl group, (7) optionally substituted lower alkenyl group, (8) substituted (9) optionally substituted aralkyl group, (10) optionally substituted aralkyl group, (11) optionally substituted cycloalkyl group, (12) lower haloalkyl Group, (13) olepoxyl group which may be esterified or amidified, (14) thiol bamoyl group, (15) acyl group, (16) amidyl group, (17) hydroxyl group which may be substituted (18) an optionally substituted sulfanyl group, (19) a substituted An optionally substituted alkylsulfinyl group, (20) an optionally substituted aryl
  • the substituent of the "optionally substituted hydrocarbon” and the "lower alkyl group” of the “optionally substituted lower alkyl group” for R 2 are, for example, methyl, ethyl, ⁇ _propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl And C1 to C4 alkyl groups.
  • Examples of the substituent which the “lower alkyl group” may have include, for example, (1) a nitro group, (2) an oxo group, (3) a halogen atom (eg, fluorine, chlorine, bromine, etc.), (4) ) A cyano group, (5) a methylene group, (6) a lower alkyl group (for example, having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, etc.) (7) a lower alkenyl group (for example, bier, allyl, isopropyl, 1-butenyl, 2-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, An alkenyl group having 2 to 5 carbon atoms such as 1-pentenyl and 2-pentenyl); (8) a lower alkynyl group (an alkynyl
  • alkoxycarbonyl Amino e.g., methoxy Cal Poni Rua amino, ethoxy Cal Poni Rua amino, tert - Butoxycarponylamino, etc., aryloxylponylamino (for example, phenoxycarponylamino, naphthyloxycarponylamino, etc.), aralkyloxycarbonylamino (for example, benzyloxycarponylamino, phenethyloxycarponylamino, etc.) ), Alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, etc.), arylsulfonylamino (eg, benzenesulfonylamino, naphthylsulfony
  • Examples of the “lower alkenyl group” of the “optionally substituted lower alkenyl group” as the substituent of the “optionally substituted hydrocarbon” represented by R 2 include, for example, vinyl and allyl. ), Isoprobenyl, 1-butenyl, 2-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1 pentenyl, 2-pentenyl and the like.
  • the substituent which the “lower alkenyl group” may have include the “optionally substituted lower” as a substituent of the “optionally substituted hydrocarbon” represented by R 2 above. The same number and the same as the substituents that the “alkyl group” may have.
  • Examples of the “lower alkynyl group” of the “optionally substituted lower alkynyl group” as the substituent of the “optionally substituted hydrocarbon” represented by R 2 include, for example, ethynyl, propargyl, 2- Examples thereof include alkynyl groups having 2 to 5 carbon atoms, such as lower alkynyl groups such as butynyl and 2-pentynyl. Examples of the substituent which the “lower alkynyl group” may have include a “optionally substituted lower alkyl group” as a substituent of the aforementioned “optionally substituted hydrocarbon” represented by R 2. And the same number and the same as the substituents that may be possessed.
  • Examples of the “aryl group” of the “optionally substituted arylyl group” as the substituent of the “optionally substituted hydrocarbon” represented by R 2 include, for example, phenylyl, 2_, 3-or 4 And aryl groups having 6 to 12 carbon atoms such as -tolyl, 1- or 2-naphthyl, 2-, 3- or 4-biphenyl.
  • Examples of the substituent which the “aryl group” may have include a substituent of the “optionally substituted hydrocarbon” represented by R 2 above. And the same number and the same as the substituents which the “optionally substituted lower alkyl group” may have.
  • Examples of the “aralkyl group” of the “optionally substituted aralkyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R 2 include, for example, benzyl, 2-phenethyl, 3-phenyl Examples thereof include aralkyl groups having 7 to 13 carbon atoms such as propyl, 1- or 2-naphthylmethyl, 2-, 3- or 4-biphenylmethyl.
  • substituent which the “aralkyl group” may have include “optionally substituted lower alkyl” as a substituent of the aforementioned “optionally substituted hydrocarbon” for R 2. And the same number and the same as the substituents which the group may have.
  • Examples of the “cycloalkyl group” of the “optionally substituted cycloalkyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R 2 include, for example, cyclopropyl, cyclobutyl, cyclopentyl, C3-C8 cycloalkyl groups such as cyclohexyl, cycloheptyl and cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl , Bicyclo [3.3.1] Noel, picicyclo [3.2.2] Noel and adamantyl.
  • Examples of the substituent which the “cycloalkyl group” may have include a “optionally substituted lower alkyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R 2 above. And the same number and the same as the substituents which may be possessed.
  • lower haloalkyl group as a substituent of the “optionally substituted hydrocarbon” represented by R 2 , for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-Trifluoroethyl, 1,1,2,2-Tetrafluoroethyl, 1,1,2,2,2-pentafluorofluorethyl, 3-Fluoro mouth pill, 3,3-Diflu Trifluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4-fluorobutyl, 4,4-difluorobutyl, 4,4,4-trifluorobutyl, 3,3,4,4,4-pentyl butyl, 5-fluoropentyl, 5,5-difluoropentyl, 5,5,5-trifluoropentyl, 4,4,5,5,5-
  • alkoxycarbonyl group examples include, for example, those having 2 to 2 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, hexoxycarbonyl, dodecyloxycarbonyl, hexadecyoxycarbonyl and the like. 18 alkoxycarbonyl groups.
  • the “alkoxy group” may have a substituent, and the substituent may be a “substituted hydrocarbon” represented by R 2 described above. The same number and the same as the substituents which the lower alkyl group which may be substituted "may have.
  • alkenyloxycarbonyl group examples include those having 2 carbon atoms such as allyloxycarbonyl, octa-2,6-genyloxycarbonyl, dodeforce-2,6,10-trienyloxycarbonyl. To 18 alkenyloxycarbonyl groups.
  • the “alkenyloxycarbonyl group” may have a substituent, and the substituent may be a “substituted hydrocarbon” represented by R 2 described above as a substituent of “optionally substituted hydrocarbon”. And the same number and the same as the substituents which the lower alkyl group which may be substituted "may have.
  • aryloxycarbonyl group for example, phenoxycarbonyl, 1-naphthoxycarponyl, 21-naphthoxycarponyl and the like can be mentioned.
  • the “aryloxycarbonyl group” may have a substituent, and the substituent may be a “substituted hydrocarbon” as a substituent of the “optionally substituted hydrocarbon” represented by R 2. And the same number and the same as the substituents which the lower alkyl group may have.
  • aralkyloxycarbonyl group examples include aralkyloxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, and 3-phenylpropoxycarbonyl.
  • the “aralkyloxycarbonyl group” may have a substituent, and the substituent is the “substituted or substituted” represented by R 2 described above.
  • the same number and the same as the substituents which the “optionally substituted lower alkyl group” may have as a substituent of the “optionally substituted hydrocarbon”.
  • substituent of the “N-monosubstituted carpamoyl group” examples include lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.), lower alkenyl (eg, Bier, Aryl, isopropenyl, propenyl, butenyl, pentenyl, hexenyl, etc., cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aryl (eg, phenyl) , 1-naphthyl, 2-naphthyl), aralkyl (eg, benzyl, phenethyl, etc.), heterocyclic group (for example, “substituted as a substituent of“ optionally substituted hydro
  • Lower alkyl, lower alkenyl, cycloalkyl, ⁇ Li - Le, Ararukiru, heterocyclic group may have a substituent, examples of the substituent group, represented by R 2 "which may be substituted As the substituent for the "good hydrocarbon", the same number and the same substituents as the substituent which the "optionally substituted lower alkyl group” may have.
  • the substituent of the “N, N-disubstituent rubamoyl group” means a disubstituted group having two substituents on a nitrogen atom, and is the same as the substituent in the above “N-monosubstituent rubamoyl”.
  • two substituents may be combined with a nitrogen atom to form a cyclic amino.
  • examples of the cyclic amino group rubamoyl include N-pyrrolidylcarbonyl, N-imidazolylcarbonyl, and N-imidazolylcarbonyl.
  • acyl group as a substituent of the “optionally substituted hydrocarbon” represented by R 2 , a hydrogen atom or a substituent having one of the above-mentioned monosubstituent rubamoyl groups on the nitrogen atom And carbonyl, such as a lower alkanoyl group such as formyl group, acetyl and propionyl, or an aroyl group such as benzoyl and naphthyl.
  • an optionally substituted lower alkyl group As the substituent of the ⁇ optionally substituted hydroxyl group '' as the substituent of the ⁇ optionally substituted hydrocarbon '' represented by R 2 , an optionally substituted lower alkyl group, Lower alkenyl group which may be substituted, lower alkynyl group which may be substituted, aryl group which may be substituted, aralkyl group which may be substituted, cycloalkyl group which may be substituted, esterification Or an amidated propyloxyl group, an optionally substituted alkylsulfanylthiocarbonyl group, an optionally substituted aralkylsulfanylthiocarbonyl group, an optionally substituted alkylsulfonyl group, An arylsulfonyl group which may be substituted, an optionally substituted N-imidazolylthiol haponyl, an optionally substituted N-morpholylthio haponyl, a
  • the “substituted hydrocarbon” represented by R 2 may be a “substituted hydrocarbon”.
  • esterified or amidated carboxyl group refers to the optionally esterified or amidated lipoxyl as a substituent of the aforementioned “optionally substituted hydrocarbon” represented by R 2.
  • alkylsulfanylthiocarponyl group include methylsulfanylthiocarponyl, ethylsulfanylthiocarponyl, tert-butoxysulfanylthiocarponyl, and the like.
  • Examples of the "good aralkylsulfanylthiocarbonyl group” include benzylsulfanylthiocarbonyloxy and the like, and the "optionally substituted alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, Examples of the “optionally substituted arylsulfonyl group” include benzenesulfonyl, p-toluenesulfonyl, m-toluenesulfonyl, o-toluenesulfonyl and the like.
  • optionally substituted alkylsulfanylthiocarbonyl group includes, for example, the optionally substituted hydrocarbon represented by R 2 above.
  • R 2 the optionally substituted hydrocarbon represented by R 2 above.
  • substituents which the “lower alkyl group which may be substituted” may have. Examples of the substituent which may be possessed by the ⁇ optionally substituted N-imidazolylthiol compound '' and the ⁇ optionally substituted N-morpholylthio compound '' are those represented by R 2 described above.
  • substituent of the "optionally substituted hydrocarbon” the same number and the same substituents as the “optionally substituted lower alkyl group” may have.
  • hydroxyl protecting group examples include 2-tetrahydropyranyl, trimethylsilyl, triethylsilyl, tert-butyldiphenylsilyl and the like.
  • Examples of the “optionally substituted sulfanyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R 2 include, for example, a sulfanyl group, methylsulfanyl, methysulfanyl, isopropylsulfanyl, tert- Examples thereof include an alkylsulfanyl group such as butylsulfanyl, an arylsulfanyl group such as phenylsulfanyl, and an aralkylsulfanyl group such as benzylsulfanyl.
  • substituents which the “optionally substituted sulfanyl group” may have include “substituted or substituted hydrocarbon” as a substituent of the aforementioned “optionally substituted hydrocarbon” for R 2.
  • substituents which the “lower alkyl group which may be optionally present” may have.
  • Examples of the “optionally substituted alkylsulfinyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R 2 include, for example, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl and the like.
  • Examples of the substituent which the “optionally substituted alkylsulfinyl group” may have include “substituted or substituted hydrocarbon” as a substituent of the aforementioned “optionally substituted hydrocarbon” for R 2. The same number and the same as the substituents which the “lower alkyl group which may be optionally present” may have.
  • Examples of the “optionally substituted arylsulfinyl group” as a substituent of the “optionally substituted hydrocarbon” for R 2 include, for example, benzenesulfinyl, toluenesulfinyl and the like.
  • the "arylsulf optionally substituted” As has also been have substituents Iniru group ", it said; have the” optionally substituted lower alkyl group "as the substituent of the" hydrocarbon which may be substituted "represented by 2 And the same number and the same as the substituents which may be included.
  • Examples of the “optionally substituted alkylsulfonyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R 2 include, for example, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, butylsulfonyl and the like. Is mentioned.
  • Examples of the substituent which the “optionally substituted alkylsulfonyl group” may have include “substituted hydrocarbon” as a substituent of the aforementioned “optionally substituted hydrocarbon” for R 2. The same numbers and the same as the substituents which the lower alkyl group which may be optionally possessed "may have.
  • Examples of the "optionally substituted arylsulfonyl group" as a substituent of the "optionally substituted hydrocarbon” represented by R 2 include, for example, benzenesulfonyl, toluenesulfonyl, naphthylsulfonyl and the like. .
  • Examples of the substituent which the “optionally substituted arylsulfonyl group” may have include a substituent of the “optionally substituted hydrocarbon” represented by R 2 above. The same number and the same thing as the substituent which the "lower alkyl group which may be substituted" may have are mentioned.
  • Examples of the “sulfonic acid group which may be esterified or amidated” as a substituent of the “optionally substituted hydrocarbon” represented by R 2 include, for example, a sulfonic acid group, methyl sulfonic acid, and sulfonic acid Ethyl, sulfonic acid amide, N-methylsulfonic acid amide and the like.
  • amino or di-substituted amino with an amino group an alkyl group or an aralkyl group Groups, acylamino, alkoxyl propylonamino, aryloxycarbonylamino, aralkyloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino and the like.
  • Amino group j mono- or di-substituted with an alkyl group or an aralkyl group j includes, for example, methylamino, ethylamino, isopropylamino, dimethylamino, methylamino, ethylmethylamino, benzylamino, benzylmethylamino and the like.
  • ⁇ Can be.
  • the "amino group mono- or di-substituted by an alkyl group or an aralkyl group” May have a substituent, and the substituent may be a ⁇ optionally substituted lower alkyl group '' as a substituent of the ⁇ optionally substituted hydrocarbon '' represented by R 2 above. And the same number and the same as the substituents that may be possessed.
  • Acylamino includes, for example, formylamino, acetylamino, propionylamino, butyrylamino, isoptyrylamino, valerylamino, isovaleramino, pivaloylamino, benzoylamino, phenacylamino and the like.
  • the “acylamino” may have a substituent, and the substituent may be a “optionally substituted lower” as a substituent of the “optionally substituted hydrocarbon” shown in the above 2 The same number and the same as the substituents that the “alkyl group” may have.
  • the “alkoxyl ponylamino” includes, for example, methoxycarbonylamino, ethoxycarbonylamino, tert-butoxycarponylamino and the like.
  • the “alkoxy compound / amino” may have a substituent, and the substituent may be a substituent of the “optionally substituted hydrocarbon” represented by R 2 described above .
  • the same number and the same as those of the substituent which the “optionally substituted lower alkyl group” may have are exemplified.
  • aryloxycarbonylamino includes, for example, phenoxycarbonylamino, naphthyloxycarbonylamino and the like.
  • the “aryloxycarbonylamino” may have a substituent, and the substituent may be a “optionally substituted hydrocarbon” represented by R 2 described above. The same number and the same as the substituents which the "lower alkyl group which may be substituted” may have.
  • Alkyloxycarbonylamino includes, for example, benzyloxycarponylamino, phenethyloxycarbonylamino and the like.
  • the “aralkyloxycarbonylamino” may have a substituent, and the substituent may be a “substituted hydrocarbon” as a substituent of the “optionally substituted hydrocarbon” for R 2.
  • the same numbers and the same as the substituents that the “lower alkyl group which may be substituted” may have.
  • Alkylsulfonylamino includes, for example, methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino and the like.
  • the “alkylsulfonylamino” may have a substituent, and the substituent may be a “substituted hydrocarbon” as a substituent of the aforementioned “optionally substituted hydrocarbon” represented by R 2. The same number and the same as the substituents which the lower alkyl group which may be substituted "may have.
  • arylsulfonylamino includes, for example, benzenesulfonylamino, naphthylsulfonylamino and the like.
  • the “arylsulfonylamino” may have a substituent, and the substituent may be a “optionally substituted hydrocarbon” represented by R 2 described above. The same number and the same as the substituents which the lower alkyl group which may be substituted "may have.
  • Examples of the “optionally substituted heterocyclic group” as a substituent of the “optionally substituted hydrocarbon” represented by R 2 include, for example, an aliphatic monocyclic nitrogen-containing heterocyclic group and an aromatic monocyclic group. Examples include a cyclic nitrogen-containing heterocyclic group, a condensed nitrogen-containing heterocyclic group, an oxygen-containing monocyclic or condensed heterocyclic group, and a sulfur-containing monocyclic or condensed heterocyclic group.
  • Aliphatic monocyclic nitrogen-containing heterocyclic group refers to, for example, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, piperazyl, pyrazolyl, morpholinyl, morpholinyl Oxazinyl, thiazinyl, azepinyl, diazepinyl, oxazepinyl, thiazepinyl and the like.
  • the “aliphatic monocyclic nitrogen-containing heterocyclic group” may have a substituent, and the substituent is a substituent of the “optionally substituted hydrocarbon” represented by R 2 above. And the same number and the same as the substituents which the "optionally substituted lower alkyl group” may have.
  • Aromatic monocyclic nitrogen-containing heterocyclic group means, for example, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrazinyl Is mentioned.
  • the “aromatic monocyclic nitrogen-containing heterocyclic group” may have a substituent, and the substituent may be a “optionally substituted hydrocarbon” represented by R 2 described above. As the substituent, the same number and the same as those of the "optionally substituted lower alkyl group" may be mentioned. You.
  • “Fused nitrogen-containing heterocyclic group” is, for example, benzopyrrolidinyl, benzimidazolidinyl, benzopyrazolidinyl, benzoxazolidinyl, benzoisoxazolidinyl, benzothiazolidinyl, benzoisothiazolidinyl Benzopiperidyl, benzopiperidyl, benzopyrazinyl, benzomorpholinyl, benzothiomorpholyl, benzoxazinyl, benzothiazinyl, benzozepinyl, benzodiazepinyl, benzoxazepinyl, benzothiazepinel, indolyl, isoindolyl, 1H-indazolyl , Benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, m-benzotriazolyl, benzoxoxadiazolyl
  • the “condensed nitrogen-containing heterocyclic group” may have a substituent, and the substituent may be a “substituted hydrocarbon” represented by R 2 described above.
  • R 2 substituted hydrocarbon
  • Oxygen-containing monocyclic or fused heterocyclic group means, for example, oxilanyl, oxenyl, oxolanyl, dioxolanyl, furyl, pyranyl, tetrahydroviranyl, dioxanyl, benzofuranyl, isobenzofuranyl, benzopyrael, isobenzopyranyl, benzol Dioxanyl, 7-oxabicyclo [2.2.1] heptyl), 9-oxabicyclo [3.3.1] nonyl, and the like.
  • the “oxygen-containing monocyclic or condensed heterocyclic group” may have a substituent, and the substituent may be any of the above-mentioned “optionally substituted hydrocarbon” represented by R 2 .
  • substituent “substituted The same numbers and the same as the substituents that the “lower alkyl group which may be substituted” may have.
  • the “sulfur-containing monocyclic or condensed heterocyclic group” includes, for example, phenyl, thioxolanyl, tetrahydrothiopyrael, dithianil, benzothenyl and the like.
  • the “sulfur-containing monocyclic or condensed heterocyclic group” may have a substituent, and the substituent may be a substituent of the “optionally substituted hydrocarbon” represented by R 2 described above.
  • R 2 the same number and the same as the substituent which the "lower alkyl group which may be substituted” may have.
  • alkylenedioxy group as a substituent of the "optionally substituted hydrocarbon” represented by, for example, methylenedioxy, ethylenedioxy and the like can be mentioned.
  • Examples of the “optionally substituted cycloalkenyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R 2 include a cycloalkenyl group having 3 to 8 carbon atoms (eg, 2-cyclopropenyl, 2-cyclobutenyl, 2-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 4-cyclooctenyl and the like.
  • Examples of the substituent which the “cycloalkenyl group” may have include a “optionally substituted lower alkyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R 2 above. And the same number and the same as the substituents that may be possessed.
  • hydrocarbon group as the “optionally substituted hydrocarbon group” represented by R 3 and R 4 examples include the hydrocarbon as the “optionally substituted hydrocarbon group” represented by the aforementioned R 2 And the same.
  • Preferable examples include an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and the like.
  • the ⁇ optionally substituted heterocyclic group '' represented by R 3 or R 4 may be ⁇ optionally substituted '' as a substituent of the ⁇ optionally substituted hydrocarbon '' represented by R 2 And the same as the “good complex ring group”.
  • Examples of the nitrogen-containing heterocyclic ring as “an optionally substituted nitrogen-containing heterocyclic ring represented by R 3 and R 4 together with the nitrogen atom to which they are bonded” include, in addition to a carbon atom, May contain 1 to 4 heteroatoms selected from atoms, sulfur atoms, nitrogen atoms, etc. 3- to 8-membered monocyclic heterocycles or condensed bicyclic or tricyclic heterocycles And fused heterocyclic groups. Among them, a preferable example is a 5- to 7-membered nitrogen-containing heterocyclic ring. Particularly preferred examples include azepier, piperidyl, piperazyl, N-methylbiperazyl, pyrrolidyl, morpholyl, and the like.
  • R 3, R 4 are both nitrogen-containing heterocyclic ring which may be substituted, such connexion represent together with the nitrogen atom to which they are attached", "is substituted represented by R 2 And the same number as the substituents of the "optionally substituted hydrocarbon group".
  • R 1 is preferably —SR 2 (R 2 represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and in particular, R 2 is substituted. Those which are good hydrocarbon groups are preferred.
  • R 2 is an optionally substituted alkyl group (optionally substituted alkyl group having 1 to 8 carbon atoms) and an optionally substituted alkenyl group (optionally substituted An alkenyl group having 2 or 8 carbon atoms, an aralkyl group which may be substituted (an aralkyl group having 7 to 10 carbon atoms which may be substituted), a cycloalkyl group which may be substituted (substituted) And a cycloalkyl group having 3 to 8 carbon atoms which may be substituted.
  • R 2 is preferably an alkyl group having 1 to 8 carbon atoms which may be substituted, and more preferably an alkyl group having 4 to 8 carbon atoms which may be substituted by a halogen atom. Are preferred.
  • the hydrocarbon group as the ⁇ optionally substituted hydrocarbon group '' represented by R 5 is the same as the hydrocarbon group as the ⁇ optionally substituted hydrocarbon group '' represented by the aforementioned R 2 Things.
  • an alkyl group having 1 to 8 carbon atoms an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and a cycloalkyl having 3 to 8 carbon atoms
  • the group is preferably a cycloalkenyl group having 3 to 8 carbon atoms.
  • an alkyl group having 1 to 6 carbon atoms is preferable, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isobenzyl, 2-methylbutyl, hexyl, isobutyl Hexyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylpentyl, and 3,3-dimethylpentyl are preferred.
  • acyl group represented by R 5 is the same as the “acyl group” as a substituent of the “optionally substituted hydrocarbon group” represented by R 2 .
  • the “carboxyl group which may be esterified or amidated” represented by R 5 means “esterification or amide as a substituent of the aforementioned“ optionally substituted hydrocarbon group ”represented by R 2. And the like. Among them, an alkoxycarbonyl group having 2 to 18 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxyl-proponyl, tert-butoxycarbonyl, hexyloxyl-proponyl, dodecyloxycarbonyl, hexadecyloxycarbonyl and the like is preferable.
  • the “optionally substituted heterocyclic group” represented by R 5 includes the same as the “optionally substituted heterocyclic group” represented by R 2 .
  • the hydrocarbon group as the ⁇ optionally substituted hydrocarbon group '' represented by R 6 is the same as the hydrocarbon group as the ⁇ optionally substituted hydrocarbon group '' represented by the aforementioned R 2 Things.
  • Preferable examples include an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms. Among them, alkyl groups having 1 to 6 carbon atoms, A phenyl group and a benzyl group are preferred. ,
  • acyl group represented by R 6 is the same as the “acyl group” as a substituent of the aforementioned “optionally substituted hydrocarbon group” represented by R 2 .
  • the ⁇ optionally esterified or amidated olepoxyl group '' represented by R 6 means ⁇ esterification or a hydrocarbon group which may be substituted '' represented by R 2 above. And the like.
  • the cyclic hydrocarbon or heterocyclic ring formed by R 5 and R 6 together may contain, in addition to carbon atoms, one to three atoms selected from nitrogen, oxygen, sulfur and the like. Or an unsaturated 5- to 8-membered monocyclic carbocyclic or heterocyclic ring, or a bicyclic fused carbocyclic or heterocyclic ring containing these.
  • cycloalkyl eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • cycloalkenyl eg, cyclopentenyl, cyclohexenyl, cyclohexenyl, cycloheptenyl, etc.
  • aromatic hydrocarbon ring eg, phenyl) , Naphthyl, etc.
  • oxygen-containing ring for example, furyl, oxolanyl, tetrahydroviranyl, oxepinyl, benzofuranyl, benzopyranyl, etc.
  • nitrogen-containing ring for example, pyrrolidyl, piperidyl, pyridyl, azepinyl, indolyl, quinolinyl, benzoxazepinyl, etc.
  • Sulfur-containing rings eg, phenyl, tetrahydrothiopyranyl,
  • Cyclic hydrocarbon or heterocyclic ring and R 5 and R 6 are you connexion formed such together may have a substituent, examples of the substituent group, be "substituted represented by R 2 The same number and the same as the substituents of the “good hydrocarbon group”.
  • R 5 is preferably an optionally substituted hydrocarbon group, a cyano group, an acyl group, an optionally esterified or amidated propyloxyl group, or an optionally substituted heterocyclic group.
  • An optionally substituted hydrocarbon group is preferred.
  • alkyl groups having 1 to 12 carbon atoms alkenyl groups having 2 to 12 carbon atoms, alkynyl groups having 2 to 12 carbon atoms, aryl groups having 6 to 10 carbon atoms, and 7 carbon atoms.
  • Preferred are an aralkyl group having 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, and a cycloalkenyl group having 3 to 8 carbon atoms.
  • alkyl groups having 1 to 8 carbon atoms alkenyl groups having 2 to 8 carbon atoms, aryl groups having 6 to 10 carbon atoms, aralkyl groups having 7 to 10 carbon atoms, cycloalkyl groups having 3 to 8 carbon atoms And a cycloalkenyl group having 3 to 8 carbon atoms is preferred.
  • a hydrocarbon group having 1 to 6 carbon atoms particularly an alkyl group having 1 to 6 carbon atoms is preferable, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Preferred are isopentyl, 2-methylbutyl, hexyl, isohexyl, 2-ethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl and 3,3-dimethylbutyl.
  • R 6 is preferably an optionally substituted hydrocarbon group.
  • an alkyl group having 1 to 8 carbon atoms an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and the like are preferable.
  • a hydrocarbon group having 1 to 6 carbon atoms especially an alkyl group having 1 to 6 carbon atoms (methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2 -Methylbutyl, hexyl, isohexyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, etc., particularly methyl and ethyl) are preferred.
  • a compound forming a benzene ring which may be substituted together with R 5 and R 6 or a cyclohexene ring which may be substituted may also be mentioned as a preferable example.
  • Examples of the substituent of the ⁇ optionally substituted hydroxyl group '' represented by R 7 include an optionally substituted hydrocarbon group, an optionally substituted alkylsulfonyl group, and an optionally substituted An arylsulfonyl group, an optionally substituted alkyl group, and an optionally substituted arylcarbonyl group.
  • a hydroxyl group is preferable.
  • an alkyl group having 1 to 6 carbon atoms, a benzyl group and the like are preferable.
  • a substituent of the optionally substituted hydrocarbon group as a substituent of the “optionally substituted hydroxyl group a substituent of the “optionally substituted hydrocarbon group” represented by R 2 above Similar numbers and similar ones are included.
  • Examples of the optionally substituted alkylcarbonyl group and the optionally substituted arylcarbonyl group as the substituent of the ⁇ optionally substituted hydroxyl group '' represented by R 7 include, for example, Examples thereof include an alkylcarbonyl group having a good carbon number of 1 to 4, an optionally substituted benzoyl group, and the like. Among them, an acetyl group, a propionyl group, a benzoyl group and the like are preferable.
  • substituent of the arylcarbonyl group which may be substituted include the same numbers and the same substituents as those of the “optionally substituted hydrocarbon group” for R 2 .
  • Examples of the hydrocarbon group as the “optionally substituted hydrocarbon group” represented by R 8 and R 9 include the hydrocarbon as the “optionally substituted hydrocarbon group” represented by the aforementioned R 2 Examples are the same as the groups.
  • Preferable examples include an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms. Among them, an alkyl group having 1 to 6 carbon atoms, a phenyl group, a benzyl group and the like are preferable.
  • the substituent of the “optionally substituted hydrocarbon group” represented by R 8 and R 9 is the same as the substituent of the “optionally substituted hydrocarbon group” represented by R 2 described above. , And the like.
  • the cyclic hydrocarbon or heterocyclic ring formed by R 5 and R 8 together may contain 1 to 3 atoms selected from nitrogen, oxygen, sulfur, etc., in addition to carbon. Or an unsaturated 5- to 8-membered monocyclic carbocyclic or heterocyclic ring, or a bicyclic fused carbocyclic or heterocyclic ring containing these.
  • cycloalkyl eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • cycloalkenyl eg, cyclopentenyl, cyclohexenyl, cyclohexenyl, cycloheptenyl, etc.
  • aromatic hydrocarbon ring eg, phenyl
  • oxygen-containing ring for example, frill, oxorael, tetrahydropyranyl, oxepinyl, benzofuranyl, benzopyranyl, etc.
  • nitrogen-containing ring for example, pyrrolidyl, piperidyl, pyridyl, azepinyl, indolyl, quinolinyl, benzoxazepiel, etc.
  • Sulfur-containing rings eg, phenyl, tetrahydrothiopyranyl, be
  • the cyclic hydrocarbon or heterocyclic ring formed by R 5 and R 8 together may have a substituent, and the substituent may be ⁇ substituted or substituted '' represented by R 2 above. And the same number and the same as the substituents of the "optionally substituted hydrocarbon group".
  • the cyclic hydrocarbon or heterocyclic ring formed by combining R 8 and R 9 may include one to three atoms selected from a nitrogen atom, an oxygen atom, a sulfur atom, and the like in addition to a carbon atom. Examples thereof include a saturated or unsaturated, 5- to 8-membered monocyclic carbocyclic or heterocyclic ring, or a bicyclic fused carbocyclic or heterocyclic ring containing these.
  • cycloalkyl eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • cycloalkenyl eg, cyclopentenyl, cyclohexenyl, cyclohexenyl, cycloheptenyl, etc.
  • aromatic hydrocarbon ring eg, phenyl
  • oxygen-containing ring for example, furyl, oxazolanyl, tetrahydropyranyl, oxepiel, benzofuranyl, benzopyranyl, etc.
  • nitrogen-containing ring for example, pyrrolidyl, piperidyl, pyridyl, azepinyl, indolyl, quinolinyl, benzoxazepiel, etc.
  • Sulfur-containing rings eg, phenyl, tetrahydrothioviranyl, benzo
  • the cyclic hydrocarbon or heterocyclic ring formed by R 8 and R 9 together may have a substituent, and the substituent may be ⁇ optionally substituted '' represented by R 2 described above. And the same number and the same as the substituents of the "hydrocarbon group".
  • an optionally substituted hydrocarbon group is preferable.
  • an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, a phenyl group having 6 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms are preferable. That is, an alkyl group having 1 to 6 carbon atoms, a phenyl group, a benzyl group and the like are preferable.
  • RIG represents a hydrogen atom, one ZR 15 or —P (O) R 16 R 17 .
  • the hydrocarbon group of the ⁇ optionally substituted hydrocarbon group '' represented by R 15 of ZR 15 examples include the same as the hydrocarbon group.
  • an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and a cycloalkyl group having 3 to 8 carbon atoms are preferable.
  • the substituent of the “optionally substituted hydrocarbon group” represented by 5 is the same as or similar to the substituent of the “optionally substituted hydrocarbon group” represented by R 2 above. Is mentioned. Of these, an optionally substituted alkyl group having 1 to 4 carbon atoms, an optionally substituted alkenyl group having 2 to 4 carbon atoms, a halogen atom such as fluorine, chlorine, and bromine, and having 1 to 4 carbon atoms Examples of the substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a Bier group, and the like. Examples include fluorine, chlorine, bromine, a methoxy group, and an ethoxy group.
  • - ZR 1 5 and R 1 5 in the "optionally substituted heterocyclic group" represented is as the substituent of the "optionally substituted hydrocarbon" represented by R 2 ' Heterocyclic group which may be substituted "and the like.
  • a phenyl group which may be substituted a quinolyl group which may be substituted, and a benzoxazidi which may be substituted Azolyl group, optionally substituted pyridyl group, optionally substituted benzothiadiazolyl group, optionally substituted benzozoenyl group, optionally substituted oxazolidinyl group, optionally substituted
  • An benzodioxanyl group, a substituted or unsubstituted dibenzofuranyl group and a morpholyl group are preferred, and particularly a optionally substituted phenyl group, an optionally substituted benzothiadiazolyl group and an optionally substituted
  • a preferred example is a pyridyl group
  • Z is -S0 2 _, -SO-, -CON 18 S0 2 - (R 18 is (:. 6 alkyl), -CONR 19 - (R 19 is - 6 alkyl) or - CO- shown R 18 and R the C Bok 6 alkyl represented by 1 9, for example, methyl, Echiru, propyl, iso-propyl, heptyl, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl, and the like to.
  • the “optionally substituted hydrocarbon group” represented by R 16 and R 17 is the same as the hydrocarbon group represented by the aforementioned R 2 3 ⁇ 4 “optionally substituted hydrocarbon group” And the like.
  • an alkyl group having 1 to 12 carbon atoms an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, Examples thereof include a 3-8 cycloalkyl group and a C3-8 cycloalkenyl group.
  • an alkyl group having 1 to 6 carbon atoms an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and the like are preferable.
  • methyl, ethyl, phenyl, benzyl and the like are preferable.
  • the substituent of the ⁇ optionally substituted hydrocarbon group '' represented by R 16 and R 17 is the same as the substituent of the ⁇ optionally substituted hydrocarbon group '' represented by R 2 And the like.
  • R 16 and R 17 examples include, for example, an optionally substituted hydrocarbon group.
  • an alkyl group having 1 to 8 carbon atoms examples thereof include an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms. Among them, 1 to 6 carbon atoms And an alkyl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and the like.
  • substituent of the optionally substituted hydrocarbon group as the substituent of the “optionally substituted hydroxyl group” include the substituent of the “optionally substituted hydrocarbon group” represented by R 2 above. Similar numbers and similar ones are included.
  • the “optionally substituted hydroxyl group” represented by R 16 and R 17 is preferably a hydroxyl group substituted by an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, or the like.
  • the ⁇ optionally substituted amino group '' represented by R 16 and R 17 includes the ⁇ substituted amino group '' as a substituent of the ⁇ optionally substituted hydrocarbon '' represented by R 2 above. And the like. " Preferably, methyl, ethyl, phenyl, benzyl and the like are mentioned.
  • R 16 and R 17 are an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, a hydroxyl group substituted with an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms. And a hydroxyl group substituted with methyl, ethyl, phenyl, benzyl, methyl, a hydroxyl group substituted with ethyl, and a hydroxyl group substituted with phenyl.
  • ZR 15 Z and R 15 are as defined above
  • Z is —S ⁇ 2 — or 1 CO—
  • R 15 is an optionally substituted aryl group, an optionally substituted aralkyl group, and an optionally substituted heterocyclic ring. What is a group is preferable.
  • Z is —SO 2 — or 1 CO—
  • R 15 is an optionally substituted aralkyl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms which may be substituted, Those which are heterocyclic groups which may be substituted are preferred.
  • Z is -S ⁇ 2-
  • R 15 may be substituted with methyl, ethyl, propyl, isopropyl, vinyl, fluorine, chlorine, bromine, methoxy, ethoxy, etc.
  • Phenyl, benzyl, phenyl, benzothiadiazolyl, or Z is —CO—
  • R 15 is methyl, ethyl, propyl, isopropyl, vinyl, fluorine, chlorine, bromine, methoxy And a pyridyl group which may be substituted with an ethoxy group or the like.
  • R 11 represents a hydrogen atom or a hydrocarbon group which may be substituted. .
  • the hydrocarbon group of the ⁇ optionally substituted hydrocarbon group '' represented by R 11 is the same as the hydrocarbon group of the ⁇ optionally substituted hydrocarbon group '' represented by the aforementioned R 2 Things.
  • Preferable examples include an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms. Of these, an alkyl group having 1 to 6 carbon atoms, a benzyl group and the like are preferable, and an alkyl group having 1 to 4 carbon atoms is particularly preferable.
  • the substituent of the ⁇ optionally substituted hydrocarbon group '' represented by R 11 is the same as or similar to the substituent of the ⁇ optionally substituted hydrocarbon group '' represented by R 2 One.
  • R 11 is preferably a hydrogen atom.
  • the nitrogen-containing heterocyclic ring which may be formed by combining R 1Q and R 11 is
  • ring B represents an optionally substituted 5- to 8-membered ring
  • R 17 has the same meaning as described above, and ring B 1 to ring B 12 each represent a nitrogen-containing heterocyclic ring which may further have a substituent].
  • the substituent which the ring B 1 to ring B 12 may have is the same as the substituent which the ⁇ optionally substituted hydrocarbon group '' represented by R 15 may have Means things.
  • Examples of the nitrogen-containing heterocyclic ring which may be formed by R 1 Q and R 11 together include:
  • ring B 2 and ring B 3 represent a nitrogen-containing heterocyclic ring which may further have a substituent.
  • an alkyl group having 1 to 12 carbon atoms an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms, and a 7 to 10 carbon atom
  • an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms are preferable.
  • substituent of the “optionally substituted hydrocarbon group” represented by R 12 and R 13 include the substitution of the “optionally substituted hydrocarbon group” represented by the aforementioned R 2 The same number and the same as the group can be mentioned.
  • Examples of the nitrogen-containing heterocyclic ring which may be replaced together with R 12 and R 13 together with the nitrogen atom to which they are bonded include the aforementioned ⁇ R 3 and R 4 are both those wherein Nitrogen-containing heterocycles which may be substituted together with the nitrogen atom to be bonded ”. Particularly preferred examples include piperidyl, piperazyl, N-methylpiperazyl, pyrrolidyl, morpholyl and the like.
  • Examples of the substituent of the “nitrogen-containing heterocyclic ring which may be substituted by both R 12 and R 13 forming a nitrogen atom to which they are bonded to —” are those represented by the aforementioned R 2 The same number and the same as the substituents of the “optionally substituted hydrocarbon group”.
  • R 12 is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms.
  • Preferred are a group, an aralkyl group having 7 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkenyl group having 3 to 8 carbon atoms, and the like.
  • an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms are preferable.
  • R 13 is preferably a hydrogen atom.
  • the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R 14 the hydrocarbon group represented by the aforementioned “optionally substituted hydrocarbon group” represented by R 2 And the same as the group.
  • an alkyl group having 1 to 12 carbon atoms an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, not having 6 carbon atoms
  • an aryl group having 10 carbon atoms an aralkyl group having 7 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, and a cycloalkenyl group having 3 to 8 carbon atoms.
  • an alkyl group having 1 to 4 carbon atoms and an aralkyl group having 7 to 10 carbon atoms are preferable.
  • the substituent of the “optionally substituted hydrocarbon group” represented by R 14 is the same as or similar to the substituent of the “optionally substituted hydrocarbon group” represented by the aforementioned R 2. And the like.
  • One ZR 15 represented by R 14 include the same as one ZR 15 represented by R 1Q.
  • an optionally substituted hydrocarbon group is preferable.
  • an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, A cycloalkenyl group having 3 to 8 carbon atoms and the like are preferable, and an alkyl group having 1 to 6 carbon atoms and an aralkyl group having 7 to 10 carbon atoms are particularly preferable.
  • R 1 is-(S) n — R 2 ,
  • the isocyanate compound represented by R 1 G —NC ⁇ is used in an amount of 0.1 to 10 equivalents, preferably 0.2 to 5 equivalents, more preferably 1 to 2 equivalents, based on the amount of the raw material.
  • the isocyanate compound represented by R 1 Q- NCO is preferably a sulfonyl isocyanate compound in which R 10 is R 15 SO 2 , more preferably a benzene ring in which R 15 may be substituted,
  • benzenesulfonyl isocyanate, p-toluenesulfonyl isocyanate, P-fluorobenzenesulfonyl isocyanate, P-chlorobenzenesulfonyl isocyanate, and p-bromobenzenesulfonyl isocyanate are particularly preferable.
  • isocyanates can be prepared from the corresponding amide by a method known per se.
  • This reaction is advantageously performed in a solvent.
  • These reactions are usually performed in a solvent that does not affect the reaction.
  • Solvents are not specified as long as they do not affect the reaction, but amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), halogenated Hydrocarbon solvents (eg, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chloroform benzene, etc.), nitrile solvents (eg, acetonitrile, etc.), ester solvents (eg, ethyl formate, Ethyl acetate, tert-butyl acetate, etc.), ketone solvents (eg, acetone, methyl ethyl ketone, methyl isobutyl
  • octogenated hydrocarbon solvents eg, pyridine, 2, 4, 6- Aromatic bases such as trimethylpyridine, picoline, 4-dimethylaminopyridine, 2,6-lutidine, 1,8-diazabicyclo [5,4,0] -7-indenecene, and tertiary such as triethylamine and dimethylalanine Amin, etc.).
  • pyridine 2, 4, 6- Aromatic bases such as trimethylpyridine, picoline, 4-dimethylaminopyridine, 2,6-lutidine, 1,8-diazabicyclo [5,4,0] -7-indenecene, and tertiary such as triethylamine and dimethylalanine Amin, etc.
  • the base is used in an amount of 0 to 10 equivalents, preferably 0 to 1 equivalent, the reaction temperature is — 40 ° C to 15 ° C, preferably 0 ° C to 100 ° C, and the reaction time is 2 minutes to 96 hours, preferably 5 minutes to 60 hours.
  • the mercapto compound represented by ROC ⁇ CH 2 CH 2 SH is used in an amount of 0.5 to 20 equivalents, preferably 1 to 10 equivalents, more preferably 2 to 5 equivalents, based on the amount of the raw material.
  • the base include alkali metal hydride or alkaline earth metal hydride (eg, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal alkoxide (eg, sodium methoxide, sodium ethoxide, Sodium tert-butoxide, etc.), inorganic bases (eg, sodium bicarbonate, sodium carbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium hydroxide, sodium hydroxide), organic bases (eg, sodium tert-butoxide) Aromatic bases such as pyridine, 2,4,6-trimethylpyridine, picoline, 4-dimethylaminopyridine, 2,6-lutidine, 1,8_diazabicyclo [5,4,0] -7_indene, Ter
  • the base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents. These reactions are usually advantageously performed in a solvent.
  • Solvents are not specified as long as they do not affect the reaction, but amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), ether solvents (eg, , Tetrahydrofuran, getyl ether, dioxane, dimethoxyethane, etc.), sulfoxide solvents (eg, dimethyl sulfoxide), alcohol solvents (eg, methanol, ethanol, 2-propanol, tert-butanol, etc.), nitrile Solvent (eg, acetonitrile, etc.), ester solvent (eg, ethyl formate, ethyl acetate, tert-butyl acetate, etc.), hydrocarbon solvent (eg, hexane, benzene, toluene, etc.), halogenated carbon Hydrogen solvents (e.g., dichloromethane
  • N, N-dimethylformamide, N, N-dimethylacetamide, methanol, ethanol, 2-propanol, tert-butanol, pyridine, tetrahydrofuran, dioxane, dimethoxyethane, acetonitrile, etc. preferable.
  • the reaction temperature is from 140 to 150 ° C., preferably from 0 ° C. to 100 ° C.
  • the reaction time is from 5 minutes to 96 hours, preferably from 30 minutes to 48 hours.
  • the imidazolidine compound represented by the general formula (III) or a salt thereof is used as a raw material and reacted with a base to give an imidazolidine compound represented by the general formula (IV) (R represents the above alkyl group) or a compound thereof. Get the salt.
  • Examples of the base include the bases shown in the above Reaction 2, and preferable examples are For example, an alkali metal hydride, an alkali metal alkoxide, an inorganic base, an organic base, an alkyl lithium, or an alkali metal amide is preferable. And 4-dimethylaminopyridine, methyllithium, butyllithium, lithium disopropylamide, lithium pistrimethylsilylamide and the like are particularly preferred.
  • the base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents. These reactions are usually advantageously performed in a solvent.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, and preferably an amide solvent, an ether solvent, an alcohol solvent, a nitrile solvent, an organic base solvent Solvents, or a mixture thereof, among which N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, 2-propanol, tert-butanol, acetonitrile, pyridine Etc. are particularly preferred.
  • the reaction temperature is 140 ° C. to 150 ° C., preferably 2 Ot: to 120 ° C., and the reaction time is 5 minutes to 96 hours, preferably 30 minutes to 24 hours. .
  • the above Reaction 2 and Reaction 3 can be advantageously performed by continuously performing the reaction without isolating and purifying the product during the reaction.
  • the above 5-dichloromethylene imidazolidine compound represented by the general formula (II) or a salt thereof as a raw material with the above mercapto compound represented by the general formula ROCOCH 2 CH 2 SH in the presence of a base, the general formula An imidazolidine compound represented by (IV) or a salt thereof is obtained.
  • a ketone compound having a leaving group L at the octyl position represented by the general formula (V) L represents a halogen atom such as chlorine, bromine or iodine or a sulfonyloxy group such as methanesulfonyloxy, P-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.
  • L represents a halogen atom such as chlorine, bromine or iodine
  • a sulfonyloxy group such as methanesulfonyloxy, P-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.
  • the leaving group L is a halogen atom.
  • the compound represented by the general formula (V) or a salt thereof, in which the leaving group L is a sulfonyloxy group is a compound known per se represented by the corresponding -hydroxyketone compound, for example, the method shown in Reaction 10 below. It can be prepared by sulfonylation of a hydroxyl group by the method described in the above.
  • L is preferably a halogen atom such as chlorine, bromine or iodine, and more preferably chlorine or bromine. It is.
  • the ketone compound or a salt thereof is used in an amount of 0.2 to 10 equivalents, preferably 1 to 5 equivalents, more preferably 1 to 3 equivalents, based on the raw material.
  • the base include the bases shown in Reaction 2 above, and preferable examples thereof include, for example, alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, alkyllithiums, and alkali metal amides.
  • the base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, and preferably, an amide solvent, an ether solvent, a ketone solvent, an ester solvent, and a nitrile solvent are used. Solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, organic base solvents, etc., and mixtures thereof.
  • N, N-dimethylformamide, N, N-dimethylileacetamide, titra Hydrofuran, dioxane, dimethoxyethane, acetate, 2-butenonone, ethyl acetate, tert-butyl acetate, acetatetonitrile, toluene, dichloromethane, chloroform, 1,2-dichloroethane, pyridine and the like are particularly preferred.
  • the reaction temperature is from 140 ° C to 150 ° C, preferably from 0 to 100 ° C
  • the reaction time is from 5 minutes to 96 hours, preferably from 30 minutes to 48 hours.
  • the imidazothiazine compound represented by the general formula (VI) (R represents the above-mentioned alkyl group) or a salt thereof is subjected to a dehydration reaction in the presence of an acid, whereby the compound represented by the general formula (VII) is obtained.
  • R represents the above alkyl group.
  • Preferred examples of the acid used include, for example, octaacetic acid (eg, trifluoroacetic acid), inorganic acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, etc.), and organic carboxylic acids.
  • Acids eg, formic acid, acetic acid, citric acid, tartaric acid, oxalic acid, etc.
  • Lewis acids eg, zinc monoacetic acid, boron trifluoride etherate, etc.
  • organic sulfonic acids eg, methanesulfonic acid, octanesulfonic acid, Benzenesulfonic acid, P-toluenesulfonic acid, camphorsulfonic acid, etc.
  • trifluoroacetic acid hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic acid, P-toluenesulfonic acid, camphorsulfonic acid, etc. Is particularly preferred.
  • the acid is used in an amount of 0.05 to 10 equivalents, preferably 0.1 to 5 equivalents, and more preferably 0.2 to 2 equivalents, based on the raw material.
  • the reaction is advantageously carried out by coexisting a dehydrating agent to remove the usually generated water.
  • a dehydrating agent molecular sieves 4A, acid anhydride (eg, acetic anhydride, propionic anhydride, benzoic anhydride, etc.) are used.
  • the amount is 5% to 10 times, preferably 10% to 5 times, or 10% by weight of the raw material.
  • the solvent is not specified as long as it does not affect the reaction, but is preferably an organic acid-based solvent (eg, formic acid, acetic acid, propionic acid, etc.), an amide-based solvent (eg, N, N-dimethylformamide, N, N —Dimethylacetamide, etc.), ether solvents (eg, tetrahydrofuran, getylether, dioxane, dimethoxyethane, etc.), sulfoxide solvents (eg, dimethylsulfoxide, etc.), alcohol solvents (eg, methanol, ethanol, propanol, Isopropanol, isobutanol, tert-butanol, etc., nitrile solvents (eg,
  • acetic acid, N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, tert-butanol, acetonitrile, ethyl acetate, tert-butyl acetate, toluene, xylenes, chloroform, 1,2- Dichloroethane is preferred.
  • the reaction temperature is ⁇ 4 Ot: to 180 ° C, preferably 0 ° C to 120 ° C, and the reaction time is 5 minutes to 120 hours, preferably 10 minutes to 72 hours. .
  • the imidazothiazine compound represented by the general formula (VIII) is obtained by reacting the imidazothiazine compound represented by the general formula (VII) (R represents the above alkyl group) or a salt thereof with a base. A compound or a salt thereof is obtained.
  • Examples of the base include the bases shown in Reaction 2 above, and preferable examples thereof include, for example, alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, alkyllithiums, and alkali metal amides.
  • alkali metal hydrides sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazavisic mouth [5,4,0] -7-Pendecene, methyllithium, butyllithium, lithium diisopropylamide, and lithium bistrimethylsilylamide are particularly preferred.
  • the base is used in an amount of 1 to 20 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents.
  • These reactions are usually advantageously performed in a solvent.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, preferably an amide solvent, an ether solvent, an alcohol solvent, a nitrile solvent, an organic base. Solvent, or a mixture of these solvents. Among them, N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, 2-propanol, tert-butanol, Acetonitrile, pyridine and the like are particularly preferred.
  • the reaction temperature is ⁇ 40 ° C. to 15 Ot: preferably 20 ° C. to 120 °, and the reaction time is 5 minutes to 96 hours, preferably 30 minutes to 24 hours.
  • L is a halogen atom such as chlorine, bromine, iodine, etc., or methanesulfonyloxy, P-toluenesulfonyl, trifluoromethanesulfonyloxy, etc. Sulfonyloxy group and the like are preferable.
  • General formula: 2 a compound represented by one L or compound leaving group L is Nono androgenic atom of its salt corresponding alcohol Ichiru compound R 2 - 0 H or a hydroxyl by a method per se publicly known salts thereof Can be prepared by halogenating Among the compounds represented by the general formula R 2 —L or a salt thereof, the compound in which the leaving group L is a sulfonyloxy group can be converted from R 2 — ⁇ H to a compound represented by, for example, the method shown in Reaction 10 below. It can be prepared by sulfonylating a hydroxyl group by a known method.
  • the compound represented by the above general formula R 2 -L or a salt thereof is used in an amount of 0.2 to 20 equivalents, preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents to the starting material.
  • the base include the bases shown in the above Reaction 2, and preferable examples thereof include, for example, hydrogenated metal alkoxides, metal alkoxides, inorganic bases, organic bases, alkyllithiums, and metal alkoxides.
  • Amides and the like are preferable, and sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, triethylamine, disopropylethylamine, pyridine, 4-dimethylaminopyridine , 1,8-Diazavicic mouth [5,4,0] -7-indene, methyllithium, butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide and the like are particularly preferable. Of these, liquid ones are also used as solvents.
  • the base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents. These reactions are usually advantageously performed in a solvent.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, preferably an amide solvent, ether solvent, ketone solvent, ester solvent, nitrile Solvents, alcohol-based solvents, hydrocarbon-based solvents, organic base-based solvents, and the like, or a mixture thereof.
  • the solvent shown in Reaction 2 above is used, preferably an amide solvent, ether solvent, ketone solvent, ester solvent, nitrile Solvents, alcohol-based solvents, hydrocarbon-based solvents, organic base-based solvents, and the like, or a mixture thereof.
  • N, N-dimethylform Muamide, N-methylpyrrolidone, tetrahydrofuran, dioxane, dimethoxyethane, acetone, 2-butanone, ethyl acetate, tert-butyl acetate, acetonitrile, toluene, pyridine and the like are particularly preferred.
  • reaction temperature is ⁇ 20 ° C. to 20 O, preferably 20 ° C. to 120 ° C.
  • the reaction time is 5 minutes to 120 hours, preferably 20 minutes to 72 hours.
  • Reaction 6 and reaction 7_ (a) can also be performed in a concatenated manner.
  • the alcohol compound represented by the general formula R 2 —OH or a salt thereof is used in an amount of 0.2 to 20 equivalents, preferably 1 to 10 equivalents, and more preferably 1 to 5 equivalents to the starting material.
  • the dehydrating condensing agent include phosphine monoazodicarboxylates and phosphine monoazodicarboxylates reported in the Mitsunobu reaction [Synthes is, p. 1, 1989] [Journal of the Society of Synthetic Organic Chemistry] 55, 631, 1997] are advantageously used as the dehydrating condensing agent.
  • Examples of the phosphine include triaryl phosphine, triaryl phosphine such as tri-0-tolyl phosphine, and the like, or trialkyl phosphine such as trimethyl phosphine and tributyl phosphine, among which triphenyl phosphine and tributyl phosphine are preferable.
  • Examples of the azodicarboxylate include acetyl dicarboxylate, diisopropyl azodicarboxylate, and the like.
  • azodicarboxylic acid amides include N, N, ⁇ ', ⁇ '-tetramethyl azodicalpoxamide, ⁇ , ⁇ , N', N'-tetraisopropyl azodicarpoxamide, 1, tri (azodicarponyl) And dipiperidine.
  • the dehydrating condensing agent is used in an amount of 1 to 20 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents. It is preferable to use the same moles of phosphine and azodicarboxylic acid ester or azodicarboxylic acid amide.
  • These reactions are usually advantageously performed in a solvent.
  • the solvent is not specified as long as it does not affect the reaction.
  • amide solvents Preferably used are amide solvents, ether solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents, octogenated hydrocarbon solvents, organic base solvents, etc., or a mixture thereof.
  • the reaction temperature is between 120 ° C and 150 ° C, preferably between 20 ° C and 120 ° C, and the reaction time is between 5 minutes and 120 hours, preferably between 20 minutes and 60 hours. is there.
  • a thiol compound represented by the general formula R 2 —SH (where R 2 represents an aryl group which may have a substituent) from an imidazothiazine compound represented by the general formula (VIII) or a salt thereof as a raw material.
  • the thiol compound represented by the general formula R 2 —SH or a salt thereof is used in an amount of 0.2 to 20 equivalents, preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents, based on the amount of the raw material.
  • the dehydrating condensing agent for example, the phosphine and azodicarboxylic acid ester or azodicarboxylic acid amide mentioned in the above reaction 7- (b) are advantageously used. Examples include acetyldiazolate azodicarboxylate and diisopropyl azodicarboxylate.
  • azodicarboxylate amides examples include N, N, N ', N, -tetramethylazodicarpoxamide, 1,1- (azodicarpoxamide). Nyl) dipiperidine and the like are preferred.
  • the dehydrating condensing agent is used in an amount of 1 to 20 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents. It is preferable that phosphine and azodicarboxylic acid ester or azodicarboxylic acid amide be used in the same mole number. These reactions are usually advantageously performed in a solvent.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, and preferably, an amide solvent, an ether solvent, a ketone solvent, an ester solvent, and nitrile are used. Solvent, hydrocarbon solvent, halogenated hydrocarbon solvent, organic base solvent, etc.
  • the reaction temperature is -20 ° C to 120 ° C, preferably 20 ° C to 80 ° C, and the reaction time is 10 minutes to 240 hours, preferably 20 minutes to 120 hours.
  • R 1 is -NR 3 R 4 ,
  • R 1 is -SR 2 ,
  • Imidazolidine compound represented by the general formula (X) (Z represents a S0 2.) Or As a salt as a raw material, Amin or its salt with a base represented by R 3 R 4 NH or R 12 R 13 NH To give an imidazolidine compound (Z represents S ⁇ 2 ) represented by the general formula (XI) or (XII) or a salt thereof.
  • the amine represented by R 3 R 4 NH or R 12 R 13 NH or a salt thereof is 1 to 50 Equivalents, preferably 2 to 20 equivalents, more preferably 2 to 10 equivalents are used. Of these, liquid ones are also used as solvents. These amines are also advantageously used as salts with suitable acids.
  • Examples of the acid include octaacetic acid (eg, trifluoroacetic acid), inorganic acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, etc.), and organic carboxylic acid (eg, formic acid, acetic acid) , Citric acid, tartaric acid, oxalic acid, etc.), organic sulfonic acids (eg, methanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid, camphorsulfonic acid, etc.) are used, among which hydrochloric acid, formic acid, acetic acid , Methanesulfonic acid, P-toluenesulfonic acid and the like are particularly preferred.
  • octaacetic acid eg, trifluoroacetic acid
  • inorganic acid eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
  • the acid is usually used in an equimolar amount to the amine.
  • the base include the bases shown in the above Reaction 2, and preferable examples include, for example, hydrogenated alkali metal, alkoxide of alkali metal, inorganic base, organic base, and alkali metal amide.
  • the base is used in an amount of 0.1 to 20 equivalents, preferably 0.5 to 10 equivalents, and more preferably 1 to 5 equivalents. These reactions are usually advantageously carried out in a solvent.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in the above Reaction 2, etc. is used, and preferably an amide solvent, an ether solvent, an alcohol solvent, a nitrile solvent, Examples include organic base solvents and the like, or a mixed solvent thereof. Among them, N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, 2-propanol, tert-butanol , Acetonitrile, pyridine and the like are particularly preferred.
  • the reaction temperature is from ⁇ 40 ° C. to 150 ° C., preferably from 20 ° to 120 ° C. (: the reaction time is from 5 minutes to 96 hours, preferably from 30 minutes to 24 hours.
  • R 1 is one SR 2 , XY is
  • the base include the bases shown in Reaction 2 above, and preferable examples include, for example, alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, alkyllithiums, and alkali metal amides.
  • sodium hydride, potassium tert-butoxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0]- 7-Pendecene, methyllithium, butyllithium, lithium disopropylamide, lithium pistrimethylsilylamide and the like are particularly preferred.
  • liquid ones are also used as solvents.
  • the base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents.
  • L is preferably a halogen atom such as chlorine, bromine or iodine, or a cyano group or an imidazole group.
  • the compound represented by the above general formula R 15 —Z—L is used in an amount of 0.2 to 20 equivalents, preferably 1 to 1 equivalent to the raw material. 0 equivalents, more preferably 1 to 5 equivalents are used.
  • These reactions are usually advantageously performed in a solvent.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, and preferably an amide solvent, an ether solvent, a ketone solvent, an ester solvent, a nitrile solvent.
  • the reaction temperature is from 180 ° C. to 150 ° C., preferably from 0 to 100 ° C., and the reaction time is from 1 minute to 120 hours, preferably from 5 minutes to 48 hours.
  • Examples of the base include the bases shown in the above-mentioned Reaction 9-1 (a), and preferable examples include, for example, alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, alkyllithiums, and alkalis. Metal amides and the like are preferred, and sodium hydride, potassium tert-butoxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazapicyclo 0]-7-Pendecene, methyllithium, butyllithium, And lithium pistrimethylsilylamide are particularly preferred. Of these, liquid ones are also used as solvents.
  • the base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents.
  • L is preferably a halogen atom such as chlorine, bromine, and iodine.
  • the compound represented by the above general formula R 16 R 17 P ( ⁇ ) 1 L is used in an amount of 0.2 to 20 equivalents, preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents, based on the amount of the raw material.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in the above reaction 9- (a) or the like is used, preferably an amide solvent, an ether solvent, a ketone solvent, an ester solvent, Examples include nitrile-based solvents, alcohol-based solvents, hydrocarbon-based solvents, organic base-based solvents, and the like, or a mixed solvent thereof. Dimethoxyethane, acetone, 2-butanone, ethyl acetate, tert-butyl acetate, acetonitrile, toluene, pyridine and the like are particularly preferred.
  • the reaction temperature is -80 to 150 ° C, preferably 0 to 100 ° C, and the reaction time is 1 minute to 120 hours, preferably 5 minutes to 48 hours.
  • imidazothiazine compound represented by the general formula (XIII) or a salt thereof as a starting material the general formula R 18 _Z- NCO (Z represents S_ ⁇ 2 or a single bond.) Represented by the 'Isoshi Aneto acids or their By reacting with a salt, an imidazothiazine compound represented by the general formula (X ”) or a salt thereof is obtained.
  • the reaction is advantageously performed in the presence of a base.
  • a base The base shown in the above reaction 9-1 (a) and the like are preferable.
  • Preferred examples include, for example, alkali metal hydride, alkali metal alkoxide, inorganic base, organic base, alkyl lithium, and alkali metal amide.
  • Sodium hydride, potassium tert-butoxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabisic D [5, 4, 0]- 7-Pendecene, methyllithium, butyllithium, lithium diisopropylamide, lithium pistrimethylsilylamide and the like are particularly preferred. Of these, liquid ones are also used as solvents.
  • the base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents.
  • the isocyanate represented by the general formula R 18 —Z-NCO is used in an amount of 0.2 to 20 equivalents, preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents, based on the amount of the raw material. These reactions are usually and advantageously effected in a solvent.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in the above reaction 9-1 (a) is used, and preferably an amide solvent, an ether solvent, a ketone solvent, an ester solvent, Examples include nitrile solvents, alcohol solvents, hydrocarbon solvents, organic base solvents, and mixtures thereof.N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, dioxane , Dimethoxyethane, acetone, 2-butanone, ethyl acetate, tert-butyl acetate, acetonitrile, toluene, pyridine and the like are particularly preferred.
  • the reaction temperature ranges from 80 ° C to 150 ° C, preferably from 0 ° C to 100 ° C, and the reaction time ranges from 1 minute to 120 hours, preferably from 5 minutes to 48 hours.
  • condensing agent examples include N, N'-carbonyldiimidazole, benzotriazolyl-N-hydranide salt, N, N, -disocyanate.
  • Preferred examples thereof include, for example, N, N dicyclohexylcarboimide, Particularly preferred are getyl cyanophosphate, and triethyl hydrochloride-3- (3-dimethylaminopropyl) carbodiimide.
  • the condensing agent is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents.
  • Examples of the base include the bases shown in the above reaction 9-1 (a). Preferred examples include alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, 7-alkyllithiums, and alkalis.
  • Metal amides and the like are preferable, and sodium hydride, potassium tert-butoxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0 ] -7-Pendecene, methyllithium, butyllithium, lithium disopropylamide, lithium pistrimethylsilylamide and the like are particularly preferred. Of these, liquid ones are also used as solvents.
  • the base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents. Formula R 1 5 -.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in the above reaction 9-1 (a) is used, and preferably an amide solvent, an ether solvent, a ketone solvent, or an ester solvent Solvents, nitrile-based solvents, alcohol-based solvents, hydrocarbon-based solvents, organic base-based solvents and the like, or a mixture thereof, among which N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, Dioxane, dimethoxyethane, acetone, 2-butanone, ethyl acetate, tert-butyl acetate, acetonitrile, toluene, pyridine and the like are particularly preferred.
  • Anti The reaction temperature is
  • imidazothiazine compound represented by (X IV) Z represents a S_ ⁇ 2.
  • a salt thereof as a raw material, subjecting the hydroxyl group in the formula a conversion reaction of the leaving group L, to Accordingly, imidazothiazine compound represented by the general formula (XV) (Z represents a S_ ⁇ 2.) or a salt thereof.
  • the conversion reaction to the leaving group L ′ include a halogenation reaction with a halogenating agent and a sulfonic acid esterification reaction.
  • halogenating agent examples include hydrogen halide (eg, hydrogen iodide, hydrogen bromide, hydrogen chloride, etc.) or halogenating agent (eg, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, Organophosphorus compounds such as phosphorus halides such as phosphorus bromide, triphenylphosphine monocarbon tetrachloride, triphenylphosphine monobromine, triphenylphosphine mono-N-bromosuccinimide, triphenylphosphite methyl iodide, or thionyl chloride, oxalyl chloride , Phosgene, etc.).
  • hydrogen halide eg, hydrogen iodide, hydrogen bromide, hydrogen chloride, etc.
  • halogenating agent eg, phosphorus trichloride, phosphorus pentachloride, phosphorus
  • the halogenating agent is used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents. Of these, liquid ones are also used as solvents. These halogenation reactions are advantageously performed in a solvent.
  • Solvents include water, organic acid solvents (eg, formic acid, acetic acid, etc.), ketone solvents (eg, acetone, methylethyl ketone, methyl isobutyl ketone, etc.), amide solvents (eg, N, N-dimethylformamide) , Dimethylacetamide, etc.), halogenated hydrocarbon solvents (eg, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene), alcohol solvents (eg, tert- Butanol), nitrile solvents (eg, acetonitrile), ester solvents (eg, ethyl formate, ethyl acetate,
  • reaction temperature is ⁇ 20 to 150, preferably to 100 ° C.
  • reaction time is 2 minutes to 48 hours, preferably 5 minutes to 10 hours.
  • the hydroxyl group of the raw material is converted to a sulfonyl halide (eg, methanesulfonyl chloride, benzenesulfonyl chloride, P-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, etc.) or a sulfonic anhydride (eg, methanesulfone Acid anhydride, benzenesulfonic anhydride, P-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.) in the presence of a suitable base.
  • a sulfonyl halide eg, methanesulfonyl chloride, benzenesulfonyl chloride, P-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, etc.
  • the sulfonyl halide or sulfonic anhydride is used in an amount of 0.2 to 20 equivalents, preferably 1 to 10 equivalents, and more preferably 1 to 5 equivalents, based on the starting material.
  • the base include the bases shown in the above Reaction 2, and preferable examples thereof include, for example, an alkali metal hydride, an inorganic base, an organic base, and an alkali metal amide.
  • potassium triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] -7-indene, lithium diisopropylamide, lithium pistrimethylsilylamide and the like.
  • liquid ones are also used as solvents.
  • the base is used in an amount of 1 to 20 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents.
  • the sulfonyloxy group formed in the sulfonic acid esterification reaction can be converted to a halogen group by reacting with an appropriate inorganic halide (eg, sodium iodide, potassium iodide, sodium bromide, potassium bromide, etc.). It is possible.
  • the inorganic halide is used in an amount of 1 to 50 equivalents, preferably 1 to 20 equivalents, and more preferably 1 to 10 equivalents, based on the raw material. These reactions are usually performed in a solvent that does not affect the reaction.
  • the solvent examples include those used in the above-mentioned halogenation reaction except for water, and among them, acetone, methylethylketone, N, N-dimethylformamide, dimethylacetamide, dichloromethane, and chloroform And 1,2-dichloroethane, acetonitrile, ethyl acetate, tert-butyl acetate, tetrahydrofuran, getyl ethere, dioxane, dimethoxyethane, hexane, toluene, pyridine, and the like, or a mixed solvent thereof. These are particularly preferably water-free solvents.
  • the reaction temperature is from 120 to 200, preferably from 20 ° C. to 12 Ot: and the reaction time is from 5 minutes to 120 hours, preferably from 20 minutes to 72 hours.
  • the imidazothiazine compound represented by the general formula (XV) (Z represents so 2 ) or a salt thereof is reacted with a base or an acid to obtain the compound represented by the general formula (XVI).
  • Examples of the base include the bases shown in Reaction 2 above, and preferable examples thereof include, for example, alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, and alkali metal amides. , Potassium tert-butoxide, sodium carbonate, potassium carbonate, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] -7-indene, lithium diisopropylamide, lithium pistrimethylsilylamide Etc. are particularly preferred.
  • the base is used in an amount of 1 to 20 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents.
  • Examples of the acid include the acids shown in the above Reaction 5, among which, for example, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, methanesulfonic acid, P-toluenesulfonic acid, camphorsulfonic acid And boron trifluoride etherate complex are particularly preferred. Of these, liquid ones are also used as solvents.
  • the acid is used in an amount of 0.05 to 10 equivalents, preferably 0.1 to 5 equivalents, and more preferably 0.2 to 2 equivalents, based on the raw material. These reactions are advantageously carried out usually in a solvent.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in the above Reaction 2 or Reaction 5 is used, and preferably, an organic acid solvent, an amide solvent, an ether solvent, or an alcohol solvent Solvents, nitrile-based solvents, hydrocarbon-based solvents, halogenated hydrocarbon-based solvents, organic base-based solvents, and the like, or a mixture thereof.
  • reaction temperature is —40 ° C. to 200 ° C., preferably 0 to 12 O, and the reaction time is 5 minutes to 120 hours, preferably 30 minutes to 48 hours.
  • R 1 is — SR 2 , Fifteen
  • the imine represented by the general formula (IV) Dazorijin compounds Z is S 0 2, R indicates the alkyl group.
  • the general formula (XV III) imidazolidine represented Ru compounds Z is S_ ⁇ 2, R is obtained.) or a salt thereof shows the alkyl group .
  • Imida Zorijin compound represented by the general formula (XV III) Z is S_ ⁇ 2, R represents the alkyl group.
  • imidazolidine compound represented by the general formula (XIX) Z is S 0 2, R represents the alkyl group.
  • an imidazolysine compound represented by the general formula (XIX) or a salt thereof is used as a starting material, and a ketone having a leaving group L at the ⁇ -position represented by the above general formula (V)
  • a ketone having a leaving group L at the ⁇ -position represented by the above general formula (V) By reacting the compound or a salt thereof in the presence of a base, an imidazothiazine compound represented by the general formula (XX) or a salt thereof is obtained.
  • the imidazothiazine compound represented by the general formula (XX) ( ⁇ represents so 2 ) or a salt thereof is reacted with an acid to form the compound represented by the general formula (X) or (XXI).
  • the acid include the acids shown in Reaction 5 above, among which, for example, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid And boron trifluoride etherate are particularly preferred. Of these, liquid ones are also used as solvents.
  • the acid is used in an amount of 0.05 equivalents, preferably 10 equivalents, preferably 0.1 to 5 equivalents, more preferably 0.2 to 2 equivalents, based on the raw material.
  • These reactions are usually advantageously performed in a solvent.
  • the solvent is not specified as long as it does not affect the reaction, but the solvents described in Reaction 5 above are used, and preferably, organic acid solvents, amide solvents, ether solvents, alcohol solvents, nitriles Solvents, hydrocarbon solvents, haptic hydrocarbon solvents, organic base solvents, etc., and mixtures thereof.
  • reaction temperature is between 14O: to 200 ° C, preferably not 0 to 120 ° C, and the reaction time is 5 minutes to 120 hours, preferably 30 minutes to 48 hours.
  • R is _SR 2 .
  • imidazolidine compound represented by (Z is S_ ⁇ 2 are shown.
  • a salt thereof as a raw material represented by the general formula (XX III) (R represents an alkyl group such as methyl, ethyl, propyl, isopropyl, 2-ethylhexyl) or a salt thereof in the presence of a base.
  • R represents an alkyl group such as methyl, ethyl, propyl, isopropyl, 2-ethylhexyl
  • Z represents so 2
  • R 1 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
  • organometallic reagents or their equivalents examples include alkyl lithium (eg, methyl lithium, ethyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc.), alkyl magnesium hydride (eg, Methylmagnesium bromide, ethylmagnesium bromide, n-butylmagnesium bromide, n-pentylmagnesium bromide, n-hexylmagnesium bromide, etc., alkyl zinc halides (eg, methyl zinc bromide, getyl zinc bromide, etc.) Alkyl zinc (eg, dimethyl zinc, diethyl zinc, etc.), alkyl aluminum (eg, trimethyl aluminum, etc.) are used.
  • alkyl lithium eg, methyl lithium, ethyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc.
  • an arbitrary halide can be converted into an organolithium, an organomagnesium halide or an alkyl zinc halide by a method known per se as a raw material and used in this reaction.
  • the metal hydride include lithium aluminum hydride, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, and the like.
  • the organic metal reagent or its equivalent or metal hydride is used in an amount of 0.5 to 20 equivalents, preferably 1 to 10 equivalents. These reactions can be advantageously performed in the presence of an appropriate organic phosphorus compound or the like.
  • the organic phosphorus compound include triarylphosphine (eg, triffee).
  • the organic phosphorus compound is used in an amount of 1 to 50 equivalents, preferably 1 to 10 equivalents, based on the amount of the raw material.
  • reaction can be performed in the presence of an appropriate inorganic salt (eg, lithium iodide, lithium bromide, lithium chloride, cerium chloride, etc.).
  • the inorganic salt is used in an amount of 1 to 50 equivalents, preferably 1 to 10 equivalents, based on the raw material.
  • These reactions are usually performed in a solvent that does not affect the reaction.
  • the solvent examples include amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, etc.), ether solvents (eg, tetrahydrofuran, getyl ether, dioxane, dimethoxetane, etc.), Hydrocarbon solvents (eg, hexane, benzene, toluene, etc.), organic base solvents (eg, pyridine, 2,4,6-trimethylpyridine, picoline, 2,6-lutidine, 1,8-diazabicyclo [5 , 4, 0] -7-dendene and the like, or a mixed solvent thereof.
  • amide solvents eg, N, N-dimethylformamide, N, N-dimethylacetamide, etc.
  • ether solvents eg, tetrahydrofuran, getyl ether, dioxane, dimethoxetane, etc.
  • Hydrocarbon solvents
  • reaction temperature is from 100 to 150, preferably from 140 to 120, and the reaction time is from 2 to 120 hours, preferably from 10 to 4 hours. 8 hours.
  • An imidazothiazine compound represented by the general formula (XXV) or a salt thereof is obtained by reacting an imidazothiazine compound represented by the general formula (XX) (Z represents CO) or a salt thereof with an acid. Get the salt.
  • Examples of the acid include the acids shown in the above Reaction 5, among which, for example, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, methanesulfonic acid, P-toluenesulfonic acid, camphorsulfonic acid And boron trifluoride etherate complex are particularly preferred. Of these, liquid ones are also used as solvents.
  • the acid is used in an amount of 0.05 to 10 equivalents, preferably 0.1 to 5 equivalents, more preferably 0.2 to 2 equivalents, based on the raw material. These reactions are usually advantageously performed in a solvent.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in the above Reaction 2 or Reaction 5 is used, and preferably an organic acid solvent, an amide solvent, an ether solvent, or an alcohol.
  • the reaction temperature is from ⁇ 40 to 200, preferably from 0 ° C. to 120 ° C., and the reaction time is from 5 minutes to 120 hours, preferably from 30 minutes to 48 hours.
  • an imidazothiazine compound represented by the general formula (XXV) or a salt thereof as a raw material and reacting with the general formula R 14 — L (L represents a leaving group) or a salt thereof in the presence of a base
  • a base include the bases shown in the above Reaction 2.
  • Preferred examples are, for example, alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, alkyllithiums, and alkali metal amides.
  • the base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents.
  • L is preferably a halogen atom such as chlorine, bromine or iodine.
  • R 1 4 is compound of represented by R 1 5 Z-, L is chlorine, bromine, a halogen atom such as iodine or Metansuru Honiruokishi, p - toluenesulfonyl O carboxymethyl, such as triflate Ruo b methanesulfonyl two Ruoki Shi Sulfonyloxy groups and the like are preferred.
  • the compound represented by the above general formula R 14 -L or a salt thereof is used in an amount of 0.2 equivalents, preferably 1 to 10 equivalents, and more preferably 1 to 5 equivalents to the raw material. . These reactions are advantageously carried out usually in a solvent.
  • the solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, and preferably an amide solvent, an ether solvent, a ketone solvent, an ester solvent, Examples include tolyl solvents, alcohol solvents, hydrocarbon solvents, organic base solvents, and the like, and mixtures thereof, among which N, N_dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, dioxane, dimethyloxetane, Acetone, 2-butanone, ethyl acetate, tert-butyl acetate, acetonitril, toluene, pyridine and the like are particularly preferred.
  • the reaction temperature is from 180 to 150, preferably from 0 to 100 T, and the reaction time is from 1 to 120 hours, preferably from 5 to 48 hours.
  • R 1 is — SR 2 ,
  • an isocyanate represented by the general formula R 14 -NC ⁇ (R 14 represents an optionally substituted hydrocarbon group) is reacted in the presence of an acid, and then reacted with a base As a result, a 5-dichloromethyleneimidazolidine compound represented by the general formula (XXV II) or a salt thereof is obtained.
  • the isocyanate compound represented by R 14 -NCO is used in an amount of 0.1 to 10 equivalents, preferably 0.2 to 5 equivalents, more preferably 1 to 2 equivalents, based on the amount of the raw material.
  • the isocyanate compound represented by R 14 -NC 0 is preferably such that R 14 is, for example, methyl
  • Particularly preferred is isocyanate which is a group, benzyl group, n-butoxycarbonylmethyl group, ethoxycarbonylmethyl group, ethoxycarbonylethyl group and the like.
  • the acid catalyst examples include Lewis acids (eg, boron trifluoride ether complex, zinc chloride, aluminum chloride, titanium tetrachloride, tin tetrachloride, etc.), organic sulfonic acids (eg, methanesulfonic acid, octanesulfonic acid, benzene) Sulfonic acid, P-toluenesulfonic acid, camphorsulfonic acid, etc., haloacetic acid (eg, trifluoroacetic acid, etc.), inorganic acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, etc.) Among them, Lewis acids are preferable, and aluminum chloride is particularly preferable.
  • Lewis acids eg, boron trifluoride ether complex, zinc chloride, aluminum chloride, titanium tetrachloride, tin tetrachloride, etc.
  • organic sulfonic acids
  • the acid is used in an amount of 0.1 to 10 equivalents, preferably 0.2 to 5 equivalents, more preferably 1 to 2 equivalents, based on the amount of the raw material.
  • This reaction is advantageously performed in a solvent. These reactions are usually performed in a solvent that does not affect the reactions.
  • Solvents are not specified as long as they do not affect the reaction, but amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), halogenated carbon Hydrogen-based solvents (eg, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene), nitrile solvents (eg, acetonitrile, etc.), ester solvents (eg, ethyl formate, ethyl acetate) , Tert-butyl acetate, etc.), ketone solvents (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), ether solvents (eg, tetrahydrofuran, getyl ether, diisopropyl ether, dioxan, dimethyloxetane, etc
  • halogenated hydrocarbon solvents halogenated hydrocarbon solvents, ester solvents, ether solvents, hydrocarbon solvents, and the like are preferable, and dichloromethane, chloroform, tetrahydrofuran, ethyl ether, and toluene are particularly preferable.
  • the reaction temperature is ⁇ 40 ° C. to 150 ° C., preferably O to 100 ° C., and the reaction time is 2 minutes to 96 hours, preferably 5 minutes to 60 hours.
  • Examples of the base to be used include the bases shown in the above Reaction 2, and preferable examples thereof include, for example, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycline [5,4,0] -7-pentadecene , Triethylamine, Dimethylaniline, Sodium carbonate, Carbonated Liu And the like.
  • the base is used in an amount of 0 to 10 equivalents, preferably 0 to 1 equivalent.
  • the reaction temperature is 14 to 150, preferably Ot: to 100, and the reaction time is 2 to 96 hours, preferably 5 to 60 hours. is there.
  • Examples of the acid to be used include the acids shown in the above Reaction 5, etc., among them, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ⁇ -toluenesulfonic acid, camphorsulfonic acid and the like. preferable. Of these, liquid ones are also used as solvents.
  • the acid is used in an amount of 0.1 to 20 equivalents, preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents, based on the amount of the raw material. These reactions are advantageously carried out usually in a solvent.
  • the solvent is not specified as long as it does not affect the reaction.
  • the solvent include, for example, water in addition to the solvent shown in Reaction 5 above, and preferably water, formic acid, acetic acid, ⁇ , ⁇ -dimethylformamide, Examples thereof include tetrahydrofuran, dioxane, dimethoxetane, dimethyl sulfoxide, methanol, ethanol, propanol, isopropanol, isobutanol, tert-butanol, and acetonitrile, or a mixed solvent thereof.
  • the reaction temperature is between 140 ° C. and 180 ° C., preferably Ot: 120
  • the reaction time is between 10 minutes and 72 hours, preferably between 30 minutes and 48 hours.
  • a 5_dichloromethyleneimidazolidine compound represented by the general formula (XXVI II) or a salt thereof is used as a raw material, and expressed by a general formula R ⁇ COCH 2 CH 2 SH in the presence of a base.
  • R represents an alkyl group such as methyl, ethyl, propyl, isopropyl, 2-ethylhexyl, etc.
  • XX IX an imidazolidine compound represented by the general formula (XX IX). Or to obtain its salt.
  • imidazo represented by the general formula (XX IX) Using a lysine compound (R represents the above-mentioned alkyl group) or a salt thereof as a raw material, a ketone compound represented by the general formula (V) having a leaving group L at the cH position or a salt thereof is reacted in the presence of a base. As a result, an imidazothiazine compound represented by the general formula (XX) (R represents the above alkyl group) or a salt thereof is obtained.
  • an imidazothiazine compound represented by the general formula (XXX) (R represents the above alkyl group) or a salt thereof is subjected to a dehydration reaction in the presence of an acid.
  • an imidazothiazine compound represented by the general formula (XXXI) (R represents the above alkyl group) or a salt thereof is obtained.
  • an imidazothiazine compound represented by the general formula (XX XI) (R does not have the above-mentioned alkyl group) or a salt thereof is used as a raw material and reacted with a base to give a general compound.
  • An imidazothiazine compound represented by the formula (XXXII) or a salt thereof is obtained.
  • an imidazothiazine compound represented by the general formula (XXXII) is used as a starting material, and in the presence of a base, a compound represented by the general formula R 2 — L (L is a leaving group To obtain an imidazothiazine compound represented by the general formula (XXXIII).
  • substituents may have functional groups that decompose and react under each reaction condition.However, their protection and deprotection after the reaction can be performed by a method known per se. it can. The conversion of various functional groups that may be present on each substituent can be performed by a method known per se.
  • the hydrolysis is advantageously performed in the presence of, for example, an acid or a base.
  • the acid include the acid shown in Reaction 5 above
  • examples of the base include the base shown in Reaction 3 above.
  • hydrochloric acid sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, P-toluenesulfone Acid, camphorsulfonic acid, etc.
  • sodium hydride sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, carbonic acid
  • potassium hydroxide sodium methoxide, sodium ethoxide, potassium tert-butoxide
  • sodium carbonate carbonic acid
  • potassium hydroxide triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] -7-pinedecene and the like are preferable.
  • the acid or base is used in an amount of 0.1 to 20 equivalents, preferably 1 to 5 equivalents, based on the starting material.
  • These reactions are usually advantageously performed in a solvent that does not affect the reaction, and water, the solvent shown in the above Reaction 2, or the like is used. Among them, water, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, 2-propanol, tert-butanol, acetonitrile, pyridine and the like, or a mixed solvent containing these waters are preferable.
  • the reaction temperature is from ⁇ 20 ° C. to 20 ° C., preferably from 20 ° C. to 120 ° C.
  • the reaction time is from 5 minutes to 120 hours, preferably from 20 minutes to 72 hours.
  • the starting compound when a functional group such as an esterified or amidated carboxyl group, a cyano group, or a carbonyl group is reduced to be converted to a formyl group, a hydroxymethyl group, an aminomethyl group, a hydroxyl group, or the like, the starting compound is used. It is obtained by subjecting it to a reduction reaction.
  • a functional group such as an esterified or amidated carboxyl group, a cyano group, or a carbonyl group
  • the starting compound is used. It is obtained by subjecting it to a reduction reaction.
  • This reaction involves metal hydride (eg, lithium aluminum hydride, sodium aluminum hydride, lithium borohydride, sodium borohydride, sodium cyanoborohydride, etc.), aluminum hydride (eg, hydrogen Diisobutylaluminum, etc.), dipolane (eg, borane-tetrahydrofuran, polan-methanol, etc.), dialkylborane (eg, di-sec-butylbutyl, ditexylporan, 9-boravisic [3,3,1] norpolonene, etc.)
  • the reaction is carried out by reacting with a reducing agent in an inert solvent.
  • the inert solvent examples include ether solvents (eg, tetrahydrofuran, methyl ether, dioxane, dimethyloxetane, etc.), hexane, benzene, toluene and the like.
  • the reducing agent is used in an amount of 1 to 20 equivalents, preferably 1 to 5 equivalents, and the reaction temperature is from 170 ° C to 1.50 ° C, preferably from 0 to 100 ° C.
  • the reaction time is 10 minutes to 48 hours, preferably 1 hour to 20 hours.
  • the desired product When the desired product is obtained in a free state by each of the above-mentioned reactions, it may be converted into a salt according to a conventional method, and when the desired product is obtained as a salt, the free form is obtained according to a conventional method Alternatively, it can be converted to another salt.
  • the compound thus obtained or a salt thereof can be obtained by known means, for example, phase transfer, concentration, solvent extraction, fractionation,
  • the salt of the compound described in the present specification is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, or a basic salt. Or a salt with an acidic amino acid.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt
  • Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, ⁇ , ⁇ '-dibenzylethylene. And salts with diamine and the like.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, -Salts with toluenesulfonic acid and the like.
  • Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ordinine, and the like.
  • Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. Salts.
  • the compound (I) of the present invention may be a hydrate or a non-hydrate.
  • the compound (I) used in the present invention may have one asymmetric carbon in the skeleton and thus may have two kinds of optical isomers. Each of these isomers and a mixture thereof are also described in the present invention. Included in the invention. When the substituent has an asymmetric carbon atom or an unsaturated bond, a stereoisomer or a geometric isomer is similarly produced, and the isomers and mixtures thereof are also included in the present invention.
  • the compound of the present invention has a sulfur atom in its structure, which may be oxidized by an oxidizing agent (eg, hydrogen peroxide or m-chloroperbenzoic acid) according to a conventional method. Sulfonated compounds are also included in the present invention.
  • the compound of the present invention may have an amide, imide, amidino, guanidino or peridode group in its structure or as a substituent, and these compounds have a resonance structure in which the double bond is isomerized. In some cases, these resonance structural compounds are also included in the present invention.
  • the compound (I) of the present invention may be used as a prodrug.
  • a prodrug a compound which is converted into a compound (I) by a reaction with an enzyme or gastric acid under physiological conditions in a living body, that is, a compound which is oxidized enzymatically , A compound that undergoes reduction, hydrolysis, etc., and changes to the compound (I), and a compound, which undergoes hydrolysis, etc., due to stomach acid or the like, to change to the compound (I).
  • Examples of the prodrug of the compound (I) include compounds in which the amino group of the compound (I) is acylated, alkylated, and phosphorylated (eg, the amino group of the compound (I) is icosanoylated, alanylated, pentylamino).
  • Carponylated (5-methyl-2-oxo- 1,3-dioxolen-141-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, bivaloyoxymethylated, tert-butylated compounds
  • the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloyylated, succinylated) , Fumarylation, aranylation, dimethylaminomethylcarbonylated compounds, etc.);
  • Compounds e.g., compound (I) is converted to ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, Ethoxycarponyloxetyl ester
  • Compounds that inhibit cartilage matrix degradation can be used as preventive and therapeutic agents for osteoarthritis and diseases caused by cartilage destruction.
  • Compounds that inhibit proteoglycan degradation, compounds that inhibit type I collagen degradation, and that inhibit the production of cartilage matrix-degrading enzymes such as matrix meta-oral proteinase 13 (MMP-13) and aggrecanases Compound and MMP gene expression suppression The compound having an effect is used as a prophylactic / therapeutic agent for diseases caused by osteoarthritis and cartilage destruction.
  • MMP-13 matrix meta-oral proteinase 13
  • Compounds that inhibit proteodalican degradation, compounds that inhibit type II collagen degradation, compounds that inhibit the production of cartilage matrix-degrading enzymes such as MMP-13 and aglycanase, and those that inhibit MMP gene expression Preferred examples of the compound having the following are condensed imidazolidine derivatives, and more specifically, the compound (I) or a salt thereof or a sulfoxide thereof.
  • the compound (I) or a salt thereof or a sulfoxide thereof has excellent proteoglycan release inhibitory activity, collagen II degradation inhibitory activity, and cartilage matrix degrading enzyme production inhibitory activity such as MMP-13 and aggrecanase.
  • the therapeutic agent for cartilage disease of the present invention containing Compound (I) or a salt thereof as an active ingredient is particularly useful for cartilage disease before the lesion reaches the bone itself, in terms of preventing deterioration of the cartilage tissue condition. Yes, it can be applied not only to treatment of osteoarthritis, rheumatoid arthritis and diseases caused by cartilage destruction, but also to prevention of these diseases.
  • the compound (I) or its salt or its sulfoxide has an excellent inhibitory effect on the expression of the MMP gene (particularly the MMP-13 gene), and is useful as a safe preventive and therapeutic agent for all MMP-related diseases. is there.
  • compound (I) or a salt thereof or a sulfoxide thereof exhibits an inhibitory action on proteoglycan release, an inhibitory action on collagen type I degradation, and an inhibitory action on cartilage matrix degrading enzyme production such as MMP-13 and aglycanase.
  • Substrates, specifically t inhibit the degradation of proteodalican and type II collagen. That is, it has an effect as a proteodalican degradation inhibitor, a type I collagen degradation inhibitor, and a cartilage matrix degrading enzyme inhibitor.
  • cartilage destruction As a result, it has a strong inhibitory effect on cartilage destruction, so it can be used for various cartilage diseases (deformation) in mammals (eg, humans, rats, guinea pigs, mice, cats, dogs, puppies, cows, pigs, etc.). Osteoarthritis and diseases caused by cartilage destruction), for example, for the prevention and treatment of osteoarthritis involving cartilage, rheumatoid arthritis involving cartilage, or cartilage destruction in joints etc. in related diseases Can be used for various cartilage diseases (deformation) in mammals (eg, humans, rats, guinea pigs, mice, cats, dogs, puppies, cows, pigs, etc.). Osteoarthritis and diseases caused by cartilage destruction), for example, for the prevention and treatment of osteoarthritis involving cartilage, rheumatoid arthritis involving cartilage, or cartilage destruction in joints etc. in related diseases Can be used for
  • Compound (I) or its salt or its sulfoxide has an excellent MMP gene (Especially the MMP-13 gene) has an expression-suppressing effect, and in addition to all MMP-related diseases, for example, the above-mentioned joint diseases (eg, osteoarthritis, rheumatoid arthritis, etc.), osteoporosis, Cancer (eg, primary, metastatic or recurrent, breast, prostate, cancer, stomach, lung, colon (colon, rectum, anal), esophagus, duodenum, head and neck (tongue) Cancer, pharyngeal cancer, laryngeal cancer), brain tumor, schwannoma, non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, bile duct cancer, uterine cancer (uterine body cancer, cervical cancer), ovarian cancer, bladder Cancer, skin cancer, hemangiomas, malignant lymphomas, malignant melanomas, thyroid cancer, bone tumors, hemangiomas, an
  • the compound (I) or a salt thereof or a sulfoxide thereof when used as an agent for preventing or treating cartilage disease, the compound (I) or a salt thereof is mixed with a pharmaceutically acceptable carrier according to a conventional method to obtain a drug having a dosage form suitable as a medicament.
  • Solid preparations such as tablets, capsules, granules, powders, and suppositories; or liquid preparations such as syrups, drops, solutions, suspensions, and injections, orally or parenterally It can be administered. .
  • Pharmaceutically acceptable carriers include various organic or inorganic carrier materials commonly used as drug substances, such as excipients, lubricants, binders, and disintegrants in solid preparations; solvents and dissolution in liquid preparations. It is formulated as an auxiliary, suspending agent, tonicity agent, buffer, soothing agent, stabilizing agent, anticoagulant, and the like. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.
  • Preferred examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light gay anhydride, and the like.
  • Preferred examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Suitable examples of the binder include, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, and hydroxypropylmethyl.
  • cellulose bilipyrrolidone Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylsuniform sodium and the like.
  • Preferred examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • solubilizing agent examples include, for example, polyethylene glycol, propylene glycol, D-mannitol, cyclodextrins, twins, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, and carbonic acid.
  • solubilizing agent include, for example, polyethylene glycol, propylene glycol, D-mannitol, cyclodextrins, twins, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, and carbonic acid.
  • Sodium and sodium citrate examples include, for example, polyethylene glycol, propylene glycol, D-mannitol, cyclodextrins, twins, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, and carbonic acid.
  • Sodium and sodium citrate examples include, for example, polyethylene glycol, propylene glycol, D-mannitol, cyclodext
  • suspending agent examples include surfactants such as, for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; And hydrophilic polymers such as benzyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • tonicity agent include sodium chloride, glycerin, D-manniyl, glucose, sorbyl, and the like.
  • Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate.
  • Preferable examples of the soothing agent include benzyl alcohol and the like.
  • Preferable examples of the stabilizer include polyethylene glycol, polylactic acid and the like.
  • Preferred examples of the coagulant include dextran sulfate, heparin and the like.
  • Preferred examples of preservatives include, for example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.
  • the compound (I) or a salt thereof or a sulfoxide thereof is dissolved in a conventional aqueous diluent and used as a solution.
  • Diluents include glucose aqueous solution, physiological saline, Ringer's solution, and nutritional supplement solution.
  • the prophylactic / therapeutic agent of the present invention can also be produced by dissolving the suspension and shaping it into microcapsules, spheres, rods, needles, pellets, films and the like. Further, the prophylactic / therapeutic agent of the present invention may be formed into a sustained-release preparation containing compound (I) or a salt thereof or a sulfoxide thereof and a biodegradable high molecular compound.
  • the preparation of the sustained-release preparation can be in accordance with the method described in JP-A-9-1265355.
  • the ratio of containing compound (I) or a salt thereof or a sulfoxide thereof is about 0.1 to about 95% by weight, preferably about 1 to about 50% by weight, based on the whole preparation.
  • Compound (I) or a salt thereof or a sulfoxide thereof is preferably used as an oral preparation.
  • Compound (I) or a salt thereof or a sulfoxide thereof can be directly administered to a cartilage disease-affected site when formed into a topical preparation and administered. In this case, injection is preferable.
  • Parenteral preparations for topical administration eg, injection preparations for intramuscular, subcutaneous, organ, joint, etc., solid preparations such as implants, granules, powders, liquid preparations such as suspensions, ointments, etc.
  • topical administration eg, injection preparations for intramuscular, subcutaneous, organ, joint, etc., solid preparations such as implants, granules, powders, liquid preparations such as suspensions, ointments, etc.
  • It can also be administered as
  • compound (I) or a salt thereof or a sulfoxide thereof is dispersed in a dispersant (eg, a surfactant such as Tween 80, HCO-60, carboxymethyl cellulose, sodium alginate, hyaluronic acid).
  • a dispersant eg, a surfactant such as Tween 80, HCO-60, carboxymethyl cellulose, sodium alginate, hyaluronic acid.
  • preservatives eg, methyl paraben, propyl paraben, etc.
  • tonicity agents eg, sodium chloride, mannitol, sorbitol, glucose, etc.
  • buffering agents eg, calcium carbonate, etc.
  • a practical injectable preparation can be obtained by preparing an aqueous suspension together with a pH adjuster (eg, sodium phosphate, potassium phosphate, etc.).
  • vegetable oils such as sesame oil and corn oil, or mixtures of these with phospholipids such as lecithin, or dispersed with medium-chain fatty acid triglycerides (eg, migliol 812) are used as oily suspending agents. Make injections that can be used.
  • a compound e.g., a hyaluronic acid formulation for injection (eg, Kaken Pharmaceutical Co., Ltd .: Aru Note)
  • a dispersion medium It can be prepared by dispersing I) or a salt thereof or a sulfoxide thereof.
  • Hyaluronic acid used in the dispersion medium may be a non-toxic salt thereof, for example, an alkali such as sodium or potassium.
  • Metal salts, salts of alkaline earth metals such as magnesium, calcium and the like can be mentioned, and particularly, sodium salts are preferably used.
  • Hyaluronic acid and non-toxic salts thereof have a molecular weight of about 200,000 to 500,000 (viscosity method), preferably about 500,000 to 300,000, and more preferably about 700,000 to 250,000. Things are used.
  • the final concentration of hyaluronic acid or sodium hyaluronate in this dispersant is preferably less than 1% (W / V) as a viscosity, and is preferable in terms of various operations and ease of administration, and particularly about 0.02 to 1%. It is more preferably less than about 0.1 to 1% (W / V).
  • the dispersion medium may contain a pH adjuster, a local anesthetic, an antibiotic, a solubilizer, an isotonic agent, an anti-adsorption agent, glycosaminodalican, a polysaccharide, etc. by a method known per se. Good.
  • Preferred examples thereof include mannitol, sorbitol, salt, glycine, ammonium acetate, or a water-soluble protein that can be injected into a body fluid without substantially exhibiting pharmacological activity.
  • glycosaminodalican examples include hyaluronic acid, chondroitin, chondroitin sulfate A, chondroitin sulfate C, dermatan sulfate, heparin, heparan sulfate, and keutane sulfate.
  • polysaccharide examples include an acidic polysaccharide such as arginic acid.
  • the above-mentioned water-soluble protein may be any protein which is soluble in water, physiological saline or buffer, and includes, for example, human serum albumin, human serum globulin, collagen, gelatin and the like.
  • the pH adjuster include glycine, ammonium acetate, citrate, hydrochloric acid, sodium hydroxide and the like.
  • the local anesthetic include chlorobutanol and xylocaine hydrochloride.
  • Examples of the antibiotic include gentamicin and the like.
  • the solubilizer include glycerin and polyethylene glycol 400.
  • the tonicity agent include mannitol, sorbitol, sodium chloride and the like.
  • the above-mentioned adsorption inhibitor include polyoxyethylene sorbitol monooleate.
  • the content of the water-soluble protein is preferably 0.05 to 5 Omg, more preferably 0.5 to 2 Omg, per one administration of the preparation. Preferably, it is more preferably 0.75 to 1 O mg.
  • the formulation is Acid or a salt thereof (eg, sodium phosphate, potassium phosphate, etc.).
  • the concentration of sodium phosphate or potassium phosphate in the injection is about 0.1 mM to 50 mM, and about lmM to 10 mM. Is preferred.
  • 'Aseptic preparations include, but are not particularly limited to, a method of sterilizing the entire production process, a method of sterilizing with gamma rays, and a method of adding a preservative.
  • the agent of the present invention Since the agent of the present invention has an excellent cartilage destruction inhibitory activity (cartilage matrix degrading enzyme production inhibitor and proteodalican degradation inhibitor), it can be used for cartilage diseases (eg, osteoarthritis, osteoarthritis of the knee, rheumatoid arthritis). And the destruction of articular cartilage (disease caused by cartilage destruction) and the like in the similar diseases.
  • the agent of the present invention can be used together with other therapeutic agents for joint diseases.
  • Compound (I) or its salt or its sulfoxide is used as a cartilage destruction inhibitor (a cartilage matrix degrading enzyme production inhibitor and a proteodalican degradation inhibitor)
  • Drugs to be combined include anti-inflammatory steroids (eg, prednisolone, hydrocortisone, methylprednisolone, dexamethasone, vesamethasone, etc.), non-steroidal anti-inflammatory analgesics
  • hyaluronic acid preparations eg, sodium hyaluronate, etc.
  • COX-II inhibitors eg, celecoxib, lefecoxib, etc.
  • In-polymer preparations eg, Remicade, Enbrel, Kinneret, etc.
  • the agent of the present invention is used as a safe and highly efficacious preparation suitable for prevention and treatment of cartilage disease, maintenance of cartilage tissue, and the like. For example, it is possible to efficiently exert the inhibitory effect on cartilage destruction locally, and to improve the quality of life of patients who are impaired in daily life due to fatigue due to joint cartilage or pain due to destruction.
  • compound (I) or a salt thereof or a sulfoxide thereof is used as a prophylactic / therapeutic agent for cartilage disease
  • the daily dose depends on the condition and weight of the patient, the method of administration, and the release rate from the preparation.
  • Adult (weight 5 O kg) for administration 1 About 5 to about 2,000 mg, preferably about 30 to about 50 Omg, of the compound (I) or its salt or its sulfoxide per person, is administered in 1 to 3 divided doses.
  • the dose may be determined according to the type and content of compound (I) or a salt thereof or a sulfoxide thereof, the dosage form, the duration of drug release, the animal to be administered (eg, Humans, rats, mice, cats, dogs, puppies, cattle, pigs, and other mammals) vary depending on the purpose of administration, but when applied by parenteral administration, for example, from about 0.1 to about 10 Omg of compound (I) or a salt thereof or a sulfoxide thereof may be released from the administration preparation.
  • the animal to be administered eg, Humans, rats, mice, cats, dogs, puppies, cattle, pigs, and other mammals
  • parenteral administration for example, from about 0.1 to about 10 Omg of compound (I) or a salt thereof or a sulfoxide thereof may be released from the administration preparation.
  • the pharmaceutical composition of the present invention has low toxicity and can be used safely.
  • the compound when the compound was orally administered to rats at a dose of 30 OmgZkg / day, no abnormal findings were observed.
  • the following example compounds are excellent in absorbability when administered orally, and can be advantageously used for oral preparations.
  • the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
  • the percentage (%) in the solution is expressed by weight Z volume percent unless otherwise specified.
  • the mixing ratio of the solvent is indicated by the volume ratio unless otherwise specified.
  • the 1H and 13 C nuclear magnetic resonance (NMR) spectra were obtained using DPX-300 or AC-300 spectra using tetramethylsilane as an internal standard (Bulliki, Germany), The values were measured with a Gemini 200 or Mercury 300 spectrum meter (Varian, USA) and ⁇ 6 values are shown in ppm.
  • s is singlet
  • d is doublet
  • t is triplet
  • Q is quartet
  • sept represents a sevenfold line
  • m represents a multiple line
  • b or br represents a wide line, respectively.
  • dd is a double double line
  • ddd is a double double double line
  • dt is a double triple line
  • dq is a double quadruple line
  • brd ⁇ ⁇ wide double line, and so on They may be displayed in combination. Coupling constants are shown in Hz.
  • ADDP (1, 1,-(azodicarbonyl) dipiperidine) 1, ⁇ -(azodicarponyl) dipiperidine
  • DIAD diisopropyl azodicarboxylate
  • DMAP 4_N, N-dimethhy1 am i nopyr idine
  • ADAN (31.9 g, 0.233 mol, manufactured by Junsei Chemical Co., Ltd.) is dissolved in getyl ether (300 ml, hereinafter abbreviated as ether), and stirred at room temperature while stirring with P-toluenesulfonyl isocyanate (36.0 ml). , Purity 98%, manufactured by Tokyo Chemical Industry Co., Ltd.), and the mixture was stirred at room temperature for 14 hours. The resulting precipitate was collected by filtration, washed with diethyl ether, and dried to give a pale yellow powder of the title compound (74.3 g, 0.222 mol).
  • Benzyl isocyanate (20 g) was added to a dichloromethane (400 ml) solution of ADAN (19.4 g), and aluminum chloride (18.9 g) was added in three portions. After stirring at the same temperature for 1 hour, water (150 ml) was added, and the organic solvent was distilled off. To the remaining aqueous layer were added ethyl acetate (150 ml), water (150 ml) and 0.5 M citrate (150 ml), and the mixture was stirred for 5 minutes. After the organic 'solvent was distilled off, the precipitate was collected by filtration, washed with water, and dried to obtain 58.6 g of a colorless powder.
  • the obtained compound was dissolved in acetone (400 ml), carbonated lime (39.2 g) was added, and the mixture was heated under reflux for 50 minutes. After cooling to room temperature, water (400 ml) was added, and the mixture was adjusted to pH 3 with about 500 ml of IN hydrochloric acid. The precipitate was collected by filtration, washed with water (100 ml), and dried to give the title compound (31.2 g, 77%).
  • R 10 is —ZR 15 (compound in which ⁇ is S ⁇ 2 and R 15 is 4_phenoxyphenyl group)
  • R 10 is -ZR 15 (Z is S ⁇ 2 , R 15 is a 4-chlorophenyl group))
  • Ethanol (310 ml) was added to the compound synthesized in Reference Example 1-1 (30.8 g, 92.2 mmol) and potassium carbonate (29.3 g, 0.212 mol), and the mixture was stirred at room temperature while stirring with ethyl 3_mercaptopropionate (24.2 g). ml, 0.180 mol) was added dropwise over about 6 hours, and the reaction mixture was stirred at room temperature for 12 hours. 1N Hydrochloric acid (240 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes.
  • R 10 is —ZR 15 (Z is S ⁇ 2 , R 15 is a p-bromophenyl group),
  • N, N-dimethylaminopyridine (0.21 g, 1.72 mmol) was added 16 hours after the start of the reaction, and p-bromobenzenesulfonyl chloride (0.89 g, 3.43 mmol) was added 18 hours later.
  • concentration of the reaction solution the residue was diluted with ethyl acetate (500 ml), washed with 0.3 N hydrochloric acid, 0.1 N hydrochloric acid, water, and saturated saline, and then dried over sodium sulfate.
  • Ethanol (27 ml) was added to the compound synthesized in Reference Example 2-4 (1.35 g, 2.45 bandol) and carbonic acid rim (407 mg, 2.95 bandol), and the mixture was stirred at 80 ° C for 2 hours. After concentration of the reaction solution, the residue was diluted with ethyl acetate-THF (1: 1, 60 ml) and washed with 0.1N hydrochloric acid (60 ml). The aqueous layer was extracted with ethyl acetate (30 ml), combined with the organic layer, washed with brine, and dried over sodium sulfate.
  • IR Infrared absorption spectrum (IR) (in KBr): 3069, 3027, 2965, 2936, 2911, 1481 cm- 1 .
  • Methanesulfonyl chloride (0.652 ml, 8.42 mmol) was added to a solution of 4,4,5,5,5-pentafluoroethanol (1.00 g, 5.61 ol) in tetrahydrofuran (20.0 ml). And triethylamine (1.57 ml, 11.2 mmol) were sequentially added under ice-cooling. After stirring the reaction mixture at room temperature for 3 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was water washed to give after drying (MgSO 4), solvent was evaporated under reduced pressure to give the title compound (1.42 g, 993 ⁇ 4) as an oil-like product.
  • Methanesulfonyl chloride (1.95 ml, 25. 2) was added to a solution of 5,5,6,6,6-pentafluorohexanol (3.23 g, 16.8 t) obtained in Reference Example 8 in tetrahydrofuran (60.0 ml). mmol) and triethylamine (4.69 ml, 33.6 maraudal 01) were sequentially added under ice cooling. After stirring the reaction mixture at room temperature for 2 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO 4), solvent was evaporated under reduced pressure to give the title compound (4.13 g, 913 ⁇ 4) as an oil.
  • R 2 Gabe Njiru group in formula (XVI II), the synthesis of Z is S0 2, R 15 is p- Toruiru group, and R is an Echiru group
  • ADAN (10.8 g, 79.1 mmol) was dissolved in dichloromethane (220 ml), and isocyanate was dissolved.
  • Ethyl acetate (10.0 g, 75.1 dust ol) was added, and the mixture was cooled to, and aluminum chloride (2 g, 75.1 ol) was added in several portions.
  • the precipitate was filtered, washed with ether, ice-cold water, and water, and dried to obtain a pale yellow powder (14.2 g, 46.6 mmol).
  • Acetonitrile 60 ml was added to the compound synthesized in Reference Example 13-2 (3.05 g, 10.3 mmol) and carbonated carbonate (4.29 g, 31.0 ol) and suspended, and methyl 3-mercaptopropionate (2.34 ml) was added. , 20.7 mmol was added dropwise, and the mixture was stirred at room temperature for 2 hours, and further stirred at 8 for 40 minutes. After concentrating the reaction solution, 1N hydrochloric acid (31 ml), water (80 ml) and ethyl acetate (100 ml) were added and mixed, and the organic layer was extracted with a 2% aqueous sodium hydrogen carbonate solution.
  • the aqueous layers were combined, adjusted to pH 3, and extracted with ethyl acetate.
  • the organic layer was washed with a 7% saline solution and a saturated saline solution, and then dried with sodium sulfate.
  • the solvent was distilled off under reduced pressure, methanol was added to the residue, and the resulting precipitate was collected by filtration, washed with methanol, and dried to give the title compound as an orange oil (3.20 g, 8.50 benzyl) .
  • IR (KBr) V 3368, 3200, 3071, 2953, 2924, 2907, 2868, 1765, 1730, 1634, 1574, 1499 CDT 1 .
  • IR (Br) V 3300-2800, 2961, 1703, 1671, 1570, 1507 cm “ 1 .
  • N-Boc-6-amino-1-hexyl mesylate (purity 80.4, 6.39 g, 40.5 thigh 01) was obtained from 6-amino-1-hexanol (5.0 g, 40.5 thigh ol). A colored oil was obtained.
  • Deoxo-Fluor TM (5.06 g, 22.9 mmol) was added dropwise over 30 minutes to a solution of 4-oxocyclohexanecarbethylate (2.29 g, 13.4 mmol) in dichloromethane (20 ml) with stirring with stirring for 30 minutes. After warming, the reaction was stirred at room temperature for 6 hours. The reaction solution was poured into ice (50 g), and extracted with ethyl acetate (100 ml) and getyl ether (30 ml).
  • Lithium aluminum hydride (purity 80%, 0.402) was added to a solution of ethyl cis-4- (2-tetrahydroviranyl) oxycyclohexanecarboxylate (4.14 g, 15.4 benzyl) in THF (80 ml) while stirring at 0 ° C. g, 8.47 mmol) was added in several portions, and the mixture was stirred for 2.5 hours with TC.
  • the extract was purified by extraction with ethyl acetate, and cis-4- (2-tetrahydropyranyl) oxycyclohexanemethanol (purity 90%) was added. , 3.67 g, 15.4 mmol, quant.).
  • Cis-4- (2-tetrahydropyranyl) oxycyclohexanemethanol (purity 90%, 3.67 g, 15.4 mmol) and triethylamine (2.56 ml, 18.5 mmol) in THF (70 ml) were stirred at 0 with methane.
  • a solution of sulfonyl chloride (1.87 g, 16.2 ml) in THF (5 ml) was added dropwise over 20 minutes, and the reaction solution was stirred at 0 ° C for 2.5 hours.
  • the crude material (5.27 g) obtained by extraction with ethyl acetate was purified by silica gel (50 g) chromatography (elution solvent, ethyl acetate-hexane, 2: 8-3: 7), and cis-4- A pale yellow oil of (2-tetrahydrobilanyl) oxycyclohexylmethyl mesylate (3.76 g, 12.9 ol, 83.5%) was obtained.
  • the reaction solution was poured into ice-water (about 80 g) in which sodium carbonate (1.51 g, 18.1 mol) was dissolved, and extracted with ethyl acetate-hexane (1: 1, 60 nil) and ethyl acetate (50 ml).
  • the organic layer was washed with saturated sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated to give a yellow oil.
  • This was subjected to chromatography on silica gel (20 g) (ethyl acetate-hexane, 1: 9-4: 6), and the ethyl acetate-hexane (2: 8-3: 7) fraction was concentrated to dryness. Later, it was diluted with Jetil ether.
  • Lithium aluminum hydride (purity 80, 2.41 g, 50.9 t) was added to a solution of 3,3-dimethyldaltaric anhydride (purity 953 ⁇ 4, 6.92 g, 46.2 t) in THF (140 ffll) while stirring at 0 ° C. ) was added in several portions, and the mixture was stirred (TC for 2 hours, room temperature for 13 hours, and heated to reflux for 4.5 hours. Ethyl acetate (20 ml) was added to the reaction solution, and the mixture was stirred.
  • the reaction solution was neutralized by adding sodium hydrogen carbonate, and purified by extraction with ethyl acetate to obtain a colorless oil of adamantan-1-methyl acetate (10.8 g, quant.).
  • Triethylamine (3.07 ml, 22.2 mmol) was added to a solution of adamantane-1-ethanol (3.33 g, 18.5 mmol) and methanesulfonyl chloride (2.24 g, 19.4 mmol) in THF (70 ml) for 20 minutes while stirring at 0. And dropped.
  • the reaction solution was stirred at 0 ° C for 2 hours.
  • the reaction solution was purified by extraction with ethyl ethyl diisopropyl acetate (1: 1) to give adamantan-toethyl methanesulfonate (5.30 g, 18.5 mmol, quant.) As a pale yellow oil.
  • reaction solution was purified by extraction with ethyl acetate-hexane (1: 1), and adamantan methanesulfonate 1- Methyl (purity 903 ⁇ 4, 4.27 g, 15.8 mmol, quant.) was obtained as a pale yellow oil.
  • a suspension of adamantane trimethyl methanesulfonate (purity 90%, 4.27 g, 15.8 mmol) and sodium iodide (7.10 g, 47.4 mmol) in 2-butanone (85 ml) was heated under reflux for 3.5 days.
  • the reaction mixture was extracted with ethyl acetate-hexane (2: 3), purified by silica gel (40 g) chromatography (hexane), and purified with 1-odomethyladamantane (2.20 g, 7.96 bandol, 50.4%) as a white solid.
  • the crude substance obtained by ethyl acetate extraction was purified by silica gel (20 g) chromatography (ethyl acetate-hexane, 2: 8-3: 7), and (2S, 4R) -N-Boc-4- (2 A colorless oil of -tetrahydrobilanyloxy) pyrrolidine-2-methyl mesylate (1.35 g, 3.55 mmol, 96.9%) was obtained.
  • trans-2-hydroxymethylcyclohexane-1-methyltosylate (2.21 g, 7.41 mmol) and acetic anhydride (6 ml) in pyridine (12 ml) was stirred at room temperature for 11 hours.
  • the reaction solution was concentrated to dryness to give trans-2-acetoxymethylcyclohexane-methyltosylate (2.54 g, 7.4 mmol, quant.) As a colorless oil.
  • trans-2-Acetoxymethylcyclohexane-1-methyltosylate (2.54 g, 7.4 t ol) and sodium iodide (3.33 g, 22.2 t ol) suspended in 2-butane nonone (55 ml)
  • the liquid was heated at reflux for 2.5 hours.
  • the reaction mixture was extracted with ethyl acetate-hexane (1: 4), concentrated to dryness, and trans-2-iodomethylcyclohexane-1-methyl acetate (1.98 g, 6.68 mmol, 90.1) was obtained as a colorless oil. Obtained as a product.
  • Lithium aluminum hydride (purity 803 ⁇ 4, 2.12 g) was added to a solution of dimethyl cis-cyclohexane-1,4-dicarbonate (8.19 g, 37.2 mmol) obtained above in THF (160 ml) while stirring at 0 ° C. , 44.7 mmol) was added in several portions, and the mixture was stirred at 0 ° C for 80 minutes. Extract with ethyl acetate-THF (4: 1), dry and concentrate to dryness to obtain cis-cyclohexane-1,4-dimethanol (purity 87%, 6.18 g, quant., 8% trans-isomer A colorless oil was obtained.
  • Triethylamine (27.2) was added to a solution of 3_methyl-1,3_butanediol (20.66 g, purity 90%, 0.179 mol) and methanesulfonyl chloride (14.7 ml, 0.187 mol) in THF (300 ml) with stirring at 0 ° C. ml, 0.196 mol) was added dropwise over 80 minutes, and the reaction solution was stirred at 0 ° C for 1.5 hours.
  • the reaction mixture was extracted with getyl ether-hexane (1: 1), washed with water, dried and concentrated to dryness to give 3-methyl-3-hydroxybutyl mesylate (purity 80.5%, 39.3 g, 0.174 mol). Obtained as a yellow oil.
  • Methanesulfonyl chloride (2.09 ml, 27.1) was added to a solution of 6,6,7,7,7-pentafluorofuranol (3.72 g, 18.0 mmol) obtained in Reference Example 51 in tetrahydrofuran (80.0 ml). mmol) and triethylamine (5.03 ml, 36.1 bandol) were sequentially added under ice-cooling. After stirring the reaction mixture at room temperature for 3.5 hours, 1 hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried '(MgSO 4), solvent was evaporated under reduced pressure to give the title compound (3.80 g, 74%) as an oil.

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Abstract

L'invention concerne des composés représentés par la formule générale (I) et présentant une excellente activité d'inhibition contre la dégradation de la matrice du cartilage; ou leurs sels ou sulfoxydes, formule dans laquelle R1 représente -(S)¿n?-R?2(où R2¿ représente hydrocarbyle facultativement substitué ou analogue; et n représente un nombre entier de 0 à 2) ou analogue; R5 représente hydrogène, hydrocarbyle facultativement substitué ou analogue; le symbole (II) est un groupe représenté par la formule générale (III) ou analogue; et le symbole (IV) est un groupe représenté par la formule générale (V) ou analogue [où R6 représente hydrogène, hydrocarbyle facultativement substitué, ou analogue; R10 représente -ZR15 (où Z représente -SO¿2?- ou analogue; et R?15¿ représente hydrocarbyle facultativement substitué ou analogue) ou analogue; et R11 représente hydrogène ou analogue].
PCT/JP2002/004640 2001-05-15 2002-05-14 Derives d'imidazolidine fusionnes, leur procede de preparation et d'utilisation Ceased WO2002092606A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004069999A3 (fr) * 2003-02-04 2004-10-07 Takeda Chemical Industries Ltd Procede de criblage
WO2009084653A1 (fr) 2007-12-28 2009-07-09 Takeda Pharmaceutical Company Limited Procédé pour le criblage d'un agent protégeant les cellules
US7964615B2 (en) 2005-05-20 2011-06-21 Almirall, S.A. Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the β2 adrenergic receptor
US8178679B2 (en) 2007-11-28 2012-05-15 Almirall, S.A. Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the β2 adrenergic receptors
US8524908B2 (en) 2009-03-12 2013-09-03 Almirall, S.A. Process for manufacturing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one
US9067922B2 (en) 2013-04-19 2015-06-30 Pfizer Limited Chemical compounds
US9108918B2 (en) 2011-10-07 2015-08-18 Almirall, S.A. Process for preparing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one via a novel intermediate
US9346759B2 (en) 2012-03-20 2016-05-24 Almirall, S.A. Polymorphic crystal forms of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one, heminapadisytlate as agonist of the β2 adrenergic receptor
WO2018208557A1 (fr) 2017-05-10 2018-11-15 Arixa Pharmaceuticals, Inc. Dérivés de 3-(((((2s,5r)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1 ]octan-6-yl)oxy)sulfonyl)oxy)-2,2-diméthylprop noate et composés apparentés utilisés en tant que promédicaments administrés par voie orale d'inhibiteurs de bêta-lactamase pour le traitement d'infections bactériennes
WO2019070595A1 (fr) 2017-10-02 2019-04-11 Arixa Pharmaceuticals, Inc. Dérivés d'aztréonam et utilisations associées
CN110156620A (zh) * 2019-07-02 2019-08-23 中节能万润股份有限公司 一种氨甲环酸的制备方法
WO2020072442A1 (fr) 2018-10-01 2020-04-09 Arixa Pharmaceuticals, Inc. Dérivés de relebactam et utilisations associées

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WO1993025555A1 (fr) * 1992-06-12 1993-12-23 Farmitalia Carlo Erba S.R.L. Derives d'imidazo(5,1-c)(1,4)benzoxazine-1-one utilises comme antagonistes de 5ht3
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WO1998039313A1 (fr) * 1998-03-04 1998-09-11 Monsanto Company Composes d'acide hydroxamique sulfonamide thioaryle
US6066658A (en) * 1996-09-06 2000-05-23 Takeda Chemical Industries, Ltd. Condensed 4,5,6,7-tetrahydrobenzo[C]thiophenes as enhancer for cell differentiation induction factor action
WO2001030781A2 (fr) * 1999-10-20 2001-05-03 Tanabe Seiyaku Co., Ltd. Inhibiteurs d'adhesion cellulaire induite par alphalbeta¿2?

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US4179276A (en) * 1977-02-01 1979-12-18 E. I. Du Pont De Nemours And Company Novel imidazothiazine-1,3 (2H)-diones
WO1993025555A1 (fr) * 1992-06-12 1993-12-23 Farmitalia Carlo Erba S.R.L. Derives d'imidazo(5,1-c)(1,4)benzoxazine-1-one utilises comme antagonistes de 5ht3
WO1995032208A1 (fr) * 1994-05-25 1995-11-30 Pharmacia S.P.A. DERIVES IMIDAZOLYLALKYLES D'IMIDAZOL(5,1-c)(1,4)BENZOXAZIN-1-ONE ET LEUR UTILISATION COMME AGENTS THERAPEUTIQUES
AU3106997A (en) * 1996-06-14 1998-01-07 Kaken Pharmaceutical Co., Ltd. Bicyclic hydantoin derivatives, intermediates for the preparation thereof, process for the preparation of them, and herbicides containing the same as active ingredient
US6066658A (en) * 1996-09-06 2000-05-23 Takeda Chemical Industries, Ltd. Condensed 4,5,6,7-tetrahydrobenzo[C]thiophenes as enhancer for cell differentiation induction factor action
WO1998039313A1 (fr) * 1998-03-04 1998-09-11 Monsanto Company Composes d'acide hydroxamique sulfonamide thioaryle
WO2001030781A2 (fr) * 1999-10-20 2001-05-03 Tanabe Seiyaku Co., Ltd. Inhibiteurs d'adhesion cellulaire induite par alphalbeta¿2?

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004069999A3 (fr) * 2003-02-04 2004-10-07 Takeda Chemical Industries Ltd Procede de criblage
US7964615B2 (en) 2005-05-20 2011-06-21 Almirall, S.A. Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the β2 adrenergic receptor
US8242177B2 (en) 2005-05-20 2012-08-14 Almirall, S.A. Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the β2 adrenergic receptor
US8178679B2 (en) 2007-11-28 2012-05-15 Almirall, S.A. Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the β2 adrenergic receptors
WO2009084653A1 (fr) 2007-12-28 2009-07-09 Takeda Pharmaceutical Company Limited Procédé pour le criblage d'un agent protégeant les cellules
US8450070B2 (en) 2007-12-28 2013-05-28 Takeda Pharmaceutical Company Limited Method for screening of cell-protecting agent
US8524908B2 (en) 2009-03-12 2013-09-03 Almirall, S.A. Process for manufacturing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one
US9108918B2 (en) 2011-10-07 2015-08-18 Almirall, S.A. Process for preparing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one via a novel intermediate
US9346759B2 (en) 2012-03-20 2016-05-24 Almirall, S.A. Polymorphic crystal forms of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one, heminapadisytlate as agonist of the β2 adrenergic receptor
US9067922B2 (en) 2013-04-19 2015-06-30 Pfizer Limited Chemical compounds
WO2018208557A1 (fr) 2017-05-10 2018-11-15 Arixa Pharmaceuticals, Inc. Dérivés de 3-(((((2s,5r)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1 ]octan-6-yl)oxy)sulfonyl)oxy)-2,2-diméthylprop noate et composés apparentés utilisés en tant que promédicaments administrés par voie orale d'inhibiteurs de bêta-lactamase pour le traitement d'infections bactériennes
WO2019070595A1 (fr) 2017-10-02 2019-04-11 Arixa Pharmaceuticals, Inc. Dérivés d'aztréonam et utilisations associées
WO2020072442A1 (fr) 2018-10-01 2020-04-09 Arixa Pharmaceuticals, Inc. Dérivés de relebactam et utilisations associées
CN110156620A (zh) * 2019-07-02 2019-08-23 中节能万润股份有限公司 一种氨甲环酸的制备方法
CN110156620B (zh) * 2019-07-02 2022-04-15 中节能万润股份有限公司 一种氨甲环酸的制备方法

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