Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • 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
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• the present invention relates to a novel prodrug and a production method thereof.
• any pharmaceutical agent is required to show stable and good absorbability.
• a prodrug is defined to be a compound pharmacologically inactive but converted to a pharmaceutical compound that exhibits a pharmacological activity by the action of enzyme and the like in the living body or during the absorption process in the living body.
• prodrug For forming a prodrug, esterification of a carboxyl group, acylation, carbonic acid esterification or carbamoylation of a hydroxyl group, and the like of a pharmaceutical compound have been widely used.
• pharmaceutical compounds to be formed into prodrugs do not necessarily have a functional group such as a carboxyl group, a hydroxyl group and the like.
• a nitrogen-containing heterocycle has been often recognized as a partial structure of a compound having a pharmacological action, and moreover, a nitrogen-containing heterocycle sometimes forms a structure of a fused ring.
• a nitrogen-containing heterocycle sometimes forms a structure of a fused ring.
• many useful therapeutic drugs having a nitrogen-containing heterocycle as a partial structure are known, a pharmacological importance of this partial structure can be appreciated.
• many of the compounds having a nitrogen-containing heterocycle show poor absorbability because of poor solubility and the like. Consequently, many such compounds could not be put to practice because of absorbability, even if usefulness as pharmaceutical compounds can be expected from their pharmacological actions.
• prodrugs include many problematic prodrugs for general application as prodrugs of a wide range of pharmaceutical compounds, because they are associated with problems in terms of safety such as generation of formaldehyde, acetaldehyde and the like during the reproductive process of the original pharmaceutical compound (i.e., parent compound) in the living body, insufficient absorbability, incomplete reproduction of parent pharmaceutical compound and the like.
• the technique for forming a prodrug based on the modification of a nitrogen-containing heterocycle at the present stage is not entirely sufficient.
• a compound having a useful pharmacological action which could not be put to practical use due to low absorbability and the like, may be developed as a pharmaceutical product.
• the present invention has been made in such situation, and provides development of a novel prodrug and a means therefor.
• the present inventors have conducted intensive studies in an attempt to develop a prodrug based on the modification of a nitrogen-containing heterocycle and to find a means therefor, and as a result, found usefulness of not only a pharmaceutical compound useful as a prophylactic or therapeutic drug, which has a nitrogen-containing heterocycle as a partial structure (hereinafter sometimes to be simply referred to as a therapeutic drug), but also a compound represented by the following formula (I) as a prodrug of a therapeutic drug having other eliminatable proton as a partial structure thereof, which resulted in the completion of the present invention.
• the present invention provides the following.
• X 1 and X 2 represent an oxygen atom and a sulfur atom, respectively. Both X 1 and X 2 preferably represent an oxygen atom.
• W represents a “chain divalent hydrocarbon group optionally having substituent(s)”, or the formula: —W 1 -Z-W 2 — wherein W 1 and W 2 are each a “chain divalent hydrocarbon group” or a bond, and Z is a divalent group such as a “divalent hydrocarbon ring group optionally having substituent(s)”, a “divalent heterocyclic group optionally having substituent(s)”, an oxygen atom, SO n wherein n is 0, 1 or 2 or >N-E wherein E is a hydrogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), a lower alkanoyl group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a thiocarbamoyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a sulfamo
• W′ is a “chain divalent hydrocarbon group optionally having substituent(s)”, or divalent group represented by the formula: —W 1 ′-Z′-W 2 ′— wherein W 1 ′ and W 2 ′ are each a “chain divalent hydrocarbon group” or a bond, and Z′ is a “divalent hydrocarbon ring group optionally having substituent(s)” or a “divalent heterocyclic group optionally having substituent(s)”.
• W′ is preferably a “chain divalent hydrocarbon group optionally having substituent(s)”.
• chain divalent hydrocarbon group of the “chain divalent hydrocarbon group optionally having substituent(s)” represented by W, W′ and “chain divalent hydrocarbon group” represented by W 1 , W 1 ′, W 2 and W 2 ′
• a C 1-6 alkylene group e.g., methylene, ethylene, trimethylene etc.
• a C 2-6 alkenylene group e.g., ethenylene etc.
• a C 2-6 alkynylene group e.g., ethynylene etc.
• the chain divalent hydrocarbon group for W and W′ may have 1 to 6 substituents similar to those for the “benzene ring optionally having substituent(s)” represented by ring B to be mentioned below at substitutable positions thereof.
• the “chain divalent hydrocarbon group” of the “chain divalent hydrocarbon group optionally having substituent(s)” represented by W and W′ and “chain divalent hydrocarbon group” represented by W 1 , W 1 ′, W 2 and W 2 ′ a methylene group and an ethylene group are preferable.
• W and W′ an ethylene group is particularly preferable.
• Z is an oxygen atom, SO n or >N-E (n and E are as defined above)
• the “chain divalent hydrocarbon group” represented by W 1 is preferably a hydrocarbon group having 2 or more carbon atoms.
• hydrocarbon ring of the “divalent hydrocarbon ring group optionally having substituent(s)” represented by Z and Z′
• an alicyclic hydrocarbon ring, an aromatic hydrocarbon ring and the like can be mentioned, with reference given to one having 3 to 16 carbon atoms, which may have 1 to 4 substituents similar to those for the “benzene ring optionally having substituent(s)” represented by ring B at substitutable positions thereof.
• substituent(s) represented by ring B at substitutable positions thereof.
• hydrocarbon ring for example, cycloalkane, cycloalkene, arene and the like are used.
• a cycloalkane in the “divalent hydrocarbon ring group optionally having substituent(s)” represented by Z and Z′ for example, a lower cycloalkane and the like are preferable, and, for example, C 3-10 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, bicyclo[2.2.1]heptane, adamantane etc., and the like are generally used.
• a cycloalkene in the “divalent hydrocarbon ring group optionally having substituent(s)” represented by Z and Z′ for example, a lower cycloalkene is preferable, and, for example, C 4-9 cycloalkene such as cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene etc., and the like are generally used.
• a C 6-14 arene such as benzene, naphthalene, phenanthrene etc., and the like are preferable, and, for example, phenylene and the like are generally used.
• a heterocycle in the “divalent heterocyclic group optionally having substituent(s)” represented by Z and Z′ a 5- to 12-membered “aromatic heterocycle” or “saturated or unsaturated non-aromatic heterocycle” containing, as ring-constituting atom (ring atom), 1 to 3 (preferably 1 or 2) kinds of at least 1 (preferably 1 to 4, more preferably 1 or 2) hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom etc., and the like can be mentioned, which may have 1 to 4 substituents similar to those for the “benzene ring optionally having substituent(s)” represented by ring B to be mentioned below at substitutable positions thereof.
• an aromatic heterocycle in the “divalent heterocyclic group optionally having substituent(s)” represented by Z and Z′ an aromatic monocyclic heterocycle, a fused aromatic heterocycle and the like can be mentioned.
• aromatic monocyclic heterocycle for example, a 5- or 6-membered aromatic monocyclic heterocycle such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine etc., and the like can be mentioned.
• fused aromatic heterocycle for example, a 8- to 12-membered fused aromatic heterocycle such as benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, benzothiazole, 1,2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pteridine, carbazole, carboline, acridine, phenoxazine, phenothiazine, phenazine, phenoxathiin, thianthrene, phenanthridine, phenanthroline, indolizine, pyrrolo[1,2-b]pyridazine,
• a saturated or unsaturated non-aromatic heterocycle in the “divalent heterocyclic group optionally having substituent(s)” represented by Z and Z′ for example, a 3- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocycle (aliphatic heterocycle) such as oxirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, piperazine, azepane, oxepane, thiene, oxazepane, thiazepane, azocane, oxocane, thiocane, oxazocane, thiazocane etc., and the like can be mentioned.
• oxirane
• These may be oxo-substituted and may be, for example, 2-oxoazetidine, 2-oxopyrrolidine, 2-oxopiperidine, 2-oxoazepane, 2-oxoazocane, 2-oxotetrahydrofuran, 2-oxotetrahydropyran, 2-oxotetrahydrothiophene, 2-oxothiane, 2-oxopiperazine, 2-oxooxepane, 2-oxooxazepane, 2-oxothiepane, 2-oxothiazepane, 2-oxooxocane, 2-oxothiocane, 2-oxooxazocane, 2-oxothiazocane and the like.
• the two bonds from the “hydrocarbon ring group” of the “divalent hydrocarbon ring group optionally having substituent(s)” or the “heterocyclic group” of the “divalent heterocyclic group optionally having substituent(s)” represented by Z and Z′ may be present at any bondable position.
• hydrocarbon group optionally having substituent(s) and “heterocyclic group optionally having substituent(s)” represented by E is as defined in the following.
• lower alkanoyl group represented by E, for example, formyl, a C 1-6 alkyl-carbonyl group such as acetyl, propionyl, butyryl, isobutyryl etc., and the like can be used.
• lower alkoxycarbonyl group represented by E, for example, a C 1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc., and the like are used.
• aralkyloxycarbonyl represented by E, for example, a C 7-11 aralkyloxy-carbonyl group such as benzyloxycarbonyl etc., and the like are used.
• lower alkylsulfinyl group represented by E, for example, a C 1-6 alkylsulfinyl group such as methylsulfinyl, ethylsulfinyl etc., and the like are used.
• lower alkylsulfonyl group represented by E, for example, a C 1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl etc., and the like are used.
• the “mono-lower alkylsulfamoyl group” represented by E for example, a mono-C 1-6 alkylsulfamoyl group such as methylsulfamoyl, ethylsulfamoyl etc., and the like are used.
• arylsulfamoyl group represented by E, for example, a C 6-10 arylsulfamoyl group such as phenylsulfamoyl, naphthylsulfamoyl etc., and the like are used.
• arylsulfinyl group represented by E, for example, a C 6-10 arylsulfinyl group such as phenylsulfinyl, naphthylsulfinyl etc., and the like are used.
• arylsulfonyl group represented by E, for example, a C 6-10 arylsulfonyl group such as phenylsulfonyl, naphthylsulfonyl etc., and the like are used.
• arylcarbonyl group represented by E, for example, C 6-10 aryl-carbonyl group such as benzoyl, naphthoyl etc., and the like are used.
• the “carbamoyl group optionally having substituent(s)” represented by E is, for example, a group of the formula —CONR 2 R 3 wherein R 2 and R 3 are each a hydrogen atom, a hydrocarbon group optionally having substituent(s) or a heterocyclic group optionally having substituent(s), and in the formula —CONR 2 R 3 , R 2 and R 3 may form a ring together with the adjacent nitrogen atom, and the like.
• R is a hydrogen atom, a “hydrocarbon group optionally having substituent(s)” or a “heterocyclic group optionally having substituent(s)”, R′ is “a hydrocarbon group optionally having substituent(s)” or a “heterocyclic group optionally having substituent(s)”.
• R can be bonded to W and R′ can be bonded to W′.
• a C 1-6 hydrocarbon group optionally having substituent(s) is preferable and a lower (C 1-6 ) alkyl group is particularly preferable.
• the “hydrocarbon group optionally having substituent(s)” and “heterocyclic group optionally having substituent(s)” represented by R and R′ are as defined in the following. A detailed explanation of the case where R is bonded to W and where R′ is bonded to W′ is given in the following.
• D 1 and D 2 are each a bond, an oxygen atom, a sulfur atom or >NR 1 , and in the formula, R 1 is a hydrogen atom or a hydrocarbon group optionally having substituent(s).
• R 1 is a hydrogen atom or a hydrocarbon group optionally having substituent(s).
• the present invention excludes a case where D 1 and D 2 are both respectively a bond.
• each of D 1 and D 2 is preferably a bond or an oxygen atom, and particularly preferably, D 1 is an oxygen atom and D 2 is an oxygen atom or a bond.
• the “hydrocarbon group optionally having substituent(s)” represented by R 1 is as defined in the following.
• D 1 ′ is an oxygen atom or a sulfur atom and D 2 ′ is an oxygen atom, or D 1 ′ is a sulfur atom and D 2 ′ is a bond.
• Y is a “hydrocarbon group optionally having substituent(s)” or a “heterocyclic group optionally having substituent(s)”.
• a C 1-6 hydrocarbon group optionally having substituent(s) or a saturated heterocyclic group optionally having substituent(s), which contains, as ring-constituting atom, 1 to 4 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom is referable.
• a C 1-6 hydrocarbon group optionally having substituent(s) or a saturated oxygen-containing heterocyclic group optionally having substituent(s), which further contains, as ring-constituting atom, 1 to 3 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom is preferable.
• the “hydrocarbon group optionally having substituent(s)” and “heterocyclic group optionally having substituent(s)” represented by Y are as defined in the following.
• hydrocarbon group of the “hydrocarbon group optionally having substituent(s)” represented by the above-mentioned E, R, R′, R 1 and Y
• a saturated or unsaturated aliphatic hydrocarbon group for example, a saturated or unsaturated alicyclic hydrocarbon group, a saturated or unsaturated alicyclic-aliphatic hydrocarbon group, an aromatic hydrocarbon group, an aromatic-saturated or unsaturated alicyclic hydrocarbon group and the like can be mentioned, with preference given to those having 1 to 16, more preferably 1 to 6, carbon atoms.
• alkyl group alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, cycloalkylalkyl group, cycloalkenylalkyl group, aryl group and arylalkyl group and the like.
• the “alkyl group” is preferably a lower alkyl group (C 1-6 alkyl group) and the like, and, for example, a C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethylpropyl, hexyl etc., and the like are generally used.
• a lower alkyl group (C 1-6 alkyl group) is preferable, particularly a methyl group is preferable.
• alkenyl group is preferably a lower alkenyl group and the like, and, for example, a C 2-7 alkenyl group such as vinyl, 1-propenyl, allyl, isopropenyl, butenyl, isobutenyl, 2,2-dimethyl-pent-4-enyl etc., and the like are generally used.
• alkynyl group is preferably a lower alkynyl group and the like, and, for example, a C 2-6 alkynyl group such as ethynyl, propargyl, 1-propynyl etc., and the like are generally used.
• the “cycloalkyl group” is preferably a lower cycloalkyl group and the like, and, for example, a C 3-10 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptanyl and adamantyl etc., and the like are generally used.
• the “cycloalkenyl group” is preferably a lower cycloalkenyl group, and, for example, a C 3-10 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-5-en-2-yl etc., and the like are generally used.
• the “cycloalkylalkyl group” is preferably a lower cycloalkylalkyl group, and, for example, a C 4-9 cycloalkylalkyl group such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and cyclohexylethyl etc., and the like are generally used.
• the “cycloalkenylalkyl group” is preferably a lower cycloalkenylalkyl group, and, for example, C 4-9 cycloalkenylalkyl such as cyclopentenylmethyl, cyclohexenylmethyl, cyclohexenylethyl, cyclohexenylpropyl, cycloheptenylmethyl, cycloheptenylethyl and bicyclo[2.2.1]hept-5-en-2-ylmethyl etc., and the like are generally used.
• the “aryl group” is preferably a C 6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl etc., and the like, and, for example, phenyl group and the like are generally used.
• arylalkyl group contains, as the aryl moiety, the “aryl group” defined above, and as the alkyl moiety, the “alkyl group” defined above.
• aryl group defined above
• alkyl moiety the “alkyl group” defined above.
• a C 6-14 aryl-C 1-6 alkyl group is preferable, and, for example, benzyl, phenethyl and the like are generally used.
• the “hydrocarbon group” of the “hydrocarbon group optionally having substituent(s)” represented by the above-mentioned E, R, R′, R 1 and Y may have, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), a nitro group, a cyano group, a hydroxy group, a thiol group, a sulfo group, a sulphino group, a phosphono group, an optionally halogenated lower alkyl group (e.g., C 1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethylpropyl, hexyl and the like, a mono-, di- or tri-halogeno-C 1-6 alkyl group such as chloro
• hydrocarbon group of the “hydrocarbon group optionally having substituent(s)” for R 2 and R 3 , for example, a lower alkyl group (e.g., alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl group and the like), a lower alkenyl group (e.g., alkenyl group having 2 to 6 carbon atoms such as vinyl, allyl group and the like), a lower alkynyl group (e.g., alkynyl group having 2 to 6 carbon atoms such as ethynyl, propargyl group and the like), a cycloalkyl group (e.g., cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group and the like), a cycloalkenyl group (e.g., cycloalkenyl group
• heterocyclic group of the “heterocyclic group optionally having substituent(s) ” represented by R 2 and R 3
• a 5- to 12-membered monocyclic or fused heterocyclic group containing 1 or 2 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom such as pyridyl, pyrrolidinyl, piperazinyl, piperidinyl, 2-oxoazepinyl, furyl, decahydroisoquinolyl, quinolyl, indolyl, isoquinolyl, thienyl, imidazolyl, morpholinyl etc., and the like can be mentioned.
• substituent for the “hydrocarbon group optionally having substituent(s)” and “heterocyclic group optionally having substituent(s)” for R 2 and R 3 for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), a lower alkyl group (e.g., alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl group and the like), a lower alkenyl group (e.g., alkenyl group having 2 to 6 carbon atoms such as vinyl, allyl group and the like), a lower alkynyl group (e.g., alkynyl group having 2 to 6 carbon atoms such as ethynyl, propargyl group and the like), a cycloalkyl group (e.g., cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl,
• ring formed by R 2 and R 3 together with the adjacent nitrogen atom for example, pyrrolidine, piperidine, homopiperidine, morpholine, piperazine, tetrahydroquinoline, tetrahydroisoquinoline and the like can be mentioned.
• hydrocarbon group of the “hydrocarbon group optionally having substituent(s)” represented by the above-mentioned E, R, R′, R 1 and Y may have 1 to 5, preferably 1 to 3, the aforementioned substituent at substitutable positions of the hydrocarbon group, wherein, when the number of substituents is not less than 2, each substituent is the same or different.
• heterocyclic group of the “heterocyclic group optionally having substituent(s)” represented by the above-mentioned E, R, R′ and Y, a 5- to 12-membered aromatic heterocyclic group and saturated or unsaturated non-aromatic heterocyclic group containing, as ring-constituting atom (ring atom), 1 to 3 (preferably 1 or 2) kinds of at least 1 (preferably 1 to 4, more preferably 1 to 3) hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom and the like can be mentioned.
• heterocyclic group of the “heterocyclic group optionally having substituent(s)” represented by Y
• a saturated oxygen-containing heterocyclic group containing, as ring atoms, 1 to 4, more preferably 1 to 3, hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom etc., and the like are preferable, particularly a 5- to 12-membered saturated oxygen-containing heterocyclic group and the like are preferable.
• aromatic heterocyclic group an aromatic monocyclic heterocyclic group, an aromatic fused heterocyclic group and the like can be mentioned.
• aromatic monocyclic heterocyclic group for example, a 5- or 6-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl etc., and the like can be mentioned.
• aromatic fused heterocyclic group for example, a 8- to 12-membered aromatic fused heterocyclic group (preferably a heterocyclic group wherein the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring, or a heterocyclic group wherein the same or two different heterocyclic groups of the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group are condensed), such as benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxal
• saturated or unsaturated non-aromatic heterocyclic group for example, a 3- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, oxepanyl, thiepanyl, oxazepanyl, thiazepanyl, azocanyl, oxocanyl, thiocanyl, oxazocanyl, thiazocanyl and the like can be mentioned.
• aliphatic heterocyclic group such as oxi
• oxo-substituted examples thereof include 2-oxoazetidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxoazepanyl, 2-oxoazocanyl, 2-oxotetrahydrofuryl, 2-oxotetrahydropyranyl, 2-oxothiolanyl, 2-oxothianyl, 2-oxopiperazinyl, 2-oxooxepanyl, 2-oxooxazepanyl, 2-oxothiepanyl, 2-oxothiazepanyl, 2-oxooxocanyl, 2-oxothiocanyl, 2-oxoooxazocanyl, 2-oxothiazocanyl and the like.
• a 5-membered non-aromatic heterocyclic group such as 2-oxopyrrolidinyl and the like is preferable.
• the “heterocyclic group” of the “heterocyclic group optionally having substituent(s)” represented by the above-mentioned E, R, R′ and Y may have, for example, those similar to the “substituent” of the “hydrocarbon group optionally having substituent(s)” represented by the aforementioned E, R, R′, R 1 and Y and the like are used.
• heterocyclic group of the “heterocyclic group optionally having substituent(s)” represented by E, R, R′ and Y may each have 1 to 5, preferably 1 to 3, substituents mentioned above at substitutable positions of the heterocyclic group, and when the number of substituents is two or more, the substituents are the same or different.
• R and W in the compound of the present invention is explained below.
• the position of the bond between R and W is not particularly limited as long as R and W can be bonded.
• R′ and W′ are bonded.
• the bondable position of R and R′ is the position where the “hydrocarbon group” and “substituent” of the “hydrocarbon group optionally having substituent(s)” defined above for R and R′ can be bonded, and the position where the “heterocyclic group” and “substituent” of the “heterocyclic group optionally having substituent(s)” defined above for R and R′ can be bonded.
• R and W, and R′ and W′ can be bonded at the bondable position thereof and can form a ring together with the adjacent nitrogen atom.
• a saturated nitrogen-containing ring e.g., azetidine, pyrrolidine, piperidine, homopiperidine etc.
• an unsaturated nitrogen-containing ring e.g., tetrahydropyridine etc.
• an aromatic nitrogen-containing ring e.g., pyrrole etc.
• a hetero ring e.g., piperazine, morpholine etc.
• a fused ring e.g., indole, indoline, isoindole, isoindoline, tetrahydroquinoline, tetrahydroisoquinoline etc.
• a fused ring e.g., indole, indoline, isoindole, isoindoline, tetrahydroquinoline, tetrahydr
• the ring formed by R and W, or R′ and W′, which are bonded at each bondable position thereof, together with the adjacent nitrogen atom may have 1 to 4 substituents at substitutable positions thereof. When the number of substituents is 2 or more, the substituents are the same or different.
• the substituents of the “hydrocarbon group optionally having substituent(s)” and “heterocyclic group optionally having substituent(s)” defined for R and R′, and the substituents of the “chain divalent hydrocarbon group optionally having substituent(s)” defined for W and W′ can be mentioned.
• halogen atom e.g., fluorine, chlorine, bromine, iodine etc.
• C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethylpropyl, hexyl etc., and the like can be mentioned.
• R and W By the bond between R and W, or R′ and W′, for example, and the like are formed, but the ring is not limited to these. These may have substituents as defined above, and it would be understood for those of ordinary skill in the art that they may also have an isomer.
• X represents a leaving group, such as a halogen atom, a benzotriazolyl group, a (2,5-dioxypyrrolidin-1-yl)oxy group and the like.
• a halogen atom such as fluorine, chlorine, bromine, iodine and the like is preferable, and chlorine is particularly preferable.
• the “metal cation” is exemplified by alkali metal ion (e.g., Na + , K + , Li + , Cs + and the like), with preference given to Na + .
• alkali metal ion e.g., Na + , K + , Li + , Cs + and the like
• the “quaternary ammonium ion” is exemplified by tetramethylammonium ion, tetraethylammonium ion, tetrapropylammonium ion, tetrabutylammonium ion and the like, with preference given to tetrabutylammonium ion.
• a pharmacologically acceptable basic salt can be formed between an acidic group in a molecule and an inorganic base or an organic base etc
• a pharmacologically acceptable acid addition salt can be formed between a basic group in a molecule and an inorganic acid or an organic acid etc.
• Examples of the inorganic basic salt of a prodrug compound of the present invention such as compound (I) and the like include salt with alkali metal (e.g., sodium, potassium and the like), alkaline earth metal (e.g., calcium and the like), ammonia etc., and the like
• examples of the organic basic salt of a prodrug compound of the present invention such as compound (I) and the like include salt with dimethylamine, triethylamine, piperazine, pyrrolidine, piperidine, 2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, collidine etc., and the like.
• Examples of the acid addition salt of a prodrug compound of the present invention such as compound (I) and the like include inorganic acid salt (e.g., hydrochloride, sulfate, hydrobromide, phosphate and the like), organic acid salt (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate,. methanesulfonate, p-toluenesulfonate and the like) and the like.
• inorganic acid salt e.g., hydrochloride, sulfate, hydrobromide, phosphate and the like
• organic acid salt e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate,. methanesulfonate, p-toluenesulfonate and the like
• examples of the “hydrate” include 0.5 hydrate-5.0 hydrate. Of these, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate and 2.0 hydrate are preferable.
• the parent compound H-A i.e., a compound obtained by eliminating the eliminatable modification group from compound (I) and the like, which are prodrugs
• the prodrug compound of the present invention such as compound (I) and the like is not particularly limited as long as it is a therapeutic agent having a group capable of bonding to a carbon atom of a modification group (side chain) eliminatable from a prodrug, via a carbon-oxygen bond, a carbon-sulfur bond or a carbon-nitrogen bond.
• the prodrug of the present application is specifically an optionally fused, nitrogen-containing heterocyclic group optionally having substituent(s), which is a compound represented by the formula (II): wherein —B 1 —B 2 is a group remaining from elimination of hydrogen from a pharmaceutical compound H—B 1 —B 2 wherein H—B 1 — is a hydroxyl group, a thiol group, an amide group or an optionally fused, nitrogen-containing heterocycle optionally having substituent(s), which is capable of bonding to a carbon atom of a modification group (side chain) eliminatable from a prodrug, via a carbon-oxygen bond, a carbon-sulfur bond or a carbon-nitrogen bond, and other symbols are as defined above, or a salt thereof.
• substituent(s) is a compound represented by the formula (II): wherein —B 1 —B 2 is a group remaining from elimination of hydrogen from a pharmaceutical compound H—B 1 —B 2 wherein H—B 1
• a compound wherein B 1 is a nitrogen-containing heterocyclic group optionally having substituent(s), which is capable of bonding to a carbon atom of a modification group (side chain) eliminatable from a prodrug, via a carbon-nitrogen bond, and which has an optionally fused ring
• B 1 is a nitrogen-containing heterocyclic group optionally having substituent(s), which is capable of bonding to a carbon atom of a modification group (side chain) eliminatable from a prodrug, via a carbon-nitrogen bond, and which has an optionally fused ring
• a compound wherein the nitrogen-containing heterocyclic group represented by B 1 is a 5 or 6-membered aromatic heterocyclic group containing 1 to 4 nitrogens
• a compound wherein the nitrogen-containing aromatic heterocycle of the nitrogen-containing heterocyclic group represented by B 1 is imidazole, pyrrole, pyrazole, isoxazole, oxazole, thiazole or triazole.
• ring A is a “pyridine ring optionally having substituent(s)”.
• the pyridine ring of a “pyridine ring optionally having substituent(s)” for A ring optionally has 1 to 4 substituents.
• substituent for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), a hydrocarbon group optionally having substituent(s) (e.g., alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, n-propyl group etc.
• an amino group optionally having substituent(s) e.g., amino; amino group mono-substituted or di-substituted by an alkyl group having 1 to 6 carbon atoms such as methylamino, dimethylamino, ethylamino, diethylamino group etc. and the like
• an amide group e.g., formamide, acetamide and the like C 1-3 acylamino group etc.
• a lower alkoxy group optionally having substituent(s) e.g., alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, 2,2,2-trifluoroethoxy, 3-methoxypropoxy group etc. and the like
• a lower alkylenedioxy group e.g., C 1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy etc. and the like
• substituent(s) e.g., amino; amino group mono-substit
• substituents of the “pyridine ring optionally having substituent(s)” for ring A can have, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), a lower alkyl group (e.g., alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl group etc., and the like), a lower alkenyl group (e.g., alkenyl group having 2 to 6 carbon atoms such as vinyl, allyl group etc., and the like), a lower alkynyl group (e.g., alkynyl group having 2 to 6 carbon atoms such as ethynyl, propargyl group etc., and the like), a cycloalkyl group (e.g., cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopenty
• substituents and the substitutable positions of the substituents of the “pyridine ring optionally having substituent(s)” for ring A are not particularly limited, 1 to 3 above-mentioned substituents are preferably substituted at any of the 3-, 4- and 5-positions of a pyridine ring.
• ring B shows “a benzene ring optionally having substituent(s)” or “an aromatic monocyclic heterocycle optionally having substituent(s)”, which is condensed with an imidazole moiety, with preference given to the former.
• the benzene ring of the “benzene ring optionally having substituent(s)” for ring B optionally has 1 to 4 substituents at substitutable positions, and as the substituent, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), a hydrocarbon group optionally having substituent(s) (e.g., alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, n-propyl group etc., and the like), an amino group optionally having substituent(s) (e.g., amino; amino group mono- or di-substituted by alkyl group having 1 to 6 carbon atoms, such as methylamino, dimethylamino, ethylamino, diethylamino group and the like etc.), an amide group (e.g., C 1-3 acylamino group such as formamide, acetamide and the like etc.),
• substituents of the “benzene ring optionally having substituent(s)” for ring B can have, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), a lower alkyl group (e.g., alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl group and the like etc.), a lower alkenyl group (e.g., alkenyl group having 2 to 6 carbon atoms such as vinyl, allyl group and the like etc.), a lower alkynyl group (e.g., alkynyl group having 2 to 6 carbon atoms such as ethynyl, propargyl group and the like etc.), a cycloalkyl group (e.g., cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,
• benzene ring optionally having substituent(s)” for ring B, benzene ring is preferable.
• aromatic monocyclic heterocycle of the “aromatic monocyclic heterocycle optionally having substituent(s)” for ring B, for example, a 5 or 6-membered aromatic monocyclic heterocycle, such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like, and the like can be mentioned.
• aromatic monocyclic heterocycle for ring B, among others, pyridine ring is preferable. They
• the position of condensation between the “aromatic monocyclic heterocycle” of the “aromatic monocyclic heterocycle optionally having substituent(s)” and an imidazole moiety is not particularly limited.
• the present invention is not limited to the prodrug exemplified above.
• the present invention can be preferably applied to a pharmaceutical compound having a nitrogen-containing heterocycle, particularly a nitrogen-containing heterocycle, which is a fused ring, especially a pharmaceutical compound having a nitrogen-containing aromatic heterocycle.
• a modification group (side chain) eliminatable from the prodrug of the present invention into a nitrogen atom of the ring of a compound having imidazole, pyrazole, pyrrole, isoxazole, oxazole, thiazole or triazole, more preferable application can be achieved, because rapid expression of efficacy, prolongation of the efficacy, improvement of the chemical stability and the like can be afforded.
• nitrogen-containing heterocycle as a partial structure capable of bonding to a modification group (side chain) eliminatable from a prodrug” of compound (II), a nitrogen-containing aromatic heterocycle is particularly preferable.
• a nitrogen-containing heterocycle of the “optionally fused, nitrogen-containing heterocyclic group optionally having substituent(s)” of compound (II), for example, and the like can be mentioned.
• nitrogen-containing aromatic heterocycle in the nitrogen-containing aromatic heterocyclic group included in the “optionally having substituent(s) nitrogen-containing heterocyclic group” of compound (II) for example, imidazole, pyrrole, pyrazole, isoxazole, oxazole, thiazole and triazole can be mentioned.
• the prodrug compound of the present invention such as compound (I) and the like can be produced by the following Method A. wherein each symbol in the formula is as defined above.
• the prodrug compound of the present invention such as compound (I) and the like or a salt thereof can be obtained by condensation of a therapeutic drug or preventive drug H-A (III) having a partial structure capable of bonding to an eliminatable modifying group (side chain) of a prodrug, via a carbon-nitrogen bond, a carbon-sulfur bond or a carbon-oxygen bond, or a salt thereof, with compound (IV) or a salt thereof or compound (V) or a salt thereof, in the presence or absence of a base.
• a therapeutic drug or preventive drug H-A (III) having a partial structure capable of bonding to an eliminatable modifying group (side chain) of a prodrug via a carbon-nitrogen bond, a carbon-sulfur bond or a carbon-oxygen bond, or a salt thereof, with compound (IV) or a salt thereof or compound (V) or a salt thereof, in the presence or absence of a base.
• the salts of compound (I), compound (III), compound (IV) and compound (V) are exemplified by, for example, acid addition salts such as inorganic acid salt (e.g., hydrochloride, sulfate, hydrobromide, phosphate and the like), organic acid salt (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate and the like), and the like can be mentioned.
• inorganic acid salt e.g., hydrochloride, sulfate, hydrobromide, phosphate and the like
• organic acid salt e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-tol
• the reaction of Method A is generally conducted in a solvent, and a solvent that does not inhibit the reaction of Method A is selected as appropriate.
• solvent include ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether and the like), esters (e.g., ethyl formate, ethyl acetate, butyl acetate and the like), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane and the like), hydrocarbons (e.g., n-hexane, benzene, toluene and the like), amides (e.g., formamide, N,N-dimethylformamide, N,N-dimethylacetamide and the like), ketones (
• the amount of compound (IV) or a salt thereof or compound (V) or a salt thereof to be used is generally 1-10 mol, preferably 1-3 mol, relative to 1 mol of compound (III) or a salt thereof.
• Method A The reaction of Method A is carried out within a temperature range of from about 0° C. to 100° C., preferably 20° C. to 80° C.
• the reaction time of Method A varies depending on the kind of compounds (III), (IV), (V) or a salt thereof and solvent, reaction temperature and the like, but it is generally 1 min.-96 hrs., preferably 1 min.-72 hrs., more preferably 15 min.-24 hrs.
• the base in Method A is, for example, an inorganic base (e.g., sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate etc.), a tertiary amine (e.g., triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, ⁇ -collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 4-dimethylaminopyridine and the like); alkylene oxides (e.g., propylene oxide, epichlorohydrin etc.) and the like.
• the amount of the base to be used is generally 0.01 mol-10 mol, preferably 1 mol-3 mol, relative to 1 mol of compound (III) or a salt thereof.
• the compound (IV) and a salt thereof can be produced according to a method known per se or a method analogous thereto.
• X is a chlorine atom
• it can be obtained by reacting a compound represented by the formula (VIII): wherein each symbol is as defined above, or a salt thereof with phosgene, trichloromethyl chloroformate, bis(trichloromethyl)carbonate, thiophosgene and the like in the presence of an acid scavenger in a solvent (e.g., tetrahydrofuran, acetonitrile, dichloromethane etc.).
• a solvent e.g., tetrahydrofuran, acetonitrile, dichloromethane etc.
• compound (IV) can be also obtained by treating ethylcarbamate, which is obtained by reacting compound (VIII) or a salt thereof with ethyl chloroformate, with phosphorus oxychloride according to the method described in Synthetic Communications, vol. 17, p. 1887 (1987) or a method analogous thereto.
• salt of compound (VIII) for example, acid addition salts such as inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.), and the like can be mentioned.
• inorganic acid salts e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.
• organic acid salts e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.
• inorganic bases e.g., sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate etc.
• tertiary amine e.g., triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, ⁇ -collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 4-dimethylaminopyridine etc.
• the compound (VIII) and a salt thereof can be produced according to a method known per se or a method analogous thereto.
• compound (VIII) when D 1 is other than a bond, compound (VIII) can be obtained by condensing a compound represented by the formula (IX): wherein R 4 is a hydrogen atom or nitrogen-protecting group, and other symbols are as defined above, or a salt thereof with carboxylic acid or thionic acid represented by the formula (X): wherein each symbol is as defined above, or a reactive derivative thereof (e.g., anhydride, halide etc.), or a salt thereof in a suitable solvent (e.g., ethyl acetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide etc., followed by deprotection as necessary.
• a suitable solvent e.g., ethyl acetate, tetrahydrofuran, dichloromethane, N,N-d
• salt of compound (IX) for example, acid addition salts such as inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.) etc., and the like can be mentioned.
• inorganic acid salts e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.
• organic acid salts e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.
• compound (VIII) when D 1 is a bond, compound (VIII) can be obtained by condensing carboxylic acid or thionic acid represented by the formula (XI): wherein each symbol is as defined above, or a reactive derivative thereof (e.g., anhydride, halide etc.), or a salt thereof with a compound represented by Y-D 2 -H in a suitable solvent (e.g., ethyl acetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide etc.), followed by deprotection, as necessary.
• a suitable solvent e.g., ethyl acetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide etc.
• salt of compound (XI) for example, acid addition salts such as inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.) and the like, salts with alkali metal (e.g., sodium, potassium etc.), alkaline earth metal (e.g., calcium etc.), ammonia etc., and the like, and for example, organic base such as dimethylamine, triethylamine, piperazine, pyrrolidine, piperidine, 2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, collidine etc., and the like can be mentioned.
• inorganic acid salts e
• R 4 in the formulas (IX) and (XI) for example, a formyl group, a C 1-6 alkyl-carbonyl group (e.g., acetyl, ethylcarbonyl etc.), a benzyl group, a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, an allyloxycarbonyl group, a C 7-10 aralkyl-carbonyl group (e.g., benzylcarbonyl etc.), a trityl group and the like are used.
• These groups may be substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine etc.), a nitro group and the like.
• a method for removing such protecting groups a method known per se or a method analogous thereto is used, which is, for example, a method using an acid, a base, reduction, UV light, palladium acetate etc., and the like are used.
• Compound (V) or a salt thereof can be produced by a method known per se or a method analogous thereto. For example, it can be obtained by reacting a compound represented by the formula (XII): wherein each symbol is as defined above, or a salt thereof with phosgene, tri-chloromethyl chloroformate, bis(tri-chloromethyl)carbonate, thiophosgene and the like in the presence or absence of an acid scavenger in a solvent (e.g., tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethylformamide etc.).
• a solvent e.g., tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethylformamide etc.
• salt of compound (XII) for example, acid addition salts such as inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.) and the like, and the like can be mentioned.
• inorganic acid salts e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.
• organic acid salts e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.
• inorganic bases e.g., sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate etc.
• tertiary amines e.g., triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, ⁇ -collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 4-dimethylaminopyridine etc.
• Compound (XII) or a salt thereof can be produced by a method known per se or a method analogous thereto.
• D 1 when D 1 is other than a bond, it can be obtained by condensing a compound represented by the formula (XIII): wherein R 4 is a hydrogen atom or a nitrogen-protecting group, and other symbols are as defined above, or a salt thereof, with carboxylic acid or thionic acid represented by the formula (X): wherein each symbol is as defined above, or a reactive derivative thereof (e.g., anhydride, halide etc.), or a salt thereof, in a suitable solvent (e.g., ethyl acetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide etc.), and deprotection as necessary.
• a suitable solvent e.g., ethyl acetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide
• salts of compound (XIII) for example, acid addition salts such as inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.) and the like, and the like can be mentioned.
• inorganic acid salts e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.
• organic acid salts e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.
• the compound when D 1 is a bond, the compound can be obtained by condensing carboxylic acid or thionic acid represented by the formula (XIV): wherein each symbol is as defined above, or a reactive derivative thereof (e.g., anhydride, halide etc.), or a salt thereof, with a compound represented by Y-D 2 -H in a suitable solvent (e.g., ethyl acetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide etc.), followed by deprotection as necessary.
• a suitable solvent e.g., ethyl acetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide etc.
• salts of compound (XIV) for example, acid addition salts such as inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.) and the like, for example, salts with alkaline metal (e.g., sodium, potassium etc.), alkaline earth metal (e.g., calcium etc.), ammonia and the like, and the like, and, for example, organic basic salts with dimethylamine, triethylamine, piperazine, pyrrolidine, piperidine, 2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, collidine and the like, and the like can be mentioned.
• a formyl group for example, a C 1-6 alkyl-carbonyl group (e.g., acetyl, ethylcarbonyl etc.), a benzyl group, a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, an allyloxycarbonyl group, a C 7-10 aralkyl-carbonyl group (e.g., benzylcarbonyl etc.), a trityl group and the like are used.
• These groups may be substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine etc.), a nitro group and the like.
• Compound (VI) or a salt thereof can be produced by a method known per se or a method analogous thereto.
• the compound can be obtained by reacting a compound represented by the formula (XV): wherein each symbol is as defined above, or a salt thereof, with phosgene, trichloromethyl chloroformate, bis(tri-chloromethyl)carbonate, thiophosgene and the like, in the presence of an acid scavenger, in a solvent (e.g., tetrahydrofuran, acetonitrile, dichloromethane etc.).
• a solvent e.g., tetrahydrofuran, acetonitrile, dichloromethane etc.
• the compound can be also obtained by treating ethylcarbamate obtained by reacting compound (XV) or a salt thereof with chloroethyl formate with phosphorus oxychloride by a method described in Synthetic Communications, vol. 17, p. 1887 (1987) or a method analogous thereto.
• salts of compound (XV) for example, acid addition salts such as inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.) and the like, and the like can be mentioned.
• inorganic acid salts e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.
• organic acid salts e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.
• inorganic bases e.g., sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate etc.
• tertiary amines e.g., triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, ⁇ -collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 4-dimethylaminopyridine etc.
• Compound (XV) or a salt thereof can be produced by a method known per se or a method analogous thereto.
• the compound when D 1 ′ is other than a bond, the compound can be obtained by condensing a compound represented by the formula (XVI): wherein R 4 is a hydrogen atom or a nitrogen-protecting group, and other symbols are as defined above, or a salt thereof with carboxylic acid or thionic acid represented by the formula (XVII): wherein each symbol is as defined above, or a reactive derivative thereof (e.g., anhydride, halide etc.), or a salt thereof, in a suitable solvent (e.g., ethyl acetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide etc.), followed by deprotection as necessary.
• a suitable solvent e.g., ethyl acetate, tetrahydrofuran, dichloromethane, N,N-d
• salts of compound (XVII) for example, acid addition salts such as inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.) and the like, and the like can be mentioned.
• inorganic acid salts e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.
• organic acid salts e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.
• the compound when D 1 ′ is a bond, the compound can be obtained by condensing carboxylic acid or thionic acid represented by the formula (XVIII): wherein each symbol is as defined above, or a reactive derivative thereof (e.g., anhydride, halide etc.), or a salt thereof, with a compound represented by Y-D 2 ′-H in a suitable solvent (e.g., ethyl acetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide etc.), followed by deprotection as necessary.
• a suitable solvent e.g., ethyl acetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide etc.
• salts of compound (XVIII) for example, acid addition salts such as inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.) and the like, for example, salts with alkaline metal (e.g., sodium, potassium etc.), alkaline earth metal (e.g., calcium etc.), ammonia and the like, and, for example, organic basic salts with dimethylamine, triethylamine, piperazine, pyrrolidine, piperidine, 2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, collidine and the like, and the like can be mentioned.
• a formyl group for example, a C 1-6 alkyl-carbonyl group (e.g., acetyl, ethylcarbonyl etc.), a benzyl group, a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, an allyloxycarbonyl group, a C 7-10 aralkyl-carbonyl group (e.g., benzylcarbonyl etc.), a trityl group and the like are used.
• These groups may be substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine etc.), a nitro group and the like.
• the prodrug of the present invention can be used according to a pharmaceutical agent containing the parent compound. That is, as long as the parent compound is free of toxicity, a prodrug of the present invention, into which a eliminatable modification group is introduced, is free of toxicity and safe, and can be used for the prophylaxis or treatment by safely administering to mammals, including human, in a suitable dosage form according to the dose, subject of administration, administration route, target disease and the like, in the case of administration of the parent compound of the prodrug.
• the content of the prodrug of the present invention such as compound (I) and the like or a salt thereof, is about 0.01 to 100% by weight relative to the entire composition.
• a representative compound (VII) contained in the prodrug compound of the present invention such as compound (I) and the like is used as an anti-ulcer agent
• its dose to an adult is about 0.5 to 1,500 mg/day, preferably about 5 to 150 mg/day, based on the active ingredient, when, for example, the compound is orally administered to an adult human (60 kg).
• the prodrug compound of the present invention such as compound (I) or a salt thereof may be administered once daily or in 2 or 3 divided portions per day.
• Other ordinary pharmaceutical additives such as preservatives, anti-oxidants, coloring agents, sweetening agents, souring agents, bubbling agents and flavorings may also be used as necessary.
• excipients include, for example, lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic anhydride, titanium oxide and the like.
• Such “lubricants” include, for example, magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc, stearic acid and the like.
• binder include, for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, crystalline cellulose, starch, polyvinylpyrrolidone, powdered acacia, gelatin, pullulan, low-substituted hydroxypropyl cellulose and the like.
• Such “disintegrants” include (1) crosslinked povidone, (2) what is called super-disintegrants such as crosslinked carmellose sodium (FMC-Asahi Chemical) and carmellose calcium (Gotoku Yakuhin) etc, (3) carboxymethyl starch sodium (e.g., product of Matsutani Chemical), (4) low-substituted hydroxypropyl cellulose (e.g., product of Shin-Etsu Chemical), (5) cornstarch, and so forth.
• super-disintegrants such as crosslinked carmellose sodium (FMC-Asahi Chemical) and carmellose calcium (Gotoku Yakuhin) etc
• carboxymethyl starch sodium e.g., product of Matsutani Chemical
• low-substituted hydroxypropyl cellulose e.g., product of Shin-Etsu Chemical
• Said “crosslinked povidone” may be any crosslinked polymer having the chemical name 1-ethenyl-2-pyrrolidinone homopolymer, including polyvinylpyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer, and is exemplified by Colidon CL (produced by BASF), Polyplasdon XL (produced by ISP), Polyplasdon XL-10 (produced by ISP), Polyplasdon INF-10 (produced by ISP) and the like.
• PVPP polyvinylpyrrolidone
• Colidon CL produced by BASF
• Polyplasdon XL produced by ISP
• Polyplasdon XL-10 produced by ISP
• Polyplasdon INF-10 produced by ISP
• water-soluble polymers include, for example, ethanol-soluble water-soluble polymers [e.g., cellulose derivatives such as hydroxypropyl cellulose (hereinafter also referred to as HPC) etc, polyvinylpyrrolidone and the like], ethanol-insoluble water-soluble polymers [e.g., cellulose derivatives such as hydroxypropylmethyl cellulose (hereinafter also referred to as HPMC) etc., methyl cellulose, carboxymethyl cellulose sodium and the like, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like] and the like.
• HPC hydroxypropyl cellulose
• HPMC hydroxypropylmethyl cellulose
• Such “basic inorganic salts” include, for example, basic inorganic salts of sodium, potassium, magnesium and/or calcium. Preferred are basic inorganic salts of magnesium and/or calcium. More preferred are basic inorganic salts of magnesium.
• Such basic inorganic salts of sodium include, for example, sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate and the like.
• Such basic inorganic salts of potassium include, for example, potassium carbonate, potassium hydrogen carbonate and the like.
• Such basic inorganic salts of magnesium include, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg 6 Al 2 (OH) 16 CO 3 4H 2 O), and alumina hydroxide magnesium.
• Preferred are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like.
• Such basic inorganic salts of calcium include, for example, precipitated calcium carbonate, calcium hydroxide, etc.
• solvents include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
• dissolution aids include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
• Such “suspending agents” include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, monostearic glycerol etc; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose etc., and the like.
• surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, monostearic glycerol etc
• hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose,
• Such “isotonizing agents” include, for example, glucose, D-sorbitol, sodium chloride, glycerol, D-mannitol and the like.
• buffers include, for example, buffer solutions of phosphates, acetates, carbonates, citrates etc, and the like.
• Such “soothing agents” include, for example, benzyl alcohol and the like.
• Such “preservatives” include, for example, p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
• antioxidants include, for example, sulfites, ascorbic acid, ⁇ -tocopherol and the like.
• Such “coloring agents” include, for example, food colors such as Food Color Yellow No. 5, Food Color Red No. 2, Food Color Blue No. 2 etc; food lake colors, red oxide and the like.
• sweetening agents include, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like.
• Such “souring agents” include, for example, citric acid (citric anhydride), tartaric acid, malic acid and the like.
• Such “bubbling agents” include, for example, sodium bicarbonate and the like.
• Such “flavorings” may be synthetic substances or naturally occurring substances, and include, for example, lemon, lime, orange, menthol, strawberry and the like.
• the prodrug compound of the present invention may be prepared as a preparation for oral administration in accordance with a method known per se, by, for example, compression-shaping in the presence of a carrier such as an excipient, a disintegrant, a binder, a lubricant, or the like, and subsequently coating the preparation as necessary by a method known per se for the purpose of taste masking, enteric dissolution or sustained release.
• a carrier such as an excipient, a disintegrant, a binder, a lubricant, or the like
• an intermediate layer may be provided by a method known per se between the enteric layer and the pharmaceutical compound-containing layer for the purpose of separation of the two layers.
• a prodrug such as the compound (I) and the like of the present invention for preparing a prodrug such as the compound (I) and the like of the present invention as an orally disintegrating tablet, available methods include, for example, a method in which a core containing crystalline cellulose and lactose is coated with a prodrug such as the compound (I) and the like of the present invention and, where necessary, a basic inorganic salt, and then further coated with a coating layer containing a water-soluble polymer to give a composition, which is coated with an enteric coating layer containing polyethylene glycol, further coated with an enteric coating layer containing triethyl citrate, still further coated with an enteric coating layer containing polyethylene glycol, and finally coated with mannitol to give fine granules, which are mixed with additives, and shaped.
• enteric coating layer includes, for example, a layer consisting of a mixture of one or more kinds from aqueous enteric polymer substrates such as cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, methacrylic acid copolymers (e.g., Eudragit L30D-55 (trade name; produced by Rohm), Colicoat MAE30DP (trade name; produced by BASF), Polyquid PA30 (trade name; produced by Sanyo Chemical) etc), carboxymethylethyl cellulose, shellac and the like; sustained-release substrates such as methacrylic acid copolymers (e.g., Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), etc.) and the like; water-soluble polymers; plasticizers such as triethyl citrate, polyethylene glycol, acetylated mono
• additive includes, for example, water-soluble sugar alcohols (e.g., sorbitol, mannitol, maltitol, reduced starch saccharides, xylitol, reduced palatinose, erythritol, etc.), crystalline cellulose (e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591 (crystalline cellulose carmellose sodium) etc), low-substituted hydroxypropyl cellulose (e.g., LH-22, LH-32, LH-23, LH-33 (Shin-Etsu Chemical), mixtures thereof etc) and the like.
• binders, souring agents, bubbling agents, sweetening agents, flavorings, lubricants, coloring agents, stabilizers, excipients, disintegrators etc. are also used.
• the prodrug compound of the present invention may be used in combination with 1 to 3 other active ingredients for the purpose of enhancing the efficacy or allowing exertion of efficacy while suppressing the side effects.
• a combined use of compound (VII) with an antibacterial agent is preferable for eradicating H. pylori. More specifically, a combined use of the compound of the present invention with clarithromycin and/or metronidazole is preferable.
• Such “other active ingredients” and a prodrug such as the compound (I) and the like of the present invention may be mixed, prepared as a single pharmaceutical composition [e.g., tablets, powders, granules, capsules (including soft capsules), liquids, injectable preparations, suppositories, sustained-release preparations, etc.], in accordance with a method known per se, and used in combination, and may also be prepared as separate preparations and administered to the same subject simultaneously or at a time interval.
• a single pharmaceutical composition e.g., tablets, powders, granules, capsules (including soft capsules), liquids, injectable preparations, suppositories, sustained-release preparations, etc.
• room temperature means about 15-30° C.
• reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.45 g) as a colorless oil.
• reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
• a dusting powder consisting of the remaining components is coated on sucrose•starch spherical granules while spraying a hydroxypropyl cellulose solution, thereby producing spherical granules, which spherical granules are vacuum dried and passed through a round sieve to give granules.
• the development of a prodrug based on the modification of a ring-constituting nitrogen atom of a wide range of pharmaceutical compounds having a nitrogen-containing heterocycle has been made possible.
• the present invention is applicable to the development of a prodrug based on the modification of a functional group having an eliminatable proton, such as a hydroxyl group, an amino group, an amide group and the like, it provides a prodrug of a therapeutic drug or a pharmaceutical compound having a pharmacological action, which generally has such an eliminatable proton, and a means thereof.
• the present invention provides a prodrug of an existing therapeutic drug or a pharmaceutical compound having a pharmacological action, and a means therefor.
• Forming such a prodrug affords improvement of chemical stability, improvement of absorbability, regulation of the level of pharmacological action, prolongation of pharmacological action, reduction of side effects, improvement of bad taste, reduction of irritation, expansion of selectivity of prescription of preparation, improvement of administration route, small sizing of preparation, low cost of preparation and the like.

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