WO2000016776A1 - Preparations a administrer par voie buccale a liberation lente - Google Patents

Preparations a administrer par voie buccale a liberation lente Download PDF

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Publication number
WO2000016776A1
WO2000016776A1 PCT/JP1999/005046 JP9905046W WO0016776A1 WO 2000016776 A1 WO2000016776 A1 WO 2000016776A1 JP 9905046 W JP9905046 W JP 9905046W WO 0016776 A1 WO0016776 A1 WO 0016776A1
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Prior art keywords
group
derivative
quinoline
optionally substituted
ring
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PCT/JP1999/005046
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English (en)
Japanese (ja)
Inventor
Kazuhiro Okochi
Toshihiro Shimizu
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Takeda Chemical Industries, Ltd.
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Priority to AU56521/99A priority Critical patent/AU5652199A/en
Publication of WO2000016776A1 publication Critical patent/WO2000016776A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a sustained release preparation for oral administration containing quinoline or a quinazoline derivative or a thienopyridine or a thienopyrimidine derivative.
  • Japanese Unexamined Patent Publication No. Hei 6—2 9 3 6 3 4 discloses a plain tablet containing a low-melting oily substance and having improved abrasion resistance. It has been. This uncoated tablet has the above-described excellent properties of improved abrasion resistance, but also has the properties of high disintegration and high dissolution. However, when a plain tablet containing a drug is administered orally, the drug is released into the gastrointestinal tract at one time, and some drugs may show high blood levels.
  • Drugs such as anti-inflammatory drugs such as arthritis drugs, anti-rheumatic drugs, bone formation promoters, and drugs that prevent or treat immunity-related diseases are required to act over a long period of time .
  • anti-inflammatory drugs such as arthritis drugs, anti-rheumatic drugs, bone formation promoters, and drugs that prevent or treat immunity-related diseases are required to act over a long period of time .
  • the present inventors have conducted intensive studies to achieve sustained release from the preparation and to smoothen the blood concentration after oral administration.As a result, quinoline or a quinazoline derivative or a chenopyridine or a thienopyrimidine derivative had a gel-forming substance. And, if necessary, a disintegration aid, especially a saccharide, to control the release of quinoline or quinazoline derivatives or thienopyridine or chenopyrimidine derivatives. After finding that it can be provided, further research based on this finding The present invention has been completed.
  • the present invention is a.
  • a sustained-release oral preparation comprising (i) a quinoline or quinazoline derivative or a chenoviridine or a thienopyrimidine derivative and (ii) a gel-forming substance,
  • the quinoline or quinazoline derivative has the formula (x) n- one R
  • Y is a nitrogen atom or C—G (G is an esterified or amidated propyloxyl group, an optionally substituted acyl group, an optionally protected hydroxyalkyl group, or a halogen atom.
  • R 1 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X 1 represents an oxygen atom or an optionally oxidized sulfur atom, and n represents 0 or 1 and k represent 0 or 1.
  • G and R 1 may combine with each other to form a ring.
  • Ring A and ring B may each have a substituent.
  • Y is C_G ′′ (G ′ ′′ represents a carboxyl group which may be esterified), and R 1 is substituted with a nitrogen-containing unsaturated heterocyclic group which may have a substituent. and has CI_ 4 alkyl group (provided that the constituting nitrogen atom of a nitrogen-containing unsaturated heterocyclic group is bound to the ⁇ 3 i 4 alkyl group), preparation of (12) above, wherein n is 0 ,
  • R 2 and R 3 are the same or different and each represents a hydrogen atom, a halogen atom, or an optionally substituted alkyl group, and R 2 and R 3 may be bonded and replaced It may form a 5- to 7-membered ring.
  • W is a nitrogen atom, C—G ′ (wherein, G ′ represents an optionally esterified propyloxyl group or a halogen atom),
  • X 2 is an oxygen atom, Or a group represented by the formula: (CH 2 ) Q — (wherein Q is an integer of 0 to 5), and R 4 is a heterocyclic group which may be substituted Or a substituted or unsubstituted amino group, respectively.
  • Ring D may be substituted.
  • R 2 and R 3 are combined to form an optionally substituted 5- to 7-membered ring, and W is C — G ′ (where G ′ is an ester Wherein R 4 is a heterocyclic ring which may be substituted, wherein R 4 is an optionally substituted heterocyclic group or a halogen atom.
  • Y is a nitrogen atom or C-G (G is a carboxyl group which may be esterified or amidated, an optionally substituted acyl group, a hydroxyalkyl group which may be protected or a halogen atom.
  • R 1 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X 1 represents an oxygen atom or an optionally oxidized sulfur atom, and n represents 0 or 1. And k represents 0 or 1.
  • G and R 1 may combine with each other to form a ring. Ring A and ring B may each have a substituent.
  • Y is C_G ′′ (G ′ ′′ represents a carboxyl group which may be esterified), and R 1 is substituted with a nitrogen-containing unsaturated heterocyclic group which may have a substituent.
  • Alkyl group (provided that the nitrogen atom constituting the nitrogen-containing unsaturated heterocyclic group is Wherein n is 0.
  • the quinoline derivative or quinazoline derivative is ethyl 4- (3,4-dimethoxyphenyl) —6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-1-
  • R 2 and R 3 are the same or different and each represents a hydrogen atom, a halogen atom, or an optionally substituted alkyl group, and R 2 and R 3 may be bonded and replaced It may form a 5- to 7-membered ring.
  • W is a nitrogen atom, C-G '(wherein G' represents a propyloxyl group or a halogen atom which may be esterified),
  • X 2 is an oxygen atom, May be A sulfur atom or a formula — (CH 2 ) q — (wherein Q is an integer of 0 to 5); and
  • R 4 is an optionally substituted heterocyclic group or a substituted And each represents a diamino group.
  • Ring D may be substituted.
  • R 2 and R 3 are combined to form an optionally substituted 5- to 7-membered ring, and W is C-G ′ (where G ′ is an ester A carboxyl group or a halogen atom which may be optionally substituted.)
  • R 4 is a heterocyclic ring which may be substituted
  • Y represents a nitrogen atom or C_G (G represents an esterified or amidated propyloxyl group, an optionally substituted acyl group, an optionally protected hydroxyalkyl group, or a halogen atom.
  • R 1 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X 1 represents an oxygen atom or an optionally oxidized sulfur atom, and n represents 0 or 1. , K represents 0 or 1.
  • G and R 1 may combine with each other to form a ring. Ring A and ring B may each have a substituent.
  • Y is C-G '' (G '' represents a carboxyl group which may be esterified), and R 1 is a nitrogen-containing unsaturated heterocyclic group which may have a substituent. is substituted CI- 4 alkyl group (provided that the constituting nitrogen atom of a nitrogen-containing unsaturated heterocyclic group is bound to the C i_ 4 alkyl group), (14) above, wherein n is 0 Use of,
  • R 2 and R 3 are the same or different and each represents a hydrogen atom, a halogen atom, or an optionally substituted alkyl group, and R 2 and R 3 may be bonded and replaced It may form a 5- to 7-membered ring.
  • W is nitrogen atom, one G C a group represented by '(wherein, G' is. Showing the esterified carboxyl group which may or halo gen atom,),
  • X 2 is an oxygen atom, optionally oxidized A sulfur atom or a group represented by the formula — (CH 2 ) Q — (wherein q represents an integer of 0 to 5), and R 4 represents an optionally substituted heterocyclic group or The amino groups that may be substituted are respectively shown.
  • Ring D may be substituted.
  • R 2 and R 3 are combined to form an optionally substituted 5- to 7-membered ring, and W is C-G '(where G' is A carboxyl group which may be esterified, or a halogen atom.) Wherein R 4 is a heterocyclic ring which may be substituted; About. BEST MODE FOR CARRYING OUT THE INVENTION
  • the quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative contained in the sustained-release oral preparation of the present invention may be any as long as it can be used as a medicament.
  • These derivatives include anti-inflammatory effects (especially anti-arthritic effects), anti-rheumatic effects, bone resorption inhibiting effects, immunomodulatory effects, and / or immune site forces [eg, interleukin-2 (IL-2), Interferonase (IFN-r) and the like] Compounds having an effect on production suppression are preferred.
  • Specific examples of the quinoline or quinazoline derivative contained in the sustained-release oral preparation of the present invention include:
  • thienopyridine or thienopyri 'derivative contained in the sustained release oral preparation of the present invention include, for example,
  • examples of the hydrocarbon residue in the optionally substituted hydrocarbon residue represented by R 1 include an aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue, and an alicyclic ring. And aliphatic hydrocarbon residues, aromatic carbocycle-aliphatic hydrocarbon residues, aromatic hydrocarbon residues and the like.
  • aliphatic hydrocarbon residue examples include a saturated aliphatic hydrocarbon residue having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, isopentyl) , Neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, deci Le etc.), unsaturated aliphatic hydrocarbon residues from 2 to 1 0 carbon atoms (e.g., C 2 - 1 0 alkenyl group, C 2 - 10 alkynyl group, and specific examples thereof, For example, vinyl (Ethenyl), aryl, 1-probenyl, 2-probenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1 1-propen
  • the alicyclic hydrocarbon residue, a saturated alicyclic hydrocarbon residues e.g. carbon number 3 ⁇ 8, C 3 - 8 cycloalkyl group, and specific examples thereof include e.g. consequent opening, cyclobutyl , cyclopentyl, cyclohexyl, Shikurohepu chill, and the like Shikurookuchiru) and, furthermore, C 7 -.
  • bicyclo alkyl group e.g., bicyclo [2, 2, 1] heptyl, bicyclo [2, 2, 2] Octyl, bicyclo [3,2,1] octyl, bicyclo [3,2,2] nonyl, bicyclo [3,3,1] nonyl, bicyclo [4,2,1] nonyl, bicyclo [4,3, 1] decyl, etc.
  • an unsaturated alicyclic hydrocarbon residue having 5 to 8 carbon atoms eg, a C 5 _ 8 cycloalkenyl group, a C 5 _ 8 cycloalkadienyl group.
  • Specific examples thereof include 1-cyclopentenyl, 2- Cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cyclopentenyl, 2,4-cyclohexenyl, 2,5-cyclohexenyl, 2,4-cyclohexenyl, etc.).
  • the alicyclic monoaliphatic hydrocarbon residue has 4 to 9 carbon atoms (e.g., cyclobutane) among the above-mentioned alicyclic hydrocarbon residue and aliphatic hydrocarbon residue bonded.
  • aromatic carbocyclic monoaliphatic hydrocarbon residue examples include phenylalkyl having 7 to 9 carbon atoms (eg, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and 1-phenylpropyl). , Carbon number 1 :! To 13 naphthylalkyl (for example, ⁇ -naphthylmethyl, ⁇ -naphthylethyl, 3-naphthylmethyl, / 3-naphthylethyl) and the like.
  • naphthylalkyl for example, ⁇ -naphthylmethyl, ⁇ -naphthylethyl, 3-naphthylmethyl, / 3-naphthylethyl
  • aromatic hydrocarbon residue examples include a C6-C14 aryl group such as phenyl, naphthyl (eg, hinaphthyl, 3-naphthyl), anthryl, phenanthryl, and acenaphthylenyl.
  • the heterocyclic group in the optionally substituted heterocyclic group represented by R 1 includes, for example, (i) 5 to 7 containing one sulfur, nitrogen or oxygen atom.
  • Membered heterocyclic group (ii) 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, (iii): 5 to 6-membered containing! To 2 nitrogen atoms and one sulfur or oxygen atom
  • these heterocyclic groups may be fused to a 6-membered ring containing up to 2 nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom. Further, it may be a non-aromatic heterocyclic group.
  • heterocyclic group examples include, for example, (1) for example, chenyl, furyl, pyrazole, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,4-oxaziazolyl, 1,2, 3-oxosaziazolyl, 1,3,4-oxaxazolyl, furazanil, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,
  • Hetero selected from oxygen, sulfur, nitrogen, etc. in addition to carbon atoms such as 2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl
  • a bicyclic or tricyclic fused heterocyclic group containing 1 to 4 atoms is exemplified.
  • the non-aromatic heterocyclic group include a 3 to 7-membered heterocyclic group containing 1 to 4 sulfur, nitrogen or oxygen atoms, oxilanyl, azetidinyl, oxedinyl, cesinyl, Pyrrolidinyl, tetrahydrofuryl, thiolanyl, piberidinyl, tetrahydropyranyl, morpholiel, thiomorpholinyl, piperazinyl and the like.
  • the hydrocarbon residue or heterocyclic group represented by R 1 in the above formula [I] has 1 to 3 substituents at any substitutable position on the chain or the ring. Is also good. Examples of such a substituent include an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, a halogen atom, a nitro group, and a substituted group.
  • Examples of the aliphatic chain hydrocarbon group as the substituent include a linear or branched aliphatic hydrocarbon group, for example, an alkyl group (preferably an alkyl group having 1 to 10 carbon atoms), alkenyl Groups (preferably an alkenyl group having 2 to 10 carbon atoms), an alkynyl group (preferably an alkynyl group having 2 to 10 carbon atoms) and the like.
  • an alkyl group preferably an alkyl group having 1 to 10 carbon atoms
  • alkenyl Groups preferably an alkenyl group having 2 to 10 carbon atoms
  • an alkynyl group preferably an alkynyl group having 2 to 10 carbon atoms
  • alkyl group examples include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, Crest Examples include syl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, and decyl.
  • alkenyl group examples include, for example, vinyl, aryl, isopropyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1 Butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4 —Hexenyl, 5-hexenyl and the like.
  • alkynyl group examples include, for example, ethynyl, 1-propyl,
  • the alicyclic hydrocarbon group as the substituent C 3 saturated or unsaturated - 1Q alicyclic hydrocarbon group (e.g., c 3 - 10 cycloalkyl group, c 3 _ 8 Shikuroaruke sulfonyl group, c 4 _ 8 such cycloalkadienyl group).
  • cycloalkyl group examples include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, Bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.
  • C 3 _ s cycloalkenyl group e.g., 2-Shikurobe pentene _ 1 _ I le, 3-cyclopentene - 1 _ I le, hexene one to 2-cyclopropyl
  • Examples thereof include 1-yl and 3-cyclohexene-11-yl, and among them, a cycloalkenyl group having 5 to 7 carbon atoms is preferable.
  • C 4 _ 8 cycloalkadienyl group examples include, for example, 2,4-cyclopentene-1-yl, 2,4-cyclohexadiene-1-yl, 5-cyclohexadene-1-yl; and among them, a cycloalkadienyl group having 5 to 7 carbon atoms is preferable.
  • the aryl group as the substituent is preferably a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, and preferable examples thereof include, for example, phenyl, naphthyl, anthryl, Examples thereof include phenanthryl and acenaphthylenyl, and among them, phenyl, 1-naphthyl and 2-naphthyl are preferable.
  • the aromatic heterocyclic group as the substituent include (01) a 5- to 7-membered heterocyclic group containing one sulfur, nitrogen or oxygen atom, and (ii) 2 to 4 nitrogen atoms.
  • a 5- to 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur or oxygen atom, and (iii) an aromatic monocyclic heterocyclic group For example, furyl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4, oxazazolyl , 2,3 —thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3 —triazolyl, 1,2,4 —triazolyl, tetrazolyl, pyridyl,
  • non-aromatic heterocyclic group as the substituent include a 3 to 7-membered heterocyclic group containing 1 to 4 sulfur, nitrogen or oxygen atoms, oxilanyl, azetidinyl, oxedynyl. , Quinyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piberidinyl, tetrahydroviranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like.
  • halogen examples include fluorine, chlorine, bromine and iodine, and fluorine and chlorine are particularly preferred.
  • amino group which may be substituted as the substituent examples include (i) an amino group, and (ii) a substituted amino group [alkyl having 1 to 10 carbons, alkenyl having 2 to 10 carbons, carbon An amino group having one or two substituents of an alkynyl having 2 to 10 carbon atoms, an acyl group having 1 to 10 carbon atoms, or an aromatic group or a heterocyclic group having 6 to 12 carbon atoms (eg, methylamino Dimethylamino, ethylamino, methylamino, dibutylamino, diarylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinylamino, etc.).
  • a substituted amino group alkyl having 1 to 10 carbons, alkenyl having 2 to 10 carbons, carbon
  • Examples of the optionally substituted acyl group as the substituent include (i) formyl, and (ii) alkyl having 1 to 10 carbons, alkenyl or aromatic having 2 to 10 carbons.
  • a carbonyl group bonded eg, acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentane luponyl, cyclohexanecarbonyl, cycloheptanecarbonyl, cycloheptanylcarbonyl) , 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.).
  • Examples of the optionally substituted hydroxyl group as the substituent include (i) a hydroxyl group, and (ii) an appropriate substituent, particularly one used as a protecting group for a hydroxyl group. And a hydroxyl group (for example, alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyloxy, aryloxy, etc.).
  • alkoxy examples include alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy). , Isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.).
  • alkenyloxy examples include alkenyloxy having 2 to 10 carbon atoms (eg, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy, etc.). Is preferred.
  • alkynyloxy an alkynyloxy having 2 to 10 carbon atoms (eg, ethynyloxy, 2-propynyloxy, etc.) is preferable.
  • aralkyloxy for example, phenyl- 2- alkyloxy (eg, benzyloxy, phenethyloxy, etc.) can be mentioned.
  • acyloxy are alkanoyloxys having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, petyriloxy, isobutyryloxy, etc.).
  • aryloxy examples include phenoxy, 4-chlorophenoxy and the like.
  • Examples of the thiol group which may be substituted as the substituent include a thiol group and a thiol group having an appropriate substituent on the thiol group, in particular, a thiol group having a thiol group used as a protective group (for example, alkylthio, alkenylthio, Alkynylthio, aralkylthio, acylthio, arylthio, etc.).
  • alkylthio examples include alkylthio having 1 to 10 carbon atoms (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, Hexylthio, heptylthio, nonylthio, cyclobutyl Ruthio, cyclopentylthio, cyclohexylthio, etc.) are preferred.
  • alkylthio having 1 to 10 carbon atoms eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentyl
  • alkenylthio examples include alkenylthio having 2 to 1.0 carbon atoms (eg, allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio, 2-cyclopentenylmethylthio, 2-cyclohexenyl And methylthio).
  • alkynylthio alkynylthio having 2 to 10 carbon atoms (eg, ethylthio, 2-propynylthio, etc.) is preferable.
  • aralkylthio examples include phenyl C alkylthio (eg, benzylthio, phenethylthio, etc.).
  • an alkanolthio having 2 to 4 carbon atoms eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.
  • acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc. is preferable.
  • arylthio examples include phenylthio and 41-chlorophenylthio.
  • Examples of the carboxyl group which may be esterified as the substituent include (i) a carboxyl group, and (ii) a carboxyl group bonded to an alkyl group having 1 to 6 carbon atoms (that is, an alkoxy group such as methoxycarbonyl).
  • the substituent in the hydrocarbon residue or the heterocyclic group represented by R 1 may further have one or more, preferably 1 to 3 suitable substituents at any substitutable positions. You may have.
  • substituents include, for example, 10 alkyl group, C 2 _ 10 alkenyl, C 0 alkynyl group, C 3 - 8 cycloalkyl group, C 3 _ 8 cycloalkenyl group, C 4 - 8 cycloalkadienyl group, Ariru group, an aromatic heterocyclic group , Non-aromatic heterocyclic group, aralkyl group (eg, aryl
  • —Ci—6 alkyl group, etc. amino group, N-monosubstituted amino group, ⁇ , ⁇ ⁇ ⁇ -disubstituted amino group, amidino group, acyl group, carbamoyl group, ⁇ _monosubstituted carbamoyl group (eg, Methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, etc.), ⁇ , ⁇ -disubstituted rubamoyl group ( ⁇ , ⁇ ⁇ ⁇ ⁇ _dimethylcarbamoyl, ⁇ , ⁇ ⁇ -getylcarbamoyl, piperidinocarbamoyl, morpholino carbamoyl, etc.) , Sulfamoyl groups, ⁇ _monosubstituted sulfamoyl groups (eg, methylsulfamoyl, eth
  • Alkoxycarbonyl group eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.
  • hydroxyl group (: trialkoxy group, C 2 _ 10
  • substituents include a nitro group, a nitroso group, an oxo group, etc. Specific examples of such a substituent include the same as those described above as the substituent on the hydrocarbon residue, the heterocyclic group and the amino group.
  • the optionally substituted hydrocarbon residue represented by R 1 is preferably a compound represented by the formula —CH 2 —X 3 —Z 1 wherein X 3 is An oxygen atom, an optionally oxidized sulfur atom or — (CH 2 ) X — (wherein X represents an integer of 0 to 5), Z 1 represents an optionally substituted hydrocarbon residue, And a heterocyclic group which may be substituted with X 3 by a ring-constituting atom.].
  • the optionally oxidized sulfur atom represented by X 3 include a thio group, a sulfinyl group, and a sulfonyl group, and a thio group is particularly preferable.
  • X 3 is preferably 1 (CH 2 ) X _ (where X is an integer of 0 to 2, and more preferably X is 0).
  • the hydrocarbon residue may be substituted represented by Z 1, include the same ones as exemplified as an optionally substituted hydrocarbon residue which may be substituted represented by the aforementioned R 1.
  • X 3 which is illustrated as a optionally substituted heterocyclic group represented by the aforementioned R 1 Among them, the same as those bonded to X 3 via a ring-constituting atom can be mentioned.
  • an aromatic 5-membered heterocyclic group containing 2 to 3 hetero atoms eg, an oxygen atom, a nitrogen atom, and a sulfur atom is preferable.
  • Z 2 represents a nitrogen-containing unsaturated heterocyclic group which may be substituted, which is bonded at a constituent nitrogen atom.
  • the nitrogen-containing unsaturated heterocyclic group of the optionally substituted nitrogen-containing unsaturated heterocyclic group include unsaturated heterocycles containing one or more nitrogen atoms as ring-constituting atoms.
  • an unsaturated heterocyclic group examples include, for example, imidazole-1-yl, pyrazole-11-yl, 1,2,4-triazole-11-yl, 1,2,2 4-triazole-4-yl, 1, 2, 3-triazole-1-yl, 1, 2, 3-triazo-l 2-yl, pyro-l-l-yl, tetrazo-l-l 1-yl, 2-pyrroline-1-yl, 3-pyrroline-1-yl, 2-imidazoline-111-yl, 2-pyrazolin-1-1-yl, 3-pyrazolin-l-yl, etc.
  • a membered nitrogen-containing unsaturated heterocyclic group is preferable, and these may form a condensed ring (eg, benzimidazole-1-yl, indole-1-yl, 1H-indazole-1 —Yl, benzotriazole— 1-yl, benzotriazole—2-yl, isoindoyl 2-yl, 7-purinyl, 1H-pyrro [1 , 2—a] Imidazole—11-yl, 1 H—pyro mouth [1, 2— b] [1,2,4] triazo-1-yl, 1,8a-dihydroimidazo [1,2-a] pyridine-1-yl, 1,8a-dihydro [1,2,4 ] Triazolo [1,5-a] pyridine-1-yl, 3,3a-dihydro [1,2,4] triazolo [1,5-a] pyrimidine_3-yl, 1,8a-dihydro Imidazo [
  • a group represented by the formula — (CH 2 ) Z — Z 3 is a preferred example.
  • z is an integer of 1 to 4
  • Z 3 is a formula —N (R 5 ) (R 6 ) wherein R 5 and R 6 are the same or different, and are hydrogen or substituted Or an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group, or R 5 and R 6 may be bonded to each other to form an optionally substituted heterocyclic group.]
  • an optionally substituted amino group is optionally substituted amino group.
  • heterocyclic group of the hydrocarbon residue or the optionally substituted heterocyclic group in the optionally substituted hydrocarbon residue represented by R 5 and R 6 each of those exemplified for R 1 described above is exemplified.
  • the same as the hydrocarbon residue in the optionally substituted hydrocarbon residue or the heterocyclic group in the optionally substituted heterocyclic group can be mentioned.
  • R 5 and R 6 may combine with each other to form a ring.
  • _N (R 5 ) (R 6 ) include, for example, 1-pyrrolidinyl, 1 _imidazolidinyl, 1-pyrazolidinyl , 1-piperidyl, piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, homopyrazine-111, 1,2,4-triazole- 1-yl, 1,3,4-triazole — 1-yl, 1-pyrazol, 1-yl, imidazole-1-yl, 1, 2, 3 _triazo-1-yl, 1,2,3-triazol 2-yl, tetrazol-1 _ Yl, benzimidazo 1-ruil, India, 1-ruil, 1H-indazol-11-yl and the like.
  • These rings may have 1 to 3 substituents at any substitutable position on the ring.
  • substituents include the same ones as those exemplified as the substituent on the optionally substituted hydrocarbon residue and the optionally substituted heterocyclic group represented by R 1 .
  • the substituent may further have a substituent, and the substituent which may further have a substituent may further have a substituent in the above-described substituent of the hydrocarbon residue or the heterocyclic group. The same substituents as those described above may be used.
  • the hydrocarbon residue and the heterocyclic group represented by R 5 and R 6 may have 1 to 3 substituents at any substitutable position on the chain or the ring.
  • substituents include the same as those exemplified as the substituent on the optionally substituted hydrocarbon residue and the optionally substituted heterocyclic group represented by R 1 .
  • the substituent may further have a substituent, and as the substituent which may further have a substituent, the substituent of the above-mentioned hydrocarbon residue or heterocyclic group further has a substituent. And the same substituents as those described above.
  • examples of the optionally substituted heterocyclic group represented by R 4 are the same as the examples of the optionally substituted heterocyclic group represented by R 1 described above. Things.
  • R 4 specific examples of the optionally substituted amino group represented by R 4 include the formula: N (R 5 ) (R 6 ) wherein R 5 and R 6 are as defined above. And having the same meaning as above].
  • examples of the optionally oxidized sulfur atom represented by X 1 or X 2 include a thio group, a sulfinyl group and a sulfonyl group, and a thio group is particularly preferable. .
  • the carboxyl group which may be esterified and represented by G or G ′ includes (i) a carbonyl group, (ii) a carboxyl group and 1 to 6 carbon atoms.
  • alkoxyl propyl such as methoxycarbonyl, ethoxycarbonyl, propoxyl propyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.
  • those in which a carboxyl group is bonded to an alkenyl group having 3 to 6 carbon atoms ie, alkenyloxycarbonyl, For example, allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyloxycarbonyl, etc.
  • alkenyloxycarbonyl For example, allyloxycarbonyl, croty
  • the aralkyl group in the aralkyloxycarbonyl group means an alkyl group having an aryl group as a substituent (arylalkyl group).
  • arylalkyl group e.g., phenyl, etc. naphthyl and the like, even if they have a same substituents having good multi heterocyclic group optionally substituted represented by R 1 Good.
  • the alkyl group a lower alkyl group having 1 to 6 carbon atoms is preferable.
  • aralkyl group examples include, for example, benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like, among which benzyl, phenethyl and the like are preferable.
  • the amidated carboxyl group represented by G is one C ON (R 7 ) (R 8 ) (wherein R 7 and R 8 have the same meanings as R 5 and R 6 above) ).
  • the acyl group represented by G is a formyl group or a formula
  • R 9 represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an aryl group having 6 to 14 carbon atoms.
  • R 9 represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an aryl group having 6 to 14 carbon atoms.
  • R 9 represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an aryl group having 6 to 14 carbon atoms.
  • G is a hydroxyalkyl group
  • ⁇ alkyl group of such hydroxyalkyl group an alkyl group having 1 to 8 carbon atoms include among shown as examples of the hydrocarbon residue represented by R 1.
  • the hydroxyalkyl group is preferably —CH 7 OH or —CH (OH) —R 10 (R 10 is represented by R 1 above.
  • Examples of the hydrocarbon residue include an alkyl group having 1 to 7 carbon atoms. ).
  • R 1 Q in this formula is preferably methyl, ethyl and the like.
  • G is a protected hydroxyalkyl group
  • the protected hydroxy in this group has the formula —CHzOCOR 11 or 1 CH (OC ⁇ R 12 ) —R 10 (where R 10 is as defined above, R 11 and R 12 each represent an alkyl group, an aralkyl group or an aryl group which may have a substituent.
  • R 11 and R 12 each represent an alkyl group, an aralkyl group or an aryl group which may have a substituent.
  • the alkyl group represented by R 11 and R 12 an alkyl group having 1 to 6 carbon atoms, e.g., methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec- heptyl, tert- butyl and the like.
  • the ⁇ aralkyl group represented by R 11 and R 12 means such as Ce-i 4 Ariru alkyl group having 1 to 4 carbon atoms group as a substituent (Ce ⁇ . ⁇ Li one Roux alkyl group).
  • the C 6 - The 10 Ariru group e.g., phenyl, naphthyl and the like.
  • As the ⁇ La alkyl group e.g., benzyl, phenethyl, 3-phenylpropyl, (1 one-naphthyl) methyl, (2- Naphthyl) methyl and the like.
  • G ′ is a halogen atom
  • examples of such a halogen atom include chlorine, bromine, iodine, and fluorine, preferably chlorine or bromine.
  • R 12 is hydrogen, an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group, and z 4 is an optionally substituted hydrocarbon residue.
  • a heterocyclic group which may be substituted or an amino group which may be substituted, and other symbols have the same meanings as described above.
  • examples of the optionally substituted hydrocarbon residue and the optionally substituted heterocyclic group represented by R 12 and Z 4 include those exemplified as R 1 described above. And the same.
  • Specific examples of the optionally substituted amino group represented by z 4, can be mentioned those similar to those of the optionally substituted amino group represented by Z 3 described above.
  • R 2 and R 3 may be bonded to each other to form a 5- to 7-membered ring formed with a carbon atom on the adjacent thiophene ring (that is, a vinylene group).
  • the 5- to 7-membered ring formed by bonding R 2 and R 3 to each other includes (i) a C 5 _ 7 alicyclic hydrocarbon group, or (ii) 1 to 4 oxygen atoms, 1 to 4 sulfur atoms which may be oxidized or C which may be substituted. Examples thereof include a 5- to 7-membered heterocyclic group containing one nitrogen atom which may be substituted with alkyl (preferably Ci- 4 alkyl).
  • R 2 and R 3 moiety of the 5-7 membered ring to which R 2 and R 3 are bonded to each other to form the
  • M is a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted acyl group, an optionally substituted sorbamoyl group, an optionally substituted It represents a thiocarbamoyl group or an optionally substituted sulfonyl group.
  • Examples of the optionally substituted hydrocarbon residue represented by M include the same as the optionally substituted hydrocarbon residue represented by R 1 .
  • the optionally substituted hydrocarbon group which may be substituted represented by M Ji optionally substituted E - 4 alkyl group (e.g., methyl, Echiru, isopropyl, propyl, heptyl, benzyl, phenethyl, 2- , 3- or 4-pyridylmethyl, a C alkyl group which may be substituted with a phenyl group, etc.).
  • Examples of the optionally substituted acyl group represented by M include those exemplified as the acyl group as a substituent of the optionally substituted hydrocarbon residue and heterocyclic group represented by R 1 above. And the same acyl group.
  • Examples of the optionally substituted carbamoyl group represented by M include those represented by R 13 NHC 0— (R 13 is as defined above for R 1 ).
  • Examples of the optionally substituted thiocarbamoyl group represented by M include those represented by RNHCS— (R 13 has the same meaning as R 1 above).
  • Embedded image As the optionally substituted sulfonyl group represented by M, Embedded image (R 13 is as defined above for R 1 ).
  • Examples of the optionally substituted hydrocarbon residue represented by M include a (: toe. Alkyl group [especially, alkyl (eg, methyl, ethyl, propyl, isopropyl, etc.)] or a phenyl group. Good C Kill groups are preferred.
  • the phenyl group as a substituent on the chain of the optionally substituted C 4 alkyl group represented by M further has one or more, preferably 13 substituents at any substitutable position.
  • the substituent may be the same as the substituents on the hydrocarbon residue and the heterocyclic group represented by R 1.
  • Lower alkoxycarbonyl groups eg, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.
  • hydroxyl group eg, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.
  • phenyl C ⁇ alkyl eg, benzyl, phenethyl, 4-methoxybenzyl, etc.
  • the optionally substituted 5- to 7-membered ring (—R 2 —R 3 —) formed by bonding R 2 and R 3 to each other one CH 2 —N (CH 3 ) —CH 2 —CH 2 —, — CH 2 -N (one CH 2 _C 6 H 5 ) _CH 2 — CH 2- , one CH 2 — N (-CH 2 -B-OCH3) one CH 2 — CH 2 _ (B is p— shows a phenylene group), - CH 2 - NH- CH 2 _CH 2 - and the like are preferable.
  • R 2 and R 3 are both methyltransferase group
  • R 2 and R 3 are each other Ini bonded to over R 2 - R 3 _ is _CH 2 - N (M) —CH 2 —CH 2 — (M is a hydrogen atom, C i_ 3 alkyl or benzyl) and a 6-membered ring containing a nitrogen atom.
  • ring A and ring B may have a substituent, and examples of such a substituent include a halogen atom, a nitro group, and an optionally substituted C i.
  • An alkyl group may be substituted.
  • Alkynyl group, a hydroxy group which may be substituted, an optionally substituted thiol group, an optionally substituted amino group, optionally substituted Ashiru group (for example, C physician 10 Arukanoiru groups, C 2 - 0 Arukenoiru group, C 2 - 10 Arukinoiru group), is optionally esterified carboxyl group or replacement even though which may be aromatic ring group used.
  • halogen shown as a substituent on ring A and ring B examples include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferred.
  • the alkyl group may be any of linear alkyl having 1 to 10 carbons, branched alkyl having 3 to 10 carbons, and cyclic alkyl having 3 to 10 carbons, such as methyl, ethyl, propyl, and the like.
  • alkynyl group may be a hydrocarbon residue represented by R or Z 1 and a heterocyclic ring at any substitutable position.
  • the group may have 1 to 3 substituents similar to the substituents described above.
  • the optionally substituted hydroxyl group shown as the substituent for ring A and ring B include ( ⁇ ) a hydroxyl group, and (ii) an appropriate substituent for the hydroxyl group, particularly one used as a protective group for the hydroxyl group.
  • Hydroxyl groups for example, alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acysiloxy, aryloxy, etc.).
  • alkoxy examples include alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, Pentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.).
  • alkoxy having 1 to 10 carbon atoms eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, Pentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.
  • alkenyloxy examples include alkenyloxy having 2 to 10 carbon atoms (eg, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexyl). Xenilmethoxy).
  • the alkynyloxy includes alkynyloxy having 2 to 10 carbon atoms.
  • aralkyloxy examples include phenyl Ci- 4 alkoxy (eg, benzyloxy, phenethyloxy, etc.).
  • an alkanoyloxy having 2 to 4 carbon atoms eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.
  • acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc. is preferable.
  • aryloxy examples include phenoxy, 4-chlorophenoxy and the like.
  • the optionally substituted thiol groups shown as the substituents on ring A and ring B include (i) a thiol group, and (ii) an appropriate substituent for the thiol group, in particular, protection of the thiol group.
  • a thiol group for example, alkylthio, alkenylthio, alkynylthio, aralkylthio, acetylsilthio, arylthio and the like having the one used as a group can be mentioned.
  • alkylthio examples include alkylthio having 1 to 10 carbon atoms (eg, methylthio).
  • O ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio Are preferred.
  • alkenylthio examples include alkenylthio having 2 to 10 carbon atoms (eg, allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio, 2-cyclopentenylmethylthio, and 2-cycloalkyl). Hexenylmethylthio).
  • alkynylthio examples include alkynylthio having 2 to 10 carbon atoms (eg, ethylthio, 2-propynylthio, etc.).
  • Ararukiruchio for example phenylene Lou C Bok 4 alkylthio (e.g., benzylthio, etc. Fuenechiruchio) and the like.
  • an alkanolthio having 2 to 4 carbon atoms eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.
  • acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc. is preferable.
  • arylthio examples include phenylthio, 41-cloth phenylthio and the like.
  • the optionally substituted amino group shown as a substituent on ring A and ring B includes (i) an amino group, and (ii) an alkyl having 1 to 10 carbons, and an alkyl having 2 to 10 carbons.
  • the optionally substituted sacyl groups shown as substituents for ring A and ring B include (i) formyl, and (ii) alkyl having 1 to 10 carbons and alkenyl having 2 to 10 carbons. Alkynyl having 2 to 10 carbon atoms or aromatic group having 6 to 12 carbon atoms bonded to a carbonyl group (eg, acetyl, propionyl, petite) Ryl, isobutyryl, valeryl, isovaleryl, bivaloyl, hexanoyl, heptanyl, octanoyl, cyclobutanecarbonyl, cyclopentane, luponyl, cyclohexane, luponyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinyl, etc. Are listed.
  • Examples of the optionally esterified carbonyl represented by the substituents of ring A and ring B include (i) a carboxyl group, and (ii) a carbonyl group having 1 to 6 carbon atoms.
  • alkoxycarbonyl for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec_butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl
  • a carboxyl group bonded to an alkenyl group having 3 to 6 carbon atoms ie, alkenyloxycarbonyl, for example, allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxy
  • Carbonyl 3-hexenyloxycarbonyl
  • aromatic hydrocarbon residues e.g., phenyl, naphthyl, anthryl, etc.
  • heterocyclic aromatic Group residues eg, pyridyl, furyl, chenyl, imidazolyl, thiazolyl, etc.
  • Such substituents on ring A and ring B may be substituted at any substitutable position on each ring, and may be substituted with 1 to 4 identical or different groups.
  • the adjacent substituents are linked to form one (CH 2 ) t — or — O— (CH 2 ), — O— (where And t is an integer of 3 to 5, and 1 is an integer of 1 to 3), and such a ring may be formed together with a carbon atom of a benzene ring.
  • ring A is substituted with at least one alkoxy group (preferably a -3alkoxy group), more preferably at least one methoxy. More preferably, ring A is substituted with two identical or different alkoxy groups (preferably Ci 3 alkoxy groups), preferably methoxy. Specifically, for example, it is particularly preferable that ring A is substituted with two methoxy groups at the 6-position and the 7-position of the quinoline ring or the quinazoline ring.
  • ring B is substituted with at least one alkoxy group (preferably (3 ⁇ 3 alkoxy group), more preferably at least one methoxy or isopropoxy. More preferably, ring B is the same or It is substituted by two different alkoxy groups (preferably c ⁇ 3 alkoxy groups), for example, ring B is replaced by a methoxy or isopropoxy group at position 3 and at position 4 Particularly preferred is a case where the compound represented by the above formula [II] has at least one alkoxy group (preferably an alkoxy group), more preferably at least one methoxy or isopropoxy group. More preferably, ring D is
  • ring D is substituted at the 4-position with a methoxy group.
  • Y is C—G ′ ′′ (G ′ ′′ represents a carboxyl group which may be esterified), and R 1 has a substituent.
  • be 4 are substituted in good nitrogen-containing unsaturated heterocyclic group optionally alkyl group (provided that is bound to the C Bok 4 alkyl group Te constituting nitrogen atom smell of nitrogen-containing unsaturated heterocyclic group) And a compound in which n is 0.
  • R 2 and R 3 are particularly preferably bonded to form an optionally substituted 5- to 7-membered ring.
  • R 2 and R 3 are Bond with each other to form a 5- to 7-membered ring formed with a hydrogen atom on the adjacent thiophene ring (that is, a vinylene group), and G 'of C-G' represented by W represents a Haguchigen atom Compounds.
  • a pharmaceutically acceptable salt is preferable, for example, a salt with an inorganic base, a salt with an organic base, and an inorganic acid. And salts with organic acids, salts with basic or acidic amino acids, and the like.
  • the salt with the inorganic base include alkali metal salts (eg, sodium Salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), aluminum salts, ammonium salts and the like.
  • Preferred examples of the salt with the organic base include, for example, trimethylamine, tritylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, ⁇ ′-dibenzylethylenediamine and the like. And salts thereof.
  • salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • 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, ⁇ — And salts with toluenesulfonic acid and the like.
  • Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
  • Preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, etc. Is mentioned.
  • sodium salts and potassium salts are most preferred.
  • quinoline or quinazoline derivative, thienopyridine or chenobilimidine derivative or a salt thereof in the present invention may be a hydrate.
  • the quinoline or quinazoline derivative or the thienopyridine or chenobilimidine derivative in the present invention is described in, for example, Japanese Patent Application Laid-Open No. Hei 6-30652 (European Patent Application Publication No. 5- 5-56771).
  • Kaihei 7—1 1 8 2 6 6 Publication ( ⁇ ⁇ — ⁇ -6 880 7 0 Publication), Japanese Unexamined Patent Publication No. 7-69890 ( ⁇ ⁇ —A— 6 3 4 1 6 9 )
  • Japanese Patent Application Laid-Open No. 8-535419 Japanese Patent Application Laid-Open No. 6-86630
  • a water-soluble polymer compound is suitable as the gel-forming substance contained in the sustained-release oral preparation of the present invention.
  • the water-soluble polymer compound is preferably about 2 to 360 mPa's, more preferably about 2 to 400 mPa's, and still more preferably 2 to 150 mPa-s.
  • a compound having a viscosity of 2% (W / W) aqueous solution in terms of dry matter (measured under conditions of 20 ° C. ⁇ 0.1 ° C.) is preferred.
  • the water-soluble polymer compound include a cellulose derivative, a polyvinyl polymer compound, and a polyhydric alcohol.
  • cellulose derivative examples include hydroxypropyl methylcellulose (eg, grade TC-5EW (viscosity: 2-4 mPa's), TC-5 MW (viscosity: 3-6 mPa-s), TC-5 (Viscosity: 4 to 8 iPa-s), TC-5S (viscosity 12 to 18 mPa-s), 60 SH—50 (viscosity: 40 to 60 mPa's), 65 SH-50 ( Viscosity: 40 to 60 mPa's), 65 SH—400 (viscosity: 320 to 480 mPa's), 90—SH400 (viscosity: 320 to 480 mPa-s), 90 SH-30 00F (viscosity: 2400 to 360 000 mPa's)], hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, croscarmellose sodium, carmellose calcium and the like.
  • polyvinyl polymer examples include polyvinylpyrrolidone and carboxyvinyl polymer.
  • polyhydric alcohol a polyhydric alcohol which is solid at 25 ° C. is used herein, and examples thereof include polyethylene glycol (preferably a polyhydric alcohol having an average molecular weight of about 8,000 to 700,000). Tylene glycol), polypropylene alcohol, polyglycerin and the like.
  • the gel-forming substance preferably a cellulose derivative, more preferably hydroxypropylmethylcellulose or hydroxypropylcellulose, more preferably hydroxypropylmethylcellulose is used.
  • saccharides are preferable.
  • the saccharides include sugar alcohols (eg, erythritol, sorbitol) , Mannitol, maltitol, xylitol, reduced starch saccharified product, reduced paratinose, etc.), monosaccharides (eg, glucose, mannose, xylose, galactose, evening lose, etc.), polysaccharides (eg, maltose) , Lactose (lactose). Sucrose and the like.
  • Erythritol or sorbitol is more preferably used as the saccharide.
  • the oral sustained-release preparation of the present invention further comprises (3) a disintegration aid, (1) quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative: (2) gel-forming substance: (3) disintegration aid It is preferable to use an amount of about 1: about 0.1 to about 50: about 0.01 to about 50 by weight, and about 1: about 0.1 to about 50: about 0 by weight. It is more preferable to use an amount of from about 0.5 to about 30, and most preferably from about 1: about 0.2 to about 20: about 0.:! To 20 by weight.
  • the gel-forming substance is preferably at least about 10% by weight, more preferably about 10 to 99.9% by weight, more preferably about 10% by weight, based on the whole preparation. 15 to 95% by weight, particularly preferably about 20 to 90% by weight.
  • the disintegration aid is preferably about 1% by weight or more, more preferably about 1 to 90% by weight, and still more preferably about 3 to 90% by weight, based on the whole preparation. 70% by weight, particularly preferably about 5 to 50% by weight, and most preferably about 5 to 23% by weight.
  • the sustained release oral preparation of the present invention is formed into, for example, tablets, granules and the like. Capsules containing granules may also be used. At that time, the gel-forming substance and the disintegration aid may be blended inside the preparation or coated on the preparation surface. Sustained-release oral tablets are prepared by mixing the active ingredient and other pharmaceutical additives and then directly pressing (tableting), or once pressing, granulating and granulating and pressing. Tablets) can also be obtained. Alternatively, after granulating a mixture containing the active ingredient and the excipient into a sized powder, other pharmaceutical ingredients may be mixed and tableted.
  • the granulated powder can be prepared by a conventional method such as a wet granulation method and a dry granulation method using a binder.
  • Preferred granulated powder is obtained by a wet granulation method, for example, a stirring granulation method, a fluidized granulation method and the like.
  • the average particle size of the granulated powder is, for example, about 0.1 to 200 m, and more preferably about 10 to 500 m.
  • the tablet of the present invention can be formulated according to a generally used method known per se.
  • a pharmaceutically acceptable carrier can be blended with the drug used in the present invention and formed into a tablet.
  • the pharmaceutically acceptable carrier various organic or inorganic carrier materials commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants and the like are compounded. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.
  • these pharmaceutically acceptable carriers are the aforementioned gel-forming substances or compounds having an action as a disintegration aid, the compounding ratio and the compounding ratio in the oral preparation of the present invention are as follows: It shall be calculated by adding the compounding amount of the compound.
  • Preferable examples of the excipient include lactose, sucrose, D-mannitol, erythritol, starch, crystalline cellulose, light caffeic anhydride and the like.
  • Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, arsenic starch, partially pregelatinized starch, sucrose, D-mannitol, trehalose, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like. Is mentioned.
  • crystalline cellulose is used.
  • Preferred examples of the disintegrant include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethylstarch, and low-substituted hydroxypropylcellulose. Lulose and the like.
  • a preparation for oral administration can be prepared by coating in a manner known per se for the purpose of taste masking, enteric coating or sustaining.
  • the coating agent include hydroxypropyl methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Bull Mouth Nick F68, cellulose acetate phthalate, and hydroxypropylmethylcellulose. Evening rate, hydroxymethyl cellulose acetate succinate, Eudragit (manufactured by ROHM, Germany, methacrylic acid / acrylic acid copolymer) and the like.
  • preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • the antioxidant include, for example, sulfite and ascorbic acid.
  • the coloring agent include titanium oxide, iron sesquioxide (red iron), and edible pigments.
  • Sweetening agents include aspartame, saccharin sodium, dipotassium glycyrrhizinate, stevia and the like.
  • the sustained release oral preparation of the present invention when produced as a granule, (1) quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative and (2) a gel-forming substance, and if necessary, (3) a disintegration aid After mixing, the mixture is kneaded, granulated, dried and sized using a binding solution dissolved in an appropriate solvent in a conventional manner to produce granules.
  • the granules can be filled into capsules to make capsules.
  • the release period of the drug can be appropriately adjusted by the amount of the gel-forming substance and the like, or the amount of the gel-forming substance and the disintegration aid and the like.
  • the sustained release oral preparation of the present invention usually exhibits a sustained release time of about 1 to 48 hours, preferably about 1 to 24 hours, more preferably about 3 to 24 hours.
  • quinoline or a quinazoline derivative, a cynopyridine or a thienopyrimidine derivative or a salt thereof has an anti-inflammatory effect.
  • the sustained-release oral preparation of the present invention can be used as an agent for preventing or treating all arthritis exhibiting inflammatory symptoms in joints.
  • arthritis include rheumatoid arthritis.
  • the sustained-release oral preparation of the present invention can be used as a prophylactic or therapeutic agent for rheumatism or the like.
  • the sustained-release oral preparation of the present invention provides a bone destruction associated with arthritis, a bone resorption inhibitor, and a bone coarser. It can be used as a prophylactic and therapeutic agent for porosis and the like.
  • the sustained-release oral preparation of the present invention can be used to prevent diseases that are considered to be involved in immunity. It can be used as a therapeutic agent or as a preventive and therapeutic agent for rejection after Z and organ transplantation.
  • a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative or a salt thereof produces an immunomodulatory effect or an immune cytokine [eg, interleukin-12 (IL-2), inferon-feron-a (IFN- ⁇ ), etc.).
  • an immune cytokine eg, interleukin-12 (IL-2), inferon-feron-a (IFN- ⁇ ), etc.
  • the sustained-release oral preparation of the present invention can be used as a prophylactic or therapeutic agent for diseases considered to be involved in immunity including autoimmune diseases.
  • target diseases include, for example, systemic erythematosus, inflammatory bowel disease (ulcerative colitis, Crohn's disease), multiple sclerosis, psoriasis, chronic hepatitis, bladder cancer, breast cancer, cervical cancer, chronic lymphoid disease Leukocytes, chronic myelogenous leukemia, colorectal cancer, colon cancer, rectal cancer, Helicobacter pylori infection, Hodgkin's disease, insulin-dependent diabetes mellitus, malignant melanoma, multiple myeloma, non-Hodgkin's lymphoma, non-small cell Lung cancer, ovarian cancer, peptic ulcer, prostate cancer, septic shock, tuberculosis, infertility, atherosclerosis, Behcet's disease, asthma, atopic dermatitis, nephritis, whole body sexually transmitted fungal infection, acute bacterial meningitis, acute myocardial infarction, acute inflammation, acute viral
  • the sustained-release oral preparation of the present invention includes systemic erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, localized ileitis or multiple sclerosis, etc. It is used as a prophylactic or therapeutic agent.
  • the oral preparation of the present invention has low toxicity, it can be safely used for mammals (eg, humans, cows, peas, pigs, dogs, cats, mice, rats, rabbits, etc.).
  • mammals eg, humans, cows, peas, pigs, dogs, cats, mice, rats, rabbits, etc.
  • the sustained-release oral preparation of the present invention is used as a highly efficacious preparation because it releases a fixed amount of a drug over a long period of time and thus provides stable drug efficacy.
  • the dosage of the sustained-release oral preparation of the present invention varies depending on the type, content, dosage form, administration target animal, etc. of the quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative contained therein.
  • Adults (assuming a body weight of 50 Kg) can administer about 10 to 50 Omg per person 3 times a day or once a day.
  • the present invention will be described more specifically with reference to Examples, Reference Examples, and Experimental Examples, but the present invention is not limited thereto.
  • Compound A 400 g, hydroxypropyl methylcellulose (grade T C- 5MW, Shin-Etsu Chemical Co., Ltd.) 324 g and erythritol 40 g were tumbled into a fluidized granulator (MP-10, manufactured by PALEC), supply air temperature 65 ° C, atomization speed 19 g Under the conditions of / min, fluidized granulation was performed while spraying 400 g of 10% by weight of hydroxypropylmethylcellulose.
  • MP-10 fluidized granulator
  • the tablets were sized using a power mill (Showa Giken Co., Ltd., P-3) with a panning size of 1.5 mm ⁇ .
  • the rectified powder thus obtained was again used with a tableting machine (Correct 19 K AWC, manufactured by Kikusui Seisakusho) to produce 429 mg tablets per tablet with a 1 Ommci) corner punch (tableting pressure 1.0 tonZ Pestle)
  • a tableting machine Correct 19 K AWC, manufactured by Kikusui Seisakusho
  • the product is dried to a product temperature of 33 ° C, 600 g of the granulated powder is weighed, and 15 g of crystalline cellulose (grade Avicel PHI 01, manufactured by Asahi Kasei Corporation), light gay anhydride (grade Silica 320, grade) 6.1 g of YK F) and 6.1 g of magnesium stearate were added and mixed.
  • crystalline cellulose grade Avicel PHI 01, manufactured by Asahi Kasei Corporation
  • light gay anhydride grade Silica 320, grade
  • 6.1 g of YK F 6.1 g of magnesium stearate
  • the tablets were sized using a paper mill (Showa Giken Co., Ltd., P-3) with a punching size of 1.5 mm ⁇ i).
  • the obtained rectified powder was again used with a tableting machine (Correct 19K AWC, manufactured by Kikusui Seisakusho) to obtain a tablet of 400 mg per tablet with a 10 mm ⁇ corner punch. to nZ punch). Examples 3 to 6
  • Compound A 2 g Hydroxypropylmethylcellulose 1.42 g (grade TC-5 MW), crystalline cellulose (grade Avicel PH 101, manufactured by Asahi Kasei Corporation) 10 Omg, light silicic anhydride (grade Silica 320) , YK F Co., Ltd.) 40 mg, magnesium stearate 4 Omg, additive 40 mg [lactose (Example 13), croscarmellose sodium (Axidisol, Asahi Kasei Corporation) (Example 14) ), Low-substituted hydroxypropyl cellulose (grade LH-31) (Example 15), carmellose calcium Pum (grade ECG-505) (Example 16) was weighed and mixed in a mortar. The mixed powder (40 Omg) was weighed and tableted using a universal testing machine (Shimazu Seisakusho) with a 10 mm ⁇ corner punch at a tableting pressure of 1.0 to nZcm 2 to produce tablets.
  • Compound A 478.9 g, lactose, 21.8 g, and corn starch, 127.9 g, were charged into a tumbling fluidized-granulator (MP-10, manufactured by PALEK), and the air supply temperature was 70 ° C and the spray rate Under the condition of 10 gZmin, fluid granulation was performed while spraying 520 g of a 6% by weight aqueous solution of hydroxypropyl cell mouth. After granulation, the product was dried to a product temperature of 45 ° C, and the dried product was pulverized with a power mill (Showa Giken Co., Ltd., P-3, punch size 1.2 ⁇ ) to obtain sized powder.
  • MP-10 tumbling fluidized-granulator
  • Example 4 The disintegration time of the tablets produced in Examples 4, 13, 14, 14, 15 and 16 was examined using a disintegration tester (Toyama Sangyo Co., Ltd.) without a disc according to the Japanese Pharmacopoeia collapse test method.
  • the tablet obtained in Example 4 has 160 minutes
  • the Example 13 tablet has 130 minutes
  • the Example 14 tablet has 90 to 120 minutes
  • the Example 15 tablet has 140 minutes.
  • the time of the tablet of Example 16 was 130 minutes.
  • Each tablet obtained in Reference Example 1 and Examples 1 to 12 was precisely weighed (WT), and a 0.6% aqueous sodium lauryl sulfate (SLS) solution (900 ml) was used. The test was conducted at 50 rpm according to the paddle method. Over time, 2 ml of the sample was sampled, filtered through a 0.45 m membrane filter, 1 ml was accurately measured, and 8 ml of the mobile phase was accurately measured and diluted to obtain a sample solution. Separately, 0 mg of Compound A was precisely weighed (WS), and the mobile phase was added to make exactly 100 ml. 1 ml of this solution was accurately measured, and 8 ml of the mobile phase was accurately measured and diluted to obtain a standard solution.
  • WT 0.6% aqueous sodium lauryl sulfate
  • Acetonitrile (48 g) was added dropwise to a mixture of a 1.6 M solution of n-butyllithium in hexane (728 ml) and tetrahydrofuran (900 ml) at 170 ° C. After stirring at 170 for 20 minutes, a solution of 4-methoxybenzoyl chloride (100 g) in tetrahydrofuran (200 ml) was added dropwise at the same temperature. The reaction mixture was further stirred at the same temperature for 30 minutes, and then acidified with 4N hydrochloric acid.
  • the oral preparation of the present invention has excellent sustained-release properties, it can be advantageously used as a sustained-release oral preparation in terms of smoothing the blood concentration, maintaining the effect, and preventing side effects.
  • the oral preparation of the present invention since the oral preparation of the present invention has good flowability of the granulated product during its production, tableting properties are improved.
  • the release of the drug can be controlled, in particular, controlled release.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On produit ces préparations à administrer par voie buccale à libération lente en mélangeant (1) un dérivé de la quinoléine ou de la quinazoline ou un dérivé de thiénopyridine ou de thiénopyrimidine à (2) une substance gélifiante et, éventuellement, à une substance facilitant la désagrégation.
PCT/JP1999/005046 1998-09-18 1999-09-16 Preparations a administrer par voie buccale a liberation lente WO2000016776A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56521/99A AU5652199A (en) 1998-09-18 1999-09-16 Sustained release oral preparations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP26523498 1998-09-18
JP10/265234 1998-09-18

Publications (1)

Publication Number Publication Date
WO2000016776A1 true WO2000016776A1 (fr) 2000-03-30

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PCT/JP1999/005046 WO2000016776A1 (fr) 1998-09-18 1999-09-16 Preparations a administrer par voie buccale a liberation lente

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003018590A1 (fr) * 2001-08-24 2003-03-06 Takeda Chemical Industries, Ltd. Procede de production d'un derive de la thienopyridine
WO2004067001A1 (fr) * 2003-01-29 2004-08-12 Takeda Pharmaceutical Company Limited Procede pour realiser une preparation enrobee
JP2005220024A (ja) * 2003-01-29 2005-08-18 Takeda Chem Ind Ltd 被覆製剤の製造方法
CN1761465B (zh) * 2003-01-29 2010-10-13 武田药品工业株式会社 制备被覆制剂的方法
US8637079B2 (en) 2007-02-01 2014-01-28 Takeda Pharmaceutical Company Limited Solid preparation comprising alogliptin and pioglitazone

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH069388A (ja) * 1992-06-24 1994-01-18 Kodama Kk 徐放性塩酸オキシブチニン製剤
JPH07118266A (ja) * 1993-01-28 1995-05-09 Takeda Chem Ind Ltd キノリンまたはキナゾリン誘導体およびそれらを含んでなる医薬
JPH09136845A (ja) * 1986-07-18 1997-05-27 Euro Celtique Sa 徐放性経口医薬用組成物及びその調製基剤並びに前記組成物の製造方法
JPH1017497A (ja) * 1996-07-02 1998-01-20 Takeda Chem Ind Ltd 徐放性製剤およびその製造方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09136845A (ja) * 1986-07-18 1997-05-27 Euro Celtique Sa 徐放性経口医薬用組成物及びその調製基剤並びに前記組成物の製造方法
JPH069388A (ja) * 1992-06-24 1994-01-18 Kodama Kk 徐放性塩酸オキシブチニン製剤
JPH07118266A (ja) * 1993-01-28 1995-05-09 Takeda Chem Ind Ltd キノリンまたはキナゾリン誘導体およびそれらを含んでなる医薬
JPH1017497A (ja) * 1996-07-02 1998-01-20 Takeda Chem Ind Ltd 徐放性製剤およびその製造方法

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003018590A1 (fr) * 2001-08-24 2003-03-06 Takeda Chemical Industries, Ltd. Procede de production d'un derive de la thienopyridine
WO2004067001A1 (fr) * 2003-01-29 2004-08-12 Takeda Pharmaceutical Company Limited Procede pour realiser une preparation enrobee
JP2005220024A (ja) * 2003-01-29 2005-08-18 Takeda Chem Ind Ltd 被覆製剤の製造方法
CN1761465B (zh) * 2003-01-29 2010-10-13 武田药品工业株式会社 制备被覆制剂的方法
JP4567340B2 (ja) * 2003-01-29 2010-10-20 武田薬品工業株式会社 被覆製剤の製造方法
US7976853B2 (en) 2003-01-29 2011-07-12 Takeda Pharmaceutical Company Limited Process for producing coated preparation
US8637079B2 (en) 2007-02-01 2014-01-28 Takeda Pharmaceutical Company Limited Solid preparation comprising alogliptin and pioglitazone

Also Published As

Publication number Publication date
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