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WO1998029136A1 - Compose tricyclique stabilise - Google Patents

Compose tricyclique stabilise Download PDF

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Publication number
WO1998029136A1
WO1998029136A1 PCT/JP1997/004819 JP9704819W WO9829136A1 WO 1998029136 A1 WO1998029136 A1 WO 1998029136A1 JP 9704819 W JP9704819 W JP 9704819W WO 9829136 A1 WO9829136 A1 WO 9829136A1
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Prior art keywords
group
pharmaceutical composition
optionally substituted
acid
dihydro
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PCT/JP1997/004819
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English (en)
Inventor
Soichiro Imoto
Minoru Yoshioka
Toshio Kashihara
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Priority to AU53402/98A priority Critical patent/AU5340298A/en
Publication of WO1998029136A1 publication Critical patent/WO1998029136A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to a stabilized pharmaceutical composition containing the tricyclic compound.
  • ring A' is a nitrogen-containing heterocyclic ring, having two nitrogen atoms as hetero-atoms; ring Q may be substituted;
  • J is an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted mercapto group
  • R a is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group (hereinafter called as the compound (la)) and a salt thereof, have inhibiting activity of platelet derived growth factor (PDGF) action, antihypertensive activity, ameliorating activity of renal diseases and activity of lowering lipid level (Japanese Unexamined Published Application H8( 1996 ) -81467 :W0 96/02542).
  • PDGF platelet derived growth factor
  • Japanese Unexamined Published Patent Application (Tokkyo Kohyo Koho) H7 ( 1995 ) -507809 (WO 94/07488) discloses a method for stabilizing carboxamides which are prone to hydrolysis and easily oxidizable in nonaqueous environments with medium-chain fatty acid triglycerides and Japanese Unexamined Published Patent Application S61 ( 1986 ) -65825 (CA 1272449) describes the solubilization and stabilization of anthralin with plant-derived C 6 . 12 saturated fatty acid triglyceride bases.
  • no report is available on the stabilization of any pharmaceutical composition containing a tricyclic compound.
  • tricyclic compounds which is the tricyclic condensed heterocyclic ring containing nitrogen-atom in which three kind of rings are condensed into, comprising nitrogen-atom at the head of bridge in the condensed ring, for example, the compound (la), especially a compound of the formula (la'): wherein D is an optionally substituted divalent hydrocarbon group;
  • X a is a bond, an oxygen atom or a sulfur atom
  • R a is a hydrogen atom or an optionally substituted hydrocarbon group
  • R a and D may form a ring together with the adjacent nitrogen atom
  • R a and R a may form a ring together;
  • R a is an electron-withdrawing group; and
  • Q and R a are same meanings as defined in the above- formula (la) (hereinafter called as the compound (la')) or a pharmaceutically acceptable salt, whose characteristic feature of the chemical structure lies in the tricyclic condensed heterocyclic ring represented by the formula:
  • the present invention relates to the stabilized pharmaceutical composition containing tricyclic compounds or a pharmaceutically acceptable salt in an oleaginous base. More specifically, example of tricyclic compounds in the present invention, is a tricyclic compound of the formula (I):
  • ring A is a nitrogen-containing heterocyclic ring, having at least one substituent; ring Q may be substituted;
  • R is a hydrogen atom, a halogen atom, an optionally substituted hydroxy group, an optionally substituted hydrocarbon group or an acyl group.
  • preferable examples are the above-compound (la).
  • nitrogen-containing heterocyclic ring used in the present specification means, for example, 5- to 10-membered ring containing, one nitrogen atoms as hetero-atoms . Among them, 5- or 6-membered ring is widely used. These ring may be saturated or unsaturated, and may contain 1 or 2 hetero atoms (e.g. sulfur atom, oxygen atom, nitrogen atom) . More specifically, for example, the following ones
  • N nitrogen-containing heterocyclic rings
  • nitrogen-containing heterocyclic rings may be substituted with 1 or 2 oxo or thioxo groups.
  • divalent hydrocarbon group used in the present specification means, for example, divalent liner hydrocarbon groups including C,_ 15 alkylene groups (e.g. methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, hepta ethylene and octamethylene) , C 2 . ⁇ 6 alkenylene groups (e.g. vinylene, propenylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene and 3-pentenylene) , C 2 _ 16 alkynylene groups (e.g.
  • C,_ 15 alkylene groups e.g. methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, hepta ethylene and octamethylene
  • C 2 . ⁇ 6 alkenylene groups e.g. vinylene, propenylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2-penteny
  • C ⁇ _ 15 alkylene groups e.g. methylene, ethylene, popylene, butylene, pentamethylene, hexamethylene, heptamethylene and octamethylene
  • C 2 _ 16 alkenylene groups e.g. vinylene, propenylene, 1- butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene and 3-pentenylene
  • 16 alkynylene groups (e.g. ethynylene, propynylene, 1-butynylene, 2-butynylene, 1- pentynylene, 2-pentynylene and 3-pentynylene) , are preferable.
  • the said "divalent hydrocarbon group” may contain -N(R 4a )- (R a is a hydrogen atom or an optionally substituted hydrocarbon group) at the terminal or in between.
  • the said "divalent liner hydrocarbon group” optionally have substituents, as those substituents , mention is made of, for example, optionally substituted alkyl groups, optionally substituted aralkyl groups and optionally substituted aryl groups, and optionally substituted alkyl groups are preferable.
  • substituents which "alkyl group”, “aralkyl group” and “aryl group” optionally have, as the substituents of "divalent liner hydrocarbon group” include the substituents of "an optionally substituted hydrocarbon group” as defined after, and numbers of the substituents may range from 1 to 4.
  • the said "phenylene group” may be substituted.
  • substituents which the said "phenylene group” optionally have, mention is made of 1 to 4 selected from, for example, (i) halogen atoms (e.g. fluorine, chlorine, bromine and iodine), (ii) C ⁇ _ 4 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl and butyl), (i ⁇ ) Cj_. 4 alkoxy groups (e.g. methoxy, ethoxy, propoxy and isopropoxy) , (iv) C 4 alkylthio groups (e.g.
  • halogen atoms e.g. fluorine, chlorine, bromine and iodine
  • C ⁇ _ 4 alkyl groups e.g. methyl, ethyl, propyl, isopropyl and butyl
  • Cj_. 4 alkoxy groups e.g. methoxy, ethoxy, propoxy and isopropoxy
  • C ⁇ _ 4 alkoxy- carbonyl groups e.g. methoxycarbonyl , ethoxycarbonyl and propoxycarbonyl
  • sulfone group e.g. C,. 4 alkylsulfonyl groups (e.g. methylsulfonyl, ethylsulfonyl and propylsulfonyl)
  • carbamoyl group and (xviii) mono- or di- C ⁇ _ 4 alkyl-carbamoyl groups e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N,N- diemthylcarbamoyl and N,N-diethylcarbamoyl
  • halogen atom used in the present specification means, for example, fluorine, chlorine, bromine and iodine .
  • hydrocarbon group of the term “optionally substituted hydrocarbon group” used in the present specification means, for example, alkyl group, cycloalkyl group, alkenyl group, aralkyl group and aryl group .
  • substituents which the said "hydrocarbon group” optionally have use is made of, the substituents which the said "alkyl group”, “cycloalkyl group”, “alkenyl group”, “aralkyl group” and “aryl group” optionally have.
  • alkyl group use is made of, for example, "straight-chain or branched C,. 15 alkyl group” such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl , hexyl , heptyl , octyl, nonyl, decyl, undecyl, tridecyl, tetradecyl and pentadecyl .
  • cycloalkyl group use is made of, for example, "C 3 . 8 cycloalkyl group” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • substituents which the said "alkyl group” and “cycloalkyl group” optionally have include (i) nitro group, (ii) hydroxy group, (iii) cyano group, (iv) carba oyl group, (v) mono- or di- C alkyl- carbamoyl groups (e.g. N-methylcarbamoyl, N- ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N- diethylcarbamoyl) , (vi) carboxy group, (vii) C ⁇ _ 4 alkoxy-carbonyl groups (e.g.
  • the said "alkyl group” optionally have 1 to 5 of these substituents at any substituable positions.
  • alkyl group examples include C j _. 6 straight-chain or branched alkyl groups such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl .
  • substituents which the said "C ⁇ _ ⁇ alkyl groups" optionally have, use is made of 1 to 3 of, for example, halogen atoms, C ⁇ _ 4 alkoxy group, hydroxy group, C ⁇ _ 4 alkoxy-carbonyl groups, carboxy group, carbamoyyl group, mono- or di- Cj__ 4 alkylcarbamoyl groups and pyridylthio group.
  • alkenyl group examples include "C 2 . 18 alkenyl groups” such as vinyl, allyl, isopropenyl, 3- butenyl, 3-octenyl and 9-octadecenyl .
  • substituents which the said "alkenyl groups” optionally have use is made of, for example, 1 to 3 substituents selected from the same ones as the above-mentioned substituents which "alkyl group” optionally have.
  • alkenyl group examples include C 2 . 6 alkenyl groups such as vinyl, allyl, 2- butenyl and 3-butenyl.
  • substituents which the said "C 2 . 6 alkenyl groups” optionally have use is made of, for example, 1 to 3 substituents selected from the same ones as the above-mentioned substituents which "Ci.g alkyl group” optionally have.
  • aralkyl group use is made of, for example, C 7 .
  • aralkyl groups which are specifically exemplified by phenyl- C 1-6 alkyl groups such as benzyl, phenethyl, 3-phenylpropyl and 4-phenylbutyl , and naphthyl- Cj_ 6 alkyl group such as ( 1-naphthyl )methyl , 2-(l-naphthyl)ethyl and 2-( 2-naphthyl) ethyl .
  • phenyl- C 1-6 alkyl groups such as benzyl, phenethyl, 3-phenylpropyl and 4-phenylbutyl
  • naphthyl- Cj_ 6 alkyl group such as ( 1-naphthyl )methyl , 2-(l-naphthyl)ethyl and 2-( 2-naphthyl) ethyl .
  • substituents which the said "aralkyl group” optionally have, include halogen atoms (e.g. fluorine, chlorine, bromine and iodine), Cj. 4 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl and butyl), C 2 . 6 alkenyl groups (e.g. vinyl, allyl, 2- butenyl and 3-butenyl), C ⁇ _ 3 alkanoyl groups (e.g. for yl and acetyl), Cj__ alkoxy groups (e.g.
  • halogen atoms e.g. fluorine, chlorine, bromine and iodine
  • Cj. 4 alkyl groups e.g. methyl, ethyl, propyl, isopropyl and butyl
  • C 2 . 6 alkenyl groups e.g. vinyl, allyl, 2- butenyl and 3-butenyl
  • C j __ 4 alkoxy-carbonyl groups e.g. methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl and isopropoxycarbonyl
  • carbamoyl group mono- or di- C ⁇ alkyl-carbamoyl groups (e.g. N-methylcarbamoyl, N- ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N- diethylcarbamoyl) and mono- or di- C ⁇ _ 4 alkenyl- carbamoyl groups (e.g. N-vinylcarbamoyl) .
  • the said "aralkyl group” optionally have 1 to 4 of these substituents at any substituable position.
  • aryl group use is made of, for example, aromatic monocyclic, dicyclic or tricyclic C 6 _ 1 aryl groups exemplified by phenyl, 1-naphthyl, 2- naphthyl , phenanthryl and anthryl .
  • halogen atoms e.g. fluorine, chlorine, bromine and iodine
  • C,_ 4 alkyl groups e.g. methyl, ethyl, propyl, isopropyl and butyl
  • C ⁇ halogeno-alkyl group e.g. trifluoromethyl, trifluoroethyl, trichloromethyl
  • C ⁇ _ 4 alkoxy groups e.g. methoxy, ethoxy, propoxy and isopropoxy
  • C ⁇ alkylthio groups e.g.
  • acetyl, propionyl and butyryl (xv) Cj__ 4 alkoxy-carbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl) , (xvi) sulfone group, (xvii) C,_ 4 alkylsulfonyl groups (e.g. methylsulfonyl, ethylsulfonyl and propylsulfonyl) , (xviii) carbamoyl group, (xix) mono- or di- C,_ 4 alkyl-carbamoyl groups (e.g.
  • the said "aryl group” optionally have 1 to 4, preferably 1 or 2, of these substituents at any substitutable positions.
  • Examples of the aryl group having oxo group include benzoquinonyl, naphthoquinolyl and anthraquinonyl .
  • the term "electron-withdrawing group" used in the present specification is exemplified by (i) -S0 2 R a ,
  • R a - and -C00R a especially -S0 2 R a is commonly used.
  • R a stands for an optionally substituted hydrocarbon group
  • R a 5 stands for a hydrogen atom or an optionally substituted hydrocarbon group
  • R a stands for an
  • R a and R a independently stand for a hydrogen atom or an
  • R 7 8 optionally substituted hydrocarbon group, or R a and R a form, combined with the adjacent nitrogen atom, an nitrogen atom-containing heterocyclic ring.
  • acyl group used in the present specification is exemplified by the acyl group derived from carboxylic acid, which is exemplified by alkoxycarbonyl group, alkylcarbonyl group and alkanoyl group .
  • alkoxycarbonyl group use is made of C,_ 6 alkoxy-carbonyl groups including, for example, methoxycarbonyl , ethoxycarbonyl, propoxycarbonyl , isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl , tert-butoxycarbonyl , pentyloxycarbonyl , isopentyloxycarbonyl , neopentyloxycarbonyl and tert-pentyloxycarbonyl .
  • alkylcarbamoyl group use is made of mono-Ci.
  • ⁇ -N-alkylcarbamoyl groups for example, N- methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl and N-butylcarbamoyl, and di-C ⁇ - ⁇ N-dialkylcarbamoyl groups, for example, N,N-dimethylcarbamoyl , N,N- diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N- dibutylcarbamoyl and N-ethyl-methylcarbamoyl, and 4- to 6-membered cyclic carbamoyl groups formed by combination of the dialkyl portions with each other (e.g. 1-azetidinylcarbonyl, morpholinocarbonyl, 1- pyrrolidinylcarbonyl, 1-piperidinocarbonyl and 1- piperazinylcarbonyl) .
  • alkanoyl group use is made of C ⁇ _ 10 alkanoyl group including, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaroyl and hexanoyl .
  • heterocyclic group in the term “optionally substituted heterocyclic group” in this specification includes 5- or 6-membered monocyclic heterocyclic groups which contain 1 to 4 hetero-atoms selected from, for example, oxygen, sulfur and nitrogen, and bicyclic fused heterocyclic groups which contain 1 to 6 hetero- atoms selected from, for example, oxygen, sulfur and nitrogen.
  • the monocyclic heterocyclic group may be 5- or 6-membered monocyclic aromatic heterocyclic groups which contain 1 to 4 hetero-atoms selected from oxygen, sulfur and nitrogen and saturated or unsaturated monocyclic nonaromatic heterocyclic groups.
  • the examples of them are thienyl (e.g. 2-thienyl, 3-thienyl, etc.), furyl (e.g. 2-furyl, 3-furyl, etc.), pyranyl, 2H-pyrrolyl, pyrrolyl (e.g. 2-pyrrolyl, 3-pyrrolyl, etc.), imidazolyl (e.g.
  • monocyclic heterocyclic groups may be saturated or partially saturated, and such saturated or partially saturated monocyclic heterocyclic groups may, for example, be pyrrolidinyl (e.g. 2-pyrrolidinyl, 3-pyrrolidinyl, etc.), pyrrolinyl (e.g. 2-pyrrolin-3-yl, etc.), imidazolinyl (e.g. 2- imidazolin-4-yl, etc.), piperidyl (e.g. 2-piperidyl, 3- piperidyl, etc.), piperazinyl (e.g. 2-piperazinyl, etc.) and morpholinyl (e.g. 3-morpholinyl, etc.).
  • pyrrolidinyl e.g. 2-pyrrolidinyl, 3-pyrrolidinyl, etc.
  • pyrrolinyl e.g. 2-pyrrolin-3-yl, etc.
  • imidazolinyl e.g. 2- imidazolin-4
  • the bicyclic fused heterocyclic group may be bicyclic fused aromatic heterocyclic groups which contain 1 to 6 hetero-atoms selected from oxygen, sulfur and nitrogen, or saturated or unsaturated bicyclic fused nonaromatic heterocycle groups .
  • These typical examples are benzodioxanyl (e.g. 1, 4-benzodioxan-2-yl, etc.), isobenzofuranyl (e.g. 1-benzofuranyl, etc.), chromenyl (e.g. 2H-chromen-3-yl, etc.), benzothienyl (e.g. 2- benzothienyl, etc.), indolizinyl (e.g.
  • 2-indolizinyl , 3-indolizinyl, etc. isoindolyl (e.g. 1-isoindolyl , etc.), 3H-indolyl (e.g. 3H-indol-2-yl, etc.), indolyl (e.g. 2-indolyl, etc.), lH-indazolyl (e.g. lH-indazol- 3-yl, etc.), purinyl (e.g. 8-purinyl, etc.), isoquinolyl (e.g. 1-isoquinolyl , 3-isoquinolyl, etc.), quinolyl (e.g.
  • the bicyclic fused heterocyclic group may be partially saturated, and such partially saturated bicyclic fused heterocyclic group includes isochromanyl (e.g.
  • 3-isochromanyl, etc. indolinyl (e.g. 2-indolinyl, etc.), isoindolinyl (e.g. 1- isoindolinyl, etc.), 1,2, 3,4-tetrahydro-2-quinolyl, 1,2,3, 4-tetrahydro-3-isoquinolyl , etc .
  • the substituent group which the said "heterocyclic group” optionally have includes the same groups as those mentioned as the substituent group which may be substituted on the "aryl” in said "optionally substituted hydrocarbon group", and the number of the substituents may range from 1 to 4 (preferably 1 to 3).
  • the substituent group on the "optionally substituted hydroxy group” used in the present specification includes (i) C ⁇ _ 6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), (ii) phenyl, (iii) C 7 . 10 aralkyl (e.g.
  • benzyl, etc. (iv) formyl, (v) C ⁇ _ 6 alkyl-carbonyl (e.g. methylcarbonyl, ethylcarbonyl, etc.), (vi) phenyloxycarbonyl, (vii) C 7 . 10 aralkyloxy-carbonyl (e.g. benzyloxycarbonyl, etc.), (viii) pyranyl, (ix) furanyl and (x) silyl, each of which may be substituted.
  • the substituent group which may be substituted on these groups includes halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.), C 1 . 4 alkyl (e.g.
  • the ring A stands for a nitrogen-containing heterocyclic ring containing the nitrogen atom at the head of the bridge in the condensed ring, which be further substituted with oxo or thioxo .
  • ring A Preferable examples of the ring A include 5- or 6- membered nitrogen-containing heterocyclic ring optionally substituted with 1 or 2 oxo groups. Especially, the following ones are commonly employed.
  • the ring A may be substituted with the substituents as mentioned after.
  • the ring Q may be substituted.
  • Examples of the "substituent" which ring Q may have includes (i) nitro, (ii) hydroxy, (iii) cyano, (iv) carbamoyl, (v) mono- or di-C 1-4 alkyl-carbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N,N- dimethylcarbamoyl, N,N-diethylcarbamoyl , etc.), (vi) carboxy, (vii) Ci_ 4 alkoxy-carbonyl (e.g.
  • Cj__ 4 alkyl e.g. methyl, ethyl, propyl, isopropyl, etc.
  • halogeno-C 1 . 4 alkyl e.g. trifluoromethyl, trichloromethyl, 2 , 2 , 2-trifluoroethyl, etc.
  • Ring Q may have 1 to 3 of these substituents at any substitutable positions on the ring Q, and the ring Q is preferably unsubstituted.
  • R include a hydrogen atom, optionally substituted hydroxy group, optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted aralkyl groups, optionally substituted aryl groups, alkoxy carbonyl groups, alkylcarbamoyl groups and alkanoyl groups; especially a hydrogen atom, C ⁇ _ 6 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl and butyl) or phenyl group are commonly used, more preferably, hydrogen atom, methyl group .
  • substituents of the ring A include halogen atom, mercapto group, optionally substituted hydroxy group, optionally substituted hydrocarbon group, acyl group of -Y -Z in which Y is a bond or an optionally substituted divalent hydrocarbon group and Z is a basic group which may be bonded via oxygen atom, -NR 3 -, -CO-, -CS-, -S0 2 N(R 3 )- or -S(0) r - (wherein
  • R is a hydrogen or an optionally substituted hydrocarbon group and r is 0, 1 or 2 ) .
  • basic group used in the present specification means, for example, (1) (i) an optionally substituted amino group and/or (ii) a group with a molecular weight of not greater than 1000 (preferably not greater than 300), such as a hydrocarbon group which has 1 to 10 (preferably 1 to 5) heterocyclic group containing 1 to 4 hetero-atoms selected from nitrogen, oxygen and sulfur, as terminal and/or interrupting groups and (2) a group of the formula: -Z-A-N-B-X-R R wherein all symbols are of the same meanings as defined hereinbefore .
  • optionally substituted amino group includes N-mono-substituted amino and N,N-di-substituted amino.
  • N-mono-substituted amino means an amino group having one substituent group, and examples of these substituents include alkyl group (especially C ⁇ _ 15 alkyl and C 3 _ 8 cycloalkyl), aryl group (especially C 6 . 14 aryl), heterocyclic ring (especially 5- or 6-membered monocyclic aromatic heterocyclic ring) , and aralkyl group (especially C 7 . 16 aralkyl) as mentioned above.
  • the "N,N-di-substituted amino” means an amino group having two substituent groups . One of these two substituent groups are of the same substituent groups as mentioned for "N-mono-substituted amino".
  • the other substituent group are the above-mentioned alkyl group (especially C 1 . 15 alkyl and C 3 . 8 cycloalkyl), aryl group (especially C 6 . 14 aryl) and aralkyl group (especially C 7 _ 16 aralkyl).
  • the two substituents on the amino group may form a cyclic amino group taken together with the adjacent nitrogen atom.
  • Examples of the cyclic amino group are 1-azetizinyl, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl and 1- piperazinyl having the above-mentioned alkyl group (especially C 15 alkyl or C 3 . 8 cycloalkyl), aryl group
  • heterocyclic group which contains 1 to 4 nitrogen examples include (i) 5- or 6-membered heterocyclic groups such as imidazolyl, 2H-pyrrolyl, pyrrolyl, pyrazolyl, isoxazolyl, furazanyl, pyrrolidinyl, imidazolidinyl , imidazolinyl, pyrazolidinyl, pyrazolinyl, pyridyl , pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, thiomorpholinyl, morpholinyl, etc.
  • 5- or 6-membered heterocyclic groups such as imidazolyl, 2H-pyrrolyl, pyrrolyl, pyrazolyl, isoxazolyl, furazanyl, pyrrolidinyl, imidazolidinyl , imidazolinyl, pyrazolidinyl, pyrazolinyl,
  • bicyclic or tricyclic fused heterocyclic groups such as indolizinyl, isoindolyl, 3H-indolyl, indolyl, lH-indazolyl, purinyl, 4H- quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl , quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4H-carbazolyl, carbazolyl, ⁇ -carbolinyl, phenanthridinyl , acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, etc.
  • hydrocarbon group in the term "hydrocarbon group having 1 to 10 (preferably 1 to 5) heterocyclic groups containing 1 to 4 nitrogen as terminal and/or interrupting groups" may be, for example, the same group as the "optionally substituted hydrocarbon group" as mentioned above .
  • the "basic group” may be bonded to Y° either directly or via oxygen (-0-), nitrogen [-N(R )-], carbonyl (-CO-), thiocarbonyl (-CS-), -S(0) r - (wherein r is to 0, 1 or 2 ) , or a combination thereof: -CO-N- (R 3 )-, -CS-N(R 3 )-, -S(0) n -N(R 3 )-, -COO- , -CS-O- (wherein R is a hydrogen atom or an optionally substituted hydrocarbon group) .
  • the "hydrocarbon group” and “substituent" on the hydrocarbon group of the "optionally substituted hydrocarbon group” as mentioned for R include the same groups for the "optionally substituted hydrocarbon group" as mentioned hereinbefore.
  • alkyl alkyl, cycloalkyl, alkenyl, “aralkyl”, “aryl”, and “substituent” on these group of the “optionally substituted alkyl, cycloalkyl, alkenyl, aralkyl or aryl group" used in the present specification, for example, be the same groups as those respectively mentioned for said "optionally substituted hydrocarbon group".
  • the ring formed jointly by R and A may, for example, be an optionally substituted heterocyclic group Q, which contains 1 to 4 nitrogen atoms .
  • the ring formed jointly by R and B may, for example, be an optionally substituted heterocyclic group Q 2 which contains 1 to 4 nitrogen atoms .
  • the ring formed jointly by R and A may for example, be an optionally substituted heterocyclic group Q 3 which contains 1 to 4 nitrogen atoms .
  • the ring formed jointly by R and R may, for example, be an optionally substituted heterocyclic group Q 4 which contains 1 to 4 nitrogen atoms .
  • the ring formed jointly by R and R may, for example, be an optionally substituted heterocyclic group Q 5 which contains 1 to 4 nitrogen atoms .
  • Ring Q x includes a group of the formula:
  • Ring Q 2 includes a group of the formula:
  • Ring Q 3 includes a group of the formula:
  • Ring Q 4 includes a -grOoup of the formula:
  • Ring Q 5 includes a group of the formula:
  • the substituent which may be substituted on the ring Q l f ring Q 2 , ring Q 3 , ring Q 4 and ring Q 5 includes the same groups as mentioned for the substituent on said "optionally substituted heterocyclic group".
  • the number of substituents may range from 1 to 4.
  • Examples of the compound of the formula (I) which is the object of the present invention include, typically, the compound of the formula (la):
  • ring A' is a nitrogen-containing heterocyclic ring, having two nitrogen atoms as hetero-atoms; ring Q may be substituted;
  • J is an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted mercapto group; and R a is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, which is disclosed in Japanese Published Unexamined Patent Application H8 ( 1996) -81467 (WO 96/02542).
  • Preferable examples of the compound (la) include the compound (la').
  • preferable examples of the ring A' include heterocyclic ring which contains two nitrogen atoms .
  • ring A' include heterocyclic ring substituted with oxo or thioxo group, especially 5- or 6-membered nitrogen-containing heterocyclic ring optionally substituted with one or two oxo groups and for example
  • examples of the optionally substituted hydrocarbon group represented by J include those described in respect of the above-mentioned "optionally substituted hydrocarbon group”.
  • the ring Q may have, use is made of the same ones as the above-mentioned and preferably, ring Q is unsubstituted .
  • R a As the "halogen atom”, “optionally substituted hydrocarbon group” and “acyl group” represented by R a , use is made of the same ones as the above-mentioned and preferable examples of R a are hydrogen atom and C ⁇ _ 6 alkyl group (preferably methyl group) .
  • Examples of the substituents which the hydroxy group or the mercapto group represented by J optionally have, include optionally substituted hydrocarbon group, the groups comprising at least one nitrogen atom and/or the groups comprising at least one electron-withdrawing groups .
  • substituents which the hydroxy group or the mercapto group represented by J optionally have, include optionally substituted hydrocarbon group.
  • optionally substituted hydrocarbon group use is made of the same ones as the above-mentioned “optionally substituted hydrocarbon group " .
  • substituents which the hydrocarbon group, the hydroxy group and the mercapto group represented by J optionally have, include the groups comprising at least one nitrogen atom and/or the groups comprising at least one electron-withdrawing group, especially the groups comprising an amino group substituted with at least one electron-withdrawing group.
  • the group comprising at least one nitrogen atom use is made of, for example, alkylaminoalkyl groups aralkylaminoalkyl groups, arylaminoalkyl groups , alkylaminoaralkyl groups , aralkylaminoaralkyl groups, arylaminoaralkyl groups, alkylaminoaryl groups, aralkylaminoaryl groups, arylaminoaryl groups , aminoalkyl groups , aminoaralkyl group and aminoaryl groups .
  • the group comprising at least one electron- withdrawing group use is made of, for example, the hydrocarbon groups comprising at least one "electron- withdrawing group" as mentioned above.
  • the group comprising an amino group which is substituted with at least one electron-withdrawing group use is made of, for example, the hydrocarbon groups comprising an amino group substituted with at least one "electron-withdrawing group" as mentioned above .
  • the preferable examples of J include the groups represented by the formula:
  • D stands for an optionally substituted divalent hydrocarbon group. Specific examples of the group include those represented by (i)
  • R a , R a , R a , R a , R a , R a and R a independently stand for a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group, and, R a and R a ; R a and R a ;, R a and R a ; R a or R a and R a 2 ; R a u or R a z and R a ; , or, R a or R a and R a may respectively be combined to form rings, and R a 9 or R a ⁇ may be combined with R a 13
  • R a and R a , R a and R a , and R a and R a are exemplified by C 3 _ 8 cycloalkyl groups including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the rings formed by combination of R a or R a and R a ; R a or R a and R a ; or R a or R a and R a are exemplified by azetidinyl, pyrrolidinyl or piperidino .
  • the rings formed by combination of R a or R a with R a or R a , respectively are exemplified by C 3 . 8 cycloalkyl groups including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl .
  • R a to R a include a hydrogen atom or C 1 _ 4 alkyl groups (e.g. methyl, ethyl, propyl and isopropyl), and, especially, a hydrogen atom or methyl group is commonly used.
  • D include C 2 . 10 alkylene groups (e.g. ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene and octamethylene) , and, among them, especially C 3 . 8 alkylene groups (e.g. ethylene, propylene, butylene, pentamethylene, hexamethylene and heptamethylene) are commonly employed.
  • alkylene groups e.g. ethylene, propylene, butylene, pentamethylene, hexamethylene and heptamethylene
  • X a stands for a bond, an oxygen atom or a sulfur atom.
  • X a is a bond.
  • R a z stands for a hydrogen atom or an optionally substituted hydrocarbon ggrroouupp,, aanndd,, RR aa aanndd DD mmay form a ring together with the adjacent nitrogen atom.
  • R a include a hydrogen atom, optionally substituted alkyl groups or optionally substituted alkenyl groups, especially a hydrogen atom is commonly used.
  • R a stands for an electron-withdrawing group, or may form a ring together with R a and the adjacent nitrogen atom.
  • the electron-withdrawing group include (i) -S0 2 R a (R a stands for an optionally substituted hydrocarbon group), (ii) -C0-R a (R a stands for a hydrogen atom or an optionally substituted hydrocarbon group), (iii) -COOR a (R a stands for an optionally substituted
  • R a and R a may form a ring together with the adjacent nitrogen atom) .
  • Examples of the electron-withdrawing group include -S0 2 R a a , -CO-R a 5a and -COOR a 6a (R a 4a , R a 5a and R a 6a each stand for an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group), especially -S0 2 R a a (R a a stands for an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group) is commonly used among others .
  • R a include an optionally substituted alkyl group, especially a halogeno- C ⁇ alkyl group (e.g. chloromethyl, trifluoromethy1, 2,2,2- trifluoroethyl and 3 , 3 , 3-trifluoropropyl) .
  • a halogeno- C ⁇ alkyl group e.g. chloromethyl, trifluoromethy1, 2,2,2- trifluoroethyl and 3 , 3 , 3-trifluoropropyl
  • R a include an optionally substituted alkyl group, especially a halogeno- C ⁇ . 6 alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3,3, 3-trifluoropropyl) .
  • R a include an optionally substituted alkyl group, especially a halogeno- Cj. 6 alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3,3, 3-trifluoropropyl) .
  • R a and R a include a hydrogen atom or an optionally substituted alkyl group, especially a hydrogen atom or a halogeno- C ⁇ alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3, 3, 3-trifluoropropyl) .
  • a hydrogen atom or a halogeno- C ⁇ alkyl group e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3, 3, 3-trifluoropropyl
  • Examples of the ring, which R a and R a form together with the adjacent nitrogen atom, include pyrrolidin-2-one, piperidin-2-one, indolin-2-one, isoindolin-1-one, isoindolin-1, 3-dione, oxazolidin-2- one, oxazolidin-2 , 4-dione, thiazolidin-2-one, thiazolidin-2, 4-dione and 1, 2-benzisothiazol-3 (2H)-one.
  • These rings may have substituents such as electron- withdrawing groups.
  • electron-withdrawing group use is made of, for example, the above- mentioned "electron-withdrawing groups”.
  • preferable examples of J include a group of the formula:
  • D a is a bond or an optionally substituted divalent hydrocarbon group
  • ring W is an optionally substituted nitrogen-containing heterocyclic group
  • R b is an electron-withdrawing group.
  • D a is preferably an optionally substituted divalent hydrocarbon.
  • the "optionally substituted divalent hydrocarbon” is of the same meaning as defined in above.
  • the "divalent hydrocarbon” is preferably, for example, divalent liner hydrocarbon such as C 15 alkylene group (e.g. methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene, octamethylene) , C 2 _i 6 alkenylene group (e.g. vinylene, propenylene, 1-butenylene, 2- butenylene, 1-pentenylene, 2-pentenylene, 3- pentenylene) , C 2 . 16 alkynylene group (e.g.
  • the "divalent hydrocarbon group” is C : . 15 alkylene group (e.g. methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene, octamethylene) .
  • the substituent of the "divalent hydrocarbon group” is exemplified by the same substituents as those of the “divalent hydrocarbon group” as mentioned above.
  • Preferable examples of the substituent of the divalent liner hydrocarbon are C 1-6 alkyl group (e.g. methyl, ethyl, propyl, isopropyl, buthyl ) and phenyl group.
  • the substituent of the phenylene group is exemplified by the same substituents as those of the phenylene group as mentioned above.
  • D a is preferably a C 1-6 alkylene (e.g. methylene, ethylene, propylene, butylene, pentamethylene, trimethylene, tetramethylene) .
  • examples of the optionally substituted nitrogen-containing heterocyclic ring of ring W are preferably an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic ring. These ring may be saturated or unsaturated.
  • nitrogen-containing heterocyclic ring is the moiety:
  • the substituent of the "nitrogen-containing heterocyclic group” is exemplified by the same one as the substituent of ring Q.
  • R b is exemplified by the same one as above-mentioned, Ri, IS preferably -S0 2 R a (R a is an optionally substituted hydrocarbon group), -COR a (R a is a hydrogen atom is an optionally substituted hydrocarbon group) or -COOR a (R a is an optionally substituted hydrocarbon group) and more preferably -S0 2 R a (R a is an optionally substituted hydrocarbon group) or -COR a (R a is a hydrogen atom or an optionally substituted hydrocarbon group) .
  • R a , R a and R a are an optionally halogenated hydrocarbon group (e.g. C ⁇ alkyl group which may have 1 to 5 halogen atoms such as methyl, ethyl, propyl, isopropyl, butyl, chloromethyl, trifluoromethyl, 2 , 2 , 2-trifluoroethyl , 3,3,3- trifluoropropyl, or pentafluoroethyl) .
  • C ⁇ alkyl group which may have 1 to 5 halogen atoms such as methyl, ethyl, propyl, isopropyl, butyl, chloromethyl, trifluoromethyl, 2 , 2 , 2-trifluoroethyl , 3,3,3- trifluoropropyl, or pentafluoroethyl
  • X b stands for an oxygen atom or a sulfur atom, and the other symbols are of the same meaning as defined above, especially the compounds (a) and (c).
  • X b stands for an oxygen atom or a sulfur atom, and the other symbols are of the same meaning as defined above, especially the compounds (a) and (c).
  • a compound wherein ring Q is unsubstituted, is preferable;
  • R a stands for a hydrogen atom, an optionally substituted alkyl group or an optionally substituted alkenyl group, is preferable, and, especially those wherein R a stands for a hydrogen atom or a C j . 6 alkyl group (e.g. methyl, ethyl, propyl, isopropyl and butyl), is commonly used;
  • R a stands for a hydrogen atom or a C 6 alkyl group (e.g. methyl, ethyl, propyl, isopropyl and butyl), is preferable, and, especially those wherein R a stands for a hydrogen atom, is commonly used;
  • D stands for a C 2 _ 10 alkylene group (e.g. ethylene, propylene, butylene, pentamethylene, hexamethylene and octamethylene), is preferable, and, especially those, wherein B stands for a C 3 . 8 alkylene group (e.g. propylene, butylene, pentamethylene, hexamethylene and heptamethylene) , are preferable;
  • R a stands for an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group
  • R a stands for a halogeno- Cj.g alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3 , 3 , 3-trifluoropropyl ) , is preferable.
  • salts of the compound (la) mention is especially made of pharmaceutically acceptable salts and physiologically acceptable acid salts.
  • These salts are exemplified by those with inorganic acids (e.g. hydrochloric acid, phosphoric acid, hydrobromic acid and sulfuric acid) or with organic acids (e.g. acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methansulfonic acid and benzenesulfonic acid) .
  • inorganic acids e.g. hydrochloric acid, phosphoric acid, hydrobromic acid and sulfuric acid
  • organic acids e.g. acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methansulfonic acid and benzen
  • the compound (la) of the present invention when it has an acid group such as carboxylic group, it may form a salt with, for example, an inorganic base (e.g. an alkali metal or an alkaline earth metal such as sodium, potassium, calcium and magnesium, or ammonia) or an organic base (e.g. a tri- Ci. 3 alkylamine such as triethylamine) .
  • an inorganic base e.g. an alkali metal or an alkaline earth metal such as sodium, potassium, calcium and magnesium, or ammonia
  • an organic base e.g. a tri- Ci. 3 alkylamine such as triethylamine
  • the compound (la) or a salt thereof have, in some instances, asymmetric carbons in the molecule. When two kinds of sterioisomers of R-configuration and S- configurated isomers, are present, each of them and a mixture of them are all included in the scope of the present invention.
  • the compound (la) may be used as a hydrate or a non-hydrate .
  • the compound (la) and salts thereof used in the pharmaceutical composition of the present invention are compounds having triazonaphthylene ring having one oxo group which is oxidizable. These are set forth as follows: 4 , 5-dihydro-4- [ 5- ( trifluoromethanesulfonamide ) pentan-1- yl]-3H-l, 4, 8b-triazaacenaphthylen-3-one, 4 ,5-dihydro-4-[ 4- (trifluoromethanesulfonamide )butan-l- yl ] -3H-1 , 4 , 8b-triazaacenaphthylen-3-one, 4 , 5-dihydro-4- [ 3- ( trifluoromethanesulfonamide )propan-1- yl ] -3H-1 , 4 , 8b-triazaacenaphthylen-3-one, 4 , 5-dihydro-2-
  • l,2-dihydro-l-[2-( 1- trifluoromethanesulfonylpiperidin-4-yl ) ethan-1-yl ] - 1,4, 7b-triazacyclopento[c,d]inden-2-one and their salts are preferable.
  • the compound (la) are a compound wherein
  • R a is a hydrogen atom or C j _ 6 alkyl group (preferably methyl group)
  • J is a group of the formula:
  • the tricyclic compound (la) or a salt thereof used in the present invention is the known compound and can be synthesized by methods disclosed in the Japanese
  • the oleaginous base for use in the present invention can be any oily substance that can be used as a pharmaceutical base and contributes to stabilization of tricyclic compounds.
  • higher saturated fatty acids, fatty acid ester of alcohol (oils, hydrogenated oils, waxes, etc.), higher alcohols, phospholipids, sterols, sterol esters, and hydrocarbons are among such bases.
  • fatty acid esters of alcohols are suited, for routine use.
  • the "fatty acid” of said "fatty acid ester of alcohol” may be, for example, a monocarboxylic acid and a dicarboxylic acid.
  • the dicarboxylic acid include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, phthalic acid, isophthalic acid, terephthalic acid, and sebacic acid.
  • the monocarboxylic acid include C 2 .
  • straight-chain saturated fatty acids such as acetic acid (C 2 ) , propionic acid (C 3 ) , butyric acid (C 4 ), valeric acid (C ), caproic acid (C 6 ) , heptanoic acid (C 7 ), caprylic acid (C 8 ) , nonanoic acid (C 9 ) , capric acid (C 10 ), undecanoic acid (C ⁇ ), lauric acid (C 12 ), tridecanoic acid (C 13 ), myristic acid (C 14 ), pentadecanoic acid (C 15 ), palmitic acid (C 16 ), margaric acid (C 17 ), stearic acid (C 18 ) , nonadecanoic acid (C 19 ), arachic acid (C 20 ) , heneicosanoic acid (C 21 ), behenic acid (C 22 ), tricosanoic acid (C 23 ), and lignoceric acid (C
  • 19 branched fatty acids such as isolauric acid, 11-methyldodecanoic acid, isomyristic acid, 13-methyltetradecanoic acid, isopalmitic acid, 15-methylhexadecanoic acid, isostearic acid, 17-methyloctadecanoic acid, isoarachic acid, 19-methyleicosanoic acid, 9-methylundecanoic acid, 10-methyldodecanoic acid, 11-methyltridecanoic acid, 12-methyltetradecanoic acid, 13- methylpentadecanoic acid, 14-methylhexadecanoic acid, 15-methylheptadecanoic acid, 16-methyloctadecanoic acid, etc.; and C 4 .
  • isolauric acid such as isolauric acid, 11-methyldodecanoic acid, isomyristic acid, 13-methyltetradecanoic acid, isopalmitic acid, 15-
  • hydroxy-fatty acids such as ⁇ - hydroxybutanoic acid, ⁇ -hydroxybutanoic acid, 3- hydroxynonanoic acid, 2-hydroxydecanoic acid, 2- hydroxylauric acid, 2-hydroxytetradecanoic acid, 3- hydroxymyristic acid, 2-hydroxyhexadecanoic acid, 2- hydroxyoctadecanoic acid, 12-hydroxystearic acid, 2- hydroxyeicosanoic acid, 2-hydroxydocosanoic acid, ricinolic acid, and ricinelaidic acid.
  • straight- chain saturated fatty acids preferably C 6 . 22 medium- chain fatty acids, and particularly C 8 . 20 fatty acids are suited for routine use.
  • the "alcohol" of said "fatty acid ester of alcohol” includes, for example, straight-chain or branched C 2 _ 18 monohydric alcohols such as methyl alcohol, ethyl alcohol, n-propyl alcohol, n-butyl alcohol, n-pentyl alcohol, n-hexyl alcohol, n-heptyl alcohol, n-octyl alcohol, n-decyl alcohol, n-lauryl alcohol, n-myristyl alcohol, n-cetyl alcohol, n- octadecyl alcohol, isopropyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, isopentyl alcohol, tert-pentyl alcohol, etc.; dihydric alcohols such as ethylene gl col, propylene glycol, 1,3- propanediol, etc., and trihydric alcohols such as glycerol .
  • the "fatty acid ester of alcohol” includes the esters formed by the said fatty acid with the said alcohols, and saturated or unsaturated waxes and fatty acid glycerides (mono-, di-, and triacylglycerols ) are particularly useful .
  • Those esters may be whichever of synthetic compounds and naturally-occurring substances.
  • naturally-occurring substances may contain not only one or more fatty acid alcohol esters but also concomitant substances such as free fatty acids and hydrocarbons.
  • fatty acid esters of glycerol or polyglycerol are used widely.
  • the percentage of esterified hydroxy groups based on the total number of hydroxy groups available in said "fatty acid ester of glycerol or polyglycerol" is preferably not less than about 60% and more preferably not less than about 80%.
  • the preferred degree of polymerization of said polyglycerol is 2 to 16.
  • Fatty acid esters of glycerol or polyglycerol can be used each alone or in combination. These are used selectively in such a way that the degree of esterification of the ester or the esters taken together will be preferably at least about 60%, more preferably not less than about 80%.
  • the fatty acid ester of glycerol is preferably the fatty acid triglyceride ( triacylglycerol) available upon bonding of 3 moles of the fatty acid to each mole of glycerol by the ester linkage.
  • the fatty acid of said fatty acid triglyceride may be one and the same kind of fatty acid or different kinds of fatty acids.
  • preferred fatty acids are C 4 _ 22 saturated fatty acids. The more preferred are C 6 . 18 saturated fatty acids. Particularly, C 8 . 10 medium-chain saturated fatty acids are used widely.
  • glycol fatty acid ester includes various commercial esters such as Miglyol 810 (caprylic/capric triglyceride, fatty acid composition: 65-75% caprylic acid and 25-35% capric acid) , Miglyol 812 (caprylic/capric triglyceride, fatty acid composition: 50-65% caprylic acid and 30-45% capric acid), Miglyol 829 (glyceryl succinate di(caprylate/caprate) , fatty acid composition: 35-45% caprylic acid, 20-30% capric acid, and 12-16% succinic acid), Miglyol 840 (propylene glycol dicaprylate, fatty acid composition: 65-80% caprylic acid and 15-30% capric acid), Dynasan 110 (caprylic acid triglyceride), Dynasan 112 (lauric acid triglyceride), Dynasan 114 (myristic acid triglyceride), Dynasan 116 (palmitic acid
  • the preferred polyglycerol fatty acid ester has a degree of polymerization of glycerol between 2 and 16 as mentioned above.
  • the particularly preferred degree of polymerization is 2-10.
  • the fatty acid is preferably saturated.
  • saturated fatty acids each containing 6-22 carbon atoms, preferably 8-18 carbon atoms, can be mentioned.
  • the fatty acid moiety of the ester may be one and the same kind of fatty acid or a plurality of different fatty acids.
  • polyglycerol fatty acid esters literally run the whole gamut of combinations of the degree of polymerization of glycerol, the kind of fatty acid, and the degree of esterification, they can be invariably used for the purposes of the invention.
  • the "polyglycerol fatty acid ester” includes various commercial esters such as PS-310 (tetraglycerol pentastearate) , MS-310 (tetraglycerol monostearate) , HB-310 (tetraglycerol hexabehenate) , PO-310 (tetraglycerol pentaoleate) , PO-500 (hexaglycerol monostearate), DAO-750 (decaglycerol decaoleate) , DAS- 750 (decaglycerol decastearate) , etc., all of which are available from Sakamoto Pharmaceutical Co.
  • esters can be used alone or in combination. It is also possible to use them in combination with other oleaginous bases such as glycerol fatty acid esters .
  • the oil mentioned above includes but is not limited to soybean oil, olive oil, rapeseed oil, peppermint oil, sesame oil, castor oil, tsubaki oil, wheat germ oil, fennel oil, corn oil, sunflower oil, cottonseed oil, coconut oil, peanut oil, etc., inclusive of hydrogenated versions thereof, beef tallow, and lard.
  • wax includes but is not limited to carnauba wax, sperm wax, bees wax, and white Japan wax.
  • the above-mentioned "higher saturated fatty acid” includes C 8 . 22 fatty acids, inclusive of their salts, which are among the above-mentioned fatty acids, e.g. caprylic acid, capric acid, palmitic acid, stearic acid, behenic acid, etc.
  • the "higher alcohol” includes C 10 - 2 o alcohols such as cetyl alcohol and stearyl alcohol, among others.
  • the "phospholipid” includes, for example, hydrogenated lecithin.
  • the "sterol or its ester” includes, for example, cholesterol, -cholestane, ⁇ -cholestanol, epicoprostanol, demosterol, fucosterol, lanosterol, ergosterol, ⁇ -sitosterol, C 2 . 24 saturated fatty acid cholesterol esters, and C 14 . 24 unsaturated fatty acid cholesterol esters (1-6 double bonds).
  • the "hydrocarbon” includes, for example, paraffin and microcrystalline wax.
  • the above oleaginous bases can be used alone or in a suitable combination.
  • the preferred oleaginous bases for use in the present invention are fatty acid esters of glycerol or polyglycerol.
  • the pharmaceutical composition of the present invention is an oral preparation of a tricyclic compound which has been stabilized by an ingenious pharmaceutical contrivance.
  • the "pharmaceutical composition” includes both liquid and solid compositions, and can be manufactured by the per se known production technology. For example, the following methods can be mentioned.
  • the cyclazine compound is added to the base and dispersed therein by stirring or otherwise to give the desired composition.
  • the base When an oleaginous base which is solid at atmospheric temperature (5-30°C) is employed, the base is liquefied in the first place, then the tricyclic compound is dispersed therein, and the dispersion is allowed to solidify.
  • the oleaginous base is warmed at least to its melting point and the tricyclic compound is dissolved or dispersed in the melt.
  • This dispersion is then cooled to solidify.
  • the dispersion may be molded into granules or pellets where necessary.
  • the conventional molding techniques can be used for the purpose. Taking granules as an example, spherical granules or beads about 0.1 - about 1000 ⁇ m in diameter are preferred.
  • the per se known procedures can be employed for such molding.
  • the method which comprises dispersing the above-mentioned solution or dispersion of the tricyclic compound in an aqueous phase the so-called spray drying method, and the spray chilling method which comprises preparing fine oil droplets and quenching them to solidify can be mentioned.
  • the "aqueous phase” is optionally supplemented with a dispersant (e.g. Tween 80, carboxymethylcellulose, polyvinyl alcohol, etc.) or the like.
  • the amount of the oleaginous base relative to the cyclazine compound in the composition can be selected from the range of about 1:0.1 - 1:100000 (w/w) , preferably 1:1 - 1:10000 (w/w), according to the physicochemical characteristics (e.g. solubility, dispersibility, etc.) of this and other auxiliary ingredients, the effective dose of the cyclazine compound, and the final dosage form.
  • the more preferred range is about 1:10 - about 1:1000 (w/w). However, this range is not critical insofar as the tricyclic compound can be completely contained with the oleaginous base.
  • the concentration or content of the tricyclic compound in the composition can be judiciously selected according to the physicochemical characteristics of the composition.
  • the concentration of this active ingredient is about 0.0005 - 30% (w/v) , preferably about 0.005 - 25% (w/v) .
  • the content of the active ingredient is about 0.01-90% (w/w), preferably about 0.1-50% (w/w).
  • preservatives e.g. benzyl alcohol, ethyl alcohol, benzalkonium chloride, phenol, chlorobutanol, etc.
  • antioxidants e.g. butylhydroxyanisole, propyl p rrogallate, ascorbyl palmitate, ⁇ -tocopherol, DHT, etc.
  • viscosity increasing agent e.g. lecithin, hydroxypropyl cellulose, aluminum stearate, etc.
  • the liquid or solid pharmaceutical composition of the present invention can be administered orally in the conventional manner.
  • the liquid composition can be directly administered into the digestive canal using a catheter or a tube for gastric gavage .
  • the composition can be administered orally in the routine manner.
  • the composition can be processed into a suitable dosage form such as powders, capsules, tablets, etc. and administered in the usual manner.
  • the pharmaceutical composition for oral administration according to the present invention can be manufactured by the known technology or any technology analogous thereto, as a principle.
  • various additives which are routinely used in pharmaceutical manufacture can be added for controlling the rate of release of the active ingredient or according to formulation necessities.
  • various excipients e.g. lactose, corn starch, talc, crystalline cellulose, powdered sucrose, magnesium stearate, mannitol, light anhydride silic acid, magnesium carbonate, calcium carbonate, L- cysteine, etc.
  • binders e.g.
  • starch sucrose, gelatin, gum arable powder, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose , hydroxypropylmethylcellulose , polyvinylpyrrolidone, pullulan, dextrin, etc.), disintegrators (e.g. carboxymethylcellulose calcium, low-viscosity hydroxypropylcellulose, croscarmellose sodium, etc.), anionic surfactants (e.g. sodium alkyl sulfates etc.), nonionic surfactants (e.g.
  • polyethoxylated sorbitan fatty acid esters polyoxyethylene fatty acid esters, polyethoxylated castor oil derivatives, etc.
  • antacids and mucous membrane protectants e.g. magnesium hydroxide, magnesium oxide, aluminum hydroxide, aluminum sulfate, magnesium aluminate metasilicate, magnesium aluminate silicate, sucralfate, etc.
  • cyclodextrins and the corresponding carboxylic acid derivatives e.g.
  • maltosyl- ⁇ -cyclodextrin maltosyl- ⁇ -cyclodextrin, maltosyl- ⁇ - cyclodextrincarboxylic acid, etc.
  • coloring agents corrigents, adsorbents, antiseptics, wetting agents, antistatics, disintegration retardants, and so on.
  • the level of addition for such additives can be judiciously selected from the range not adversely affecting the stability and absorption kinetics of the active ingredient .
  • SEC soft elastic capsules
  • the SEC shell may be of any known form and the capsule geometry inclusive of its size, capsule sheet composition, and the method for production may also be freely selected.
  • geometry any of globular, oval, oblong, tubular, spindle-shaped, self- cut, geminal (twin), square, heart-shaped, and other forms can be freely selected within the size range of generally about 1 mg - about 10 g net content.
  • gelatin e.g.
  • alkalinized gelatin supplemented with a suitable plasticizer
  • a suitable plasticizer includes but is not limited to glycerin, polyvinyl alcohol, sorbitol, mannitol, polyethylene glycol, and polyvinylpyrrolidone .
  • a coloring agent, antiseptic, flavoring agent, corrigent, etc . may also be added to the capsule sheet .
  • the encapsulation technology that can be used includes but is not limited to the plate method, rotary die method, and seamless encapsulation method, although the rotary die method is preferred.
  • Such dosage forms can be provided by granulating a solid pharmaceutical composition prepared as described hereinbefore or a uniform mixture of said composition with said additives in the presence of a suitable solvent such as water.
  • the granulation can be carried out using any of the common granulating machines such as the rotary granulator, stirring granulator, fluidized-bed granulator, centrifugal granulator, rotary fluidized-bed granulator, etc., pressure granulators such as the roller compactor, and rotary compression type machines.
  • any of the above-mentioned granulators can be employed, although a rotary machine is preferred.
  • the resulting mixed powders or granules can be filled in hard capsule shells to provide hard capsules .
  • the common hard capsule shell includes gelatin shells within the capacity range of about 0.13-1.37 ml net content and such capsule shells can be filled by means of a disc, compression, or Auger type filling machine.
  • the pharmaceutical composition of the present invention can be provided in tabular dosage forms.
  • the geometry, inclusive of size, of such tablets can be freely selected. For example, ellipsoidal, football- shaped, or heart-shaped tablets can be manufactured, with or without a dividing score. Referring to tablet machines, the tablets can be manufactured using whichever of an eccentric machine and a rotary machine.
  • the pharmaceutical composition of the present invention can be coated with an enteric coating to provide enteric dosage forms.
  • the "enteric coating” comprises an enteric polymer which is substantially insoluble in the acidic region but at least partially soluble in the weakly acidic through basic region.
  • the acidic region mentioned above is the range of pH about 0.5 - about 4.5, preferably about 1.0 - about 2.0
  • the weakly acidic through basic region is the range of pH about 5.0 - about 9.0, preferably about 6.0 - about 7.5.
  • cellulose acetate phthalate hydroxypropylmethylcellulose , hydroxypropylmethylcellulose phthalate , hydroxypropylmethyl acetate succinate (Shin-Etsu Chemical), methacrylic copolymers (Eudragit L-30D-55, L100-55, L100, S100, etc., all trademarks of Rhein-
  • the coating technology that can be used includes the conventional methods such as pan coating, fluidized-bed coating, rotary coating, etc.
  • the spray coating method can also be used.
  • the proportion of said water or organic solvent may, for example, somewhere between 25 and 99 weight %.
  • organic solvent there is no particular limitation on the kind of organic solvent, and various solvents such as alcohols (e.g. methanol, ethanol, isopropyl alcohol, etc.), ketones (e.g. acetone etc.), halogenated hydrocarbons (e.g. chloroform, dichloromethane, trichloromethane, etc.), among others, can be employed.
  • the capsule shells may for example be gelatin capsule shells .
  • the pharmaceutical composition of the present invention can also be used in the conventional dosage forms other than oral ones, for example dosage forms for external application (e.g. transnasal DDS , transdermal DDS, etc.), suppositories (e.g. rectal and vaginal suppositories), and parenteral dosage forms (e.g. dosage forms for intravenous, intraarterial, intramuscular, subcutaneous, intraorgan, intraperitoneal, or intrafocal injection) .
  • dosage forms for external application e.g. transnasal DDS , transdermal DDS, etc.
  • suppositories e.g. rectal and vaginal suppositories
  • parenteral dosage forms e.g. dosage forms for intravenous, intraarterial, intramuscular, subcutaneous, intraorgan, intraperitoneal, or intrafocal injection.
  • the pharmaceutical composition of the present invention (hereinafter sometimes referred to briefly as the present composition) can be administered to mammalian animals (e.g. the mouse, rat, hamster, rabbit, cat, dog, bovine, horse, sheep, monkey, human, etc.), with assurance of safety and uncompromised expression of the very favorable pharmacologic actions of the cyclazine compound.
  • mammalian animals e.g. the mouse, rat, hamster, rabbit, cat, dog, bovine, horse, sheep, monkey, human, etc.
  • the compound (la) inclusive of its pharmaceutically acceptable salt for use in the present invention has very favorable PDGF inhibitory activity, antihypertensive activity, antinephropathic (renal disease ameliorating) activity, and hypolipidemic activity, and is of low toxicity.
  • the pharmaceutical composition comprising compound (la) or a salt thereof can be safely used for preventing or treating hypertension, renal diseases [e.g. acute renal failure, diabetic nephropathy, nephritis (e.g. chronic or acute glomerulonephritis such as mesangial proliferative glomerulonephritis, endocapillary proliferative glomerulonephritis, membranoproliferative glomerulonephritis type I, II, III, crescentic glomerulonephritis, diffuse sclerosing glomerulonephritis), etc.], arteriosclerosis, restenosis after PTCA and other vascular diseases, rheumatoid arthritis, cancers, and hyperlipemia, among other diseases.
  • renal diseases e.g. acute renal failure, diabetic nephropathy, nephritis (e.g. chronic or acute glomerulonephritis such as mesangial prolifer
  • the present composition may optionally contain one or more other medicinally active ingredients in addition to compound (la) or its salt.
  • additional active ingredients there is no particular limitation on such additional active ingredients insofar as the object of the invention may still be successfully accomplished, and those active ingredients may be incorporated in suitable proportions .
  • active ingredients are diuretics, angiotensin II receptor antagonists, calcium channel blockers, ACE inhibitors, chymase inhibitors, HMG-CoA reductase inhibitors, and squalene synthase inhibitors, among others.
  • the dosage of the present composition comprising compound (la) or a salt thereof depends on the route of administration and the patient's clinical status, age and body weight, among other factors. However, when the composition is to be administered orally to an adult patient with hypertension, the recommended dosage as compound (la) or its salt is 0.01-300 mg/kg/day, preferably 0.5-50 mg/kg/day, and more preferably 5-30 mg/kg/day, which may be administered once a day or in a few divided doses daily.
  • the route of administration may be oral or non-oral .
  • a daily dose of 0.1 to 30 mg/kg, preferably 0.05 to 50 mg/kg, more preferably 2 to 30 mg/kg, in terms of the compound (la) or a salt thereof is given once or divided into several times .
  • the pharmaceutical composition of the present invention is advantageous in that the oxidative decomposition of the oxygen-labile tricyclic compound and the consequent formation of oxidation products are inhibited to improve its shelf-life and that the diminution of the pharmacologic actions of the compound in the course of manufacture and/or by gastric acid and other digestive juices after administration is well suppressed. Therefore, in the pharmaceutical composition of the present invention, the tricyclic compound retains its pharmacologic activities intact throughout the usual storage period and can be expected to exhibit its therapeutic efficacy with greater certainty after oral administration.
  • ethyl 2-chloro-2- formylacetate (K salt) (700 mg, 3.69 mM) and 6-amino-2- methylpyridine (399 mg, 3.69 mM) were added to ethanol (20 ml), and after addition of acetic acid (0.53 ml, 9.23 mM) , the mixture was refluxed for 3 hours. The solvent was then distilled off under reduced pressure and the residue was dissolved in ethyl acetate (20 ml)- purified water (20 ml) . To this solution was added a saturated aqueous solution of NaHC0 3 until the water layer had been brought to pH 8.
  • Trans-4-(tert-butoxycarbonylmethyl)amino-l- cyclohexanemethanol (i) Synthesis of trans-4-(tert-butoxycarbonylmethyl ) amino-1-cyclohexanecarboxylic acid To a suspension of 23.6 g (150 mM) of trans-4- aminomethyl-cyclohexane-1-carboxylic acid in 150 ml of water and 100 ml of THF, was added 20.8 ml (150 mM) of triethylamine and then 32.7 g (150 mM) of di-tert-butyl carbonate dropwise at room temperature. The reaction mixture was stirred at room temperature for two hours .
  • 1,4 , 8b-triazaacenaphthylen-3-one (580 mg, 1.44 mM) in ethanol (10 ml) was added 12N-hydrochloric acid (0.24 ml, 2.88 mM) and the mixture was stirred. This solution was concentrated under reduced pressure and the resulting precipitate was recovered by filtration.
  • the solution was 2N aqueous NaOH solution until the solution became pHIO with ice-cooling and was extracted with 100 ml of ethyl acetate.
  • the organic layer was washed 100 ml of saturated aqueous NaCl solution and dried over MgS0 4 and the solvent was distilled off under reduced pressure.
  • soft elastic capsules were prepared as follows. After the medium-chain fatty acid triglyceride (Panasate 875) was melted in a water bath, glycerol monostearate was dispersed therein and the mixture was allowed to cool. To this mixture was added compound A and the composition was dispersed with Polytron homogenizer for 3 minutes. The resulting dispersion was dispensed using a rotary capsule filling machine to provide soft gelatin capsules . Alkali-treated gelatin was used as the capsule shell material and glycerol and sorbitol were used as plasticizers .
  • Control Example 1 Using HPC-L as a binder, compound A, lactose, and corn starch were kneaded in a mortar and the kneaded mass was dried in vacuo. This dried mass was pulverized in a mortar, sieved, and blended with corn starch and magnesium stearate. Using a rotary tablet machine, the mixture was compressed to provide tablets in accordance with the recipes shown in Table 3.
  • Example 2 The preparations obtained in Examples 1 and 2 and Control Example 1 were respectively stored in stoppered containers at 35°C for 16 weeks. Then, the amount of oxidative decomposition products was investigated as in Example 1. It was found that whereas the oxidative decomposition rate of the tablets according to Control Example 1 was 3.8%, the oxidative decomposition of the soft gelatin capsules according to Examples 2 and 3 had been invariably suppressed to 0.3%. Test Example 2
  • Compound A was mixed with the various antioxidants (citric acid, ascorbic acid, sodium hydrogensulfite) in a uniform ratio of 1:1.
  • the oxidative decomposition rate in Compound A single or Compound A mixed with antioxidants were investigated after 4 weeks in stoppered contains at 40 °C. The results are shown in Table 4.
  • the present invention provides a pharmaceutical composition which contains an oleginous base and a tricyclic compound or a pharmaceutically acceptable salt .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique qui contient une base oléagineuse et un composé tricyclique ou un sel pharmaceutiquement acceptable.
PCT/JP1997/004819 1996-12-27 1997-12-25 Compose tricyclique stabilise Ceased WO1998029136A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53402/98A AU5340298A (en) 1996-12-27 1997-12-25 Stabilized tricyclic compound

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JP34925696 1996-12-27
JP8/349256 1996-12-27

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WO1998029136A1 true WO1998029136A1 (fr) 1998-07-09

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000054775A1 (fr) * 1999-03-12 2000-09-21 Basf Ag Forme galenique pharmaceutique stable pour anhydrate de paroxetine
US8362030B2 (en) 2008-03-14 2013-01-29 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.R.L. Tricyclic derivatives as inhibitors of poly(ADP-ribose) polymerase (PARP)
WO2022089406A1 (fr) * 2020-10-26 2022-05-05 上海青煜医药科技有限公司 Composé hétérocyclique condensé contenant de l'azote, son procédé de préparation et son utilisation

Citations (6)

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Publication number Priority date Publication date Assignee Title
US4105791A (en) * 1976-03-22 1978-08-08 The Dow Chemical Company Hypolipidemic cycloalkylaminobenzoic acids
GB2164254A (en) * 1984-08-30 1986-03-19 Oreal Stable topical compositions of anthralin
EP0474126A1 (fr) * 1990-09-04 1992-03-11 Fujisawa Pharmaceutical Co., Ltd. Onguents à base de composés tricycliques
WO1994007488A1 (fr) * 1992-10-07 1994-04-14 Pfizer Inc. Compositions pharmaceutiques de 2-oxindole-1-carboxamide a substitution en position 3
WO1995027492A1 (fr) * 1994-04-07 1995-10-19 Smithkline Beecham P.L.C. Base libre de l'halofantrine destinee au traitement du paludisme et compositions
WO1996002542A1 (fr) * 1994-07-15 1996-02-01 Takeda Chemical Industries, Ltd. Composes tricycliques, leur production et utilisation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4105791A (en) * 1976-03-22 1978-08-08 The Dow Chemical Company Hypolipidemic cycloalkylaminobenzoic acids
GB2164254A (en) * 1984-08-30 1986-03-19 Oreal Stable topical compositions of anthralin
CA1272449A (fr) * 1984-08-30 1990-08-07 Jean-Pierre Laugier Composition stable d'anthraline dans des triglycerides d'acides gras satures d'origine vegetale ayant de 6 a 12 atomes de carbone
EP0474126A1 (fr) * 1990-09-04 1992-03-11 Fujisawa Pharmaceutical Co., Ltd. Onguents à base de composés tricycliques
WO1994007488A1 (fr) * 1992-10-07 1994-04-14 Pfizer Inc. Compositions pharmaceutiques de 2-oxindole-1-carboxamide a substitution en position 3
WO1995027492A1 (fr) * 1994-04-07 1995-10-19 Smithkline Beecham P.L.C. Base libre de l'halofantrine destinee au traitement du paludisme et compositions
WO1996002542A1 (fr) * 1994-07-15 1996-02-01 Takeda Chemical Industries, Ltd. Composes tricycliques, leur production et utilisation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000054775A1 (fr) * 1999-03-12 2000-09-21 Basf Ag Forme galenique pharmaceutique stable pour anhydrate de paroxetine
US6596309B2 (en) 1999-03-12 2003-07-22 Basf Aktiengesellschaft Stable pharmaceutical dosage form for paroxetin anhydrate
US8362030B2 (en) 2008-03-14 2013-01-29 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.R.L. Tricyclic derivatives as inhibitors of poly(ADP-ribose) polymerase (PARP)
WO2022089406A1 (fr) * 2020-10-26 2022-05-05 上海青煜医药科技有限公司 Composé hétérocyclique condensé contenant de l'azote, son procédé de préparation et son utilisation

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