WO2001076582A1 - Micro-emulsions huile dans eau contenant des composes tricycliques ou des preconcentres de ceux-ci - Google Patents

Micro-emulsions huile dans eau contenant des composes tricycliques ou des preconcentres de ceux-ci Download PDF

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Publication number
WO2001076582A1
WO2001076582A1 PCT/JP2001/002617 JP0102617W WO0176582A1 WO 2001076582 A1 WO2001076582 A1 WO 2001076582A1 JP 0102617 W JP0102617 W JP 0102617W WO 0176582 A1 WO0176582 A1 WO 0176582A1
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substituent
ring
lower alkyl
concentrate
optionally
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PCT/JP2001/002617
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English (en)
Japanese (ja)
Inventor
Kohsaku Kawakami
Takayoshi Yoshikawa
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Shionogi & Co., Ltd.
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Priority to AU2001244610A priority Critical patent/AU2001244610A1/en
Publication of WO2001076582A1 publication Critical patent/WO2001076582A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention improves the bioavailability (hereinafter referred to as BA), and reduces the effects of the type of food, the presence / absence and the amount of intake on BA, and reduces the individual differences in BA. For microemulsions or pre-concentrates. Background art
  • JP-A-2-2-12929, JP-A-5-186365 and JP-A-7-138161 have cyclosporine or macrolide as the main agent, and 1,2-propylene.
  • a microemulsion pre-concentrate containing a hydrophilic phase such as glycol, a lipophilic phase such as glycerin trifatty acid ester and mixed mono-, di-, and tri-glycerides and a surfactant is described.
  • WO 96/1 32 773 describes a preconcentrate of Mike D emulsion containing a poorly soluble drug as the main drug, but the only drugs actually used are cyclosporine and macrolide. The effect on other drugs is not shown. Furthermore, none of these suggests the use of the glycerin monofatty acid ester used in the present invention alone.
  • W097 / 39999, WO98 / 04508 and W099 / 38829 describe a tricyclic compound used as a main ingredient in the composition of the present invention. There is no mention of pre-concentrate Absent. Disclosure of the invention
  • a micro-emulsion of the above-mentioned compound (I) achieves a much more improved BA effect than expected. More specifically, the present invention relates to a microemulsion or a pre-concentrate thereof having excellent BA, and reducing the influence of the type of meal, the presence or absence and the amount of intake on BA, and the individual difference of BA. The purpose is to provide.
  • the present invention is a.
  • a ring, B ring and C ring may each independently have an aromatic carbocyclic ring or a substituent which may have a substituent, or may be condensed with a benzene ring A 5 or 6 membered heterocycle,
  • ring A ⁇ , ring B and / or ring C are a 5-membered hetero ring which may have a substituent, WW 2 and / or W 3 represent a bond.
  • X is a single bond, one 0—, one CH 2 —, —NR 1 — (where R 1 is hydrogen, lower alkyl, lower alkenyl or lower alkylcarbonyl which may have a substituent) or one S (0 ) p— (where p is an integer from 0 to 2)
  • Y is hydrogen, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), lower alkenyl optionally having substituent (s), optionally having substituent (s) Lower alkynyl, optionally substituted acyl, cycloalkyl optionally substituted, cycloalkenyl optionally substituted, lower alkoxycarbonyl optionally substituted , Even if it has a substituent A good sulfamoyl, an amino which may have a substituent, a aryl which may have a substituent or a 5- or 6-membered heterocyclic group which may have a substituent,
  • R 1 and Y are joined together to form (CH 2 ) m—, — (CH 2 ) 2 -Q- (CH 2 ) 2-, where Q is CH 2 , 0, S or NR, ,
  • Y may be halogen;
  • Y may be a lower alkylsulfonyl optionally having a substituent or an arylsulfonyl optionally having a substituent.
  • a pharmaceutically acceptable salt or solvate thereof and a glycerin monofatty acid ester and / or a propylene glycol monofatty acid ester and a surfactant, and an oil-in-water microemer. Roussillon pre-concentrate,
  • the main drug has the formula (la): , 13 R 12 R. R ° R 3 R 4
  • R 4, R 5, R 6, R 7, R 8, R g, R 10, R 1 1 R 1 2, R 13, R 14 and R 1 5 are each independently hydrogen, halogen, Hydroxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), carboxy or lower alkoxycarbonyl,
  • X 1 and X 2 are each independently 10 —, —CH 2 — or 1 NH—, and Y 1 and Y 2 are each independently a lower alkyl which may have a substituent. Is an aryl lower alkyl which may have or a lower alkenyl which may have a substituent)
  • the active ingredient has the formula (lb):
  • ring C may have a substituent, and is a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms, and when ring C is a 5-membered heterocyclic ring, W 3 represents a bond, and other symbols are the same as [3].)
  • [6] 0.1 to 20% by weight of the active ingredient based on the whole pre-concentrate, and 10 to 90% of glycerin monofatty acid ester and / or propylene dalicol monofatty acid ester
  • the pre-concentrate according to any one of [1] to [5], comprising 5 to 80% by weight of a surfactant.
  • a pharmaceutical preparation comprising the pre-concentrate according to any one of [1;] to [9],
  • An oil-in-water microemulsion comprising the pre-concentrate according to any one of [1] to [9] and a hydrophilic component in an amount of 2 to 100 times (weight ratio) of the pre-concentrate, [14] The oil-in-water microemulsion according to [13], wherein the hydrophilic component is water, alcohol and / or polyol.
  • oil-in-water type microemulsion preconcentrate refers to an oily solution containing a lipophilic component and a surfactant, and is administered to a living body when mixed with a large amount of a hydrophilic component. It is designed to form an oil-in-water microemulsion when mixed with gastric juice. Also, the pre-concentrate has a small amount of hydrophilic A component may be contained, and in this case, a water-in-oil type microemulsion is obtained. This acts as a pre-concentrate of the oil-in-water microemulsion, and forms an oil-in-water microemulsion when mixed with a large amount of a hydrophilic component.
  • Microemulsion is an equilibrated solubilizing solution. Usually, it is solubilized in a slightly liquid but incompatible liquid, and has an average particle diameter of 1 nm to 100 nm or less, more preferably about 5 nm to 20 nm. It is known that because it is thermodynamically stable, it remains transparent or translucent without suspension for a long period of time even at room temperature.
  • any of the above compounds (I) is suitably used as the crude drug, but the following compounds are preferred.
  • Ring A which may have a substituent (halogen, hydroxy, lower alkyl, lower alkoxy, carboxy or lower alkoxycarbonyl), pyridine ring, pyrimidine, pyridazine ring or pyrazine.
  • a ring is A 1)
  • ring A is a benzene ring, a pyridine ring or a pyrimidine ring each of which may have a substituent (halogen, hydroxy or lower alkoxy) (hereinafter, ring A is A 2);
  • ring A is a benzene ring or a pyridin ring each of which may be substituted with halogen (hereinafter, ring A is A 3);
  • ring A is a benzene ring which may be substituted with halogen
  • ring A is a pyridine ring which may be substituted with halogen
  • B has a substituent (halogen, hydroxy, lower alkyl which may have a substituent, lower alkoxy which may have a substituent, or A benzene ring which may have (hereinafter, B ring is B 1) a compound,
  • ring B is a benzene ring which may have a substituent (halogen, hydroxy, lower alkyl, lower alkoxy or lower alkoxycarbonyl) (hereinafter, ring B is B 2),
  • C ⁇ is a benzene ring, pyridine ⁇ , pyrimidine ring, pyridazine ring or virazine ring (these are halogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylamino, cycloalkyl lower alkylamino and z or lower alkenyl) Which may be substituted by amino) (hereinafter, c ⁇ is c 1)
  • C ring is a benzene ring or pyridine ⁇ (these are halogen, lower alkyl, lower A compound which may be substituted with alkoxy, prenyloxy, lower alkylamino, cycloalkyl lower alkylamino and / or prenylamino) (hereinafter, the C ring is C 2),
  • Y is Y 1
  • Y is Y 2
  • R 6 and R 7 is hydrogen and the other is halogen a
  • R 8 , R 9 , R 1 Q and R 11 are each independently hydrogen, hydroxy, lower alkyl, lower alcohol Xy or lower alkoxycarbonyl, other symbols are as defined in [1])
  • —X 1 —Y 1 and —X 2 —Y 2 each represent a lower alkylamino which may have a substituent or a lower alkyl which may have a substituent.
  • a compound which is alkenylamino and the other is prenyloxy,
  • One X 2 -Y 2 when one X 1 -Y 1 is Pureniruokishi is a good lower Arukeniruamino have a lower Arukiruamino or a substituent but it may also have a substituent group
  • one X 1 - Y 1 is one X 2 when it is Pureniruamino - Y 2 is a substituted lower Arukeniruo carboxymethyl have a substituted lower Arukiruokishi be substituted or a substituent
  • ring A, ring B and ring C each independently may have a benzene ring or a substituent which may have a substituent, and may contain 1 or 2 heteroatoms.
  • WW 2 and Z or W 3 are bonded when the A or B ring and / or the C ring is a 5-membered hetero ring which may have a substituent.
  • X 3 is one 0— or one NH—
  • R c and R d are each independently hydrogen, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), lower alkynyl optionally having substituent (s), substitution Lower alkoxy optionally having a group, lower alkylthio optionally having a substituent, lower alkenyloxy optionally having a substituent, lower alkynylo optionally having a substituent Xy, cycloalkyl optionally having substituent (s), aryl which may have substituent (s), or 5- or 6-membered heterocyclic group optionally having substituent (s), Together form an optionally substituted cycloalkylidene with the carbon atoms attached together;
  • R e is each independently hydrogen, lower alkyl, lower alkoxy or amino
  • R f is each independently hydrogen, lower alkyl, lower alkoxy or amino
  • n is an integer of 0 to 2
  • s is It is an integer of 2 to 6.
  • halogen includes fluorine, chlorine, bromine and iodine. Particularly, fluorine and chlorine are preferred.
  • “Lower alkyl” includes straight-chain or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms.
  • Substituents of “lower alkyl optionally having substituent (s)” include halogen; hydroxy; lower alkoxy optionally substituted by lower alkoxy; acyl; acyloxy; carboxy; lower alkoxycarbonyl; mercapto; Lower alkylthio; hydroxy, lower alkyl or aramino optionally substituted with an optionally substituted substituent; hydroxy, lower alkoxy, carboxy lower alkoxy, aryl lower alkoxy or 5 Which may be substituted with a 6-membered or 6-membered heterocyclic group; hydrazono, which may be substituted with carbamoyl or lower alkoxycarbonyl; lower alkyl, lower alkenyl, substituent Substituted with lower alkylidene or cycloalkylidene optionally having Hydrazino which may be substituted; lower alkyl, lower alkenyl, aminooxy optionally substituted with lower alkylidene or cycloalkylidene which
  • lower alkyl moiety of “lower alkoxy” is the same as the above “lower alkyl”.
  • Substituents of "optionally substituted lower alkoxy” include halogen; hydroxy; lower alkoxy; acyl; acyloxy; carboxy; lower alkoxycarbonyl; lower alkylthio; and lower alkyl which may be substituted with alkyl.
  • “Lower alkylidene” refers to a divalent hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms, and specifically includes methylidene, Examples include ethylidene, propylidene, isopropylidene, butylidene, pentylidene, hexylidene, heptylidene, octylidene, nonylidene, and desylidene.
  • substituent of the “optionally substituted lower alkylidene” examples include a lower alkenyl optionally having a substituent, a lower alkoxy optionally having a substituent, Lower alkylthio which may have a substituent, cycloalkyl which may have a substituent, aryl which may have a substituent or 5-membered which may have a substituent Or a 6-membered heterocyclic group.
  • “Lower alkenyl” refers to a straight or branched chain having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, having one or more double bonds at any position. Alkenyl. Specifically, vinyl, propenyl (2-propenyl, etc.), isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentayl genenyl, hexenyl, isohexenyl, hexogenyl , Heptenyl, octenyl, nonenyl, decenyl and the like.
  • the lower alkenyl part of “lower alkenylamino” is the same as the above “lower alkenyl”.
  • the substituent of the “lower alkenyloxy optionally having a substituent” is the same as the substituent of the “lower alkoxy optionally having a substituent”.
  • lower alkynyl includes linear or branched alkynyl having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Ethynyl, propynyl (such as 2-propynyl), butynyl (such as 2-butynyl), pentynyl, hexynyl, heptynyl, octynyl, noninyl, and decynyl. These have one or more triple bonds at arbitrary positions, and may further have a double bond.
  • the substituent of the “optionally substituted lower alkynyl” is the same as the above-mentioned “optionally substituted lower alkoxy”.
  • ⁇ Acyl '' refers to a group containing 1 to 20 carbon atoms, preferably 1 to 15 carbon atoms, more preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 6 carbon atoms. It includes 1-4 straight-chain or branched chain aliphatic acyl, C 4-9, preferably C 4-7 cycloaliphatic acyl and aroyl.
  • formyl, acetyl, propionyl, butyryl, isoptyryl, valeryl, piperoyl, hexanoyl, acryloyl, propioloyl, methyl acryloyl, crotonyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctyl Includes carbonyl and benzoyl.
  • “Arroyl” means an aromatic acyl formed by removing hydroxy from an aromatic carboxylic acid.
  • the substituent of "optionally substituted acyl” is the same as the above-mentioned “optionally substituted lower alkoxy” substituent, and the cycloaliphatic acyl and arylo are lower alkyl. As a substituent.
  • the substituent is particularly preferably halogen.
  • “Lower alkylcarbonyl” includes aliphatic acetyls having 2 to 4 carbon atoms, and includes acetyl, propionyl, butyryl, isoptyryl and the like. In particular, acetyl is preferred.
  • Cycloalkyl is a carbocyclic group having 3 to 6 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • the substituent of "cycloalkyl optionally having substituent (s)" is substituted with lower alkyl, halogen, hydroxy, carboxy, lower alkoxycarbonyl, lower alkoxy, lower alkylenedioxy, lower alkoxy. Amino or aryl or a 5- or 6-membered heterocyclic group, and one or more optional May be substituted.
  • Cycloalkenyl includes those having one or more double bonds at any position in the above cycloalkyl ring, and specifically includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentenyl, Hexenyl and cyclohexagenyl and the like.
  • the substituent of "cycloalkenyl optionally having substituent (s)” is the same as the substituent of the above “cycloalkyl”.
  • Cycloalkylidene includes a divalent carbocyclic group having 3 to 6 carbon atoms, and specifically includes cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.
  • the substituent of the “cycloalkylidene optionally having substituent (s)” is the same as the substituent of the above “cycloalkyl”, and is preferably an unsubstituted cycloalkylidene.
  • Examples of the substituent of "amino which may have a substituent (s)" include lower alkyl which may have a substituent (here, the substituent means lower alkoxy, cycloalkyl, Good amino (substituent is arylo which may be substituted with acyloxy lower alkoxy), aryl which may have a substituent (substituent is lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl) or A lower alkenyl group; a lower alkynyl group; a cycloalkyl group; a lower alkyl group, a carboxy group, an acyl group, an aryl group which may be substituted with a lower alkoxycarbonyl group; a lower alkyl group optionally substituted with a lower alkyl group; [Where the substituent is halogen or heptoxy] Lower ring carbonyloxy etc.]; lower alkylsulfonyl and the like.
  • “Sulfamoyl optionally having a substituent” includes sulfamoyl and the like which may be substituted with lower alkyl, lower alkenyl, lower alkynyl and the like.
  • “Aromatic carbocycle” is a monocyclic or polycyclic aromatic carbocycle, including a benzene ring, It includes naphthalene ⁇ , anthracene ⁇ , phenanthrene ⁇ and indene rings. Particularly, a benzene ring is preferable.
  • Aryl is a group obtained by removing one hydrogen from a monocyclic or polycyclic aromatic carbocyclic ring, and includes phenyl, naphthyl, anthryl, phenanthryl, indenyl and the like. Particularly preferred is phenyl.
  • the substituents of the "optionally substituted aromatic carbocycle" and the "optionally substituted aryl” are halogen; hydroxy; substituted by halogen or carboxy.
  • Lower alkyl which may be substituted with halogen, aryl, heteroaryl or lower alkoxy; lower alkenyl; lower alkynyl; cycloalkyl; lower alkenyloxy; lower alkynyloxy; cycloalkoxy; Lower alkoxycarbonyl; lower alkenylthio; lower alkynylthio; lower alkyl, cycloalkyl lower alkyl, aryl lower alkyl, heteroaryl lower alkyl, lower alkenyl, cyclyl Alkyl optionally substituted with alkyl, halogen, lower alkoxycarbonyl or lower alkylsulfonyl, amino; lower alkyl, lower alkenyl, lower alkylidene which may have a substituent (s) Or hydrazino optional
  • halogen hydroxy; lower alkyl optionally substituted by halogen; lower alkoxy optionally substituted by aryl or lower alkoxy; lower alkenyloxy; acyloxy; lower alkylthio; lower alkyl, lower alkenyl , Amino optionally substituted by halogen or lower alkylsulfonyl optionally substituted by halogen; nitro; lower alkylsulfonyl; lower alkylsulfonyloxy optionally substituted by halogen; or It is arylsulfonyloxy.
  • aryl portion of "aryl sulfonyl”, “aryl sulfonyoxy” and “aryl lower alkyl” is the same as the above “aryl", and phenyl is particularly preferable.
  • the substituents of "arylsulfonyl optionally having substituent (s)” and “aryl lower alkyl optionally having substituent (s)” are the same as those of the above “aryl which may have substituent (s)". It is the same as the substituent, and an unsubstituted one is particularly preferable.
  • the “5- or 6-membered heterocycle” includes a 5- or 6-membered heterocycle having at least one heteroatom in the ring arbitrarily selected from ⁇ , S, and N.
  • a pyrrole ring imidazole ring, pyrazole II, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazole ring, triazine II, isoxazolyl ring, oxazole ring, oxaziazole ring, isothiazole ring, thiazole ring, thiazole ring, Aromatic hetero ring such as thiadiazole ⁇ , furan ring and thiophene ring, tetrahydropyran ring, dihydropyridine ⁇ , dihydropyridazine ring, dihydrovirazine ring, dioxane ring, oxathiolan ⁇ , thian ring
  • the “5- or 6-membered heterocycle” in the ring A, the ring B or the ring C is preferably 2,5-pyridinedyl and 2,5-pyrimidinedyl.
  • 5- or 6-membered hetero atom containing 1 or 2 hetero atoms refers to a pyrrole ring, imidazole ring, pyrazole II, pyridine ring in the above "5- or 6-membered hetero atom”.
  • Aromatic heterocyclic ring dioxane ring, oxathiolane ring, thiane ring, dihydric pyridine ring, pyrrolidine ring, pyrroline ring, imidazolidine ring, imidazoline ring, virazolidine ring, pyrazoline ring, It includes alicyclic heterocycles such as a lysine ring, a piperazine ring and a morpholine ring. Particularly, an aromatic hetero ring is preferable.
  • Mashiku is 4-pyridyl, 2-off Lil, 3 full Lil, 2-thienyl, 3-Choi two 1,2-dihydropyridine-1-yl, 2,3-dihydropyridazine-6-1yl, 1,2-dihydropyrazine-15-yl and the like.
  • Examples of "5- or 6-membered hetero ring which may be condensed with a benzene ring” include an indole ring, an isoindole ring, a benzoimidazole ring, an indazole ⁇ ⁇ ⁇ , a cinnoline ⁇ , and a phthalazine ring.
  • a 5- or 6-membered hetero ring which may have a substituent and "A 5- or 6-membered hetero ring which may have a substituent and may be condensed with benzene ⁇ ”
  • substituent for “ ⁇ ” include halogen; hydroxy; lower alkyl optionally substituted by hydroxy or alkoxy; halogen, aryl or a 5- or 6-membered heterocyclic group.
  • Optionally lower alkyl (substituent is cycloalkyl or 5- or 6-membered heterocyclic group), halogen Conversion which may be Ashiru, lower alkenyl, cycloalkyl properly mono- or di-optionally substituted amino lower alkyl sulfonyl; optionally substituted with lower alkyl sulfonyl imino; lower alkyl, lower Alkenyl, hydrazino optionally substituted with lower alkylidene or cycloalkylidene which may have a substituent; lower alkyl, lower alkenyl, substituted with lower alkylidene or cycloalkylidene which may have a substituent
  • substituents of the "optionally substituted 5- or 6-membered hetero ring containing 1 or 2 hetero atoms" are the same as described above, but are preferably substituted with lower alkyl Or unsubstituted.
  • X, V 1 or V 2 may be directly bonded to a hetero atom which is a constituent atom of the A ring, B ⁇ or C ring.
  • R a and R b together form a connexion one (CR e R f) s-" has such together with the N atom to which R a and R 3 ⁇ 4 are attached connexion, a substituent May form a nitrogen-containing saturated hetero ring, for example, aziridine which may have a substituent, azetidine which may have a substituent, or a substituent which may have a substituent. ⁇ pi-D-lysine, optionally substituted piperidine and optionally substituted perhydrazepine (where the substituents are lower alkyl, lower alkoxy, Or amino).
  • a plurality of R e and a plurality of R f may each independently represent hydrogen, lower alkyl, lower alkoxy or amino, and specifically, one (CH 2 ) 2- , one (CH 2 ) 3 -,- CH (Me) (CH 2 ) 3 —, one CH 2 CH ( ⁇ Me) (CH 2 ) 3 —, one (CH 2 ) 3 CH (NH 2 ) (CH 2 ) 2 — and the like.
  • Pharmaceutically acceptable salts of the compound (I) according to the present invention include, for example, salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid; formic acid, acetic acid, liquor Salts of organic acids such as lithic acid, lactic acid, cunic acid, fumaric acid, maleic acid, and succinic acid; salts of organic salts such as ammonium, trimethylammonium, and triethylammonium; Examples thereof include salts of alkali metals such as potassium and potassium, and salts of alkaline earth metals such as calcium and magnesium.
  • mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid
  • formic acid acetic acid, liquor Salts of organic acids such as lithic acid, lactic acid, cunic acid, fumaric acid, maleic acid, and succinic acid
  • Compound (I) may contain a solvate, and is preferably a hydrate. Further, it may contain all stereoisomers (for example, atrob isomers).
  • Compound (I) can be produced, for example, by the methods described in W097 / 39999, WO98 / 045008, W099 / 38829, and the like. Further, it can be synthesized by the following method.
  • the compound (Ic) can be produced from a compound represented by the formula (II) (hereinafter, referred to as compound (II)) and a compound represented by the formula (III) (hereinafter, referred to as compound (III)). it can.
  • the substituent L is a leaving group such as halogen, lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonyloxy, or arylsulfonyloxy, etc. Yes, other symbols are as defined above)
  • Compounds (II) and (III) are converted to a suitable solvent (eg, benzene, toluene, acetone, acetonitril, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, pyridine, methanol, ethanol, etc.). ) In the presence of a base (for example, sodium hydride, potassium butoxide, pyridine, triethylamine, potassium carbonate, sodium hydroxide or potassium hydroxide, etc.) at 0 ° C The reaction is carried out for several minutes to several tens of hours under heating to obtain the desired compound (Ic).
  • a base for example, sodium hydride, potassium butoxide, pyridine, triethylamine, potassium carbonate, sodium hydroxide or potassium hydroxide, etc.
  • the compound (II) is reacted with hydrazine in an appropriate solvent (eg, toluene, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, pyridine, methanol or ethanol) or without a solvent to react with the compound.
  • an appropriate solvent eg, toluene, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, pyridine, methanol or ethanol
  • an appropriate solvent eg, toluene, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, pyridine, methanol or ethanol
  • the obtained compound is combined with a carbonyl compound (IV) such as ketone or aldehyde,
  • a carbonyl compound (IV) such as ketone or aldehyde
  • dehydration condensation in the presence of an acid catalyst gives the target compound (I c ′).
  • a suitable solvent eg, toluene, tetrahydrofuran, dioxane, or methylene chloride.
  • acid hydrochloric, such as acetic acid or perchloric acid
  • the compound (Ic) in which Ra and Rb are hydrogen can also be synthesized from a compound represented by the formula (II ') (hereinafter, referred to as compound (II')).
  • a suitable base eg, sodium hydride, potassium teptoxide.
  • the compound (I c) is obtained by reacting a compound represented by the formula (V) (hereinafter, referred to as compound (V)) with a compound represented by the formula (VI) (hereinafter, referred to as compound (VI)). It can also be manufactured.
  • M and is one of dihydric Dorokishiboriru, or di-lower alkyl boryl a di-lower Arukokishiboriru, the other is halogen or - 0 S 0 2 (C q F 2 q + 1) (q is 0 And the other symbols are as defined above.
  • the compound (V I) a known compound may be used, or a compound obtained by the same method as the above compounds (I c) and (I c,) may be used.
  • One of the substituents M and D is a Suzuki reaction (Chemical Communication 1997, 866, Journal of Synthetic Organic Chemistry, 1993, Vol. 51, No. 11) , P. 91 to p. 100), any of which can be used, and is preferably dihydroxyboryl.
  • the other may be any applicable leaving group in reaction Suzuki, such as halogen or - a 0 S 0 2 (C q F 2 a + 1) (where q is an integer from 0 to 4), etc.
  • halogen, trifluorene sulfonyloxy hereinafter referred to as 0 Tf
  • 0 Tf trifluorene sulfonyloxy
  • bromine, iodine or OTf is most preferable.
  • substituents on the A ring, B ⁇ and C ring of the compounds (V) and (VI) and —X—Y are groups that do not affect the Suzuki reaction, such as halogen and 1 S 0 2 (C q F 2 q + 1 ) (where q is an integer of 0 to 4), and may be any group. Even if any of the substituents on ring A, ring B and ring C is halogen, the substituent This reaction can proceed without hindrance if the reactivity with the substituent D is higher than these.
  • the substituent Q when the substituent Q is hydroxy, it can be converted to halogen under ordinary conditions, and a suitable sulfonylating agent (eg, methanesulfonyl chloride, ⁇ -toluenesulfonyl chloride) Or anhydrous trifluorene Sulfonic acid) can also be used to obtain the target compound.
  • a suitable sulfonylating agent eg, methanesulfonyl chloride, ⁇ -toluenesulfonyl chloride
  • anhydrous trifluorene Sulfonic acid can also be used to obtain the target compound.
  • a suitable protecting group such as benzyl, t-butyldimethylsilyl, or methoxymethyl
  • an appropriate oxidizing agent eg, hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, oxone monopersulfate compound (eg, hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, oxone monopersulfate compound) Etc.
  • an appropriate oxidizing agent eg, hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, oxone monopersulfate compound
  • the above-mentioned Suzuki reaction is most efficient, convenient and preferred, but as described in WO98 / 0508, the boryl group in the above-mentioned scheme is used.
  • the reaction can be carried out using silicon, zinc, tin or the like.
  • a compound having a substituent that hinders the above reaction may be protected with a suitable protecting group in advance, and then eliminated at a suitable stage by a usual method. For example, if hydroxy hinders the reaction, protect it with methoxymethyl, methanesulfonyl, benzyl, trifluoromethanesulfonyl, t-butyldimethylsilyl, etc. and remove it at an appropriate stage. I just need. Since the compound (I) has an inhibitory action on IgE antibody production and an inhibitory action on the differentiation of Th0 cells into Th2 cells, the microemulsion of the present invention and its pre-concentrate are immunosuppressive or antiallergic. Can be used as an agent.
  • an immunosuppressant or an antiallergic agent containing the microphone mouth emulsion of the present invention or a pre-concentrate thereof can be used for the prevention or treatment of transplant immunity (chronic GVHD), autoimmune disease, atopic allergic disease and the like. Useful.
  • the glycerin monofatty acid ester (hereinafter may be referred to as MG) used in the present invention is preferably MG having 8 to 12 carbon atoms in each fatty acid (for example, glycerin monoporic acid ester, glycerin monoporic acid ester). Glycerin monolau Phosphate ester, etc.).
  • MG glycerin monofatty acid ester
  • Glycerin monolau Phosphate ester etc.
  • a product known under the trade name of Homotex-1 P ⁇ manufactured by Kao Corporation
  • These can be used alone, but two or more kinds of MG may be mixed and used at an arbitrary ratio.
  • propylene glycol monofatty acid ester preferably, a monoester of a medium-chain fatty acid having 8 to 12 carbon atoms in the fatty acid is used.
  • MP propylene glycol mono-propyl ester, propylene glycol mono-propyl ester, propylene glycol monolaurate ester, and the like, and more specifically, known under the trade name of Cefsol 218 (manufactured by Nikko Chemicals Co., Ltd.). Things may be used. These can be used alone, but it is also possible to use a mixture of two or more MPs.
  • MG alone or MP alone can achieve the expected effect sufficiently, these may be mixed in any ratio.
  • the surfactant used for the pre-emulsion concentrate of the present invention is not particularly limited, but a hydrophilic surfactant is preferred.
  • a hydrophilic surfactant is preferred.
  • alkyl sulfates eg, sodium lauryl sulfate, sodium cetyl sulfate, etc.
  • sucrose fatty acid esters eg, sodium cholate, sodium deoxycholate
  • sulfosuccinate esters eg, disodium succinate
  • Octyl sulfosuccinate eg, disodium succinate
  • polyoxyethylene dalicol alkyl ether eg, set macrogol 100, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, etc.
  • polyethylene glycol fatty acid ester eg, polyethylene glycol monostearin) Acid ester, etc.
  • polyoxyethylene glycolated vegetable oil polyoxyethylene glycolated hydrogenated vegetable oil (eg, polyoxyethylene hydrogenated castor oil
  • polyoxyethylene glycolated polypropylene glycol for example, pull nick) F 87, Pull mouth nick F68, Pull mouth nick P123, Pull mouth nick P84, Pluronic F127, Pluronic L-44, etc.
  • Preferred are polyoxyethylene glycolated hydrogenated vegetable oil, polyoxyethylene glycolated sorbin fatty acid ester, polyoxyethylene glycolated polypropylene glycol or polyethylene glycol alkyl ether. Any of these surfactants may be used alone, or any of several (preferably about 2 to 3) may be appropriately selected and used.
  • the microemulsion pre-concentrate of the present invention contains 0.1 to 20% by weight, preferably 0.5 to 20% by weight, most preferably 1 to 20% by weight of the compound (I) which is the main drug, based on the whole pre-concentrate. ⁇ 10% by weight, MG and / or MP at 10-90% by weight, preferably 20-80% by weight, most preferably 45-75% by weight, and surfactant at 5-80% by weight, preferably Contains from 10 to 70% by weight, most preferably from 20 to 50% by weight. If the active ingredient is more than this range, it will not completely dissolve in the base and the pharmacological effect will be reduced. Conversely, the pharmacological effect expected when the amount is too small is not obtained.
  • the expected pharmacological effect cannot be obtained due to a low concentration of the active ingredient in the ester, and a microemulsion is difficult to be formed due to a low concentration of the surfactant. It becomes. Conversely, if the amount is less than this range, the solubility of the active ingredient is reduced, and the expected BA is not achieved. If the amount of the surfactant is higher than this range, the solubility of the active ingredient is reduced, and the expected BA is not achieved. On the other hand, when the amount is less than this range, it is difficult to form a microemulsion, and the effect of improving oral absorbability is insufficient, and the expected pharmacological effect cannot be obtained.
  • Part of MG and / or MP is propylene glycol difatty acid ester (hereinafter sometimes referred to as DP), glycerin difatty acid ester (hereinafter DG) And / or glycerin trifatty acid ester (hereinafter sometimes referred to as TG).
  • DP propylene glycol difatty acid ester
  • DG glycerin difatty acid ester
  • TG glycerin trifatty acid ester
  • Propylene glycol difatty acid esters eg, propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol dilaurate, etc.
  • glycerine difatty acid esters each of which preferably has 8 to 12 carbon atoms in each fatty acid.
  • glycerin dicaprylate glycerin dicaprylate, etc.
  • glycerin trifatty acid esters eg, glycerin tri-2-ethylhexanoate, glycerin tricaprylate, glycerin tricaprate, etc.
  • Cefsol 228 (Nikko Chemicals), PDD (Nikko Chemicals), TriFat S-308 (Nikko Chemicals), Triesta F-810 (Nikko Chemicals) ), OD0 (Nissin Essential Oil Co.), Miglyol (Mizpa Trading Co., Ltd.), Panaset (Nippon Oil & Fats Co., Ltd.), Cocona Ido (Kao Corporation), Millitol GM (Henkeir Hakusui), TC G (High-grade alcohol) Industrial products), Sun Fat MCT-6 (Taiyo Kagaku), actors (RIKEN Biyumin), etc., may be used.
  • MG or MP is an essential component for forming a microemulsion, and the effect of the present invention cannot be obtained if the entire amount of MG and MP is replaced with DP, DG and / or TG.
  • the proportion of total ester is 10-90% by weight, preferably 20-80% by weight, most preferably 45-75% by weight, based on the whole pre-concentrate. What is necessary is just to make it.
  • the total ratio of MG and MP in all the esters is preferably at least 10%, more preferably at least 30%. If the ratio of MG and MP is less than this, microemulsion is difficult to form, which is not preferable.
  • microemulsion pre-concentrate of the present invention may contain a small amount of a hydrophilic component in addition to the above components.
  • the hydrophilic component is water (for example, water for injection) or alcohol (for example, water). Or a polyol (such as glycerin, propylene glycol or polyethylene glycol) or a mixture thereof.
  • these hydrophilic components may include a salt having a buffering effect and / or an isotonic effect.
  • physiological saline, Ringer's solution, phosphate buffer, Mcllvaine buffer, Tris / HCl buffer and the like may be used.
  • the amount of the hydrophilic component to be added is preferably about 30% by weight or less, preferably about 0.1 to 20% by weight, more preferably about 3 to 3% by weight, based on the whole microemulsion pre-concentrate after adding the hydrophilic component. What is necessary is just to make it 10 weight%.
  • the pre-concentrate is a water-in-oil type microemulsion, but acts as a pre-concentrate of an oil-in-water microemulsion.
  • ice-philic component is optional. Even without the addition, the pre-concentrate of the microemulsion of the present invention is formed, and the effect is sufficiently achieved. However, when the above amount of the hydrophilic component is added, it becomes possible to formulate various water-soluble pharmaceutical additives (for example, a water-soluble stabilizer and the like) described later in the pre-concentrate.
  • water-soluble pharmaceutical additives for example, a water-soluble stabilizer and the like
  • the microemulsion of the present invention When a large amount of a hydrophilic component is added to the microemulsion preconcentrate of the present invention and mixed, the microemulsion of the present invention is obtained.
  • the hydrophilic component are the same as described above.
  • the addition amount is optional, but is 2 to 100 times (weight ratio), preferably 3 to 50 times (weight ratio), and more preferably 3 to 10 times (weight ratio) the microemulsion pre-concentrate. Ratio).
  • weight ratio weight ratio
  • weight ratio weight ratio
  • weight ratio weight ratio
  • weight ratio weight ratio
  • the amount for obtaining a medicinal effect becomes too large, which is not preferable as a pharmaceutical preparation.
  • the amount is small, the viscosity is too high to be taken as a liquid agent, and the feeling of taking the drug is poor.
  • the method of formulating the microemulsion of the present invention or its pre-concentrate is not particularly limited, and can be obtained, for example, as follows.
  • ordinary pharmaceutical additives may be added at an appropriate stage.
  • preservatives methyl paraben, butyl paraben, etc.
  • chelating agents eg, sodium EDTA
  • absorption promoters potassic acid, oleic acid, linolenic acid, arachidonic acid, 5-methoxysalicylic acid, azone, octylglucopyranoside, salicylic acid
  • sodium, sodium glycocholate, sodium sodium EDTA, sodium phosphate, sodium deoxycholate, lauryl maltoside polycarboxylic acid, oxycarboxylic acid, etc.
  • antioxidants ⁇ -tocopherol, butylhydroxytoluene, Petrohydroxy sodium, fat-soluble vitamin C, L-cystine, L-arginine, sodium thiosulfate, etc.
  • microemulsion thus obtained or its pre-concentrate can be made into a formulation in an appropriate form by a conventional method.
  • Preferred formulations include capsules of pre-concentrates, ready-to-use preparations of pre-concentrates, and microemulsion liquids.
  • the preparation for use at the time of use may be prepared by diluting the microemulsion pre-concentrate with water or the like as needed at the time of ingestion to prepare a microemulsion and taking it.
  • a particularly preferred formulation is a pre-concentrated soft capsule.
  • the dose of the microemulsion of the present invention or its pre-concentrate is preferably set in consideration of the patient's age, weight, type and degree of disease, and the like.
  • the dose may be in the range of about 0.1 to 500 mg / day, preferably about 1 to 200 mg / day, and may be administered once to several times a day.
  • Compound (I) includes poorly water-soluble compounds.
  • BA is affected by meals after administration after meals and fasting. Significant differences can also be expected.
  • the microemulsion of the present invention or its pre-concentrate can efficiently absorb the compound (I) even under fasting without bile acid, and the effects on BA, such as the presence or absence of food intake and individual differences, are significantly reduced, and medicine It can be used as a preparation with high therapeutic effect and high AIJC.
  • the BA of the preparation of the present invention is much higher than the BA when compound (I) is formulated in another form. It is also extremely excellent in comparison with the BA improving effect of microemulsification of a compound generally used as a medicine.
  • the feature of the present invention resides in that a microphone mouth emulsion was successfully formed by combining the compound (I), MG and / or MP, and a surfactant, and a highly useful formulation was obtained. Another feature is that DP, DG and / or TG are added as necessary to improve the solubility and absorption of the active ingredient. The composition ratio of these components is also an important feature for achieving the effects of the present invention.
  • Blood is separated from blood plasma by refrigerated centrifugation (3,000 rpm x 15 min.), And plasma is treated with deproteinization (15,000 rpm x 5 iniii.) By adding an acetonitrile / methanol 1: 1 mixture. Was determined.
  • composition of the formulation used is as follows.
  • Formulation A was prepared in a microemulsion and administered.
  • H-PT Homotex PT
  • Mcllvaine Buffer 0.2mo 1/1, pH7.5
  • X 1 is NH
  • Y 1 is prenyl
  • X 2 is 0, and Y 2 is prenyl
  • R ⁇ (1 -2) In the formula (la), R 4 R 5 R 6 R 7 R 12 R 14 and: R 15 is hydrogen, R 8 R 9 R 10 and R 11 are methyl, R A compound wherein 13 is fluorine, ⁇ 1 is 11 and ⁇ - ⁇ is prenyl, X 2 is 0 and ⁇ 2 is prenyl
  • Table 2 shows the results.
  • a suspension of the compounds (1-1) and (1-2) in 0.5% methylcellulose (MC) was used and administered similarly at 50 mg / dog.
  • MC methylcellulose
  • Test Example 2 Oral administration test using a rat
  • composition of the pre-concentrate used is as follows.
  • the pre-concentrate was diluted with about 2.7-fold Ringer's solution, prepared in a microemulsion, and administered.
  • H-PT Homotex PT
  • Table 4 shows the results.
  • a suspension of compound (I-1) at 10 mg / m 1 in methylcellulose (MC), a Sefsol solution, and a homotex PT solution were used.
  • the dose was administered at 20 mg / kg-rat.
  • H-PT Homotex PT
  • Test Examples 1 and 2 show that the formulation of the present invention exhibits high AUC.
  • microemulsion pre-concentrate The above components were mixed to obtain a microemulsion pre-concentrate.
  • Example 3 The above components were mixed and mixed with 5 g of water to obtain a microemulsion, Example 3
  • the above components were mixed to obtain a pre-concentration of microemulsion and prepared into a soft capsule.
  • the microemulsification of compound (I) makes it possible to produce a formulation that has high bioavailability and is less affected by the presence or absence of food and the amount of food intake. Was. This effect far exceeds the effects generally expected from microemulsification. Therefore, a preparation using the microemulsion of the present invention or a pre-concentrate thereof is a very excellent pharmaceutical preparation for microbial administration.

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Abstract

L'invention porte sur des micro-émulsions qui contiennent chacune un agent principal sélectionné dans le groupe comprenant des composés de la formule générale (I), des sels de ceux-ci acceptables d'un point de vue pharmaceutique et des solvates de ces composés et de leurs sels, un monoester de glycérol avec un acide gras et/ou un monoester de propylène glycol avec un acide gras, et un tensioactif, et des préconcentrés de ces micro-émulsions. Dans cette formule, les noyaux A, B et C représentent chacun un carbo ou hétérocycle aromatique éventuellement substitué ou analogue, à condition qu'un ou plusieurs des noyaux A, B et C représentent chacun un hétérocycle à 5 éléments, W1, W2 et/ou W3 correspondants représentant chacun une liaison ; X représente une liaison simple, -O-, -CH¿2?- ou analogue ; et Y représente un alkyle inférieur, un alcényle inférieure ou analogue.
PCT/JP2001/002617 2000-04-05 2001-03-29 Micro-emulsions huile dans eau contenant des composes tricycliques ou des preconcentres de ceux-ci WO2001076582A1 (fr)

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