WO2006095542A1 - Composition pharmaceutique comprenant un compose amine - Google Patents

Composition pharmaceutique comprenant un compose amine Download PDF

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Publication number
WO2006095542A1
WO2006095542A1 PCT/JP2006/302629 JP2006302629W WO2006095542A1 WO 2006095542 A1 WO2006095542 A1 WO 2006095542A1 JP 2006302629 W JP2006302629 W JP 2006302629W WO 2006095542 A1 WO2006095542 A1 WO 2006095542A1
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Prior art keywords
methyl
ylmethyl
amino
imidazol
group
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PCT/JP2006/302629
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English (en)
Japanese (ja)
Inventor
Koichi Niimura
Shigeyuki Kikumoto
Masashi Yamamoto
Hiraku Tohmiya
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Kureha Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • composition comprising an amine compound
  • the present invention relates to a hygroscopic and Z or safety improved pharmaceutical composition
  • a hygroscopic and Z or safety improved pharmaceutical composition comprising an amine compound as an active ingredient, an improved hygroscopic property of an amine compound, and a Z or stability method.
  • the present invention also relates to a complex of cyclodextrin and an amine compound represented by the formula (1), and use and production thereof.
  • the pharmaceutical composition or complex obtained in the present invention has remarkably improved hygroscopicity and Z or safety, and is extremely useful when used as a raw material for various preparations such as tablets, capsules, powders and the like. It is a useful form.
  • a method for stably taking out an amine compound having a basic group in a molecule in a crystalline state a method of forming a salt by acting an acidic component is known.
  • the types of salts of acidic components used as ethical drugs are hydrochloride, acetate, sulfate, nitrate, lactate, maleate, adipate, and benzene.
  • Non-patent Document 1 Sulfonate, citrate, dodecyl sulfate, fumarate, hippurate, methanesulfonate, oleate, phosphate, stearate, succinate, sulfosalicylate, tannate, Tartrate, terephthalate, p-toluenesulfonate, etc. are known (Non-patent Document 1).
  • the compound of the formula (1) is an amine compound developed by the present inventors as a compound having antiviral properties (Patent Document 1, Patent Document 2). Corresponding crystalline salts are obtained by acting.
  • cyclodextrin is used together with active ingredients of pharmaceuticals for the purposes of 1. Stabilization of pharmaceuticals, 2. Solubilization of pharmaceuticals (improving solubility), 3. Powders of liquid or volatile pharmaceuticals It has been. Furthermore, cyclodextrin is applied to pesticides' pesticides (sustained action) , Avoidance of harmful effects on human body due to volatilization in the air), application to food (heat of food fragrance, stabilization against light, prevention of volatilization, removal of undesirable taste), application to dye (fibers such as nylon) (Non-patent document 2). However, there is no known report example other than Patent Document 3 in which the hygroscopic property, which is a property of the compound itself, is improved by compounding with cyclodextrin.
  • Patent Document 3 describes that the hygroscopicity or deliquescence of a pharmaceutical can be improved by adding a matrix forming agent and a filler to an active ingredient, and cyclodextrin is mentioned as a matrix forming agent. It is not suggested that it can be applied to the amine compound of formula (1) of the present invention to solve a specific problem.
  • polyethylene glycol is known to be used as a pharmaceutical additive in ointment and suppository bases, tablet coating agents, solubilizers, suspending agents, emulsifiers, and the like. . It is also used as a base for surfactants and cosmetics, and as a material, it can be applied to fibers (used for polyurethane foam and spandex), and applied to membranes (used for tests using osmotic pressure). Application to battery materials (insulating materials, electrolyte solvents) and application to drug delivery systems (inhibition of drug degradation and release) have been reported.
  • Non-patent Document 3 Polyethylene glycol is used as a moisture-proofing agent (Non-patent Document 3), but this is added to the drug substance in the formulation process, and the drug substance itself is mixed with the drug compound. It does not improve hygroscopicity or deliquescence.
  • Patent Document 3 also describes an example in which PEG is used as a matrix forming agent. However, it can be applied to the amine compound of formula (1) of the present invention to solve a specific problem. It is not something that suggests.
  • Patent Document 1 Japanese Patent No. 3714948
  • Patent Document 2 International Publication 2005Z085209 Pamphlet
  • Patent Document 3 International Publication No. 2004/060353 Pamphlet
  • Non-patent literature l Latest C.G.Wermuth Drug Discovery Chemistry Volume 2 p349 (Technomic)
  • Non-Patent Document 2 Falmasia, 16 ⁇ (1980), Nol. P34-37
  • Non-Patent Document 3 Pharmaceutical Additives Encyclopedia 2000 (2000) p262-265
  • An object of the present invention is to improve the hygroscopicity or deliquescence of a salt formed from an amine compound represented by formula (1) and an acid.
  • the present invention provides an active pharmaceutical ingredient such as stability, bitterness, solubility, and absorbability (BA: bioavailability), as well as improving hygroscopicity or deliquescence of the amine compound of formula (1).
  • the issue is to obtain the necessary characteristics.
  • Preferred properties when handling the drug substance include excellent stability, low hygroscopicity, large force specific gravity, constant fluidity, powder, etc. Is required.
  • amine compounds it is a common practice to select salts with the lowest possible hygroscopicity by forming salts by the action of various acids as described above. In the case of aminic compounds of), we still faced the problem that the hygroscopicity could not be improved. Therefore, in the present invention, the hygroscopic property of the salt is remarkably improved and the stability is improved by forming a yarn compound of polyethylene glycol and Z or cyclodextrin which does not form a salt with respect to the amine compound. It has been found that it becomes a solid that satisfies the necessary properties as a drug substance.
  • the composition in a pharmaceutical composition containing an amin compound of formula (1) as an active ingredient by adding polyethylene glycol and ⁇ or cyclodextrin to the amin compound of formula (1), the composition is hygroscopic. At the same time, stability, bitterness, solubility, and absorbability could be satisfied.
  • FIG. 1 shows a comparison of the hygroscopicity of an inclusion compound of an amine compound and cyclodextrin of the present invention and an amine compound alone.
  • FIG. 2 shows a comparison of the absorbability of the amine compound and cyclodextrin clathrate of the present invention and the amine compound alone.
  • FIG. 3 shows a powder X-ray diffraction pattern of Compound No. 3 of the present invention.
  • FIG. 4 shows a powder X-ray diffraction pattern of Compound No. 7 of the present invention.
  • FIG. 5 shows a powder X-ray diffraction pattern of Compound No. 9 of the present invention.
  • FIG. 6 shows a powder X-ray diffraction pattern of ⁇ -cyclodextrin.
  • FIG. 7 shows a comparison of the hygroscopicity of the inclusion compound of the amine compound of the present invention and cyclodextrin, the composition of the amine compound of the present invention and polyethylene glycol, and the amine compound alone.
  • FIG. 8 shows a comparison of the hygroscopicity of the inclusion compound of the amine compound of the present invention and cyclodextrin, the composition of the amine compound of the present invention and polyethylene glycol, and the amine compound alone.
  • FIG. 9 shows a comparison of the hygroscopicity of the inclusion compound of the amine compound of the present invention and cyclodextrin, the composition of the amine compound of the present invention and polyethylene glycol, and the amine compound alone.
  • FIG. 10 shows a comparison of the hygroscopicity of the inclusion compound of the amine compound of the present invention and cyclodextrin, the composition of the amine compound of the present invention and polyethylene glycol, and the amine compound alone.
  • FIG. 11 shows the clathrate of the amine compound of the present invention and cyclodextrin, the composition of the amine compound of the present invention and polyethylene glycol, and the hygroscopicity of the amine compound alone.
  • FIG. 12 shows the composition of the amine compound of the present invention and polyethylene glycol, and the hygroscopicity of the amine compound alone.
  • FIG. 13 shows the composition of the amine compound of the present invention and polyethylene glycol and the hygroscopicity of the amine compound alone.
  • FIG. 14 shows the composition of the amine compound of the present invention and polyethylene glycol, and the hygroscopicity of the amine compound alone.
  • FIG. 15 shows the composition of the amine compound of the present invention and polyethylene glycol, and the hygroscopicity of the amine compound alone.
  • FIG. 16 shows the effect of the ratio of the amount of amine compound and polyethylene glycol on the hygroscopicity of the composition of the amine compound and polyethylene glycol of the present invention.
  • FIG. 17 shows the influence of the type of polyethylene glycol on the hygroscopicity of the composition of the amine compound of the present invention and polyethylene glycol.
  • FIG. 18 shows the influence of the quantitative ratio of an amine compound and polyethylene glycol on the hygroscopicity of the composition of the amine compound and polyethylene glycol of the present invention.
  • FIG. 19 shows the influence of the type of polyethylene glycol on the hygroscopicity of the composition of the amine compound of the present invention and polyethylene glycol.
  • the amine compound of the present invention is a compound represented by the following formula (1).
  • a and A are each a monocyclic or polycyclic heteroaromatic ring that may be independently substituted.
  • n, n and n represent an integer of 1 to 3.
  • W is an optionally substituted alkylene group having 1 to 5 carbon atoms, an optionally substituted monocyclic or polycyclic heteroaromatic ring, an optionally substituted monocyclic or polycyclic aromatic ring, V may be substituted, partially saturated, and represents a polycyclic heteroaromatic ring.
  • X is an alkylene group having 1 to 5 carbon atoms that may be substituted, an alkenylene group having 2 to 6 carbon atoms that may be substituted, or an amide, amide-containing sulfonamide, urea, or thiourea of the following formula (2): Any group is shown.
  • An alkyl group having 2 to 15 carbon atoms that may be substituted an alkyl group having 1 to 15 carbon atoms that may be substituted, a cyclic alkyl group having 3 to 15 carbon atoms that may be substituted, and methanesulfo -L group, p-toluenesulfol group, phenol group, acyl group, carboxy group, cyano group, alkoxycarboxy group and phenoxycarboxy group.
  • n and n represent an integer of 0 to 3.
  • R to R are a hydrogen atom, an optionally substituted alkyl group having 1 to 5 carbon atoms, and an optionally substituted carbon.
  • Y is an optionally substituted alkylene group having 1 to 5 carbon atoms, an optionally substituted cyclic alkylene group having 3 to 10 carbon atoms, an optionally substituted monocyclic aromatic ring or heteroaromatic ring, 0, S, NR
  • R is a hydrogen atom, an optionally substituted alkyl group of 1 to 5 carbon atoms,
  • C2-C6 alkyl group C1-C5 alkyl group which may be substituted, C3-C10 cyclic alkyl group which may be substituted, methanesulfol group, p- Toluene sulfo group, phenol group, acyl group, carboxy group, cyano group, alkoxycarboxy group and phenoxycarboxy group are shown.
  • B and B are optionally substituted alkyl groups having 1 to 15 carbon atoms, and optionally substituted 3 to 15 carbon atoms.
  • “may be substituted” means a hydroxy group, a thiol group, a formyl group, a carboxy group, a sulfonyl group, an amino group, an amide group, a strong rubamoyl group, a cyano group, an alkoxy group, and an alkoxycarboxyl.
  • alkylamino group alkylamino group, acylamino group, alkoxycarboamino group, alkylthio group, aminosulfol group, dialkylaminosulfol group, methanesulfonyl group, p-toluenesulfol group, phenol group, halogen atom , Morpholino group, tetrahydrofuranyl group, 5-methyl-2-oxo-1, 3-dioxol-4-yl group, 3-oxo-1,3 dihydro-isobenzofurol group, acyloxy group, alkoxycarbo-loxy group, etc. Represent.
  • the alkoxy group means that an alkyl group, a cyclohexyl group, or a cinnamyl group which may be substituted through an oxygen atom is bonded.
  • the acylamino group is an alkyl group or a phenyl group that is a carbocyclic group.
  • the alkyl group is bonded to the oxygen atom through the carbonyl group, and the alkoxycarboxoxy group is bonded to the amino group through the carbonyl group. It represents that an alkoxy group is bonded to an oxygen atom via a carbonyl group.
  • the compound of the formula (1) is, in particular, a compound in which n, n and n ⁇ are A, A
  • cyclodextrin means only ⁇ , ⁇ , ⁇ type natural cyclodextrin, for example, a hydroxyalkyl such as a methyl group or a hydroxypropyl group in the side chain.
  • Cyclodextrin derivatives in which a carboxyalkyl group such as a carboxy group or a carboxymethyl group, a sulfobutyl group, etc. are introduced are also preferred.
  • Cyclodextrins are natural types of ⁇ , ⁇ , ⁇ , and j8-CD Is most preferred
  • the pharmaceutical composition comprising the amine compound of formula (1) of the present invention and cyclodextrin It is preferable that the amine compound and the cyclodextrin form a complex, and the complex is not limited to the force that is mainly an inclusion complex of cyclodextrin.
  • the mixing ratio of cyclodextrin to the amine compound is preferably 1: 0.5 to 10 in molar ratio.
  • a clathrate compound with a molar ratio of 1: 2 may be formed, or a clathrate compound with a ratio of 1: 3 or 1: 2-4 may be formed.
  • Hygroscopicity and stability increase as the ratio increases
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a complex of an amine compound and cyclodextrin as an active ingredient.
  • the complex of the present invention is particularly used for the treatment or prevention of viral diseases such as AIDS, rheumatic disease improvement, and cancer metastasis disease improvement.
  • the polyethylene glycol (sometimes referred to as "PEG") of the present invention is a polymer compound having a structure in which ethylene glycol is polymerized, and has various liquid powers such as waxy and paraffinic solids having viscosity depending on the degree of polymerization.
  • various liquid powers such as waxy and paraffinic solids having viscosity depending on the degree of polymerization.
  • Polyethylene glycol 200 has an average molecular weight of 190-210
  • polyethylene glycol 300 has an average molecular weight of 280-320
  • polyethylene glycol 400 has an average molecular weight of 380-420
  • polyethylene glycol 600 has an average molecular weight of 570-630
  • polyethylene glycol 1000 has an average molecular weight of 950- 1050
  • polyethylene glycol 1500 has an average molecular weight of 500 to 600
  • polyethylene glycol 1540 has an average molecular weight of 1300 to 1600
  • polyethylene glycol 2000 has an average molecular weight of 1800 to 2200
  • polyethylene glycol 4000 has an average molecular weight of 2600 to 3800
  • polyethylene glycol 6000 has an average molecular weight. 7300-9300
  • polyethylene glycol 20000 refers to those having an average molecular weight of 15000-25000.
  • polyethylene glycol used is polyethylene glycol 2000, polyethylene glycol. Coal 4000, polyethylene glycol 6000, and polyethylene glycol 20000 are preferable, and polyethylene glycol 6000 is particularly preferable.
  • the mixing ratio of the polyethylene glycol to the amine compound can be any weight ratio, but is preferably from 1: 0.1 to 100. A particularly preferred weight ratio is 1: 1 to 10.
  • Hygroscopicity is suppressed as the molecular weight of polyethylene glycol increases, and hygroscopicity is suppressed as the amount ratio of polyethylene glycol increases.
  • Examples of the amine compound forming the pharmaceutical composition with the polyethylene glycol or cyclodextrin of the present invention or the complex of the amine compound and cyclodextrin include the following.
  • an amine compound represented by the formula (1), polyethylene glycol, and an active ingredient having ⁇ or cyclodextrin strength are known pharmacologically acceptable carriers and excipients.
  • the dose may vary depending on the type and severity of the disease, the compound and route of administration, the age, sex, and weight of the patient, but for oral administration, usually 0.1 to 5000 mg, especially 1 to 300 Omg, is administered per adult. It is preferable. In the case of a prodrug, it is particularly preferable to administer 1 to 5000 mg.
  • the present invention also includes an invention of a method for producing a pharmaceutical composition comprising the amine compound represented by the formula (1), polyethylene glycol and Z or cyclodextrin, and the formula (
  • the present invention also relates to a hygroscopic improvement and Z or stability method characterized in that the amine compound represented by 1) contains polyethylene glycol and Z or cyclodextrin.
  • the complex or inclusion complex of the amine compound of the present invention and cyclodextrin can be produced by various methods. That is, by mixing a compound with a suitable cyclodextrin, such as j8-cyclodextrin, and reacting in a suitable solvent system such as ethanol / water, the desired complex or inclusion complex can be obtained.
  • a suitable cyclodextrin such as j8-cyclodextrin
  • a suitable solvent system such as ethanol / water
  • Other well-known methods such as freeze drying, kneading, solvent evaporation, coprecipitation, melting, and spray drying are also possible.
  • Examples 1 to: LO represents a production example of a complex of a preferred amine compound described above or an amine compound and cyclodextrin.
  • LO represents a production example of a complex of a preferred amine compound described above or an amine compound and cyclodextrin.
  • compounds that are not shown in the following production examples are already known from International Publication 2004Z024697 pamphlet or 2005Z085209 pamphlet. It can manufacture with reference to a manufacturing method.
  • N- (4-aminobutyl) strength ruvamic acid t-butyl ester 500 mg is dissolved in methanol 10 ml, propionaldehyde (Tokyo Kasei Co., Ltd.) 0.418 ml, sodium cyanoborohydride 404 mg and orthoacetic acid 1.60 g of trimethyl was added and stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off, chloroform was added, washed with distilled water and saturated brine, and dried over anhydrous sodium sulfate.
  • Example 1-3 Synthesis of (4-Hydroxymethyl-benzyl) -force rubamic acid t-butyl ester 35.7 g of the compound obtained in Example 1-2 was dissolved in 800 ml of anhydrous THF and placed in an ice bath. 10.2 g of aluminum lithium hydride was added and stirred for 2 days under a nitrogen atmosphere. After completion of the reaction, methanol and then aqueous sodium potassium tartrate solution were stirred overnight. This was extracted with black mouth form, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 29.2 g of the title compound as a white solid.
  • Example 1-3 17.6 g of the compound obtained in Example 1-3 was dissolved in 400 ml of black mouth form, 88.2 g of manganese dioxide (chemically treated product) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered through Celite and the solvent was Distilled off to give 20.4 g of the title compound as a white solid.
  • Example 1-5 Synthesis of ⁇ 4-[(4-dipropylamino-ptylamino) -methyl] -benzyl ⁇ -force rubamic acid t-butyl ester
  • Example 1-6 Synthesis of [[4- (t-Butoxycarbo-lamino-methyl) -benzyl]-(4-dipropylamino-butyl) -amino] -acetic acid ethyl ester
  • ⁇ -Z ⁇ :, ⁇ ⁇ U SS I, ⁇ ⁇ ⁇ ⁇ 3 ⁇ 43 ⁇ 4 91-,- ⁇ [-[ ⁇ -(:: ⁇ - ⁇ -[ ⁇ -( ⁇ /-S-/ —, ⁇ - ⁇ - ⁇ - ⁇ ]
  • Example 1-11 [(4-Dipropylamino-butyl)-(4- ⁇ [(1 ⁇ -imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino]- Methyl ⁇ -benzyl) -amino] -acetic acid ester ⁇ -cyclodextrin inclusion complex [I compound ⁇ .4]
  • Example 2-l Synthesis of (4- ⁇ [(4-Dipropylamino-ptyl) -methyl-amino] -methyl ⁇ -benzyl) -carnomic acid t-butyl ester
  • Example 2- 2 Synthesis of N- (4-aminomethyl-benzyl) -N-methyl- ⁇ ', ⁇ '-dipropyl-butane-1,4-diamine
  • Example 2-3 ⁇ - (4- ⁇ [(1 ⁇ -imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl ⁇ -benzyl) -N Of 2-methyl-N ', ⁇ '-dipropyl-butane-1, 4-diamin [I compound ⁇ .5]
  • Example 2-2 12.6 g of the compound obtained in Example 2-2 was dissolved in 250 ml of anhydrous methanol, 6.76 ml of trimethyl orthoformate and 4.36 g of 2-imidazole carboxaldehyde were added, and the mixture was stirred at room temperature for 2 hours and a half in a nitrogen atmosphere. Next, 1.56 g of sodium borohydride was added in an ice bath, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, distilled water was added and stirred for a while. This was extracted with black mouth form, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate.
  • Example 2-4 N- (4- ⁇ [(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl ⁇ -benzyl) -N Of 2-methyl-N ', ⁇ '-dipropyl-butane-1,4-diamin tartrate [I compound ⁇ ⁇ .6]
  • Example 7-1 450 mg of the compound obtained in Example 7-1 was dissolved in 5.0 ml of absolute ethanol, and 5.00 ml of 4 mol / l salt-hydrogen dioxane solution was added and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off. An lmol / 1 sodium hydroxide aqueous solution was extracted with a cake form, washed with saturated saline, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 83 mg of the title compound 2 as a colorless oil.
  • Example 7-3 Synthesis of ⁇ 4-[(4-Dipropylaminomethyl-benzylamino) -methyl] -benzyl ⁇ -carnomic acid t-butyl ester
  • Example 7-2 283 mg of the compound obtained in Example 7-2 was dissolved in 6.0 ml of anhydrous methanol, 281 ⁇ 1 of trimethyl orthoformate and 453 mg of the compound described in Example 1-4 were added, and the mixture was stirred overnight at room temperature in a nitrogen atmosphere. Next, 97.3 mg of sodium borohydride was added in an ice bath, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, and distilled water was added and stirred for a while. This was extracted with black mouth form, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. It was. The solvent was distilled off to obtain 875 mg of the title compound as a colorless oil.
  • Example 7-4 Synthesis of (4- ⁇ [(4-Dipropylaminomethyl-benzyl) -methyl-amino] -methyl ⁇ -benzyl) -force rubamic acid t-butyl ester
  • Example 7-3 454 mg of the compound obtained in Example 7-3 was dissolved in 10 ml of methanol, and 130 mg of sodium cyanoborohydride, 1.00 ml of acetic acid and 61.3 ⁇ 1 of a 37% aqueous formaldehyde solution were added and stirred overnight at room temperature in a nitrogen atmosphere. . After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform and added with lmol / 1 aqueous sodium hydroxide solution and stirred for a while. This was extracted with black mouth form, washed with saturated saline, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 75.7 mg of the title compound as a colorless oil.
  • Example 7-5 Synthesis of (4- ⁇ [(4-Aminomethyl-benzyl) -methyl-amino] -methyl ⁇ -benzyl) -dipropyl-amine
  • Example 7-4 75.7 mg of the compound obtained in Example 7-4 was dissolved in 1.0 ml of anhydrous methanol, and 1.00 ml of 4 mol / l salt-hydrogen dioxane solution was added and stirred at room temperature for 2.5 hours. After completion of the reaction, the solvent was distilled off. To this, lmol / 1 aqueous sodium hydroxide solution was extracted with cake form, washed with saturated saline, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 70.8 mg of the title compound as a colorless oil.
  • Example 7-6 (4- ⁇ [(4- ⁇ [(1 ⁇ -imidazol-2-ylmethyl)-(1-methyl-1H-imidazole-2-ylmethyl) -amino] -methyl ⁇ -benzyl ) -Methyl-amino] -methyl ⁇ -benzyl) -dipropyl-amine hydrochloride [Compound No. 32]
  • Example 7-5 The compound obtained in Example 7-5 (70.8 mg) was dissolved in anhydrous methanol (2.0 ml), and trimethyl orthoformate (32.9 ⁇ l) and 2-imidazole carboxaldehyde (21.2 mg) were stirred overnight at room temperature in a nitrogen atmosphere. Next, 15.2 mg of sodium borohydride was added to the ice bath and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, and distilled water was added and stirred for a while. This was extracted with black mouth form and washed with saturated saline, and the organic layer was anhydrous sodium sulfate. And dried.
  • Example 8-l Synthesis of [2- (2-Amino-ethoxy) -ethyl] -carnomic acid t-butyl ester
  • Example 8-2 Synthesis of [2- (2-dipropylamino-ethoxy) -ethyl] -strength rubamic acid t-butyl ester
  • Example 8-1 279 mg of the compound obtained in Example 8-1 was dissolved in 5.5 ml of anhydrous methanol, trimethyl orthoformate 374 1 and sodium cyanoborohydride 257 mg were added, and propionaldehyde 246 1 was added in an ice bath at room temperature. Stir overnight. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, and distilled water was added and stirred for a while. This was extracted with black mouth form, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. Remove the solvent and remove the residue with silica gel column chromatography. Purification by matography (hexane / ethyl acetate) gave 130 mg of the title compound as a colorless oil.
  • Example 8-2 128 mg of the compound obtained in Example 8-2 was dissolved in 2.0 ml of anhydrous methanol, 2.00 ml of 4 mol / l hydrogen chloride dioxane solution was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. To this, lmol / 1 aqueous sodium hydroxide solution was extracted with cake form, washed with saturated saline, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 81.0 mg of the title compound as a colorless oil.
  • Example 8- 4 Synthesis of 4- (4- ⁇ [2- (2-dipropylamino-ethoxy) -ethylamino] -methyl ⁇ -benzyl) -force rubamic acid t-butyl ester
  • Example 8-5 Synthesis of (4- ⁇ [(4-Dipropylaminomethyl-benzyl) -methyl-amino] -methyl ⁇ -benzyl) -force rubamic acid t-butyl ester
  • Example 8-4 67.2 mg of the compound obtained in Example 8-4 was dissolved in 1.5 ml of methanol, and 31.1 mg of sodium borohydride, 150 ⁇ 1, acetic acid 150 ⁇ 1, and 37% aqueous formaldehyde 18.6 ⁇ 1 were added at room temperature under a nitrogen atmosphere. Stir overnight. After completion of the reaction, the solvent was distilled off, dissolved in black mouth form, saturated aqueous sodium hydrogen carbonate solution was added and stirred for a while. This was extracted with black mouth form, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate.
  • Example 8-6 Synthesis of (2- ⁇ 2-[(4-aminomethyl-benzyl) -methyl-amino] -ethoxy ⁇ -ethyl) -dipylpyramine
  • Example 8-5 102 mg of the compound obtained in Example 8-5 was dissolved in 1.0 ml of anhydrous methanol, 1.00 ml of 4 mol / l hydrogen chloride dioxane solution was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. To this, lmol / 1 aqueous sodium hydroxide solution was extracted with cake form, washed with saturated saline, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 78.5 mg of the title compound as a colorless oil.
  • Example 8-7 (2- ⁇ 2-[(4- ⁇ [(1 ⁇ -imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl ⁇ -Benzyl) -methyl-amino] -ethoxy ⁇ -ethyl) -dipropyl-amine hydrochloride [I compound No.33]
  • Example 8-6 78.5 mg of the compound obtained in Example 8-6 was dissolved in 1.6 ml of anhydrous methanol, 40.1 ⁇ 1 of trimethyl orthoformate and 25.8 mg of 2-imidazolecarboxaldehyde were added, and the mixture was stirred overnight at room temperature in a nitrogen atmosphere. Next, 18.5 mg of sodium borohydride was added in an ice bath, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, and distilled water was added and stirred for a while. This was extracted with black mouth form, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate.
  • Example 9-2 Synthesis of 4- ⁇ [(1 ⁇ -imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyltobenzoic acid methyl ester
  • Example 9-3 Synthesis of 4- ⁇ [(1 ⁇ -imidazole-2-ylmethyl)-(1-methyl-1H-imidazole-2-ylmethyl) -amino] -methyltobenzoic acid
  • the compound 208.lmg obtained in Example 9-4 was dissolved in 8.4 ml of DMF, and WSCI 182.lmg and 128.4 mg of HOBt were added thereto. After stirring at room temperature for 1 hour, 0.141 ml of dipropylamine was added. Stir at room temperature for 16 hours. After the reaction, the solvent was distilled off. It was dissolved in black mouth form and washed with lmol / 1 hydrochloric acid, lmol / 1 aqueous sodium hydroxide solution. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 285.8 mg of the title compound as a colorless oil.
  • ⁇ X ⁇ - ⁇ -[ ⁇ -( ⁇ /-S-/ —, ⁇ - ⁇ - ⁇ - ⁇ )-( ⁇ /
  • Example 10-2 Synthesis of ⁇ , ⁇ -bis- (1 ⁇ -imidazol-2-ylmethyl) -butane-1,4-diamine 933 mg of the compound obtained in Example 10-1 was dissolved in 10 ml of methanol. Then, 10 ml of a 4 mol / l hydrogen chloride / dioxane solution was added at room temperature, followed by stirring at room temperature for 17 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was azeotroped with methanol and concentrated. This was dissolved in methanol, and ion exchange resin IRA-410 was added to adjust the pH to 8. The resin was filtered and the filtrate was concentrated to dryness to give 735 mg of the title compound as a yellow oil.
  • Example 10-3 Synthesis of (5- ⁇ 4- [Bis- (1H-imidazol-2-ylmethyl) -amino] -butylcarbamoyl ⁇ -pentyl) -force rubamic acid-1-butyl ester
  • Example 10-3 81 mg of the compound obtained in Example 10-3 was dissolved in 8 ml of methanol, 8 ml of 4 mol / l hydrogen chloride / dioxane solution was added at room temperature, and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was azeotroped with methanol and concentrated. This was dissolved in methanol, and ion exchanged resin IRA-410 was added to adjust the pH to 8. The resin was filtered off and the filtrate was concentrated to dryness to give 629 mg of the title compound as a yellow oil.
  • Example 10-5 Synthesis of 6-dipropylamino-hexanoic acid ⁇ 4- [bis- (1H-imidazol-2-ylmethyl) -amino] -butyramide hydrochloride [Compound No. 60]
  • Example 10-4 629 mg of the compound obtained in Example 10-4 is dissolved in 12 ml of ethanol, and 1.48 g of sodium triacetoxyborohydride is added at room temperature, and 1-propanal 380 ⁇ 1 is slowly stirred at ⁇ 10 ° C. The mixture was added dropwise and stirred at room temperature under a nitrogen atmosphere for 19 hours. After completion of the reaction, the mixture was poured into 30 ml of a saturated aqueous solution of sodium bicarbonate under ice cooling. The solvent was distilled off under reduced pressure, the residue was dissolved in black mouth form, water was added, and the aqueous layer was extracted with black mouth form. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate.
  • Test Examples 1 to 4 show a hygroscopic test, a solubility test, an absorptivity test, and a powder X-ray analysis for the complex of the amine compound of the present invention and cyclodextrin.
  • Test Example 1 Hygroscopicity test
  • Example 1-9 [Compound No. 2], salt obtained in Example 2-4 [Compound No. 6], obtained in Example 1-10
  • an electronic balance AG245 manufactured by METTLER TOLEDO
  • the weight at the time when a certain period of time passed was measured, and the weight increase was calculated.
  • the measured values for indoor conditions were 23-24 ° C for temperature and 52-64% for humidity. Changes in the weight ratio of each sample are shown in Table 2 and Fig. 1.
  • the amine compound represented by the general formula (1) of the present invention is significantly less hygroscopic than the salt by forming a cyclodextrin clathrate. I know that.
  • Test Example 2 Solubility test The solubility test was conducted in accordance with the method shown in the 14th revised Japanese Pharmacopoeia. That is, the compound obtained in Example 8 [Compound No. 1], the compound obtained in Example 2-3 [Compound No. 5], and the clathrate obtained in Example 1-10 [Compound No. .3] and the clathrate [Compound No. 7] obtained in Example 2-5 were weighed and placed in water (Japanese Pharmacopoeia purified water manufactured by Kyoei Pharmaceutical Co., Ltd.) for 5 minutes at 20 ⁇ 5 ° C. Each time it was vigorously shaken for 30 seconds, the degree of dissolution within 30 minutes was observed, and it was compared with the term for solubility indicated in the 14th revised Japanese Pharmacopoeia. The results and solubility in water are shown in Table 3.
  • Example 2-5 After 5-week-old rats (Crj: CD (SD) IGS, male) were preliminarily raised for 1 week, 30 mg of the salt [Composite No. 6] obtained in Example 2-4 was added to the locally purified water 1.5 What was dissolved in ml was orally administered by lml / kg. Further, 90 ml of the clathrate [I compound No. 7] obtained in Example 2-5 was dissolved in 15 ml of pharmacologically purified water and orally administered at 10 ml / kg. About 0.35 ml of blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration to obtain plasma.
  • Test Example 4 Powder X-ray diffraction
  • Example 10 The inclusion body obtained in Example 10 [Compound No. 3], the inclusion body obtained in Example 2-5 [Compound No. 7], and the complex obtained in Example 2-7 [ Compound ⁇ .9] and ⁇ -cyclodextrin were pulverized in an agate mortar to obtain a measurement sample, and X-ray diffraction was measured with an X-ray diffractometer (RAD-C, Rigaku Corporation). The X-ray tube voltage / tube current was 40 kV / 80 mA.
  • Fig. 3 is Compound No. 3
  • Fig. 4 is Compound No. 7
  • Fig. 5 is Compound No. 9
  • Fig. 6 is a powder X-ray diffraction pattern of -cyclodextrin.
  • Example 5-1 Of the compound described in Example 17-8, a polyethylene glycol composition of Compound No. 17 prepared by the above-mentioned method, Salt [Compound ⁇ .19], Inclusion body [Compound No. 20] obtained in Example 6-1; Polyethylene glycol composition of Compound No. 19 prepared by the above-described method. After weighing using an electronic balance (AG245 manufactured by METTLER TOLEDO), temperature 25. C, put in a tester (mu-2002 manufactured by Isuzu) set to 75% humidity. In the polyethylene glycol composition, the ratio between the salt of the amine compound and the polyethylene glycol is 1: 3 by weight. The weight at a certain time (d is the number of days) was measured, and the weight increase was calculated. Changes in the weight ratio of each sample are shown in Tables 5-9 and Figures 7-11.
  • the amine compound represented by the formula (1) of the present invention is a cyclodextrin inclusion body or a polyethylene glycol composition, so that the cyclodextrin inclusion body and the polyethylene glycol composition are of the same level.
  • the hygroscopicity is significantly reduced compared to salt.
  • the salt of the amine compound represented by the formula (1) of the present invention is significantly hygroscopic compared to the salt by forming a composition to which polyethylene glycol is added. 'Less sex, it's gone!
  • Example 1-9 [Composite No. 2] was prepared. Stir for 30 minutes. Evaporate the solvent and dry to dry, the weight ratio of compound No. 2 to polyethylene glycol Obtained various compositions. Similarly, a small amount of methanol was dissolved in various polyethylene glycols having different degrees of polymerization in a 70 ° C hot water bath and dissolved in methanol there. The salt obtained in Example 2-4 [Compound No. 6] was added and allowed to stir for 30 minutes. The solvent was distilled off and dried to obtain compositions having various weight ratios of Compound No. 6 and polyethylene glycol.
  • compositions were weighed using an electronic balance (AG245, manufactured by METTLER TOLEDO), and then placed in a tester (Isuzu-2002) set at a temperature of 25 ° C and a humidity of 75%. The weight at a certain time elapsed was measured and the weight increase was calculated. Changes in the weight ratio of each sample are shown in Tables 12 and 13 for the types of polyethylene glycol and the weight ratio of Compound No. 2 or Compound No. 6 and polyethylene glycol. Figures 16 to 19 show graphs analyzed by weight ratio of type, compound No. 2 or compound No. 6 and polyethylene glycol.
  • Test Example 6 Stability test
  • Example 1-8 The compound obtained in Example 1-8 [Compound No. 1], the salt obtained in Example 1-9 [Compound No. 2], and the clathrate obtained in Example 1-10 [ Compound No. 3] was weighed and then placed in a stability tester for 60 ° C (Incubator (IS-82) Yamato Kagaku Co., Ltd.). After 4 weeks, HPLC analysis (HPLC column: YMC-PACK ODS-AM302 (150 ⁇ 4.6 mm ID, S-5 ⁇ m, 120A)) manufactured by YMC was used to calculate the purity. Table 14 shows the purity of Compound No.1, Compound No.2, and Compound No.3.
  • the amine compound represented by the formula (1) of the present invention has a markedly increased stability compared to the free amine compound or salt by using a cyclodextrin clathrate. That's right.
  • Test Example 7 Activity test
  • HIV-1-infected MT with 96-well microtiter plate with various concentrations of test compound
  • the improvement effect of rheumatic diseases and cancer metastasis possessed by the amine compound represented by the formula (1) is predicted not to change even when polyethylene glycol and Z or cyclodextrin are contained.
  • the present invention it is possible to improve the hygroscopicity and Z or stability of the amine compound represented by the formula (1), which is difficult to handle due to lack of significant hygroscopicity or stability.

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Abstract

Le problème à résoudre dans le cadre de cette invention consiste à améliorer l’hygroscopicité et/ou la stabilité d’un composé amine représenté par la formule (1). La solution proposée consiste à mélanger le composé amine à un complexe comprenant de la cyclodextrine ou du polyéthylène glycol afin d’améliorer fortement l’hygroscopicité et/ou la stabilité d’un sel du composé, ce qui permet de produire un matériel solide qui satisfait aux conditions nécessaires pour une utilisation en tant que principe actif pharmaceutique (p. ex., la stabilité).
PCT/JP2006/302629 2005-03-04 2006-02-15 Composition pharmaceutique comprenant un compose amine WO2006095542A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010510306A (ja) * 2006-11-22 2010-04-02 エスケー ケミカルズ カンパニー リミテッド シブトラミンとベータ−シクロデキストリンの包接複合体
WO2012158707A1 (fr) 2011-05-16 2012-11-22 Genzyme Corporation Utilisation d'antagonistes de cxcr4
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9267934B2 (en) 2010-10-26 2016-02-23 University Of South Alabama Methods and compositions for ameliorating pancreatic cancer
US9284275B2 (en) 2007-01-11 2016-03-15 Critical Outcome Technologies Inc. Inhibitor compounds and cancer treatment methods

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61130219A (ja) * 1984-11-30 1986-06-18 Dainippon Pharmaceut Co Ltd 塩酸メクロフエノキサ−ト組成物
JPH04202131A (ja) * 1990-11-29 1992-07-22 Tanabe Seiyaku Co Ltd 長期間安定な経口用医薬製剤
JPH05178765A (ja) * 1991-06-21 1993-07-20 Takeda Chem Ind Ltd 溶解性が向上した難水溶性薬物組成物
JP2001261553A (ja) * 2000-03-22 2001-09-26 Tanabe Seiyaku Co Ltd 経口投与製剤
WO2004024697A1 (fr) * 2002-09-11 2004-03-25 Kureha Chemical Industry Company, Limited Composes amines et leurs utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61130219A (ja) * 1984-11-30 1986-06-18 Dainippon Pharmaceut Co Ltd 塩酸メクロフエノキサ−ト組成物
JPH04202131A (ja) * 1990-11-29 1992-07-22 Tanabe Seiyaku Co Ltd 長期間安定な経口用医薬製剤
JPH05178765A (ja) * 1991-06-21 1993-07-20 Takeda Chem Ind Ltd 溶解性が向上した難水溶性薬物組成物
JP2001261553A (ja) * 2000-03-22 2001-09-26 Tanabe Seiyaku Co Ltd 経口投与製剤
WO2004024697A1 (fr) * 2002-09-11 2004-03-25 Kureha Chemical Industry Company, Limited Composes amines et leurs utilisation

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010510306A (ja) * 2006-11-22 2010-04-02 エスケー ケミカルズ カンパニー リミテッド シブトラミンとベータ−シクロデキストリンの包接複合体
US9284275B2 (en) 2007-01-11 2016-03-15 Critical Outcome Technologies Inc. Inhibitor compounds and cancer treatment methods
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9422282B2 (en) 2010-04-01 2016-08-23 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9624220B2 (en) 2010-04-01 2017-04-18 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9267934B2 (en) 2010-10-26 2016-02-23 University Of South Alabama Methods and compositions for ameliorating pancreatic cancer
US9827224B2 (en) 2010-10-26 2017-11-28 University Of South Alabama Methods and compositions for ameliorating pancreatic cancer
WO2012158707A1 (fr) 2011-05-16 2012-11-22 Genzyme Corporation Utilisation d'antagonistes de cxcr4

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