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WO2000053592A1 - Promoteurs de l'ostéogenèse - Google Patents

Promoteurs de l'ostéogenèse Download PDF

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Publication number
WO2000053592A1
WO2000053592A1 PCT/JP2000/001334 JP0001334W WO0053592A1 WO 2000053592 A1 WO2000053592 A1 WO 2000053592A1 JP 0001334 W JP0001334 W JP 0001334W WO 0053592 A1 WO0053592 A1 WO 0053592A1
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WO
WIPO (PCT)
Prior art keywords
group
isobutyl
tert
hydroxyl groups
acetyl
Prior art date
Application number
PCT/JP2000/001334
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English (en)
Japanese (ja)
Inventor
Toshinori Ishizuya
Shunichi Ikuta
Toyonobu Uzawa
Masayuki Hori
Original Assignee
Asahi Kasei Kabushiki Kaisha
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Asahi Kasei Kabushiki Kaisha filed Critical Asahi Kasei Kabushiki Kaisha
Priority to AU28296/00A priority Critical patent/AU2829600A/en
Publication of WO2000053592A1 publication Critical patent/WO2000053592A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease

Definitions

  • the present invention relates to an osteogenesis promoter. More specifically, the present invention relates to an osteogenesis promoting agent containing a specific taxoid as an active ingredient. Further, the present invention relates to a method for promoting bone formation, which comprises administering a bone formation promoting agent containing a specific taxoid as an active ingredient to a patient having bone failure.
  • the use of the bone formation promoting agent of the present invention significantly promotes bone formation at a bone defect, and is extremely effective in treating a bone fracture, treating a bone defect by surgical bone removal, and preventing a bone disease. is there.
  • the present invention relates to a novel antioxidant which is effective as an active ingredient of an osteogenesis promoter.
  • Fractures are disorders that occur in humans of all ages for various reasons.
  • fracture healing takes a relatively long time.
  • a bone defect due to a complex fracture requires a very long healing period and may not be completely healable.
  • fractures can severely disrupt a patient's daily life. Therefore, early removal of a fractured patient from the bed is dependent on the prognosis of the patient, Q ⁇ L (Qua1ity of Li fe) is a very important subject in various respects.
  • Fracture healing is a locally occurring phenomenon. At this time, it is known that the state of the fracture site changes over time through the steps of inflammation induction, callus formation, and remodeling.
  • bone formation promoting factors include bone morphogenetic factors (Bone Morphogenic Protein, BMP) (; Bone Miner. Res., 13, 1483-1490, 1998). ), Fibrobl as i Growth Factor, FGF
  • All of these bone formation promoting factors are peptides or proteins having a molecular weight of 50,000 or more.
  • all of these bone formation promoting factors are peptide bioactive substances.
  • a peptide bioactive substance is rapidly metabolized in a living body and is inactivated. Therefore, even if the above-mentioned bone formation promoting factor is directly administered to a patient for the purpose of treating a fracture, A sufficient effect cannot be obtained.
  • peptide bioactive substances generally have poor chemical stability.
  • various preparations have been reported which attempt to stabilize the active ingredient of a peptide-type physiologically active substance, but a product having satisfactory quality for clinical application has not yet been obtained.
  • bone formation is often suppressed by administration of a substance having a bone resorption inhibiting action.
  • a substance having a bone resorption inhibiting action for example, bisphosphonates, which are known to exhibit a bone resorption inhibiting effect, are known to inhibit the healing of fractures (/. Bone Miner. Res. 14, 1999).
  • the present inventors have solved the above-mentioned problems, and have contained, as an active ingredient, a low-molecular-weight compound that is chemically stable and has a strong bone formation promoting action.
  • Intensive research was conducted to develop an osteogenesis promoter that can be applied not only to the treatment of fractures but also to the repair of bone defects.
  • a specific taxoid represented by the formula (I) described below has a strong bone formation promoting action.
  • a pharmaceutical composition containing a specific taxoid represented by the formula (I) as an active ingredient i.e., an osteogenesis promoter
  • bone formation is remarkably promoted.
  • the present inventors have found that the present invention is extremely effective in treatment, treatment of a bone defect by surgical bone removal, prevention of bone disease, and the like, and have completed the present invention.
  • a main object of the present invention is to use a specific taxoid represented by the formula (I), which is a low molecular weight compound that is chemically stable and has a strong bone formation promoting action, as an active ingredient.
  • Including Another object of the present invention is to provide a bone formation promoter which can be applied not only to the treatment of fractures but also to the repair of bone defects.
  • Another object of the present invention is to provide a method for promoting bone formation, which comprises administering the above-mentioned bone formation promoting agent to a patient having bone failure.
  • Still another object of the present invention is to provide a specific quinoid represented by the formula (I), which is an active ingredient of the above-mentioned bone formation promoting agent.
  • FIG. 1 shows the 1 H—NMR spectrum of compound AZ42005 prepared in Example 1,
  • FIG. 6 shows the 1 H-NMR spectrum of the compound AZ4202 produced in Example 6,
  • FIG. 7 shows 1 H of compound AZ 4 202 2 prepared in Example 7.
  • FIG. 8 shows the 1 H of compound AZ 4 0 2 3 prepared in Example 8.
  • FIG. 9 shows the 1 H-NMR spectrum of the compound AZ4240 produced in Example 9,
  • FIG. 10 shows the results of the compound AZ 4 0 25 produced in Example 10.
  • FIG. 11 shows that of the compound AZ 4 0 2 6 prepared in Example 11
  • FIG. 12 shows the i H—N M R spectrum of the compound AZ 420 207 prepared in Example 12;
  • FIG. 13 is a diagram showing the ALP activity promoting activity of noccle-ixel in rat calvaria-derived osteoblast-like cells, where one of the figures indicates ALP activity;
  • FIG. 14 shows the effect of paclitaxel on increasing the calcium level in the cell layer and promoting the formation of bone-like nodules in rat calvaria-derived osteoblast-like cells. Hataichi indicates the amount of calcium, and bite indicates the number of bone-like nodules;
  • FIG. 4 is a photomicrograph ( ⁇ 40) of a rat calvarial-derived osteoblast-like cell
  • Figure 16 shows micrographs (40 ⁇ magnification) of rat calvaria-derived osteoblast-like cells on day 7 of the culture in the group supplemented with 0.3 ng Zm1 at a non-crytaxel concentration of 0.3 ng. ) Is a diagram;
  • Figure 17 is a photomicrograph ( ⁇ 40) of rat calvaria-derived osteoblast-like cells on day 7 of culture in the paclitaxel concentration 1 ng Zm1 addition group. R;
  • Figure 18 is a photomicrograph ( ⁇ 40) of rat calvarial-derived osteoblast-like cells on day 7 of culture in the group containing 3 ng Zm1 of Paxixel concentration. Ri;
  • FIG. 19 is a graph showing the effect of nocicle taxel on the formation of bone-like nodules in rat osteoblasts.
  • One of the figures is a graph showing 1 ng Zm1, 1 and 1 indicate the number of bone-like nodules formed in each of the nocicle taxel 3 ng / m1 and 1 and 1 ngm1 groups, respectively. The number of bone-like nodules formed in the group is shown.
  • X and Y may be the same or different and are each independently a hydroxyl group or a group which can be converted to a hydroxyl group in a living body;
  • R 1 is a group consisting of an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a phenyl group, a naphthyl group, a furyl group and a phenyl group.
  • R 2 comprises an alkyl group having 1 to 6 carbon atoms, a phenyl group, a naphthyl group, a furyl group, a phenyl group, an alkoxy group having 1 to 10 carbon atoms, and an alkylamino group having 1 to 6 carbon atoms.
  • R 3 is a hydrogen atom, or an alkyl group having 1 to 6 carbon atoms, an alkylcarbonyl group having an alkyl group having 1 to 6 carbon atoms, a benzoyl group, a naphthyl group, a fluoro group, A dialkylcarbamoyl group having a tenyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms and two alkyl groups having 1 to 3 carbon atoms, wherein the alkyl groups may be the same or different. At least one taxoid represented by the formula:
  • an osteogenesis-promoting agent comprising:
  • X and Y are each independently a hydroxyl group or a group which can be converted into a hydroxyl group in a living body;
  • R 1 is an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 2 to 6 carbon atoms.
  • R 2 is a group consisting of an alkyl group having 1 to 6 carbon atoms, a phenyl group, a naphthyl group, a furyl group, a phenyl group, an alkoxy group having 1 to 10 carbon atoms, and an alkylamino group having 1 to 6 carbon atoms.
  • R 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an alkylcarbonyl group having an alkyl group having 1 to 6 carbon atoms, a benzoyl group, a naphthyl group, a fluoryl group, a tenyl group, It has an alkoxycarbonyl group having 1 to 6 carbon atoms and two alkyl groups having 1 to 3 carbon atoms, and is selected from the group consisting of a dialkylcarbamoyl group which may be the same or different. At least one taxoid represented by
  • An osteogenesis promoter comprising:
  • R 1 is an isobutyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, a 3-pentyl group, a 2-methyl-1-propenyl group, a cis-12-butenyl group or a phenyl group;
  • a group selected from the group consisting of: R 2 is a pentyl group, a 2,2—dimethylpropyl group, a phenyl group, a 3—furyl group, a benzyloxy group, a tert—butoxy group, a tert—amyloxy group, an isopropoxy group, a A group selected from the group consisting of a damantyloxy group and a tert-butylamino; and
  • R 3 is a hydrogen atom or a group selected from the group consisting of a methyl group, an acetyl group, a benzoyl group, a butanol group, a methoxycalileponyl group and an N, N-dimethylcarbamoyl group.
  • X and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a S tert -butoxy group
  • R 3 is an acetyl group
  • X and Y are both hydroxyl groups, and R 1 force 2 — methyl-
  • R 3 is acetyl group, 3'-desphenyl- 3 '-(2-methyl-1-probenylyl) 1 10 — ⁇ acetyl docetaxel;
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a tert-butoxy group, R 3 is a hydrogen atom, and 3′-desphenyl-3 '—Isobutyl Le;
  • X and Y are both hydroxyl groups
  • R 1 is a cis-2-butenyl group
  • R 2 is a S tert -butoxy group
  • R 3 is an acetyl group
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a tert-butoxy group, and R 3 is an N, N-dimethylcalilevamoylyl group; 3 '—Desulfation relay 3' —Iso butyral relay 1 0 — ⁇ -1 (N, N—Dimethylcarnomoyl)
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a tert-butoxy group, R 3 is a methyl group, and 3′-desphenyl is 3 '-isoptyl-10-0-methyl docetaxel;
  • X and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a tert-butyloxy group
  • R 3 is a benzyl group
  • X and Y are both hydroxyl groups, and R 1 is an isobutyl group
  • R 1 is an isobutyl group
  • R 2 is a tert-butoxy group and R 3 is a butanol group
  • X ′ and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a tert-butoxy group
  • R 3 is a methoxycarbonyl group.
  • X and Y are both hydroxyl groups, R 1 is a tert-butyl group, R 2 is a tert-butoxy group, and R 3 is an acetyl group. 3'-tert-butyl-1 0-O-acetyl docetaxel;
  • X and Y are both hydroxyl groups
  • R 1 is an isopropyl group
  • R 2 is s' tert —butoxy group
  • R 3 is an acetyl group
  • 3 ′ des Hueneru 3 '— Isopropil 1 1 0 — ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • X and Y are both hydroxyl groups
  • R 1 is a 3-pentyl group
  • R 2 is a tert-butoxy group
  • R 3 is an acetyl group
  • R 1 is an isobutyl group
  • R 2 is a tert-amyloxy group
  • R 3 is an acetyl group.
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is an isopropoxy group, and R 3 is an acetyl group, de N-benzoyl_N— Isopropoxycalireponil 1 3'-desphenyru 3'-isobutyl paclitaxel;
  • X and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a benzyloxy group
  • R 3 is an acetyl group.
  • Benzyloxycarbonyl — 3 ' desphenyrelay 3' —isobutanol
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is an adamantyloxy group, and R 3 is an acetyl group. 3'-desphenyl-1'-isobutyl paclitaxel;
  • X and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is an S 2, 2—dimethylpropyl group
  • R 3 is an acetyl group.
  • 3 ′ Des Fouenru 3 ′ —Iso Butyl No.
  • X and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a pentyl group
  • R 3 is an acetyl group.
  • 3 '1 Death Fern 3' Isobutyl powder
  • X and ⁇ are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a tert-butylamino group
  • R 3 is an acetyl group.
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a 3_furyl group, and R 3 is an acetyl group. (3—Froyl) 1 3 ′ —Death Phenyl 3′—Isobutyl
  • X and Y are both hydroxyl groups, R 1 is a phenyl group, R 2 is a phenyl group, and R 3 is an acetyl group;
  • Docetaxel wherein X and Y are both hydroxyl groups, R 1 is a phenyl group, R 2 is a tert-butoxy group, and R 3 is a hydrogen atom
  • the group capable of being converted into a hydroxyl group in the above-mentioned organism defined as at least one of Y and Y is a carbonyloxy group formed by bonding a hydrophilic low molecular weight organic group.
  • acyloxy group derived from an amino acid selected from the group consisting of serine, threonine, triptophan, tyrosine and valin, and salts thereof
  • R 4 and R 5 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • n is an integer from 1 to 4)
  • the group defined as at least one of X and Y, which can be converted into a hydroxyl group in vivo is 3.
  • the carbonyloxy group bonding the above-mentioned hydrophilic polymer compound directly or through a low-molecular-weight spacer has the following groups:
  • n an integer of 1 to 4,
  • PEG represents a monovalent poly (ethylene glycol) residue.
  • PEG is a group selected from the group consisting of
  • the surgical bone removal can be performed in the treatment of pseudoarthritis, spinal fusion, human joint replacement, osteotomy, bone lengthening, bone replacement, dental implant transplantation, periodontal surgery.
  • the dose per dose to an adult patient is 50 kg body weight, and the amount of at least one taxoid is 1 ng to 5 O mg. 13.
  • R 2 is tert-amino, isopropoxy, benzyloxy, adamantyloxy, 2,2—dimethylpropyl, pentyl, tert-butylamino and 3—furyl
  • R 3 is an acetyl group
  • R 1 is cis-2-butenyl or 3-pentyl
  • R 2 is a tert-butoxy group
  • R 3 is an acetyl group
  • R 1 is an isobutyl group
  • R 2 is a tert-butoxy group
  • R 3 is a benzoyl group or a butyl group).
  • An osteogenesis-promoting agent comprising:
  • An osteogenesis promoter comprising:
  • An osteogenesis-promoting agent comprising:
  • X and Y are each independently a hydroxyl group or a group which can be converted into a hydroxyl group in a living body;
  • R 1 is a group consisting of an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a phenyl group, a naphthyl group, a furyl group and a phenyl group.
  • R 2 represents an alkyl group having 1 to 6 carbon atoms, phenyl group, naphthyl group, furyl group, phenyl group, an alkoxy group having an alkyl group having 1 to 10 carbon atoms, and an alkylamido having 1 to 6 carbon atoms.
  • R 3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, Benzoi group, naphthoyl group, full acryloyl group, tenofovir I group, having 1 to 6 carbon atoms An alkoxycarbonyl group and two alkyl groups having 1 to 3 carbon atoms, wherein the alkyl groups are the same. A group selected from the group consisting of dialkyl moieties which may be different from each other)
  • a method for promoting bone formation comprising administering to a patient having bone failure an amount of at least one kind of evening squirt represented by the formula, which is effective for bone formation.
  • composition comprising at least one kind of evening water (I) and at least one kind of taxoid (I) and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutically acceptable carrier diluent or excipient.
  • R 1 is an isobutyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, a 3-pentyl group, a 2-methyl-1-propenyl group, a cis-12-butenyl group or a phenyl group;
  • R 2 is a pentyl group, a 2,2—dimethylpropyl group, a phenyl group, a 3—furyl group, a benzyloxy group, a tert—butoxy group, a tert—amyroxy group, an isopropoxy group, A group selected from the group consisting of an adamantyloxy group and tert_butylamino;
  • R 3 is a hydrogen atom, or a methyl group, an acetyl group, a benzoyl group, a butyl group, a methoxycarbonyl group and N, N — The method according to the above item 20 or 21, wherein the group is selected from the group consisting of dimethylcarbamoyl groups.
  • X 'and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a tert-butoxy group
  • R 3 is an acetyl group.
  • 3' isobutyl—1 0—
  • X and Y are both hydroxyl groups, and R 1 is 2-methyl-
  • R 1 is a propenyl group
  • R 2 is a tert-butoxy group
  • R 3 is an acetyl group
  • 3′ desphenyl 3 ′ — (2—methyl-1—probe Nil) 1-10 — acetyl acetyl docetaxel
  • X ′ and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a tert-butoxy group, and R 3 is a hydrogen atom.
  • ' Isobutyl butylcell;
  • X and Y are both hydroxyl groups, R 1 is a cis-2-butenyl group, R 2 is a tert-butoxy group, and R 3 is Is an acetyl group, 3'-desphenyl-3 '-(cis-2-butenyl) 1-110-O-acetyl-dosexyl;
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a tert-butoxy group, and R 3 is an N, N-dimethylcarbamoyl group; '—Desphenyl— 3' —Isobutyl-1 10 — N- (N, N—Dimethylilerecalilenomoyl) Doceta Xerile;
  • X and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a tert-butoxy group
  • R 3 is a methyl group, 3′-desphenyl-3 '—Isobutyl— 10 — 0-methyl docetaxel;
  • X and Y are both hydroxyl groups;
  • R 1 is an isobutyl group;
  • R 2 is a tert-butyloxy group;
  • R 3 is a benzyl group; Lou 3 '— Isobutyl 1 10 — ⁇
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a stert-butoxy group, and R 3 is a bushyl group; Air relay 3'-isobutyl- 10-butanol
  • X and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a tert-butoxy group
  • R 3 is a methoxycarbonyl group
  • 0 X and Y are both hydroxyl groups
  • R 3 is acetyl group.
  • X and Y are both hydroxyl groups, R 1 force isopropyl group, R 2 force tert-butoxy group, R 3 is acetyl group, 3′-desphenyl— 3 '— Isopropyl 1 10 — ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ;
  • 3′ desphenyiru, wherein X and Y are both hydroxyl groups, R 1 is a 3-pentyl group, R 2 is a tert-butoxy group, and R 3 is an acetyl group.
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a tert-amyloxy group, and R 3 is an acetyl group.
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is an isopropoxy group, and R 3 is an acetyl group.
  • A, day N benzoyl N —isopropoxycarbonyl 1 3 ′ —desphenyru 3 ′ —isobutyrino, ° Clitaxel;
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a benzyloxy group, and R 3 is an acetyl group, de N-benzoyl N-benzyl Oxycarbonyl-3'-desphenyl-3'-isobutylpacyl
  • X- and Y- are both hydroxyl groups, R 1 -isobutyl groups, R 2 is adamantyloxy groups, and R 3 is acetyl groups.
  • N-benzoyl-N Adamantholoxyl 3'-desphenyl-1'-isobutyl paclitaxel;
  • X and Y are both hydroxyl groups;
  • R 1 is an isobutyl group;
  • R 2 is a 2,2—dimethylpropyl group;
  • R 3 is an acetyl group; Benzoyl N- (3,3-dimethylbutanol) 1-3'-desphenyl-1'-isobutyl-no-Crytaxel;
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a pentyl group, and R 3 is an acetyl group; de-N-benzoyl relay N-hexanoy Relay 3 '-Desulfur 3'-Isobutanol
  • X and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a tert_butylamino group
  • R 3 is an acetyl group.
  • Lou N tert—butyl Aminocarbonyl-1'-desphenyl_3'-isobutyl-nor-x
  • X and Y are both hydroxyl groups, R 1 is isobutyl group, R 2 is 3 — furyl group, and R 3 is acetyl group, data N — benzoyl N — (3 — Floirille) 1 3 ′ — Death phenyl 1 3 ′ — Isobutyl acrylate
  • X and Y are both hydroxyl groups, R 1 is a phenyl group, R 2 is a phenyl group, and R 3 is an acetyl group;
  • X and Y are both hydroxyl groups, R 1 is a phenyl group, R 2 is a tert-butoxy group, and R 3 is a hydrogen atom.
  • the group which can be converted to a hydroxyl group in vivo as defined above as at least one of X and Y is 24.
  • R 4 and R 5 may be the same or different and each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • n is an integer from 1 to 4)
  • the group which can be converted into a hydroxyl group in vivo as defined above as at least one of X and Y is a hydrophilic group.
  • the carbonyloxy group bonding the above-mentioned hydrophilic polymer compound directly or through a low molecular weight compound is the following group:
  • n an integer of 1 to 4,
  • PEG represents a monovalent poly (ethylene glycol) residue.
  • PEG is a group selected from the group consisting of
  • the surgical bone removal is a treatment for pseudoarthritis, spinal fusion, human It is intended for any of joint replacement, osteotomy, bone distraction, bone replacement, dental implant transplantation, and treatment of periodontal disease. 29. The method described in 29 above.
  • the bone formation promoting agent is an injection, a solid preparation, a suspension or an ointment.
  • the bone formation promoting agent is administered in a dose of lng to 50 kg per 50 kg body weight of the at least one evening kiss. the preceding paragraph, characterized by administering mg.
  • the bone formation promoting agent of the present invention comprises a bone formation-effective amount of the following formula (I):
  • X and Y may be the same or different and are each independently a hydroxyl group or a group which can be converted into a hydroxyl group in a living body;
  • R 1 is a group consisting of an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a phenyl group, a naphthyl group, a furyl group and a phenyl group; A group selected from;
  • R 2 is a group consisting of an alkyl group having 1 to 6 carbon atoms, a phenyl group, a naphthyl group, a furyl group, a phenyl group, an alkoxy group having 1 to 10 carbon atoms, and an alkylamino group having 1 to 6 carbon atoms.
  • R 3 is a hydrogen atom, or an alkyl group having 1 to 6 carbon atoms, an alkylcarbonyl group having an alkyl group having 1 to 6 carbon atoms, a benzoyl group, a naphthyl group, a fluoryl group, a tenyl group, or a carbon number.
  • the evening kiss represented by the above formula (I) (hereinafter simply referred to as “sun kiss”) used as an active ingredient in the bone formation promoting agent of the present invention (I)) has an osteogenesis promoting action.
  • ALP alkaline phosphatase
  • X and Y are each independently a hydroxyl group or a group which can be converted into a hydroxyl group in vivo.
  • a group that can be converted into a hydroxyl group in a living body means a group that can be converted into a hydroxyl group in a living body by an enzymatic or non-enzymatic reaction, and is a field related to a so-called prodrug. Since many examples are known in the above, those groups can be appropriately used.
  • a carbonyloxy group formed by bonding a hydrophilic low-molecular organic group or a hydrophilic high-molecular compound directly or through a low-molecular spacer. It is preferable to use a carbonyldioxy group which is bonded through a bond.
  • R 4 and R 5 may be the same or different and each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
  • n is an integer from 1 to 4)
  • hydrophilic polymer compounds examples include polysaccharides such as dextran, proteins such as albumin, polyethylene glycol, polyacrylic acid, polyacrylamide, and the like. Synthetic polymers such as polylysine and polylactic acid can be mentioned.
  • the above-mentioned low molecular weight spacer is defined as the above-mentioned liquid (I) And a low-molecular-weight compound having a group capable of binding to the above-mentioned hydrophilic polymer compound.
  • a low-molecular-weight compound having a group capable of binding to the above-mentioned hydrophilic polymer compound examples thereof include ⁇ -amino acid, 3-amino acid, and ⁇ -amino acid.
  • Amino acids such as monoamino acids and amino alcohols such as peptides, ethanolamines, propanolamines, etc., which are formed by binding a plurality of them, malonic acid, cono, and citrate
  • dicarboxylic acids such as dartaric acid and diols such as ethylene glycol and propylene glycol.
  • Suitable depending on the type of the oxoid (I) and the hydrophilic polymer compound described above. Use a suitable one.
  • a carbonyloxy group in which a hydrophilic polymer compound is bonded directly or via a low molecular weight spacer is preferably selected from the following groups:
  • n an integer of 1 to 4,
  • PEG indicates a monovalent poly (ethylene glycol) residue. It is preferable to use a group selected from the group consisting of:
  • both X and Y are more preferably hydroxyl groups.
  • R 1 comprises an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a phenyl group, a naphthyl group, a furyl group and a phenyl group. Selected from the group And is preferably an isobutyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, a 3-pentyl group, a 2-methyl-1-propenyl group, a cis-2-butenyl group. And a group selected from the group consisting of phenyl groups.
  • R 2 is a group consisting of an alkyl group having 1 to 6 carbon atoms, a phenyl group, a naphthyl group, a furyl group, a phenyl group, an alkoxy group having 1 to 10 carbon atoms, and an alkylamino group having 1 to 6 carbon atoms. And preferably a pentyl group, a 2,2-dimethylpropyl group, a phenyl group, a 3-phenyl group, a benzyloxy group, a tert-butoxy group, a tert-amyloxy group. And a group selected from the group consisting of isopropyl group, adamantyloxy group and tert-butylamino.
  • R 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an alkylcarbonyl group having an alkyl group having 1 to 6 carbon atoms, a benzoyl group, a naphthyl group, a fluoryl group, a tenyl group, It has an alkoxycarbonyl group having a prime number of 1 to 6 and two alkyl groups having a carbon number of 1 to 3, and is selected from the group consisting of dialkyl moieties having the same or different alkyl groups.
  • a group consisting of a hydrogen atom or a group consisting of a methyl group, an acetyl group, a benzoyl group, a butyl group, a methoxycarbonyl group and an N, N-dimethylcarbamoyl group. It is a group selected from
  • the evening liquid (I) is X ′ and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a tert-butoxy group
  • R 3 is an acetyl group
  • 3′ desphenyl-1 3 ′ —Iso-butyl- 10 —O-acetyl-dosedoxel (AZ4201);
  • X and Y are both hydroxyl groups
  • R 1 is a 2-methyl-1-propenyl group
  • R 2 is a tert-butoxy group
  • R 3 is an acetyl group.
  • ' Desphenyl— 3' — (2—Methyl-1 monopropenyl) 1 10 —Polyacetyl docetaxel (AZ4202);
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a tert-butoxy group, and R 3 is a hydrogen atom.
  • AZ4203 Isobutyl docetaxel
  • X and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a stert-butoxy group
  • R 3 is a methyl group.
  • X and Y are both hydroxyl groups, R 1 -isobutyl group, R 2 is tert-butoxy group, R 3 is butynoyl group; — 3 '— isobutyl — 10 — 0—
  • X ′ and Y ′ are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is a tert-butoxy group
  • R 3 is a methoxycearliestponyl group.
  • X and Y are both hydroxyl groups, and R 1 force A butyl group, R 2 is a tert-butoxy group, and R 3 is an acetyl group, 3′-desphenysolate 3 ′ -tert-butyl-1- 10 —0-acetyl Docetaxel (AZ4202);
  • X and Y are both hydroxyl groups;
  • R 1 is an isopropyl group;
  • R 2 is a stert-butoxy group;
  • R 3 is an acetyl group;
  • 3′ desphenyleyl, wherein X and Y are both hydroxyl groups, R 1 is a 3-pentyl group, R 2 is a tert-butoxy group, and R 3 is an acetyl group.
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a tert-amyloxy group, and R 3 is an acetyl group.
  • X- and Y- are both hydroxyl groups, R 1 is an isobutyl group, R 2 is an isopropoxy group, and R 3 is an acetyl group.
  • I-so-propoxycarbonyl One 3 '— Dess Fuenru 3' — Isobutyl butyl resin (AZ4202 1);
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a benzyloxy group, and R 3 is an acetyl group; de-N-benzoyl-N-benzyl Oxycarbonyl-3'-desphenyru 3'-isobutylpaclitaxel (AZ42022);
  • X- and Y- are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is an adamantyloxy group
  • R 3 is an acetyl group.
  • N adamantyloxyl ponyl _ 3 ′ —desphenyru 3 ′ —isobutyl paclitaxel (AZ 4 0 2 3);
  • X and Y are both hydroxyl groups
  • R 1 is an isobutyl group
  • R 2 is S 2, 2-dimethylpropyl group
  • R 3 is an acetyl group.
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a pentyl group, and R 3 is an acetyl group; de-N-benzoyl N-hexanoyl One 3 'one desulfur 3'-isobutyl package (AZ42025);
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a tert-butylamino group, and R 3 is an acetate group.
  • X and Y are both hydroxyl groups, R 1 is an isobutyl group, R 2 is a 3 -furyl group, and R 3 is an acetyl group.
  • R 1 is an isobutyl group
  • R 2 is a 3 -furyl group
  • R 3 is an acetyl group.
  • X and Y are both hydroxyl groups, R 1 is a phenyl group, R 2 is a phenyl group, and R 3 is an acetyl group;
  • X and Y are both hydroxyl groups, R 1 is a phenyl group, R 2 is a tert-butoxy group, and R 3 is a hydrogen atom.
  • the following compound (I) is used. It is more preferable to use a clear or docetaxel, and most preferable to use a paclitaxel.
  • taxoids such as paclitaxel
  • Some taxoids (I) are known to be contained in natural raw materials, for example, the bark of yew trees. Natural ingredients Thus, it can be isolated by a known method, for example, a method using a combination of chromatographies, and used as an active ingredient of the bone formation promoting agent of the present invention.
  • the compounds AZ4201, AZ4202, AZ4203, AZ422 0 4, AZ 4 2 0 7, AZ 4 2 0 8, AZ 4 2 0 1 1, AZ 4 2 0 1 2, AZ 4 2 0 1 4, AZ 4 2 0 16 and docetaxel are known
  • the production method is described in the following literature.
  • AZ4201, AZ4202, AZ4203 and AZ4204 were prepared by Ojima et al., Bioorg. Med. Chem. Lett., It can be synthesized based on the description in 4, 2631-2934, 1994.
  • AZ4207, AZ4208 and AZ4201 are described in Ojima et a based on the description of J. Med. Chem., 39, 3889-3896, 1996. Can be synthesized.
  • the compounds AZ4202, AZ4201 and AZ42016 can be synthesized based on the description in Japanese Patent Publication No. 5084969. Can be.
  • Docetaxelire can be synthesized based on the description of Ojima eta 1., Tetrahedron Lett., 34, 4149-4152, 1993.
  • Other compounds i.e., compounds AZ4205, AZ4209, AZ42010.0.AZ4210, AZ42420, AZ4202 AZ42 0 2 2, AZ 4 2 0 2 3, AZ 4 2 0 2 4, AZ 4 2 0 2 5, AZ 4 2 0 2 6, AZ 4 2 0 2 7 are new compounds, but synthesis of the above known compounds
  • known methods for example, Georg eta, Bioorg. Med. Chem. Lett., 4, 1825-1830; Georg et al., Bioorg. Med. Chem. Lett., 4, 335 -338, 1994; Kant eta on Tetrahedron Let t., 35,
  • TBS tert-butyldimethylsilyl group
  • B 0 c tert-butoxycarbonyl group
  • the aldehyde R 1 —CH ⁇ (R 1 is the same as defined in formula (I) above) is condensed with p-anisidine to give an aldimimine ( ⁇ ) (this reaction is illustrated Absent) .
  • the procedure for exchanging the p-methoxyphenyl group for a Boc group is to introduce a tert-butoxy group as R 2 in taxoid (I) used as an active ingredient in the present invention. (The method for obtaining taxoid (I), which is a group other than the R 2 tert-butoxy group, will be described later).
  • TBS-C1 tert-butyldimethylsilyl chloride
  • the substituent R 3 introduction reagent has the following formula:
  • R 6 represents an alkyl group having 1 to 6 carbon atoms, an alkylcarbonyl group having an alkyl group having 1 to 6 carbon atoms, a benzyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms, and 1 to 3 carbon atoms.
  • X represents a halogen atom.
  • the compound represented by can be used.
  • R 7 represents an alkyl group having 1 to 6 carbon atoms. It is also possible to use a compound represented by
  • bacatin derivative (VIII) is reacted with the above compound (VI) or (VT) in the presence of hexamethyldisilazane sodium salt, and the 2 ′ hydroxyl group is changed to a TBS group (or TIPS group).
  • a oxoide (K) compound (IX)
  • TES group triethylsilyl group
  • Taxoid (X) (compound (X)) is obtained.
  • the obtained compound (X) corresponds to an amino acid (I) in which both X and Y are hydroxyl groups, R 2 is a tert-butoxy group, and R 3 is not a hydrogen atom.
  • R 2 can be exchanged for a group other than a tert-butoxy group.
  • the compound (X) is reacted with trifluoroacetic acid to remove the Boc group bonded to the nitrogen atom of the compound (X), and to remove the 3′-amino group and the 2′- and 7-position hydroxyl groups.
  • Protected evening oxide (X ') (compound (X')) (not shown) is obtained.
  • R 2 is a taxoid (I) which is a group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, a phenyl group, a naphthyl group, a furyl group and a phenyl group
  • R 2 introduction reagent the following formula:
  • R 8 represents a group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, a phenyl group, a naphthyl group, a furyl group and a phenyl group,
  • Y represents a halogen atom.
  • R 8 has the same meaning as described above.
  • the reaction is usually performed in the presence of a suitable condensing agent to promote the reaction.
  • a suitable condensing agent examples include dihexyl carbyl imide and water-soluble carbodiimide hydrochloride (l-ethyl-3- (3′-dimethylaminopropyl) carbodiiinide-HCl).
  • R 9 represents an alkyl group having 1 to 10 carbon atoms
  • Y represents a halogen atom.
  • R 9 has the same meaning as described above.
  • the oxoide (I) is prepared as the reagent for introducing a substituent R 2 ,
  • R 1 Q represents an alkyl group having 1 to 6 carbon atoms.
  • X and Y are both hydroxyl groups
  • R 2 is a group other than a tert-butoxy group
  • R 3 is a hydrogen atom (non-hydrogen atom).
  • compound (X) when producing taxoid (I) in which X and / or Y can be converted to a hydroxyl group in a living body, compound (X) can be produced by an appropriate method depending on the type. Alternatively, a group that can be converted into a hydroxyl group in a living body is introduced into the 2′-position and the 7-position or the 7-position of (XI).
  • X and / or Y force S a carbonyloxy group formed by bonding a hydrophilic low molecular organic group as described above, or a hydrophilic high molecular compound directly or via a low molecular spacer
  • the carboxylic acid corresponding to these groups is converted to a compound (X) or (XI) in the presence of a suitable condensing agent.
  • a suitable condensing agent By reacting with, the desired taxoid (I) can be obtained.
  • condensing agents include dicyclo Hexyl carbodiimide, water-soluble carbodiimide hydrochloride (1-ethyl-3- (3'-dimethyl-afflino-propyl) carbodiimide-HCl) and the like can be mentioned.
  • an appropriate protecting group is selectively introduced only to the hydroxyl group at either the 2′-position or the 7-position of compound (X) or (XI) by an appropriate method.
  • a group that can be converted into a hydroxyl group in the body is introduced, and then the protecting group introduced into the 2′-position or 7-position hydroxyl group is removed by an appropriate method, then either the 2′-position or the 7-position is obtained. It is possible to introduce a group that can be converted into a hydroxyl group in the living body only at the time.
  • the reagent for introducing a protecting group is not particularly limited as long as it is a compound capable of introducing a protecting group into a hydroxyl group, and a reagent for introducing a protecting group suitable for production of a desired compound (I) can be appropriately selected.
  • bacatin derivative ( ⁇ ′) is reacted with the above compound (VI) (or compound (VI,)) in the same manner as described above in the presence of hexamethyldisilazane sodium salt to give 2 ′ ⁇ ⁇
  • the S group (or TIPS group) the hydroxyl group at the 7-position is protected with a TES group, and a protecting group is introduced at the hydroxyl group at the 10-position (IX ') to obtain a compound (IX').
  • the protecting group introduced into the 2′-position, 7-position and 10-position hydroxyl group of the obtained compound (IX ′) is removed by an appropriate method, and the 2′-position, 7-position and 10-position hydroxyl group are removed.
  • the deprotected taxoid (X ') (compound (X')) is obtained.
  • the obtained compound (X ′) corresponds to a taxoid (I) in which X and Y are both hydroxyl groups, R 2 is a tert-butoxy group, and R 3 is a hydrogen atom.
  • the obtained compound (X ⁇ ) has an amino group (X) wherein X and Y are both hydroxyl groups, R 2 is a group other than tert-butoxy group, and R 3 is a hydrogen atom. Equivalent to. Further, the protecting group introduced into the 2′-position and the 7-position hydroxyl group of the compound (K ′) (or (XI ′)) is removed by an appropriate method, and the 2′-position and the 7-position hydroxyl group are deprotected.
  • Taxoid (K ') (compound ((')) in which the hydroxyl group at the 0-position is protected (or a substituent R 2 is introduced into the amino group at the 3'-position, and the hydroxyl groups at the 2'- and 7-positions are removed.
  • a protected oxoide (XI ′) (compound (XI ′))) in which the hydroxyl group at the 10-position is protected can be obtained.
  • the compound ( ⁇ ') or (() obtained by the same method as that for introducing a group capable of being converted into a hydroxyl group in vivo at the 2'-position and the ⁇ - or 7-position of the compound (X) or (XI).
  • XI ') by introducing a group that can be converted to a hydroxyl group in vivo at the 2'-position and / or 7-position of the XI'), and removing the protecting group introduced at the 10-position hydroxyl group by an appropriate method.
  • X and ⁇ or ⁇ ⁇ are groups that can be converted to a hydroxyl group in a living body, and can produce taxoid (I) in which R 3 is a hydrogen atom.
  • Osteoblasts are cells that differentiate from undifferentiated mesenchymal cells, and are activated by the resorption of bone.
  • Various osteoblasts present in the bone matrix (the above-described TGF — 3, IGF—I, BMP, etc.) Stimulation by offspring (parathyroid hormone, activated vitamin D, etc.) promotes their differentiation and proliferation, and activates their functions.
  • osteoblasts In osteoblasts in the early to middle stages of differentiation, the activity of alkaline phosphatase (ALP) in the cell membrane is significantly increased. In the late stages of differentiation, osteoblasts form a monolayer on the bone surface, and are responsible for the formation of bone organic matrix, calcification, and metabolism of electrolytes (especially calcium ion), and osteogenesis. .
  • ALP alkaline phosphatase
  • Osteoblasts also have the function of regulating the activation of osteoclasts, the cells responsible for bone resorption (Stein and Lian, "Molecular Mechanisms mediating Developmental and Hormone-regulated Expression of Genes in Osteoblasts ", CELLULAR AND MOLECULAR BIOLOGY OF BONE, Noda ed., ACADEMIC PRESS, INC., 1993; Clinical Orthopedics, 200, 100-113, 1985; Clinical Orthopedics, 289, 292-312, 1993; Zo. Bone Miner Res., 14, 1805-1815, 1999).
  • the degree of promotion (or inhibition) of bone formation by the action of the sample compound is determined by determining the ALP activity in osteoblasts, It can be evaluated using the amount of calcium, the formation of bone-like nodules and the like as indices. In other words, when osteoblasts are cultured in the presence of the sample compound, if the increase in ALP activity, the increase in the amount of calcium in the cell layer, the promotion of bone-like nodules, etc. are observed, the sample compound will It can be evaluated as having a promoting effect. These indicators In other words, using the formation of bone-like nodules as an index, the degree of promotion (or suppression) of bone formation can be most appropriately evaluated.
  • Bone-like nodules are island-shaped structures formed by osteoblasts calcifying the surrounding matrix (mainly composed of type I collagen). Activated osteoblasts produce a substrate around themselves, so that a slightly raised substrate can be observed from the bottom of an incubator such as a petri dish. Eventually, the matrix becomes calcified by osteoblasts, resulting in white deposits that can be observed with the naked eye. Most of the osteoblasts after osteoid nodule formation cover the surface of the deposits, except that some of them are embedded within the deposits.
  • osteoblasts a cell population (such as “osteoblasts”) that has the same characteristics as osteoblasts, such as exhibiting high ALP activity and having a calcifying function.
  • osteoblast-1 ike cels blast-like cells
  • Osteoblast cells can be obtained from neonatal rat calvaria by various methods, for example, the method described in Example 13 described below.
  • evening squid (I) which is an active ingredient in the osteogenesis promoter of the present invention, has an osteogenesis promoting effect.
  • paclitaxel which is a typical compound as an evening squid (I)
  • osteoclasts There has been no report on the osteogenesis-promoting effects of retaxel and its related compounds.
  • taxoid (I) promotes bone formation has not been elucidated. However, it is thought that evening squid acts directly on osteoblasts to promote their differentiation and enhances osteogenic function.
  • the osteogenesis-promoting agent of the present invention can be produced by mixing at least one kind of resin with a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutically acceptable carrier diluent or excipient.
  • the carrier used in the present invention is not particularly limited, and gelatin sponge, porous hydroxyapatite, lactate-glycolic acid copolymer, glycolic acid co-prolactone copolymer and the like are used as the carrier. Can be used.
  • the bone formation promoting agent of the present invention can be prepared into a dosage form suitable for each drug form by adding a pharmaceutically acceptable auxiliary.
  • auxiliaries include, for example, base materials, stabilizers, preservatives, preservatives, suspending agents, solubilizers, dissolution aids, emulsifiers, lubricants, binders, molding agents Binders, flavoring agents, coloring agents, fragrances, soothing agents, buffers and the like.
  • auxiliary component When preparing the new bone formation promoting agent of the present invention using these adjuvants, for example, a pharmaceutical excipient list (Medical Regulations Committee of the Tokyo Pharmaceutical Manufacturers Association and the Medical Regulations of the Osaka Pharmaceutical Manufacturers Association) Auxiliary components may be selected as appropriate based on the description of the committee). The use amount of the auxiliary component can be selected according to the form of the osteogenesis promoter, as long as it is within a pharmaceutically acceptable range.
  • the use of the bone formation promoting agent of the present invention is not particularly limited, but it can be favorably used for treatment of a fracture or treatment of a bone defect caused by surgical bone removal.
  • a fracture includes a re-fracture, a fracture with a poor prognosis, and the like.
  • surgical bone removal is used for treating pseudoarthritis, spinal fusion, artificial joint replacement, osteotomy, bone distraction, bone replacement, dental implant transplantation, and periodontal surgery. Including those performed for the purpose of treating diseases.
  • bone formation promoting agent of the present invention By administering the bone formation promoting agent of the present invention to a fracture surface of a bone or a gap between a bone and a graft (biomaterial, autogenous bone, or the like), bone regeneration or early growth of the graft against the bone can be achieved. In addition, firm fixing can be achieved.
  • the dosage form of the osteogenesis promoter of the present invention there is no particular limitation on the dosage form of the osteogenesis promoter of the present invention, but general dosage forms of the osteogenesis promoter, for example, injections, solid preparations, suspensions, ointments, rectal absorbents It can be used as a vaginal absorption agent, a transdermal absorption agent, a nasal absorption agent, a pulmonary absorption agent, an oral absorption agent, an oral administration agent and the like.
  • the osteogenesis promoter of the present invention is preferably a preparation for topical administration. More preferably, it is a suspension or an ointment.
  • the bone formation promoting agent of the present invention When used as an injection, it can be administered intramuscularly or intravenously.
  • the osteogenesis promoter of the present invention When used as a solid preparation or ointment shaped into a stick, needle, sphere, film, etc., it is used by embedding or applying it to the site of bone damage or bone defect. be able to.
  • the bone formation promoting agent of the present invention When used as a rectal absorbent or a vaginal absorbent, it is generally prepared as a suppository.
  • the bone formation promoting agent of the present invention when used as a nasal absorbent or a transdermal absorbent, it can be prepared as a preparation containing an appropriate absorption enhancer, and as a pulmonary absorbent. Alternatively, it can be prepared as an aerosol composition containing a suitable dispersant or water and a propellant.
  • the bone formation promoting agent of the present invention when used as an oral absorption agent, it can be prepared as a sublingual tablet or a tape containing an appropriate absorption promoting agent.
  • the osteogenesis promoter of the present invention when used for oral administration, it can be prepared as a liposome preparation or a microcapsule preparation.
  • Content of evening kiss (I) in the bone formation promoter of the present invention Is not particularly limited as long as it is effective for bone formation. If the carrier used has a sustained release property, the content of taxoid (I) is appropriately changed based on the sustained release property. You can.
  • the bone formation-promoting agent of the present invention can be used together with evening squid (I) together with other drugs for treating bone diseases, such as calcium salts, vitamin D, bismuth K, parathyroid hormone, sex hormones, and bismuth. It may contain phosphonates, ibliflavones, fluorine compounds, prosthetic darandins, TGF-iS, IGF-1 and IGF-2, FGF, BMP and the like.
  • other drugs for treating bone diseases such as calcium salts, vitamin D, bismuth K, parathyroid hormone, sex hormones, and bismuth. It may contain phosphonates, ibliflavones, fluorine compounds, prosthetic darandins, TGF-iS, IGF-1 and IGF-2, FGF, BMP and the like.
  • the dosage of the osteogenesis promoter of the present invention is not particularly limited as long as it is an amount effective for bone formation.
  • the patient's age, gender, body weight, medical condition, and the content of the active ingredient evening squid (I) are included. It depends on the amount.
  • the lower limit of the dose of the bone formation promoter of the present invention per adult patient per administration is at least 50 kg of body weight and at least one kind of evening squid (I). Usually, it is 100 ng, preferably 10 g or more, and more preferably 250 g or more.
  • the upper limit of the dose is usually 50 mg, preferably 1.25 mg, per 50 kg of body weight, and the amount of at least one kind of evening squid (I). Preferably it is lmg.
  • paclitaxel which is a typical compound as xenoid (I), which is an active ingredient of the osteogenesis promoter of the present invention, as described above, is currently used as an anticancer agent and a therapeutic agent for rheumatism Used.
  • Taxol Product Information Summary Japan Standard Product Classification No. 8 7 4 2 According to 4
  • 210 mg Zcm 2 body surface area
  • Intravenous infusion can be performed over 3 hours.
  • paclitaxel when used as a therapeutic agent for rheumatism, for example, 1 to 10 mg Z kg of noclitaxel is administered to a patient as a therapeutic agent for rheumatism.
  • US Patent Nos. 5,583,153 when paclitaxel is used as a therapeutic agent for rheumatism, for example, 1 to 10 mg Z kg of noclitaxel is administered to a patient as a therapeutic agent for rheumatism.
  • the dose is lower than that in the case of using the above-mentioned application, and the weight per 1 kg of body weight is used.
  • the weight per 1 kg of body weight is used.
  • converted to a dose of it is usually in the range of 2 ng to lmg.
  • taxoid (I) exhibits an osteogenesis promoting effect when the dose is within a certain range. No or no facilitation of bone formation.
  • the administration period of the agent of the present invention is, in principle, a period during which a bone lesion, disorder, or defect is clinically observed. However, if the clinician determines that recovery is necessary depending on the etiology or condition, the administration of the osteogenesis-promoting agent can be continued.
  • the typical frequency of administration is once a week or once every three months.
  • the agent for promoting osteogenesis of the present invention When the agent for promoting osteogenesis of the present invention is administered to a patient having bone insufficiency, bone formation at a bone defect is remarkably promoted, so that treatment of a fracture, treatment of a bone defect by surgical bone removal, treatment of a bone, It is extremely effective in preventing diseases.
  • the bone formation promoting agent containing the above-mentioned oxoid (I) and a pharmaceutically acceptable carrier, diluent or excipient is administered to a patient having bone failure.
  • a method for promoting bone formation is provided.
  • the taxoid (I) is administered in the form of an osteogenesis promoter comprising the taxoid (I) and a pharmaceutically acceptable carrier, diluent or excipient. Is preferred.
  • the measurement was performed using a JMS-AX500 mass spectrometer manufactured by JEOL Ltd. of Japan.
  • the matrix used was m-nitrobenzene alcohol.
  • the sample for the iH—NMR spectrum was prepared as follows.
  • test was performed using F 2 5 4 (product number: 1, 0 5 7 15).
  • the developed TLC plate is visually observed under an ultraviolet lamp (wavelength: 254 nm), or the developed TLC plate is subjected to an ethanol-saturated solution of ammonium limolybdate ammonium. After immersion in the sample, the sample was heated with a heat gun and the sample was colored on a plate.
  • the sample was subjected to high performance liquid chromatography (chiral HPLC) using an optically active stationary phase, and the area ratio of the peaks corresponding to the two optical isomers in the obtained chromatogram was determined. This was taken as the enantiomeric excess.
  • Detection Absorbance for ultraviolet light with a wavelength of 254 nm
  • THF Tetra hydrofuran
  • reaction mixture was added 10 ml of a saturated aqueous solution of ammonium chloride, and the mixture was extracted twice with 20 ml of ether. The organic layer was washed with 20 ml of saturated saline, dried over 5 g of anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • reaction mixture was added 30 ml of a saturated aqueous solution of ammonium chloride, and the mixture was extracted twice with 30 ml of ether. Saturate organic layer After washing with 30 ml of brine, the extract was dried over 5 g of anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • FIG. 3 shows the 1 H-NMR spectrum of AZ42009.
  • the obtained reaction mixture was neutralized by adding 50 ml of a saturated aqueous solution of sodium bicarbonate, and then extracted twice with 50 ml of clog form.
  • the organic layer was dried over 10 g of anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Figure 1 shows the 1H—NMR spectrum of AZ42020.
  • FIG. 6 shows the 1 H-NMR spectrum of AZ42021.
  • FIG. 7 shows the 1 H-NMR spectrum of AZ42022.
  • FIG. 8 shows the 1 H-NMR spectrum of AZ42023.
  • FIG. 9 shows the 1 H-NMR spectrum of AZ42424.
  • FIG. 10 shows the 1 H-NMR spectrum of AZ42025.
  • FIG. 11 shows the 1 H-NMR spectrum of AZ42026.
  • FIG. 12 shows the 1 H-NMR spectrum of AZ42027.
  • Skull caps were aseptically collected from a 1-day-old SD rat (manufactured by Japan Charls River, Japan). The collected calvaria was minced and 0.1% collagenase, 0.05% trypsin and
  • the released cells were recovered by shaking for 20 minutes at room temperature in phosphate buffered saline containing 4 mM EDTA and 2Na. This operation was repeated six times, and the recovered cells from the latter four times were defined as osteoblast-like cells.
  • Osteoblast-like cells were cultured in a C ⁇ ⁇ 2 incubator at 37 ° C in a dish using an ⁇ medium containing 10% fetal serum as a culture medium. Five days after the start of the culture, the osteoblast-like cells were washed with phosphate-buffered saline containing 0.1% collagenase, 0.05% trypsin and 4 mM EDTA2Na. Peel from culture dish After detachment, the cells were seeded on a Falcon 6-well plate at a cell density of 3.73 ⁇ 10 4 cells Zcm 2 . As a subsequent culture solution, an ⁇ medium containing 10% fetal calf serum, 5 mM 3-glycerol phosphate and 50 ng / m I ascorbic acid was used.
  • paclitaxel manufactured by Wako Pure Chemical Industries, Japan
  • lot number JCQ93354 was used after dissolving in DMSO.
  • the medium was replaced with a culture solution containing paclitaxel at the same concentration as the first addition.
  • DMSO solvent
  • the alkaline phosphatase (ALP) activity, calcium content and the number of bone-like nodules in the cell layer were measured by Ishizuya et al., /. Clin. Invest., 99 , 2961 -970, 1997.
  • the measurement results are shown in FIGS. 13 and 14.
  • Fig. 15 shows a micrograph of rat calvarial-derived osteoblast-like cells in the group without addition of paclitaxel on the 7th day of culture, and the group with 0.3 ng Zm1 containing paclitaxel was added. , 1 ng Zm1 addition group and The micrographs of rat calvaria-derived osteoblast-like cells in the 3 ng Zml-added group are shown in FIGS. 16 to 18, respectively. All cells were fixed with a phosphate-buffered formalin solution and stained with von Kossa (Mallory, FB, Pathologica 1 Technique, New York, Hafner Publishing Co., 1991, p. 144). Then, it was inspected at a magnification of 40 times.
  • the black part in the figure is a calcified bone-like nodule positive for von Kossa staining, and the calcified bone-like nodule in the noclitaxel 0.3 to 3 ng Zm1 added dose-dependently compared to the paclitaxel non-added group. Increased ossified nodules (black area) were observed.
  • Osteoblast-like cells were prepared in the same manner as in Example 13 and seeded at a cell density of 3.73 ⁇ 10 4 cells Z cm 2 on a Falcon 6-well plate.
  • Example 13 Two days after seeding the cells on a Falcon 6-well plate, the same plasmid mixture used in Example 13 was used at concentrations of 1 ng Zml, 3 ng / ml, and 10 ng Zml. Was added to the cultured cells. Each group of paclitaxel-added cells was cultured for 1 hour, 3 hours, 6 hours, 24 hours or 48 hours. After culturing the cells together with the paclitaxel for a certain period of time as described above, the culture solution was replaced with a culture solution containing no paclitaxel, and the cells were cultured until the total culture period was 7 days. In addition, an experimental group was set up in which each of the concentrations of paclitaxel was continuously cultured for 7 days.
  • DMSO used for dissolution of taxel was used as a control.
  • the culture medium was changed on the second and fifth days from the start of culture.
  • the number of bone-like nodules formed 7 days after the start of the drug treatment was determined according to the method described in Ishizuya et al., Clin. Invest., 1997, 99, 296-2970.
  • Figure 19 shows the results.
  • the sexual treatment as in the case of the 7-day sustained treatment, bone-like nodule formation was suppressed to less than the number of bone-like nodules in the solvent-added group.
  • Docetaxel was synthesized by the method described in Ojima et al., Tetrahedron Lett., 34, 4149-4152, 1993.
  • AZ 4207, AZ 4208 and AZ 4201 are described in Ojima et al.,; Med. Chem., 39, 3889-3896, 1996. It was synthesized by the method described above.
  • the AZ421012, AZ42410 and AZ42016 were synthesized according to the method described in Japanese Patent Application Laid-Open No. H8-50849.
  • Osteoblast cells were treated in the same manner as in Example 13 by using the evening solution of the concentration shown in Table 1 below in place of the evening solution, and the cells for osteoblasts after 7 days of culture were used.
  • the number of calculi for bone was measured. Specifically, cells stained with von Kossa were observed under a microscope as in Example 13, and the number of calcified bones and nodules formed was counted for each well. Table 1 shows the results.
  • Compound AZ4203 did not show osteo-nodule formation promoting action at a concentration of 0.3 ng Zml, but a strong promoting action of bone-like nodule formation at a concentration of 1-3 ng / m1. An effect was observed. As described above, all of the evaluated evening kisses showed a promoting effect on bone-like nodule formation. Table 1 Bone-like nodule formation of taxoid in primary cultured rat osteoblasts (St action
  • the use of the bone formation promoting agent of the present invention significantly promotes bone formation in a bone defect, and is extremely effective in treating a bone fracture, treating a bone defect by surgical bone removal, and preventing a bone disease.

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Abstract

L'invention porte sur des promoteurs de l'ostéogenèse contenant des taxoïdes représentés par la formule générale (I) dans des quantités efficaces pour permettre l'ostéogenèse. Dans cette formule, X et X représentent chacun, indépendamment, un hydroxyle ou un groupe convertible en hydroxyle in vivo ; R1¿ représente un alkyle, alcényle, alkynyle, phényle, naphtyle, furyle ou thiényle ; R2 représente alkyle, phényle, naphtyle, furyle, thiényle, alcoxy ou alkylamino ; et R3 représente un hydrogène, alkyle, alkylcarbonyle, benzoyle, naphtoyle, furoyle, thénoyle, alcoxycarboyle ou dialkylcarbamoyle.
PCT/JP2000/001334 1999-03-05 2000-03-06 Promoteurs de l'ostéogenèse WO2000053592A1 (fr)

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WO2001057032A1 (fr) * 2000-02-02 2001-08-09 Florida State University Research Foundation, Inc. Taxanes substitues par un ester en c10 comme agents antitumoraux
WO2001057033A1 (fr) * 2000-02-02 2001-08-09 Florida State University Research Foundation, Inc. Taxanes substitues par carbamoyloxy au niveau de c10 en tant qu'agents antitumoraux
WO2001057031A1 (fr) * 2000-02-02 2001-08-09 Florida State University Research Foundation, Inc. Taxanes a substitution carbonate en c10 utilisees comme agents antitumoraux
WO2001057013A1 (fr) * 2000-02-02 2001-08-09 Florida State University Research Foundation, Inc. Formulations de taxane possedant une solubilite amelioree
EP1285920A1 (fr) * 2001-07-31 2003-02-26 Florida State University Research Foundation, Inc. Taxanes substitués par ester en C10 utilisés comme agents anticancereux
EP1285919A1 (fr) * 2001-07-31 2003-02-26 Florida State University Research Foundation, Inc. Taxanes substitués par carbonate en C10 utilisés comme agents anticancereux
WO2003041717A1 (fr) * 2001-11-12 2003-05-22 Ono Pharmaceutical Co., Ltd. Preparation pelliculaire persistante pour administration localisee contenant un derive de prostaglandine
US6649632B2 (en) 2000-02-02 2003-11-18 Fsu Research Foundation, Inc. C10 ester substituted taxanes
US6844341B2 (en) 2001-02-17 2005-01-18 Astrazeneca Ab Pyrimidine derivatives for inhibition of cell proliferation
JP2006508926A (ja) * 2002-09-20 2006-03-16 エンゾン，インコーポレーテッド アミノ酸タキサン誘導体の製造方法およびその誘導体を含有するポリマーコンジュゲート
SG125888A1 (en) * 2001-08-01 2006-10-30 Univ Florida State Res Found C10 carbonate substituted taxanes
SG129990A1 (en) * 2001-08-01 2007-03-20 Univ Florida State Res Found C10 ester substituted taxanes
US7589111B2 (en) 2004-02-13 2009-09-15 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
JP2011511808A (ja) * 2008-02-07 2011-04-14 バイオミメティック セラピューティクス， インコーポレイテッド 仮骨延長のための組成物および方法
US8242166B2 (en) 2008-03-31 2012-08-14 Florida State University Research Foundation, Inc. C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes

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Cited By (26)

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WO2001057032A1 (fr) * 2000-02-02 2001-08-09 Florida State University Research Foundation, Inc. Taxanes substitues par un ester en c10 comme agents antitumoraux
WO2001057033A1 (fr) * 2000-02-02 2001-08-09 Florida State University Research Foundation, Inc. Taxanes substitues par carbamoyloxy au niveau de c10 en tant qu'agents antitumoraux
WO2001057031A1 (fr) * 2000-02-02 2001-08-09 Florida State University Research Foundation, Inc. Taxanes a substitution carbonate en c10 utilisees comme agents antitumoraux
WO2001057013A1 (fr) * 2000-02-02 2001-08-09 Florida State University Research Foundation, Inc. Formulations de taxane possedant une solubilite amelioree
US7524869B2 (en) 2000-02-02 2009-04-28 Florida State University Research Foundation, Inc. Taxanes having a C10 ester substituent
US7256213B2 (en) 2000-02-02 2007-08-14 Florida State University Research Foundation, Inc. Taxanes having a C10 carbonate substituent
US6906088B2 (en) 2000-02-02 2005-06-14 Fsu Research Foundation, Inc. Taxanes having a C10 carbamoyloxy substituent
US7230013B2 (en) 2000-02-02 2007-06-12 Florida State University Research Foundation, Inc. C10 carbamoyloxy substituted taxane compositions
US6596737B2 (en) 2000-02-02 2003-07-22 Fsu Research Foundation, Inc. C10 carbamoyloxy substituted taxanes
US6649632B2 (en) 2000-02-02 2003-11-18 Fsu Research Foundation, Inc. C10 ester substituted taxanes
US6660866B2 (en) 2000-02-02 2003-12-09 Psu Research Foundation, Inc. C10 carbonate substituted taxanes
US7056946B2 (en) 2000-02-02 2006-06-06 Fsu Research Foundation, Inc. C10 carbonate taxane compositions
US6844341B2 (en) 2001-02-17 2005-01-18 Astrazeneca Ab Pyrimidine derivatives for inhibition of cell proliferation
JP2003055360A (ja) * 2001-07-31 2003-02-26 Florida State Univ Research Foundation Inc Ｃ１０エステル置換タキサン
EP1285919A1 (fr) * 2001-07-31 2003-02-26 Florida State University Research Foundation, Inc. Taxanes substitués par carbonate en C10 utilisés comme agents anticancereux
EP1285920A1 (fr) * 2001-07-31 2003-02-26 Florida State University Research Foundation, Inc. Taxanes substitués par ester en C10 utilisés comme agents anticancereux
SG125888A1 (en) * 2001-08-01 2006-10-30 Univ Florida State Res Found C10 carbonate substituted taxanes
SG129990A1 (en) * 2001-08-01 2007-03-20 Univ Florida State Res Found C10 ester substituted taxanes
JPWO2003041717A1 (ja) * 2001-11-12 2005-03-03 小野薬品工業株式会社 プロスタグランジン誘導体を有効成分とする局所投与用持続性フィルム状製剤
WO2003041717A1 (fr) * 2001-11-12 2003-05-22 Ono Pharmaceutical Co., Ltd. Preparation pelliculaire persistante pour administration localisee contenant un derive de prostaglandine
JP2006508926A (ja) * 2002-09-20 2006-03-16 エンゾン，インコーポレーテッド アミノ酸タキサン誘導体の製造方法およびその誘導体を含有するポリマーコンジュゲート
US7589111B2 (en) 2004-02-13 2009-09-15 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8003812B2 (en) 2004-02-13 2011-08-23 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
JP2011511808A (ja) * 2008-02-07 2011-04-14 バイオミメティック セラピューティクス， インコーポレイテッド 仮骨延長のための組成物および方法
JP2015180705A (ja) * 2008-02-07 2015-10-15 バイオミメティック セラピューティクス， インコーポレイテッド 仮骨延長のための組成物および方法
US8242166B2 (en) 2008-03-31 2012-08-14 Florida State University Research Foundation, Inc. C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes

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