WO2000078351A1 - Promoteurs de l'osteogenese - Google Patents

Promoteurs de l'osteogenese Download PDF

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Publication number
WO2000078351A1
WO2000078351A1 PCT/JP2000/003969 JP0003969W WO0078351A1 WO 2000078351 A1 WO2000078351 A1 WO 2000078351A1 JP 0003969 W JP0003969 W JP 0003969W WO 0078351 A1 WO0078351 A1 WO 0078351A1
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Prior art keywords
alkyl
aralkyl
hydrogen
formula
represents hydrogen
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PCT/JP2000/003969
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English (en)
Japanese (ja)
Inventor
Kazuyuki Itoh
Kiyoko Yoshioka
Hideki Yoshikawa
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Mitsubishi Pharma Corporation
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Priority to AU52504/00A priority Critical patent/AU5250400A/en
Publication of WO2000078351A1 publication Critical patent/WO2000078351A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • 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
    • 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
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention relates to an osteogenesis promoter. More specifically, the present invention relates to an osteogenesis promoter comprising a compound having Rho kinase inhibitory activity.
  • osteoblasts play a central role in bone formation
  • osteoclasts play a central role in bone resorption. This balance of bone remodeling works by linking osteoclast and osteoblast cell lines. In other words, it is thought that systemic and local regulators form a complex network at each stage of bone reconstruction, act on osteoblasts and osteoclasts, and maintain bone turnover. I have.
  • calcium preparations, active vitamin D3 preparations, estrogen preparations, calcitonin preparations, bisphosphonates, etc. are used as prophylactic and therapeutic agents for bone diseases.
  • Bone resorption inhibitors such as estrogen preparations, calcitonin preparations, bisphosphonate preparations are particularly used. Mainly used.
  • bone resorption inhibitors are sometimes administered only to limited subjects or their effects may not be reliable. At present, sufficient therapeutic effects have not been obtained.
  • fluorine is a clinically usable substance that promotes bone formation.
  • the safety margin of administration is narrow, and there is a problem with long-term administration.
  • growth factors such as parathyroid hormone (PTH), osteoinductive factor (BMP), insulin-like growth factor (IGF), and fibroblast growth factor (FGF) are known as substances promoting bone formation.
  • PTH parathyroid hormone
  • BMP osteoinductive factor
  • IGF insulin-like growth factor
  • FGF fibroblast growth factor
  • TGF-3 transforming growth factor /?
  • BMP osteoinductive factor
  • IGF inulin-like growth factor
  • FGF fibroblast growth factor
  • the differentiated osteoblast group consists of collagen, mainly type I, alkaline phosphatase (alkaline phosphatase), osteopectin (.osteonectin), osteopontin, osteopontin, bone sialoprotein, and osteocalcin. It produces extracellular matrix such as osteocalcine), induces further differentiation, and forms bone tissue (Grainger, D ⁇ , et al., Nature Med.1. ⁇ 932-937 (1995)). Therefore, for bone formation, it is important to induce the differentiation of undifferentiated mesenchymal cells into osteoblasts that play a central role in bone formation.
  • these undifferentiated mesenchymal cells are derived not only from osteoblasts, but also from other bone marrow stromal cells including chondrocytes, muscle, and fat cells, which make up the skeletal system. This suggests that it is necessary to consider induction of differentiation of the mesenchymal cells into osteoblasts together with regulation of differentiation into other cell lines.
  • Rh is activated by receiving signals from various cell membrane receptors, and activated Rho activates smooth muscle contraction, cell motility, cell adhesion, cell morphology change, and cell proliferation via the actomyosin system. It has been shown to function as a molecular switch for various cellular phenomena such as It is now being clarified that Rho kinase present downstream of the Rho-mediated signal transduction pathway plays an important role in the response of Rho to the above-mentioned cellular phenomena.
  • undifferentiated mesenchymal cells migrate locally, and then are induced to differentiate into myotube cells, leading to formation of muscle and blood vessels. Induction of differentiation of these undifferentiated mesenchymal cells into myotube cells has been shown to be involved in Rho (Mol. Cell Biol., 18,
  • Rho kinase inhibitory activity a compound represented by the following general formula (I) has been reported (WO 98/06433).
  • isoquinoline sulfonamide derivatives and isoquinoline derivatives also have Rho kinase inhibitory activity (WO 98/06433 and Naunyn-Schmiedeberg's Archives of Pharmacology 385 (1 ) Suppl., R219, 199 8) o
  • Rho kinase inhibitory activity are widely used as antihypertensives, angina pectoris, cerebral vasospasm inhibitors, asthma, peripheral circulatory disorders, premature birth prevention, arteriosclerosis, It is useful as a cancer drug, anti-inflammatory drug, immunosuppressant drug, autoimmune disease drug, anti-AIDS drug, osteoporosis drug, retinopathy drug, brain function improving drug, contraceptive drug, gastrointestinal infection preventive drug, W098 / 06433.
  • compounds represented by the general formula (I) are powerful and persistent drugs for treating hypertension, angina pectoris, renal and peripheral circulatory disorders, cerebral vasospasm, etc. It is already known to be useful as a prophylactic / therapeutic agent for cardiovascular diseases such as renal and peripheral arteries, and as a therapeutic drug for asthma (Japanese Patent Application Laid-Open Nos. 62-89679 and 3-218356). JP-A-4-273821, JP-A-5-194401, JP-A-6-41080 and W095 / 28387).
  • the isoquinoline sulfonamide derivatives described in the above-mentioned W098 / 06433 are vasodilators, therapeutic agents for hypertension, cerebral function improving agents, anti-asthmatic agents, cardioprotective agents, platelet aggregation inhibitors, psychiatric treatments Agent, anti-inflammatory agent, agent for treating or preventing hyperviscosity syndrome, agent for treating glaucoma, agent for reducing intraocular pressure, agent for improving motor paralysis in cerebral thrombosis, agent for preventing and treating viral infections, and inhibitor of transcriptional regulator (Japanese Patent Publication No. 57-200366, Japanese Patent Application Laid-Open No. 61-227581, Japanese Patent Application Laid-Open No.
  • the isoquinoline derivative described in Suppl., R219, 1998) is known to be useful as an agent for preventing or treating brain tissue damage due to vasospasm (W097 / 28130).
  • WO 98/06433 describes that a compound having a Rh kinase inhibition activity is useful as a therapeutic agent for osteoporosis. This is based on the finding that integrin activation and cell adhesion induction, which are considered to be involved in absorption, are suppressed. Therefore, there is no description in the publication that suggests that a compound having a Rh kinase inhibitory activity has a bone formation promoting effect.
  • An object of the present invention is to solve the above-mentioned problems relating to osteogenesis, especially osteogenesis in bone diseases, and an object of the present invention is to provide a useful osteogenesis promoting agent and / or a bone having an osteogenesis promoting action. To prevent and treat diseases.
  • the present inventors have conducted intensive studies in order to solve the above problems, and as a result, it has been found that a compound having a Rho kinase inhibitory activity enhances the production of osteoinductive factor (BMP) from mesenchymal cells, When applied to differentiated mesenchymal cells, it significantly increases the amount of osteovontin, alkaline phosphatase (ALP) activity and osteocalcin, which are osteoblast differentiation markers, that is, has an excellent bone formation promoting effect.
  • the present invention was found to be useful as an osteogenesis promoting agent and as a prophylactic / therapeutic agent for a bone disease having an osteogenesis promoting action, thereby completing the present invention.
  • the present invention is as follows.
  • An osteogenesis promoter comprising a compound having Rho kinase inhibitory activity.
  • the compound having Rho kinase inhibitory activity is represented by the following general formula (I)
  • Ra —— C II——— NI—— Rc (1) ' (Where Ra is the formula
  • R represents hydrogen, alkyl, or a substituent which may have a substituent on the ring.
  • R represents cycloalkyl, cycloalkylalkyl, phenyl or aralkyl;
  • R 6 is hydrogen, alkyl or a formula: — NR 8 R 9 (where R 8 and R 9 are the same or different and represent hydrogen, alkyl, aralkyl or phenyl.), And R 7 is hydrogen. , Alkyl, aralkyl, phenyl, nitro or cyano, or R 6 and R 7 are bonded to each other to further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring. Represents a group forming a heterocyclic ring which may be optionally substituted.
  • R 1 represents hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring.
  • R and R 1 are bonded together with an adjacent nitrogen atom to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent.
  • the group to be formed is shown.
  • R 2 represents hydrogen or alkyl.
  • R 3 and R 4 are the same or different and are hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyl oxy, cyano, acyl, mercapto, alkylthio, aralkylthio, alkoxycarbonyl, alkoxycarbonyl Indicate rubbamoyl, mono-dialkyl rubamoyl or azide.
  • A is the formula
  • R 1 Q and R 11 are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl. Alternatively, R 1Q and R 11 are bonded to form a cyclo 1, m and n each represent 0 or an integer of 1 to 3).
  • L represents hydrogen, alkyl, aminoalkyl, mono'dialkylaminoalkyl, tetrahydrofurfuryl, rubamoylalkyl, phthalimidalkyl, amidino, or
  • B represents hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxycarbonylalkyl, monoaminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridyl .
  • Q 1 represents hydrogen, halogen, hydroxyl, aralkyloxy or cetylmethyl.
  • W represents alkylene
  • Q 2 represents hydrogen, halogen, a hydroxyl group or aralkyloxy.
  • X represents alkylene
  • Q 3 represents hydrogen, halogen, hydroxyl, alkoxy, nitro, amino, 2,3-dihydrofuryl or 5-methyl-3-oxo-1,2,3,4,5-tetrahydropyridazine-6-yl.
  • Y represents a single bond, alkylene or alkenylene.
  • a broken line indicates a single bond or a double bond.
  • R 5 represents hydrogen, hydroxyl, alkoxy, alkoxycarbonyloxy, alkanoyloxy or aralkyloxycarbonyloxy.
  • R b represents hydrogen, alkyl, aralkyl, aminoalkyl or mono'dialkylaminoalkyl.
  • R c represents a nitrogen-containing heterocyclic ring which may have a substituent.
  • the osteogenesis promoter according to the above (1) which is an amide compound represented by the formula: or an isomer thereof and / or a pharmaceutically acceptable acid addition salt thereof.
  • Rho kinase inhibitory activity is represented by the following general formula (1,):
  • R represents hydrogen, alkyl or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring.
  • R 1 represents hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring.
  • R ′ and R 1 are bonded to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent together with an adjacent nitrogen atom in the ring. Is shown.
  • R 2 represents hydrogen or alkyl.
  • R 3 and R 4 are the same or different and each represents hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyle, mercapto, alkylthio, aralkylthio, ethoxycarbonyl, alkoxycarbonyl, Indicates rubamoyl, mono-dialkyl levamoyl or azide.
  • R 1 D and R 11 are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl.
  • R 1Q and R 11 are 1, m and n each represent 0 or an integer of 1 to 3).
  • Rb represents hydrogen, alkyl, aralkyl, aminoalkyl or mono'dialkylaminoalkyl.
  • R c represents a nitrogen-containing heterocyclic ring which may have a substituent.
  • the compound having Rho kinase inhibitory activity is (+)-trans-41- (1-aminoethyl) -1- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1H- Pyro mouth [2,3-b] Pyridine-14-yl) 1-41 (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-pyridyl) 14-1 (1-aminoethyl) benzamide and (R)-(+)-N- (1H-pyro-port [2,3-b] pyridine-14-yl) -14- (1-aminoethyl) benzamide
  • the bone formation promoting agent according to the above (1) which is a compound selected from the group consisting of and / or a pharmaceutically acceptable acid addition salt thereof.
  • Rho kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) -1- (4-viridylcarbamoyl) cyclohexane and / or a pharmaceutically acceptable acid thereof.
  • the bone formation promoter according to the above (1) which is an addition salt.
  • the compound having a Rh kinase inhibition activity is an amide compound represented by the general formula (I), particularly, the general formula (1 ′), an isomer thereof, and / or a pharmaceutically acceptable acid addition salt thereof.
  • the compound having Rho kinase inhibitory activity is (+)-trans-41- (1-aminoethyl) 1-1- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1 H-Pyro mouth [2,3-b] Pyridine-1-yl) 4- (1-Aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-pyridyl) -1- 4- (1-Aminoethyl) benzamide and (R)-(+)-N- (1H-pyrro [2,3-b] pyridin-4-yl) 1-4- (1-aminoethyl) benzamide
  • the pharmaceutical composition for preventing and / or treating bone diseases according to the above (8) which is a compound selected from the group consisting of: and / or a pharmaceutically acceptable acid addition salt thereof.
  • Rho kinase inhibitory activity is (+)-trans-4_ (1-aminoethyl) 1-1- (4-pyridylcarbamoyl) cyclohexane and / or a pharmaceutically acceptable acid addition salt thereof.
  • a method for preventing and treating a bone disease which comprises administering to a patient an effective amount of a compound having Rho kinase inhibitory activity.
  • the compound having a Rh kinase inhibition activity is an amide compound represented by the general formula (I), particularly, the general formula ( ⁇ ), an isomer thereof and / or a pharmaceutically acceptable acid addition salt thereof.
  • the compound having Rho kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) -11- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1H- Pyro mouth [2,3-b] Pyridine-14-yl) 1-41- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4- Pyridyl) —4- (1-aminoethyl) benzamide and (R)-(+) — N- (1H-pyro mouth [2,3-b] pyridine-14-yl) 14- (1— (13)
  • the compound having a Rh kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) -11- (4-pyridylcarbamoyl) cyclohexane and / or a pharmaceutically acceptable acid thereof.
  • the compound having Rho kinase inhibitory activity is an amide compound represented by the general formula (I), particularly, the general formula (1 ′), an isomer thereof and / or a pharmaceutically acceptable acid addition salt thereof.
  • the compound having Rho kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) 1-1- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1H —Pyro mouth [2,3-b] pyridine-14-yl) -14- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-pyridyl) —4 — (1-Aminoethyl) benzamide and (R)-(+)-N- (1H-pyrro [2,3-b] pyridin-4-yl) 1-4- (1-aminoethyl) benzamido (18)
  • Rho kinase inhibitory activity is (+)-trans-4- (1-aminoethyl) -11- (4-pyridylcarbamoyl) cyclohexane and / or a pharmaceutically acceptable acid thereof.
  • Figure 1 shows the effect of (+)-trans-14- (1-aminoethyl) 1-1- (4-) on the differentiation of 10T1 / 2 cells and MC3T3-E1 cells into osteoblasts.
  • Pirijiruka Rubamoiru cyclohexane 2 HC 1 ⁇ 1 H 2 0 ( hereinafter, illustrates the effect of Y- 27 632).
  • Figure 2 shows the effect of Y-27632 on the differentiation of ST2 cells into osteoblasts.
  • FIG. 3 shows the effect of Y-27632 on osteobontin mRNA expression in 10 T1 / 2 cells.
  • a is an RNA blot image showing a change in the amount of osteobontin (OPN) mRNA.
  • FIG. 4 shows the effect of Y-27632 on BMP-4 mRNA expression in S ⁇ ⁇ ⁇ ⁇ 2 cells.
  • FIG. 5 shows the relationship between ALP activity and Rho activity in 10 T1 / 2 cells.
  • a is a graph showing changes in ALP activity in cells expressing active exogenous Rh in addition to endogenous R ho.
  • b is an immublot image showing the result of examining the expression status of endogenous Rho or active exogenous Rho in each cell using an antibody.
  • the osteogenesis promoting agent may be any one that activates any stage of osteogenesis as long as it has an activity to promote osteogenesis.
  • osteoinductive factor refers to a protein having BMP activity that acts on undifferentiated mesenchymal cells to differentiate them into chondrocytes and osteoblasts.
  • BMP— :! To 10 and 15 and the like.
  • the bone disease according to the present invention includes metabolic bone diseases including osteoporosis, fibrous ostitis, osteomalacia, pageet's disease, etc., which occur when the balance between bone resorption and bone formation in bone tissue is disrupted, and orthopedic surgery. Bone diseases such as fractures, bone defects, low back pain and osteoarthritis, and periodontal diseases in the dental field.
  • the application of the present invention to the repair of periodontal tissue defects, the stabilization of artificial dental roots, the repair of jaw formation, the cleft palate, and the like in periodontal diseases are also included in the prevention and treatment of bone diseases of the present invention.
  • Rho kinase in the present invention is a cell activated by activation of Rho. N / threonine kinase.
  • ROK Hi ROK II: Leung, T. et al., J. Biol. Chem., 270. 29051-29054, 1995
  • p 160 RO CK ROK?, ROCK— I: Ishizaki, T. et al., The EMBO J., 15 (8), 1885-1893, 1996) and other proteins with serine / threonine kinase activity.
  • the compound having a Rh kinase activity used as the active ingredient of the present invention may be any compound having a Rh kinase inhibitory activity.
  • Specific examples include the amide compounds, isoquinoline sulfonamide derivatives and isoquinoline derivatives described in WO 98/06433 and WO 97/28130.
  • the amide compound represented by the general formula (I) is preferred, and the amide compound is particularly preferred.
  • one kind of compound having Rho kinase inhibitory activity may be contained alone or, if necessary, several kinds may be used in combination. Further, in the present invention, a compound having Rho kinase inhibitory activity and another bone resorption inhibitor and / or bone formation promoter can be used in combination.
  • calcium preparations for example, calcium preparations, vitamins D, calcitonins, bisphosphonates, estrogens sex hormones, fluorides such as sodium fluoride, parathyroid hormones (PTHs), insulin-like growth factors (IGFs), fiber Blast growth factor (FGF).
  • PTHs parathyroid hormones
  • IGFs insulin-like growth factors
  • FGF fiber Blast growth factor
  • R, R, an alkyl with carbon number 1-1 0 straight-chain or branched and the alkyl in R 1, methyl, Echiru, propyl, isopropyl building, butyl, I Sobuchiru, secondary Examples thereof include butyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Alkyl having 1 to 4 carbon atoms is preferable.
  • R, R ' denotes cyclopropyl Cycloalkyl in R 1, cyclobutyl, cyclopentyl, cyclohexyl, a number 3-7 cycloalkyl carbons of heptyl and the like cyclohexylene.
  • R, R ', and cycloalkylalkyl in R 1 is cycloalkyl portion is the number of 3 to 7 carbon cycloalkyl, alkyl portion is of one to six carbon atoms straight-chain or branched alkyl (Methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), which is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclopentyl Ethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclopropylbutyl, cyclopentylbutyl,
  • Aralkyl in R, R, and R 1 has 1 to 4 carbon atoms as the alkyl moiety, and includes benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, and 4-phenylbutyl. And phenylalkyl.
  • R, R ', cycloalkyl which may have a substituent on the ring at R 1, a cycloalkyl alkyl, phenyl, and the substituents of Ararukiru is halogen (chlorine, bromine, full Uz arsenide, iodine), Alkyl (synonymous with alkyl in R, R,, R 1 ), alkoxy (linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, shows a Kishiruokishi like secondary butoxy, tertiary butoxy, Penchiruokishi to,.), Ararukiru (H, synonymous with Ararukiru in R ,, R 1), haloalkyl (R, alkyl as indicated in R ,, R 1 Is substituted with 1 to 5 halogens, such as fluoromethyl, difluoromethyl
  • a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent together with an adjacent nitrogen atom in which R and 1 or R ′ and R 1 are bonded to each other;
  • a 5- to 6-membered ring or a bonded ring thereof is preferable.
  • 1-pyrrolidinyl, piberidino, 1-piperazinyl, morpholino, thiomorpholino, 1-imidazolyl, 2,3-dihydrothiazo For example, one-to-one and three-by-one.
  • the substituent on the nitrogen atom which may have a substituent include alkyl, aralkyl, haloalkyl and the like. Wherein alkyl, ⁇ La alkyl, haloalkyl R, R ', the same meaning as in the R 1.
  • the alkyl in R 2 has the same meaning as the alkyl in R, R ′ and R 1 .
  • R 3 , R 4 halogen, alkyl, alkoxy, aralkyl is R, R ′, Shows in R 1 is as defined above.
  • the acyl in R 3 and R 4 is an alkanoyl having 2 to 6 carbon atoms (such as acetyl, propionyl, butyryl, valeryl, and vivaloyl), a benzoyl, or a phenylalkanoyl group having 2 to 4 carbon atoms. Indicates phenyl (phenylacetyl, phenylpropionyl, phenylbutyryl, etc.).
  • the Arukiruamino in RR 4 a Arukiruamino having an alkyl number 1 of 6 linear or branched carbon atoms in the alkyl part, Mechiruamino, E Chiruamino, propylamino, isopropylamino, Buchiruamino, isobutyl Amino, Secondary butylamino, tertiary butylamino, pentylamino, hexylamino, etc.
  • the acylamino in R 3 and R 4 is an acylamino having 2 to 6 carbon atoms such as alkanol, benzoyl, or alkanol having an alkanoyl moiety having 2 to 4 carbon atoms, such as acetylamino. , Propionylamino, butyrylamino, phenyl, "relylamino, bivaloylamino, benzoylamino, phenylacetylamino, phenylpropionylamino, phenylbutyrylamino and the like.
  • the alkylthio represented by R 3 and R 4 is an alkylthio having a linear or branched alkyl having 1 to 6 carbon atoms in the alkyl portion, and is methylthio, ethylthio, propylthio, isopropylthio, butylthio. , Isobutylthio, secondary butylthio, tertiary butylthio, pentylthio, hexylthio and the like.
  • the aralkyloxy represented by R 3 and R 4 has an aralkyl having an alkyl having 1 to 4 carbon atoms in the alkyl part thereof, and is benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, 3 — Phenylpropyloxy, 4-phenylbutyloxy and the like are shown.
  • the aralkylthio in RR 4 has an aralkyl having an alkyl having 1 to 4 carbon atoms in the alkyl portion thereof, and includes benzylthio, 1-phenylethylthio, 2-phenylphenylthio, 3-phenylpropylthio, 4—Fueni And rubutylthio.
  • the alkoxycarbonyl in R 3 and R 4 has a straight-chain or branched-chain alkoxy having 1 to 6 carbon atoms in the alkoxy moiety, and includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Examples include sopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, secondary butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
  • the mono'dialkyl carbamoyl represented by R 3 and R 4 is a carbamoyl mono- or di-substituted by an alkyl having 1 to 4 carbon atoms, such as methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, and getylcarbamoyl.
  • methylcarbamoyl dimethylcarbamoyl
  • ethylcarbamoyl ethylcarbamoyl
  • getylcarbamoyl getylcarbamoyl.
  • Propyl carbamoyl dipropyl carbamoyl, butyl carbamoyl, dibutyl carbamoyl and the like.
  • the alkoxy in R 5 R, R ' the same meaning as alkoxy at R 1.
  • the alkoxycarbonyl O alkoxy in R 5 be one having a number 1-6 straight-chain or branched alkoxy carbon alkoxy part, main Tokishikaru Boniruokishi, ethoxycarbonyl O alkoxy, propoxycarbonyl O alkoxy , Isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, secondary butoxycarbonyloxy, tertiary butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy, etc. Shown.
  • the Arca Noi Ruo carboxymethyl at R 5 be one having from 2 to 6 ⁇ Rukanoiru carbon number Arukanoiru section shows Asechiruokishi, propionyl Ruo carboxy, butyl Riruokishi, Bareriruokishi, the Bibaroiruokishi like.
  • the aralkyloxycarbonyloxy in R 5 has an aralkyl having an alkyl having 1 to 4 carbon atoms in the alkyl portion thereof, and is a benzyloxycarbonyloxy, an 11-phenylethyloxy. Carbonyloxy, 2-phenyl-2-ethylcarbonyloxy, 3-phenylpropyloxycarbonyl And 4-phenylbutyroxycarbonyloxy and the like.
  • the alkyl in R 6 has the same meaning as the alkyl in R, R ′ and R 1 .
  • Alkyl at R 8 and R 9 has the same meaning as alkyl at R, R, and R 1
  • aralkyl at R 8 and R g has the same meaning as aralkyl at R, R, and R 1 .
  • Alkyl in R 7 is R, R,, have the same meaning as alkyl at R 1, Ararukiru the definitive in R 7 is, R, R, is synonymous with Ararukiru in R 1.
  • a group in which R 6 and R 7 are bonded to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent is imidazole 1- Yl, thiazole-2-yl, oxazole-2-yl, imidazoline-2-yl, 3,4,5,6-tetrahydropyridine-1-yl, 3,4,5,6-tetrahydrobilimidine 1-2-yl, 1,3-oxazoline-12-yl, 1,3-thiazoline-2-yl or halogen, alkyl, alkoxy, haloalkyl, nitro, amino, phenyl, aralkyl, etc.
  • Benzoimidazole-2-yl benzothiazol-1-yl, benzoxazol-2-yl and the like which may be used.
  • halogen, alkyl, alkoxy, Haroa alkyl, and Ararukiru R, R ' the same meaning as in the R 1.
  • substituent on the nitrogen atom which may have a substituent include aralkyl, aralkyl, haloalkyl and the like.
  • alkyl, Araru kill, and haloalkyl R, R ' the same meaning as in the R 1.
  • the hydroxyalkyl represented by R 1 Q and R 11 is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms substituted with 1 to 3 hydroxy, such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and the like.
  • R 1 1 is R
  • R 1 1 has the same meaning as alkyl at R ,
  • R 11 is synonymous with aralkyl in R, R ', R 1 .
  • the cycloalkyl formed by the combination of R 1 ⁇ R 11 is also the same as the cycloalkyl in R, R,, and R 1 .
  • Alkyl in L is R, R ', the same meaning as alkyl at R 1.
  • the aminoalkyl in L is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms which is substituted by amino, such as aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminoalkyl. Aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl and the like.
  • the mono-dialkylaminoalkyl in L is an aminoalkyl which is mono- or di-substituted by alkyl having 1 to 4 carbon atoms, such as methylaminomethyl, dimethylaminomethyl, ethylaminomethyl, acetylaminomethyl, and propylaminomethyl. Examples include nomethyl, dipropylaminomethyl, butylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, 2-getylaminoethyl and the like.
  • L-rubamoylalkyl in L is a straight- or branched-chain alkyl having 1 to 6 carbon atoms, which is substituted with l-rubamoyl, for example, l-rubamoylmethyl, 2--lumbamoylethyl, 1-lumbamoylethyl , 3-power rubamoyl propyl, 4 -power rubamoyl butyl, 5-power lubamoyl pentyl, 6-power rubamoyl hexyl and the like.
  • l-rubamoyl for example, l-rubamoylmethyl, 2--lumbamoylethyl, 1-lumbamoylethyl , 3-power rubamoyl propyl, 4 -power rubamoyl butyl, 5-power lubamoyl pentyl, 6-power rubamoyl hexyl and the like.
  • the fluorimidalkyl in L is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms which is substituted by phthalimid.
  • phthalimidomethyl 2-fluorimidethyl, 1- Fluorimidethyl, 3-phthalimidopropyl, 4-phthalimidbutyl, 5-phthalimidopentyl, 6-phthalimidhexyl and the like.
  • Alkoxy at B is R, R ', the same meaning as alkoxy at R 1.
  • Ararukiru in B is R, R ', the same meaning as Ararukiru in R 1.
  • Aralkyloxy in B is synonymous with aralkyloxy in R 3 and R 4 o
  • Aminoalkyl in B has the same meaning as aminoalkyl in L.
  • the hydroxyalkyl for B is the same as the hydroxyalkyl for R 1 Q and R 11 .
  • the alkanoyloxyalkyl in B is a straight-chain or branched alkyl having 1 to 6 carbons substituted by an alkanoyloxy having an alkanoyl moiety having 2 to 6 carbons.
  • the alkoxycarbonylalkyl in B is a straight-chain or branched-chain alkyl having 1 to 6 carbons substituted by an alkoxycarbonyl having an alkoxy moiety having 1 to 6 carbons.
  • Halogen in the QQ ⁇ Q 3 is R, R,, Ru halogen synonymous der in R 1.
  • the aralkyloxy in QQ 2 is synonymous with the aralkyloxy in R 3 and R 4 .
  • the alkoxy in Q 3 has the same meaning as the alkoxy in R, R ′ and R 1 .
  • the alkylene in W, X and Y is a linear or branched alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • the alkenylene in Y is a linear or branched alkenylene having 2 to 6 carbon atoms, such as vinylene, propenylene, butenylene, pentenylene and the like.
  • the Ararukiru in Rb R, R ' the same meaning as Ararukiru in R 1.
  • the aminoalkyl for Rb has the same meaning as the aminoalkyl for L.
  • the mono-dialkylaminoalkyl for Rb has the same meaning as the mono-dialkylaminoalkyl for L.
  • the nitrogen-containing heterocyclic ring represented by Rc is, when monocyclic, pyridine, pyrimidine, pyridazine, triazine, pyrazole, or triazole, and when condensed ring, virolobilizine (1H-pyromouth [2,3-b] pyridine , 1H-pyro mouth [3,2-b] pyridine, 1H-pyro mouth [3,4-1b] pyridine, etc.), virazolobiridine (1H-pyrazo mouth [3,4-1b] pyridine, 1H —Pyrazo mouth [4,3—b] pyridine, etc.), imidazoviridine (1H-imidazo [4,5—b] pyridine, etc.), pyro-mouth virimidine (1H-pyro-mouth [2,3_d] pyrimidine, 1 H-Pyro mouth [3,2-d] bilimidine, 1 H-Pyro mouth [3,4-d] Birimidine, etc.), Birazolopyrim
  • the carbon atom in the ring may be carbonyl, for example, 2,3-dihydro-2-pyroxypyridine, 2,3-dihydro-1,2,3-dioxopyrropyridine , 7,8-dihydro-7-oxo-1,8_naphthyridine, 5,6,7,8-tetrahydro-17-oxo-1,1,8-naphthyridine and the like.
  • these rings may be halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro, amino, alkylamino, cyano, formyl, acyl, aminoalkyl, mono- or dialkylaminoalkyl, azide, carboxy, alkoxycarbonyl, alkavamoyl, monoalkyl ⁇ Dialkyl Lubamoyl, Alkoxy Al It may be substituted by a substituent such as kill (methoxymethyl, methoxyl, methoxypropyl, ethoxymethyl, ethoxyl, ethoxypropyl, etc.) or hydrazino which may have a substituent.
  • kill methoxymethyl, methoxyl, methoxypropyl, ethoxymethyl, ethoxyl, ethoxypropyl, etc.
  • hydrazino which may have a substituent.
  • alkyl, Ararukiru examples of the substituent of the human Dorajino be substituted, alkyl, Ararukiru, nitro, force Shiano etc.
  • alkyl, Ararukiru is R, R ', alkyl in R 1, Ararukiru synonymous
  • methylhydrazino, ethylhydrazino, benzylhydrazino and the like are exemplified.
  • the compound used as the compound having the Rh-kinase inhibitory activity of the present invention may be a pharmaceutically acceptable acid addition salt, which includes inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and methanesulfone.
  • Organic acids such as acid, fumaric acid, maleic acid, mandelic acid, citric acid, tartaric acid, and salicylic acid.
  • the compound having a carboxyl group may be a salt with a metal such as sodium, potassium, calcium, magnesium, and aluminum, or a salt with an amino acid such as lysine.
  • a metal such as sodium, potassium, calcium, magnesium, and aluminum
  • a salt with an amino acid such as lysine.
  • their monohydrate, dihydrate, 1/2 hydrate, 1/3 hydrate, 1/4 hydrate, 2/3 hydrate And 3/2 hydrate are also included in the present invention.
  • an optical isomer a racemate or a cis-trans isomer thereof exists in the compound having the Rh kinase inhibitory activity
  • all of these can be used in the present invention.
  • the isomer can be isolated by a conventional method or can be produced by using each isomer material.
  • Rh kinase inhibition activity especially compounds represented by the general formula (I), isomers thereof and / or pharmaceutically acceptable acid addition salts thereof, include humans, Since it has an osteogenesis promoting effect on mammals such as horses, dogs, mice and rats, it is useful as an osteogenesis promoter and for the prevention and treatment of the various bone diseases mentioned above.
  • a compound having Rho kinase inhibitory activity When a compound having Rho kinase inhibitory activity is used as a medicine, it is prepared as a general pharmaceutical preparation and administered orally or parenterally.
  • a compound having Rho kinase inhibitory activity is mixed with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.).
  • a pharmaceutically acceptable carrier excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.
  • a pharmaceutically acceptable carrier excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.
  • a pharmaceutically acceptable carrier excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.
  • additives such as sucrose, lactose, cellulose sugar, D-mannitol, maltitol, dextran, starches, agar, alginate, chitin, chitosan, pectin, tran gum , Gum arabic, gelatin, collagen, casein, albumin, calcium phosphate, sorbitol, glycine, carboxymethylcellulose, polyvinylpyrrolidone, hydro
  • xypropylcellulose, hydroxypropylmethylcellulose, glycerin, polyethylene glycol, sodium hydrogencarbonate, magnesium stearate, and nylon are used.
  • the tablets can be made into tablets coated with a usual coating as required, for example, sugar-coated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multilayer tablets.
  • animal and vegetable oils in the case of semi-solid preparations, animal and vegetable oils (olive oil, corn oil, castor oil, etc.), mineral oils (vaseline, white petrolatum, solid paraffin, etc.), waxes (jojoba oil, carnapa wax, beeswax, etc.), A partially or totally synthesized glycerin fatty acid ester (eg, lauric acid, myristic acid, norremic acid) is used.
  • examples of these commercially available products include Witebsol (manufactured by Dynamid Nobel), Pharmasol (manufactured by NOF Corporation), and the like.
  • additives such as sodium chloride, glucose, sorbitol, glycerin, olive oil, propylene glycol, ethyl alcohol and the like can be mentioned.
  • a sterile aqueous solution such as physiological saline, isotonic solution, or oily solution such as sesame oil or soybean oil is used.
  • a suitable suspending agent such as sodium carboxymethylcellulose, a nonionic surfactant, and a solubilizing agent such as benzyl benzoate or benzyl alcohol may be used in combination.
  • an aqueous solution or an aqueous solution is used, and particularly, a sterile aqueous solution for injection is used.
  • Buffers preferably borate buffer, acetate buffer, carbonate buffer, etc. to reduce irritation
  • isotonic agents preferably borate buffer, acetate buffer, carbonate buffer, etc. to reduce irritation
  • isotonic agents preferably borate buffer, acetate buffer, carbonate buffer, etc. to reduce irritation
  • dissolution aids e.g., sodium metabisulfite
  • preservatives e.g., sodium metabisulfite
  • thickeners chelates
  • additives such as an agent, a ⁇ adjuster (11 is usually preferably adjusted to about 6 to 8.5) and an aromatic agent may be appropriately added.
  • the carrier may be a natural polymer substance such as collagen-fipurin coagulate, or a polylactic acid glycolic acid.
  • an artificial polymer substance that can be decomposed in a living body is used.
  • this agent can be used by coating the surface of the bone or tooth to be transplanted with an adhesive substance such as collagen paste or fibrin glue.
  • artificial bones and artificial roots made of metal, ceramic, glass, and other natural or artificial inorganic materials (eg, hydroxyapatite, etc.) are used.
  • the amount of the compound having Rh kinase inhibition activity which is an active ingredient in these preparations, is 0.1 to 100% by weight of the preparation, and suitably 1 to 50% by weight.
  • the dosage may vary depending on the patient's condition, weight, age, etc., but in the case of oral administration, it is usually about 1 to 50 Omg per adult per day, and it may be administered once or in several divided doses. Is preferred.
  • the compound of the present invention (Y-27632), lactose, corn starch and crystalline cellulose were mixed, kneaded with polyvinylpyrrolidone-30 size liquid, and granulated through a 20 mesh sieve. After drying at 50 ° C for 2 hours, the mixture was passed through a 24-mesh sieve, talc and magnesium stearate were mixed, and a tablet having a diameter of 12 Omg was prepared using a 7 mm diameter punch.
  • the compound of the present invention (Y_27632), lactose and corn starch are mixed, kneaded using polyvinylpyrrolidone K30 size liquid, and granulated through a 20-mesh sieve. After drying at 50 ° C for 2 hours, the mixture is passed through a 24 mesh sieve, talc and magnesium stearate are mixed, and the mixture is filled into hard capsules (No. 4) to produce 120 mg capsules.
  • Formulation example 3 Injection
  • mice undifferentiated mesenchymal cells (10T1 / 2 cells, MC3T3-E1 cells and ST2 cells), the activity of AL-lipophosphatase (ALP) as an indicator of osteoblast differentiation And the amount of osteocalcin production was measured.
  • 10 T 1/2 cells (supplied from RI KEN CE LLBANK (RCB0247)) were prepared in Basal Medium Eagle + 10% FCS supplemented with Y-27632 (0, 3, 5, 10, 20, 30 ⁇ M). 5% C0 2 presence and incubated 37 ° C, 72 hours.
  • the ALP activity contained in the cells was measured by the p-nitrophenyl phosphate substrate method (alkaline phospha B-test ⁇ ), and the amount of osteocalcin in the culture supernatant was further reduced. It was measured by the RIA method (Biotec).
  • MC 3 T 3- E 1 cells (sale from RI KEN CELL BANK (RCB 1 126 )) is also attached to, 5% C ⁇ 2 presence in MEM alpha medium + 1 0% FCS containing a Y- 27632, 37 ° C After culturing for 72 hours, ALP activity was measured in the same manner.
  • Y-27632 (10 ⁇ M) is applied to 10 T 1/2 cells, and the mRNA amount of osteobontin, which is strongly expressed at the early stage of osteoblast differentiation, is measured by RNA plotting over 1 to 4 days.
  • RNA plotting over 1 to 4 days.
  • ST-2 cells were treated with 10-M Y-27632, and the mRNA level of BMP-4, one of the osteoinductive factors, was measured over a period of 1 to 3 days by the RNA blot method. .
  • the active Rho (Va1_Rho) expression vector is transfected into 10 T1 / 2 cells by a method using ribofectamine to express exogenous active Rh. / 2 cells (hereinafter also referred to as Rho-expressing 10T1 / 2 cells) were prepared (Itoh, K., et al., Nature Med. Feb; 5 (2): p221-225 (1999)). 5% C ⁇ 2 presence in each cell similarly Basal Medium Eagle + 1 0% FCS in Experimental Example 1, after incubation 37 ° C, 48 hours, was studied the change of ALP activity by the expression of the activated Rho . The expression of active Rho was confirmed by the Western-producing method (immunoblotting) using a Rho antibody, and the ALP activity was measured in the same manner as in Experimental Example 1. As a control, cells expressing only one vector were used (mock).
  • Rho-expressing 10T1 / 2 cells have lower ALP activity than normal mesenchymal cells (which do not express activated Rho), and increased Rho activity suppresses differentiation into osteoblasts. Wax was shown (column V in Fig. 5). Therefore, it is presumed that suppression of Rho activity by a compound having Rho kinase inhibitory activity (Y-27632) promotes differentiation induction into osteoblasts and promotes bone formation.
  • Rho kinase inhibitory activity increase the production of osteoinductive factor (BMP) in mesenchymal cells, and Acts on osteoblasts by acting on leaf cells to significantly increase osteobontin production, alkaline phosphatase (ALP) activity and osteocalcin production, which are differentiation markers for osteoblasts. It has an excellent osteogenesis promoting action by having a differentiation induction action of Useful as a preventive and remedy for the disease.
  • BMP osteoinductive factor
  • ALP alkaline phosphatase
  • a compound having Rho kinase inhibitory activity can be used for osteoporosis, fibrous osteomyelitis, osteomalacia, etc. which occur when the balance between bone resorption and bone formation in bone tissue is disrupted due to the above-mentioned bone formation promoting action.

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Abstract

L'invention porte sur des promoteurs de l'ostéogenèse qui contiennent des composés ayant une activité inhibitrice de la Rho kinase. Des composés ayant une activité inhibitrice de la Rho kinase, tels que (+)-trans-4-(1-aminoéthyl)-1-(4-pyridylcarbamoyl)cyclohexane, augmentent la production de la protéine de morphogénèse de l'os (BMP) dans les cellules mésenchymateuses. De plus, lorsque des cellules mésenchymateuses non différenciées sont traitées avec ces composés, la productivité de l'ostéopontine (qui est un marqueur de différenciation des ostéoblastes), l'activité de la phosphatase alcaline (PhoA) et la productivité de l'ostéocalcine sont remarquablement élevées. Ainsi, ces composés exercent dans les ostéoblastes un effet inducteur de différenciation capable de stimuler l'ostéogenèse, ce qui les rend utiles comme promoteurs de l'ostéogenèse et/ou comme agents prophylactiques ou thérapeutiques pour les maladies osseuses.
PCT/JP2000/003969 1999-06-18 2000-06-16 Promoteurs de l'osteogenese WO2000078351A1 (fr)

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Cited By (18)

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JP2003055226A (ja) * 2001-08-15 2003-02-26 Asahi Kasei Corp 骨形成促進剤および骨形成促進組成物
EP1953152A1 (fr) 2002-09-24 2008-08-06 Bayer Corporation Processus de préparation d'inhibiteurs à kinase RHO de quinazoline et intermédiaires associés
EP1854484A4 (fr) * 2005-02-16 2010-02-10 Astellas Pharma Inc Remède contre la douleur contenant un inhibiteur de la protéine rho-kinase
WO2010058679A1 (fr) * 2008-11-18 2010-05-27 国立大学法人 九州大学 Promoteur de la réduction de fracture
WO2010096746A1 (fr) 2009-02-20 2010-08-26 Cellular Dynamics International, Inc. Procédés et compositions pour la différenciation de cellules souches
WO2010099539A1 (fr) 2009-02-27 2010-09-02 Cellular Dynamics International, Inc. Différenciation de cellules pluripotentes
WO2011047300A1 (fr) 2009-10-16 2011-04-21 The Scripps Research Institute Induction de cellules pluripotentes
US8211919B2 (en) 2005-09-02 2012-07-03 Astellas Pharma Inc. Amide derivatives as rock inhibitors
WO2012146936A1 (fr) 2011-04-28 2012-11-01 Cxr Biosciences Limited Dérivés de pyrrolnitrine
WO2013163171A1 (fr) 2012-04-24 2013-10-31 Kaufman Dan S Procédé de développement de cellules tueuses naturelles à partir de cellules souches
WO2014153230A1 (fr) 2013-03-14 2014-09-25 The Regents Of The University Of California Production in vitro de cellules de précurseurs d'éminence ganglionnaire médiane
WO2017064119A1 (fr) 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de la non-perfusion des capillaires de la rétine
US9732319B2 (en) 2010-12-22 2017-08-15 Fate Therapeutics, Inc. Cell culture platform for single cell sorting and enhanced reprogramming of iPSCs
RU2628370C2 (ru) * 2015-12-28 2017-08-16 Федеральное государственное бюджетное учреждение "Центральный научно-исследовательский институт травматологии и ортопедии имени Н.Н. Приорова" Министерства здравоохранения Российской Федерации (ФГБУ "ЦИТО им. Н.Н. Приорова" Минздрава России) Способ хирургического лечения гетеротопической оссификации с выполнением локального нейромоделирования спастического синдрома пациента
WO2020193802A1 (fr) 2019-03-28 2020-10-01 Fundación De La Comunidad Valenciana Centro De Investigación Príncipe Felipe Conjugués polymères et leurs utilisations
US11268069B2 (en) 2014-03-04 2022-03-08 Fate Therapeutics, Inc. Reprogramming methods and cell culture platforms
US11441126B2 (en) 2015-10-16 2022-09-13 Fate Therapeutics, Inc. Platform for the induction and maintenance of ground state pluripotency
EP4088719A1 (fr) 2015-10-13 2022-11-16 Institut National de la Santé et de la Recherche Médicale (INSERM) Procédés et compositions pharmaceutiques pour le traitement de non-perfusion capillaire rétinienne

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003055226A (ja) * 2001-08-15 2003-02-26 Asahi Kasei Corp 骨形成促進剤および骨形成促進組成物
EP1953152A1 (fr) 2002-09-24 2008-08-06 Bayer Corporation Processus de préparation d'inhibiteurs à kinase RHO de quinazoline et intermédiaires associés
EP1854484A4 (fr) * 2005-02-16 2010-02-10 Astellas Pharma Inc Remède contre la douleur contenant un inhibiteur de la protéine rho-kinase
US8211919B2 (en) 2005-09-02 2012-07-03 Astellas Pharma Inc. Amide derivatives as rock inhibitors
WO2010058679A1 (fr) * 2008-11-18 2010-05-27 国立大学法人 九州大学 Promoteur de la réduction de fracture
US20120040908A1 (en) * 2008-11-18 2012-02-16 Megmilk Snow Brand Co., Ltd. Fracture repair promoter
WO2010096746A1 (fr) 2009-02-20 2010-08-26 Cellular Dynamics International, Inc. Procédés et compositions pour la différenciation de cellules souches
US8372642B2 (en) 2009-02-27 2013-02-12 Cellular Dynamics International, Inc. Differentiation of pluripotent cells
WO2010099539A1 (fr) 2009-02-27 2010-09-02 Cellular Dynamics International, Inc. Différenciation de cellules pluripotentes
US10100282B2 (en) 2009-02-27 2018-10-16 FUJIFILM Cellular Dynamics, Inc. Differentiation of pluripotent cells
WO2011047300A1 (fr) 2009-10-16 2011-04-21 The Scripps Research Institute Induction de cellules pluripotentes
EP3235901A1 (fr) 2009-10-16 2017-10-25 The Scripps Research Institute Induction de cellules pluripotentes
US10844356B2 (en) 2010-12-22 2020-11-24 Fate Therapeutics, Inc. Cell culture platform for single cell sorting and enhanced reprogramming of iPSCs
US9732319B2 (en) 2010-12-22 2017-08-15 Fate Therapeutics, Inc. Cell culture platform for single cell sorting and enhanced reprogramming of iPSCs
WO2012146936A1 (fr) 2011-04-28 2012-11-01 Cxr Biosciences Limited Dérivés de pyrrolnitrine
EP3567102A1 (fr) 2012-04-24 2019-11-13 Dan S. Kaufman Procédé de développement de cellules tueuses naturelles à partir de cellules souches
WO2013163171A1 (fr) 2012-04-24 2013-10-31 Kaufman Dan S Procédé de développement de cellules tueuses naturelles à partir de cellules souches
WO2014153230A1 (fr) 2013-03-14 2014-09-25 The Regents Of The University Of California Production in vitro de cellules de précurseurs d'éminence ganglionnaire médiane
EP3656849A1 (fr) 2013-03-14 2020-05-27 The Regents of The University of California Production in vitro de cellules de précurseurs d'éminence ganglionnaire médiane
US11268069B2 (en) 2014-03-04 2022-03-08 Fate Therapeutics, Inc. Reprogramming methods and cell culture platforms
WO2017064119A1 (fr) 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de la non-perfusion des capillaires de la rétine
EP4088719A1 (fr) 2015-10-13 2022-11-16 Institut National de la Santé et de la Recherche Médicale (INSERM) Procédés et compositions pharmaceutiques pour le traitement de non-perfusion capillaire rétinienne
US11441126B2 (en) 2015-10-16 2022-09-13 Fate Therapeutics, Inc. Platform for the induction and maintenance of ground state pluripotency
RU2628370C2 (ru) * 2015-12-28 2017-08-16 Федеральное государственное бюджетное учреждение "Центральный научно-исследовательский институт травматологии и ортопедии имени Н.Н. Приорова" Министерства здравоохранения Российской Федерации (ФГБУ "ЦИТО им. Н.Н. Приорова" Минздрава России) Способ хирургического лечения гетеротопической оссификации с выполнением локального нейромоделирования спастического синдрома пациента
WO2020193802A1 (fr) 2019-03-28 2020-10-01 Fundación De La Comunidad Valenciana Centro De Investigación Príncipe Felipe Conjugués polymères et leurs utilisations

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