WO1989003830A1 - 2-pyridinylmethyle (sulfinyle ou thio)benzimidazoles permettant le traitement de maladies relatives aux pertes osseuses - Google Patents

2-pyridinylmethyle (sulfinyle ou thio)benzimidazoles permettant le traitement de maladies relatives aux pertes osseuses Download PDF

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Publication number
WO1989003830A1
WO1989003830A1 PCT/SE1988/000575 SE8800575W WO8903830A1 WO 1989003830 A1 WO1989003830 A1 WO 1989003830A1 SE 8800575 W SE8800575 W SE 8800575W WO 8903830 A1 WO8903830 A1 WO 8903830A1
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WO
WIPO (PCT)
Prior art keywords
carbon atoms
alkyl
treatment
alkoxy
compound
Prior art date
Application number
PCT/SE1988/000575
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English (en)
Inventor
Rolf HÅKANSON
Per Lindberg
Björn Wallmark
Kalervo Väänänen
Original Assignee
Aktiebolaget Hässle
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
Priority claimed from SE8704247A external-priority patent/SE8704247D0/xx
Priority claimed from SE8704436A external-priority patent/SE8704436D0/xx
Application filed by Aktiebolaget Hässle filed Critical Aktiebolaget Hässle
Priority to KR1019890701208A priority Critical patent/KR890701580A/ko
Priority to AU26216/88A priority patent/AU617721B2/en
Publication of WO1989003830A1 publication Critical patent/WO1989003830A1/fr
Priority to DK322289A priority patent/DK322289D0/da

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is related to a novel method for the treatment of several bone affecting diseases, especially osteoporosis, which are characterized by loss of bone mass,
  • bone formation which is associated with the number and activity of osteoblasts, that is cells associated with the production of bone in the organism
  • bone loss which is associated with the number and activity of osteoclasts, that is cells associated with the absorption and removal of bone
  • osteoporosis can be mentioned, Paget's disease of bone, hyperparathyroidism and related disorders, and several malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcemia.
  • osteoporosis bone formation as well as bone resorption are disturbed, resulting in loss of bone tissue, decreased bone mass, and bone fragility. Osteoporosis predominantly affects the elderly, but also other groups such as post-menopausal women, where an estrogen deficit is believed to be a significant etiological factor, and immobilized patients. At this point it is not possible to clear up the whole picture of the disease mechanism and estimate which is the primary cause of. osteoporosis. However, about 25% of osteoporotic females belong to what is called “rapid bone losers” and at least in those patients the bone resorption rate is probably increased. Landry and Fleisch showed in immobilization induced osteoporosis that bone resorption rate is accelerated, (Landry, M. and Fleisch, H.: The influence of immobilization on bone formation as evaluated the incorporation of tetracyclines. J. Bone Joint Surg. 46B:764, 1964).
  • osteoporosis comprise fractures, especially hip fractures, but also vertebral fractures and fractures of the proximal radius, and complication of such fractures.
  • the present methods for the treatment of osteoporosis include exercise; administration of estrogen, especially for postmenopausal women; and consumption of calcium or calcium containing material such as milk.
  • Calcitonin a hormone associated with calcium metabolism, has also been used in the treatment of osteoporosis.
  • malignant tumors are known to be associated by hypercalcemia which is due to increased osteoclastic activity. This is a common complication for instance in the case of breast cancer and prostate cancer which are both one of the most common malignant tumors.
  • Hypercalcemia is due to both systemic and local fractors.
  • Some malignant cells are known to secrete agents which stimulate bone resorption (Sato, K, Fujii, Y., Kachivehi, T., Kasono, K., Shizume, K.: Production of interleukin 1 alpha (IL-1 ⁇ )-like activity and colony stimulating activity by clonal squanous cell carcinomas derived from patients with hypercalcemia and leucocytosis.
  • IL-1 ⁇ interleukin 1 alpha
  • Paget's disease (or osteitis deformans) of bone is a disease of unknown etiology where bone resorption and remodelling are increased leading sometimes even to the fractures of affected bone. Bone pain is the main indication of treatment in these patients. In these patients there is highly elevated local osteoclastic bone destruction. The incidence of osteitis deformans is very low in Scandinavian countries. In England it has been estimated to be present in 3-4% of population on the basis of autopsy studies (Anderson's Textbook of Pathology 1986). It is very rare in patients under 40 years. Calcitonin and diphosphonates are also used in the treatment of Paget's disease.
  • a further object of the invention is to provide compounds which improve the incorporation of calcium into the skeleton.
  • Heterocyclylalkylsulfinylbenzimidazoles and heterocyclylalkylthiobenzimidazoles are known in the art, as are methods for using these compounds to reduce gastric acid secretion.
  • compounds of the general formula I as well as prodrugs and pharmaceutically acceptable salts thereof are effective as inhibitors of basal and stimulated bone resorption.
  • the compounds of the formula I are useful as medicals for the treatment of osteoporosis, Paget's disease of bone, hyperparathyroidism, both primary and secondary, malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcinemia, immobilizationinduced osteoporosis, parodontal diseases and prostetic and implant-related bone losses.
  • X is -S- or -SO-; R 1 , R 2 , R 3 and R 4 which are the same or different, are
  • aryl-thio -sulfinyl, -sulfonyl, -sulfonyloxy, oxysulfonyl, -sulfonamido or -aminosulfonyl, whereby each aryl group optionally is substituted by 1-3 substituents, the same or different and selected from halogen, CF 3 and (1-5C)alkoxy
  • arylalkyl or arylalkoxy containing 1-6 carbon atoms in the alkyl and alkoxy parts, respectively, whereby the aryl part optionally is substituted by 1-3 substituents, the same or different and selected from halogen, CF 3 , (1-5C) alkyl and (1-5C)alkoxy
  • each aryl group optionally is substituted by 1-3 substituents, the same or different and selected from halogen, CF 3 , (1-5C)alkyl and (1-5C)alkoxy
  • R 7 is (a) H
  • aryloxy whereby the aryl group optionally is substituted by 1 or 2 substituents, the same or different and selected from halogen, CF 3 , (1-3C)alkyl or (1-3C)alkoxy
  • arylalkyl or arylalkoxy containing 1-7 carbon atoms in the alkyl resp. alkoxy part whereby the aryl part optionally is substituted by 1 or 2 substituents, the same or different and selected from halogen, CF 3 , (1-3C)alkyl and (1-3C)alkoxy
  • alkenyloxy containing 1-7 carbon atoms in the alkenyl part (i) alkynyloxy containing 1-7 carbon atoms in the alkenyl part (j) alkylthio containing 1-7, preferably 1-3 carbon atoms in the alkyl part (k) arylthio or arylalkylthio containing 1-3, preferably
  • R 10 is (a) alkyl containing 1-6 carbon atoms
  • Examples of pharmaceutically acceptable salts are alkali salts such as sodium and potassium salts, and calcium and magnesium salts.
  • prodrug is intended to cover compounds which after administration to the patient are converted to a compound of the formula I. More particulary, examples of prodrugs of compounds of the formula I are of the formula
  • R 1 1 is (a) H
  • R 12 is (a) alkyl containing 1-6 carbon atoms
  • aryl optionally substituted with alkyl containing 1-4 carbon atoms, alkoxy containing 1-4 carbon atoms, halogen, CF 3 , alkanoyl containing 2-5 carbon atoms
  • aryloxy optionally substituted with alkyl containing 1-4 carbon atoms, alkoxy containing 1-4 carbon atoms, halogen, CF 3 , alkanoyl containing 2-5 carbon atoms or alkoxycarbonyl containing 2-5 carbon atoms
  • arylalkoxy containing 1-5 carbon atoms in the alkoxy part wherein the aryl part optionally is substituted with alkyl containing 1-6 carbon atoms and/or alkoxy containing 1-6 carbon atoms;
  • R 13 is (a) H
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 13 are exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cycl opentyl ethyl, and cycl ohexylmethy 1.
  • Lower alkyl groups containing 1-4 carbon atoms are especially preferred.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 R 10 , and R 12 are exemplified by methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentoxy i-pentoxy, n-hexoxy, cyclopropoxy, cyclopentoxy, cyclohexoxy, cyclopropylmethoxy, cyclopenty Imethoxy, cycl opentylethoxy, and cyclohexylmethoxy.
  • Lower alkoxy groups are preferred, especially those containing 1-4 carbon atoms.
  • a lower alkoxy group having especially preferred 1-3 carbon atoms e.g. methoxy, ethoxy, n-propoxy or isopropoxy.
  • Halogen in the definitions of R 1 , R 2 , R 3 , R 4 , and R 12 is chloro, bromo, fluoro and iodo, preferably chloro, bromo, and fluoro.
  • R 1 , R 2 , R 3 , R 4 , and R 7 when representing alkylthio or alkylsulfinyl is the alkyl preferably a lower alkyl having especially preferred 1-4 carbon atoms, e.g. methylthio, methylsulfinyl, ethylthio, ethyl sulfinyl, isopropylthio, n-butylsulfinyl or isobutylthio.
  • the group aryl when present in R 1 , R 2 , R 3 , R 4 , R 7 , R 10 , and R 12 has preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenyl group.
  • R 1 , R 2 , R 3 , R 4 , R 7 , and R 1 2 representing an aryloxy or arylthio group have preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenoxy or phenylthio group.
  • Alkanoyl in R 12 contains from 1 to 6 carbon atoms and is preferably HCO, CH 3 CO, CH 3 CH 2 CO, CH 3 (CH 2 ) 2 CO, or HC(CH 3 ) 2 CO.
  • Alkoxycarbonyl in R 12 contains an alkoxy group as illustrated under "alkoxy" above.
  • the groups arylalkyl, arylalkoxy, and arylalkylthio, when present in R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 12 have preferably up to 10 carbon atoms in the aryl group. Especially preferred are 6 carbon atoms in the aryl group and 1-3 carbon atoms in the alkyl group or alkoxy group, respectively, e.g. phenylmethyl, phenylethyl, pheny Imethoxy, phenylethoxy, phenylpropyl, phenylisopropoxy, phenylmethylthio, and phenylethylthio.
  • R 1 , R 2 , R 3 , R 4 , and R 7 representing an alkoxyalkyl or alkoxyalkoxy group are exemplified by methoxymethoxy, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxyethyl, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy and propoxyethoxy.
  • R 7 representing an alkenyloxy or alkynyloxy group has preferably 2-7 carbon atoms, especially preferred 3-4 carbon atoms, e.g. allyloxy, propargyloxy, 2-butenyloxy and 2-butynyloxy.
  • R 2 and R 3 and R 4 are -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -,
  • R 6 and R 7 , or R 7 and R 8 representing a 5- or 6-membered saturated or unsaturated ring is preferably a saturated carbocyciic ring or a saturated ring containing an oxygen or a sulphur atom in the 4-position in the pyridine ring, e.g.
  • R 1 , R 2 , R 3 and R 4 when representing haloalkoxy is preferably a lower haloalkoxy.
  • Especially preferred are lower fluoroalkoxy, or fluorochloroalkoxy groups, e.g. OCF 3 , OCHF 2 , OCF 2 CHF 2 ,
  • R 7 when representing alkoxy is exemplified by OCH 2 CF 3 , OCH 2 CF 2 CF 3 and OCH 2 CF 2 CHF 2 .
  • R 1 , R 2 , R 3 and R 4 representing hydroxyalkyl is exemplified by
  • R 7 when representing a dialkylamino group is preferably -N(CH 3 ) 2 , or -N(C 2 H 5 ) 2 .
  • Example 1 Effect of Example 1 and Example 2 on parathyroid hormone induced bone resorption in vitro
  • the compounds of the formula I are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
  • the pharmaceutical formulation contains a compound of the invention in combination with a pharmaceutically acceptable carrier.
  • the carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule.
  • These pharmaceutical preparations are a further object of the invention.
  • the amount of active compounds is between 0.1-95 % by weight of the preparation, between 0.2-20 % by weight in preparations for parenteral use and between 1 and 50 % by weight in preparations for oral administration.
  • the typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 mg per day of active substance.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Procédé de traitement de l'ostéoporose, de la maladie osseuse de Paget, de l'hyperparathyroïdisme, de néoplasmes malins provoquant l'hypercalcémie, de maladies parodontales et de pertes osseuses relatives à des implants, consistant à administrer à un patient souffrant d'une des maladies précitées, une quantité d'un composé de formule (I), un promédicament, ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/SE1988/000575 1987-10-30 1988-10-27 2-pyridinylmethyle (sulfinyle ou thio)benzimidazoles permettant le traitement de maladies relatives aux pertes osseuses WO1989003830A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
KR1019890701208A KR890701580A (ko) 1987-10-30 1988-10-27 골(骨)손실에 관련된 질병 치료용 2-피리디닐메틸(술피닐 또는 티오) 벤즈이미다졸
AU26216/88A AU617721B2 (en) 1987-10-30 1988-10-27 2-pyridinylmethyl (sulfinyl or thio) benzimidazoles for treatment of diseases related to bone loss
DK322289A DK322289D0 (da) 1987-10-30 1989-06-28 2-pyridinylmetyl-(sulfinyl eller tio)-benzimidazoler til behandling af sygdomme med relation til knoglebrud

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE8704247-9 1987-10-30
SE8704247A SE8704247D0 (sv) 1987-10-30 1987-10-30 Method of treatment
SE8704436A SE8704436D0 (sv) 1987-11-13 1987-11-13 Anvendning av antisekretoriska substanser for nya indikationer
SE8704436-8 1987-11-13

Publications (1)

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WO1989003830A1 true WO1989003830A1 (fr) 1989-05-05

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PCT/SE1988/000575 WO1989003830A1 (fr) 1987-10-30 1988-10-27 2-pyridinylmethyle (sulfinyle ou thio)benzimidazoles permettant le traitement de maladies relatives aux pertes osseuses
PCT/SE1988/000573 WO1989003829A1 (fr) 1987-10-30 1988-10-27 Omeprazole permettant le traitement de maladies relatives a la perte osseuse

Family Applications After (1)

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PCT/SE1988/000573 WO1989003829A1 (fr) 1987-10-30 1988-10-27 Omeprazole permettant le traitement de maladies relatives a la perte osseuse

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EP (1) EP0338066A1 (fr)
JP (1) JPH02501930A (fr)
KR (1) KR890701580A (fr)
AU (1) AU2621888A (fr)
DK (1) DK322289D0 (fr)
HU (1) HU886738D0 (fr)
IL (2) IL88207A (fr)
MY (1) MY103790A (fr)
WO (2) WO1989003830A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0434405A1 (fr) * 1989-12-21 1991-06-26 American Home Products Corporation Imidazo(4,5-c)pyridines comme agents antiostéoporotiques
EP0912549A1 (fr) * 1996-06-20 1999-05-06 The Board Of Regents, The University Of Texas System Composes et procedes d'obtention de preparations pharmacologiquement actives et leurs utilisations
KR100453916B1 (ko) * 2002-03-11 2004-10-20 주식회사 코오롱 1,2,5,6-테트라히드로피리디닐벤즈이미다졸 유도체 및 그제조방법

Families Citing this family (9)

* Cited by examiner, † Cited by third party
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SE8804628D0 (sv) * 1988-12-22 1988-12-22 Ab Haessle New compounds
JP2694361B2 (ja) * 1989-02-09 1997-12-24 アストラ アクチエボラグ 抗菌剤
PL165898B1 (pl) * 1990-06-20 1995-02-28 Astra Ab Sposób wytwarzania nowych pochodnych dwualkoksyplrydynylobenzlmldazolu PL
SE9002206D0 (sv) * 1990-06-20 1990-06-20 Haessle Ab New compounds
US6316020B1 (en) * 1999-08-26 2001-11-13 Robert R. Whittle Pharmaceutical formulations
DE10040052A1 (de) * 2000-08-11 2002-03-07 Univ Eberhard Karls Verwendung von Protonenpumpen-Hemmern zur Behandlung von Entzündungen, insbesondere von Erkrankungen des Bewegungsapparates
GB0403165D0 (en) * 2004-02-12 2004-03-17 Ct Novel uses for proton pump inhibitors
KR100638649B1 (ko) 2006-06-27 2006-10-31 신한전기공업주식회사 절연보강된 코일을 구비한 건식 변압기
CN103826632B (zh) * 2011-08-26 2017-04-12 国立大学法人名古屋大学 骨形成促进剂及其用途

Citations (3)

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SE416649B (sv) * 1974-05-16 1981-01-26 Haessle Ab Forfarande for framstellning av foreningar som paverkar magsyrasekretionen
US4472409A (en) * 1981-11-05 1984-09-18 Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects
EP0197013A1 (fr) * 1985-03-01 1986-10-08 Aktiebolaget Hässle Benzimidazoles substitués pour la fabrication d'un médicament pour le traitement de maladies intestinales inflammatoires

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE416649B (sv) * 1974-05-16 1981-01-26 Haessle Ab Forfarande for framstellning av foreningar som paverkar magsyrasekretionen
US4472409A (en) * 1981-11-05 1984-09-18 Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects
EP0197013A1 (fr) * 1985-03-01 1986-10-08 Aktiebolaget Hässle Benzimidazoles substitués pour la fabrication d'un médicament pour le traitement de maladies intestinales inflammatoires

Non-Patent Citations (3)

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Title
Calcified Tissue International, Vol. 38, 1986, J. TUUKKANEN & H.K. VAANANEN, "Omeprazole, a specific inhibitor of H+-K+-ATPase, inhibits bone resorption in vitro", pages 123-125. *
Nature, Vol. 290, 12 March 1981, pages 159-161. *
S. YOUSUF ALI, "Cell mediated calcification and matrix vesicles. Proceedings of the IV International conference on matrix vesicles, Cambridge, 1-5 July 1985", publ. 1986, by Excerpta Medica (Amsterdam), pages 143-146. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0434405A1 (fr) * 1989-12-21 1991-06-26 American Home Products Corporation Imidazo(4,5-c)pyridines comme agents antiostéoporotiques
US5081253A (en) * 1989-12-21 1992-01-14 American Home Products Corporation Imidazo(4,5-c)pyridines as antiosteoporotic agents
EP0912549A1 (fr) * 1996-06-20 1999-05-06 The Board Of Regents, The University Of Texas System Composes et procedes d'obtention de preparations pharmacologiquement actives et leurs utilisations
EP0912549A4 (fr) * 1996-06-20 2002-01-02 Univ Texas Composes et procedes d'obtention de preparations pharmacologiquement actives et leurs utilisations
US6720344B2 (en) 1996-06-20 2004-04-13 The Board Of Regents Of The University Of Texas System Methods and compositions for stimulating osteoblast proliferation or treating malignant cell proliferation and methods for selecting osteoblast proliferation stimulants
KR100453916B1 (ko) * 2002-03-11 2004-10-20 주식회사 코오롱 1,2,5,6-테트라히드로피리디닐벤즈이미다졸 유도체 및 그제조방법

Also Published As

Publication number Publication date
DK322289A (da) 1989-06-28
KR890701580A (ko) 1989-12-21
IL88207A0 (en) 1989-06-30
DK322289D0 (da) 1989-06-28
WO1989003829A1 (fr) 1989-05-05
EP0338066A1 (fr) 1989-10-25
IL88206A0 (en) 1989-06-30
HU886738D0 (en) 1990-02-28
MY103790A (en) 1993-09-30
AU2621888A (en) 1989-05-23
JPH02501930A (ja) 1990-06-28
IL88207A (en) 1993-03-15

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