WO1998000438A1 - Steroid bisphosphonates - Google Patents
Steroid bisphosphonates Download PDFInfo
- Publication number
- WO1998000438A1 WO1998000438A1 PCT/GB1997/001748 GB9701748W WO9800438A1 WO 1998000438 A1 WO1998000438 A1 WO 1998000438A1 GB 9701748 W GB9701748 W GB 9701748W WO 9800438 A1 WO9800438 A1 WO 9800438A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- steroid
- hydroxy
- compound
- compounds
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
Definitions
- This invention concerns steroid derivatives and in particular bisphosphonate derivatives of hydroxy steroids for use in the prevention or treatment of osteoporosis and related bone disorders.
- Hydroxy steroids such as oestradiol and testosterone have been proposed for use in the treatment of osteoporosis, either by inhibition of bone resorption or stimulation of bone formation, and bisphosphonates such as disodium etidronate and clodronate are also known as bone resorption inhibitors.
- Certain bisphosphonate derivatives of steroids have also recently been proposed for these purposes in EP-A-0496520 and EP-A-0548884.
- the steroidal group is linked to the bisphosphonate group by a carbamate or carbonate group, and EP-A-0548884 describes steroid bisphosphate ethers.
- the compounds of the invention are thus of interest in the prevention or treatment of osteoporosis and other bone disorders such as Paget ' s disease, bone metastases and malignant hypercalcaemia .
- the compounds of the invention are derivatives of hydroxy steroids which are themselves bone resorption inhibitors or bone formation stimulators and thus useful in the prevention or treatment of osteoporosis, the derivatives having at least one group A in place of a hydroxy group on the steroid molecule, where A is a group of the formula
- X is: (i) St-O-CO- where St is the residue of the hydroxy steroid given by removal of an OH group,
- R 1 is an alkyl, alkenyl, cycloalkyl, aralkyl or aryl group, any of which may optionally be substituted, or
- the compounds of the invention may thus have the formula St-A where St and A are as defined above.
- Particular groups of compounds of interest are those of the formulae :
- the steroid contains more than one hydroxy group, only one is usually replaced by a group A, but the invention includes derivatives of such compounds in which two or more hydroxy groups are replaced by A groups .
- the structural variety of the compounds of the invention allows their hydrolysis properties to be modulated as required.
- most known steroid- bisphosphonate conjugates, particularly oestradiol- biphosphonates hydrolyse very rapidly whereas slower hydrolysis and hence slower release of the steroid is often desirable.
- Compounds of formula (1) above such as the compound (4) below which contains two steroid units are resistant to hydrolysis and thus advantageous when a slower rate of steroid release is required.
- compounds containing only one steroid unit are less resistant to hydrolysis and thus more suitable when rapid steroid release is required.
- the compounds of formula (1) also enable two different steroid units to be included in the same molecule, and this allows steroids of different activities to be delivered at the same time.
- the parent hydroxy steroid may be an oestrogen, androgen, anabolic steroid, glucocorticoid or progestagen which inhibits bone resorption or stimulates bone formation, such as for example 17 ⁇ -oestradiol , oestrone, testosterone, norethindrone, androsterone, norethandrolone and nandrolone .
- These compounds generally have a hydroxy group at the 3- or 17- position or both, and further examples of hydroxy steroids which may be used are listed in EP-A 0496520.
- R 1 may be a C x . 6 alkyl (e.g. methyl, ethyl, isopropyl or t -butyl ) , C 2 . 6 alkenyl (e.g. allyl) , C 3 . 8 cycloalkyl (e.g. cyclopentyl or cyclohexyl) , phenyl (Ci.g) alkyl or a mono- or bicyclic aryl group (e.g. phenyl or naphthyl) .
- the alkyl and alkenyl groups may for example be substituted by one or more halogen atoms (e.g.
- the compounds of the invention are capable of forming salts with bases and examples of such salts are alkali metal (e.g. sodium) and alkaline earth metal (e.g. calcium) salts. Some compounds of the invention exist in enantiomeric forms and all such forms are included.
- the compounds of the invention are useful in the prevention or treatment of osteoporosis and the other bone disorders referred to above in man and animals and they may be formulated for these purposes as pharmaceutical compositions together with one or more pharmaceutically acceptable carriers, excipients or diluents.
- the active ingredient in these compositions may for example be a compound (4) , (5) or (6) shown above .
- compositions of the invention may be in a form suitable for oral, buccal, parenteral or topical administration.
- compositions may be in the form of, for example, tablets, lozenges or capsules containing pharmaceutically acceptable excipients such as binding agents, fillers, lubricants, disintegrants or wetting agents.
- pharmaceutically acceptable excipients such as binding agents, fillers, lubricants, disintegrants or wetting agents.
- the tablets may also be coated by known methods.
- Liquid preparations for oral administration may be in the form of solutions, syrups or suspensions and may contain pharmaceutically acceptable additives such as- suspending agents, emulsifying agents, non- aqueous vehicles and preservatives.
- compositions may also be formulated for use by injection and may be presented in unit dose form, e.g. in ampoules.
- the compositions for injection may be in the form of suspensions, solutions or emulsions, in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, solubilising and/or dispersing agents.
- compositions may also be in a form suitable for topical administration, e.g. transdermal patches, ointments, creams and lotions.
- the compounds of the invention may be administered in combination with other pharmaceutically active ingredients .
- the total daily dosages of compounds of the invention employed in medicine will suitably be in the range 0.001-10.0 mg/kg bodyweight and these may be given in divided doses, i.e. 1-4 times per day.
- R 7 and R 3 are C ⁇ alkyl groups, e.g. ethyl, and may be the same or different
- StOH hydroxy steroid
- the transesterification of (7) may be effected in the presence of a base catalyst such as DMAP (dimethylaminopyridine) , for example in a hydrocarbon solvent at any suitable temperature up to reflux.
- a base catalyst such as DMAP (dimethylaminopyridine)
- the parent hydroxy steroid contains a further hydroxy group which is to remain in the final product, this should be protected during the transesterification reaction (for example as a benzyl ether) and the protecting group subsequently removed.
- the hydrolysis of the ester (8) may be carried out with a tri (C ! _ 6 alkyl) silyl halide such as trimethylsilyl bromide, for example in a halogenated hydrocarbon solvent .
- the bisphosphonates (7) may be prepared by first reacting a methylene bisphosphonate (9)
- dialkylmalonate in which the alkyl group is R 2 as defined above
- a base catalyst e.g. sodium ethoxide
- the reaction may be carried out in the presence of a base and an activating agent such as EDCI (N-(3- ethyldimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride) .
- EDCI N-(3- ethyldimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
- the phosphonate ester groups may then be removed by hydrolysis as described above to give the required bisphosphonic acid.
- the hydroxy steroid contains a further hydroxy group which is to be retained, it should be protected during the reaction and subsequently removed.
- the acids (11) can be prepared from a methylidene compound (10) above by addition of a dibenzyl malonate, in the presence of a non-nucleophilic base catalyst, to give the ester (12)
- Tetraethyl ethylene bisphosphonate (47.4 g, 0.165 mol , l.Oequiv.), paraformaldehyde (24.75 g, 0.825 mol,
- Toluene-p-sulfonic acid (0.15 g, catalytic) was added to a solution of crude tetraethyl (2-methoxy) ethylidene bisphosphonate 15 in toluene (250 ml) .
- the reaction mixture was heated overnight, under reflux conditions, after this period of time elimination had gone to completion.
- the reaction mixture was washed with aqueous HCl IM (3 x 100ml) and extracted into CH 2 C1 2 (200ml) .
- the organic fraction was collected and dried with anh. MgS0 4 , the solvent was removed under reduced pressure final traces of solvent were removed under high vacuum.
- the desired product 17 was isolated as an oil in excellent yield (43.8g / 95.1%) .
- Tetraethyl ethylidene bisphosphonate 16 (1.00 g, 3.33 mmol, 1.0 equiv.), and dibenzyl malonate (0.83 ml, 0.946 g, 3.33 mmol, 1.0 equiv.) were dissolved in tetrahydrofuran (15 ml).
- the reaction mixture was washed with water (30 ml), and the product extracted into CH 2 C1 2 .
- the organic layer was collected, dried with anh. MgS0 4 , and the solvent removed under reduced pressure.
- the crude product was absorbed onto silica gel and purified by silica gel flash column chromatography, 1-3% methanol/ CH 2 C1 2 were used as eluents.
- Testosterone (0.500 g, 1.73 mmol, 2.2 equiv.), 17 (0.363 g, 0.788 mmol, 1.0 equiv.), and 4- ⁇ N,N- dimethylamino)pyridine, were dissolved in toluene (7 ml) and heated under reflux, under an atmosphere of nitrogen. After 10 days reflux, more testosterone (0.250 g, 0.86 mmol, 1.1 equiv.) was added to the reaction mixture, and heated under reflux conditions for another 6 days. The reaction was stopped and washed with saturated aqueous ammonium chloride . The product was extracted into CH 2 Cl 2 , and dried with anh. MgS0 4 .
- (27) may be converted to the corresponding bisphosphonic acid by the method of Example 5.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU9902880A HUP9902880A3 (en) | 1996-06-28 | 1997-06-26 | Steroid bisphosphonates, process for their production and medicaments containing the same |
PL97330781A PL330781A1 (en) | 1996-06-28 | 1997-06-26 | Steroidic phosphonates |
CA002259309A CA2259309A1 (en) | 1996-06-28 | 1997-06-26 | Steroid bisphosphonates |
EP97929384A EP0912598A1 (en) | 1996-06-28 | 1997-06-26 | Steroid bisphosphonates |
SK1751-98A SK175198A3 (en) | 1996-06-28 | 1997-06-26 | Bisphosphonate derivatives of hydroxy steroids, process for their preparation and pharmaceutical composition containing them |
BR9710074-9A BR9710074A (en) | 1996-06-28 | 1997-06-26 | "steroidal bisphosphanates" |
IL12778197A IL127781A0 (en) | 1996-06-28 | 1997-06-26 | Steroid bisphosphonates |
AU33506/97A AU3350697A (en) | 1996-06-28 | 1997-06-26 | Steroid bisphosphonates |
JP10503922A JP2000513372A (en) | 1996-06-28 | 1997-06-26 | Steroid bisphosphonate |
US09/147,430 US6140518A (en) | 1996-06-28 | 1997-06-26 | Steroid bisphosphonates |
EE9800454A EE9800454A (en) | 1996-06-28 | 1997-06-26 | Steroidal bisphosphonates |
IS4931A IS4931A (en) | 1996-06-28 | 1998-12-22 | Bisfosfónatsterar |
NO986112A NO986112L (en) | 1996-06-28 | 1998-12-23 | Steroidal bisphosphonates |
APAP/P/1998/001431A AP9801431A0 (en) | 1996-06-28 | 1998-12-28 | Steroid bisphosphonates. |
BG103123A BG103123A (en) | 1996-06-28 | 1999-01-27 | Steroid biphosphonates |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9613722.9A GB9613722D0 (en) | 1996-06-28 | 1996-06-28 | Chemical compounds |
GB9613722.9 | 1996-06-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998000438A1 true WO1998000438A1 (en) | 1998-01-08 |
Family
ID=10796129
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1997/001748 WO1998000438A1 (en) | 1996-06-28 | 1997-06-26 | Steroid bisphosphonates |
Country Status (23)
Country | Link |
---|---|
US (1) | US6140518A (en) |
EP (1) | EP0912598A1 (en) |
JP (1) | JP2000513372A (en) |
KR (1) | KR20000022262A (en) |
CN (1) | CN1226253A (en) |
AP (1) | AP9801431A0 (en) |
AU (1) | AU3350697A (en) |
BG (1) | BG103123A (en) |
BR (1) | BR9710074A (en) |
CA (1) | CA2259309A1 (en) |
CZ (1) | CZ432398A3 (en) |
EE (1) | EE9800454A (en) |
GB (1) | GB9613722D0 (en) |
HU (1) | HUP9902880A3 (en) |
IL (1) | IL127781A0 (en) |
IS (1) | IS4931A (en) |
NO (1) | NO986112L (en) |
PL (1) | PL330781A1 (en) |
SK (1) | SK175198A3 (en) |
TR (1) | TR199900490T2 (en) |
WO (1) | WO1998000438A1 (en) |
YU (1) | YU59898A (en) |
ZA (1) | ZA975749B (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001013922A1 (en) * | 1999-08-19 | 2001-03-01 | The Royal Alexandra Hospital For Children | Drug for treating fractures |
US6436386B1 (en) | 2000-11-14 | 2002-08-20 | Shearwater Corporation | Hydroxyapatite-targeting poly (ethylene glycol) and related polymers |
AU781068B2 (en) * | 1999-08-19 | 2005-05-05 | Sydney Children's Hospitals Network (Randwick and Westmead) (incorporating The Royal Alexandra Hospital for Children), The | Drug for treating fractures |
US7829074B2 (en) | 2001-10-18 | 2010-11-09 | Nektar Therapeutics | Hydroxypatite-targeting poly(ethylene glycol) and related polymers |
US8282785B2 (en) | 2007-03-23 | 2012-10-09 | Metso Paper, Inc. | Roll cover and a covered roll |
US8440787B2 (en) | 2007-10-23 | 2013-05-14 | Nektar Therapeutics | Hydroxyapatite-targeting multiarm polymers and conjugates made therefrom |
WO2017079260A1 (en) * | 2015-11-02 | 2017-05-11 | University Of Rochester | Phosphonate-chloroquine conjugates and methods using same |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8586781B2 (en) | 1998-04-02 | 2013-11-19 | Mbc Pharma, Inc. | Bone targeted therapeutics and methods of making and using the same |
US7598246B2 (en) * | 1998-04-02 | 2009-10-06 | Mbc Pharma, Inc. | Bisphosphonate conjugates and methods of making and using the same |
US6896871B2 (en) | 1998-04-02 | 2005-05-24 | Mbc Research, Inc. | Biphosphonate conjugates and methods of making and using the same |
ATE451382T1 (en) | 1999-01-20 | 2009-12-15 | Takara Bio Inc | 4-SUBSTITUTED-3,6-ANHYDRO-GALACTOSE DERIVATIVES AND THEIR PHARMACEUTICAL USE |
CA2443857C (en) * | 2001-04-10 | 2012-06-26 | Mbc Research, Inc. | Bisphosphonate conjugates and methods of making and using the same |
EA200401565A1 (en) * | 2002-05-24 | 2005-04-28 | Неофарм, Инк. | METHOD FOR OBTAINING CARDIOLYPINE OR ANALOGUE OF CARDIOLIPINE (OPTIONS), METHOD FOR OBTAINING LIPOSOME AND COMPOSITION OF CARDIOLIPINE FOR TREATING DISEASES (OPTIONS) |
JP2006518701A (en) * | 2002-05-24 | 2006-08-17 | ネオファーム、インコーポレイティッド | Cardiolipin composition, process for its production and use |
US20050277611A1 (en) * | 2002-10-16 | 2005-12-15 | Neopharm, Inc. | Cationic cardiolipin analoges and its use thereof |
US20060078560A1 (en) * | 2003-06-23 | 2006-04-13 | Neopharm, Inc. | Method of inducing apoptosis and inhibiting cardiolipin synthesis |
EP2739154B1 (en) | 2011-08-01 | 2018-06-27 | MBC Pharma, Inc. | Vitamin b6 derivatives of nucleotides, acyclonucleotides and acyclonucleoside phosphonates |
EP2750711A2 (en) * | 2011-08-31 | 2014-07-09 | Mallinckrodt LLC | Remote assembly of targeted nanoparticles using h-phosphonate-ene/-yne hydrophosphonylation reactions |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992005187A1 (en) * | 1990-09-18 | 1992-04-02 | Boehringer Mannheim Gmbh | NEW 17-β-OESTRADIOL DERIVATIVES, A METHOD OF PREPARING THEM, AND DRUGS CONTAINING THEM |
EP0496520A1 (en) * | 1991-01-22 | 1992-07-29 | Merck & Co. Inc. | Novel bone acting agents |
FR2683527A1 (en) * | 1991-11-12 | 1993-05-14 | Bretagne Occidentale Universit | gem-Bisphosphonate (gem-Diphosphonate) prodrugs of steroids derived from cortisone |
EP0548884A1 (en) * | 1991-12-26 | 1993-06-30 | Hoechst Japan Limited | Biphosphonate derivative |
EP0555845A2 (en) * | 1992-02-14 | 1993-08-18 | Mitsubishi Kasei Corporation | Steroid derivatives |
-
1996
- 1996-06-28 GB GBGB9613722.9A patent/GB9613722D0/en active Pending
-
1997
- 1997-06-26 JP JP10503922A patent/JP2000513372A/en active Pending
- 1997-06-26 CN CN97196785A patent/CN1226253A/en active Pending
- 1997-06-26 CA CA002259309A patent/CA2259309A1/en not_active Abandoned
- 1997-06-26 SK SK1751-98A patent/SK175198A3/en unknown
- 1997-06-26 TR TR1999/00490T patent/TR199900490T2/en unknown
- 1997-06-26 HU HU9902880A patent/HUP9902880A3/en unknown
- 1997-06-26 BR BR9710074-9A patent/BR9710074A/en not_active Application Discontinuation
- 1997-06-26 EE EE9800454A patent/EE9800454A/en unknown
- 1997-06-26 IL IL12778197A patent/IL127781A0/en unknown
- 1997-06-26 US US09/147,430 patent/US6140518A/en not_active Expired - Fee Related
- 1997-06-26 PL PL97330781A patent/PL330781A1/en unknown
- 1997-06-26 KR KR1019980710682A patent/KR20000022262A/en not_active Application Discontinuation
- 1997-06-26 WO PCT/GB1997/001748 patent/WO1998000438A1/en not_active Application Discontinuation
- 1997-06-26 EP EP97929384A patent/EP0912598A1/en not_active Ceased
- 1997-06-26 CZ CZ984323A patent/CZ432398A3/en unknown
- 1997-06-26 AU AU33506/97A patent/AU3350697A/en not_active Abandoned
- 1997-06-27 ZA ZA975749A patent/ZA975749B/en unknown
-
1998
- 1998-12-22 IS IS4931A patent/IS4931A/en unknown
- 1998-12-23 NO NO986112A patent/NO986112L/en not_active Application Discontinuation
- 1998-12-23 YU YU59898A patent/YU59898A/en unknown
- 1998-12-28 AP APAP/P/1998/001431A patent/AP9801431A0/en unknown
-
1999
- 1999-01-27 BG BG103123A patent/BG103123A/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992005187A1 (en) * | 1990-09-18 | 1992-04-02 | Boehringer Mannheim Gmbh | NEW 17-β-OESTRADIOL DERIVATIVES, A METHOD OF PREPARING THEM, AND DRUGS CONTAINING THEM |
EP0496520A1 (en) * | 1991-01-22 | 1992-07-29 | Merck & Co. Inc. | Novel bone acting agents |
FR2683527A1 (en) * | 1991-11-12 | 1993-05-14 | Bretagne Occidentale Universit | gem-Bisphosphonate (gem-Diphosphonate) prodrugs of steroids derived from cortisone |
EP0548884A1 (en) * | 1991-12-26 | 1993-06-30 | Hoechst Japan Limited | Biphosphonate derivative |
EP0555845A2 (en) * | 1992-02-14 | 1993-08-18 | Mitsubishi Kasei Corporation | Steroid derivatives |
Non-Patent Citations (1)
Title |
---|
J. GUERVENOU ET AL, PHOSPHORUS, SULFUR AND SILICON AND THE RELATED ELEMENTS, vol. 88, no. 1-4, 1995, pages 1 - 13, XP002040871 * |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001013922A1 (en) * | 1999-08-19 | 2001-03-01 | The Royal Alexandra Hospital For Children | Drug for treating fractures |
AU781068B2 (en) * | 1999-08-19 | 2005-05-05 | Sydney Children's Hospitals Network (Randwick and Westmead) (incorporating The Royal Alexandra Hospital for Children), The | Drug for treating fractures |
US6436386B1 (en) | 2000-11-14 | 2002-08-20 | Shearwater Corporation | Hydroxyapatite-targeting poly (ethylene glycol) and related polymers |
US8372422B2 (en) | 2000-11-14 | 2013-02-12 | Nektar Therapeutics | Hydroxyapatite-targeting poly(ethylene glycol) and related polymers |
US8784849B2 (en) | 2000-11-14 | 2014-07-22 | Nektar Therapeutics | Hydroxyapatite-targeting poly(ethylene glycol) and related polymers |
US7829074B2 (en) | 2001-10-18 | 2010-11-09 | Nektar Therapeutics | Hydroxypatite-targeting poly(ethylene glycol) and related polymers |
US8282785B2 (en) | 2007-03-23 | 2012-10-09 | Metso Paper, Inc. | Roll cover and a covered roll |
US8440787B2 (en) | 2007-10-23 | 2013-05-14 | Nektar Therapeutics | Hydroxyapatite-targeting multiarm polymers and conjugates made therefrom |
US8815227B2 (en) | 2007-10-23 | 2014-08-26 | Nektar Therapeutics | Hydroxyapatite-targeting multiarm polymers and conjugates made therefrom |
US9173947B2 (en) | 2007-10-23 | 2015-11-03 | Nektar Therapeutics | Hydroxyapatite-targeting multiarm polymers and conjugates made therefrom |
WO2017079260A1 (en) * | 2015-11-02 | 2017-05-11 | University Of Rochester | Phosphonate-chloroquine conjugates and methods using same |
US10660884B2 (en) | 2015-11-02 | 2020-05-26 | University Of Rochester | Phosphonate-chloroquine conjugates and methods using same |
Also Published As
Publication number | Publication date |
---|---|
IL127781A0 (en) | 1999-10-28 |
KR20000022262A (en) | 2000-04-25 |
CA2259309A1 (en) | 1998-01-08 |
BG103123A (en) | 1999-10-29 |
CZ432398A3 (en) | 1999-05-12 |
NO986112D0 (en) | 1998-12-23 |
AU3350697A (en) | 1998-01-21 |
PL330781A1 (en) | 1999-06-07 |
TR199900490T2 (en) | 1999-05-21 |
HUP9902880A3 (en) | 2001-09-28 |
CN1226253A (en) | 1999-08-18 |
GB9613722D0 (en) | 1996-08-28 |
US6140518A (en) | 2000-10-31 |
BR9710074A (en) | 2000-01-18 |
YU59898A (en) | 1999-11-22 |
JP2000513372A (en) | 2000-10-10 |
EP0912598A1 (en) | 1999-05-06 |
SK175198A3 (en) | 1999-06-11 |
IS4931A (en) | 1998-12-22 |
AP9801431A0 (en) | 1998-12-31 |
NO986112L (en) | 1999-02-23 |
ZA975749B (en) | 1998-07-27 |
EE9800454A (en) | 1999-06-15 |
HUP9902880A2 (en) | 2000-03-28 |
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