WO2001051497A1 - Novel bisphosphonates and uses thereof - Google Patents
Novel bisphosphonates and uses thereof Download PDFInfo
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- WO2001051497A1 WO2001051497A1 PCT/GB2001/000140 GB0100140W WO0151497A1 WO 2001051497 A1 WO2001051497 A1 WO 2001051497A1 GB 0100140 W GB0100140 W GB 0100140W WO 0151497 A1 WO0151497 A1 WO 0151497A1
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- 0 CC1(OC(CCC*(*)CCCC2)C2O1)[U] Chemical compound CC1(OC(CCC*(*)CCCC2)C2O1)[U] 0.000 description 5
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
Definitions
- the present invention relates to novel derivatives of bisphosphonate compounds, and to their use in the treatment and/or prevention of such conditions as hypercalcaemia of malignancy, Paget's disease, osteoporosis, metastatic cancer in bone and soft tissue, and periodontal disease.
- Bisphosphonates are synthetic compounds, structurally related to pyrophosphate, in that two phosphonates are attached to a common atom. More specifically, bisphosphonates of particular interest contain a P-C-P bond, whereas pyrophosphate has a P-O-P bond. The difference in the two chemical bonding schemes means that bisphosphonates are resistant to enzymatic hydrolysis in osseous tissue, for example.
- Bisphosphonates are potent inhibitors of bone resorption and have been successfully used in the treatment and/or prevention of hypercalcaemia associated with periodontal disease, osteoporosis, bone malignancy and metastatic cancer of the bone.
- bisphosphonates have been successfully used in the treatment and/or prevention of conditions which involve abnormal calcium and phosphate metabolism, such as Paget's disease.
- Bisphosphonates are also used to treat other more rare disorders such as mastocytosis, fibrous displasia, Gaucher's disease and osteogenesis imperfecta.
- Bisphosphonates have further been used to inhibit mineralisation in the treatment of heterotropic ossification and myositis ossificans progressiva.
- bisphosphonates have found use in the stabilisation of prostheses such as in total hip replacement.
- US-A-5,403,829 teaches that the main effect of the bisphosphonates is their ability to inhibit bone resorption. Contrary to the effect on mineralisation, the mechanism involved in bone resorption is cellular [c.f. Fleisch, Drugs 42: 919-44 (1991)].
- the half-life of circulating bisphosphonates is very short; in the order of minutes to hours. Of any a given bisphosphonate dose, 20 to 50% is taken up by the skeleton, while the rest is excreted in the urine. The half-life in bone, however, is far longer and depends upon the turnover rate of the skeleton itself.
- US-A-5,409,911 discloses prostaglandin-bisphosphonate compounds that are effective as delivery agents of prostaglandins to treat osteoporosis and related bone diseases. The compounds also simultaneously deliver a bisphosphonate which inhibits bone resorption.
- US-A-5, 428,181 discloses bisphosphonates that show significant therapeutic effects on bone diseases such as osteoporosis, rheumatoid arthritis and osteoarthritis.
- US-A-5,668,120 discloses methods of inhibiting alveolar bone resorption or the undesirable movement of teeth of a human or other animal.
- the invention relates to iontophoretic delivery of a bisphosphonic acid compound or pharmaceutically acceptable salt and ester thereof, to the oral tissue.
- the glycoside and orthoester glycoside derivatives of bisphosphonate compounds have markedly enhanced intestinal abso ⁇ tion. They have, thus, enhanced bioavailability, enabling them to be given orally, and substantially reducing the amount of compound needed to be administered and/or reducing the amount of time elapsed before a therapeutic effect occurs. In addition, at effective concentrations, the cytotoxicity of these compounds is substantially reduced.
- the present invention provides a glycoside or orthoester glycoside derivative of a therapeutically useful bisphosphonate compound, or pro-drug thereof, preferably wherein the bisphosphonate compound is useful in the treatment and/or prevention of hypercalcaemia or osteoporosis.
- any therapeutically active bisphosphonate compound, or pro-drug thereof maybe derivatised to form a compound of the invention. Indeed, not only can those compounds currently prescribed be prepared as glycosides or orthoester glycosides (which terms are used interchangeably herein, except as otherwise indicated, or apparent), but also those compounds which have not been prescribable, at least orally, owing to either low bioavailability and/or cytotoxicity when given orally.
- the present invention provides a compound of formula (I):
- G is a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or G is an orthoester glycoside moiety of the Formula (II):
- A' is a glycofuranosyl or glycopyranosyl ring
- R is hydrogen; R is hydrogen or a straight or branched chain glycosidic residue containing 1-
- each Rj which may be the same or different, is hydrogen, alkyl, aryl, benzyl or alkali metal cation, or two -ORi groups, on the same phosphorus atom, taken together with -(CH 2 ) 2 - -(CH 2 ) 3 - or -CH 2 C(CH 3 ) 2 CH 2 - form a heterocyclic ring containing one phosphorus, two oxygens and two or three carbons;
- Q is selected from the group consisting of:
- n is 0 or 1 and m is an integer from 1 to 8;
- Rt and R which may be the same or different, are hydrogen, -SO 3 H, a lower aliphatic group which may optionally contain one or more heteroatoms and which contains at least one -SO 3 H group or a covalent bond to Y,
- R 8 and R 9 which maybe the same or different, are: (a) a covalent bond to Y, -NO 2 or -NH 2 ;
- R ⁇ is hydrogen, alkyl, phenyl, acyl, benzoyl, aralkyl, halogen, allyl or a covalent bond to Y;
- R ⁇ 2 and R ⁇ 3 can be the same or different and are hydrogen, alkyl, phenyl, acyl, benzoyl, aralkyl or a covalent bond to Y; a is 1 or 2; b is 1 to 4;
- R c and R d which may be the same or different in each instance, are hydrogen or alkyl; with the proviso that when the ring containing R 8 is a pyridine ring, b is 1 to 3; p is 1 to 5; with the proviso that only one of A', R4, R 5 , R 6 , R 7 R 8 , R 9 Rio, R ⁇ , R 12 and R ⁇ 3 is a covalent bond to Y;
- Y is chosen from the group consisting of optionally substituted C ⁇ - 10 alkylene, aryl, heteroaryl, heterocyclo, a steroidal hormone, a compound exhibiting oestrogenic activity or a prostaglandin; and pharmaceutically acceptable salts or esters thereof.
- the compounds of the present invention possess a P-C-P linkage, in order to best mimic pyrophosphates.
- each OR] is the same or different and is OH or a hydrolysable group, or two ORi groups on the same phosphorus atom form a substituted or unsubstituted 5, 6 or 7 membered heterocyclic ring;
- R is H, alkyl or halogen or is a group -O-G, -S-G, - H-G or -NR ⁇ 2 -G;
- each G is the same or different and is hydrogen or a straight or branched chain glycosidic residue or glycosidic orthoester residue, amino derivative or sulphate thereof, provided that at least one group G is a glycosidic residue or glycosidic orthoester residue,
- X is O, S, NH or NR 12 ; each R 12 is the same or different and is hydrogen, alkyl, phenyl, acyl, benzoyl or aralkyl;
- Q is an optionally substituted alkylene or alkenylene group or is an optionally substituted alkylene containing at least one O, S or NH or is O, S or NH, or is a direct bond to Y;
- Y represents a binary or tertiary alkyl-substituted amine, C MO alkylene, aryl, heteroaryl, heterocyclyl, a steroidal hormone, a group exhibiting oestrogenic activity or a prostaglandin, said group Y being optionally substituted;
- Ri may conveniently represent: alkyl, for example methyl, ethyl, propyl, t-butyl; aryl, for example phenyl; aralkyl, for example benzyl; any of which may be optionally substituted, for example by lower alkyl or halogen; or Rj may represent a suitable cation, such as ammonium or substituted ammonium, or an alkali metal cation, for example sodium or potassium.
- Ri represents an alkyl group
- this may conveniently be a Q.
- ⁇ alkyl such as methyl, ethyl, propyl, butyl, methylpropyl, t-butyl, pentyl, dimethylpropyl, hexyl, dimethylbutyl or ethylbutyl.
- alkyl groups are mentioned herein, then they are generally preferably as exemplified above.
- prefe ⁇ ed alkyl groups contain 1 or 2 carbon atoms.
- Methyl and ethyl groups are particularly prefe ⁇ ed, especially methyl.
- R is halogen and, in general, when halogen is specified herein, then this is usefully chloro, fluoro, bromo or iodo, especially chloro.
- R contains a glycoside or orthoester glycoside, then this is generally as exemplified below, and the group is preferably an -O-G or -N-G group.
- G represents a glycosidic residue
- it is prefe ⁇ ed that it contain 1-20 glycosidic units.
- G is a glycosidic orthoester residue, then it is prefe ⁇ ed that it have the Formula (II):
- A' represents a glycofuranosyl or glycopyranosyl ring or amino derivative thereof
- R a is hydrogen, C ⁇ - alkyl, C 7 _ ⁇ o aralkyl, phenyl; or phenyl substituted by chloro, fluoro, bromo, iodo, C ⁇ - alkyl or C ⁇ - alkoxy; or naphthyl; and R b is hydrogen or a straight or branched chain glycosidic residue containing 1 -20 glycosidic units per residue.
- G has less than 10 and, more preferably, 3 or less glycosidic units.
- Specific examples are those containing 1 or 2 glycosidic units in the glycoside residue, such as glucose and sucrose, with one being most prefe ⁇ ed.
- glycosidic units are meant glycopyranosyl or glycofuranosyl, as well as their sulphates, amino sugar and/or deoxy derivatives.
- the configuration of each unit may be D or L, although D is generally prefe ⁇ ed.
- the residues may be homopolymers, random or alternating polymers, or block copolymers of these monomers.
- the acyl groups are acetyl or propionyl.
- Other prefe ⁇ ed R 5 groups are phenyl, nitrophenyl, halophenyl, lower alkyl substituted phenyl, lower alkoxy substituted phenyl and the like or benzyl, lower alkoxy substituted benzyl and the like.
- glycopyranose or glycofuranose ring or amino derivative thereof may be fully or partially acylated or completely deacylated.
- the completely or partially acylated glycoside is useful as a defined intermediate for the synthesis of the deacylated material.
- Useful protecting groups include, but are not limited to, acetyl, benzoyl, nicotinoyl, benzyl, methyl and phenyl.
- glycopyranosyl structures are glucose, mannose, galactose, gulose, allose, altrose, idose, or talose.
- the prefe ⁇ ed ones are derived from fructose, ribose, arabinose or xylose.
- prefe ⁇ ed diglycosides are sucrose, cellobiose, maltose, lactose, trehalose, gentiobiose, and melibiose.
- the prefe ⁇ ed ones may be raffmose or gentianose.
- Prefe ⁇ ed aminosugar derivatives are N-acetyl-D-galactosamine, N- acetyl-D-glucosamine, N-acetyl-D-mannosamine, N-acetylneuraminic acid, D-glucosamine, D-lyxosylamine, D-galactosamine, chondroitin, and the like.
- active units as chondroitin sulphate and D-glucosamine sulphate may also be employed, as such sub-units independently have advantageous therapeutic osteopathic properties, and can enhance or complement the activity of the bisphosphonate compound.
- the individual glycosidic rings may be bonded by 1-1, 1-2, 1-3, 1-4, 1-5 or 1-6 bonds, most preferably 1-2, 1-4 and 1-6.
- the linkages between individual glycosidic rings may be ⁇ or ⁇ .
- Q is an alkylene group
- this preferably contains up to 7 carbons in the chain, with methylene, ethylene, propylene, butylene and pentylene being prefe ⁇ ed. These may be substituted, if desired, preferably with methyl, ethyl or halogen.
- Q may be, or contain, O, S or NH. It is generally prefe ⁇ ed that there be no more than two of these chain members and that, where there are two, then they be spaced by at least a methylene group. Preferably, however, Q only contains one of O, S and NH. Any such O, S or NH may be linked directly to the methylenic carbon of the bisphosphonate group, or maybe spaced apart therefrom by one or more carbon atoms.
- Prefe ⁇ ed meanings for Q are, O, S, NH and unsubstituted alkylene.
- Y represents an amine
- the nitrogen is preferably directly linked to Q.
- these may, optionally, form a heterocyclyl group with the nitrogen to which they are attached.
- the or each alkyl substituent may be substituted by, for example, halogen, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl groups.
- the alkyl group or groups are unsubstituted or are substituted by one or two halogen atoms
- Y is C MO alkylene, then it is preferably as defined above, or is a cycloalkyl group containing 3 to 7 carbons. Prefe ⁇ ed alkylene groups contain 1 to 4 carbon atoms, more preferably 1 or 2.
- Y is aryl
- this will generally contain between 6 and 14 ring members and may be substituted by such groups as OH, halo, NH and alkyl, with halogen and alkyl being prefe ⁇ ed, where there is a substituent.
- aryl groups are phenyl, chlorophenyl and naphthyl.
- Y represents a heteroaryl group
- this will generally contain between 5 and 10 ring members, of which one, two or three may be selected from N, S and O.
- prefe ⁇ ed heteroatoms are N
- exemplary heteroaryls include pyrazolyl, imidazolyl and pyridinyl. Where such groups are substituted, then this may be as exemplified above for aryl.
- Y is a heterocyclic group
- this may generally be as exemplified for heteroaryl, provided that the ring is not completely unsaturated.
- Substituents may be as exemplified above, and suitable examples of heterocyclic groups include pyrrolidinyl and pyrimidinyl.
- Y represents a steroidal hormone, a group exhibiting oestrogenic activity or a prostaglandin, then these may generally be as exemplified below.
- Prefe ⁇ ed meanings for Y are alkyl, tertiary amine, aryl, heteroaryl, cycloalkyl, heterocyclyl, optionally further substituted by methyl or chloro groups.
- Y are chosen from the group consisting of C ⁇ - ⁇ o alkylene, aryl, heteroaryl, heterocyclyl, a steroidal hormone, a compound exhibiting oestrogenic activity or a prostaglandin, any of which may be optionally substituted with alkyl, alkoxy, substituted alkoxy, acyl, amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyl-heteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,
- At least 3 Ri groups are hydrogen atoms.
- pharmaceutically acceptable is generally meant that administration of the compound to a patient is, on balance, therapeutically advantageous.
- Suitable salts are organic and inorganic acid salts, and are exemplified below.
- esters may be organic or inorganic.
- Pro-drugs may be any suitable derivative of a compound of the invention which breaks down in vivo to yield a suitable bisphosphonate or glycoside or orthoester glycoside thereof.
- the glycosylated compounds of the invention may frequently, in and of themselves, be pro-drugs, in that the glycosyl group will frequently be deleted in vivo to yield the parent compound.
- the compounds of the invention appear to be active without having to be cleaved.
- the above compounds are derivatised on a free OH, NH 2 or SH grouping. Where such a grouping is not available, or where it is desired to provide a glycoside elsewhere, then it is prefe ⁇ ed to further substitute the compound with an OH or NH group which may then be derivatised. Such additional groups are prefe ⁇ ed to be distal from the bisphosphonate moiety.
- the invention further provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier therefor.
- a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier therefor.
- one or more compounds of the present invention for use in the treatment and/or prophylaxis of a condition susceptible of treatment by bisphosphonates, especially those indicated herein.
- a method of treatment of a condition treatable by administration of a bisphosphonate compound comprising administration of a non-toxic, efficacious amount of a compound of the present invention to a patient in need thereof.
- non-toxic has the same meaning as the term "pharmaceutically acceptable”.
- the prefe ⁇ ed route of administration is per os or by transdermal patch, as the glycosides and orthoester glycosides of the present invention also have enhanced skin penetration properties over the underivatised compounds.
- the compounds of the present invention may be used according to well known methods of using bisphosphonates and derivatives thereof, e.g. for use in treating conditions characterised by bone loss (e.g., post-menopausal osteoporosis, ovariectomy patients, senile osteoporosis, patients undergoing long-term treatment of corticosteroids, side effects from glucocorticoid or steroid treatment, patients suffering from Cushings's syndrome, gonadal dysgenesis, periarticular erosions in rheumatoid arthritis, osteoarthritis, Paget's disease, osteohalisteresis, osteomalacia, hypercalcaemia of malignancy, " osteopenia due to bone metastases, periodontal disease, and hype ⁇ arathyroidism).
- bone loss e.g., post-menopausal osteoporosis, ovariectomy patients, senile osteoporosis, patients undergoing long-term treatment of corticosteroids, side effects from glu
- Useful pharmaceutically acceptable salts include acid addition salts, e.g., salts with inorganic acids such as HCl, HBr, sulphuric, sodium hydrogen sulphate, phosphoric acid, sodium dihydrogen phosphate, and disodium hydrogen phosphate, as well as salts with organic acids such as formic, acetic, benzoic, carbonic and the like.
- pharmaceutically acceptable salts may be obtained with an inorganic base such as an alkali or alkaline earth metal hydroxide [e.g. LiOH, NaOH, KOH, or Ca(OH) 2 ] or an organic base such as choline hydroxide, spermidine, spermine, glucamine, triethylamine and the like.
- the invention further provides glycosides or orthoester glycosides of the bisphosphonate compounds described in US-A-5,409,911. Included in such compounds are prostaglandin derivatives having the Formulae (III) and (IV):
- R 15 is hydrogen or alkyl
- R 14 and R ⁇ 6 which may be the same or different, are hydrogen, a glycoside or orthoester glycoside as described herein, tetrahydropyran (THP) or
- each g which may be the same or different, is an integer between 1 and 10 and each R 17 , which may be the same or different, is independently hydrogen, alkyl, aryl or benzyl; and J is -NH- -C(R ⁇ 5 ) , or absent;
- L is: (1) -OR 18 , wherein R ⁇ is alkyl
- E is -NRis- -O-, or -S-;
- L is -NH— , -C(Ri 5 ) 2 - or absent; with the proviso that at least one hydroxy group on the compounds of
- Formulae (BI) and (IV) is substituted by a glycoside or orthoester glycoside as described herein; and pharmaceutically acceptable salts or esters thereof.
- the invention also provides the glycosides and orthoester glycosides of the hydroxy containing bisphosphonate compounds described in US-A-5,668,120. Included in such compounds are compounds having the Formula (V):
- R' is hydrogen, -NH 2 , -OH or CI; j is an integer from 0 to 7; each R 20 , which may be the same or different, is hydrogen, substituted or unsubstituted, saturated or unsaturated alkyl having from 1 to about 4 carbon atoms;
- X' is -NH- quaternary amine, oxygen, sulphur, or a single bond; and R ⁇ is a substituted carbocycle or substituted heterocycle; and pharmaceutically acceptable salts or esters thereof; with the proviso that at least one hydroxy group on R ⁇ is substituted by a glycoside or orthoester glycoside as described herein.
- the invention also provides the glycosides and orthoester glycosides of the hydroxy containing bisphosphonate compounds described in US-A-5,602,115. Included in such compounds are compounds having the Formula (VI):
- each R which may be the same or different, is hydrogen, alkyl, benzyl, phenyl optionally substituted with 1 to 5 substituents selected from nitro, fluoro, chloro, alkyl or where both -OR" on the same P are taken together with -CH 2 CH 2 - -CH 2 CH 2 CH 2 - or -CH 2 C(CH 3 ) 2 CH 2 - to form a heterocyclic ring containing one -P-, two -O- and two or three carbon atoms;
- R 2 ⁇ is alkyl, phenyl optionally substituted with 1 to 5 substituents selected from halo, -NO 2 , -CN, -CF 3 , alkyl, cycloalkyl, -OH, alkoxy, phenoxy, alkylthio or -NC(O)R 25 ;
- R 25 is alkyl, naphthalene optionally substituted with 1 or 2 phenyl; or naphthalene optionally substituted with 1 to 7 substituents selected from halo, -NO 2 , -CN, -CF 3 , alkyl, cycloalkyl, -OH, alkoxy, phenoxy, alkylthio or -N(CH 3 ) 2 ;
- R 22 , R 23 and R 2 which may be the same or different, are hydrogen, alkyl, phenyl optionally substituted with 1 to 5 substituents selected from halo, -NO 2 , -CN, -CF 3 , alkyl, cycloalkyl, -OH, alkoxy, phenoxy, alkylthio, -NC(O)R 25 ; naphthalene optionally substituted with 1 or 2 phenyl; or naphthalene optionally substituted with 1 to 7 substituents selected from halo, -NO
- Z 2 is -O - -(CH 2 ) k - -S(O) k - -NZ3-, -NS(O) 2 Z 4 -, -NC(O)Z 5 ;
- k is 0, 1 or 2;
- Z 3 is hydrogen, alkyl, cycloalkyl, phenyl, 2-pyridinyl, 3-pyridinyl or 4- pyridinyl;
- Z is alkyl or phenyl optionally substituted with 1 to 5 substituents selected from halo, — NO 2 , -CN, -CF 3 , alkyl, cycloalkyl, -OH, alkoxy, phenoxy, or alkylthio;
- Z 5 is alkyl; cycloalkyl; 2-, 3-, or 4-pyridinyl; naphthalene optionally substituted with 1 or 2 phenyl; naphthalene optionally substituted with 1 to 7 substituents chosen from halo, -NO 2 , -CN, -CF 3 , alkyl, cycloalkyl, -OH, alkoxy, phenoxy, alkylthio or -N(CH 3 ) 2 ; and pharmaceutically acceptable salts or esters thereof; with the proviso that there is at least one hydroxy group on the compound of
- the invention also provides the glycosides and orthoester glycosides of the hydroxy containing bisphosphonate compounds described in US-A-5,635,495. Included in such compounds are compounds having the Formula (VII):
- R 26 is hydrogen, alkyl, cycloalkyl, or phenyl optionally substituted with 1 or 2 phenyl or 1 to 5 halo, nitro, cyano, -CF 3 , alkyl, cycloalkyl, -OH, • SH, -NH 2 , alkoxy or alkylthio groups;
- R 27 is hydrogen, phenyl, halo, alkyl, cycloalkyl, -NH 2 , alkoxy, or alkylthio; each L 3 , which maybe the same or different, is hydrogen, alkyl, cycloalkyl, benzyl or where both L 3 on a single phosphorus are -CH CH 2 - - CH 2 CH 2 CH 2 - or -CH 2 C(CH 3 ) 2 CH 2 -, whereby a heterocyclic ring is formed; L 2 is -OR , -SR , mo ⁇ holinyl, piperazinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, isoxazolyl, py ⁇ olyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl; wherein R is phenyl optionally substituted with 1 or 2
- the invention also provides the glycosides and orthoester glycosides of the bisphosphonate compounds described in US-A-5 ,763 ,611. Included in such compounds are compounds of the Formula (Nm):
- L is -PO 3 H 2 or -P(O)OHL 5 ; wherein L 5 is substituted or unsubstituted alkyl;
- T 2 and R 30 which may be the same or different, are absent or are O, S or N; k and q are integers from 0 to 5 and k + q equals 0 to 5; p and s are integers from 0 to 3 and p + s is 0 to 3; r is an integer from 0 to 2 and when T 2 is absent and k + q is 0, then r is 2; each R 29 , which may be the same or different, is absent or independently selected from -SR 32 , -R 33 SR 32 , hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, hydroxy, amido, alkoxy, -CO R 34 , -N(R 3 ) ,
- R 3 ⁇ is absent, -SR 32 , -R 33 SR 2 , hydrogen, unsubstituted or substituted alkyl, unsubstituted or unsubstituted aryl, hydroxy, amido, -CO 2 R 34 , -O 2 CR 3 , -
- R 32 is hydrogen, -C(O)R 35 , -C(S)R 35 , -C(O)N(R 35 ) 2 , -CSN(R 35 ) 2 , -C(O)OR 35 or -C(S)OR 35 ;
- R 33 is substituted or unsubstituted alkyl, provided that at least one of R 29 , R 3 ⁇ and R 34 is -SR 32 or -R 33 SR 32 ;
- R 34 is hydrogen, substituted or unsubstituted alkyl or -R 33 SR 32 ;
- R 35 is hydrogen, or substituted or unsubstituted alkyl; and pharmaceutically acceptable salts or esters thereof; with the proviso that there is at least one hydroxy group on the compound of
- Formula (VET) that is substituted by a glycoside or orthoester glycoside as described herein.
- the invention further provides the glycosides and orthoester glycosides of the bisphosphonate compounds described in US-A-5, 183, 815. Included in such compounds are steroid derivatives of the Formula (TX):
- the invention also provides the glycosides or orthoester glycosides of the bisphosphonate compounds described in US-A-5,428,181. Included in such compounds are compounds of the general Formula (X):
- L 7 denotes a residue of a compound having an oestrogenic activity substituted by a glycosidoxy or orthoester glycosidoxy group; each Ri, which may be the same or different, denotes hydrogen or a C ⁇ -C 6 alkyl group;
- Xi denotes a single bond, a Ci-Cio alkylene group or a group of the formula:
- R 3 denotes hydrogen or a -Cs alkyl group
- V denotes a nitro group or a halogen
- t is an integer of 3 to 12
- u is an integer of 1 to 5
- v is an integer of 0 to 5
- w is an integer of 1 to 3; and pharmaceutically acceptable salts and esters thereof.
- Example compounds possessing oestrogenic activity include oestradiol, oestriol, genistein, daidzein, coumestrol, hexestrol and stilbestrol.
- a group of prefe ⁇ ed compoimds of the invention has the Formula (XI):
- R 38 is selected from the group consisting of hydrogen, acetyl, benzoyl, nicotinoyl, benzyl, methyl and phenyl; and each R, Ri, Y and Q is as defined; and pharmaceutically acceptable salts and esters thereof.
- each Ri in compounds of the Formula (XI) is selected from the group consisting of hydrogen, alkyl, benzyl and phenyl.
- alkyl straight- or branched-chain hydrocarbons having from 1 to 10 carbon atoms and more preferably 1 to 8 carbon atoms;
- substituted alkyl an alkyl group, preferably containing from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyl-heteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl substituted heterocyclic, cycloalkyl, substituted cycloalkyl, substituted cycloalkyl, -SH, thioalkyl, substituted thioalkyl, thioaryl, substituted
- alkoxy - the group “alkyl-O-” which includes, by way of example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butyl, t-butyl and the like; "substituted alkoxy” - the group “substituted alkyl-O-”; “cycloalkoxy” - the group “cycloalkyl-O-”; “substituted cycloalkoxy” - the group “substituted cycloalkyl-O-”; "thioalkyl” or “alkylthio” - the group “alkyl-S-”; “substituted thioalkyl” - the group “substituted alkyl-S- "; “thiocyclo alkyl” - the group “cycloalkyl-S-”; “substituted thiocycloalkyl” - the group "substituted al
- acyl - alkanoyl groups, e.g. HC(O)-, alkyl-C(O)-, substituted-alkyl-C(O)-, cycloalkyl-C(O)-, substituted-cycloalkyl-C(O)-, aryl-C(O)-, substituted- aryl-C(O)-, heteroaryl-C(O)-, substituted-heteroaryl-C(O)-, heterocyclic- C(0)- or substituted heterocyclic-C(O)-, wherein substituted alkyl, cycloalkyl, aryl and heteroaryl are defined and exemplified herein;
- aryl an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl); "aryloxy” - the group “aryl-O-”; "substituted aryl” - aryl group substituted with 1 to 3 substituents selected from hydroxy, acyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, aryl, substituted aryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl- cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyl-heteroaryl, carboxyl-substituted heteroaryl, carboxylheterocycHc, carboxyl substituted
- heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl); "substituted heteroaryl" - groups which are substituted with 1 to 3 substituents consisting of hydroxy, acyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, aryl, substituted aryl, cycloalkoxy, substituted cycloalkoxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl- substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyl- heteroaryl, carboxyl-substituted heteroaryl, carboxylheterocycHc, carboxyl substituted heterocyclic, cycloalkyl, substituted cyclo
- heterocycle a saturated or unsaturated group having a single ring or multiple condensed rings, containing 1 to 10 carbon atoms and 1 to 4 heteroatoms within the ring, wherein in fused ring systems, one or more of the rings can be aryl or heteroaryl;
- “pharmaceutically acceptable salts” includes, but is not limited to, alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., calcium and magnesium), non-toxic heavy metals (e.g., stannous and indium) or ammonium and low molecular weight substituted ammonium (e.g., mono-, di- and triethanolamine) salts, prefe ⁇ ed salts being the sodium, potassium, and ammonium salts; and "pharmaceutically acceptable esters” - unsubstituted and substituted alkyl, aryl or phosphoryl esters, non-limiting examples including, z ' -propyl, t-butyl, 2- chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, p-toluenesulphonylethyl, glycyl, sarcosyl, benzyl, phenyl, 1,2-
- 4-O-glycofuranosides 4-O-glycopyranosides, straight chained or branched 4-O-oligoglycosides and orthoester glycosides of 4-hydroxybutane-l,l-(tetra- O-isopropyl) bisphosphonate, 4-hydroxybutane-l,l-bisphosphonic acid and 4-N-glycopyranosides and 4-N-glycofuranosides of alendronate.
- Prefe ⁇ ed glycosidic units have free hydroxy groups, or hydroxy groups protected with aryl (e.g. phenyl), -CH 2 -aryl (e.g. benzyl), aroyl (e.g. benzoyl), heteroaroyl (e.g. nicotinoyl), alkyl (e.g. methyl), or alkanoyl (e.g. acetate) groups.
- aryl e.g. phenyl
- -CH 2 -aryl e.g. benzyl
- aroyl e.g. benzoyl
- heteroaroyl e.g. nicotinoyl
- alkyl e.g. methyl
- alkanoyl e.g. acetate
- the water soluble glycosidic derivatives of the aforementioned bisphosphonates may be obtained according to the general methods disclosed by Holick in US-A-4,410,515, the contents of which are fully inco ⁇ orated by reference herein.
- the compounds of the present invention can be administered in any appropriate pharmaceutically acceptable carrier for oral administration, since the glycosides and orthoester glycosides of bisphosphonate derivatives are biologically active upon oral administration.
- the compounds of the invention may also be administered in any appropriate pharmaceutical carrier for parenteral, intramuscular or topical administration. They can be administered by any means that treat and/or prevent conditions treatable with a bisphosphonate (e.g., hypercalcaemia of malignancy, Paget's disease, osteoporosis, metastatic cancer in bone and soft tissue and periodontal disease).
- the dosage administered will depend on the age, health and weight of the recipient, kind of concu ⁇ ent treatment, if any, frequency of treatment and the nature of the effect desired.
- An exemplary systemic daily dosage is about 0.1 mg to about 500 mg. Normally, from about 10 mg to lOOmg daily of the glycoside or orthoester glycoside, in one or more dosages per day, is effective to obtain the desired results.
- One of ordinary skill in the art can determine the optimal dosages and concentrations of other active glycosides of bisphosphonate derivatives with only routine experimentation.
- the compounds can be employed in dosage forms such as tablets and capsules for oral administration, as well as sterile liquid for formulations such as solutions or suspensions for parenteral use.
- a lipid vehicle can be used in parenteral administration.
- the compounds may also be administered via topical patches, ointments, gels or other transdermal applications.
- the active ingredient will ordinarily be present in an amount of at least 0.001% by weight based on the total weight of the composition, and not more than 50% by weight.
- An inert pharmaceutically acceptable carrier is preferable such as 95% ethanol, vegetable oils, propylene glycols, saline buffers, sesame oil, etc. Reference is made to Remington 's Pharmaceutical Sciences, 18 th Edition, Gennaro, et al. (eds.), 1990, for methods of preparing ' pharmaceutical compositions.
- the compounds of the invention can be administered in any appropriate pharmaceutically acceptable carrier.
- the compounds of the invention may also be administered in any appropriate pharmaceutical carrier for parenteral, intramuscular, transdermal, intravenous, intranasal or inhalation administration. They can be administered by any means that achieve their intended pu ⁇ ose.
- the compounds can be employed in dosage forms such as tablets, capsules or powder packets, or liquid solutions, suspensions or elixirs for oral administration, as well as sterile liquid for formulations such as solutions or suspensions for parenteral use.
- a lipid vehicle can be used in parenteral administration.
- the compounds may also be administered via topical patches, ointments, gels, liposomes or other transdermal applications.
- the active ingredient will ordinarily be present in an amount of at least 0.01% by weight based on the total weight of the composition, and not more than 90% by weight.
- An inert pharmaceutically acceptable carrier is preferable such as 95% ethanol, vegetable oils, propylene glycols, saline buffers, sesame oil, etc. Reference is made to Remington 's Pharmaceutical Sciences, 18 th Edition, Gennaro et al. (eds.), 1990, for methods of preparing pharmaceutical compositions.
- Topical formulations for transdermal, intranasal or inhalation administration may be prepared according to methods well known in the art.
- the compounds may be applied in any of the conventional pharmaceutical forms.
- the compounds may be administered as part of a cream, lotion, aerosol, ointment, powder, liposomes or drops.
- Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
- bases may include water and/or an oil such as liquid paraffin or a vegetable oil such as peanut oil or castor oil.
- Thickening agents which may be used include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, wool-fat, hydrogenated lanolin, beeswax and the like.
- Lotions may be formulated with an aqueous or oily base and will in general also include one or more of a stabilising agent, thickening agent, dispersing agent, suspending agent, thickening agent, colouring agent, perfume and the like.
- Powders may comprise any suitable powder base including talc, lactose, starch and the like.
- Drops may comprise an aqueous or non-aqueous base together with one or more dispersing agents, suspending agents, solubilising agents and the like.
- Prefe ⁇ ed liposomes are NOVASOMES sold by IGI, Inc. (Buena, NJ) and described in US-A-5,260,065.
- compositions may further comprise one or more preservatives including bacteriostatic agents including methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride and the like.
- the topical compositions comprise from about 0.0001% to 10% by weight, preferably, 0.001 to 0.5% by weight, more preferably, 0.01 to 0.25% by weight.
- the compounds may be administered either individually or as a mixture containing non-glycosylated, monoglycosylated, and/or bisglycosylated compounds, or a mixture of the co ⁇ esponding orthoester glycosides.
- the compounds are preferably provided substantially pure prior to formulation.
- substantially pure encompasses compounds created by chemical synthesis and/or compounds substantially free of chemicals which may accompany the compounds in the natural state, as evidenced by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
- TLC thin layer chromatography
- HPLC high performance liquid chromatography
- Animals which may be treated according to the methods of the present invention include all animals which may benefit therefrom. Included in such animals are humans, although the invention is not so limited.
- the invention further provides a method of preparing a compound of Formula (XT), as illustrated in Scheme I below:
- Ri, R, Y and Q are as defined, Y and Q together preferably representing a propylidene group and R preferably being a hydrogen, and R 8 is selected from hydrogen, acetyl, benzoyl, nicotinoyl, benzyl, methyl and phenyl; which method comprises:
- R 38 is other than hydrogen; with a group of formula Hal-Y-Q- X 3 , wherein Hal and X 3 individually represent halogen, and is preferably a 1,3-dihaloalkane, in the presence of a strong base in an aprotic solvent to give a compound of Formula (XIU):
- R and Ri are as defined, in the presence of a strong base in an aprotic solvent to give a compound of Formula (XI), wherein Ri and R 38 are other than hydrogen.
- the groups Ri and/or R 38 may then be partially or fully removed, preferably by hydrolysis.
- the invention further provides a method of preparing a compound of Formula (XV):
- R a , R , Rj, R, A, Y and Q are as defined, Y and Q together preferably representing a propylidene group and R preferably being a hydrogen, R 2 preferably being hydrogen; which method comprises: (a) reacting a glycoside having the Formula (XVI):
- R has protecting groups on each hydroxyl
- LG is a leaving group; with an alcohol of the formula (XVII):
- the groups Ri and/or the protecting groups on the orthoester glycoside may then be partially or fully removed, preferably by hydrolysis.
- LG and LG' which maybe the same or different, include bromine, chlorine, iodine, tosylate, mesylate, triflate, and the like.
- protecting groups, P' include trialkylsilyl groups (e.g.,
- TIPS aryldialkylsilyl groups
- TBDPS aryldialkylsilyl groups
- non-nucleophilic bases examples include collidine, lutidine and the like.
- Examples of protecting groups that may be present on the hydroxyl groups of the glycosidic residues of compounds of the Formula (XV), (XVI), (XV ⁇ i) and (XLX), include acetyl, benzoyl, nicotinoyl, benzyl, methyl, phenyl and the like.
- Examples of strong bases that may be used in the synthesis of compounds of Formula (XI), (XIII) and (XV) include hydrides of sodium, potassium and lithium, anion of dimethylsulphoxide (dimisyl anion), potassium and sodium salts of bistrimethylsilylamide and the like.
- the reactions are carried out in an aprotic solvent such as dimethylformamide, THF, toluene, acetonitrile, dimethylsulphoxide and the like.
- the reaction temperatures are from about -10 to 25 °C. Preferably, the reaction temperature is at about 0 °C.
- the reaction may be carried out for about 1 to 10 hours, or until TLC shows that the reaction is complete.
- the thus formed compound of Formula (XI) or (XV) is then isolated and may be purified, for example, on a silica gel column or by HPLC.
- the compounds of Formula (XI) or (XV) have protecting groups on the glycoside or orthoester glycoside moiety and groups (Ri) on the bisphosphonate moiety that may also be partially or fully removed. Ri groups on the bisphosphonate moiety may be removed by any known methods including treatment with trimethylsilyl bromide.
- the protecting groups on the glycoside or orthoester glycoside moiety are benzyl groups, then they may be removed by any known methods including treatment with trimethylsilyl bromide or by hydrogenation.
- the protecting groups on the glycoside or orthoester glycoside moiety are acetyl, benzoyl or nicotinoyl, then they may be removed by any known methods including treatment with alkali alkoxide in alcohol (e.g., sodium methoxide in methanol).
- the protection groups on the glycoside or orthoester glycoside moiety are methyl, then they may be removed by any known methods including treatment with a Lewis acid [e.g., A1C1 3 in combination with (n-Bu) NI].
- the present invention further provides a process for the preparation of a compound of formula (XX):
- aqueous medium preferably water
- a trialkylamine compound to form a salt thereof; removing the water; dissolving the salt in a water miscible, organic solvent, such as methanol; adding a compound of formula (XH):
- R 8 is as defined, and maintaining the resulting mix under such conditions as to form a trialkylamine salt of the compound of formula (XX).
- the trialkylamine may then be removed by conventional means, such as by running the salt on a cationic exchange resin.
- Prefe ⁇ ed aqueous media or solvents are distilled or deionised water. It is prefe ⁇ ed to use just water, but other, water miscible, organic solvents may also form up to about 50% of the medium.
- any suitable trialkylamine such as trimethylarnine or triethylamine, may be used, although it should be able to readily form a soluble salt of the compound of formula (XXI).
- the compound of formula (XXI) is not necessarily readily soluble in water, but that addition of trialkylamine brings it into solution by converting it into a salt.
- the water may be removed by any suitable method, such as evaporation, especially under pressure at an elevated temperature. It is not necessary to completely dry the mix beyond that degree obtainable by evaporation.
- Suitable water miscible, organic solvents include methanol, ethanol and tetrahydrofuran. What is necessary is to be able to dissolve both the salt of compound (XXI) and the glycoside compound (XII).
- the resulting mix may need to be warmed to drive the glycosidic compound into solution, after which the solution may be maintained, preferably with agitation, such as stirring, at ambient temperature, while the glycosylation reaction proceeds. This may take up to two days, or more.
- Examples 1 to 3 relate to the synthesis of [4-O-(l'-glycopyranosyl)]-4- hydroxybutane-1 , 1 -bisphosphonic acid, tetra-O-isopropyl-[4-O-(l '- glycopyranosyl)]-4-hydroxybutane-l,l-bisphosphonate and 4-O-[(2',3',4',6'- tetra-O-benzyl)- 1 '-glyco-pyranosyl)]-4-hydroxybutane- 1 , 1 -bisphosphonic acid (Scheme I).
- the product (450 mg) was obtained as brownish crystals.
- the product was characterised by spectral means.
- the composition of the product is homogenous by TLC (50% methanol-ethyl acetate).
- Aminobisphosphonic acids bearing 4-hydroxyphenyl and 4-O-glucopyranosyl- oxyphenyl substituents were synthesised utilising Beckmann rea ⁇ angement and in situ trapping of the cations with triethyl phosphite. The reaction scheme is illustrated below.
- the product was isolated by adsorbing the bisphosphonic acid moiety onto pre- washed basic ion exchange resin (100 g, Dowex-550 OH). The impurities were washed with water and the desired product was isolated by leaching with water- ammonia (1:1) mixture. The resulting solution was lyophilised and dried. The product weighed 240 mg and showed an NMR spectrum consistent with the structure.
- the precipitate was centrifuged and removed from the dichloromethane layer.
- the precipitate was neutralised with 1 mg/ml of sodium hydroxide till neutral (pH 6 to 7), requiring 13.3 mg of sodium hydroxide.
- the sodium salt of the titled bisphosphonic acid was lyophilised and a gum weighing 97 mg was obtained.
- the reaction flask was rinsed with an additional 100 ml of water and the combined solution refluxed for 5 h.
- the solution was cooled to room temperature, the pH adjusted to 4.4 with 50% NaOH (ca.120 ml) and the resulting suspension left to cool in the fridge for to 2 days.
- the white crystalline product was collected by filtration, washed with cold water (100 ml) and 95% ethanol (100 ml) and dried in vacuo at room temperature, yielding 55.63 g (88% yield).
- the reaction flask was rinsed with an additional 100 ml of water and the combined solution refluxed for 5 h. After cooling the reaction mixture to room temperature, the water and excess HCl were evaporated in vacuo (40°C).
- the resulting thick oil was diluted with distilled water (140 ml) and cooled to 0°C, the pH adjusted to 0.55 with 50% NaOH (ca. 20 ml) and the crystalline product precipitated was collected by filtration, washed with cold water (100 ml) and absolute ethanol (100 ml) and dried in vacuo at room temperature, yielding 42.18 g (87.3% yield) of white crystalline alendronate.
- the yellow foam of N-glucopyranosyl alendronate triethylamine salt (4.86 g, 5,96 mmol) was dissolved in distilled water (35 ml) and loaded on to an Amberlite resin CG-120 ( ⁇ a+ form) column and eluted with distilled water (300 ml). The appropriate fractions were collected, combined (according to the yellow colour) and evaporated to dryness, yielding a yellow foam. This was then dissolved in water (25 ml) and lyophilised to give the title compound as a yellow solid (2.87 g , 100% yield), identified as a mixture of ⁇ - and ⁇ - anomers.
- Bone reso ⁇ tion in vitro was assessed by a modification of the "bone slice assay" [Walsh et al, (1991), Application of Reflected Light Microscopy to Identify and Quantitate Resorption by Isolated Osteoclasts, Journal of Bone and Mineral Research, Vol 6: 661-671].
- Sterile, devitalised discs of dentine (diameter 4 mm) where prepared and placed in a 96 well tissue culture plate, one disc per well, and pre-wet overnight in ⁇ -MEM tissue culture medium supplemented with 10% foetal calf serum.
- the femora and tibiae where dissected from 18 day chick embryos and transfe ⁇ ed into ⁇ -MEM culture medium supplemented with 10% foetal calf serum.
- the bones were finely minced using a sha ⁇ scalpel and the resulting suspension was triturated using a sterile pipette and transfe ⁇ ed to a sterile plastic tube.
- the suspension was allowed to stand for one minute so that fragments of bone and other debris settled and the upper layer containing a bone cell suspension, including osteoclasts and other cell types, was harvested.
- Reso ⁇ tion lacunae where identified and quantitated using an Olympus BH2 microscope fitted for incident light microscopy.
- the plan area of reso ⁇ tion was determined by point counting using a xlO objective and a drawing tube. The total area of each disc was analysed.
- Figures 2 and 3 compare the effects of glycosylated and non- glycosylated alendronate, as prepared in Example 5.
- Figure 2 shows that both the alendronate and its glucoside have similar effects on reso ⁇ tion, while Figure 3 shows a clear effect on toxicity, with the glucoside exhibiting substantially no toxicity up to concentrations of lO ⁇ M whereas, at this concentration, alendronate kills the majority of cells.
Abstract
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WO2004101579A2 (en) * | 2003-05-17 | 2004-11-25 | Queen Mary & Westfield College | Substituted phosphonate fluorescent sensors and use thereof |
EP2289900A1 (en) * | 2009-08-26 | 2011-03-02 | Humboldt Universität zu Berlin | Bisphosphonates as inhibitors of acid sphingomyelinase |
US8513219B2 (en) | 2007-05-02 | 2013-08-20 | Queen Mary & Westfield College, University Of London | Substituted phosphonates and their use in decreasing amyloid aggregates |
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US5403829A (en) * | 1993-03-24 | 1995-04-04 | Leiras Oy | Use of bisphosphonates in endo-osteal bone surgery |
US5409911A (en) * | 1992-09-11 | 1995-04-25 | Merck & Co., Inc. | Prostaglandin analog for treating osteoporosis |
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US5409911A (en) * | 1992-09-11 | 1995-04-25 | Merck & Co., Inc. | Prostaglandin analog for treating osteoporosis |
US5403829A (en) * | 1993-03-24 | 1995-04-04 | Leiras Oy | Use of bisphosphonates in endo-osteal bone surgery |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2004101579A2 (en) * | 2003-05-17 | 2004-11-25 | Queen Mary & Westfield College | Substituted phosphonate fluorescent sensors and use thereof |
WO2004101579A3 (en) * | 2003-05-17 | 2005-03-17 | Queen Mary & Westfield College | Substituted phosphonate fluorescent sensors and use thereof |
US7629379B2 (en) | 2003-05-17 | 2009-12-08 | Queen Mary & Westfield College | Substituted phosphonate fluorescent sensors and use thereof |
US8513219B2 (en) | 2007-05-02 | 2013-08-20 | Queen Mary & Westfield College, University Of London | Substituted phosphonates and their use in decreasing amyloid aggregates |
EP2289900A1 (en) * | 2009-08-26 | 2011-03-02 | Humboldt Universität zu Berlin | Bisphosphonates as inhibitors of acid sphingomyelinase |
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