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WO1996031227A1 - Phosphonates, biphosphonates and pharmaceutical compositions containing them - Google Patents

Phosphonates, biphosphonates and pharmaceutical compositions containing them Download PDF

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Publication number
WO1996031227A1
WO1996031227A1 PCT/US1996/004810 US9604810W WO9631227A1 WO 1996031227 A1 WO1996031227 A1 WO 1996031227A1 US 9604810 W US9604810 W US 9604810W WO 9631227 A1 WO9631227 A1 WO 9631227A1
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Prior art keywords
zero
integer
compound
designates
amino acid
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PCT/US1996/004810
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French (fr)
Inventor
Eli Breuer
Gershon Golomb
Gordon L. Amidon
Ivan Sergeievitch Alferiev
Naama El-Hanany Rozen
Aviva Friedman-Ezra
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Yissum Research Development Company Of The Hebrew University Of Jerusalem
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Application filed by Yissum Research Development Company Of The Hebrew University Of Jerusalem filed Critical Yissum Research Development Company Of The Hebrew University Of Jerusalem
Priority to AU54461/96A priority Critical patent/AU5446196A/en
Priority to US08/930,676 priority patent/US6541454B1/en
Publication of WO1996031227A1 publication Critical patent/WO1996031227A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Calcium-related disorders in general and osteoporosis in particular are a major public health problem in developed countries.
  • Several important pathological conditions are calcium-related and involve irregularities in calcium
  • Bisphosphonates are a relatively new family of drugs used clinically in various calcium-related disorders including tumor osleolysis, and are undergoing clinical trials for osteoporosis. They are poorly absorbed following oral
  • peptidyl compounds will have better activity on bone: In particular, they can be used in cases where the formation and breakdown of bone is disturbed, for example in cases of osteoporosis''. None is claimed, regarding the absorption of such compounds from the gastrointestinal tract following oral administration.
  • the dosage is claimed, regarding the absorption of such compounds from the gastrointestinal tract following oral administration.
  • the dosage range recommended (see column 6 ) is from ."1 mg to 1000 mg, and preferably from 10 to 200 mg.” Such doses are typical for non-absorbable bisphosphonates such as etidronate and pamidronate.
  • the daily oral recommended dose of a recently approved bisphosphonate in the US, alendronate (Fosamax) is 10 mg and 40 mg, in the
  • Bisphosphonates have been approved for clinical use in Paget's disease, tumor osteolysis, and hypercalcemia of malignancy and approved in some countries for
  • the treatment protocol of pamidronate in tumor osteolyis is 1-day slow and diluted IV infusion to avoid thrombophlebitis, but treatment is repeated if norniocalcemia is not attained.
  • Another example is the chronic therapy (years) required in osteoporosis.
  • Drugs require a degree of lipophilicity to pass through the GI barrier.
  • nonpolar prodrugs are often utilized. Due to the wide variety of esterases present in the target tissue for oral prodrug- regeneration, esters are the most common prodrugs when GI absorption is considered. Acyloxymethyl esters of bisphosphonic acids were proposed however this
  • bioavailability can be achieved due to the recognition by the active carrier transporter of the intestinal mucosae and the hydrolysis to the parent drug following oral administration.
  • the prodrug in our invention is a delivery system rather than a new compound for bone diseases. Therefore, our selection of new compounds is based on enhanced absorption for the GI tract and hydrolysis to the parent compound resulting in improved oral, clinical treatment by a low dose.
  • the selection of the di/tri-peptidyl moiety is based on transporter recognition and hydrolysis and not, as in Bosies et al patent, on resorbing activity on the bone.
  • the present invention relates to novel compounds of the general formula
  • Z 1 and Z 2 are a side chain of an amino acid or hydrogen, when one or both of Z 1 and Z 2 are a
  • Z is -OH , where Q is
  • Z 3 is a bond or a spacer group selected from NH, CO, NHCO, NHCO(CH 2 ) q -CO, (CH 2 ) r CO where r is zero or an integer, and where q is and integer or zero, m is 2, 3 or 4 ,
  • n is zero an integer
  • X is -H or -OH
  • Y is -H or -NR 2 R 3 ,
  • A designates a 5- or 6-membered heterocyclic ring which contains 1, 2 or 3 nitrogen atoms, zero, 1 or 2 oxygen atoms and which may contain a sulfur atom, which contains up to and including 3 double bonds
  • R 2 and R 3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkoxy, (di) alkylaminoalkyl, alkoxyalkyl and where the ring A may be substituted by one or more conventional substituents, and to pharmaceutical compositions of improved absorption from the gastro-intestinal tract which contain as active ingredient an efficient quantity of a compound defined above.
  • n designates zero or an integer
  • n designates 2, 3 or 4;
  • R 1 and R 2 which may be identical or different, each designates a side chain of an amino acid.
  • the compounds defined above are aminoacyl derivatives when n is zero, and they are peptidyl-bisphosphonates when n is an integer as defined above.
  • amino acids can be used, and preferred ones for use in the peptidyl chain according to the invention are: proline
  • the invention furthermore relates to a method for the production of derivatives defined above, or their salts which comprises linking a desired bisphosphonate
  • the invention further relates to pharmaceutical
  • compositions, for oral administration which contain an effective quantity of a novel derivative defined above.
  • the compositions according to the present invention are characterized by high absorption from the gastrointestinal tract.
  • the dosage in humans is dependent on various factors including drug potency, age, disease type and state, and the mode of administration. Since our invention provides significantly enhanced oral absorption the dosage should be determined according to the extent of absorption of a specific peptidyl-bisphosphonate derivative. Therefore, the dose of the prodrug is typically about 20 to 100 times lower than the one usually prescribed for oral administration. One should also recall that the MW of a prodrug is higher than the active drug.
  • the effective dosage range is form about 0.001 mg to about 100 mg per patient per day, a preferred range being of the order of about 0.02 mg to 1 mg per patient, per day in oral administration.
  • novel compounds are effectively absorbed and after being absorbed, and due to enzymatic action, decomposed to provide the free active drug. It is preferred to use such peptidyl chains which are effective in balancing the negative charges of the bisphosphonates. It is possible that some of the novel conjugates are effective as such in the human body.
  • Peptidyl prodrugs of clinically approved bisphosphonates are effectively absorbed following oral administration.
  • the present prodrug strategy was based on the rationale of neutralizing the negatively charged bisphosphonate molecule by a positively charged amino acid, and or at the same time making use of the peptide carrier system serving as a transporter for the prodrug.
  • the prodrug is subsequently hydrolyzed by a mucosal cell cytosolic enzyme such as prolidase, prolinase, dipeptidase, aminotripeptidase or possibly other hepatic/plasma enzymes, or is effective as such.
  • a mucosal cell cytosolic enzyme such as prolidase, prolinase, dipeptidase, aminotripeptidase or possibly other hepatic/plasma enzymes, or is effective as such.
  • a peptidylbisphosphonate can be recognized by the nonspecific peptide transporter
  • the free amino groups on the amino acid side chain are expected to neutralize partially or fully the phosphonate negative charges.
  • Amino acids and peptides were linked to geminal-aminoalkylidenebisphosphonates (for example Pamidronate and Alendronate) by a simple chemical
  • Aminoacyl or peptidyl bisphosphonates thus obtained are reconverted to the parent drug by enzymes or alternatively may be active as such in bone diseases.
  • the Figures relate to the concentration of Phe-Pamidronate and Pamidronate in various organs 24 hours after Peroral Administration in rats, (Pro-( 3 H)Phe-( 14 C) Pam, ( 14 C) Pam, 10 mg / kg.
  • the scale indicates % of total dose.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Rheumatology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

There are provided novel derivatives of certain phosphonates and bisphosphonates, and especially of compounds of the pamidronate and alendronate type. More particularly, the invention relates to aminoacyl and peptidyl derivatives of such compounds. Furthermore, the invention relates to pharmaceutical compositions which contain as active ingredient an adequate quantity of such novel compounds. The novel pharmaceutical compositions are characterized by improved absorption in the human body after application by the oral route.

Description

PHOSPHONATES, BIPHOSPHONATES AND PHARMACEUTICAL COMPOSITIONS
CONTAINING THEM
BACKGROUND OF THE INVENTION:
Calcium-related disorders in general and osteoporosis in particular are a major public health problem in developed countries. Several important pathological conditions are calcium-related and involve irregularities in calcium
metabolism: Paget's disease, osteroporosis, hypercalcemia of malignancy, and osteolysis from bone metastases, etc.
Bisphosphonates are a relatively new family of drugs used clinically in various calcium-related disorders including tumor osleolysis, and are undergoing clinical trials for osteoporosis. They are poorly absorbed following oral
administration probably due to their high polarity and
charge, TV and IM administration is a serious obstacle
to their wide-spread use.
In the potent of Bosies et al. (U.S. Patent #4,66,895
May 19, 1907) peptidyl diphosphonic acid derivatives are described. Bosies et al. Patent hypothesize that some
peptidyl compounds will have better activity on bone: In particular, they can be used in cases where the formation and breakdown of bone is disturbed, for example in cases of osteoporosis''. Nothing is claimed, regarding the absorption of such compounds from the gastrointestinal tract following oral administration. The dosage
recommended is much higher than that needed when
effective oral absorption is takes place. The dosage range recommended (see column 6 ) is from ...."1 mg to 1000 mg, and preferably from 10 to 200 mg." Such doses are typical for non-absorbable bisphosphonates such as etidronate and pamidronate. The daily oral recommended dose of a recently approved bisphosphonate in the US, alendronate (Fosamax) is 10 mg and 40 mg, in the
treatment of osteoporosis and Paget's disease,
respectively ( American Hospital Formulary Service AHFS Drug Information, section 92:00, 1995). As is known widely, this drug is 100 to 1000 times more effective that etidronate, the drug chosen by Bosies et al, for comparison. Typical absorption of such bisphosphonates in humans is in the range of 1%. Effective hydrolysis of the prodrug to the parent drug, for e.g., pamidronate or alendronate, is achieved following oral administration in the cytosol (intestinal cells). It is clear that if a peptidyl derivative of such a drug is administered to humans Lhe dose should be reduced by 50 to 100 times, in order not to be lethal, due to the enhanced absorption of obout 50 to 100 times of the prodrug. Bosies relates only to subcutaneous injections, in comparison to a first generation bisphosphonate, etidronate. Furthermore, selection of the peptidyl derivatives is not based on recognition by the transporter system nor on the
possibility for hydrolysis to the parent drug. In their patent they seed a new compound, the administered drug being the active drug at the site of action (bone). Our invention relates specifically to the activity of the parent drug yielded form the prodrug following oral absorption.
The results are described ambiguously (+ and - system), and the activity of the compounds is compared to first generation bisphosphonate, etidronate (a non-nitrogen containing compound) rather than a more appropriate comparison to nitrogen-containing drugs such as
pamidronate, known to be more effective (pamidronate and alendronate, nitrogen containing bisphosphonates, in clinical use are 10 to 1000 times more effective than etidronate. To the best of our knowledge no further development (since 1987) nor a scientific report is available for such compounds claimed by Bosies et al. BISPHOSPHONATES
Bisphosphonates have been approved for clinical use in Paget's disease, tumor osteolysis, and hypercalcemia of malignancy and approved in some countries for
osteoporosis therapy. Most bisphosphonates are disodium salts of the tetraacids (M.W. approximately 250), and are poorly absorbed from the GI tract (approximately 1% of the oral dose is absorbed). Chronic IM or SC
administration of bisphosphonates causes irritation and necrosis, and the oral route has been associated with GI disturbances, resulting in poor patient compliance and side effects. For example, the treatment protocol of pamidronate in tumor osteolyis is 1-day slow and diluted IV infusion to avoid thrombophlebitis, but treatment is repeated if norniocalcemia is not attained. Another example is the chronic therapy (years) required in osteoporosis.
ABSORPTION BARRIERS:
Clinically, the oral route is the most common and
accepted one for delivering drugs of a low molecular weight, of up to 400-600. However, the low permeability of the intestinal epithelia towards highly polar and charged molecules impedes the effective absorption of many low molecular weight drugs. Many such drugs must be delivered parenterally by frequent injections. This is highly risky without close medical supervision. The problem is particularly acute in cases of drugs used for treatment of various chronic diseases such as cancer and age-related diseases, such as osteoporosis, which require prolonged drug treatment.
NEW DRUGS FOR CALCIUM-RELATED DISORDERS
Drugs require a degree of lipophilicity to pass through the GI barrier. In order to increase oral absorption of drugs with low membrane permeability, nonpolar prodrugs are often utilized. Due to the wide variety of esterases present in the target tissue for oral prodrug- regeneration, esters are the most common prodrugs when GI absorption is considered. Acyloxymethyl esters of bisphosphonic acids were proposed however this
did not lead to a useful drug (European Patent EP 0 416 689 A2, date of filing 29.08.90). Similarly, Fels et al. proposed pharmaceutical compositions comprising
bisphosphonates and sodium lauryl sulfate for increased oral absorption (US Patent 4,980,171, 12.25.90). One way to increase membrane permeability of drugs is by utilization of the peptide carrier system (G.L. Amidon, P.J. Sinko, M. Hu, and G.D. Leesman. In L.F. Prescott, and W.S. Nimmo (eds.).
The hypothesis of our patent is completely different from the working hypothesis of Bosies et al. We claim that by carefully selecting specific di and/or tripeptide
derivatives of bisphosphonates, enhanced oral
bioavailability can be achieved due to the recognition by the active carrier transporter of the intestinal mucosae and the hydrolysis to the parent drug following oral administration.
Thus, the prodrug in our invention is a delivery system rather than a new compound for bone diseases. Therefore, our selection of new compounds is based on enhanced absorption for the GI tract and hydrolysis to the parent compound resulting in improved oral, clinical treatment by a low dose. The selection of the di/tri-peptidyl moiety is based on transporter recognition and hydrolysis and not, as in Bosies et al patent, on resorbing activity on the bone. Thus, the present invention relates to novel compounds of the general formula
Figure imgf000009_0001
where 1 or 2 of the groups Z, Z1 and Z2 is a group
Figure imgf000009_0002
where 1 or 2 of Z1 and Z2 are a side chain of an amino acid or hydrogen, when one or both of Z1 and Z2 are a
Figure imgf000009_0003
group, Z is -OH , where Q is
Figure imgf000009_0004
where Z3 is a bond or a spacer group selected from NH, CO, NHCO, NHCO(CH2)q-CO, (CH2)rCO where r is zero or an integer, and where q is and integer or zero, m is 2, 3 or 4 ,
n is zero an integer
X is -H or -OH,
Y is -H or -NR2R3,
where A designates a 5- or 6-membered heterocyclic ring which contains 1, 2 or 3 nitrogen atoms, zero, 1 or 2 oxygen atoms and which may contain a sulfur atom, which contains up to and including 3 double bonds, where R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkoxy, (di) alkylaminoalkyl, alkoxyalkyl and where the ring A may be substituted by one or more conventional substituents, and to pharmaceutical compositions of improved absorption from the gastro-intestinal tract which contain as active ingredient an efficient quantity of a compound defined above.
Preferred compounds are of the formula
Figure imgf000010_0001
wherein n designates zero or an integer,
m designates 2, 3 or 4; and where
R1 and R2, which may be identical or different, each designates a side chain of an amino acid. The compounds defined above are aminoacyl derivatives when n is zero, and they are peptidyl-bisphosphonates when n is an integer as defined above.
A wide range of amino acids can be used, and preferred ones for use in the peptidyl chain according to the invention are: proline
phenylalanine
alanine
lysine
arginine
aspartic acid
glutamic acid
The invention furthermore relates to a method for the production of derivatives defined above, or their salts which comprises linking a desired bisphosphonate
compound, of the Pamidronate or Alendronate type, to one or more amino aiids. The invention further relates to pharmaceutical
compositions, for oral administration, which contain an effective quantity of a novel derivative defined above. The compositions according to the present invention are characterized by high absorption from the gastrointestinal tract.
The dosage in humans is dependent on various factors including drug potency, age, disease type and state, and the mode of administration. Since our invention provides significantly enhanced oral absorption the dosage should be determined according to the extent of absorption of a specific peptidyl-bisphosphonate derivative. Therefore, the dose of the prodrug is typically about 20 to 100 times lower than the one usually prescribed for oral administration. One should also recall that the MW of a prodrug is higher than the active drug. The effective dosage range is form about 0.001 mg to about 100 mg per patient per day, a preferred range being of the order of about 0.02 mg to 1 mg per patient, per day in oral administration.
In the following, the invention is described by way of illustration only with reference to representative examples. It ought to be clearly understood that the novel compounds can contain from one amino acid
''elongation'' and up to a multi-amino acid-residue peptidyl chain.
The novel compounds are effectively absorbed and after being absorbed, and due to enzymatic action, decomposed to provide the free active drug. It is preferred to use such peptidyl chains which are effective in balancing the negative charges of the bisphosphonates. It is possible that some of the novel conjugates are effective as such in the human body.
Peptidyl prodrugs of clinically approved bisphosphonates are effectively absorbed following oral administration. The present prodrug strategy was based on the rationale of neutralizing the negatively charged bisphosphonate molecule by a positively charged amino acid, and or at the same time making use of the peptide carrier system serving as a transporter for the prodrug.
Following membrane transport, the prodrug is subsequently hydrolyzed by a mucosal cell cytosolic enzyme such as prolidase, prolinase, dipeptidase, aminotripeptidase or possibly other hepatic/plasma enzymes, or is effective as such.
The rationale for the synthesis of peptidylbisphos- phonates is twofold:
a) a peptidylbisphosphonate can be recognized by the nonspecific peptide transporter, and
b) the free amino groups on the amino acid side chain are expected to neutralize partially or fully the phosphonate negative charges. Amino acids and peptides were linked to geminal-aminoalkylidenebisphosphonates (for example Pamidronate and Alendronate) by a simple chemical
procedure to afford aminoacyl - and peptidylbisphos- phonates. Aminoacyl or peptidyl bisphosphonates thus obtained are reconverted to the parent drug by enzymes or alternatively may be active as such in bone diseases.
Synthesis of a representative example:
L-Prolyl-L-phenylalanylpamidronate (Pro-Phe-Pam, see formula). Experiments were also carried out with certain compounds according to claim 1, having a heterocylclic ring in the molecule.
Results similar to the ones demonstrated above and in the Figure were obtained with these.
The Figures relate to the concentration of Phe-Pamidronate and Pamidronate in various organs 24 hours after Peroral Administration in rats, (Pro-(3H)Phe-(14C) Pam, (14C) Pam, 10 mg / kg.
The scale indicates % of total dose.
"1" related to tibia, "2" relates to kidney, liver, intestine, "3" relates to kidney and liver.
"4": F. Wingen and D. Schmahl, Arzneim. Forschung 37, 1037-1042
(1989).

Claims

CLAIMS :
1. A compound of the general formula
Figure imgf000016_0001
where 1 or 2 of the groups Z, Z1 and Z2 is a group
Figure imgf000016_0002
where 1 or 2 of Z1 and Z2 are a side chain of an amino acid or hydrogen, when one or both of Z1 and Z2 are a
Figure imgf000016_0003
group, Z is -OH, where Q is
Figure imgf000016_0004
where Z3 is a bond or a spacer group selected from NH, CO, NHCO, NHCO(CH2)q-CO, (CH)2CO where r is zero or an integer, and where q is and integer or zero,
m is 2, 3 or 4,
n is zero an integer X is -H or -OH,
Y is -H or -NR2R3,
where A designates a 5- or 6-membered heterocyclic ring which contains 1, 2 or 3 nitrogen atoms, zero, 1 or 2 oxygen atoms and which may contain a sulfur atom, which contains up to and including 3 double bonds, where R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkoxy, (di) alkylaminoalkyl, alkoxyalkyl and where the ring A may be substituted by one or more conventional substituents.
2. A compound according to Claim 1, where A designates a pyrroline, pyrrolidine, pyrazole, pyrazoline,
pyrazolidine, imidazole, pyrazine or pyridazine ring and their partially or fully reduced derivatives, which may be substituted as defined in Claim 1.
3. A compound according to Claim 1 of the formula
Figure imgf000017_0001
wherein n is zero or an integer,
m is 2 or 3,
Z1 is a side chain of an amino acid, Z2 is a side chain of an amino acid.
4. A compound according to Claim 1 where the amino acids of the peptidyl chain are selected from natural amino acids.
5. Pamidronate conjugated to a peptide chain of 1 to 8 amino acids.
6. Alendronate conjugated to a peptide chain of 1 to 8 amino acids.
7. A compound of Claim 1, where A designates
Figure imgf000018_0001
8. A pharmaceutical composition containing as active ingredient a compound of the formula
Figure imgf000018_0002
where 1 o r 2 o f the groups Z , Z 1 and Z2 is a group
Figure imgf000019_0001
where 1 of 2 of Z1 and Z2 are a side chain of an amino acid or hydrogen, when one or both of Z1 and Z2 are a
Figure imgf000019_0002
group , Z i s -OH , where Q is
Figure imgf000019_0003
where Z2 is a bond or a spacer group selected from NH, CO,
NHCO, NHCO (CH2)q-CO, (CH2)rCO where r is zero or an integer, and where q is and integer or zero,
m is 2, 3 or 4,
n is zero an integer
X is -H or -OH ,
Y is -H or -NR2R3,
where A designates a 5- or 6-membered heterocyclic ring which contains 1, 2 or 3 nitrogen atoms, zero, 1 or 2 oxygen atoms and which may contain a sulfur atom, which contains up to and including 3 double bonds, where R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkoxy, (di)alkylaminoalkyl, alkoxyalkyl and where the ring A may be substituted by one or more conventional substituents.
9. A pharmaceutical composition containing as active ingredient a compound of the formula
Figure imgf000020_0001
where the substituents are as defined in Claim 3, for oral administration.
10. A composition according to claims 8, or 9 with an enteric coating.
PCT/US1996/004810 1995-04-04 1996-04-03 Phosphonates, biphosphonates and pharmaceutical compositions containing them WO1996031227A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6432931B1 (en) 1998-06-24 2002-08-13 Merck & Co., Inc. Compositions and methods for inhibiting bone resorption
US6458772B1 (en) 1909-10-07 2002-10-01 Medivir Ab Prodrugs
WO2022159492A1 (en) * 2021-01-19 2022-07-28 William Marsh Rice University Bone-specific delivery of polypeptides

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5364846A (en) * 1991-07-12 1994-11-15 Hoechst Aktiengesellschaft N-cycloalkylaminoethane-1,1-bis (phosphonic acid) useful for the treatment of osteoporosis and degenerative joint disease

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5364846A (en) * 1991-07-12 1994-11-15 Hoechst Aktiengesellschaft N-cycloalkylaminoethane-1,1-bis (phosphonic acid) useful for the treatment of osteoporosis and degenerative joint disease

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6458772B1 (en) 1909-10-07 2002-10-01 Medivir Ab Prodrugs
US6974802B2 (en) 1998-02-13 2005-12-13 Medivir Ab Treatment of viral infections using prodrugs of 2′,3-dideoxy,3′-fluoroguanosine
US7071173B2 (en) 1998-02-13 2006-07-04 Medivir Ab Antiviral methods employing double esters of 2′, 3′-dideoxy-3′-fluoroguanosine
US6432931B1 (en) 1998-06-24 2002-08-13 Merck & Co., Inc. Compositions and methods for inhibiting bone resorption
US6699850B2 (en) 1998-06-24 2004-03-02 Merck & Co., Inc. Compositions and methods for inhibiting bone resorption
WO2022159492A1 (en) * 2021-01-19 2022-07-28 William Marsh Rice University Bone-specific delivery of polypeptides

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