EP1225903A2 - Aminoalkylenephosphonates for treatment of bone disorders - Google Patents
Aminoalkylenephosphonates for treatment of bone disordersInfo
- Publication number
- EP1225903A2 EP1225903A2 EP00972234A EP00972234A EP1225903A2 EP 1225903 A2 EP1225903 A2 EP 1225903A2 EP 00972234 A EP00972234 A EP 00972234A EP 00972234 A EP00972234 A EP 00972234A EP 1225903 A2 EP1225903 A2 EP 1225903A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- ammoalkylenephosphonate
- alk
- pharmaceutically acceptable
- acceptable salt
- ammoalkylenephophonate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000011282 treatment Methods 0.000 title description 8
- 208000020084 Bone disease Diseases 0.000 title description 3
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 19
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 15
- 239000011707 mineral Substances 0.000 claims abstract description 15
- 241000124008 Mammalia Species 0.000 claims abstract description 12
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 11
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 10
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- RCXMQNIDOFXYDO-UHFFFAOYSA-N [4,7,10-tris(phosphonomethyl)-1,4,7,10-tetrazacyclododec-1-yl]methylphosphonic acid Chemical group OP(O)(=O)CN1CCN(CP(O)(O)=O)CCN(CP(O)(O)=O)CCN(CP(O)(O)=O)CC1 RCXMQNIDOFXYDO-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910018828 PO3H2 Inorganic materials 0.000 abstract 2
- 241000700159 Rattus Species 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 208000001132 Osteoporosis Diseases 0.000 description 6
- 229940062527 alendronate Drugs 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 5
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 4
- -1 bisphosphonate alendronate Chemical class 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 102000055006 Calcitonin Human genes 0.000 description 3
- 108060001064 Calcitonin Proteins 0.000 description 3
- 229940120146 EDTMP Drugs 0.000 description 3
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 3
- 229960004015 calcitonin Drugs 0.000 description 3
- NFDRPXJGHKJRLJ-UHFFFAOYSA-N edtmp Chemical compound OP(O)(=O)CN(CP(O)(O)=O)CCN(CP(O)(O)=O)CP(O)(O)=O NFDRPXJGHKJRLJ-UHFFFAOYSA-N 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229940122361 Bisphosphonate Drugs 0.000 description 2
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 1
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 1
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009547 dual-energy X-ray absorptiometry Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000030991 negative regulation of bone resorption Effects 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940019375 tiludronate Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
Definitions
- This invention relates to the use of aminoalkylenephosphonates for treatment of bone disorders such as osteoporosis.
- This invention involves the use of aminoalkylenephosphonates, such as, for example, 1,4,7,10- tetraazacyclododecane-1 ,4,7, 10-tetramethylenephosphonic acid (DOTMP) and 3, 6, 9, 15-tetraazabicyclo [ 9.3.1] tetradeca- 1 (15) , 11, 13-triene-3, 6, 9-trimethylenephosphonic acid (PCTMP) for use in the inhibition of bone resorption.
- DOTMP 1,4,7,10- tetraazacyclododecane-1 ,4,7, 10-tetramethylenephosphonic acid
- PCTMP 6, 9, 15-tetraazabicyclo [ 9.3.1] tetradeca- 1 (15) , 11, 13-triene-3, 6, 9-trimethylenephosphonic acid (PCTMP)
- This application is directed toward use in the prevention and/or treatment of bone diseases such as osteoporosis.
- Bone is a dynamic tissue, continually undergoing remodeling. Hydroxyapati
- osteoporosis In pathological states such as osteoporosis a shift in the balance of these two processes occurs, resulting in a net loss of mineralized tissue. This loss results in impaired skeletal function and clinical fractures. Osteoporosis is an enormous public health problem affecting as many as 25 million people in the
- Bisphosphonates all contain the basic P-C-P structure. Examples such as etidronate (1-hydroxy- ethylidenebisphosphonate) , risedronate [ l-hydroxy-2- ( 3- pyridinyl ) ethylenebisphosphonate] , pamidronate (3-am ⁇ no-l- hydroxypropylidenebisphosphonate) , tiludronate (4- chlorophenylthiomethylenebisphosphonate) have already been approved for the treatment of a rare bone condition called Paget' s disease .
- Aminoalkylenephosphonates have not been investigated for these applications. It is known that these compounds have a strong affinity for bone (for example, EDTMP and DOTMP radiopharmaceutical bone agents) and have low soft tissue localization. They have unique properties such as the ability to inhibit calcium phosphate scale formation at very low concentrations .
- aminoalkylenephosphonates can inhibit bone mineral density loss.
- a screening study of various aminomethylene- phosphonates in an ovarectomized rat osteoporosis model has now shown that PCTMP is as good as, and may even be superior to, alendronate in its ability to inhibit bone mineral loss .
- the present invention relates to a method for preventing or minimizing loss of bone mineral in mammals which method comprises administering to a mammal an amount of an aminoalkylenephosphonate which is effective to prevent or minimize loss of bone mineral density.
- the present invention relates to the use of an ammoalkylenephophonate or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical formulation for preventing or minimizing loss of bone mineral in mammals.
- aminoalkylenephosphonate refers to those phosphonates and phosphonic acids which incorporate an amme moiety, whether aliphatic or cyclic, attached via the amme nitrogen through an alkylene group to the phosphonate or phosphonic acid moiety.
- the aminoalkylenephosphonates of the present invention should have at least one R-N (Alk-P0 3 H 2 ) 2 group or at least two RR' N-Alk-P0 3 H 2 groups wherein R and R' can be, same or different, aliphatic or cyclic moiety, and Alk is an alkylene group having from 1 to 4 carbon atoms.
- Non-limit g examples of the amines suitable as amme moieties in the practice of the present invention are ethylenediamme (EDA) , diethylenet ⁇ amme (DETA), t ⁇ ethylenetetraamme (TETA) , 1,4,7, 10-tetraazacyclododecane, 3, 6, 9, 15-tetraaza- b ⁇ cyclo[9.3.1] tetradeca-1 (15) ,11, 13-tr ⁇ ene, 2, 11- d ⁇ aza[3.3] (2, 6) pyridmophane, 2- (ammomethyl) pyridme, 2 , 6-b ⁇ s (ammomethyl ) pyridme .
- EDA ethylenediamme
- DETA diethylenet ⁇ amme
- TETA t ⁇ ethylenetetraamme
- 1,4,7, 10-tetraazacyclododecane 3, 6, 9, 15-tetraaza- b ⁇ cyclo[9.3.1] tetradeca-1 (15
- the alkylene group having from 1 to 4 carbon atoms contemplated by Alk m the aforementioned formulas can be straight or branched chain alkylene group.
- Non-limitmg examples of such alkylene groups are methylene, ethylene, propylene, isopropylene, and butylene.
- the preferred alkylene group is methylene (-CH 2 -) group.
- Preferred aminoalkylenephosphonates are am omethylenephosphonates .
- Particularly preferred aminoalkylenephosphonates are 1 , 4 , 7 , 10-tetraaza- cyclododecane-1 ,4,7, 10-tetramethylenephosphonic acid (DOTMP) , 3,6,9, 15-tetraazab ⁇ cyclo[9.3.1] tetradeca- 1 (15) , 11, 13-tr ⁇ ene-3, 6, 9-tr ⁇ methylenephosphon ⁇ c acid (PCTMP), N,N' -bis (methylenephosphonic ac ⁇ d)-2,ll- diaza [3.3] (2, 6) pyridmophane (BP2MP) and N, N-bis (methylene phosphonic acid) -2- (ammomethyl ) pyridme (AMPDMP) .
- DOTMP 10-tetraaza- cyclododecane-1 ,4,7, 10-tetramethylenephosphonic acid
- PCTMP 1,
- aminoalkylenephosphonates contemplated by the present invention are well known in the art and numerous methods for their preparation have been disclosed. See, for example, U.S. Patent No. 3,288,846 (Irani et al) and U.S. Patent No. 4,898,724 (Simon et al), both incorporated herein by reference.
- the aminoalkylenephosphonates of the present invention are used in an amount effective to prevent or minimize loss of bone mineral.
- the effective amount will vary depending on the mammal, ammoalkylenephosphonate used and the method of its administration (for example, oral or parenteral) .
- a person of ordinary skill in the art will know how to determine the effective amount of ammoalkylene-phosphonate .
- the aminoalkylenephosphonates of the present invention can be administered to a mammal on a daily or weekly regiment basis.
- the effective weekly parenteral dose is in the range of from about 0.01 mg to about 500 mg, preferably from about 0.1 mg to about 250 mg, most preferably from about 0.1 to about 70 mg .
- the effective daily oral dose is in the range of from about 0.1 mg to about 40 g, preferably from about 0.1 mg to about 10 g, most preferably from about 0.1 to about 5 g.
- ammoalkylenephosphonate may be administered per se or as a component of a pharmaceutically acceptable composition.
- ammoalkylenephosphonate being provided in pharmaceutical formulation, both for veterinary and for human medical use.
- Such pharmaceutical formulations comprise the active agent (the ammoalkylenephosphonate) together with one or more pharmaceutically acceptable carriers thereof and optionally any other therapeutic ingredients.
- the carrier (s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredient (s) in the formulation and not unsuitably deleterious to the recipient thereof.
- the ammoalkylenephosphonate is provided m an effective amount, as described above, and in a quantity appropriate to achieve the desired dose.
- formulations include those suitable for oral, rectal, topical, nasal, ophthalmic, or parenteral
- Formulations may be prepared by any methods well known m the art of pharmacy. Such methods include the step of bringing the ammoalkylenephosphonate into association with a carrier, which constitute one or more accessory ingredients.
- the formulation may be prepared by uniformly and intimately bringing the ammoalkylenephosphonate into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into desired formulation.
- the formulations of this invention may further include one or more accessory ingredient (s) selected from diluents, buffers, flavoring agents, binders, dismtegrants, surface active agents, thickeners, lubricants, preservatives.
- Phosphonates (5 mg/kg) were administered subcutaneously (to insure better bioavailability) .
- the rats were given doses three times during the first week and once a week thereafter.
- Bone mineral density was determined by single photon absorptiometry while the rats were under injectable anesthesia. The distal femoral metaphysis of all rats were scanned at weekly intervals for ten weeks.
- Figure 2 shows the average drop in bone mineral density, normalized to the sham-operated control group, for the ovariectomized (OVX) control group and for the treatment groups .
- the OVX group loses bone mineral density (BMD) over time.
- BMD bone mineral density
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- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A method for preventing or minimizing loss of bone mineral in mammals which method comprises administering to a mammal an amount of an aminoalkylenephosphonate which is effective to prevent or minimize loss of bone mineral density. The aminoalkylenephosphonates of the present invention should have at least one R-N(Alk-PO3H2)2 group or at least two RR´N-Alk-PO3H2 groups wherein R and R´ can be, same or different, aliphatic or cyclic moiety, and Alk is an alkylene group having from 1 to 4 carbon atoms.
Description
AMINOALKYLENEPHOSPHONATES FOR TREATMENT OF BONE
DISORDERS
This invention relates to the use of aminoalkylenephosphonates for treatment of bone disorders such as osteoporosis.
This invention involves the use of aminoalkylenephosphonates, such as, for example, 1,4,7,10- tetraazacyclododecane-1 ,4,7, 10-tetramethylenephosphonic acid (DOTMP) and 3, 6, 9, 15-tetraazabicyclo [ 9.3.1] tetradeca- 1 (15) , 11, 13-triene-3, 6, 9-trimethylenephosphonic acid (PCTMP) for use in the inhibition of bone resorption. This application is directed toward use in the prevention and/or treatment of bone diseases such as osteoporosis. Bone is a dynamic tissue, continually undergoing remodeling. Hydroxyapatite, the main inorganic constituent of bone, is constantly being deposited and resorbed. In pathological states such as osteoporosis a shift in the balance of these two processes occurs, resulting in a net loss of mineralized tissue. This loss results in impaired skeletal function and clinical fractures. Osteoporosis is an enormous public health problem affecting as many as 25 million people in the
United States alone. It is a pervasive disease that has staggering costs to society in terms of morbidity, mortality, and economics. As the population becomes more aged, the magnitude of this problem will certainly become greater.
Currently only three drugs - estrogen, calcitonin, and alendronate are approved by the FDA for use in the treatment of osteoporosis. Both estrogen and calcitonin have some drawbacks (for example, estrogen - risk of endometrial carcinoma, calcitonin - allergic reaction) and are not always successful. The recently approved
bisphosphonate alendronate (4-amιno-l- hydroxybutylidenebisphosphonate) is a member of a class of compounds that has received much attention for their potential in treating bone-related illnesses.
Bisphosphonates all contain the basic P-C-P structure. Examples such as etidronate (1-hydroxy- ethylidenebisphosphonate) , risedronate [ l-hydroxy-2- ( 3- pyridinyl ) ethylenebisphosphonate] , pamidronate (3-amιno-l- hydroxypropylidenebisphosphonate) , tiludronate (4- chlorophenylthiomethylenebisphosphonate) have already been approved for the treatment of a rare bone condition called Paget' s disease .
Aminoalkylenephosphonates have not been investigated for these applications. It is known that these compounds have a strong affinity for bone (for example, EDTMP and DOTMP radiopharmaceutical bone agents) and have low soft tissue localization. They have unique properties such as the ability to inhibit calcium phosphate scale formation at very low concentrations .
It has now been discovered that aminoalkylenephosphonates can inhibit bone mineral density loss. In fact, a screening study of various aminomethylene- phosphonates in an ovarectomized rat osteoporosis model has now shown that PCTMP is as good as, and may even be superior to, alendronate in its ability to inhibit bone mineral loss .
The present invention relates to a method for preventing or minimizing loss of bone mineral in mammals which method comprises administering to a mammal an amount of an aminoalkylenephosphonate which is effective to prevent or minimize loss of bone mineral density.
In another aspect, the present invention relates to the use of an ammoalkylenephophonate or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical formulation for preventing or minimizing loss of bone mineral in mammals.
The term "arainoalkylenephosphonate" as used herein refers to those phosphonates and phosphonic acids which incorporate an amme moiety, whether aliphatic or cyclic, attached via the amme nitrogen through an alkylene group to the phosphonate or phosphonic acid moiety. The aminoalkylenephosphonates of the present invention should have at least one R-N (Alk-P03H2) 2 group or at least two RR' N-Alk-P03H2 groups wherein R and R' can be, same or different, aliphatic or cyclic moiety, and Alk is an alkylene group having from 1 to 4 carbon atoms.
The amme moiety of the aminoalkylenephosphonates of the present invention represented by the R-N= and RR'N- in the aforementioned R-N (Alk-P03H2) 2 and RR' N-Alk-P03H2 groups is derived from either an aliphatic or a cyclic polyamme which hydrogen atoms bonded to the nitrogen atom(s) in the amme moiety are partially or completely substituted by an alkylphoshonate group. Non-limit g examples of the amines suitable as amme moieties in the practice of the present invention are ethylenediamme (EDA) , diethylenetπamme (DETA), tπethylenetetraamme (TETA) , 1,4,7, 10-tetraazacyclododecane, 3, 6, 9, 15-tetraaza- bιcyclo[9.3.1] tetradeca-1 (15) ,11, 13-trιene, 2, 11- dιaza[3.3] (2, 6) pyridmophane, 2- (ammomethyl) pyridme, 2 , 6-bιs (ammomethyl ) pyridme .
The alkylene group having from 1 to 4 carbon atoms contemplated by Alk m the aforementioned formulas can be straight or branched chain alkylene group. Non-limitmg examples of such alkylene groups are methylene, ethylene,
propylene, isopropylene, and butylene. The preferred alkylene group is methylene (-CH2-) group.
Preferred aminoalkylenephosphonates are am omethylenephosphonates . Particularly preferred aminoalkylenephosphonates are 1 , 4 , 7 , 10-tetraaza- cyclododecane-1 ,4,7, 10-tetramethylenephosphonic acid (DOTMP) , 3,6,9, 15-tetraazabιcyclo[9.3.1] tetradeca- 1 (15) , 11, 13-trιene-3, 6, 9-trιmethylenephosphonιc acid (PCTMP), N,N' -bis (methylenephosphonic acιd)-2,ll- diaza [3.3] (2, 6) pyridmophane (BP2MP) and N, N-bis (methylene phosphonic acid) -2- (ammomethyl ) pyridme (AMPDMP) .
The aminoalkylenephosphonates contemplated by the present invention are well known in the art and numerous methods for their preparation have been disclosed. See, for example, U.S. Patent No. 3,288,846 (Irani et al) and U.S. Patent No. 4,898,724 (Simon et al), both incorporated herein by reference.
The aminoalkylenephosphonates of the present invention are used in an amount effective to prevent or minimize loss of bone mineral. The effective amount will vary depending on the mammal, ammoalkylenephosphonate used and the method of its administration (for example, oral or parenteral) . A person of ordinary skill in the art will know how to determine the effective amount of ammoalkylene-phosphonate .
The aminoalkylenephosphonates of the present invention can be administered to a mammal on a daily or weekly regiment basis. Typically, for average 50 kg mammal, the effective weekly parenteral dose is in the range of from about 0.01 mg to about 500 mg, preferably from about 0.1 mg to about 250 mg, most preferably from about 0.1 to about 70 mg . Typically, for average 50 kg
mammal, the effective daily oral dose is in the range of from about 0.1 mg to about 40 g, preferably from about 0.1 mg to about 10 g, most preferably from about 0.1 to about 5 g.
In the practice of the present invention the ammoalkylenephosphonate may be administered per se or as a component of a pharmaceutically acceptable composition.
Thus, the present invention may be practiced with the ammoalkylenephosphonate being provided in pharmaceutical formulation, both for veterinary and for human medical use. Such pharmaceutical formulations comprise the active agent (the ammoalkylenephosphonate) together with one or more pharmaceutically acceptable carriers thereof and optionally any other therapeutic ingredients. The carrier (s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredient (s) in the formulation and not unsuitably deleterious to the recipient thereof. The ammoalkylenephosphonate is provided m an effective amount, as described above, and in a quantity appropriate to achieve the desired dose.
The formulations include those suitable for oral, rectal, topical, nasal, ophthalmic, or parenteral
(including subcutaneous, intramuscular, and intravenous) administration. Formulations may be prepared by any methods well known m the art of pharmacy. Such methods include the step of bringing the ammoalkylenephosphonate into association with a carrier, which constitute one or more accessory ingredients. In general, the formulation may be prepared by uniformly and intimately bringing the ammoalkylenephosphonate into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into desired formulation. In addition, the formulations of this
invention may further include one or more accessory ingredient (s) selected from diluents, buffers, flavoring agents, binders, dismtegrants, surface active agents, thickeners, lubricants, preservatives.
The following Examples are provided to illustrate the present invention, and should not be construed as limiting thereof .
Example 1
Eleven week old Female Sprague-Dawley laboratory rats (75) were fed a commercial rat diet and were allowed to drink water ad libitum. They were housed m pairs in an air-conditioned environment, and were allowed to enjoy 14 hours of illumination per day. Ten rats were sham- operated and were used as "non-osteopenic" control rats. All of the other rats were ovariectomized at 12 weeks of age. All surgeries were done under mjectable anesthesia. Ten of the ovariectomized rats were used as an "osteopenic but non-treated" control, and did not receive any phosphonate treatments. The remaining rats were given various phosphonate compounds groups of ten.
Phosphonates (5 mg/kg) were administered subcutaneously (to insure better bioavailability) . The rats were given doses three times during the first week and once a week thereafter.
Structures of the compounds tested are shown below in Figure 1.
Figure 1. Structures of Compounds Tested (Example 1
H203P- P0 33Hπ2 H203P- P03H2
H,03P- -P03H, H203P- P03H2
^P03H-
DETA- Phosphonate EDTMP
Bone mineral density was determined by single photon absorptiometry while the rats were under injectable anesthesia. The distal femoral metaphysis of all rats were scanned at weekly intervals for ten weeks.
Figure 2 below shows the average drop in bone mineral density, normalized to the sham-operated control group, for the ovariectomized (OVX) control group and for the treatment groups .
Figure 2. Average Change in BMD Normalized to sham-operated control = 0]
As can be seen, relative to the sham-operated control, the OVX group loses bone mineral density (BMD) over time. Three aminomethylenephosphonates, DOTMP,
EDTMP, and DETA-Phosphonate, all lost more BMD than the OVX group (at this dose level) . Both the alendronate and PCTMP groups maintained BMD. (Because of the difference in molecular weight, PCTMP was actually used at a lower dose level than alendronate on a mole basis.)
By week 10 , there are three statistical groupings . The sham operated controls , alendronate , and PCTMP are all statistically equivalent . The ovariectomized controls are in a group by themselves , as are the other three aminomethylenephosphonates .
Exampl e 2 :
A second study was undertaken to explore the effect of structural changes in PCTMP. The structures of the compounds tested are shown below in Figure 3. Included in the study was DOTMP at one tenth the dose, that is, 0.5 mg/kg. All other compounds were dosed at 5 mg/kg. In this study, bone mineral density was determined by dual energy X-ray absorptiometry (DEXA) . Other aspects of the study were substantially the same as in Example 1. The results of the study are shown in Figure 4 below.
Again, it can be seen that, relative to the sham- operated controls, the OVX control group lost significant BMD over the study period. As before, PCTMP shows an improvement over the OVX group. AMPDMP and BP2MP both look even better, but the best compound tested was DOTMP at 0.5 mg/kg. At this dose level it was equivalent to the sham-operated control.
Figure 3. Structures of Compounds Tested
I bO-i
BAMPDMP BP2MP
DOTMP
Figure 4. Average Change in BMD [Normalized to sham-operated control = 0)
-0.060
4 5
Week
Claims
1. A method for preventing or minimizing loss of bone mineral in mammals which method comprises administering to a mammal an amount of an ammoalkylenephosphonate or a pharmaceutically acceptable salt thereof which is effective to prevent or minimize loss of bone mineral density.
2. The method according to Claim 1 wherein said ammoalkylenephosphonate has at least one R-N (Alk-P03H2) 2 group wherein R can be an aliphatic or cyclic moiety, and Alk is an alkylene group having from 1 to 4 carbon atoms.
3. The method according to Claim 1 wherein said ammoalkylenephosphonate has at least two RR' N-Alk-P03H2 groups wherein R and R' can be, same or different, aliphatic or cyclic moiety, and Alk is an alkylene group having from 1 to 4 carbon atoms.
4. The method according to Claim 2 or Claim 3 wherein the amme moiety of the ammoalkylenephosphonate represented by the R-N= and RR'N- in the R-N (Alk-P03H2) 2 and RR' N-Alk-P03H2 groups is derived from either an aliphatic or a cyclic polyamme m which hydrogen atoms bonded to the nitrogen atoms m the amme moiety are partially or completely substituted by an alkylphoshonate group.
5. The method according to Claim 1 wherein said ammoalkylenephosphonate is an ammomethylenephosphonate .
6. The method according to Claim 1 wherein said ammoalkylenephosphonate is 3,6,9,15- tetraazabicyclo [9.3. l]tetradeca-l(15), 11, 13-trιene-3,6,9- trimethylenephosphonic acid (PCTMP) .
7 . The method according to Claim 1 wherein said ammoal kyl enephosphonate is 1 , 4 , 7 , 10- tetraazacyclododecane- 1 , 4 , 7 , 10-tetramethylenephos phonic acid ( DOTMP ) .
8 . The method according to Claim 1 wherein said ammoal kylenephosphonate is N , N ' -bis (methylenephosphonic acid) -2 , l l -dιaza [ 3 . 3 ] ( 2 , 6 ) pyπdinophane ( BP2MP ) .
9. The method according to Claim 1 wherein said ammoalkylenephosphonate is N, -bis (methylenephosphonic acid) -2- (ammomethyl) pyridme (AMPDMP) .
10. The use of an ammoalkylenephophonate or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical formulation for preventing or minimizing loss of bone mineral in mammals.
11. The use of an ammoalkylenephophonate or a pharmaceutically acceptable salt thereof according to Claim 10 wherein said ammoalkylenephosphonate has at least one R-N (Alk-P03H2) 2 group wherein R can be an aliphatic or cyclic moiety, and Alk is an alkylene group having from 1 to 4 carbon atoms .
12. The use of an ammoalkylenephophonate or a pharmaceutically acceptable salt thereof according to Claim 10 wherein said ammoalkylenephosphonate has at least two RR' N-Alk-P03H2 groups wherein R and R' can be, same or different, aliphatic or cyclic moiety, and Alk is an alkylene group having from 1 to 4 carbon atoms.
13. The use of an ammoalkylenephophonate or a pharmaceutically acceptable salt thereof according to
Claim 11 or Claim 12 wherein the amme moiety of the ammoalkylenephosphonate represented by the R-N= and RR' N- rn the R-N (Alk-P03H2) _ and RR' N-Alk-P03H2 groups is derived from either an aliphatic or a cyclic polyamme in which hydrogen atoms bonded to the nitrogen atoms in the amme moiety are partially or completely substituted by an alkylphoshonate group.
14. The use of an ammoalkylenephophonate or a pharmaceutically acceptable salt thereof according to Claim 10 wherein said ammoalkylenephosphonate is an ammomethylenephosphonate .
15. The use of an ammoalkylenephophonate or a pharmaceutically acceptable salt thereof according to Claim 10 wherein said ammoalkylenephosphonate is
3,6,9, 15-tetraazabicyclo [9.3.1] tetradeca-1 (15) , 11, 13- trιene-3, 6, 9-trimethylenephosphonιc acid (PCTMP).
16. The use of an ammoalkylenephophonate or a pharmaceutically acceptable salt thereof according to
Claim 10 wherein said ammoalkylenephosphonate is 1,4,7, 10-tetraazacyclododecane-l ,4,7,10- tetramethylenephosphonic acid (DOTMP).
17. The use of an ammoalkylenephophonate or a pharmaceutically acceptable salt thereof according to Claim 10 wherein said ammoalkylenephosphonate is N,N'- bis (methylenephosphonic acid) -2, 11- diaza[3.3] (2 , 6) pyridmophane (BP2MP) .
18. The use of an ammoalkylenephophonate or a pharmaceutically acceptable salt thereof according to Claim 10 wherein said ammoalkylenephosphonate is N,N- bis (methylenephosphonic acid) -2- (aminomethyl) pyridine (AMPDMP) .
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16001999P | 1999-10-18 | 1999-10-18 | |
| US160019P | 1999-10-18 | ||
| PCT/US2000/028713 WO2001028567A2 (en) | 1999-10-18 | 2000-10-17 | Aminoalkylenephosphonates for treatment of bone disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1225903A2 true EP1225903A2 (en) | 2002-07-31 |
Family
ID=22575141
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00972234A Withdrawn EP1225903A2 (en) | 1999-10-18 | 2000-10-17 | Aminoalkylenephosphonates for treatment of bone disorders |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1225903A2 (en) |
| JP (1) | JP2003512331A (en) |
| CN (1) | CN1378454A (en) |
| AU (1) | AU1092601A (en) |
| CA (1) | CA2382877A1 (en) |
| WO (1) | WO2001028567A2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012172271A1 (en) * | 2011-06-17 | 2012-12-20 | Centre National De La Recherche Scientifique | Bifunctional phosphonate chelating agents |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4937333A (en) * | 1989-08-04 | 1990-06-26 | The Dow Chemical Company | Method for purifying aminomethylenephosphonic acids for pharmaceutical use |
| IL106159A0 (en) * | 1992-06-30 | 1993-10-20 | Dow Chemical Co | Targeted delivery of growth factors for bone regeneration |
| US5714604A (en) * | 1993-05-06 | 1998-02-03 | The Dow Chemical Company | Process for the preparation of azamacrocyclic or acyclic aminophosphonate ester derivatives |
| US5385893A (en) * | 1993-05-06 | 1995-01-31 | The Dow Chemical Company | Tricyclopolyazamacrocyclophosphonic acids, complexes and derivatives thereof, for use as contrast agents |
| US5902825A (en) * | 1997-01-07 | 1999-05-11 | Mitreoak, Ltd. | Composition and method for the palliation of pain associated with diseases of the bone and bone joints |
-
2000
- 2000-10-17 WO PCT/US2000/028713 patent/WO2001028567A2/en not_active Ceased
- 2000-10-17 CA CA002382877A patent/CA2382877A1/en not_active Abandoned
- 2000-10-17 JP JP2001531397A patent/JP2003512331A/en active Pending
- 2000-10-17 AU AU10926/01A patent/AU1092601A/en not_active Abandoned
- 2000-10-17 CN CN00814123A patent/CN1378454A/en active Pending
- 2000-10-17 EP EP00972234A patent/EP1225903A2/en not_active Withdrawn
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| Title |
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| See references of WO0128567A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001028567A2 (en) | 2001-04-26 |
| CA2382877A1 (en) | 2001-04-26 |
| WO2001028567A3 (en) | 2001-11-29 |
| JP2003512331A (en) | 2003-04-02 |
| AU1092601A (en) | 2001-04-30 |
| CN1378454A (en) | 2002-11-06 |
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