Claims for Patent: 3,683,080

Summary for Patent: 3,683,080

Title:	COMPOSITIONS FOR INHIBITING ANOMALOUS DEPOSITION AND MOBILIZATION OF CALCIUM PHOSPHATE IN ANIMAL TISSUE
Abstract:	Compositions for inhibiting anomalous deposition and mobilization of calcium phosphates in animal tissue, comprising an effective amount of certain polyphosphonates as herein defined, and a pharmaceutical carrier; and a method for treating or preventing conditions involving pathological calcification and hard tissue demineralization in an animal comprising administering to such animal said compositions. 51 Claims, No Drawings
Inventor(s):	Marion D. Francis, Springfield Township (Hamilton County), OH (N/A)
Assignee:	The Procter & Gamble Company, Cincinnati, OH (N/A)
Application Number:	05/068,029
Patent Claims:	1. A composition in dosage unit form for inhibiting deposition and mobilization of calcium phosphate in animal tissue comprising (1) an effective but non-toxic amount, within the range from about 15 mg. to about 1,000 mg., of a polyphosphonate selected from the group consisting of wherein R.sub.1 and R.sub.2 are each hydrogen or CH.sub.2 OH; n is an integer of from 3 to 10; R.sub.3 is hydrogen, alkyl containing from one to about 20 carbon atoms, alkenyl containing from two to about 20 carbon atoms, phenyl, naphthyl, phenylethenyl, benzyl, halogen, amino, substituted amino, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, --CH(PO.sub.3 H.sub.2)(OH), or --CH.sub.2 CH(PO.sub.3 H.sub.2).sub.2 ; R.sub.4 is hydrogen, lower alkyl, amino, benzyl, halogen, hydroxyl, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, or --CH.sub.2 CH.sub.2 PO.sub.3 H.sub.2 ; and the pharmaceutically acceptable salts thereof, and (2) a pharmaceutical carrier, said composition being adapted to systemic 2. The composition of claim 1 wherein the polyphosphonate is methanehydroxydiphosphonic acid or a pharmaceutically acceptable salt 3. The composition of claim 1 wherein the polyphosphonate is ethane-1-amino-1,1-diphosphonic acid or a pharmaceutically acceptable salt 4. The composition of claim 1 wherein the polyphosphonate is methanediphosphonic acid or a pharmaceutically acceptable salt thereof. 5. The composition of claim 1 wherein the polyphosphonate is ethane-1-hydroxy-1,1,2-triphosphonic acid or a pharmaceutically acceptable 6. The composition of claim 1 wherein the polyphosphonate is propane-1,2,3-triphosphonic acid or a pharmaceutically acceptable salt 7. The composition of claim 1 wherein the polyphosphonate is butane-1,2,3,4-tetraphosphonic acid or a pharmaceutically acceptable salt 8. The composition of claim 1 wherein the polyphosphonate is hexane-1,2,3,4,5,6-hexaphosphonic acid or a pharmaceutically acceptable 9. The composition of claim 1 wherein the polyphosphonate is methanephenylaminodiphosphonic acid or a pharmaceutically acceptable salt 10. The composition of claim 1 wherein the dosage unit form is adapted to 11. The composition of claim 1 wherein the polyphosphonate is methanedichlorodiphosphonic acid or a pharmaceutically acceptable salt 12. The composition of claim 11 wherein the dosage unit form is adapted to oral administration and comprises from about 100 mg. to about 500 mg. of 13. The composition of claim 1 wherein the polyphosphonate is ethane-1-hydroxy-1,1-diphosphonic acid or a pharmaceutically acceptable 14. The composition of claim 13 wherein the dosage unit form is adapted to oral administration and comprises from about 100 mg. to about 500 mg. of 15. A method for inhibiting anomalous deposition or mobilization of calcium phosphates in animal tissue which comprises systemically administering to animals an effective but non-toxic amount of a polyphosphonate selected from the group consisting of wherein R.sub.1 and R.sub.2 are each hydrogen or CH.sub.2 OH; n is an integer of from 3 to 10; R.sub.3 is hydrogen, alkyl containing from one to about 20 carbon atoms, alkenyl containing from two to about 20 carbon atoms, phenyl, naphthyl, phenylethenyl, benzyl, halogen, amino, substituted amino, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, --CH(PO.sub.3 H.sub.2)(OH), or --CH.sub.2 CH(PO.sub.3 H.sub.2).sub.2 ; R.sub.4 is hydrogen, lower alkyl, amino, benzyl, halogen, hydroxyl, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, or --CH.sub.2 CH.sub.2 PO.sub.3 H.sub.2 ; and the pharmaceutically acceptable salts thereof, and 16. The method of claim 15 wherein the polyphosphonate is 17. The method of claim 15 wherein the polyphosphonate is 18. The method of claim 15 wherein the polyphosphonate is 19. The method of claim 15 wherein the polyphosphonate is 20. The method of claim 15 wherein the polyphosphonate is 21. The method of claim 15 wherein the polyphosphonate is 22. The method of claim 15 wherein the polyphosphonate is 23. The method of claim 15 wherein the polyphosphonate is 24. The method of claim 15 wherein the polyphosphonate is 25. The method of claim 15 wherein the polyphosphonate is 26. An animal feed composition comprising (1) a minor proportion of a polyphosphonate selected from the group consisting of wherein R.sub.1 and R.sub.2 are each hydrogen or CH.sub.2 OH; n is an integer from 3 to 10; R.sub.3 is hydrogen, alkyl containing from one to about 20 carbon atoms, alkenyl containing from two to about 20 carbon atoms, phenyl, naphthyl, phenylethenyl, benzyl, halogen, amino, substituted amino, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, --CH(PO.sub.3 H.sub.2)(OH), or --CH.sub.2 CH(PO.sub.3 H.sub.2).sub.2 ; R.sub.4 is hydrogen, lower alkyl, amino, benzyl, halogen, hydroxyl, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, or --CH.sub.2 CH.sub.2 PO.sub.3 H.sub.2 ; and the pharmaceutically acceptable salts thereof, and 27. The composition of claim 26 wherein the polyphosphonate is methanedichlorodiphosphonic acid or a pharmaceutically acceptable salt 28. The composition of claim 26 wherein the polyphosphonate is ethane-1-hydroxy-1,1-diphosphonic acid or a pharmaceutically acceptable 29. The composition of claim 26 wherein the polyphosphonate is methanehydroxydiphosphonic acid or a pharmaceutically acceptable salt 30. The composition of claim 26 wherein the polyphosphonate is ethane-1-amino-1,1-diphosphonic acid or a pharmaceutically acceptable salt 31. The composition of claim 26 wherein the polyphosphonate is methanediphosphonic acid or a pharmaceutically acceptable salt thereof. 32. The composition of claim 26 wherein the polyphosphonate is ethane-1-hydroxy-1,1,2-triphosphonic acid or a pharmaceutically acceptable 33. The composition of claim 26 wherein the polyphosphonate is propane-1,2,3-triphosphonic acid or a pharmaceutically acceptable salt 34. The composition of claim 26 wherein the polyphosphonate is butane-1,2,3,4-tetraphosphonic acid or a pharmaceutically acceptable salt 35. The composition of claim 26 wherein the polyphosphonate is hexane-1,2,3,4,5,6-hexaphosphonic acid or a pharmaceutically acceptable 36. The composition of claim 26 wherein the polyphosphonate is methanephenylaminodiphosphonic acid or a pharmaceutically acceptable salt 37. A method for treating Paget's disease comprising systemically administering to an animal afflicted therewith an effective but non-toxic amount of a polyphosphonate selected from the group consisting of wherein R.sub.1 and R.sub.2 are each hydrogen or CH.sub.2 OH; n is an integer of from 3 to 10; R.sub.3 is hydrogen, alkyl containing from one to about 20 carbon atoms, alkenyl containing from two to about 20 carbon atoms, phenyl, naphthyl, phenylethenyl, benzyl, halogen, amino, substituted amino, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, --CH(PO.sub.3 H.sub.2)(OH), or --CH.sub.2 CH(PO.sub.3 H.sub.2).sub.2 ; R.sub.4 is hydrogen, lower alkyl, amino, benzyl, halogen, hydroxyl, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, or --CH.sub.2 CH.sub.2 38. The method of claim 37 wherein the polyphosphonate is ethane-1-hydroxy-1,1-diphosphonic acid or a pharmaceutically acceptable 39. The method of claim 37 wherein the polyphosphonate is methanedichlorodiphosphonic acid or a pharmaceutically acceptable salt 40. A method for treating osteoporosis comprising administering to an animal afflicted therewith an effective but non-toxic amount of polyphosphonate selected from the group consisting of wherein R.sub.1 and R.sub.2 are each hydrogen or CH.sub.2 OH; n is an integer of from 3 to 10; R.sub.3 is hydrogen, alkyl containing from one to about 20 carbon atoms, alkenyl containing from two to about 20 carbon atoms, phenyl, naphthyl, phenylethenyl, benzyl, halogen, amino, substituted amino, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, --CH(PO.sub.3 H.sub.2)(OH), or --CH.sub.2 CH(PO.sub.3 H.sub.2).sub.2 ;R.sub.4 is hydrogen, lower alkyl, amino, benzyl, halogen, hydroxyl, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, or --CH.sub.2 CH.sub.2 41. The method of claim 40 wherein the polyphosphonate is ethane-1-hydroxy-1,1-diphosphonic acid or a pharmaceutically acceptable 42. The method of claim 40 wherein the polyphosphonate is methanedichlorodiphosphonic acid or a pharmaceutically acceptable salt 43. A method for treating arthritis comprising administering to an animal afflicted therewith an effective but non-toxic amount of a polyphosphonate selected from the group consisting of wherein R.sub.1 and R.sub.2 are each hydrogen or CH.sub.2 OH; n is an integer of from 3 to 10; R.sub.3 is hydrogen, alkyl containing from one to about 20 carbon atoms, alkenyl containing from two to about 20 carbon atoms, phenyl, naphthyl, phenylethenyl, benzyl, halogen, amino, substituted amino, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, --CH(PO.sub.3 H.sub.2)(OH), or --CH.sub.2 CH(PO.sub.3 H.sub.2).sub.2 ;R.sub.4 is hydrogen, lower alkyl, amino, benzyl, halogen, hydroxyl, --CH.sub.2 COOH,--CH.sub.2 PO.sub.3 H.sub.2, or --CH.sub.2 CH.sub.2 44. The method of claim 43 wherein the polyphosphonate is ethane-1-hydroxy-1,1-diphosphonic acid or a pharmaceutically acceptable 45. The method of claim 43 wherein the polyphosphonate is methanedichlorodiphosphonic acid or a pharmaceutically acceptable salt 46. A method for treating urolithiasis comprising administering to an animal afflicted therewith an effective but non-toxic amount of a polyphosphonate selected from the group consisting of wherein R.sub.1 and R.sub.2 are each hydrogen or CH.sub.2 OH; n is an integer of from 3 to 10; R.sub.3 is hydrogen, alkyl containing from one to about 20 carbon atoms, alkenyl containing from two to about 20 carbon atoms, phenyl, naphthyl, phenylethenyl, benzyl, halogen, amino, substituted amino, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, --CH(PO.sub.3 H.sub.2)(OH), or --CH.sub.2 CH(PO.sub.3 H.sub.2).sub.2 ; R.sub.4 is hydrogen, lower alkyl, amino, benzyl, halogen, hydroxyl, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, or --CH.sub.2 CH.sub.2 47. The method of claim 46 wherein the polyphosphonate is ethane-1-hydroxy-1,1-diphosphonic acid or a pharmaceutically acceptable 48. The method of claim 46 wherein the polyphosphonate is methanedichlorodiphosphonic acid or a pharmaceutically acceptable salt 49. A method for treating arteriosclerosis comprising administering to an animal afflicted therewith an effective but non-toxic amount of a polyphosphonate selected from the group consisting of wherein R.sub.1 and R.sub.2 are each hydrogen or CH.sub.2 OH; n is an integer of from 3 to 10; R.sub.3 is hydrogen, alkyl containing from one to about 20 carbon atoms, alkenyl containing from two to about 20 carbon atoms, phenyl, naphthyl, phenylethenyl, benzyl, halogen, amino, substituted amino, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, --CH(PO.sub.3 H.sub.2)(OH), or --CH.sub.2 CH(PO.sub.3 H.sub.2).sub.2 ; R.sub.4 is hydrogen, lower alkyl, amino, benzyl, halogen, hydroxyl, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, or --CH.sub.2 CH.sub.2 50. The method of claim 49 wherein the polyphosphonate is ethane-1-hydroxy-1,1-diphosphonic acid or a pharmaceutically acceptable 51. The method of claim 49 wherein the polyphosphonate is methanedichlorodiphosphonic acid or a pharmaceutically acceptable salt thereof.