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Claims for Patent: 4,777,163

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Claims for Patent: 4,777,163

Title: Diphosphonate derivatives, pharmaceutical compositions and methods of use for calcium disturbances
Abstract:The present invention produces alkyldiphosphonic acid derivative of the general formula: ##STR1## wherein Het is a heteroaromatic five-membered ring containing to 3 heteroatoms which can be partly hydrogenated and optionally substituted one or more times by alkyl, alkoxy, phenyl, cyclohexyl, cyclohexylmethyl, halogen or amino, and two adjacent alkyl substituents can together also form a ring, Y is a hydrogen atom or a lower alkyl radical, X is a hydrogen atom, a hydroxyl group or an amino group optionally substituted by lower alkyl and R is a hydrogen atom or a lower alkyl radical, with the proviso that Het is not a pyrazole ring; as well as the pharmacologically acceptable salts thereof. The present invention also provides processes for the prepearation of these compounds and pharmaceutical compositions containing them useful for the treatment or prophylaxis of calcium metabolism disturbances or disease as for example osteoporosis, Bechterew's disease, bone metastases, urolithiasis, heterotropic ossifications, rheumatoid arthritis osteoarthritis or degenerative arthrosis.
Inventor(s): Bosies; Elmar (Weinheim, DE), Gall; Rudi (Hirschberg, DE)
Assignee: Boehringer Mannheim GmbH (Mannheim, DE)
Application Number:07/077,228
Patent Claims: 1. An alkyldiphosphonic acid derivative of the formula: ##STR12## wherein Het is a substituted or unsubstituted heteroaromatic five-membered first ring selected from the group consisting of imidazolyl, imidazolinyl, isoxazolyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, triazolyl, oxadiazolyl and thiadiazolyl wherein said ring can be partly hydrogenated and wherein said substituents are selected from at least one of the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, phenyl, cyclohexyl, cyclohexylmethyl, halogen and amino, and wherein two adjacent alkyl substitutents of Het can together form a second ring,

Y is hydrogen or a C.sub.1 -C.sub.4 alkyl,

X is hydrogen, hydroxyl, amino, or an amino group substituted by C.sub.1 -C.sub.4 alkyl, and

R is hydrogen or a C.sub.1 -C.sub.4 alkyl,

as well as the pharmacologically acceptable salts and isomers thereof.

2. A compound of claim 1 wherein two adjacent alkyl substituents of Het together form a second ring, which bicyclic ring is hexahydrobenzimidazolyl, hexahydrobenzoxazolyl or hexahydrobenzthiazolyl.

3. The compound of claim 1 wherein the substituents are methyl, ethyl, isobutyl, methoxyethoxy, halogen or amino.

4. The compound of claim 1 wherein the second ring is a six-membered ring.

5. The compound of claim 1 wherein the halogen is fluorine, chlorine, bromine or iodine.

6. The compound of claim 1 wherein the halogen is chlorine.

7. The compound of claim 1 wherein Y is H or methyl.

8. The compound of claim 1 wherein X is hydrogen, hydroxy, amino or dimethylamino.

9. The compound of claim 1 wherein X is hydrogen or hydroxy.

10. The compound of claim 1 wherein R is hydrogen, methyl or ethyl.

11. The compound of claim 1 designated 1-hydroxy-2-(imidazole-4-yl)-ethane-1,1-diphosphonic acid and the physiologically active salt.

12. The compound of claim 1 designated 1-hydroxy-2-(4-imidazoline-2-yl)-ethane-1,1-diphosphonic acid and the physiologically active salt.

13. The compound of claim 1 designated 2-(2-amino-4-thiazoline-4-yl)-ethane-1-hydroxy-1,1-diphosphonic acid and the physiologically active salt.

14. A pharmaceutical composition for the treatment or prophylaxis of calcium metabolism disturbance or disease containing an effective amount of at least one compound of claim 1 in a pharmaceutically acceptable carrier.

15. A pharmaceutical composition for the treatment or prophylaxis of calcium metabolism disturbance or disease containing an effective amount of at least one compound of claim 3 in a pharmaceutically acceptable carrier.

16. A pharmaceutical composition for the treatment or prophylaxis of calcium matabolism disturbance or disease containing an effective amount of at least one compound from the group of 1-hydroxy-2-(imidazole-4-yl)-ethane-1,1-diphosphonic acid, 1-hydroxy-2-(4-imidazoline-2-yl)-ethane-1,1-diphosphonic acid and 2-(2-amino-4-thiazoline-4-yl)-ethane-1-hydroxy-1,1-diphosphonic acid in a pharmaceutilatty acceptable carrier.

17. A method for the treatment or prophylaxis of calcium metabolism disturbance or disease comprising administering an effective amount of at least one of a pharmaceutically acceptable compound of claim 1.

18. A method for the treatment of prophylaxis of calcium metabolism disturbance or disease comprising administering an effective amount of at least one of a pharmaceutically acceptable compound of claim 4.

19. A method for the treatment of prophylaxis of calcium metabolism disturbance or disease comprising administering an effective amount of at least one pharmaceutically acceptable compound selected from the group consisting of 1-hydroxy-2-(imidazole-4-yl)-ethane-1,1-diphosphonic acid, 1-hydroxy-2-(4-imidazoline-2-yl)-ethane-1,1-diphosphonic acid and 2-(2-amino-4-thiazoline-4-yl)-ethane-1-hydroxy-1,1-diphosphonic acid.

20. The method of claim 17 wherein the dose is 0.001-10 mg P/kg.

21. The method of claim 18 or 19 wherein the dose is 0.001-10 mg P/kg.
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