WO1989003829A1 - Omeprazole for treatment of diseases related to bone loss - Google Patents
Omeprazole for treatment of diseases related to bone loss Download PDFInfo
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- WO1989003829A1 WO1989003829A1 PCT/SE1988/000573 SE8800573W WO8903829A1 WO 1989003829 A1 WO1989003829 A1 WO 1989003829A1 SE 8800573 W SE8800573 W SE 8800573W WO 8903829 A1 WO8903829 A1 WO 8903829A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention is related to a novel method for the treatment of several bone affecting diseases, especially osteoporosis, which are characterized by loss of bone mass.
- osteoporosis which is associated with the number and activity of osteoblasts, that is cells associated with the production of bone in the organism
- bone loss which is associated with the number and activity of osteoclasts, that is cells associated with the absorption and removal of bone
- osteoporosis can be mentioned, Paget's disease of bone, hyperparathyroidism and related disorders, and several malignant neoplasms where tumor cells are producing osteoclast- activating factors and cause hypercalcemia.
- osteoporosis bone formation as well as bone resorption are disturbed, resulting in loss of bone tissue, decreased bone mass, and bone fragility. Osteoporosis predominantly affects the elderly, but also other groups such as postmenopausal women, where an estrogen deficit is believed to be a significant etiological ctor,.and immobilized patients. At this point it is not possible to clear up the whole picture of the disease mechanism and estimate which is the primary cause of osteoporosis. However, about 25% of the osteoporotic females belong to what is called "rapid bone losers" and at least in those patients the bone resorption rate is probably increased.
- Landry and Fleisch showed in immobilization induced osteoporosis that bone resorption rate was accelerated, (Landry, M. and Fleisch, H. : The influence of immobilization on bone formation as evaluated the incorporation of tetracyclines. J. Bone Joint Surg. 4 ⁇ B:764, 1964) .
- osteoporosis comprise fractures, especially hip fractures, but also vertebral fractures and fractures of the proximal radius, and complication of such fractures.
- the present methods for the treatment of osteoporosis include exercise; administration of estrogen, especially for postmenopausal women; and consumption of calcium or calcium containing material such as milk.
- Calcitonin a hormone associated with calcium metabolism, has also been used in the treatment of osteoporosis.
- malignant tumors are known to be associated by hypercalcemia which is due to increased osteoclastic activity.
- Hypercalcemia is due to both systemic and local factors.
- Some malignant cells are known to secrete agents which stimulate bone resorption (Sato, K. ,
- Paget's disease (or osteitis deformans) of bone is a disease of unknown etiology where bone resorption and remodelling are increased leading sometimes even to the fractures of affected bone. Bone pain is the main indication of treatment in these patients. In these patients there is highly elevated local osteoclastic bone destruction. The incidence of osteitis deformans is very low in Scandinavian countries. In England it has been estimated to be present in 3-4% of the population on the basis of autopsy studies (Anderson's Textbook of Pathology 1986). It is very rare in patients under 40 years. Calcitonin and diphosphonates are also used in the treatment of Paget's disease.
- prodrug is intended to cover compounds which after administration to the patient, are converted to a compound of the formula I. More particularly, examples of prodrug of compounds the formula I are of the formula
- radical R is selected from
- R 3 is (a) H
- aryl optionally substituted with alkyl containing 1-4 carbon atoms, alkoxy containing 1-4 carbon atoms, halogen, CF3, alkanoyl containing 2-5 carbon atoms, or alkoxycarbonyl containing 2-5 carbon atoms.
- aryloxy optionally substituted with alkyl containing 1-4 carbon atoms, alkoxy containing 1-4 carbon atoms, halogen, CF , alkanoyl containing 2-5 carbon atoms, or alkoxycarbonyl containing 2-5 carbon atoms.
- R is (a) H
- the group alkyl in the definitions of R , R 3 and R is exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl. cyclopentylethyl, and cyclohexylmethyl. Lower alkyl groups containing 1-4 carbon atoms are especially preferred.
- the group alkoxy in the definitions of R" 6, is exemplified by ethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, i-butoxy, s- butoxy, t-butoxy, n-pentoxy, i-pentoxy, n-hexoxy, cyclopropoxy, cyclopentoxy, cyclohexoxy, cyclopropylmethoxy, cyclopentylmethoxy, cyclopentylmethoxy, cyclopentylethoxy, and cyclohexylmethoxy.
- Lower alkoxy groups are preferred, especially those containing 1-4 carbon atoms, preferably a lower alkoxy group having especially preferred 1-3 carbon atoms, e.g. methoxy, ethoxy, n- propoxy or isopropoxy.
- Halogen in the definitions of R is chloro, bromo, fluoro and iodo, preferably chloro, bromo, and fluoro.
- the group aryl when present m R has preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenyl group.
- R representing an aryloxy group has preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenoxy group.
- Alkanoyl m R contains from 2 to 6 carbon atoms and is preferably HCO, CH3CO, CH 3 CH 2 C0, CH 3 (CH 2 ) 2 CO, or HC (CH 3 ) 2 CO.
- Alkoxycarbonyl in R contains an alkoxy group as illustrated under "alkoxy" above. Accordingly, the invention relates to
- a pharmaceutical preparation for use in the prophylactic and therapeutic treatment of each of the ailments above comprising a, compound of the formula I as active ingredient, or a prodrug or a therapeutically acceptable salt thereof
- Sprague-Dawley male rats (Alab, Sweden) weighing 175-200 g before the tests were used. They obtained a standard diet consisting of rat feed pellets (Alab, Swiss, Sweden) and tap water. Ten rats were given omeprazole (Hassle, Sweden) , 400 ⁇ mol/kg body weight, once daily orally during 26 days. Twelve rats were used as untreated controls. •
- Serum was prepared at the blood tapping from each rat and gastrin was determined by radioimmunoanalysis (Stadil, F. & Rehfeld, J.F. (1973) Determination of gstrin in serum. An evaluation of the reliability of a radioimmunossay, Scan. J. Gastroent. 8, 101-112; H kanson, R. , Kroesen, J.H., Liedberg, G., Oscarson, J., Rehfeld, J.E. & Stadil, F. (1974) Correlation between serum gastrin concentration and rat stomach histidine decarboxylase activity, J. Physiol. 243, 483-498).
- Alumets et al Alumets et al (Alumets, J. , E ⁇ Munshid, H.A., Hakanson, R.,
- Gastrectomia was prepared by resection of the stomach followed by suturation of eosophagus and duodenum end to end. Operated animals were allowed to recover for one week before treatment with omeprazole, as has been described in "Pharmacological tests".
- Fig. 1 shows the concentration of gastrin expressed as picogram/ml serum with untreated control rats (average of 12 rats respectively average of 7 rats) and with omeprazole- treated rats (average of 10 rats) after treatment for 26 days.
- Fig. 2 shows the amount of radioactive calcium which has been incorporated into the skeleton (radius respectively sternum) expressed in cpm/mg bone ashes.
- A shows the average of 12 control rats
- B shows the average of 10 omeprazole-treated rats
- C shows the average of 12 control rats
- D shows the average of 10 omeprazole-treated rats.
- the continuous lines represent the average of given number of rats and the dashed lines represent the standard error of the average value.
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Abstract
A method for the treatment of osteoporosis, Paget's disease of bone, hyperparathyroidism, malignant neoplasms causing hypercalcinemia, parodontal diseases and implant-related bone loss comprising administration to a patient suffering therefrom an amount of a compound of formula (I), or a prodrug or a pharmaceutically acceptable salt thereof.
Description
Omeprazole for treatment of diseases related to bone loss.
Field of the Invention
The present invention is related to a novel method for the treatment of several bone affecting diseases, especially osteoporosis, which are characterized by loss of bone mass.
Background of the Invention
The balance in normal subjects between, on one hand, bone formation, which is associated with the number and activity of osteoblasts, that is cells associated with the production of bone in the organism, and on the other hand, bone loss which is associated with the number and activity of osteoclasts, that is cells associated with the absorption and removal of bone, is disturbed in several bone affecting diseases. At the present time there is no good treatment for any of these diseases, among which can be mentioned osteoporosis, Paget's disease of bone, hyperparathyroidism and related disorders, and several malignant neoplasms where tumor cells are producing osteoclast- activating factors and cause hypercalcemia.
Worldwide the most urgent need is for the treatment of osteoporosis and tumor associated hypercalcemia. In some areas, e.g. in England and in some other parts of Europe there is also high incidence of Paget's disease of bone.
In osteoporosis bone formation as well as bone resorption are disturbed, resulting in loss of bone tissue, decreased bone mass, and bone fragility. Osteoporosis predominantly affects the elderly, but also other groups such as postmenopausal
women, where an estrogen deficit is believed to be a significant etiological ctor,.and immobilized patients. At this point it is not possible to clear up the whole picture of the disease mechanism and estimate which is the primary cause of osteoporosis. However, about 25% of the osteoporotic females belong to what is called "rapid bone losers" and at least in those patients the bone resorption rate is probably increased. Landry and Fleisch showed in immobilization induced osteoporosis that bone resorption rate was accelerated, (Landry, M. and Fleisch, H. : The influence of immobilization on bone formation as evaluated the incorporation of tetracyclines. J. Bone Joint Surg. 4βB:764, 1964) .
The clinical manifestations of osteoporosis comprise fractures, especially hip fractures, but also vertebral fractures and fractures of the proximal radius, and complication of such fractures.
In Finland it has been estimated that about 10% of all surgical hospital beds are used for the treatment of osteoporosis related fractures (Lϋthje, P.: Reisiluunkaulan ja trokantterin murtumapotilaiden hoito ja ennuste seka hiodon kustannukset. Thesis. Helsinki 1983).
The present methods for the treatment of osteoporosis include exercise; administration of estrogen, especially for postmenopausal women; and consumption of calcium or calcium containing material such as milk. Calcitonin, a hormone associated with calcium metabolism, has also been used in the treatment of osteoporosis.
Several malignant tumors are known to be associated by hypercalcemia which is due to increased osteoclastic activity.
s s a common comp ca on or ns ance n e case o breast cancer and prostate cancer which are both one of the most common malignant tumors. Hypercalcemia is due to both systemic and local factors. Some malignant cells are known to secrete agents which stimulate bone resorption (Sato, K. ,
Fujii, Y., Kachivehi, T., Kasono, K., Shizume, K. : Production of interleukin 1 alpha (IL-lα)-like activity and colony stimulating activity by clonal squanous cell carcinomas derived from patients with hypercalcemia and leucocytosis. In: Calcium
Regulation and Bone Metabolism Vol. 9 (eds. D.V. Cohu, T.J.
Martin, P.J. Meunier) , 1986).
In malignant hypercalcemia calcϊtonin and diphosphonate treatment has been used.
Paget's disease (or osteitis deformans) of bone is a disease of unknown etiology where bone resorption and remodelling are increased leading sometimes even to the fractures of affected bone. Bone pain is the main indication of treatment in these patients. In these patients there is highly elevated local osteoclastic bone destruction. The incidence of osteitis deformans is very low in Scandinavian countries. In England it has been estimated to be present in 3-4% of the population on the basis of autopsy studies (Anderson's Textbook of Pathology 1986). It is very rare in patients under 40 years. Calcitonin and diphosphonates are also used in the treatment of Paget's disease.
Other disease states for the treatment of which antagonists to osteoclastic activity might be useful, are parodontal diseases and prostetic and implant bone losses.
It is an object of the present invention to provide compounds which by affecting the balance between osteoblast and osteoclast activity can be useful for prophylactic and therapeutic treatment of diseases as indicated above which are associated with bone loss. It is believed that the use of these compounds will also ultimately result in an increase of the bone mass.
Outline of the invention
According to the present invention it has been found that the compound omeprazole, 5-methoxy-2-[ (4-methoxy-3,5-dimethyl- 2-pyridinyl)methyl]-sulfinyl]-IH-benzimidazole, of the formula
H
or a prodrug or a therapeutically acceptable salt thereof, is useful in the prophylactic and therapeutic treatment of osteoporosis; Paget's disease of bone; hyperparathyroidism, both primary and secondary; malignant neoplasms where tumor cells are producing osteoclast-activity factors and cause hypercalcinemia; immobilization-induced osteoporosis; parodontal diseases; and prostetic and implant-related bone losses. Examples of pharmaceutically acceptable salts are alkali salts such as sodium and potassium salts, and calci -r- and magnesium salts.
The term "prodrug" is intended to cover compounds which after administration to the patient, are converted to a compound of the formula I. More particularly, examples of prodrug of compounds the formula I are of the formula
where the radical R is selected from
R3 is (a) H
(b) alkyl containing 1-4 carbon atoms
is (a) alkyl containing 1-6 carbon atoms
(b) cycloalkyl containing 3-7 carbon atoms
(c) alkoxy containing 1-6 carbon atoms
(d) aryl
(e) aryl, optionally substituted with alkyl containing 1-4 carbon atoms, alkoxy containing 1-4 carbon atoms, halogen, CF3, alkanoyl containing 2-5 carbon atoms, or alkoxycarbonyl containing 2-5 carbon atoms.
(f) aryloxy, optionally substituted with alkyl containing 1-4 carbon atoms, alkoxy containing 1-4 carbon atoms, halogen, CF , alkanoyl containing 2-5 carbon atoms, or alkoxycarbonyl containing 2-5 carbon atoms.
(g) arylalkoxy containing 1-6 carbon atoms in the alkoxy part, wherein the aryl part optionally is substituted with alkyl containing 1-6 carbon atoms and/or alkoxy containing 1-6 carbon atoms
and
(B) O
H t -OP-OR-
OH wherein
R is (a) H
(b) alkyl containing 1-6 carbon atoms
Illustrative examples of the various radicals in the formula II are as follows. These illustrative examples will be applicable to the different radicals depending on the number of carbon atoms prescribed for each radical.
The group alkyl in the definitions of R , R3 and R is exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl.
cyclopentylethyl, and cyclohexylmethyl. Lower alkyl groups containing 1-4 carbon atoms are especially preferred.
2
The group alkoxy in the definitions of R"6, is exemplified by ethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, i-butoxy, s- butoxy, t-butoxy, n-pentoxy, i-pentoxy, n-hexoxy, cyclopropoxy, cyclopentoxy, cyclohexoxy, cyclopropylmethoxy, cyclopentylmethoxy, cyclopentylethoxy, and cyclohexylmethoxy. Lower alkoxy groups are preferred, especially those containing 1-4 carbon atoms, preferably a lower alkoxy group having especially preferred 1-3 carbon atoms, e.g. methoxy, ethoxy, n- propoxy or isopropoxy.
Halogen in the definitions of R , is chloro, bromo, fluoro and iodo, preferably chloro, bromo, and fluoro.
The group aryl when present m R has preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenyl group.
R , representing an aryloxy group has preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenoxy group.
Alkanoyl m R contains from 2 to 6 carbon atoms and is preferably HCO, CH3CO, CH3CH2C0, CH3(CH2)2CO, or HC (CH3) 2CO.
2
Alkoxycarbonyl in R contains an alkoxy group as illustrated under "alkoxy" above.
Accordingly, the invention relates to
- a method for the prophylactic and therapeutic treatment of each of the ailments above by administering to a host in need thereof of a therapeutically effective amount of a compound of the formula I, or a prodrug or a therapeutically acceptable salt thereof
a pharmaceutical preparation for use in the prophylactic and therapeutic treatment of each of the ailments above comprising a, compound of the formula I as active ingredient, or a prodrug or a therapeutically acceptable salt thereof
a compound of the formula I or a prodrug or a therapeutically acceptable salt thereof for use in the manufacture of a medicament for the prophylactic and therape treatment of each of the ailments above.
a method for improving the healing rate of bone fractures by administering to a host in need thereof of an effective amount of a compound of the formula I.
Pharmacological tests
Sprague-Dawley male rats (Alab, Stockholm, Sweden) weighing 175-200 g before the tests were used. They obtained a standard diet consisting of rat feed pellets (Alab, Stockholm, Sweden) and tap water.
Ten rats were given omeprazole (Hassle, Sweden) , 400 μmol/kg body weight, once daily orally during 26 days. Twelve rats were used as untreated controls. •
45Ca incorporation into the skeleton
2x106 cpm 45CaCl2 (Radiochemical Center, Amersham, England) were administered orally by ventricular sond. The rats were killed by tapping blood via abdominal aorta 4 hours after the peroral administration of Ca. Radius, sternum, tibia and femur were removed by dissection. Radius and sternum were cleaned, weighed and placed in an oven at 800°C during 24 hours. The ashes were weighed and dissolved in 1M HC1. 10 ml Picofluor-40 (Packard) was added, whereafter the tubes were closed and shaken vigourosly before counting in a Beckman B- counter.
Radioimmunoanalysis of crastrin
Serum was prepared at the blood tapping from each rat and gastrin was determined by radioimmunoanalysis (Stadil, F. & Rehfeld, J.F. (1973) Determination of gstrin in serum. An evaluation of the reliability of a radioimmunossay, Scan. J. Gastroent. 8, 101-112; H kanson, R. , Kroesen, J.H., Liedberg, G., Oscarson, J., Rehfeld, J.E. & Stadil, F. (1974) Correlation between serum gastrin concentration and rat stomach histidine decarboxylase activity, J. Physiol. 243, 483-498).
Operations were performed under ether anaesthesia. Fundectomia,
comprising resection of the acid producing part of the ventricle, was performed as has been described in detail by
Alumets et al (Alumets, J. , EΪ Munshid, H.A., Hakanson, R.,
Hedenbro, J. , Liedberg, G. , Oscarson, J., Rehfeld, J.F.,
Sundler, F. and Vallgren, S., Gastrin cell proliferation after chronic stimulation. Effects of vagal denervation or gastric surgery in the rat. J. Physiol. 298, 557-569 (1980)).
Gastrectomia was prepared by resection of the stomach followed by suturation of eosophagus and duodenum end to end. Operated animals were allowed to recover for one week before treatment with omeprazole, as has been described in "Pharmacological tests".
The test results are given in Fig. 1 and Fig. 2.
Description of the drawing's
Fig. 1 shows the concentration of gastrin expressed as picogram/ml serum with untreated control rats (average of 12 rats respectively average of 7 rats) and with omeprazole- treated rats (average of 10 rats) after treatment for 26 days. Fig. 2 shows the amount of radioactive calcium which has been incorporated into the skeleton (radius respectively sternum) expressed in cpm/mg bone ashes. A shows the average of 12 control rats, B shows the average of 10 omeprazole-treated rats, C shows the average of 12 control rats, D shows the average of 10 omeprazole-treated rats.
The continuous lines represent the average of given number of rats and the dashed lines represent the standard error of the average value. The stars designate the significance (i.e. the difference between control and test substance according to Student's t-test p < 0.05 = x; p < 0.01 = xx and p < 0.005 =
XX ) .
Results
Omeprazole-treated rats and fundectomized rats developed pronounced and constant hypergastrinemia, which is seen in the attached Fig. 1. The hypergastrinemia which had been developed by treatment with omeprazole-stimulated Ca-incorporation into the skeleton, which is seen in the attached Fig. 2. Hypergastrinemia caused by fundectomia did not stimulate ^Ca- incorporation into the skeleton. Neither did omeprazole- treatment in gastrectomized rats stimulate
into the skeleton.
The tests given above showed clearly that treatment with omeprazole led to increased incorporation of calcium into the skeleton. This may be due to hypergastrinemia which in turn via some factor in the acid-producing part of the stomach seems to control the incorporation of calcium into skeleton.
Claims
A method for the treatment of osteoporosis by admini¬ stering to a host in need of such treatment of a thera¬ peutically effective amount of a compound of the formula I below (Omeprazole), or a prodrug or"a therapeutically acceptable salt thereof, optionally together with a pharmaceutically acceptable carrier:
2. A method for the treatment of Paget's disease of bone by administering to a host in need of such treatment of a therapeutically effective amount of a compound of the formula I as defined in claim 1, optionally together with a pharmaceutically acceptable carrier.
3. A method for the treatment of primary and secondary hyperparathyroidism by administering to a host in need of such treatment of a therapeutically effective amount of a compound of the formula I as defined in claim 1, optionally together with a pharmaceutically acceptable carrie .
4. A method for the treatment of such malignant neoplasms where tumor cells are' roducing osteoclast-activating factors, by administering to a host in need of such treatment of a therapeutically effective amount of a compound of the formula I as defined in claim 1, optionally together with a pharmaceutically acceptable carrier.
5. A method for the treatment of parodontal diseases, by administering to a host in need of such treatment of a therapeutically effective amount of a compound of the formula I as defined in claim 1, optionally together with a pharmaceutically acceptable carrier.
6. A method for the treatment of prostetic and implant- related bone loss, by administering to a host in need of such treatment of a therapeutically effective amount of a compound of the formula I as defined in claim 1, optionally together with a pharmaceutically acceptable carrier.
7. A compound-of the formula I as defined in claim 1 for use in the manufacture of a medicament for the treatment of osteoporosis.
8. A compound of the formula I as defined in claim 1 for use in the manufacture of a medicament for the treatment of Paget's disease of bone.
9. A compound of the formula I as defined in claim 1 for use in the manufacture of a medicament for the treatment Of primary and secondary hyperparathyroidism.
10. A compound of the formula I as defined in claim 1 for use in the manufacture of a medicament for the treatment of such malignant neoplasms where tumor cells are producing osteoclast activating factors.
11. A compound of the formula I as defined in claim 1 for use in the manufacture of a medicament for the treatment of parodontal diseases.
12. A compound of the formula I as defined in claim 1 for use in the manufacture of a medicament for the treatment of prostetic and implant-related bone loss.
13. A pharmaceutical preparation for use in the treatment of osteoporosis; Paget's disease of bone; primary and secondary hyperparathyroidism; such malignant neoplasms
• where tumor cells are producing osteoclast-activating factors; such parodontal diseases which are associated with bone loss; or prostetic and implant-related bone loss; and comprising a compound of the formula I as defined in claim 1 as active ingredient.
14. A method for improving the healing rate of bone fractures by administering to a host in need thereof an effective amount of a compound of the formula I as defined in claim 1.
15. A compound as defined in claim 1 for use in the manufacture of a medicament for improving the healing rate of bone fractures.
16. A pharmceutical preparation for use in improving the healing rate of bone fractures, comprising a compound of the formula I as defined in claim 1 as active ingredient.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8704247-9 | 1987-10-30 | ||
| SE8704247A SE8704247D0 (en) | 1987-10-30 | 1987-10-30 | METHOD OF TREATMENT |
| SE8704436A SE8704436D0 (en) | 1987-11-13 | 1987-11-13 | USE OF ANTI-SECRETARY SUBSTANCES FOR NEW INDICATIONS |
| SE8704436-8 | 1987-11-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1989003829A1 true WO1989003829A1 (en) | 1989-05-05 |
Family
ID=26660006
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE1988/000575 Ceased WO1989003830A1 (en) | 1987-10-30 | 1988-10-27 | 2-pyridinylmethyl (sulfinyl or thio)benzimidazoles for treatment of diseases related to bone loss |
| PCT/SE1988/000573 Ceased WO1989003829A1 (en) | 1987-10-30 | 1988-10-27 | Omeprazole for treatment of diseases related to bone loss |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE1988/000575 Ceased WO1989003830A1 (en) | 1987-10-30 | 1988-10-27 | 2-pyridinylmethyl (sulfinyl or thio)benzimidazoles for treatment of diseases related to bone loss |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0338066A1 (en) |
| JP (1) | JPH02501930A (en) |
| KR (1) | KR890701580A (en) |
| AU (1) | AU2621888A (en) |
| DK (1) | DK322289D0 (en) |
| HU (1) | HU886738D0 (en) |
| IL (2) | IL88207A (en) |
| MY (1) | MY103790A (en) |
| WO (2) | WO1989003830A1 (en) |
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|---|---|---|---|---|
| US5081253A (en) * | 1989-12-21 | 1992-01-14 | American Home Products Corporation | Imidazo(4,5-c)pyridines as antiosteoporotic agents |
| US6316020B1 (en) * | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
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| WO2005077365A3 (en) * | 2004-02-12 | 2005-12-01 | Inst Superiore Di Sanita | Novel uses for proton pump inhibitors |
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| CN103826632A (en) * | 2011-08-26 | 2014-05-28 | 国立大学法人名古屋大学 | Osteogenesis promoter and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8804628D0 (en) * | 1988-12-22 | 1988-12-22 | Ab Haessle | NEW COMPOUNDS |
| JP2694361B2 (en) * | 1989-02-09 | 1997-12-24 | アストラ アクチエボラグ | Antibacterial agent |
| SE9002206D0 (en) * | 1990-06-20 | 1990-06-20 | Haessle Ab | NEW COMPOUNDS |
| WO1991019712A1 (en) * | 1990-06-20 | 1991-12-26 | Aktiebolaget Astra | Dialkoxy-pyridinyl-benzimidazole derivatives, process for their preparation and their pharmaceutical use |
| JPH10501253A (en) * | 1994-06-10 | 1998-02-03 | ビイク グルデン ロンベルク ヒェーミッシェ ファブリーク ゲゼルシャフト ミット ベシュレンクテル ハフツング | Helicobacter-thiophyllidine for eradication of bacteria |
| HUP9904567A3 (en) | 1996-06-20 | 2001-10-29 | Univ Texas | Use of azo, thioalkyl, thiocarbonyl derivatives substituted by fused heterocycles and/or phenyl group for the preparation of pharmaceutical compositions stimulating bone growth |
| KR100453916B1 (en) * | 2002-03-11 | 2004-10-20 | 주식회사 코오롱 | Tetrahydropyridinylbenzimidazole derivatives and method for preparing the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE416649B (en) * | 1974-05-16 | 1981-01-26 | Haessle Ab | PROCEDURE FOR THE PREPARATION OF SUBSTANCES WHICH PREVENT Gastric acid secretion |
| US4472409A (en) * | 1981-11-05 | 1984-09-18 | Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung | 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects |
| SE8500996D0 (en) * | 1985-03-01 | 1985-03-01 | Haessle Ab | METHOD OF TREATMENT |
-
1988
- 1988-10-27 WO PCT/SE1988/000575 patent/WO1989003830A1/en not_active Ceased
- 1988-10-27 KR KR1019890701208A patent/KR890701580A/en not_active Withdrawn
- 1988-10-27 JP JP63508989A patent/JPH02501930A/en active Pending
- 1988-10-27 EP EP88909854A patent/EP0338066A1/en not_active Ceased
- 1988-10-27 AU AU26218/88A patent/AU2621888A/en not_active Abandoned
- 1988-10-27 MY MYPI88001227A patent/MY103790A/en unknown
- 1988-10-27 WO PCT/SE1988/000573 patent/WO1989003829A1/en not_active Ceased
- 1988-10-27 HU HU886738A patent/HU886738D0/en unknown
- 1988-10-28 IL IL88207A patent/IL88207A/en unknown
- 1988-10-28 IL IL88206A patent/IL88206A0/en unknown
-
1989
- 1989-06-28 DK DK322289A patent/DK322289D0/en not_active Application Discontinuation
Non-Patent Citations (2)
| Title |
|---|
| CALCIFIED TISSUE INTERNATIONAL, Vol. 38, 1986, J. TUUKKANEN & H.K.VAEAENAENEN, "Omeprazole, a specific inhibitor of H+-K+-ATPase, inhibits bone resorption in vitro", pages 123-125. * |
| S. YOUSUF ALI, "Cell mediated calcification and matrix vesicles", PROCEEDINGS OF THE IV INTERNATIONAL CONFERENCE ON MATRIX VESICLES, Cambridge, 1-5 July 1985, publ. 1986, by Excerpta Medica (Amsterdam), pages 143-146. * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5081253A (en) * | 1989-12-21 | 1992-01-14 | American Home Products Corporation | Imidazo(4,5-c)pyridines as antiosteoporotic agents |
| US6316020B1 (en) * | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
| DE10040052A1 (en) * | 2000-08-11 | 2002-03-07 | Univ Eberhard Karls | Use of proton pump inhibitors for the treatment of inflammation, in particular diseases of the musculoskeletal system |
| WO2005077365A3 (en) * | 2004-02-12 | 2005-12-01 | Inst Superiore Di Sanita | Novel uses for proton pump inhibitors |
| JP2007522182A (en) * | 2004-02-12 | 2007-08-09 | イスティチュート スペリオーレ ディ サニータ | New use of proton pump inhibitors |
| KR100638649B1 (en) | 2006-06-27 | 2006-10-31 | 신한전기공업주식회사 | Dry transformer with reinforced insulation coil |
| CN103826632A (en) * | 2011-08-26 | 2014-05-28 | 国立大学法人名古屋大学 | Osteogenesis promoter and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2621888A (en) | 1989-05-23 |
| IL88206A0 (en) | 1989-06-30 |
| HU886738D0 (en) | 1990-02-28 |
| DK322289A (en) | 1989-06-28 |
| EP0338066A1 (en) | 1989-10-25 |
| DK322289D0 (en) | 1989-06-28 |
| IL88207A (en) | 1993-03-15 |
| IL88207A0 (en) | 1989-06-30 |
| JPH02501930A (en) | 1990-06-28 |
| KR890701580A (en) | 1989-12-21 |
| WO1989003830A1 (en) | 1989-05-05 |
| MY103790A (en) | 1993-09-30 |
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