Classifications

• • 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
• • 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
• • 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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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1988
  • 1988-10-27 WO PCT/SE1988/000575 patent/WO1989003830A1/en not_active Application Discontinuation
  • 1988-10-27 JP JP63508989A patent/JPH02501930A/ja active Pending
  • 1988-10-27 HU HU886738A patent/HU886738D0/hu unknown
  • 1988-10-27 WO PCT/SE1988/000573 patent/WO1989003829A1/en unknown
  • 1988-10-27 EP EP88909854A patent/EP0338066A1/de not_active Ceased
  • 1988-10-27 KR KR1019890701208A patent/KR890701580A/ko not_active Application Discontinuation
  • 1988-10-27 AU AU26218/88A patent/AU2621888A/en not_active Abandoned
  • 1988-10-27 MY MYPI88001227A patent/MY103790A/en unknown
  • 1988-10-28 IL IL88207A patent/IL88207A/xx unknown
  • 1988-10-28 IL IL88206A patent/IL88206A0/xx unknown
• 1989
  • 1989-06-28 DK DK322289A patent/DK322289A/da not_active Application Discontinuation

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