Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
  • A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• Imidazo(1,2-a)(pyridazines or pyrazines) for treatment of diseases related to bone loss.
• 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.
• bone formation 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 decreased bone mass. Osteoporosis predominantly affects the elderly, but also other groups such as postmenopausal women, where an estrogen deficit is believed to be a significant etiological factor, 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 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. 46B:764, 1964).
• 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 (Luthje, 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. None of these methods of treating osteoporosis results in increase of the bone mass.
• malignant tumors are known to be associated by hypercalcemia which is due to increased osteoclastic activity. This is a common complication for instance in the case of 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-1 ⁇ )-like activity and colony stimulating activity by clonal squanous cell carcinomas derived from patients with hypercalcemia and leucocytosis.
• IL-1 ⁇ interleukin 1 alpha
• Pacret'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 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.
• Arylalkoxy-, arylalkylamino- and arylalkylthio-substituted imidazo (1,2-a)pyridines and imidazo (1,2-a)pyrazines are known in the art, e.g. EP-Al-0068378 and EP-A1-0033094, as are methods for using these compound to reduce gastric acid secretion.
• compounds of the general formula I as well as pharmaceutically acceptable salts thereof are effective as inhibitors of basal and stimulated bone resorption and are useful as medicals for the treatment of diseases related to bone loss and increased bone resorption, such as osteoporosis, Pagefs disease of bone, hyperparathyroidism, both primary and secondary, malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcemia, immobilization-induced osteoporosis, parodontal diseases and prostetic and implant- related bone losses.
• diseases related to bone loss and increased bone resorption such as osteoporosis, Pagefs disease of bone, hyperparathyroidism, both primary and secondary, malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcemia, immobilization-induced osteoporosis, parodontal diseases and prostetic and implant- related bone losses.
• the compounds to be used according to th e i nventi on are of the fol lowing formul a I :
• A is a nonaromatic 5- or 6-membered ring containing O or 1 heteroatom selected from nitrogen, sulfur and oxygen;
• R x , B y , R z and R u are H, R 9 or R 10 ;
• R 9 represents H, loweralkyl, halogen, OH, CF 3 or loweralkoxy
• R 10 is -Z-T-Ar wherein Z represents -O-, -NH-, -SO m - or a single bond; T represents a straight- or branched chain loweralkylene group; when Z is a single bond, T also represents an ethenylene or a propenylene group wherein the unsaturated carbon is at the single bond; when Z is -O-, T also represent an allylene group wherein the saturated carbon is at the oxygen;
• n zero, one or two
• n zero, one or two
• R 4 and R 5 each independently represents H, loweralkyl, loweralkoxyloweralkyl, trifluoromethylloweralkyl, Ar-loweralkyl, Ar, or, when taken together with the nitrogen to which they are attached, form a 4-, 5- or 6-membered cyclic amino group;
• R 1 represents Ar, loweralkyl, NR 4 R 5 , B-NR 4 R 5 or Ar-loweralkyl;
• R 6 represents H, C 1 - to C 12 -alkyl, Ar or Ar-loweralkyl
• R 7 represents H or loweralkyl
• R 8 represents H, loweralkyl, loweralkoxyloweralkyl, trifluoromethylloweralkyl, Ar-loweralkyl or Ar;
• salts thereof especially acid addition salts such as hydrochloride and hydrobromide salts,
• R x is R 9 and R Y is H when G is the group
• halogen includes fluoro, chloro, bromo and iodo, with fluoro and chloro being preferred;
• lower when applied to alkyl groups, means straight and branched chain alkyl groups having up to six carbon atoms such as methyl, ethyl, propyl, butyl, t-butyl, isopropyl, neopentyl, dimethylbutyl etc., whereby methyl and ethyl are preferred;
• pyridyl includes the 2-, 3- and 4-isomers and their halogen- or loweralkyl-substituted analogues;
• thienyl and “furanyl” include the 2- and 3-isomers and their halogen- and loweralkylsubstituted analogues;
• imidazolyl included the 2- and 4-isomers and their halogen- and loweralkyl-substituted analogues
• the loweralkylene group represented by T preferably has 1-6, especially 1-3 carbon atoms as in methylene, ethylene and propylene,
• Suitable “loweralkenyl” may be the ones having 2 to 6 carbon atoms and may include vinyl, allyl, isopropenyl, 1 (or 2 or 3)-butenyl or 1 (or 2 or 3 or 4)-pentenyl.
• Suitable “loweralkadienyl” may be the ones having 3 to 6 carbon atoms and may include 1,2-propadienyl, 1,2-butadienyl, 1,3-butadienyl, 2,3-pentadienyl or 1,4-pentadienyl.
• loweralkenyloxy(lower)alkyl suitable examples may include vinyloxymethyl, allyloxymethyl and 1-allyloxyethyl.
• loweralkynyloxy(lower)alkyl suitable examples may include ethynyloxymethyl, 2-propynyloxymethyl, 2-(2-propynyloxy)ethyl and 1-(2-butynyloxy)propyl.
• the invention relates to
• a preferred group of compounds within the general formula I for use according to the present invention is that wherein G is the group
• Example 1 The compound 8-benzyloxy-3-cyanomethyl-2-methyl-imidazo- (1,2-a)pyridine (Example 1), 8-benzyloxy-3-hydroxylmethyl- 2-methyl-imidazo(1,2-a)pyridine (Example 2) and Example 3 (mentioned above) were tested. As can be seen from Table 1 the compound was found to significantly inhibit both basal bone resorption and PTH-induced bone resportion.
• the compounds of the formula I are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
• the pharmaceutical formulation contains a compound of the formula I in combination with a pharmaceutically acceptable carrier.
• the carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule.
• These pharmaceutical preparations are a further object of the invention.
• the amount of active compounds is between 0.1-95 % by weight of the preparation, between 0.2-20 % by weight in preparations for parenteral use and between 1 and 50 % by weight in preparations for oral administration.
• the typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 mg per day of active substance.

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1987
  • 1987-10-30 SE SE8704248A patent/SE8704248D0/xx unknown
• 1988
  • 1988-10-27 AU AU26203/88A patent/AU2620388A/en not_active Abandoned
  • 1988-10-27 KR KR1019890701209A patent/KR890701587A/ko not_active Application Discontinuation
  • 1988-10-27 EP EP88909620A patent/EP0339071A1/en not_active Withdrawn
  • 1988-10-27 HU HU886708A patent/HU203663B/hu not_active IP Right Cessation
  • 1988-10-27 JP JP63508894A patent/JPH02501929A/ja active Pending
  • 1988-10-27 WO PCT/SE1988/000576 patent/WO1989003833A1/en not_active Application Discontinuation
  • 1988-10-28 IL IL88205A patent/IL88205A0/xx unknown
• 1989
  • 1989-06-28 DK DK322189A patent/DK322189A/da not_active Application Discontinuation

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