IMIDAZO(1,2-a)(PYRIDAZINES OR PYRAZINES) FOR TREATMENT OF DISEASES RELATED TO BONE LOSS

Abstract: A method for the treatment of diseases related to loss of bone mass such as 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 pharmaceutically acceptable salt thereof.

Description: Imidazo(l,2-a)(pyridazines or pyrazines) 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 the 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 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) . 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 (Luthje, P.: Reisiluunkaulan ja tro antterin murtu apotilaiden hoito ja ennuste seka hiodon kustannukse . Thesis. Helsinki 1983) . The present methods for the treatment of osteoporosis include exercise; administration of estrogen, especially for postmeno- pausal 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. Several malignant tumors are known to be associated by hyper¬ calcemia 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., Shizu e, K. : Production of inter- leukin 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 calcitonin and diphcsphonate treat¬ ment has been used. 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. Other disease states for the treatment of which antagonists to osteoclastic activity might be useful, are parodontal diseases and prostetiσ 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 the 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. Prior art 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. Outline of the present invention According to the present invention it has been found that 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. The compounds to be used according to th e i nventi on are of the fol lowing formul a I : wherein G is whereby the carbon atom of the group N = C is connected R Z to the 2-position of the imidazo-moiety, thus forming an imidazo(l,2-a)pyrazine nucleus, A is a nonaromatic 5- or 6-membered ring containing O or 1 heteroatom selected from nitrogen, sulfur and oxygen; R 2 represents H, lower alkyl, CF3, B-CF3, B-Ar, Ar, B-halogen, BOR 8 , B-SO m -loweralkyl, BOC(=0)R 1 , B-NR 4 R 5 , COOR 6 , C(=0)-NR R 5 , B-CN or NR R 5 ; represents H, loweralkyl, loweralkenyl, loweralkynyl, loweralkadienyl, loweralkenyloxy (lower) alkyl, lower- alkynyloxy (lower) alkyl, carbox (lower) alkynylox (lower) - alkyl, protected carboxy (lower) alkynylox (lower) alkyl, BCN, BOR 8 , BOC(=0)-R 1 , B-NR R 5 , B-C (=S) -NR 4 R 5 , B- ' C (=0) NR 4 R 5 , B-N0 2 , B-halogen, B-NC, NO or NR 4 R 5 ; R x , X, R Z and R u are H, R 9 or R 10 ; R represents H, loweralkyl, halogen, OH, C 3 or loweralkoxy; R ° is -Z-T-Ar wherein Z represents -0-, -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 -0-, T also represent an allylene group wherein the saturated carbon is at the oxygen; Ar represent phenyl, pyridyl, thienyl, furanyl, imidazolyl or X'-, y- and/or Z' -substituted phenyl wherein each of X', y and Z r independently is hydrogen, halogen, loweralkyl, loweralkoxy, CN, CF3, OH, N0 2 , -NR 4 R 5 , -COOR 6 , -C(=0)NR 4 R 5 , -NR 7 C(=0)R 1 , -NR 7 SO m R 1 or -SO^ 1 ; B is a straight or branched chain loweralkylene group; n represents zero, one or two; m represents zero, one or two; R and R each, independently represents H, loweralkyl, lower¬ alkoxyloweralkyl, 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 grou ; R 1 represents Ar, loweralkyl, NR 4 R , B-NR 4 R 5 or Ar-loweralkyl; R 6 represents H, C-^- to C 1 _2~ a l k y 1 r Ar or Ar-loweralkyl; • 7 R represents H or loweralkyl; and R represents H, loweralkyl, loweralkoxyloweralkyl, trifluoro¬ methylloweralkyl, Ar-loweralkyl or Ar; as well as pharmaceutically acceptable salts thereof, especially acid addition salts such as hydrochloride and hydrobromide salts, provided that (a) one, and only one, of the groups R x , R^, R z and R u is R (b) not more than one of the groups R x , R^, R z and R u is R^ (c) R x is R and R^ is H when G is the group Ar As used herein, the term "halogen" includes fluoro, chloro, bromo and iodo, with fluoro and chloro being preferred; the term "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; the term "pyridyl" includes the 2-, 3- and 4-isomers and their halogen- or loweralkyl-substituted analogues; the terms "thienyl" and "furanyl" include the 2- and 3-isomers and their halogen- and loweralkylsubstituted analogues; the term "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. In the term "loweralkenyloxy(lower) alkyl", suitable examples may include vinyloxymethyl, 'allyloxymethyl and 1-allyloxyethyl. In the term "loweralkyn lox (lower)alkyl", suitable examples may include ethynyloxymethyl, 2-propynyloxymethyl, 2- (2-propynyloxy)ethyl and 1- (2-but nyloxy)propyl. 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 an effective amount of a compound of the formula I 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 a compound of the formula I for use in the manufacture of a medicament for the prophylactic and therapeutic 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 The illustrative examples given above for the various radicals in the formula I will be applicable to the different radicals depending on the number of carbon atoms prescribed for each radical. The following compounds are typical representatives of the preferred compounds of this invention: 2-Methyl-8- (2,4, 6-trimethylbenzyloxy) imidazo (1,2-a)pyridine; 8- (3, 4-Dichlorobenzyloxy) -2-methyl-imidazo (1,2-a)pyridine; 8- (2-Fluorobenzyloxy)-2-methyl-imidazo (1,2-a)pyridine; 8- (4-Fluorobenzyloxy) -2-methyl-imidazo (1,2-a)pyridine; 2-Methyl-8- (2-phenylethyl) -imidazo (1,2-a)pyridine; 8- (4-Chlorobenzyloxy) -2-methyl-imidazo (1,2-a)pyridine; 8-Benzylsulfinyl-3-cyanomethyl-2-methyl-imidazo(1,2-a)pyridine; 3-Cyanomethyl-2-methyl-8- (2-thienyl-methoxy)-imidazo (1,2-a) pyridine; 3-Cyanomethyl-2-methyl-8- (2-pyridyl-methoxy) -imidazo(1,2-a) pyridine; 3-Cyanomethyl-2-methyl-8- (4-trifluoromethylbenzyloxy) -imidazo (1,2-a)pyridine; 3-Cyanomethyl-8- (3, 4-dichlorobenzyloxy) -2-methyl-imidazo (1, 2-a) pyridine; 3-Cyanomethyl-8- (4-methoxybenzyloxy) -2-methyl-imidazo (1, 2-a) pyridine; 8- (4-t-butylbenzyloxy) -3-cyanomethyl-2-methyl-imidazo (1 , 2-a) pyridine; 8-Benzylthio-3-cyanomethyl-2-methyl-imidazo (1, 2-a) pyridine; 3-Cyanomethyl-2-methyl-8- (3-trifluoromethylbenzyloxy) imidazo (1, 2-a) pyridine; 8- (4-chlorobenzyloxy) -3-cyanomethyl-2-methyl-imidazo (1,2-a)pyridine; 8-Benzyloxy-2-methyl-imidazo(1,2-a)pyridine-3-methylpivaloate; 8- (3, 4-Dichlorobenzyloxy) -3-hydroxymethyl-2-me hyl-imidazo (1, 2-a)pyridine; 8-Benzyloxy-2-methyl-imidazo (1, 2 -a) pyridine- 3- (2-butanonitrile 8- (4-Chlorobenzyloxy) -3-hydroxymethyl-2-methyl-imidazo (1, 2-a) pyridine; 8-Benzyloxy -2-ethyl-imidazo (1,2-a)pyridine; 8-Benzyloxy-3-cyanomethyl-2-methylsulfinylmethyl-imidazo (1, 2-a)pyridine; 8-Benzyloxy-3-cyanomethyl-2-methylthiomethyl-imidazo (1,2-a)pyridine; 8-Benzyloxy-3-cyanomethyl-imidazo (1,2-a)pyridine-2-methyl-N,N- dimethylglycinate; 8- (4-Cyanobenzyloxy) -3-cyanomethyl-2-methyl-imidazo (1,2-a) pyridine; 8-Benzyloxy-2-cyanomethyl-imidazo (1,2-a)pyridine; 8-Benzyloxy-3-cyanomethyl-imidazo (1,2-a)pyridine; 8-Benzyloxy-2-methyl-imidazo (1,2-a)pyridine-3-methylacetate; 8-Benzyloxy-3-cyanomethyl-2-hydroxymethyl-imidazo (1,2-a) pyridine; 3-Hydroxymethyl-2-methyl-8- (2-phenylethoxy) -imidazo (1,2-a) pyridine; 8-Benzyloxy-2, 3-dimethyl- imidazo (1, 2-a) pyridine; 3-Cyanomethyl-2-methyl-8- (2-phenylethoxy) -imidazo (1, 2-a) pyridine; 3-Cyanomethyl-2-methyl-8- (1-phenylethoxy) -imidazo (1, 2-a) pyridine; 3-Cyanomethyl-2-methyl-8- (2-phenylethyl) -imidazo (1,2-a) pyridine; 8-Benzyloxy-2-methyl-imidazo (1, 2-a) pyridine-3-thioacetamide; 3-Hydroxymethyl-2-methyl-8- (2-phenylethyl) -imidazo (1, 2-a) pyridine; 3-Cyanoπιethyl-2-methyl- 8- (3-phenylpropoxy) -imidazo (1 , 2-a) . pyridine; 8-Benzyloxy-3-cyanomethyl-2-isopropyl-imidazo(1,2-a)pyridine; 8-Benzyloxy-3-cyanomethyl-2-ethyl-imidazo (1,2-a)pyridine; 8-Benzylamino-2,3-dimethyl-imidazo (1,2-a)pyridine; 8-Benzyloxy-3-cyanomethyl-2-methyl-imidazo (1,2-a)pyridine; 8-Benzyloxy-3-hydroxymethyl-2-methyl-imidazo (1,2-a)pyridine; 3-Hydroxymethyl-8- (2-fluorobenzyloxy) -2-methyl-imidazo (1,2-a)pyridine; 8- ( 4-t-Butylbenzyloxy) -3-hydroxymethyl-2-methyl-imidazo (1 , 2-a) pyridine; 3-Cyanomethyl-8- (2-fluorobenzyloxy-2-methyl-imidazo(1,2-a) pyridine; 3-Cyanomethyl-8- (4-fluorobenzyloxy-2-methyl-imidazo(1,2-a) pyridine; 3-Cyanomethyl-2-methyl-8- (2,4, 6-trimethylbenzyloxy)-imidazo (1,2-a)pyridine; 8-Benzylamin-3-cyanomethyl-2-methyl-imidazo (1,2-a)pyridine; 3-Cyanomethyl-2-methyl-8- (3-thienyl-metoxy) -imidazo (1,2-a) pyridine; 2,3-Dimethyl-8-[1-Ξ- (3-phenylpropenyl) ]-imidazo (1,2-a) pyridine; 2,3-Dimethyl-8-[ (2-phenyl)-ethenyl]imidazo(1,2-a)pyridine; 3-Cyanomethyl-2-methyl-8-[E- (2-phenyl-l-ethenyl) ]imidazo (1,2-a)pyridine; 3-Cyanomethyl-2-methyl-8-[E-1- (3-phenyl-propen-l-yl) ]imidazo (1,2-a)pyridine; 3-Cyanomethyl-2-methyl-6- (2-phenylethyl)imidazo (1,2-a) pyridine; 3-Amino-8-benzyloxy-2-ethyl-imidazo(1,2-a)pyridine; 3-Amino-8-benzyloxy-2,7-dimethyl-imidazo(1,2-a) yridine; 3-Amino-2-methyl-8- (2-phenylethyl) -imidazo (l r 2-a)pyridine; 3-Amino-2-meth l-8- (3-thienylmethoxy) -imidazo (1,2-a) pyridine; 3-Dimethylamino-2-methyl-8-phenylmethoxy-imidazo (1,2-a) pyridine; 3-Amino-8-benzyloxy-2, 6-dimethyl-imidazo(1,2-a)pyridine; 8-Benzyloxy-3-ethylamino-2-methyl-imidazo (1,2-a)pyridine; 3-Amino-2-methyl-8-[ (3-thienylmethyl) -a ino] -imidazo (1,2-a)pyridine; 3-Amino-2-methyl-8-[Z (2-phenylethenyl) ]-imidazo (1,2-a) pyridine; 3-Amino-8- (4-chlorophenylmethoxy)-2-methyl-imidazo(1,2-a) pyridine; 3-Amino-2-methyl-7-(2-phenylethyl)-imidazo (1,2-a)pyridine; 3-Amino-2-methyl-8- (2-thienylmethoxy) -imidazo (1,2-a) pyridine; Trans-3-Amino-2,6-dimethyl-8- (2-phenylethenyl)-imidazo (1,2-a)pyridine; 3-Amino-8-(2-fluorophenylmethoxy)-2-methyl-imidazo(1,2-a) pyridine; 3-Amino-8- (4-fluorophenylmethoxy)-2-methyl-imidazo(1,2-a) pyridine; 3-Amino-8-benzylamino-2-methyl-imidazo(1,2-a)pyridine; 3-Amino-2-methyl-8- (2-phenylethenyl) -imidazo(1,2-a)pyridine; 3-Amino-2-methyl-6- (2-phenylethyl)-imidazo(1,2-a)pyridine; 3-Amino-2-methyl-8-[E-1-(32-phenylpropen-l-yl) ]-imidazo (1,2-a)pyridine; 3-Ethylamino-2-methyl-8-(2-phenylethyl)-imidazo (1,2-a) pyridine; 3-Amino-2,7-dimethyl-8-(2-phenylethyl)-imidazo(1,2-a) pyridine; 8-Benzyloxy-3-isocyanomethyl-2-methyl-imidazo(1,2-a) pyridine; 8-benzyloxy-3-cyanomethyl-2-methyl-imidazo(1,2-a) pyrazine; 3-amino-8-benzyloxy-2-methyl-imidazo (1,2-a)pyrazine; 8-benzyloxy-3-ethylamino-2-methyl-imidazo (1,2-a) pyridine; 8-benzyloxy-3-allyl-2-methylimidazo (1,2-a)pyridine; 8-benzyloxy-3- (2-propynyl)-2-methylimidazo(1,2-a) pyridine; 8- (2-phenylethoxy)-3- (2-propynyl) -2-methylimidazo (1,2-a) pyridine; 8- (2-methylbenzyloxy)-3- (2-propynyl) -2-methylimidazo (1,2-a)pyridine: 8- (2-ethylbenzyloxy) -3- (2-propynyl) -2-methylimidazo (1,2-a) pyridine; 8- (2-isopropylbenzyloxy)-3- (2-propynyl)-2-methylimidazo (1,2-a)pyridine; 8- (2-chlorobenzyloxy)-3-(2-propynyl) -2-methylimidazo (1,2-a)pyridine; 8- (3-chlorobenzyloxy) -3- (2-propynyl) -2-methylimidazo (1,2-a)pyridine; 8- (4-chlorobenzyloxy)-3-(2-propynyl)-2-methylimidazo (1,2-a)pyridine; 8- (2-bromobenzyloxy)-3- (2-propynyl)-2-methylimidazo(1,2-a) pyridine; 8- (2-fluorobenzyloxy) -3- (2-propynyl) -2-methylimidazo (1,2-a) pyridine 8- (2, 6-dimethylbenzyloxy)-3- (2-propynyl)-2-methylimidazo (1,2-a)pyridine; 8- (2, 6-dichlorobenzyloxy)-3- (2-propynyl) -2-methylimidazo (1,2-a)pyridine; 8-benzyloxy-3- (2-propynyloxymethyl) -2-phenylimidazo (1,2-a) pyridine; 8- (2-methylbenzylamino)-3-(2-propynyloxymethyl-2- methylimidazo(1,2-a)pyridine hydrochloride; 8- (2-chlorobenzylamino)-3- (2-propynyloxymethyl)-2- methylimidazo (1,2-a)pyridine hydrochloride; 8-benzyloxy-3-allyloxymethyl-2-methylimidazo (1,2-a) pyridine; 8-benzyloxy-3-(3-carboxy-2-propynyloxymethyl)-2- methylimidazo(1,2-a)pyridine; 8-benzyloxy-3- (3-ethoxycarbonyl-2-propynyloxymethyl)-2- methylimidazo(1,2-a)pyridine; 8- (2-naphthylmethoxy)-3-(2-propynyl)-2-methylimidazo (1,2-a)pyridine; 8-(1-naphthylmethoxy)-3-(2-propynyl)-2-methylimidazo (1,2-a)pyridine; 8- (2-methylbenzylamino)-3- (2-propynyl)-2-methylimidazo (1,2-a)pyridine; 8-(2-chlorobenzylamino)-3-(2-propynyl) -2-methylimidazo (1,2-a)pyridine; 8-(2-methylbenzyloxy)-3-(1,2-propadienyl)-2-methylimidazo (1,2-a)pyridine; 8-benzyloxy-3- (2-propynyloxymethyl)-2-methylimidazo(1,2-a) pyridine hydrochloride; 8-benzyloxy-3-(2-propynyloxymethyl)-2-methylimidazo(1,2-a) pyridine 8- (1-phenylethoxy)-3- (2-propynyloxymethyl)-2-methylimidazo (1,2-a)pyridine; 8- (2-methylbenzyloxy) -3- (2-propynyloxymethyl) -2-methylimidazo (1,2-a)pyridine; 8- (2-chlorobenzyloxy) -3- (2-propynyloxymethyl) -2 -methyl imidazo (1, 2-a) pyridine ; 8- (3-chlorobenzyloxy) -3- (2-propynyloxymethyl) -2-methylimidazo (1 , 2-a) pyridine; 8- (4-chlorobenzyloxy) -3- (2-propynyloxymethyl) -2-methylimidazo (1, 2-a) pyridine ; 8- (2-bromobenzyloxy) -3- (2-propynyloxymethyl) -2-methylimidazo (1, 2-a) pyridine; 8- (2, 6-dichlorobenzyloxy)-3- (2-propynyloxymethyl) -2- methy1imidazo(1,2-a)pyridine; 8- (3,4-dichlorobenzyloxy)-3- (2-propynyloxymethyl)-2- methylimidazo(1,2-a) yridine; 8- (2,4-dichlorobenzyloxy) -3- (2-propynyloxymethyl)-2- methylimidazo(1,2-a)pyridine; 8-benzyloxy-3- (2-propynyloxymethyl)imidazo(1,2-a)pyridine. A preferred group of compounds within the general formula I for use according to the present invention is that wherein G is the group \ N C--=: C A ^ {CH 2^n Ar especially the compounds wherein n is 0. A particulary preferred compound for use according to the present invention is 3) Pharmacological tests In order to evaluate the inhibitory effect on bone resorption, and in vitro model, the mouse calvaria explant model (described in Reynolds, J.J. Organ cultures of bone: Studies on the physiology and pathology of bone resorption. In: Organ culture in biomedical research (Bulls M. , and Monnichendam M.A. eds) Cambridge University Press, p.p. 355-366, 1976) was used. In this model the effects of the compounds on the basal and the parathyroidhormone (PTH) -induced bone resorption are measured. Results 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. Table 1. Effect of Examples, on basal and parathyroid hormone-induced bone resorption in vitro % release of 4 . 5 Ca 2+ Devitalized preparation (n=6) 7 ± 0.8 Control (=basal) (n=6) 19 ± 4.0 Example 1 10~ 4 mol/l (n=6) 11 ± 0.8 p<0.001 Example 1 10~ 5 mol/l (n=6) 14 ± 2.1 p<0.02 PTH 100 ng/ml (n=6) 28 ± 6.9 PTH + Example 1 10~ 4 mol/l (n=4) 12 ± 1.6 p<0.002 PTH + Example 1 10~ 5 mol/l (n=4) 17 ± 3.3 p<0.02 % release of 45 Ca 2+ Devitalized preparation (n=5) 6.6 ± 0.5 Control (=basal) (n=5) 26.2 ± 3.2 Example 2 10 "4 mol/1 (n=4) 21.0 ± 2.3 Control (=basal) (n=5) 25.7 ± 1.9 Example 3 10~ 4 mol/1 (n=5) 7.9 ± 0.6 PTH 100 ng/ml (n=5) 34.8 ± 1.1 PTH + Example 2 10~ 4 . mol/1 (n=5) 24.0 ± 2.5 PTH 100 ng/ml (n=5) 26.6 ± 4.1 PTH + Example 3 lθ "4 mol/1 (n=5) 8.2 ± 0.3 For clinical use 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. Usually 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.

Claims: What we claim is: 1. A method for the treatment of osteoporosis by administering to a host in need of such treatment of a therapeutically effective amount of a compound of the formula I below, optionally together with a pharma¬ ceutically acceptable carrier: wherein G is whereby the carbon atom of the group N = C is connected to the 2-position of the imidazo-moiety, thus forming an imidazo (1,2- )pyrazine nucleus; A is a nonaromatic 5- or 6-membered ring containing 0 or 1 heteroatom selected from nitrogen, sulfur and oxygen; R 2 represents H, lower alkyl, CF 3 , B-CF 3 , B-Ar, Ar, B-halogen, BOR 8 , B-SO m -loweralkyl, BOC(=0)R 1 , B-NR 4 R 5 , COOR 6 , C(=0)-NR R 5 , B-CN or NR 4 R 5 ; R J represents H, loweralkyl, loweralkenyl, loweralkynyl, loweralkadienyl, loweralkenyloxy(lower)alkyl, lower- alkynyloxy(lower)alkyl, carboxy(lower) alkynylox (lower) - alkyl, protected carboxy(lower)alkynyloxy(lower)alkyl, BCN, BOR 8 , BOC(=0)-R 1 , B-NR 4 R 5 , B-C(=S)-NR 4 R 5 , B-C(=0) R R 5 , B-N0 2 , B-halogen, B-NC, NO or NR 4 R 5 ; R x , Έ&, R z and R u are H, R 9 or R 10 ; q R J represents H, loweralkyl halogen, OH, CF3 or loweralkoxy; R 10 is -Z-T-Ar wherein Z represents -0-, -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 -0-, T also represent an allylene group wherein the saturated carbon is at the oxygen; Ar represent phenyl, pyridyl, thienyl, furanyl, imidazolyl or X Λ -, y- and/or Z r -substituted phenyl wherein each of X' , Y' and Z r independently is hydrogen, halogen, loweralkyl, loweralkoxy, CN, CF3, OH, N0 2 , -NR 4 R 5 , -COOR 6 , -C(=0)NR 4 R 5 , -NR 7 C(=0)R 1 , -NR 7 SO m R 1 or -SO^ 1 ; B is a straight or branched chain loweralkylene group-; n represents zero, one or two; m represents zero, one or two; R and R each independently represents H, loweralkyl, lower¬ alkoxyloweralkyl, 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 R , B-NR R 5 or Ar-loweralkyl; represents H, C^- to C^-al !, Ar or Ar-loweralkyl; 7 R represents H or loweralkyl and; represents H, loweralkyl, loweralkoxyloweralkyl, trifluoro¬ methylloweralkyl, Ar-loweralkyl or Ar; as well as pharmaceutically acceptable salts thereof, especially acid addition salts such as hydrochloride and hydro- bromide salts, provided that (a) one, and only one, of the groups R x , R^, R z and R u is R 10 (b) not more than one of the groups R x , R^, R z and R u is R 9 (c) R x .is and R^ is H when G is the group 2. A method for the treatment of Pagefs 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 carrier. 4. A method for the treatment of such malignant neoplasms where tumor cells are producing 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 method for the treatment of disease connected with increased bone resorption 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. 8. A compound of the formula I as defined in claim 1 for use in the manufacture of a medicament for the treatment of osteoporosis. 9. A compound of the formula I as defined in claim 1 for use in the manufacture of a medicament for the treatment of Page s disease of bone. 10. 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. 11. 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 acitvating factors. 12. 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. 13. 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. 14. A compound of the formula I as defined in claim 1 for use in the manufacture of a medicament for the treatment of diseases connected with increased bone resorption. 15. A pharmaceutical preparation for use in the treatment of diseases connected with increased bone resorption; osteoporosis; Pagefs 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. 16. 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 as defined in claim 1. 17. A compound as defined in claim 1 for use in the manufacture of a medicament for improving the healing rate of bone fractures. 18. A pharmaceutical preparation for use in improving the healing rate of bone fractures, comprising a compound as defined in claim 1 as active ingredient.

Inventors: STARKE INGEMAR, VAEAENAENEN KALERVO, WALLMARK BJOERN, STARKE, INGEMAR, VAEAENAENEN, KALERVO, WALLMARK, BJOERN
Applicants: HAESSLE AB, AKTIEBOLAGET HAESSLE
Application year: 1988
Main classification: C07D471
IPC codes: A61K31, A61P5, A61P43, C07D471, C07D487, C07D491