2-PYRIDINYLMETHYL (SULFINYL OR THIO)BENZIMIDAZOLES FOR TREATMENT OF DISEASES RELATED TO BONE LOSS

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 the formula (I), or a prodrug or a pharmaceutically acceptable salt thereof.

Description: 2-Pyridinylmethyl (sulfinyl or thio)benzimidazoles 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_In ention 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 produc¬ tion 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, hyperparathyroi di sm and related disorders, and several malignant neoplasms where tumor cells ar.e producing osteocl ast-acti vati ng fac¬ tors 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 predominant l affects the elderly, but also other groups such as post- menopausal women, where an estrogen deficit is believed to be a significant etiological factor, and immobilized patients. A ' t this point it is not possible to clear u 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 re- sorption rate is probably increased. Landry and Fleisch showed in immobilization induced osteoporosis that bone resorption rate is 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 frac¬ tures, especially hip fractures, but also vertebral frac¬ tures and fractures of the proximal radius, and compli¬ cation of such fractures. In Finland it has been estimated that about 10% of all surgical hospital beds are used for the treatment of osteo¬ porosis-related fracture.s (Luthje, P.: Rei siluunkaulan ja trokantterin murtumapoti laiden 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 ac¬ tivity. This is a common complication for instance in the case of breast cancer and prostate cancer which are both one of the most comm-n malignant tumors. Hypercalcemia is due to both systemic and local fractors. 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 calcitonin and di phosphonate treatment has been used. Paget ' s disease (or osteitis deformans) of bone is a dis¬ ease of unknown etiology where bone resorption and remodel¬ ling 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 prostetic and implant bone losses. It is an object of the present invention to provide com¬ pounds which by affecting the balance between osteoblast and osteoclast activity can be useful for therapeutic and prophylactic 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 in¬ crease of the bone mass. A further object of the invention is to provide compounds which improve the incorporation of calcium into the skeleton. Prior art Heterocyclylal kyl sul fi nylbenzimi dazol es and heterocyclyl- al kylthiobenzimi dazoles are known in the art, as are methods for using these compounds to reduce gastric acid secretion . 9--! -rl i Df -.2f -.-:-! -! -.B π--§ -:D-:_i D--'§D -ri2D According to the present invention it has been found that compounds of the general formula I as well as prodrugs and pharmaceutically acceptable salts thereof are effective as inhibitors of basal and stimulated bone resorption. The compounds of the formula I are useful as medicals for the treatment of osteoporosis, Paget's disease of bone, hyper- parathyroidism, both primary and secondary, malignant neo¬ plasms where tumor cells are producing osteocl ast-acti - vating factors and cause hypercalcinemia, immobilization- induced osteoporosis, parodontal diseases and prostetic and implant-related bone losses. The compounds for use according to the invention are of the following formula I: wherein X is -S- or -SO' R 3 and which are the same or different, are (a) H (b) alkyl containing 1-8, especially 1-6 carbon atoms (c) alkoxy containing 1-8, especially 1-6 carbon atoms (d) alkoxyalkyl containing 1-3 carbon atoms in each alkyl part (e) alkoxyalkoxy containing 1-3 carbon atoms in each alkyl part ( f ) hal ogen (g) -CN (h) -CF 3 (i ) -N0 2 (j) -COR 10 (k) alkylthio containing 1-6 carbon atoms in the alkyl part (1 ) al kyl sul fi ny1 containing 1-7 carbon atoms in the alkyl part (m) aryl-thio, -sulfinyl, -sulfonyl, -sul fonyl oxy, oxysulfonyl, -sul fonamido or -aminosul fonyl , whereby each aryl group optionally is substituted by 1-3 substi tuents , the same or different and selected from halogen, CF- and (l-5C)alkoxy (n) arylalkyl or arylalkoxy, containing 1-6 carbon atoms in the alkyl and alkoxy parts, respectively, whereby the aryl part optionally is substituted by 1-3 substi tuents, the same or different and selected from halogen, CF 3 , (1-5C) alkyl and (l-5C)alkoxy (o) aryl or aryloxy, whereby each aryl group optionally is substituted by 1-3 substi tuents, the same or different and selected from halogen, CF-, (l-5C)alkyl and (l-5C)alkoxy (p) haloalkoxy containing 1-6 carbon atoms and 1-11, especially 1-6 halogen atoms (q) hydroxyalkyl containing 1-6 carbon atoms 1 2 2 3 3 4 (r) R and R , R and R or R and R together with the adjacen carbon atoms in the benzimi dazole ring form one or more 5-, 6- or 7-membered rings, which each may be saturated or unsaturated and may contain 0-3 hetero atoms " selected from N, S and 0, and whereby each ring may be optionally substituted with 1-10, suitably 1-6, or 1-4 substituents selected from alkyl groups with 1-3 carbon atoms and haloge or two or four of the mentioned substituents together form 1 2 2 one or two oxo groups (C=0), whereby if R and R , R and 3 3 4 R or R and R together with the adjacent carbon atoms in the benzimi dazole ring form two rings the rings may be condensed with each other; is (a) H ( b ) al ky l contai ni n g 1-8 , especi al ly 1 -6 carbon atoms ( c ) al koxy co ntai n i ng 1 -8 , es pec i al l y 1 -6 ca rbon atoms ( d ) h al o gen R 8 i s ( a ) H (b) alkyl containing 1-8, especially 1-5 carbon atoms (c) alkoxy containing 1-6 carbon atoms (d) halogen (e) arylalkyl containing 1-4 carbon atoms in the alkyl part R 7 is (a) H (b) alkyl containing 1-7 carbon atoms (c) alkoxy containing 1-7 carbon atoms (d) alkoxyalkyl containing 1-3 carbon atoms in each alkyl part (e) alkoxyalkoxy containing 1-3 carbon atoms in each alkyl part (f) aryloxy, whereby the aryl group optionally is substituted by 1 or 2 substituents, the same or different and selected from halogen, CF 3 , (l-3C)alkyl or (l-3C)alkoxy (g) aryl-alkyl or arylalkoxy containing 1-7 carbon atoms in the alkyl resp. alkoxy part, whereby the aryl part optionally is substituted by 1 or 2 substituents, the same or different and selected from halogen, CF 3 , (l-3C)alkyl and (l-3C)alkoxy (h) alkenyloxy containing 1-7 carbon atoms in the alkenyl part (i ) alkynyloxy containing 1-7 carbon atoms in the alkenyl part (j ) alkylthio containing 1-7, preferably 1-3 carbon atoms in the alkyl part (k) arylthio or ary1 al kyl thi o containing 1-3, preferably 1 carbon atom in the alkyl part (1 ) dialkylamino containing 1-7, preperably 1-3 carbon atoms in the alkyl parts ( m ) morphol i no (n) piperidino (o) N-methylpiperazino (p) pyrrolidono (q) fluoroalkoxy containing 2-5 carbon atoms and 1-9 fluorine atoms or R 6 and R 7 , or R 7 and R 8 together with the adjacent carbon atoms in the pyridine ring form a 5- or 6-membered, saturated or unsaturated ring, which may optionally contain an oxygen, sulphur or an optionally alkylated nitrogen atom; R 10 is (a) alkyl containing 1-6 carbon atoms (b) alkoxy containing 1-6 carbon atoms (c) aryl; o a pharmaceutically acceptable salt thereof or a prodrug or a pharmaceutically acceptable salt thereof, with the proviso that the compound 5-methoxv-2- fC4-methoχv-3,5-dimethyl-2-pyridinyl) - methy-α-sulfinyl - H-benzimidazole (omeprazole) is excluded from the scope of formula I. Examples of pharmaceutically acceptable salts are alkali salts such as sodium and potassium salts, and calcium 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 particulary, examples of prodrugs of compounds of the formula I are of the formula where e rad ca R is selected f rom wherei n R U is (a) H (b) alkyl containing 1-4 carbon atoms 12is (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, CF 3 , alkanoyl containing 2-5 carbon atoms (f) aryloxy, optionally substituted with alkyl contain¬ ing 1-4 carbon atoms, alkoxy containing 1-4 carbon atoms, halogen, CF 3 , alkanoyl containing 2-5 carbon atoms or alkoxycarbonyl containing 2-5 carbon atoms (g) arylalkoxy containing 1-5 carbon atoms in the alkoxy part, wherein the aryl part optionally is substi¬ tuted with alkyl containing 1-6 carbon atoms and/or alkoxy containing 1-6 carbon atoms; and OH wherein R 13 is (a) H (b) alkyl containing 1-6 carbon atoms, Illustrative examples of the various radicals i-n the formula I 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 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 13 are exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl , n-hexy , cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl , cyclopentylmethyl , cycl opentyl ethyl , and cycl ohexylmethy 1. Lower alkyl groups containing 1-4 carbon atoms are especially preferred. The group alkoxy in the definitions R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 R , and R are exemplified by methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentoxy i-pentoxy, n-hexoxy, cyclopropoxy , cyclopentoxy , cyclohexoxy, . cyclopropylmethoxy, cyclopent Imethox , cycl opentylethoxy , and cyclohexyl ethox . 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 i sopropoxy . 1 2 3 4 12 Halogen in the definitions of R , R , R , R , and R is chloro, bromo, fluoro and iodo, preferably chloro, bromo, and f 1 uoro. 1 2 3 4 7 In R , R , R , R , and R when representing alkylthio or al kylsul f inyl is the alkyl preferably a lower alkyl having especially preferred 1-4 carbon atoms, e.g. methyl thi o , methylsulf inyl , ethylthio, ethyl sul f inyl , i sopropy thi o, n-butyl sulfi nyl or sobuty thi o . 1 2 3 4 7 10 The group aryl when present in R , R , R , R , R , R , and 12 R has preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenyl group. 1 2 3 4 7 12 R , R , R , R , R , and R representing an aryloxy or arylthio group have preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenoxy or phenylthio group. 12 Alkanoyl in R contains from 1 to 6 carbon atoms and is preferably HCO, CH 3 C0, CH 3 CH £ C0, CH 3 (CH 2 ) 2 C0, or HC(CH 3 ) 2 C0. 12 Al koxycarbonyl in R contains an alkoxy group as illustrated under "alkoxy" above. The groups arylalkyl, arylalkoxy, and arylalkyl thio, when present in R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 12 have preferably up to 10 carbon atoms in the aryl group. Especially preferred are 6 carbon atoms in the aryl group and 1-3 carbon atoms in the alkyl group or alkoxy group, respectively, e.g. phenylmethyl , phenylethyl, phenyImethoxy, phenylethoxy, phenylpropyl , phenyl sopropoxy, phenylmethyl thio, and phenyl ethyl thio. 1 2 3 4 7 R , R , R , R , and R representing an alkoxyalkyl or alkoxyalkoxy group are exemplified by methoxymethoxy, methoxyethy 1 , methoxypropyl , ethoxymethyl , ethoxyethyl , propoxyethyl , methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy and propoxyethoxy. R representing an alkenyloxy or alkynyloxy group has preferably 2-7 carbon atoms, especially preferred 3-4 carbon atoms, e.g. allyloxy, propargylox , 2-buteny-loxy and 2-butynyloxy. Illustrative examples of ring structures formed by R 1 and R2, R 2 and R 3 and R 4 are -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 ) 5 -, -CH=CH-CH=CH-, -CH 2 C0CH 2 -, -OCHgO-, -0CH 2 CH 2 0-, -OCH 2 CH 2 CH 2 0-, -0CH 2 CH 2 -, -CH 2 CH 2 NH-, -CH=CH-CH=N-, -COCHgCO-, -SCH 2 CH 2 -, -SCH 2 S-, -SCH 2 CH 2 S-, -C(CH 3 ) 2 ~C0-C(CH 3 ) 2 ~, -0CF 2 0, OCF 0-, OCF CHF0-, -0CF 2 CHF0-, -0CF 2 CF 2 0-, and -0CF 2 CFC10-. 6 7 7 8 R and R , or R and R representing a 5- or 6-membered saturated or unsaturated ring is preferably a saturated carbocyciic ring or a saturated ring containing an oxygen or a sulphur atom in the 4-position in the pyridine ring, e.g. — CHΛCHΛCHΛ— , -CH ΛCHΛCH ΛCHΛ - , -0-CHΛCHΛ-, -0 -CH«CH nCH - , -SCH 2 CH 2 -, or SCH 2 CH 2 CH 2 -. R 1 , R2 , R 3 and R 4 when representing haloalkoxy is preferably a lower haloalkoxy. Especially preferred are lower fl uoroalkoxy , or fluorochloroalkoxy groups, e.g. 0CF 3 , 0CHF 2 , 0CF 2 CHF 2 , 0CF 2 CF 3 , 0CF 2 CF 3 , 0CF 2 C1 , 0CH 2 CF 3 . R when representing alkoxy is exemplified by 0CH o CF 3 , 0CH 2 CF 2 CF 3 and 0CH 2 CF 2 CHF 2 . R 1-, R2 , R 3 and R 4 representing hydroxyalkyl is exemplified by CH 2 0H, CH 2 CH 2 0H, CH 2 CH 2 CH 2 0H, and (CH 2 ) 4 0H. R when representing a dialkylamino group is preferably -N(CH 3 ) 2 , or -N(C 2 H 5 ) 2 . For the coπφouncts with the general formula I containing an asymmetric centre, both the pure enantio ers and the racemic mixtures are within the scope of the present invention. Accordingly, the invention relates to - a method for heP ro Phyl act i c and therapeutic treatment of eac of the ailments above by administering to a host in need there of a therapeutically effective amount of a compound of the formula I - a pharmaceutical preparation for use in the prophylactic and t peutic 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 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 In order to evaluate the inhibitory effect on bone resorption, an 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 parathyroi dhor one (PTH )-induced bone resorption are measured. Results The two compounds 5-carbethoxy-6-methyl -2-[[( 3-methyl -2-pyri di nyl )methyl]syl fi nyl] -lH-benzimi dazole (Example 1), 5-tri- fluoromethyl-2-[[(4,5-di eth l -2-pyridinyl ) methyl] -sul f inyl]- lH-benzimidazole (Example 2), 5-hydroxymethyl -2-[[( -methoxy- 3, 5- di ethyl -2-pyridinyl )methyl]sul finyl]-lH -benzimi dazole (Example 3) and 5-methoxy-2-[[( 4-methoxy-3-methyl-2-pyridinyl ) methyl]sulfinyl]-lH-benzimi azole (Example 4) were tested. As can be seen from Table 1 and Table 2 both compounds were found to significantly inhibit both basal bone resorption (Table 1) and PTH-induced bone resorption (Table 2). Table 1. Effect of Example 1 and Example 2 on basal bone resorption in vitro * %_rel . ease_of - 45 Qa 2_+_ 12.6 ± 1.85 8.9 ± 0.66 p<0.001 2iZ-.i-.l-:2-!-E 9i92§ Control (=basal) (n=5) 24.4 ± 1.6 Example 4 10 " mol/l (n=5) 14.6 ± 2.1 Table 2. Effect of Example 1 and Example 2 on parathyroid hormone induced bone resorption in vitro 45 2+ !_r§!§-ϋ.?_2f. -Q--- Control (=basal) (n=6) 8.8 ± 2.6 PTH 100 ng/rnl (n=6) 12.2 a- 2.3 PTH + Example 1 10 '4 mol/l (n=6) 6.4 ± 1.65 p<0.001 PIt ; _ -^au?2!e.2_ig ~ mol_/l_[n=6} ; 7_r_2 : _l__g<0,002 PTH 100 ng/ir-l (n = 5) 35.9 = 2.2 PItl_t_Exa!5Ele_3_10 "4 mol/l__(n=5) 25 l_±_1.9 PTH 100 ng/ml (n=5) 26.7 x 3.6 PTH + Example 4 10 "4 mol/l (n=5) 14.4 ± 0.4 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 formu¬ lation contains a compound of the invention 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 ob¬ ject 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 admin¬ istration. 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 par¬ enteral dosages will be in the range of 5 to 500 mg per day of active substance.

Claims: What we claim is: 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 pharmaceuti cally acceptable carrier: wherein X is -S- or -S0- R and R , which are the same or different, are (a) H (b) alkyl containing 1-8, especially 1-6 carbon atoms (c) alkoxy containing 1-8, especially 1-6 carbon atoms (d) alkoxyalkyl containing 1-3 carbon atoms in each alkyl part alkoxyalkoxy containing 1-3 carbon atoms in each alkyl par (g) -CN (h) -CF 3 (i ) -N0 2 (j) -COR 10 (k) alkylthio containing 1-6 carbon atoms in the alkyl part (1) al 1 sul finyl containing 1-7 carbon atoms in the alkyl par ( ) aryl-thio, -sulfinyl, -sulfonyl, -sul fon lox , oxy- sulfonyl, -sulfonamido or -aminosul fonyl , whereby each aryl group optionally is substituted by 1-3 substituents the same or different and selected from halogen, CF 3 , (1-5C) alkyl and (l-5C)alkoxy (n) arylalkyl or arylalkoxy, containing 1-6 carbon atoms in the alkyl and alkoxy parts, respectively, whereby the aryl part optionally is substituted by 1-3 substituents, the same or different selected from halogen, CF 3 , (1-5C) alkyl and (1-5C) alkoxy (o) aryl or aryloxy, whereby each aryl group optionally is substituted by 1-3 substituents, the same or different and selected from halogen, CF 3 , (l-5C)alkyl and (l-5C)alkoxy (p) haloalkoxy containing 1-6 carbon atoms and 1-11, especially 1-6 halogen atoms (q) hydroxyalkyl containing 1-6 carbon atoms (r) R 1 and R 2 , R 2 and R 3 or R 3 and R 4 together with the adjacent carbon atoms in the benzimi dazole ring form one or more 5-, 6- or 7-membered rings, which each may be saturated or unsaturated and may contain 0-3 hetero atoms selected from N, S and 0, and whereby each ring may be optionally substituted with 1-10, suitably 1-6, or 1-4 substituents selected from alkyl groups with 1-3 carbon atoms and halogen or two or four of the mentioned substituents together form 1 2 ? one or two oxo groups (C=0), whereby if R and R , R and 3 3 4 R or R and R together with the adjacent carbon atoms in the benzimi dazole ring form two rings the rings may be condensed with each other; is (a) H (b) alkyl containing 1-8, especially 1-6 carbon atoms (c) alkoxy containing 1-8, especially 1-6 carbon atoms ( d ) hal ogen R 8 i s ( a ) H (b) alkyl containing 1-8, especially 1-6 carbon atoms (c) alkoxy containing 1-6 carbon atoms (d) halogen (e) arylalkyl containing 1-4 carbon atoms in the alkyl part R 7 is (a) H (b) alkyl containing 1-7. carbon atoms (c) alkoxy containing 1-7 carbon atoms (d) alkoxyalkyl containing 1-3 carbon atoms in each alkyl part (e) alkoxyalkoxy containing 1-3 carbon atoms in each alkyl part (f) aryloxy, whereby the aryl group optionally is substituted by 1 or 2 substituents, the same or different and selected from halogen, CF 3 , (l-3C)alkyl or (l-3C)alkoxy (g) arylalkyl or arylalkoxy containing 1-7 carbon atoms in the alkyl resp. alkoxy part, whereby the " aryl part optionally is substituted by 1 or 2 substituents, the same or different and selected from halogen, CF 3 , (l-3C)alkyl and (l-3C)alkoxy (h) alkenyloxy containing 1-7 carbon atoms in the alkenyl part (i) alkynyloxy containing 1-7 carbon atoms in the alkenyl part (j) alkylthio containing 1-7, preferably 1-3 carbon atoms in the alkyl part (k) arylthio or arylal kyl thi o containing 1-3, preferably 1 carbon atom in the alkyl part (1 ) dialkylamino containing 1-7, preperably 1-3 carbon atoms in the alkyl parts (m) morpholino (n) piperi dino (o) N-methylpiperazino (p) pyrroHdino (q) fluoroalkoxy containing 2-5 carbon atoms and 1-9 fluorine atoms or and R , or R and R together with the adjacent carbon atoms in the py idine ring form a 5- or 6-membered, saturated or unsaturated ring, which may optionally contain an oxygen, sulphur or an optionally alkylated nitrogen atom; R is (a) alkyl containing 1-6 carbon atoms (b) alkoxy containing 1-6 carbon atoms (c) aryl ; or pharmaceutically acceptable salt thereof or a prodrug or a pharmaceutically acceptable salt thereof, with the proviso that the compound 5-methoxy-2- rj * 4-methoxy-3 / 5-dimethyl-2-pyridinyl)- methyl^-sulfinyl^-lH-benzimidazole (omeprazole) is excluded from the scope of formula I. 2. A method according to claim 1, wherein X is -S-. 3. A method according to claim 1, wherein X is -SO-. 4. A method according to claim 1, wherein R 1, R2, R3 and R are the same or different and selected from hydrogen, (l-4C)alkyl, ( 5-6C)cycloalkyl , ( 1-4C )alkoxy, (l-2C)alkoxy(l-2C)alkyl , (1-2C )alkoxy( 1-2C)alkoxy, halogen, CF 3 , ( 2-4C )alkanoyl , ary 1 carbonyl , ( 1-2C )al koxycarbony 1 , aryl ( 1-3C )al koxy , aryl, halo- (l-4C)alkoxy, h droxy ( 1-4C )al k 1 or (2-4C)- alkanoyl (l-3C)alkyl . 5. A method according to claim 1, wherein the pyridine fragment is 3, 5-dimethy 1 -4-methoxy- , 3-meth l -4-methox 3 5-ethyl -4-methoxy-, 4-methoxy-, 4-ethoxy-, 4-iso- propoxy-, 3, 5-dimethyl -, 3,4-dimethoxy-, , 5-dimethoxy-, 3-meth l-4-(2,2,2-trifluoro)ethoxy-, 3,4-dimethoxy-, 4,5-dimethoxy-, 3-methyl-4-ethylthio-, 3-methyl- 4,5-dimethoxy-, 3,4,5-trimethyl -, 3-ethyl -4-methoxy-, 3-n-propyl-4-methoxy-, 3-isopropyl-4-methoxy-, 3-t- butyl -4-methoxy-substituted. 6. 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 claims 1-5, optionally together with a pharmaceutically acceptable carrier. 7. A method for the treatment of primary and secondary hyperparathyro dism 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 claims 1-5, optionally together with a pharmaceutically acceptable carrier. 8. 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 claims 1-5, optionally together with a pharmaceutically acceptable carrier. 9. A method for the treatment of aradontal 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 claims 1-5, optionally together with a pharmaceutically acceptable carrier. 10. A method for the treatment of prostetic and implant- related bone loss, by administer ng to a host in need of such treatment of a therapeutically effective amount of a compound of the formula I as defined in claims 1-5, optionally together with a pharmaceut cally acceptable carrier. 11. A method for the treatment of diseases 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 claims 1-5, optionally together with a pharmaceutically acceptable carrier. 12. A compound of the formula I as defined in claims 1-5 for use in the manufacture of a medicament for the treatment of osteoporosis. 13. A compound of the formula I as defined in claims 1-5 for use in the manufacture of a medicament for the treatment of Paget's disease of bone. 14. A compound of the formula I as defined in claims 1-5 for use in the manufacture of a medicament for the treatment of primary and secondary hyperparathyroidism. • 15. A compound of the formula I as defined in claims 1-5 for use in the manufacture of a medicament for the treatment of such malignant neoplasms where tumor cells are producing osteoclast-activating factors. 16. A compound of the formula I as defined in claims 1-5 for use in the manufacture of a medicament for the treatment of parodontal diseases. 17. A compound of the formula I as defined in claims 1-5 for use in the manufacture of a medicament for the treatment of prostetic and implant-related bone loss. 18. A compound of the formula I as defined in claims 1-5 for use in the manufacture of a medicament for the treatment of diseases connected with increased bone resorption. 19. A pharmaceutical preparation for use in the treatment of osteoporosis; Paget's disease of bone; primary and secondary hyperparathyro dism; such malignant neoplasms where tumor cells are producing osteoclast-activating factors; paradontal diseases; prostetic and implant- related bone loss; and comprising a compound of the formula I as defined in claims 1-5 as active ingredient. 20. 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 claims 1 - 5. 21. A compound as defined in claims 1 - 5 for use in the manufacture of a medicament for improving the healing rate of bone fractures. 22. A pharmaceutical preparation for use in improving the healing rate of bone fractures, comprising a compound as defined in claims 1 - 5 as active ingredient.

Inventors: HAAKANSON ROLF, LINDBERG PER, VAEAENAENEN KALERVO, WALLMARK BJOERN, HAAKANSON, ROLF, LINDBERG, PER, VAEAENAENEN, KALERVO, WALLMARK, BJOERN
Applicants: HAESSLE AB, AKTIEBOLAGET HAESSLE
Application year: 1988
Main classification: C07D401
IPC codes: A61K31, A61P3, A61P43, C07D401, C07D487, C07D491, C07F9