EP0338066A1 - 2-pyridinylmethyl (sulfinyl or thio)benzimidazoles for treatment of diseases related to bone loss - Google Patents

2-pyridinylmethyl (sulfinyl or thio)benzimidazoles for treatment of diseases related to bone loss

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Publication number
EP0338066A1
EP0338066A1 EP88909854A EP88909854A EP0338066A1 EP 0338066 A1 EP0338066 A1 EP 0338066A1 EP 88909854 A EP88909854 A EP 88909854A EP 88909854 A EP88909854 A EP 88909854A EP 0338066 A1 EP0338066 A1 EP 0338066A1
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European Patent Office
Prior art keywords
carbon atoms
alkyl
treatment
alkoxy
compound
Prior art date
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EP88909854A
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German (de)
French (fr)
Inventor
Rolf Hakanson
Per Lindberg
Björn Wallmark
Kalervo Väänänen
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Hassle AB
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Hassle AB
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Priority claimed from SE8704247A external-priority patent/SE8704247D0/en
Priority claimed from SE8704436A external-priority patent/SE8704436D0/en
Application filed by Hassle AB filed Critical Hassle AB
Publication of EP0338066A1 publication Critical patent/EP0338066A1/en
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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
    • 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,
  • 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 loss of bone tissue, decreased bone mass, and bone fragility. Osteoporosis predominantly 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. 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 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).
  • 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. 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 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-1 ⁇ )-like activity and colony stimulating activity by clonal squanous cell carcinomas derived from patients with hypercalcemia and leucocytosis.
  • IL-1 ⁇ interleukin 1 alpha
  • 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 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.
  • a further object of the invention is to provide compounds which improve the incorporation of calcium into the skeleton.
  • Heterocyclylalkylsulfinylbenzimidazoles and heterocyclylalkylthiobenzimidazoles are known in the art, as are methods for using these compounds to reduce gastric acid secretion.
  • 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, hyperparathyroidism, both primary and secondary, malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcinemia, immobilizationinduced osteoporosis, parodontal diseases and prostetic and implant-related bone losses.
  • X is -S- or -SO-; R 1 , R 2 , R 3 and R 4 which are the same or different, are
  • aryl-thio -sulfinyl, -sulfonyl, -sulfonyloxy, oxysulfonyl, -sulfonamido or -aminosulfonyl, whereby each aryl group optionally is substituted by 1-3 substituents, the same or different and selected from halogen, CF 3 and (1-5C)alkoxy
  • 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 and selected from halogen, CF 3 , (1-5C) alkyl and (1-5C)alkoxy
  • each aryl group optionally is substituted by 1-3 substituents, the same or different and selected from halogen, CF 3 , (1-5C)alkyl and (1-5C)alkoxy
  • R 7 is (a) H
  • aryloxy whereby the aryl group optionally is substituted by 1 or 2 substituents, the same or different and selected from halogen, CF 3 , (1-3C)alkyl or (1-3C)alkoxy
  • 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 , (1-3C)alkyl and (1-3C)alkoxy
  • 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 arylalkylthio containing 1-3, preferably
  • R 10 is (a) alkyl containing 1-6 carbon atoms
  • Examples of pharmaceutically acceptable salts are alkali salts such as sodium and potassium salts, and calcium and magnesium salts.
  • 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
  • R 1 1 is (a) H
  • R 12 is (a) alkyl containing 1-6 carbon atoms
  • 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
  • aryloxy optionally substituted with alkyl containing 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
  • arylalkoxy containing 1-5 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;
  • R 13 is (a) H
  • 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-hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cycl opentyl ethyl, and cycl ohexylmethy 1.
  • Lower alkyl groups containing 1-4 carbon atoms are especially preferred.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 R 10 , and R 12 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, cyclopenty Imethoxy, cycl opentylethoxy, and cyclohexylmethoxy.
  • Lower alkoxy groups are preferred, especially those containing 1-4 carbon atoms.
  • 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 1 , R 2 , R 3 , R 4 , and R 12 is chloro, bromo, fluoro and iodo, preferably chloro, bromo, and fluoro.
  • R 1 , R 2 , R 3 , R 4 , and R 7 when representing alkylthio or alkylsulfinyl is the alkyl preferably a lower alkyl having especially preferred 1-4 carbon atoms, e.g. methylthio, methylsulfinyl, ethylthio, ethyl sulfinyl, isopropylthio, n-butylsulfinyl or isobutylthio.
  • the group aryl when present in R 1 , R 2 , R 3 , R 4 , R 7 , R 10 , and R 12 has preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenyl group.
  • R 1 , R 2 , R 3 , R 4 , R 7 , and R 1 2 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.
  • Alkanoyl in R 12 contains from 1 to 6 carbon atoms and is preferably HCO, CH 3 CO, CH 3 CH 2 CO, CH 3 (CH 2 ) 2 CO, or HC(CH 3 ) 2 CO.
  • Alkoxycarbonyl in R 12 contains an alkoxy group as illustrated under "alkoxy" above.
  • the groups arylalkyl, arylalkoxy, and arylalkylthio, 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, pheny Imethoxy, phenylethoxy, phenylpropyl, phenylisopropoxy, phenylmethylthio, and phenylethylthio.
  • R 1 , R 2 , R 3 , R 4 , and R 7 representing an alkoxyalkyl or alkoxyalkoxy group are exemplified by methoxymethoxy, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxyethyl, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy and propoxyethoxy.
  • R 7 representing an alkenyloxy or alkynyloxy group has preferably 2-7 carbon atoms, especially preferred 3-4 carbon atoms, e.g. allyloxy, propargyloxy, 2-butenyloxy and 2-butynyloxy.
  • 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 -,
  • R 6 and R 7 , or R 7 and R 8 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.
  • R 1 , R 2 , R 3 and R 4 when representing haloalkoxy is preferably a lower haloalkoxy.
  • Especially preferred are lower fluoroalkoxy, or fluorochloroalkoxy groups, e.g. OCF 3 , OCHF 2 , OCF 2 CHF 2 ,
  • R 7 when representing alkoxy is exemplified by OCH 2 CF 3 , OCH 2 CF 2 CF 3 and OCH 2 CF 2 CHF 2 .
  • R 1 , R 2 , R 3 and R 4 representing hydroxyalkyl is exemplified by
  • R 7 when representing a dialkylamino group is preferably -N(CH 3 ) 2 , or -N(C 2 H 5 ) 2 .
  • Example 1 Effect of Example 1 and Example 2 on parathyroid hormone induced bone resorption in vitro
  • 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 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 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.

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 suffer­ ing 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 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 loss of bone tissue, decreased bone mass, and bone fragility. Osteoporosis predominantly 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. 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 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 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 (Lüthje, 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. 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 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-1α)-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 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 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 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 increase 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
Heterocyclylalkylsulfinylbenzimidazoles and heterocyclylalkylthiobenzimidazoles are known in the art, as are methods for using these compounds 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 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, hyperparathyroidism, both primary and secondary, malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcinemia, immobilizationinduced 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-; R1, R2, R3 and R4 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) halogen
(g) -CN (h) -CF3
(i) -NO2
(j) -COR10
(k) alkylthio containing 1-6 carbon atoms in the alkyl part
(1) alkylsulfinyl containing 1-7 carbon atoms in the alkyl part
(m) aryl-thio, -sulfinyl, -sulfonyl, -sulfonyloxy, oxysulfonyl, -sulfonamido or -aminosulfonyl, whereby each aryl group optionally is substituted by 1-3 substituents, the same or different and selected from halogen, CF3 and (1-5C)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 and selected from halogen, CF3, (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, CF3, (1-5C)alkyl and (1-5C)alkoxy
(p) haloalkoxy containing 1-6 carbon atoms and 1-11, especially 1-6 halogen atoms
(q) hydroxyalkyl containing 1-6 carbon atoms (r) R1 and R2, R2 and R3 or R3 and R4 together with the adjacent carbon atoms in the benzimidazole 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 O, 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 one or two oxo groups (C=0), whereby if R1 and R2, R2 and R3 or R3 and R4 together with the adjacent carbon atoms in the benzimidazole ring form two rings the rings may be condensed with each other;
is (a) H
( b ) alky l contai ni n g 1-8 , espec ially 1 -6 carbon atoms
( c ) alkoxy co ntai n i ng 1 -8 , es pec i ally 1 -6 ca rbon atoms
( d ) halogen R8 is ( 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
R7 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, CF3, (1-3C)alkyl or (1-3C)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, CF3, (1-3C)alkyl and (1-3C)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 arylalkylthio containing 1-3, preferably
1 carbon atom in the alkyl part (l) dialkylamino containing 1-7, preperably 1-3 carbon atoms in the alkyl parts (m) morpholino (n) piperidino (o) N-methylpiperazino (p) pyrrolidono
(q) fluoroalkoxy containing 2-5 carbon atoms and 1-9 fluorine atoms
or R6 and R7, or R7 and R8 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;
R10 is (a) alkyl containing 1-6 carbon atoms
(b) alkoxy containing 1-6 carbon atoms
(c) aryl; or a pharmaceutically acceptable salt thereof or a prodrug or a pharmaceutically acceptable salt thereof, with the proviso that the compound 5-methoxv-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)- methyl]-sulfinyl]-1H-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 the radical R5 is selected f rom wherein
R 1 1 is (a) H
(b) alkyl containing 1-4 carbon atoms R12 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
(f) aryloxy, 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
(g) arylalkoxy containing 1-5 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
wherein
R13is (a) H
(b) alkyl containing 1-6 carbon atoms. Illustrative examples of the various radicals in 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 R1, R2, R3, R4, R6, R7, R8, R10, R11, R12, and R13 are exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, 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 R1, R2, R3, R4, R6, R7, R8 R10, and R12 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, cyclopenty Imethoxy, cycl opentylethoxy, 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 R1, R2, R3, R4, and R12 is chloro, bromo, fluoro and iodo, preferably chloro, bromo, and fluoro.
In R1, R2, R3, R4, and R7 when representing alkylthio or alkylsulfinyl is the alkyl preferably a lower alkyl having especially preferred 1-4 carbon atoms, e.g. methylthio, methylsulfinyl, ethylthio, ethyl sulfinyl, isopropylthio, n-butylsulfinyl or isobutylthio. The group aryl when present in R1, R2, R3 , R4, R7, R10, and R12 has preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenyl group.
R1, R2 , R3, R4 , R7, and R1 2 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.
Alkanoyl in R12 contains from 1 to 6 carbon atoms and is preferably HCO, CH3CO, CH3CH2CO, CH3(CH2)2CO, or HC(CH3)2CO.
Alkoxycarbonyl in R12 contains an alkoxy group as illustrated under "alkoxy" above.
The groups arylalkyl, arylalkoxy, and arylalkylthio, when present in R1, R2, R3, R4, R5, R7, R8, and R12 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, pheny Imethoxy, phenylethoxy, phenylpropyl, phenylisopropoxy, phenylmethylthio, and phenylethylthio.
R1, R2, R3, R4, and R7 representing an alkoxyalkyl or alkoxyalkoxy group are exemplified by methoxymethoxy, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxyethyl, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy and propoxyethoxy.
R7 representing an alkenyloxy or alkynyloxy group has preferably 2-7 carbon atoms, especially preferred 3-4 carbon atoms, e.g. allyloxy, propargyloxy, 2-butenyloxy and 2-butynyloxy.
Illustrative examples of ring structures formed by R 1 and R2,
R2 and R3 and R4 are -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2C(CH3)2CH2-,
-CH2)5-, -CH=CH-CH=CH-, -CH2COCH2-, -OCH2O-, -OCH2CH2O-,
-OCH2CH2CH2O-, -OCH2CH2-, -CH2CH2NH-, -CH=CH-CH=N-, -COCH2CO-,
-SCH2CH2-, -SCH2S-, -SCH2CH2S-, -C(CH3)2-CO-C(CH3)2-, -OCF2O,OCF2O-, OCF2CHFO-, -OCF2CHFO-, -OCF2CF2O-, and -OCF2CFClO-.
R6 and R7, or R7 and R8 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.
-CH2CH2CH2- , -CH2CH2CH2CH2- , -O-CH2CH2-, -O-CH2CH2CH2-,
-SCH2CH2-, or SCH2CH2CH2-.
R1, R2, R3 and R4 when representing haloalkoxy is preferably a lower haloalkoxy. Especially preferred are lower fluoroalkoxy, or fluorochloroalkoxy groups, e.g. OCF3, OCHF2, OCF2CHF2,
OCF2CF3, OCF2CF3, OCF2Cl, OCH2CF3.
R7 when representing alkoxy is exemplified by OCH2CF3, OCH2CF2CF3 and OCH2CF2CHF2.
R1, R2, R3 and R4 representing hydroxyalkyl is exemplified by
CH2OH, CH2CH2OH, CH2CH2CH2OH, and (CH2)4OH.
R7 when representing a dialkylamino group is preferably -N(CH3)2, or -N(C2H5)2.
For the compouncts with the general formula I containing an asymmetric centre, both the pure enantiomers and the racemic mixtures are within the scope of the present invention. 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
- 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 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 parathyroidhormone (PTH )-induced bone resorption are measured.
Results
The two compounds 5-carbethoxy-6-methyl-2-[[(3-methyl-2-pyridinyl)methyl]sylfinyl]-1H-benzimidazole (Example 1), 5-tri fluoromethyl-2-[[(4,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazole (Example 2), 5-hydroxymethyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (Example 3) and 5-methoxy-2-[[(4-methoxy-3-methyl-2-pyridinyl) methyl]sulfinyl]-1H-benzimidazole (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
% release of 45Ca2+
Control (=basal) (n=6) 12.6 ± 1.85
Example 1 10-4mol/l (n=6) 8.9 ± 0.66 p<0.001
Examele 2 10-4mol/l (n=6) 9.7 ± 1.21 p<0.008
Control (=basal) (n=5) 33.0 ± 4.1
Example 3 10-4mol/l (n=5) 20.5 ± 2.8
Control (=basal) (n=5) 24.4 ± 1.6
Example 4 10-4mol/l (n=5) 14.6 ± 2.1
Table 2. Effect of Example 1 and Example 2 on parathyroid hormone induced bone resorption in vitro
% release of 45Ca2+
Control (=basal) (n=6) 8.8 ± 2.6
PTH 100 ng/ml (n=6) 12.2 ± 2.3
PTH + Example 1 10-4mol/l (n=6) 6.4 ± 1.65 p<0.001
PTH + Example 2 10-4mol/l (n=6) 6.7 ± 2.1 g<0.002
PTH 100 ng/ml (n = 5) 35.9 ± 2.2
PTH ± Example 3 10-4mol/l (n=5) 25.1 ± 1.9
PTH 100 ng/ml (n=5) 26.7 ± 3.6
PTH + Example 4 10-4mol/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 formulation 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 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:
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 pharmaceutically acceptable carrier:
wherein
X is -S- or -SO-;
R1 , R 2, R3 and R4, 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) -CF3
(i ) -NO2
(j) -COR10
(k) alkylthio containing 1-6 carbon atoms in the alkyl part
(1) alkylsulfinyl co nta in ing 1-7 carbon atoms in the alkyl part (m) aryl-thio, -sulfinyl, -sulfonyl, -sulfonyloxy, oxysulfonyl, -sulfonamido or -aminosulfonyl, whereby each aryl group optionally is substituted by 1-3 substituents the same or different and selected from halogen, CF3, (1-5C) alkyl and (1-5C)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, CF3, (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, CF3, (1-5C)alkyl and (1-5C)alkoxy
(p) haloalkoxy containing 1-6 carbon atoms and 1-11, especially 1-6 halogen atoms
(q) hydroxyalkyl containing 1-6 carbon atoms
(r) R1 and R2, R2 and R3 or R3 and R4 together with the adjacent carbon atoms in the benzimidazole 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 O, 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 one or two oxo groups (C=0), whereby if R1 and R2 , R2 and R3 or R3 and R4 together with the adjacent carbon atoms in the benzimidazole ring form two rings the rings may be condensed with each other; R6 is (a) H
(b) alkyl containing 1-8, especially 1-6 carbon atoms
(c) alkoxy containing 1-8, especially 1-6 carbon atoms (d) halogen R8 is ( 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
R7 is (a) H
(b) alky l 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, CF3, (1-3C)alkyl or (1-3C)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, CF3, (1-3C)alkyl and (1-3C)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 arylalkylthio containing 1-3, preferably
1 carbon atom in the alkyl part (l) dialkylamino containing 1-7, preperably 1-3 carbon atoms in the alkyl parts (m) morpholino (n) piperidino (o) N-methylpiperazino (p) pyrrolidino
(q) fluoroalkoxy containing 2-5 carbon atoms and 1-9 fluorine atoms
or R6 and R7, or R7 and R8 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;
R10is (a) alkyl containing 1-6 carbon atoms
(b) alkoxy containing 1-6 carbon atoms
(c) aryl;
or 4 pharmaceutically acceptable salt thereof or a prodrug or a pharmaceutically acceptable salt thereof, with the proviso that the compound 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]-sulfinyl]-1H-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 R4 are the same or different and selected from hydrogen, (1-4C)alkyl, (5-6C)cycloalkyl, (1-4C)alkoxy,
(1-2C)alkoxy(1-2C)alkyl, (1-2C)alkoxy(1-2C)alkoxy, halogen, CF3, (2-4C)alkanoyl, arylcarbonyl,
(1-2C)alkoxycarbonyl, aryl(1-3C)alkoxy, aryl, halo- (1-4C)alkoxy, hydroxy(1-4C)alkyl or (2-4C)- alkanoyl (1-3C)alkyl.
5. A method according to claim 1, wherein the pyridine fragment is 3,5-dimethyl-4-methoxy-, 3-methyl-4-methoxy , 5-ethyl-4-methoxy-, 4-methoxy-, 4-ethoxy-, 4-iso- propoxy-, 3,5-dimethyl-, 3,4-dimethoxy-, 4,5-5imethoxy-, 3-methyl-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 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 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 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.
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 hyperparathyroidism; 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.
EP88909854A 1987-10-30 1988-10-27 2-pyridinylmethyl (sulfinyl or thio)benzimidazoles for treatment of diseases related to bone loss Ceased EP0338066A1 (en)

Applications Claiming Priority (4)

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SE8704247 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 1987-11-13

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JP2694361B2 (en) * 1989-02-09 1997-12-24 アストラ アクチエボラグ Antibacterial agent
US5081253A (en) * 1989-12-21 1992-01-14 American Home Products Corporation Imidazo(4,5-c)pyridines as antiosteoporotic agents
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
IL127559A0 (en) * 1996-06-20 1999-10-28 Univ Texas Compounds and methods for providing pharmacologically active preparations and uses thereof
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
KR100453916B1 (en) * 2002-03-11 2004-10-20 주식회사 코오롱 Tetrahydropyridinylbenzimidazole derivatives and method for preparing the same
GB0403165D0 (en) * 2004-02-12 2004-03-17 Ct Novel uses for proton pump inhibitors
KR100638649B1 (en) 2006-06-27 2006-10-31 신한전기공업주식회사 Dry type transformer having insulation reinforcement
WO2013031620A1 (en) * 2011-08-26 2013-03-07 国立大学法人名古屋大学 Osteogenesis promoter and use thereof

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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
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IL88206A0 (en) 1989-06-30
HU886738D0 (en) 1990-02-28
DK322289A (en) 1989-06-28
IL88207A0 (en) 1989-06-30
DK322289D0 (en) 1989-06-28
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AU2621888A (en) 1989-05-23

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