WO1989003833A1 - IMIDAZO(1,2-a)(PYRIDAZINES OR PYRAZINES) FOR TREATMENT OF DISEASES RELATED TO BONE LOSS - Google Patents

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

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Publication number
WO1989003833A1
WO1989003833A1 PCT/SE1988/000576 SE8800576W WO8903833A1 WO 1989003833 A1 WO1989003833 A1 WO 1989003833A1 SE 8800576 W SE8800576 W SE 8800576W WO 8903833 A1 WO8903833 A1 WO 8903833A1
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treatment
compound
formula
pyridine
imidazo
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PCT/SE1988/000576
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French (fr)
Inventor
Ingemar Starke
Björn Wallmark
Kalervo Väänänen
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Aktiebolaget Hässle
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Priority to KR1019890701209A priority Critical patent/KR890701587A/en
Publication of WO1989003833A1 publication Critical patent/WO1989003833A1/en
Priority to DK322189A priority patent/DK322189A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Imidazo(1,2-a)(pyridazines or pyrazines) for treatment of diseases related to bone loss.
  • the present invention is related to a novel method for the treatment of several bone affecting diseases, especially osteoporosis, which are characterized by loss of bone mass.
  • bone formation which is associated with the number and activity of osteoblasts, that is cells associated with the production of bone in the organism
  • bone loss which is associated with the number and activity of osteoclasts, that is cells associated with the absorption and removal of bone
  • osteoporosis can be mentioned, Paget's disease of bone, hyperparathyroidism and related disorders, and several malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcemia.
  • osteoporosis bone formation as well as bone resorption are disturbed, resulting in decreased bone mass. Osteoporosis predominantly affects the elderly, but also other groups such as postmenopausal women, where an estrogen deficit is believed to be a significant etiological factor, and immobilized patients. At this point it is not possible to clear up the whole picture of the disease mechanism and estimate which is the primary cause of osteoporosis. However, about 25 % of osteoporotic females belong to what is called “rapid bone losers" and at least in those patients the bone resorption rate is probably increased. Landry and Fleisch showed in immobilization induced osteoporosis that bone resorption rate was accelerated, (Landry, M. and Fleisch, H, : The influence of immobilization on bone formation as evaluated the incorporation of tetracyclines. J. Bone Joint Surg. 46B:764, 1964).
  • osteoporosis comprise fractures, especially hip fractures, but also vertebral fractures and fractures of the proximal radius, and complication of such fractures.
  • in Finland it has been estimated that about 10 % of all surgical hospital beds are used for the treatment of osteoporosis related fractures (Luthje, P.: Reisiluunkaulan ja trokantterin murtumapotilaiden hoito ja ennuste seka hiodon kustannukset. Thesis. Helsinki 1983).
  • the present methods for the treatment of osteoporosis include exercise; administration of estrogen, especially for postmenopausal women; and consumption of calcium or calcium containing material such as milk.
  • Calcitonin a hormone associated with calcium metabolism, has also been used in the treatment of osteoporosis. None of these methods of treating osteoporosis results in increase of the bone mass.
  • malignant tumors are known to be associated by hypercalcemia which is due to increased osteoclastic activity. This is a common complication for instance in the case of breast cancer and prostate cancer which are both one of the most common malignant tumors.
  • Hypercalcemia is due to both systemic and local factors.
  • Some malignant cells are known to secrete agents which stimulate bone resorption (Sato, K., Fujii, Y. Kachivehi, T., Kasono, K., Shizume, K.: Production of interleukin 1 alpha (IL-1 ⁇ )-like activity and colony stimulating activity by clonal squanous cell carcinomas derived from patients with hypercalcemia and leucocytosis.
  • IL-1 ⁇ interleukin 1 alpha
  • Pacret's disease (or osteitis deformans) of bone is a disease of unknown etiology where bone resorption and remodelling are increased leading sometimes even to the fractures of affected bone. Bone pain is the main indication of treatment in these patients. In these patients there is highly elevated local osteoclastic bone destruction. The incidence of osteitis deformans is very low in Scandinavian countries. In England it has been estimated to be present in 3-4 % of population on the basis of autopsy studies (Anderson's Textbook of Pathology 1986). It is very rare in patients under 40 years. Calcitonin and diphosphonates are also used in the treatment of Paget's disease.
  • Arylalkoxy-, arylalkylamino- and arylalkylthio-substituted imidazo (1,2-a)pyridines and imidazo (1,2-a)pyrazines are known in the art, e.g. EP-Al-0068378 and EP-A1-0033094, as are methods for using these compound to reduce gastric acid secretion.
  • compounds of the general formula I as well as pharmaceutically acceptable salts thereof are effective as inhibitors of basal and stimulated bone resorption and are useful as medicals for the treatment of diseases related to bone loss and increased bone resorption, such as osteoporosis, Pagefs disease of bone, hyperparathyroidism, both primary and secondary, malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcemia, immobilization-induced osteoporosis, parodontal diseases and prostetic and implant- related bone losses.
  • diseases related to bone loss and increased bone resorption such as osteoporosis, Pagefs disease of bone, hyperparathyroidism, both primary and secondary, malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcemia, immobilization-induced osteoporosis, parodontal diseases and prostetic and implant- related bone losses.
  • the compounds to be used according to th e i nventi on are of the fol lowing formul a I :
  • A is a nonaromatic 5- or 6-membered ring containing O or 1 heteroatom selected from nitrogen, sulfur and oxygen;
  • R x , B y , R z and R u are H, R 9 or R 10 ;
  • R 9 represents H, loweralkyl, halogen, OH, CF 3 or loweralkoxy
  • R 10 is -Z-T-Ar wherein Z represents -O-, -NH-, -SO m - or a single bond; T represents a straight- or branched chain loweralkylene group; when Z is a single bond, T also represents an ethenylene or a propenylene group wherein the unsaturated carbon is at the single bond; when Z is -O-, T also represent an allylene group wherein the saturated carbon is at the oxygen;
  • n zero, one or two
  • n zero, one or two
  • R 4 and R 5 each independently represents H, loweralkyl, loweralkoxyloweralkyl, trifluoromethylloweralkyl, Ar-loweralkyl, Ar, or, when taken together with the nitrogen to which they are attached, form a 4-, 5- or 6-membered cyclic amino group;
  • R 1 represents Ar, loweralkyl, NR 4 R 5 , B-NR 4 R 5 or Ar-loweralkyl;
  • R 6 represents H, C 1 - to C 12 -alkyl, Ar or Ar-loweralkyl
  • R 7 represents H or loweralkyl
  • R 8 represents H, loweralkyl, loweralkoxyloweralkyl, trifluoromethylloweralkyl, Ar-loweralkyl or Ar;
  • salts thereof especially acid addition salts such as hydrochloride and hydrobromide salts,
  • R x is R 9 and R Y is H when G is the group
  • halogen includes fluoro, chloro, bromo and iodo, with fluoro and chloro being preferred;
  • lower when applied to alkyl groups, means straight and branched chain alkyl groups having up to six carbon atoms such as methyl, ethyl, propyl, butyl, t-butyl, isopropyl, neopentyl, dimethylbutyl etc., whereby methyl and ethyl are preferred;
  • pyridyl includes the 2-, 3- and 4-isomers and their halogen- or loweralkyl-substituted analogues;
  • thienyl and “furanyl” include the 2- and 3-isomers and their halogen- and loweralkylsubstituted analogues;
  • imidazolyl included the 2- and 4-isomers and their halogen- and loweralkyl-substituted analogues
  • the loweralkylene group represented by T preferably has 1-6, especially 1-3 carbon atoms as in methylene, ethylene and propylene,
  • Suitable “loweralkenyl” may be the ones having 2 to 6 carbon atoms and may include vinyl, allyl, isopropenyl, 1 (or 2 or 3)-butenyl or 1 (or 2 or 3 or 4)-pentenyl.
  • Suitable “loweralkadienyl” may be the ones having 3 to 6 carbon atoms and may include 1,2-propadienyl, 1,2-butadienyl, 1,3-butadienyl, 2,3-pentadienyl or 1,4-pentadienyl.
  • loweralkenyloxy(lower)alkyl suitable examples may include vinyloxymethyl, allyloxymethyl and 1-allyloxyethyl.
  • loweralkynyloxy(lower)alkyl suitable examples may include ethynyloxymethyl, 2-propynyloxymethyl, 2-(2-propynyloxy)ethyl and 1-(2-butynyloxy)propyl.
  • the invention relates to
  • a preferred group of compounds within the general formula I for use according to the present invention is that wherein G is the group
  • Example 1 The compound 8-benzyloxy-3-cyanomethyl-2-methyl-imidazo- (1,2-a)pyridine (Example 1), 8-benzyloxy-3-hydroxylmethyl- 2-methyl-imidazo(1,2-a)pyridine (Example 2) and Example 3 (mentioned above) were tested. As can be seen from Table 1 the compound was found to significantly inhibit both basal bone resorption and PTH-induced bone resportion.
  • the compounds of the formula I are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
  • the pharmaceutical formulation contains a compound of the formula I in combination with a pharmaceutically acceptable carrier.
  • the carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule.
  • These pharmaceutical preparations are a further object of the invention.
  • the amount of active compounds is between 0.1-95 % by weight of the preparation, between 0.2-20 % by weight in preparations for parenteral use and between 1 and 50 % by weight in preparations for oral administration.
  • the typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 mg per day of active substance.

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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(1,2-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 trokantterin murtumapotilaiden hoito ja ennuste seka hiodon kustannukset. Thesis. Helsinki 1983).
The present methods for the treatment of osteoporosis include exercise; administration of estrogen, especially for postmenopausal women; and consumption of calcium or calcium containing material such as milk. Calcitonin, a hormone associated with calcium metabolism, has also been used in the treatment of osteoporosis. None of these methods of treating osteoporosis results in increase of the bone mass.
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 factors. Some malignant cells are known to secrete agents which stimulate bone resorption (Sato, K., Fujii, Y. Kachivehi, T., Kasono, K., Shizume, K.: Production of interleukin 1 alpha (IL-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 diphcsphonate treatment 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 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 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 :
Figure imgf000008_0001
wherein G is
Figure imgf000008_0002
whereby the carbon atom of the group is connected
Figure imgf000008_0003
to the 2-position of the imidazo-moiety, thus forming an imidazo (1,2-a)pyrazine nucleus, A is a nonaromatic 5- or 6-membered ring containing O or 1 heteroatom selected from nitrogen, sulfur and oxygen; R2 represents H, lower alkyl, CF3, B-CF3, B-Ar, Ar, B-halogen, BOR8, B-SOm-loweralkyl, BOC(=0)R1, B-NR4R5, COOR6, C(=0)-NR4R5, B-CN or NR4R5;
represents H, loweralkyl, loweralkenyl, loweralkynyl, loweralkadienyl, loweralkenyloxy (lower) alkyl, loweralkynyloxy(lower)alkyl, carboxy(lower)alkynyloxy(lower)- alkyl, protected carboxy(lower)alkynyloxy(lower)alkyl, BCN, BOR8, BOC(=0)-R1, B-NR4R5, B-C (=S) -NR4R5, B-C (=0) NR4R5, B-NO2, B-halogen, B-NC, NO or NR4R5;
Rx, By, Rz and Ru are H, R9 or R10;
R9 represents H, loweralkyl, halogen, OH, CF3 or loweralkoxy;
R10 is -Z-T-Ar wherein Z represents -O-, -NH-, -SOm- or a single bond; T represents a straight- or branched chain loweralkylene group; when Z is a single bond, T also represents an ethenylene or a propenylene group wherein the unsaturated carbon is at the single bond; when Z is -O-, T also represent an allylene group wherein the saturated carbon is at the oxygen;
Ar represent phenyl, pyridyl, thienyl, furanyl, imidazolyl or X'-, Y'- and/or Z'-substituted phenyl wherein each of X', Y' and Z ' independently is hydrogen, halogen, loweralkyl, loweralkoxy, CN, CF3, OH, NO2, -NR4R5, -COOR6, -C(=0)NR4R5, -NR7C(=0)R1, -NR7SOmR1 or -SOmR1; B is a straight or branched chain loweralkylene group;
n represents zero, one or two;
m represents zero, one or two;
R4 and R5 each independently represents H, loweralkyl, loweralkoxyloweralkyl, trifluoromethylloweralkyl, Ar-loweralkyl, Ar, or, when taken together with the nitrogen to which they are attached, form a 4-, 5- or 6-membered cyclic amino group;
R1 represents Ar, loweralkyl, NR4R5, B-NR4R5 or Ar-loweralkyl;
R6 represents H, C1- to C12-alkyl, Ar or Ar-loweralkyl;
R7 represents H or loweralkyl; and
R8 represents H, loweralkyl, loweralkoxyloweralkyl, trifluoromethylloweralkyl, 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 Rx, Ry, Rz and Ru is R10
(b) not more than one of the groups Rx, Ry, Rz and Ru is R9
(c) Rx is R9 and RY is H when G is the group
Figure imgf000010_0001
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 "loweralkynyloxy(lower)alkyl", suitable examples may include ethynyloxymethyl, 2-propynyloxymethyl, 2-(2-propynyloxy)ethyl and 1-(2-butynyloxy)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-mezhyl-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-Cyanomethyl-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-E-(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-1-ethenyl)]imidazo (1,2-a)pyridine;
3-Cyanomethyl-2-methyl-8-[E-1-(3-phenyl-propen-1-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)pyridine; 3-Amino-2-methyl-8-(2-phenylethyl)-imidazo(1 ,2-a)pyridine; 3-Amino-2-methyl-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)-amino]-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-1-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-methylimidazo (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- methylimidazo(1,2-a)pyridine;
8-(3,4-dichlorobenzyloxy)-3-(2-propynyloxymethyl)-2- methylimidazo(1,2-a)pyridine;
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
Figure imgf000019_0001
especially the compounds wherein n is 0. A particulary preferred compound for use according to the present invention is
Figure imgf000019_0002
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 45Ca2+
Devitalized preparation (n=6) 7 ± 0.8
Control (=basal) (n=6) 19 ± 4.0
Example 1 10-4mol/l (n=6) 11 ± 0.8 p<0.001
Example 1 10-5mol/l (n=6) 14 ± 2.1 p<0.02
PTH 100 ng/ml (n=6) 28 ± 6.9
PTH + Example 1 10-4mol/l (n=4) 12 ± 1.6 p<0.002
PTH + Example 1 10-5mol/l (n=4) 17 ± 3.3 p<0.02 % release of 45Ca2+
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 10-4 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 pharmaceutically acceptable carrier:
Figure imgf000024_0001
wherein G is
Figure imgf000024_0002
whereby the carbon atom of the group is connected
Figure imgf000024_0003
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;
R2 represents H, lower alkyl, CF3, B-CF3, B-Ar, Ar, B-halogen, BOR8, B-SOm-loweralkyl, BOC(=0)R1, B-NR4R5, COOR6, C(=0)-NR4R5, B-CN or NR4R5;
R3 represents H, loweralkyl, loweralkenyl, loweralkynyl, loweralkadienyl, loweralkenyloxy(lower)alkyl, loweralkynyloxy(lower)alkyl, carboxy(lower)alkynyloxy(lower)- alkyl, protected carboxy(lower)alkynyloxy(lower)alkyl, BCN, BOR8, BOC(=0)-R1, B-NR4R5, B-C (=S) -NR4R5, B-C (=0) NR4R5, B-NO2, B-halogen, B-NC, NO or NR4R5;
Rx, Ry , Rz and Ru are H, R9 or R10;
R9 represents H, loweralkyl halogen, OH, CF3 or loweralkoxy;
R10 is -Z-T-Ar wherein Z represents -O-, -NH-, -SOm- or a single bond; T represents a straight- or branched chain loweralkylene group; when Z is a single bond, T also represents an ethenylene or a propenylene group wherein the unsaturated carbon is at the single bond; when Z is -O-, T also represent an allylene group wherein the saturated carbon is at the oxygen; Ar represent phenyl, pyridyl, thienyl, furanyl, imidazolyl or X'-, Y'- and/or Z'-substituted phenyl wherein each of X', Y' and Z' independently is hydrogen, halogen, loweralkyl, loweralkoxy, CN, CF3, OH, NO2, -NR4R5, -COOR6, -C(=0)NR4R5, -NR7C(=0)R1, -NR7SOmR1 or -SOmR1;
B is a straight or branched chain loweralkylene group;
n represents zero, one or two;
m represents zero, one or two;
R4 and R5 each independently represents H, loweralkyl, loweralkoxyloweralkyl, trifluoromethylloweralkyl, Ar-loweralkyl, Ar, or, when taken together with the nitrogen to which they are attached, form a 4-, 5- or 6-membered cyclic amino group;
R1 represents Ar, loweralkyl, N R4 R5, B-N R4R5 or Ar-loweralkyl;
R6 represents H, C1- to C12-alkyl, Ar or Ar-loweralkyl;
R7 represents H or loweralkyl and;
R8 represents H, loweralkyl, loweralkoxyloweralkyl, trifluoromethylloweralkyl, 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 Rx, Ry, Rz and Ru is R10
(b) not more than one of the groups Rx, Ry, Rz and Ru is R9
(c) Rx is R9 and Ry is H when G is the group
Figure imgf000027_0001
2. 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 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.
PCT/SE1988/000576 1987-10-30 1988-10-27 IMIDAZO(1,2-a)(PYRIDAZINES OR PYRAZINES) FOR TREATMENT OF DISEASES RELATED TO BONE LOSS WO1989003833A1 (en)

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DK322189D0 (en) 1989-06-28
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