New therapeutical use of HL-receptor-blocking compounds
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 poε_menopausal women, where an estrogen deficit is believed re 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 (Lϋthje, 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 prcstats 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 sguanous 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 vey 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 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.
Outline of the Invention
According to the present invention it has been found that the class of compounds known as H2-receptor-blocking agents, as well as pharmaceutically acceptable salts thereof, are useful as prophylactic and therapeutic agents 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; immobilization-induced osteoporosis; parodontal diseases; and prostetic and implant-related bone losses.
Examples of H2-receptor-blocking agents are:
Cimetidine
2-cyano-1-methyl-3-[2-[[5-methylimidazole-4-yl)-methyl]- thio]ethyl]guanidine
Ranitidine
N-[2-[[5-[(dimethylamino)methyl]furfuryl]thio]-ethyl]-N1- methyl-2-nitro-1,1-ethene-diamine
Famotidine
3- [ [ [ [ 2- (diajminomethylene) amino] -4-thiazolyl3methyl ]thio]-N- sulfamoylpropionamidine
BL-6341 A
3-[(2-guadinyl-4-thiazolyl)methγlthioethylamino]-4-amino-
1.2.5-thiadiazole monoxide
Ebrotidine p-bromo-N-[[[2-[[[2-[(diaminomethylene)amino]-4- thiazolyl]methyl]thio]ethyl]amino]methylene]benzenesulfonamide
Zaltidine [4-(2-methylimidazol-5-yl)-2-thiazolyl]guanidine
Nizatidine
N-[2-[[[2-[(dimethylamino)methyl]-4- thiazolyl]methyl]thio]ethyl]-N1-methγl-2-nitro-1,1- ethenediamine
Ramixotidine
N-[2-[[[5-[(dimethylamino)methyl3-2-furanyl]methyl]- thio]ethyl]-3-pyridinecarboxamide 1-oxide
BMY-25271
3-amino-4-[2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino]-1 2 5 -thiadiazole 1-oxide
1-[m-[3-[[1-methyl-3-[(methylsulfonyl)methyl]-1H-1,2,4- triazol-5-yl]amino3propoxy]benzyl]piperidine
Roxatidine
N-[3-[α -piperidino-m-tolyloxy3propy13carbamoylmethyl acetate
BMY - 25368
1-[3-(piperidinomεthyl)phenoxypropγlamino]-2-amino-3,4- dioxocyclobut-1-ene
3[2-[5-(dimethylaininomethyl)-2-furanylmethylthio] ethylamino]thieno[3,4-d]isothiazole 1,1-dioxide
Donetidine
5-(1,2-dihydro-2-oxoρyrid-4-ylmethyl)-2-[2-[s-(dimethylaininomethyl)furan-2-ylmethylthio]-ethylamino]pyrimidin-4(1H)-one
Tiotidine
1-[[2-(diaminomethyleneamino)-thiazole-4-yl]methylthioethyl]-2,3-dimethylguanidine
5-(3,4-methylendioxybenzyl)-2-[2-[5-methylimidazole-4- ylmethylthio]ethylamino]-pyrimidine-4(1H)-one
Mitentidine
N-[4(-imidazol-4-yl)-phenyl3-N1-isopropylformamidine
The preferred H2-blocking agents are cimetidine and ranitidine.
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 H2-receptor-blocking agent
- a pharmaceutical preparation for use in the prophylactic and therapeutic treatment of each of the ailments above comprising a H2-receptor-blocking agent as active ingredient
- a H2-receptor-blocking agent 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 H2-receptor -blocking agent.
Pharmacological tests
Sprague-Dawley male rats (Alab, Stockholm, Sweden) weighing 175-200 g before the tests were used. They obtained a standard diet consisting of rat feed pellets (Alab, Stockholm, Sweden) and tap water. Nine rats were given ranitidine (Hassle, Sweden) 1700 μmol/kg x day, approximately 600 mg/kg body weight per day) via osmotic mini pumps (Alzet 2ML2) which had been implanted subcutaneously. The rats were treated during 26 days and mini pumps were exchanged after 14 days. The pumps were placed under the abdominal skin. Seven rats were used as untreated controls.
45Ca incorporation into the skeleton
2 × 106 cpm 45CaCl2 (Radiochemical Center, Amersham, England) were administered orally by ventricular sond. The rats were killed by tapping blood via abdominal aorta 4 hours after the peroral administration of 45Ca. Radius, sternum, tibia and femur were removed by dissection. Radius and sternum were cleaned, weighed and placed in an oven at 800°C during 24 hours. The ashes were weighed and dissolved in 1M HCl. 10 ml Picofluor-40 (Packard) was added, whereafter the tubes were closed and shaken vigourosly before counting in a Beckman β-counter.
Radioimmunoanalysis of gastrin
Serum was prepared at the blood tapping from each rat and gastrin was determined by radioimmunoanalysis (Stadil, F. & Rehfeld, J.F. (1973) Determination of gastrin in Serum. An evaluation of the reliability of a radioimmunoassay. Scan. J. Gastroent. 8, 101-112; Hakansson, R. , Kroesen, J.H. Liedberg, G., Oscarson, J., Rehfeld, J.E.. & Stadil, F. (1974) Correlation between serum gastrin concentration and rat stomach histidine decarboxylase activity, J. Physiol. 243, 483-498).
Operations were performed under ether anaesthesia. Fundectomia, comprising resection of the acid producing part of the ventricle, was performed as has been described in detail by Alumets et al (Alumets, J. , El Munshid, H.A., Hakansson, R., Hedenbro, J., Liedberg, G., Oscarson, J., Rehfeld, J.F., Sundler, F. and Vallgren, S., Gastrin cell proliferation after chronic stimulation. Effects of vagal denervation or gastric surgery in the rat. J. Physiol. 298, 557-569 (1980)). Gastrectomia was prepared by resection of the stomach followed by suturation of eosophagus and duodenum end to end. Operated animals were allowed to recover for one week before treatment with the test substance, as has been described in "Pharmacological tests". The test results are given in Fig. 1 and Fig. 2.
Description of the drawings
Fig.l shows the concentration of gastrin expressed as picogram/ml serum with untreated control rats (average of 7 rats, and with ranitidir-e-treated rats (average of 9 rats) after treatment for 26 days. Fig. 2 shows the amount of radioactive calcium which has been incorporated into the skeleton (radius respectively sternum) expressed in cpm/mg
bone ashes. E shows the average of 7 control rats, F shows the average of 9 ranitidine-treated rats, G shows the average of 7 control rats and H shows the average of 9 ranitidine-treated rats.
The continuous lines represent the average of given number of rats and the dashed lines represent the standard error of the average value. The stars designate the significance (i.e. the difference between control and test substance according to Student's t-test p < 0,05 = x; p < 0,01 = xx and p < 0,005 = xxx).
Test results
Ranitidine-treated rats and fundectomized rats developed pronounced and constant hypergastrinemia, which is seen in Fig. 1. The hypergastrinemia which had been developed by treatment with ranitidine stimulated 45Ca-incorporation into the skeleton, which is seen in Fig. 2. Hypergastrinemia caused by fundectomia did not stimulate 45Ca-incorporation into the skeleton.
The tests given above show clearly that treatment with ranitidine led to increased incorporation of calcium into the skeleton. This may be due to hypergastrinemia which in turn via some factor in the acid-producing part of the stomach seems to control the incorporation of calcium into the skeleton.
For clinical use the compounds in known manner are formulated into pharmaceutical formulations for oral, rectal, parεnteral or other mode of administration. Ihε 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 2000 mg per day of active substance.