NL8004904A - MEDICINE AGAINST BONE MINERAL RESORPTION. - Google Patents

Description

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Medicine against resorption of bone mineral.

The invention relates to a medicament against pathological absorption of bone mineral, in particular that in which the bone or tooth structure disappears,

Bone mineral resorption with the tooth structure disappearing includes, for example, surface and / or inflammatory resorption of the tooth root structure and dental ankylosis with replacement resorption.

More generally, the invention relates to an anti-osteoporosis drug. Osteoporosis is a condition in which a decrease in the density of bone tissue (collagen) and bone mineral (Ca10 (PO4) g (0H) 2 or hydroxyapatite) occurs. »» This abnormal rarefactio is due to a disturbance in the bone or bone formation by osteoblasts, which are bone or bone-forming connective tissue cells that cooperate with osteoclasts, and which are cells that break down and resorb bone tissue. Rarefactio can also be a result of excessive osteoclastic activity, or of a disturbance in the osteoblastic-osteoclastic balance. Bone rarefactio is a condition in which the mass but not the volume of the bone decreases. Osteoporosis mainly occurs in 20 adults and can manifest in countless ways, including back pain and spinal deformity. The bones become brittle, which increases the risk of fracture. Different types of osteoporosis are described in Dorland's Illustrated Medical Dictionary, 24th ed., W.B. Saunders Company, London (1965). The different types of osteoporosis include senile osteoporosis due to aging, osteoporosis that occurs after menopause and is associated with a reduction in ovarian production of estrogen following menopause, osteoporosis occurring with prolonged immophilisation, and steroidal osteoporosis as as a result of treatment with 8004904 2 anti-inflammatory steroids. Other diseases that result from long-term pathological resorption of bone mineral are Paget's disease, rheumatoid arthritis and periodontal disease. Paget's disease is characterized by bone decalcification and bone softening followed by abnormal calcification. Bone deformity occurs in both Paget's disease and rheumatoid arthritis. In rheumatoid arthritis, the inflammation of synovial tissues leads to demineralization of adjacent bone surfaces and abnormal mineralization of non-adjacent bone surfaces. In the long run, immobilization of the joints occurs due to progressive deformity of the bone structure. Periodontal disease is also characterized by pathological absorption of bone mineral. As a result, the alveolar bone that carries and holds the tooth is absorbed with the result that the affected tooth falls out.

Hyperparathyroidism (excessive function of the parathyroid glands) which stimulates osteoclastic activity can be mentioned as a cause of bone loss, and furthermore, in many neoplastic diseases, the neoplasms (new formations) which induce pathological absorption of mineral on contact with bone or bone. . Examples of such neoplasms are mammary gland carcinoma cells and plasma cytomas such as multiple myloma. Multiple myloma is known to induce the formation of excessive amounts of osteoclastic activation factor (OAP) resulting in excessive osteoclastic activity and hence bone resorption.

For other causes of bone mineral resorption, increased osteoclastic activity, disturbance of the osteoblastic-osteroclastic balance and / or infiltration of neoplastic cells into bone tissues, see: Mindy, G.R. et al., "Direct Resorption of Bone by Human Monocytes", Science 196: 1109-1111, 1977: Heersche, JNM, "The Mechanism of Osteoclastic Bone Resorption: A New Hypothesis", Proceedings, Mechanism of Localized Bone Loss, Eds. , Horton, Tarpley, and Davis, Special Supplement to 35 Calcified Tissue Abstracts, biz. 437-438, 1978: and Teitelbaum, S.L.

8004904 »N» 3 et al., "Contact-Mediated Bone Resorption by Human Monocytes in Vitro", Proceedings, Mechanism of Localized Bone Loss, Eds., Horton, Tarpley and Davis, Special Supplement to Calcified Tissue Abstracts, biz.

443, 1978.

Numerous anti-osteoporotic agents are known for treating and preventing osteoporosis, for example anabolic steroids, various phosphorus-containing agents, vitamin D and related compounds, estrogenic steroids and calcitonin.

In addition, certain aromatic carboxylic acids have become known as anti-osteoporotic agents. For details on anti-osteoporotic agents, see U.S. Patents 4,125,621 and 4,101,668.

Numerous methods have been developed to determine the anti-osteoporotic properties of a compound.

In one of these, the influence of the tested compound on the formation of cyclic AMP is determined using isolated bone tissue cells as the test medium. This method has been described by Rodan et al., J.B.C. 429: 306 (1974) and Rodan et al., Science 189: 467 (1975), and in more detail in U.S. Patent No. 4,125,621, Example 1.

An effective method to assess the inhibition of bone mineral resorption by a compound has been described by Horton, J.E. et al., "Inhibition of In Vitro Bone Resorption by a Cartilage-Derived Anticollagenase Factor", Science 199: 1342-25 1345 (March 24, 1978). This method relies on assessing the investigated compound's ability to produce hormone-stimulated osteoclastic activation factor, prostaglandin and parathyroid hormone.

Ca release by blocking fetal rat bone in vitro. For the relationship between osteoclastic activity on bone mineral resorption and the enhancement of bone mineral resorption induced by parathyroid hormone stimulation in vivo and in vitro, see Rasmussen et al., "The Physiologic and Cellular Basis of Metabolic Bone Disease" , Williams & Williams, Baltimore, 1974, biz.

144-154.

The Horton technique aforementioned for determining the inhibition of bone mineral resorption using bone tissue culture cells has been described by Raisz L.G. et al., Endocrinology 85: 446 (1969). In addition, interconnected shafts of the radius (radius bone) and ulna (ulna) from 19 day old rat foetera are radiolabelled by injecting the mother with Ca. A day later, the shafts are grown in the described medium containing (optionally) the tested compound and / or a bone resorption stimulant such as the parathyroid hormone. By adding parathyreolde hormone in an amount of, for example, 2.5 µl every 48 hours, the mineral absorption from the bone is stimulated. Culturing is carried out for 120-144 hours with the medium being replaced every 48 hours. The measure of bone mineral resorption is the percentage of Ca delivered by the bone to the medium. This percentage is determined by liquid scintillation.

The active ingredient in the medicaments according to the invention are known compounds with antiallergic activity, in particular disodium chromoglycate and related antiallergic bischromones and benzopyranes.

Disodium chromoglycate-related antiallergic chromones are described in U.S. Pat. Nos. 3,419,578, 3,519,652, 3,673,218, and 4,046,910. Disodium chromoglycate-related anti-allergic benzopyranes are described in U.S. Patents 4,159,273, 3,786,071, 3,952,104, and 4,055,654. A value-25 full compound is proxicromil (FPL 57.787), which is 6,7,8,9-tetra-hydro-5'-hydroxy-4-oxo-10-propyl-4H-naphtho ~ ~ 2,3-6. / pyran-2-carboxylic acid, described in Example 8 of the aforementioned U.S. Patent 4,159,273.

In addition, as active ingredient in the medicaments according to the invention, anti-allergic oxamic acids or derivatives thereof are suitable. Such compounds are described in U.S. Pat. Nos. 3,993,679, 4,159,278, 4,095,028, 4,089,973, 4,011,337, 4,091,011, 3,972,911, 4,067,995, 3,980,660, 4,044,148, 3,982. 006, 4.061.791, 4.017.538, 4.119.783, 35 4.113.880, 4.128.660, 4.150.140, 3.966.965, 3.963.660, 4.038.398, 80 04 90 4 ψ -Ρ 5 3,987,192 , 3,852,324, 3,368,541 and 3,836,164. A valuable antiallergic compound of this type is lodoxamide, which is the double salt of N, N '- (2-chloro-5-cyano-m-phenylene) dioxamic acid and tris- (hydroxymethyl) aminomethane.

Other anti-osteoporotic agents are described in U.S. Patents 4,125,612 and 4,101,663.

As far as disodium chromoglycate is concerned, it should be noted that this compound inhibits degranulation of mastoid cells in apegingiva (gum), but has no discernible effect on gingivitis (gingivitis) in monkeys. See

Nuki, K., el., "The Inhibition of Mast Cell Degranulation in Monkey Gingiva by Disodium Cromoglycate", J. Periodontal. Res. 10: 282-287 (1975), Goldhaber, P., "Heparin Enchancement of Factors Stimulating Bone Resorption in Tissue Culture ", Science 147: 407-408 (1965) and Shapiro, S. et al.," Mass Cell Population in Gingiva Affected by Chronic Destructive Periodontal Disease ", Periodontics 40: 276-278 (1969).

The medicaments according to the invention thus contain as active ingredient at least disodium chromoglycate, abbreviated hereinafter with DNCG or what is hereinafter referred to as an anti-allergic DNCG bio-analog, and optionally one or more other known anti-osteoporotic agents such as anabolic steroids , estrogenic steroids, vitamin D and vitamin D metabolites, phosphorus-containing compounds, inorganic fluoride-containing compounds, calcium salts and calcitonin. The antiallergic DNCG bio-analogs include antiallergic bischromones and benzopyranes other than disodium chromoglycate and further antiallergic oxamic acids or derivatives thereof (oxamates).

The medicaments of the invention are eligible for the following uses: 1) treating or preventing pathological absorption of bone mineral by systemic administration of DNCG or a DNCG bio-analog, optionally together with one or more other known anti-osteoporotic agents consisting of anabolic steroids, 35 estrogenic steroids, vitamin D or a vitamin D metabolite, 8004904 6 phosphorus-containing agents, inorganic fluoride-containing agents, calcium salts and / or calcitonin, and 2) treating inflammation with an anti-inflammatory steroid and DNCG or a DNCG bio-analogue to cure or prevent pathological resorption of bone mineral.

The medicaments of the invention can be used in conventional pharmaceutical form. For the treatment of pathological absorption of dental bone mineral or periodontal diseases, the drugs may be in the form of a dentifrice, toothpowder, mouthwash and the like. The term medicine should therefore be understood in the broadest sense.

The medicaments according to the invention are not only suitable for the treatment of humans, but also of animals such as cattle, horses, rabbits and poultry. For the treatment of animals, the medicaments may be in the form of an animal feed, animal feed supplement or animal premix

Prophylactically, the medicaments according to the invention are used in long-term treatment with high doses of anti-inflammatory steroid, in ovario hysterectomy, after menopause, in old age, in surgical treatment of affected, deformed or transplanted bone or bone tissue, in long-term space travel under decreased gravitational force, with renal dialysis, and with any chance of bone mineral absorption as with periodontal diseases.

The prophylactic dose is generally slightly lower than the treatment dose, which last dose can be increased during therapy until a maximum response is achieved. This is the case when the demineralization begins to decline to disappear completely or almost entirely or to be minimized.

DNCG is preferably administered by insufflation at a dose of 5-20 mg, or parenterally at an equivalent dose. This compound is not effective orally to inhibit bone mineral absorption. Other bischromones in DNCG are also preferably administered by insufflation. For further details in this regard, reference is made to U.S. Pat. No. 4,046,910, Oxamates and Benzopyranes can be administered orally at a dose of 0.1-100 mg. For determining the correct dose of oxamate or benzopyran, reference is made to the aforementioned United States Patent Specification 4,046,910.

As already mentioned, the medicaments for treating periodontal disease are preferably used in a form suitable for topical administration such as toothpaste, tooth powder or mouthwash. Such preparations can be prepared in the usual manner. When the DNCG bio-analog is orally active, the drug is preferably administered orally.

The drugs can be administered parenterally by intravenous injection or infusion and by subcutaneous injection. These formulations can also be prepared in a conventional manner using sterile solutions for injection and infusion.

Insofar as the active ingredients contain carboxyl groups, they may be free or in the form of esters or salts.

In combination with known anti-osteoporotic agents such as anabolic steroids, estrogenic steroids, calcium salts, inorganic fluorides and calcitonin (US Pat. No. 4,125,621), the DNCG or DNCG bio-analog content in the compositions of the invention can be significantly reduced to not lower than 50% to end bone mineral absorption. When used in combination, both types of active ingredients may be in individually packaged form prior to treatment.

Preferred examples of anti-bone mineral resorption bischromones are represented by the formula 1 wherein R1, R2, R3, R4, Rg and Rg are hydrogen, halogen (chlorine, bromine or iodine) lower alkyl (preferably alkyl with 1 -4 carbon atoms) hydroxy or lower alkoxy (preferably alkoxy with 1-4 carbon atoms) 35, and X straight or branched polymethylene with 3-7 carbon- 80 04 90 4 8 atoms including -CH ^ -CH ^ CH -CH ^ -, -CH2 ~ CH2-0-CH2-CH2-, -CE ^ -CO-CB ^ -, -CH2 ~ (o-Ph) -CH2, where o-Ph is 1,2-phenylene, - CH 2 -C (CH 2 OH) (CH 2 Cl) -CH 2 -, -CH 2 -CH (OH) -CH 2 -, or -CH 2 -CH (0H) -CH 2 -O-CH 2 -CH (OH) -CH 2 -, and the salts, esters and amides thereof.

Particular preference is given to DNCG and corresponding other salts and esters (US Pat. No. 3,419,578).

Preferred examples of oxamates having an anti-bone mineral resorption action are the oxanilic acid derivatives represented by the formula II and the phenylene dioxamic acid derivatives represented by the formula 3 wherein one of the symbols R, R, R and R represents hydrogen or cyano , a second and a third of the above-mentioned symbols hydrogen, nitro, amino, halogen (fluorine, chlorine, bromine, iodine), alkyl (preferably alkyl with 1-4 carbon atoms), hydroxy, alkoxy (preferably alkoxy with 1-4 carbon atoms) or trifluoromethyl and may be the same or different, and the remaining symbols represent hydrogen.

Listed below are the results of a study of the inhibitory activity of lodoxamide (as the double salt of N, N '- (2-chloro-5-cyano-m-phenylene) dioxamic acid and 20 tris (hydroxymethyl) aminomethane) on the calcium release from fetal rat bone with and without parathyroid hormone as a stimulant of calcium release. The study was conducted according to the method described by Horton, J.E. et al. in Science 199: 1342-1345 (1978).

45

The calcium released was radiolabeled Ca and was determined by liquid scintillation spectrometry. The amount of parathyroid hormone added was 2 µg / ml and the amount of lodoxamide added was 250 µg / ml. The results are summarized in Table A below. It shows that the oxamate effects a statistically significant reduction in the release of radioactive calcium. Table B below shows the calcium release depending on the amount of oxamate present in the medium over a period of 120 hours. If present in the medium, the amount of parathyroid hormone is again 2 µg / tal.

35 8004 904 45 9

TABLE A

Parathyroid hormone Lodoxamide Average Ca release,%, over periods of 0-48 hours 49-120 hours

Absent in the 11.64, 3.63 period of 0-48 hours

Present 29.04 41.49

Absent in the 8.95 1.99 period of 49-120 hours

Present 36.77 26.98

Absent absent 10.03 3.82

Present 37.93 37.64

TABLE B

45

Amount Average -Ca release,% lodoxamxde, g / ml Without parathyreolde With parathyroid hormone hormone 250 7.11 42.64 100 8.62 40.86 50 8.50 53.87 10 9.89 64.31 1 9.05 74.51 none 8.71 77.44 80 0 4 90 4

Claims (11)

Pharmaceutical preparation with a resilient effect on bone mineral absorption, characterized in that the preparation as active ingredient contains disodium chromoglycate and / or a biologically analogous compound, and optionally one or more anabolic steroids, estrogenic steroids, vitamin D or a vitamin D metabolite, phosphorus-containing agents, inorganic fluoride-containing agents, calcium salts and / or calcitonin. Pharmaceutical preparation according to claim 1, 10, characterized in that the biological analog of disodium chromoglycate is another anti-allergic bischromon, an anti-allergic benzopyran or an anti-allergic oxamic acid or a derivative of oxamic acid, Pharmaceutical preparation according to claim 2, characterized in that the biological analog of disodium chromoglycate is lodoxamide or proxicromil. Pharmaceutical preparation according to claims 1-3, characterized in that the preparation is in the form of a dentifrice such as toothpaste, toothpowder and mouthwash. Pharmaceutical preparation according to claims 1-3, characterized in that the preparation is in the form of an animal feed, animal feed supplement or an animal feed premix. 6. Method for treating pathological absorption of bone mineral, characterized in that the treatment is carried out with disodium chromoglycate or a biologically active analog thereof. 7. Method according to claim 6, characterized in that the treatment is carried out with a less anti-allergic bischromon than disodium chromoglycate, an anti-allergic benzopyran, or an anti-allergic oxamic acid or derivative thereof. Method according to claims 6 and 7, characterized in that the treatment is carried out with disodium chromoglycate, lodoxamide and / or proxicromil. 9. Method according to claims 6-8, characterized in that the treatment is carried out in combination with one or more 8004904 anabolic steroids, estrogenic steroids, vitamin D or a metabolite of vitamin D, phosphorus-containing agents, inorganic fluoride containing agents, calcium salts and / or calcitonin. Pharmaceutical preparation according to claims 5 1-5 and method of treatment according to claims 6-9, characterized in that the biological analog of disodium chromoglycate is a compound of the formula 1 wherein R 1, R 2, R 1, R 1, R 1, R 1 and hydrogen , halogen (chlorine, bromine or iodine) lower alkyl (preferably alkyl with 1-4 carbon atoms) hydroxy or lower alkoxy (preferably alkoxy with 1-4 carbon atoms), and X is straight chain or branched polymethylene with 3-7 carbon atoms including -ch2-ch = ch-ch2-, -ch2-ch2-o-ch2-ch2-, -ch2-co-ch2-, -CH2 ”(o-Ph) -CH2, where o-Ph I , 2-phenylene is -ch2-c (ch2oh) (ch2ci) -ch2 ”, -ch2-ch (oh) -ch2-, or -CH 2 -CH (OH) -CH 2 -O-CH 2 -CH (0H) -CH 2 -, and the salts, esters and amides thereof and / or a compound of the formula 2 and / or 3 wherein one of the symbols R2, R ^, R ^, R ^ and Rg represents hydrogen or cyano, a second and a third of the above-mentioned symbols hydrogen, nitro, amino, halogen (fluorine, chlorine, bromine, iodine), alkyl 20 (preferably alkyl with 1-4 carbon atoms), hydroxy, alkoxy (preferably alkoxy of 1-4 carbon atoms) or trifluoromethyl and may be the same or different, and the remaining symbols represent hydrogen. 11. Medicines, pharmaceutical preparations and other preparations as well as treatment methods as described in the description. 80 04 90 4