DE3033545A1 - USE OF KNOWN ANTIALLERGENIC AGENTS IN THE FIGHT AGAINST PATHOLOGICAL MINERAL RESORTION STATES - Google Patents

Description

Use of known antiallergenic agents in the fight against pathological mineral res orpti ons conditions

The invention relates to a new or »second indication area of known medicaments and using known ones Active ingredients prepared new medicines for the treatment of various conditions or diseases of Animals and humans, especially the use of known pharmacological agents in treatment pathological mineral resorption states of animals and humans »

Mineralresorptionszustände j by which treatment the invention is concerned are ACT5 states ,, the physiological, in particular pathological causes have, and in which there is a loss of skeletal or tooth structure _o

Characterized by Θ ± η @ η loss of tooth structure or structure © Mineralresorptionssustäad © include, for example, sine superficial © raid / or inflammatory resorption of the tame root structure some a © Dental ankylosis with Er = aat2resorption _o Di © tooth demineralization caused by such shock waves is known and from diagnose the treating dentist or veterinarian without further ado,

From a direct loss of skeletal structure or structure

13Ö0H / 1117

Accompanied mineral resorption states show up in the various diseases and clinical pictures. It is also known of certain mineral resorption states that they are unfavorable sequelae of numerous other diseases and clinical pictures.

A major class of mineral resorption conditions are the various forms or types of osteoporosis. Osteoporosis is the abnormal bone loss due to the inability of the osteoblasts to deposit bone matrix, excessive osteoclast activity or other disorders of the osteoblast / osteoclast balance. A loss or a thinning of bone (substance) denotes the condition that the bone is or becomes less dense, ie a density _B but no loss of volume suffers. Osteoblasts are the cells that are responsible for bone formation. In healthy vertebrates and humans, they interact with osteoclasts, that is, the cells whose function is to absorb and remove bone substance.

Osteoporosis is, in particular, a loss of bone that occurs in old age with degradation of the compacta from the inside and wide-meshed enlargement of the medullary canals. Here, there is both a loss of density of Knochenmatriss (substrate, collagen) and bone mineral C ₁₀ (PO,) g (0H) ₂ or "Hydroxyapatlt" _o Osteoporosis is typically numerous symptomatic conditions including back pain and a Accompanied deformation of the spine. Furthermore, there is bsi from osteoporosis suffering vertebrates and humans to a Knochenversprödung _t so that the susceptibility to fractures increases. There are different types of osteoporosis (see _o "Dorland's Illustrated Medical Dictionary * ³ ₀ 24th edition ₉

1300U / 1 1 17

W.B.Saunders Company, London (1965). Among the various There are types of osteoporosis that can be traced back to aging processes Age osteoporosis, a post-menopausal osteoporosis that affects the post-menopausal decreased ovarian production of estrogen is due, one due to "disuse" Osteoporosis as a result of long-term immobilization and steroid osteoporosis as a result of treatment with anti-inflammatory or anti-inflammatory steroids. Other diseases worth mentioning, the main ones Permanent pathology partly resulting from the respective mineral resorption state are Paget's disease, rheumatoid arthritis and periodontal disease. Paget's disease is caused by an initial decalcification of the bones and softening and subsequent abnormal calcium deposition. The abnormal recalcification leads to deformed bones and other unfavorable sequelae. Somewhat similar in its final appearance is the pathological mineral resorption condition resulting from rheumatoid arthritis. at In this disease state, the inflammation of synovial tissue leads to demineralization of adjacent bone surfaces and abnormal mineralization of non-contiguous surfaces. The long term effect of this The disease process is typically an immobilization of the affected joints as a result of progressive Malformation of the bone structure or the bone structure. Also tooth root skin diseases or periodontal diseases are characterized by a pathological state of mineral resorption. This leads to resorption of the alveolar bone. The alveolar bone serves as a carrier and anchoring for the teeth. Its progressive absorption leads to a loosening and a subsequent one Loss of the affected tooth.

1300U / 1 117

Also other diseases induce mineral resorption states in the skeleton, which are suitable for the afflicted animals or adversely affect people. For example, hyperparathyroidism leads to excessive formation of Parathyroid hormone, an agent known to stimulate osteoclast activity. With numerous neoplastic diseases induce pathological mineral resorption states when the neoplasms come into contact with skeletal structures, which are accompanied by pathological phenomena. So it is, for example, of the most diverse Types of mammalian or human cancer cells are known to induce such pathological conditions.

It is also known from other neoplastic diseases that they cause pathological mineral resorption states in skeletal structures bring about. Such diseases include plasmacytomas, for example imaltiples M ^ lom. . Latter Disease is known to induce the production of excessive amounts of osteoclast activating factor, resulting in a excessive osteoclast activity and consequent resorption of skeletal structures.

So far, the mineral resorption state has been attributed to the excessive activity of the osteoclasts, disturbances in the osteoblast / osteoclast balance and / or an infiltration of mineral tissue by neoplastic cells. The mineral resorption state can, however, also be influenced by the activities of other cell types alone or in combination (cf. GRMindy et al., "Direct Resorption of Bone by Human Monocytes ¹¹ , Science 196, 1109-1111 (1977); JNM Heersche," The Mechanism of Osteoclastic Bone Resorption: A New Hypothesis ". Proceedings, Mechanism of Localized Bone Loss, editors Horton, Tarpley and Davis, Special Supplement to Calcified Tissue Abstracts, pp. 437-438 (1978), and

130014/1117

S.L. Teitelbaum and coworkers, "Contact-Mediated Bone Resorption by Human Monocytes in Vitro ", Proceedings, Mechanism of Localized Bone Loss, editor Horton, Tarpley and Davis, Special Supplement to Calcified Tissue Abstracts, page 443 (1978)). Consequently, a Mineralre sorption state due to the most varied of Cells influenced processes occur and lead to a loss of bone or tooth tissue.

There are numerous anti-osteoporotic agents used to treat or prevent osteoporosis. Such means are for example anabolic steroids, various phosphorus-containing agents, vitamin D and related substances, estrogenic steroids and calcitonin. Certain aromatic carboxylic acids have also been found to be useful anti-osteoporotic Agents (see U.S. Patents 4,125,621 and 4,101,668).

There are also already a wide variety of methods for evaluating the effectiveness of anti-osteoporotic agents. According to one proposal, the effectiveness of any anti-osteoporotic agent can be determined by determining the Influence of the agent concerned on the formation of cyclic AMP using isolated bone cells as the test medium (cf. Rodan and coworkers in "J.B.C." 429, 306 (1974) and Rodan and coworkers in Science 189, 467 (1975) and U.S. Patent 4,125,621, Example 1).

An effective method for determining the inhibition of mineral absorption states by chemical means becomes by J.E. Horten and coworkers in "Inhibition of In Vitro Bone Resorption by a Cartilage-Derived Anticollagenase Factor »in the journal" Science "199, 1342-1345

130014/1117

(March 24, 1978). The method described by Horton and co-workers determines the ability of a chemical Connection to the blockade of the osteoclast activating factor, prostaglandin and the parathyroid

45

hormone-stimulated ^ Ca release from fetal rat bones in vitro. The relationship between osteoclast activity in bone resorption and acceleration of parathyroid hormone stimulation induced bone resorption states, both in vivo and in vitro, is known (see H. Rasmussen et al., "The Physiology and Cellular Basis of Metabolie Bone Disease ", Williams & Williams Publishers, Baltimore, 1974, pages 144-154).

The technique proposed by Horton for determining the inhibition of mineral resorption states makes use that of L.G. Raisz and coworkers in "Endocrinology" 85, 446 (1969) described bone culture techniques. to for this purpose ^ pieces of the radius and ulna of nineteen-day-old rat fetuses are inoculated by the mother

45
radioactively marked with ^ Ca on the day before the culture was established. The pieces are then cultured in the medium described with, if appropriate, the chemical compound to be tested and / or an agent which stimulates bone resorption, such as parathyroid hormone. Mineral resorption of the skeletal structure is stimulated by adding parathyroid hormone / ml, typically 2.5 IU every 48 h. The cultures are maintained for 120 to 144 hours, with the medium being changed every 48 hours. The pro-

45

centual release of Ca from the bones into the culture medium serves as a measure of bone resorption. The degree of mineral absorption is determined by liquid skintillation spectrometry by counting the "Oa radioactivity present per minute in the culture medium".

130014/1 117

The known compounds used according to the invention in the context of a new indication are antiallergic agents, especially disodium chromoglycate, antiallergic biological analogues of disodium chromoglycate are antiallergic bishromones that are related to disodium chromoglycate (see US Pat. No. 3,419,578,

3,519,652, 3,673,218 and 4,046,910).

Another class of antiallergic biological analogues of disodium chromoglycate are the antiallergic benzopyrans, in particular those from compounds known in U.S. Patents 4,159,273, 3,786,071, 3,952,104 and 4,055. A special mention should be made of these Compounds Proxicromil (FPL 57 787), namely 6,7,8,9-tetrahydro-5'-hydroxy-4-oxo-10-propyl-4H-naphtho [2,3-6 ] -pyran-2-carboxylic acid according to Example 8 of US Pat

4 159 273.

Another class of antiallergic biological analogues of disodium chromoglycate are those from U.S. Patents 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, 4 113 880, 4 128 660, 4 150 140, 3 966 965, 3 963 660, 4,038,398, 3,987,192, 3,852,324, 3,368,541 and 3,836,164 known antiallergic oxamic acids and their Called derivatives. A particularly important antiallergic oxamate is lodoxamide, namely N, N '- (2-chloro-5-cyano-m-phenylene) -dioxamic acid as tris (hydroxymethyl) aminomethane salt (THAM salt).

Disodium chromoglycate and its antiallergic biological analogues as well as their antiallergic effectiveness are known (cf. the US patents mentioned). Further-

1300U / 1 1 17

numerous anti-osteoporotic agents are known (See in particular U.S. Patents 4,125,612 and 4,101,663).

Although disodium chromoglycate is a mast cell degranulation to inhibit in the gums of monkeys, the disodium chromoglycate apparently shows no detectable Influence on the inflammation of the gums in monkeys (cf. K.Nuki and coworkers, "The Inhibition of Mast Cell Degranulation in Monkey Gingiva by Disodium Cromoglycate "in" J. Periodontal. Res. ", 10, 282-287 (1975) and those therein references cited, in particular P. Goldhaber, "Heparin Enhancement of Factors Stimulating Bone Resorption in Tissue Culture ", in" Science "147, 407-408 (1965), and S. Shapiro and coworkers, "Mass Cell Population in Gingiva Affected by Chronic Destructive Periodontal Disease" in "Periodontics", 40, 276-278 (1969)).

The invention relates to the use of disodium chromoglycate or a biologically active analog of disodium chromoglycate in an amount effective to inhibit or Prevention of pathological mineral resorption in mammals or humans exhibiting or susceptible to such a condition (by systemic administration of the agent in question).

According to the invention, disodium chromoglycate can be used to prevent or treat such pathological mineral resorption states or its biological analogs together with known anti-osteoporotic agents, e.g. anabolic steroids, estrogenic steroids, vitamin D and its metabolites, phosphorus-containing compounds, inorganic fluoride-containing agents, calcium salts and calcitonin can be used.

130014/1117

If inflammatory diseases are treated with anti-inflammatory or anti-inflammatory steroids, according to the invention by using a to prevent or inhibit by the respective anti-inflammatory or - adverse steroid-induced pathological mineral absorption conditions sufficient amount of disodium chromoglycate or a biological analogue of the same pathological mineral resorption states opposite effect to the administration of the respective Steroids-related pathological mineral absorption conditions are combated.

According to the invention, medicaments for the prevention or treatment of pathological mineral resorption states are available to the person skilled in the art in the form of a unit dose or dosage unit with at least one known anti-osteoporotic agent in the form of an anabolic steroid, an estrogenic one Steroid, vitamin D or its metabolites, a phosphorus-containing agent, an inorganic fluoride containing agents, calcium salts and calcitonin and, moreover, an effective amount of disodium chromoglycate or a biological analog that is effective against pathological mineral resorption states.

Furthermore, according to the invention, the person skilled in the art receives a medicament for the treatment of inflammatory diseases in the form a unit dose or dosage unit with an anti-inflammatory or anti-inflammatory steroid and additionally Disodium chromoglycate or a biological analog effective against pathological mineral absorption conditions this in a to prevent or inhibit the administration of the anti-inflammatory in question pathological or adverse steroid traceable

130014/1117

Mineral absorption conditionsxi sufficient quantity.

The invention also relates to a dentifrice against pathological mineral resorption conditions in the tooth area or diseases in the tooth root area, which (with usual application in the oral area) in a given Volume as much disodium chromog lycat or one against pathological mineral resorption states containing effective biological analogues of the same that in the dental area occurring pathological mineral resorption conditions or those attributable to the periodontal disease inhibited or prevented.

The dental care product according to the invention of the type described can also be in the form of a mouthwash.

The invention also relates to an animal feed for feeding to mammals suffering from pathological mineral resorption states suffer or are susceptible to it, which is characterized by being disodium chromoglycate or a biological analog of the same effective against pathological mineral resorption conditions in one contains such a concentration that when a certain amount is fed at given intervals the respective pathological mineral resorption state is inhibited or prevented during the relevant interval.

The feed according to the invention can also be made from a feed premix containing the active substance in question be prepared with respect to the active ingredient with regard to on its effective concentration on the dilution ratio (with other feed ingredients and the like) is to be observed.

1300U / 1 1 17

The further indication for disodium chromoclycate shown according to the invention and its biological analogs applies to animals in general, particularly mammals and (Valuable) domestic animals such as cattle, horses, rabbits and cats, chickens, turkeys, geese, ducks and the like are preferred People.

Disodium chromoglycate and its biological. Analogs for inhibition or prophylaxis Use pathological mineral resorption conditions. the Conducting proper medical therapy requires that against pathological mineral resorption conditions Effective prophylactic agents are only used in cases in which the animal to be treated is used or the patient to be treated is particularly susceptible to the occurrence of pathological mineral resorption conditions. The conditions and circumstances that make the average dentist, doctor, or veterinarian more vulnerable without further ado, are:

1. Long-term anti-inflammatory therapy or adverse steroids in high doses;

2. Removal of the ovaries and uterus;

3. menopause;

4. old age;

5. Inhibitory, repairing and / or corrective surgical operations in which the diseased, deformed and / or transplanted mineralized tissue is involved;

6. Long-term space travel under reduced conditions Gravity;

7. kidney dialysis and

8. a diagnosis of a disease or condition

1300 rev / 1 117

who has a pathological mineral resorption condition a possible consequence is, e.g. a disease of the periodontal membrane.

In the prophylactic use of the above remedies against pathological mineral resorption states, this becomes theirs Prevent effective dose in the manner still discussed later for therapeutic use accordingly the response of the respective patient or animal determined. As a rule, it is slightly below the to Treatment of pathological mineral resorption conditions required dose.

A pathological mineral absorption state which is inhibited or prevented according to the invention encompasses the most varied Appearances or pictures of the type described, in which the long-term effects on the animal or man are unfavorable and which are accompanied by a direct or indirect pathological process.

Pathological mineral resorption states do not occur in dentistry, human medicine or veterinary medicine seldom occurs so that they can be diagnosed without difficulty by the average dentist, doctor, or veterinarian can be.

The dosage rule for those used according to the invention Remedy for pathological mineral resorption states depends on the most diverse factors, e.g. the type, the Age, weight, sex and medical condition of the animal or patient, the severity of the pathological State of mineral absorption and its duration and the particular agent administered (disodium chromoglycate or the biological analogue thereof effective against pathological mineral resorption states). A through

1300U / 1 1 17

The cutting doctor, dentist or veterinary surgeon can do this without difficulty after his diagnosis of a pathological mineral resorption state the effective amount of that which can be used according to the invention to inhibit the progression of this state Identify and prescribe remedies for pathological mineral resorption conditions. Here the doctor will Dentist or veterinarian usually start with a relatively low dosage and then continue this until reaching one increase maximum response. One such response is reached when demineralization begins to decline or later practically stops completely or when it remains at a far reduced minimum value.

The agents against pathological mineral resorption states which can be used according to the invention are the various known antiallergenic agents based on disodium chromoclycate and its biological Analogs. Examples of such agents are disodium chromoclycate, other antiallergenic bischromones, antiallergenically active benzopyrans and antiallergenically active Oxamic acids and their derivatives (oxamates).

• l

When disodium chromoglycate is used as an agent for pathological mineral resorption conditions, it is preferred by insufflation at a dose of 5 to 20 mg per patient per dose or at an equivalent parenterally administered en dose. The compound in question is, when administered orally, against pathological mineral resorption conditions not effective. If the injection dose is noticeably higher than 20 mg / patient, the systemic dose must be used Carefully consider the toxicity of disodium chromoglycate to be pulled. The further dosage then results from a weighing up of the advantages of the agent in relation to any relevant toxic phenomena

1300U / 1 1 17

nations. Bischromones other than disodium chromoglycate, which are effective against pathological mineral resorption conditions, are preferably administered by injection or insufflation. The the disodium socket specified equivalent effective dosage is obtained from conventional experiments (cf. ₀ US-PS 4,046,910, in which methods are described, by which for the various against pathological Mineralresorptionszustände effective Bischromone, the relative intensity values, and hence the relative dosage determine).

The starting dose for against pathological mineral resorption conditions effective oxamates or benzopyrans when administered orally is 0.1 to 100 mg per patient per Dose. When oral doses amount to about 100 mg per The systemic toxicity of the oxamate or benzopyran in question must be administered to the patient per dose carefully determine and follow-up doses by weighing the benefits of the agent in relation to any toxic ones Appearances are determined. The effective doses for effective against pathological mineral resorption conditions Oxamates and benzopyrans result from conventional experiments (cf. US Pat. No. 4,046,910, which describes processes from which the relative strength values and consequently determine the relative dosages for the compounds used).

In order to be able to fully exploit the positive results that can be achieved according to the invention, one must - as already indicated Route of administration can be chosen which allows a systemic effect. Topical ones are particularly preferred Administrations where localized effects can be achieved after absorption. So be in treatment of pathological mineral resorption states as

130014/1117

Secondary diseases or as a result of periodontal diseases liquids to be administered orally, e.g. mouthwashes, or gels or viscous flowable masses, e.g. toothpastes and tooth gels, preferably used as carriers.

When effective against pathological mineral resorption conditions biological analogues of disodium chromoglycate known to be effective orally will be the oral route of administration preferred.

Parenteral routes of administration, as determined, provide the desired one at a suitable equivalent dosage Activity. The agents which can be used according to the invention can thus injected intravenously or infused or injected subcutaneously. Regardless of the route of administration chosen the agent effective against pathological mineral resorption conditions becomes more commonly known Formulated into a medicinal product.

When powders, pastes or gels are required, this becomes effective against pathological mineral absorption conditions Agents of the type described incorporated into a conventional dentifrice. In the case of parenteral administration sterile solutions for injection or prepared for infusion purposes.

The various carboxyl group-containing agents for pathological mineral absorption states are used in any common pharmaceutically acceptable forms used. So these funds can usually be found in Form of free acids and in ester or salt form are used.

1300U / 1 1 17

According to a further embodiment of the invention, according to the invention, the attack against pathological mineral resorption states usable agents in the form of disodium chromoglycate or its biological analogues in addition in Common forms of therapy for pathological mineral resorption conditions for use. Such common forms of therapy are, for example, the most varied of chemical ones Therapeutic measures as described in US Pat. No. 4,125,621. When performing such combination therapies one often achieves a sufficient effect against pathological mineral resorption conditions with reduced effectiveness Dose of the agent that can be used according to the invention against pathological mineral resorption states.

In this embodiment of the invention, the person skilled in the art will find new medicaments for therapy against pathological Mineral resorption conditions given. The new drugs consist of combinations of two or more active agents, one of which is the agent that can be used according to the invention and the second and further Agent consists of a known agent (s) for the treatment of osteoporosis and osteoporotic phenomena (exist). Such previously known anti-osteoporotic agents are, for example, anabolic steroids, estrogens Steroids, calcium salts, inorganic fluorides and calcitonin from various sources. Such new drugs are expediently used to inhibit pathological mineral resorption states brought. The dosage of the agents which can be used according to the invention can often be used against pathological Mineral resorption states as opposed to their sole use to inhibit or prevent the conditions concerned to decrease.

In these new drugs, the inventive

1300U / 1 1 17

settable remedies against pathological mineral resorption conditions per dose unit in an amount corresponding to the at least 50% amount of the agent in question sole use brought into use. The other usual remedies contained in it for pathological mineral resorption conditions are used in known amounts commonly used in the treatment of osteoporosis.

According to the invention, the person skilled in the art will also find new medicaments with the agents that can be used according to the invention against pathological mineral resorption conditions, as a result of the topical activity of these agents in the treatment of dental mineral absorption pathological conditions are extremely convenient to use. The new dentifrices and mouthwash contain in addition to the invention Usable agents against pathological mineral resorption states common components.

The dentifrices contain so much of the agent against pathological mineral resorption states that can be used according to the invention, that when a given amount of the dentifrice is applied to the teeth and gums the desired., effect against pathological mineral resorption states is achieved. Such dentifrices are prepared in a conventional manner. You insist in particular from combinations of the agents that can be used according to the invention against pathological mineral resorption states and customary dentifrices, e.g. commercially available toothpastes, tooth gels or tooth powders. Such dentifrices are particularly suitable for the topical treatment of pathological mineral resorption conditions as secondary Conditions related to root diseases.

In a similar way, the invention relates to other oral compositions

1300H / 1 1 17

tel with the compounds which can be used according to the invention against pathological mineral resorption conditions in solutions suitable for mouth rinsing purposes. With such means are the compounds which can be used according to the invention against pathological ones Tooth resorption conditions contained in common mouthwashes in such a concentration that a given Volume of the mouthwash one to produce the desired effect against pathological mineral resorption conditions contains a sufficient amount of the active ingredient when it comes into contact with the tissues of the oral cavity.

Finally, the invention also relates to new agents with known anti-inflammatory or anti-inflammatory steroids. These combination preparations are preferred carriers for treatment with anti-inflammatory or anti-inflammatory steroids and contain, together with a standard amount of the steroid, an effective amount of that which can be used according to the invention Compounds against pathological mineral resorption conditions.

The novel medicaments described are preferably available in the form of unit doses or dosage units posed. In this form, the medicaments contain a single dose or a given series of doses Amount of the relevant pharmacological active ingredient required over a given time interval. For combination therapy such unit doses or dosage units from a single pharmaceutical dose can contain both Means or in pairs or in some other way assigned individual subunits with or from the separate Active ingredients. The new drugs can be supplied in packs with a number of subunits intended for Administration over a longer period of time are arranged in a certain way. So both

1300U / 1 1 17

for example, according to a preferred embodiment of the
Invention of the new drug individual subunits
with smaller or larger amounts of the agents that can be used according to the invention against pathological mineral resorption states for the start of therapy and gradually increasing or decreasing amounts of those that can be used according to the invention
Include agents against pathological mineral resorption conditions for continuation of therapy.

The orally effective, according to the invention against pathological
Mineral resorption states usable compounds
the base of disodium chromoglycate or its biological analogues can also be accommodated in feed or feed premixes. The amount of active ingredient in a feed must be so large that taking into account the
usual feed regulations the desired effect
achieved against pathological mineral resorption states
will. Such feed and feed premixes
are prepared in a conventional manner. They are particularly suitable for treating animals in which
pathological mineral resorption conditions affect the economic value of the animals. Examples of pathological mineral resorption conditions that impair the economic value of animals are periodontal diseases in sheep and horses, milk fever in
lactating cattle and bone diseases in egg-laying poultry.

By using the according to the invention for another
and compounds of the type mentioned, which are known far away from the field of indications, can be effectively inhibited or controlled by systemic administration to mammals and humans.

Examples of agents which can be used according to the invention against

130014/1 1 17

Pathological mineral resorption states are compounds the formula:

COOH

where mean:

R ₁ , R ₂ , RX, R ^, Rc and Rg ₁ which can be the same or different, each a hydrogen or halogen, for example chlorine, bromine or iodine atom, a short-chain alkyl, preferably an alkyl radical with 1 to including 4 carbon atom (s), a hydroxy radical or a short-chain alkoxy, preferably an alkoxy radical having 1 to 4 carbon atoms inclusive and

X is a straight or branched-chain polymethylene radical with 3 to 7 carbon atoms inclusive or a radical of the formulas -CH ₂ -CH = CH-CH ₂ -, -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -, -CH ₂ - CO-CH ₂ -, -CH ₂ - (O-Ph) -CH ₂ , with o-Ph being a 1,2-phenylene radical, -CH ₂ -C (CH ₂ Oh) (CH ₂ CI) -CH ₂ - , -CH ₂ -CH (OH) -CH ₂ or -CH ₂ -CH (OH) -CH ₂ -O-CH ₂ -Ch (OH) -CH ₂ -, as well as their salts, esters and amides.

According to the invention, as against pathological mineral resorption conditions effective bischromone disodium chromo-glycate and various other salt and ester forms it is preferred (see US Pat. No. 3,419,578).

According to the invention as against pathological mineral resorption

1300U / 1 117

State-effective oxamates, preferred are the oxanilic acid derivatives of the formula II and the phenylenedioxam derivatives of the formula III

0 0

Il Il

NH-C-CR ₁

II

0 0

il ii
R ₁ -C -C -NH

0 0

III

where mean:,

one of the radicals R ₂ , R ,, R ^, R ₅ and Rg is a hydrogen atom or a cyano radical,

a second and a third of the radicals R ₂ , R ,, R ^, R ₅ and Rg, which can be identical or different, each a hydrogen or halogen atom, for example a fluorine, chlorine, bromine or iodine atom, a nitro -, amino, alkyl, preferably alkyl with 1 to 4 carbon atoms inclusive, hydroxy-9 alkoxy, preferably alkoxy with 1 to 4 carbon atoms inclusive or trifluoromethyl radical and

the remaining radicals R ₂ , R ,, R ^, R- and Rg are hydrogen atoms.

1300U / 1 1 17

In summary, the invention offers a surprising and highly unexpected way of using compounds known and already used in a far-off area of indication in a new area of indication.

The following example shows the excellent action of the compounds based on disodium chromoglycate which can be used according to the invention for the inhibition or control of pathological mineral resorption conditions.

example

The inhibition of bone resorption in vitro is through the blocking of the parathyroid hormone stimulated Ca release from fetal rat bones by lodoxamide, i.e. N, N '- (2-chloro-5-cyano-m-phenylene) -dioxamic acid determined in the form of their bis-tris (hydroxymethyl) aminomethane salt.

The activity of lodoxamide against pathological mineral absorption conditions is according to that described by J. E. Horton et al. in Science 199, 1342-1345 (1978) Procedure tested. The following tests are carried out:

A) There are tests, the results of which are summarized in the following Table I, with media with or without parathyroid hormone (2 μg / ml) stimulation (Column 1 of Table I) and with or without oxamate (250 μg / ml) (Column 2 of Table I). Thereafter the amounts of released radioactive calcium (percentage mean released amount) for the first 48 h (column 3-A of Table I) and for the

1300U / 1 1 17

Hours 49 to 120 (Column 3-B of Table I) are recorded. The results in Table I show that the Oxamate showed a statistically significant decrease in the release of radioactive calcium over time induced by the presence of the oxamate. The results thus demonstrate the effectiveness of the oxamate as an agent against pathological mineral resorption conditions.

B) Another experiment proves the inhibition of the release of radioactive calcium by the oxamate in a dose-dependent manner Way. Column 1 of Table II contains information about the various concentrations ^ g / ml) of the oxamate. Column 2 of Table II contains information on blank values with regard to the release of radioactive substances Calcium for 120 h (mean percentage release). Column 3 contains information about the release of radioactive calcium with stimulation by parathyroid hormone (2 μg / ml) in the presence of Oxamate. The results in Table II indicate that the oxamate exhibited a dose-dependent decrease in release radioactive calcium causes.

1300U / 1 1 17

TABLE I. 1 2 3 B.
49-120 h Stimulants Duration of the before
being in hand
of the oxamate
in h Percentage mean
lere release of 3.63
41.49 A.
0-48 h 1.99
26.98 without
Parathyroid hormone 0-48 11.64
29.04 3.82
37.64 without
Parathyroid hormone 49-120 8.95
36.77 without
Parathyroid hormone without 10.03
37.93

TABLE II 3 42.64 1 2 45
Average percentage release of approx 40.86 Oxamate in μβ / ναί Blind test with oxamate and ne-
(without oxamate or parathyroid
Parathyroid hormone
hormone) 53.87 7.11 64.31 250 8.62 74.51 100 8.50 77.44 50 9.89 10 9.05 1 8.71 without

130014/1117

Claims (1)

Henkel, Kern, Feiler & HänzeI Feten tan walte Registered Representatives before the European Patent Office MöhlstraBe37 D-8000 Munich 80 THE UPJOHN COMPANY, Tel · 089 / 982085-87 Kalamazoo, Mich., V.St.A. ^ a Telex: 0529802hnkld Telegrams: ellipsoid John Edward Horton ■ TUC 370 9-1 Wilmont Street
Framingham, Mass., V.St.A. PATENT CLAIMS 1. Use of disodium chromoglycate or one against pathological mineral resorption conditions have effective biological analogs thereof in systemic administration an amount effective to effectively treat or prevent pathological mineral absorption conditions in inhibiting or preventing pathological mineral resorption states. 2. Use of an agent according to claim 1 together with at least one known anti-osteoporotic agent in the form of an anabolic steroid, an estrogenic one Steroid, from vitamin D or a metabolite thereof, a phosphorus-containing compound, an inorganic one Fluoride-containing agent, calcium salt or calcitonin. 3. Using an anti-inflammatory or anti-inflammatory steroid along with or with disodium chromoglycate biological analogues thereof effective against pathological mineral resorption conditions in one for prevention 1300U / 1117 or inhibition of upon administration of the anti-inflammatory or steroid-induced pathological mineral resorption conditions are effective Amount in the treatment of inflammatory diseases. 4. Medicinal product in unit dose or unit dosage form for prevention or treatment pathological mineral resorption states with at least one known anti-osteoporotic agent in the form of an anabolic steroid, one estrogenic steroid, vitamin D or a metabolite thereof, a phosphorus-containing agent, an agent containing inorganic fluoride, a calcium salt or calcitonin, characterized in that that there is also such an amount of disodium chromoglycate and / or one against the pathological Mineral resorption states contain effective biological analogs of the same that put them together with the amount of the known anti-osteoporotic agent (s) one for prevention or inhibition unit dose or dosage unit effective for the pathological mineral absorption conditions concerned supplies. 5. In the form of a unit dose or dosage unit present medicament for the treatment of inflammatory diseases with an anti-inflammatory or anti-inflammatory steroid, characterized in that it additionally contains such an amount of disodium chromoglycate and / or a biological analog of the same effective against pathological mineral resorption states that thereby an effective prevention or inhibition of pathological mineral risk conditions attributable to administration of the anti-inflammatory or anti-inflammatory steroid is ensured. 1300U / 1117 6. Dentifrices for administration to mammals or humans suffering from pathological mineral resorption conditions suffer from or are susceptible to such diseases in the dental area or from periodontal diseases are characterized in that it is disodium chromoglycate and / or an anti-pathological mineral resorption condition contains effective biological analogue thereof in such a concentration that a given volume (of the dentifrice) contains so much active ingredient that when applied to the tissue an effective inhibition or prevention of pathological mineral resorption conditions in the area of the oral cavity in the dental area or pathological mineral resorption conditions as secondary phenomena of a Tooth periodontal disease is guaranteed. 7. Mouthwash for administration to mammals or humans who suffer from pathological mineral resorption conditions in the tooth area or from periodontal diseases or are susceptible to such diseases, characterized in that it contains disodium chromoglycate and / or an effective against pathological mineral resorption conditions ¹ biological analogue of the same in such a concentration that a given volume (of the mouthwash) contains so much active substance that when applied to the tissue in the area of the oral cavity, an effective inhibition or prevention of the pathological mineral resorption conditions in the tooth area or the pathological mineral resorption conditions as secondary symptoms of a periodontal disease is guaranteed. Θ. Animal feed for feeding to animals affected by pathological Mineral resorption states suffer or for that 1300U / 1 117 Occurrence of such states are susceptible, characterized in that it is disodium chromoglycate or a biological analogue of the same effective against pathological mineral resorption conditions in such a Concentration contains that given ingestion of a certain amount of feed by the animal Time intervals one to inhibit or prevent the pathological mineral resorption states during the given periods of time effective amount of active ingredient is ingested. 9. Feed premix for the preparation of animal feed for feeding to animals suffering from pathological mineral absorption conditions suffer or are prone to the occurrence of such conditions, characterized by that they have so much disodium chromoglycate or one s against pathological mineral resorption states effective biological analogues of the same contains that after dilution the feed premix with animal feed in a given ratio the amount of active ingredient in the through the animal has consumed sufficient amount of feed over a given tent space to during this Period of time to effectively inhibit or prevent the pathological mineral resorption states. 10. Use according to any one of claims 1 to 3 of disodium chromoglycate, Lodoxamide or Proxicromil as an active ingredient. 11. Means according to one of claims 4 to 9, characterized that it contains disodium chromoglycate, lodoxamide or proxicromil as an active ingredient. 130014/1117