AU740605B2 - Medicaments containing bisphosphonic acids and derivatives thereof which are provided for preventing and treating autoimmune diseases and allergies - Google Patents
Medicaments containing bisphosphonic acids and derivatives thereof which are provided for preventing and treating autoimmune diseases and allergies Download PDFInfo
- Publication number
- AU740605B2 AU740605B2 AU55033/99A AU5503399A AU740605B2 AU 740605 B2 AU740605 B2 AU 740605B2 AU 55033/99 A AU55033/99 A AU 55033/99A AU 5503399 A AU5503399 A AU 5503399A AU 740605 B2 AU740605 B2 AU 740605B2
- Authority
- AU
- Australia
- Prior art keywords
- substituted
- residue
- unsubstituted
- extracts
- derivatives
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention relates to the use of bisphosphonic acids and the derivatives thereof for producing medicaments for preventing and treating autoimmune diseases or allergies combined with the autoantigens specifically used for treating the respective autoimmune disease or combined with the allergens specifically used for treating the respective allergy. Some examples of the bisphosphonic acids or derivatives thereof which are used according to the invention include amino-hydroxy-methylidene-bisphosphonic acid (AMP), 2-amino-1-hydroxyethylidene-1,1-bisphosphonic acid (AEP), pamidronic acid, alendronic acid, 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (AHP), amidinomethylene-bisphosphonic acid (AIMP), ibandronic acid, risedronic acid, zoledronic acid, cimadronic acid, and tiludronic acid. Some examples of autoimmune diseases in which bisphosphonic acids or the derivatives thereof can be used include rheumatoid arthritis, severe myasthenia, diabetes mellitus, uveitis, and scleroderma. The bisphosphonic acids or the derivatives thereof and the autoantigens or allergens can be applied simultaneously or in succession. The preparations of the combinations can be used in solid form, as ointments, as solutions or as sprays.
Description
V
Field of the invention This invention relates to pharmaceutical preparations for the prevention and treatment of autoimmune disorders and of allergies.
It is known that autoimmune disorders, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, uveitis etc., and allergies, in particular food allergies, nickel allergy and pollen allergies etc. are attributable to an inappropriate reaction by the body's immune system.
It is furthermore known that, due these inappropriate reactions of the immune system, endogenous substances O (autoantigens) are perceived as foreign substances and a defence reaction develops against them which results in damage to the body's own tissue. Depending upon the organ system involved, some 40 autoimmune conditions have been identified. These defence reactions may be directed both against individual cell constituents and against entire cells or organs.
Allergies are known to be the result of hypersensitivity towards certain substances, the allergens, which gives rise to an over-reaction of the immune system. In other words, affected subjects react to certain substances (the allergens) with specific symptoms as a defence against the allergen.
Prior art Attempts to treat autoimmune disorders caused by inappropriate reactions of the immune system with nonspecifically acting immunosuppressants have proved entirely unsatisfactory as the use of immunosuppressants brings about a general inhibition of inflammatory reactions which may go as far as to shut down large parts of the immune system, so resulting in the occurrence of many side-effects, for example toxic damage, increased susceptibility to infectious diseases and increased risk of the occurrence of malignant diseases.
The alternative approach of avoiding the side-effects associated with the use of non-specifically acting immunosuppressants by using selective suppression (c.f.
Ann. Neurol. 37 Suppl. 1, 87-101), with action being purposefully and specifically taken against the allergens or autoantigens at various points in the defence reaction, also met with less than complete success.
One of these methods is based upon the oral or inhalatory administration of autoantigens or allergens specific to the particular disorder. While it is indeed possible in this manner to reinduce the body's resistance to these autoantigens or allergens or to enable the body to tolerate the autoantigens or allergens which have hitherto been attacked and initiate the enhanced immune response, the overall success rate of this patient desensitisation is limited because the desensitisation is inadequate (Ann. N. Y. Acad. Sci. 778, 1-27; Ann. N. Y.
Acad. Sci. 778, 243-250; Science 261, 1727-1730; Annu.
Rev. Med. 48, 341-351).
The mechanism of oral reinduction of tolerance by these substances is not yet completely understood. It may, however, be assumed that in the case of oral administration a part is played both by the immune system and by the bacterial flora of the gastrointestinal tract, the T cells (T lymphocytes), in particular the y8-T cells (The Journal of Immunology 158, 3610-3618; Res. Immunol.
147, 49-59; Immunology Letters 48, 97-102).
It was, however, entirely surprising that the reinduction of tolerance achieved with oral or inhalatory administration of autoantigens or allergens specific to the disorder was greatly promoted if the autoantigens .or allergens were administered in combination with bisphosphonic acids or the derivatives thereof. These combinations may thus successfully be used for the prevention and treatment of autoimmune disorders or allergies.
The use of bisphosphonic acids and of some of the derivatives thereof in pharmaceutical preparations is already known. The microbiostatic action of bisphosphonic acids (DE 3611522), the action thereof in the treatment of disorders of calcium and phosphate metabolism (DE 2534390, DE 2534391, DE 3334211, DE 3434667, DE 2745083), cytostatic action (DE 3425812), the lipid-reducing action thereof (Arzneimittelforschung 46, 759-762) and the ability thereof to stimulate immune cells (WO 97/38696 Al) are already known. The fact that bisphosphonic acids have an immunomodulatory action (WO 97/38696 Al) is R'y furthermore known and has been used.
However, use of these compounds is associated with many side-effects which are determined by the-mode of administration. In the case of intravenous infusion, such side-effects are fever, flu-like symptoms with violent shivering, lymphopenia and thrombocytopenia and, in the case of oral administration, they are painful swallowing, oesophagitis, oesophageal erosion, oesophageal ulceration, dyspepsia, diarrhoea etc. Moreover, oral treatment with bisphosphonates, for example, requires relatively large quantities of active substance and therapeutic success is still unsatisfactory (Drug-Saf. 14, 153-170).
It was thus not in the least obvious to use this group of compounds in combination with autoantigens or allergens in order to reinduce the body's tolerance to autoantigens or allergens.
Summary of the Invention In accordance with one aspect of the invention, there is provided a method of preventing and/or treating autoimmune diseases and/or allergies in a vertebrate comprising administering to said vertebrate a therapeutically effective amount of a bisphosphonic acid or derivative of the general formula O R, O I I II
A
3 0-P-C-P-OA 1
A
4 0 X OA 2 15<2 wherein
A
1
A
2
A
3
A
4 which may be identical or different, may be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclic residue, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium, or ammonium compounds derived from ethylene-diamine or amino acids, X, which may also be absent, may be alkylene alkenylene or hydroxyalkylene, R1, R 2 which may be identical or different, may be H, OH, NH 2 substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heterocyclic residue and further -SR 3 Cl and -NR 3
R
4 in which [I:\DayLib\LIBH]00833spec.doc:gcc 4a
R
3
R
4 which may be identical or different, may mean H, OH, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclic residue, and/or their pharmaceutically compatible salts, esters thereof as well as salts of esters and/or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, wherein the bisphosphonic acids and/or their derivatives and/or the compounds which on 0o administration form the suitable metabolites or catabolites which correspond to the above bisphosphonic acids and their derivatives are used in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the particular allergy, wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues and fragments thereof of the autoantigens or allergens instead of the autoantigens or allergens, provided that the mentioned substances respectively exhibit the same immunological characteristics as the corresponding whole molecules.
According to another aspect of the invention, there is provided a method of preventing and/or S 20 treating autoimmune diseases and/or allergies in a vertebrate comprising administering to said S:vertebrate a therapeutically effective amount of a bisphosphonic acid or derivative, of the general formula O R, O II I I
A
3 0-P-C-P-OA 1
*III
A
4 0 X OA 2
(I)
wherein 25 A 1
A
2
,.A
3
A
4 which may be identical or different may be hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may be substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, AI, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, R^X, which may also be absent, may be (CH 2 1 5 amino, [I:\DayLib\LIBH 00833spec.doc:gcc Ri, may be H, OH, R2, may be
/CH
3
-N
-NH
2
(CH
2 4
CH
3
N
-N -NH S C and/or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, wherein the bisphosphonic acids and/or their derivatives and/or the compounds which on administration form the suitable metabolites or catabolites which correspond to the above 0o bisphosphonic acids and their derivatives are used in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the particular allergy, wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues and fragments thereof of the autoantigens or allergens instead of the autoantigens or allergens, provided that the mentioned substances S.o: respectively exhibit the same immunological characteristics as the corresponding whole molecules.
According to a further aspect of the invention, there is provided the use of bisphosphonic acids and derivatives thereof for the production of pharmaceutical preparations for prevention 20 and/or treatment of autoimmune diseases and/or allergies, wherein said bisphosphonic acids and their derivatives are of the general formula R, 0 I I I
A
4 0 X OA 2 wherein Al, A 2
A
3
A
4 which may be identical or different, may be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclic residue, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as [I:\DayLib\LIB H]00833spec.doc:gcc substituted or unsubstituted ammonium, or ammonium compounds derived from ethylene-diamine or amino acids, X, which may also be absent, may be alkylene alkenylene or hydroxyalkylene, R1, R 2 which may be identical or different, may be H, OH, NH 2 substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heterocyclic residue and further -SR 3 Cl and -NR 3
R
4 in which to R 3
R
4 which may be identical or different, may mean H, OH, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclic residue, and/or their pharmaceutically compatible salts, esters thereof as well as salts of esters and/or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, wherein the bisphosphonic acids and/or their derivatives and/or the compounds which on administration form the suitable metabolites or catabolites which correspond to the above 20 bisphosphonic acids and their derivatives are used in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or i: in combination with the specific allergens for the prevention and treatment of the particular allergy, wherein, instead of the particular autoantigens or allergens, it is also possible to use 25 fragments or derivatives thereof and the analogues and fragments thereof of the autoantigens or allergens instead of the autoantigens or allergens, provided that the mentioned substances respectively exhibit the same immunological characteristics as the corresponding whole molecules.
According to another aspect of the invention, there is provided the use of bisphosphonic acids and the derivatives thereof for the production of pharmaceutical preparations for prevention and/or treatment of autoimmune diseases and/or allergies, wherein said bisphosphonic acids and their derivatives are of the general formula O R, O I I II
A
3 0-P-C-P-OA I I I
A
4 0 X OA 2
I
R
(I)
[1:\DayLib\LIBH]00833spec.doc:gcc wherein
A
1
A
2
A
3
A
4
X,
Ri, R2, which may be identical or different may be hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may be substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, which may also be absent, may be (CH 2 1 amino, may be H, OH, may be r c r
-NH
2
-N
/CH
3
-N
(CH
2 )4CH 3
-NH,
N
S Ci and/or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, wherein the bisphosphonic acids and/or their derivatives and/or the compounds which on administration form the suitable metabolites or catabolites which correspond to the above bisphosphonic acids and their derivatives are used in combination with the specific autoantigens for 20 the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the particular allergy, wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues and fragments thereof of the autoantigens or allergens instead of the autoantigens or allergens, provided that the mentioned substances respectively exhibit the same immunological characteristics as the corresponding whole molecules.
According to a further aspect of the invention, there is provided a bisphosphonic acid or derivative in combination with a specific autoantigen and/or allergen when used for preventing and/or treating autoimmune diseases and/or allergies, wherein said bisphosphonic acid or derivative is of the general formula [I:\DayLib\LIBH]00833spec.doc:gcc 0 Ri O II I II
A
3 0-P-C-P-OA I I I
A
4 0 X OA 2 R2
(I)
wherein Ai, A 2
A
3
A
4 which may be identical or different, may be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclic residue, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium, or ammonium compounds S 10 derived from ethylene-diamine or amino acids, X, which may also be absent, may be alkylene alkenylene or hydroxyalkylene,
R
1
R
2 which may be identical or different, may be H, OH, NH 2 substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or is unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heterocyclic residue and further-SR 3 CI and -NR 3
R
4 in which R3, R4, which may be identical or different, may mean H, OH, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or 20 unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclic residue, and/or their pharmaceutically compatible salts, esters thereof as well as salts of esters and/or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, wherein the bisphosphonic acids and/or their derivatives and/or the compounds which on administration form the suitable metabolites or catabolites which correspond to the above bisphosphonic acids and their derivatives are used in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the particular allergy, [I:\DayLib\LIBH]00833specdoc:gcc wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues and fragments thereof of the autoantigens or allergens instead of the autoantigens or allergens, provided that the mentioned substances respectively exhibit the same immunological characteristics as the corresponding whole molecules.
According to another aspect of the invention, there is provided a bisphosphonic acid or derivative in combination with a specific autoantigen and/or allergen when used for preventing and/or treating autoimmune diseases and/or allergies, wherein said bisphosphonic acid or derivative is of the general formula O R, 0 II I II
A
3 0-P-C-P-OA
A
4 0 X OA 2 R2 00.0 .00.
o o :0 0 0**o .0 wherein Ai, A 2
A
3
A
4
X,
R1, R2, which may be identical or different may be hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may be substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, which may also be absent, may be (CH 2 15 amino, may be H, OH, may be
-NH
2
/CH
3
-N
(CH
2 4
CH
3
-NH-
N
-NN S -Ci and/or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, wherein the bisphosphonic acids and/or their derivatives and/or the compounds which on administration form the suitable metabolites or catabolites which correspond to the above bisphosphonic acids and their derivatives are used in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or [I:\DayLib\LIBH]00833spec.doc:gcc in combination with the specific allergens for the prevention and treatment of the particular allergy, wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues and fragments thereof of the autoantigens or allergens instead of the autoantigens or allergens, provided that the mentioned substances respectively exhibit the same immunological characteristics as the corresponding whole molecules.
Description of the Invention The invention relates to a novel method of solving the hitherto unsolved problem of the prevention and treatment of autoimmune disorders and of allergies by means of pharmaceutical o1 preparations, namely to use the autoantigens or allergens hitherto used to treat autoimmune disorders and allergies in combination with bisphosphonates or the derivatives thereof.
The invention relates to the use of bisphosphonic acids and the derivatives thereof for the production of pharmaceutical preparations for the prevention and treatment of autoimmune diseases or allergies, wherein the bisphosphonic acids and the derivatives thereof which are used is are those of the general formula: [I:\DayLib\LIBH]00833spec.doc:gcc 0 Ri 0 II I II
A
3 0--P--C-P--OA I I I
A
4 0 X OA 2
I
R2 in which AI, A 2
A
3
A
4 which may be identical or different and mean hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclic residue, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, which may also be absent or may be alkylene, alkenylene or hydroxyalkylene, which may be identical or different and mean H, OH, -NH 2 a substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl or a substituted or unsubstituted heterocyclic residue or -SR 3 Cl and -NR 3
R
4 in which RI, R 2
R
3
R
4 which may be identical or different and mean H, OH, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclic residue, and the pharmaceutically compatible salts, esters thereof as well as salts of esters or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the particular allergy, wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues or fragments thereof of the autoantigens or allergens, providing that these each exhibit the same immunological characteristics as the corresponding whole molecules, and wherein the bisphosphonic acids or the derivatives thereof and the autoantigens or allergens or fragments, derivatives or analogues thereof may be administered simultaneously or in succession.
The substances may here be administered both synchronously and with a delay by simultaneous or separate administration of the active substances.
From the group of bisphosphonic acids and the derivatives thereof of the general formula I, those bisphosphonic S acids and the derivatives thereof which are preferred for use for the prevention and treatment of autoimmune disorders or allergies are of the general formula: 0 RI 0 II II
A
3 0-P-C-P--OAi I I I
A
4 0 X OA 2
I
R2
(II),
in which AI, A 2
A
3
A
4 which may be identical or different and mean hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, an aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, means H, OH, NH 2 which may also be absent or may be alkylene, alkenylene or hydroxyalkylene, in each case having 1 to 12 carbon atoms, means H, OH, -NH 2 an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional groups, or -SR 3 Cl and
-NR
3
R
4 in which
R
3
R
4 which may be identical or different and mean H, OH, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional groups.
Bisphosphonic acids and the derivatives thereof which have proved particularly effective are those of the general formula: O R 1 0 II I II
A
3 0--P-C-P--OAi (III),
A
4 0 X OA 2 in which Al, A 2
A
3
A
4 which may be identical or different and mean hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium or amnmonium compounds derived from ethylenediamine or amino acids, R1, means H, OH, X, which may also be absent or may mean
(CH
2 1 5 amidino, R2, may mean -NH 2 -N
H
(CH
2 4
-CH
3 N q-NH
SC
Some examples of these are: aminohydroxyrnethylidenebisphosphonic acid (AMP), 2-amino-l-hydroxyethylidene-l, 1-bisphosphonic acid (AEP), 3-amino-1-hydroxypropylidene-1, 1-bisphosphonic acid (pamidronic acid), 4-amino-1-hydroxybutylidene-l, 1-bisphosphonic acid (alendronic acid), 6-amino-l-hydroxyhexylidene-l, 1-bisphosphonic acid (AHP), amidinomethylenebisphosphonic acid (AIMP), 3-methylpentylamino-1-hydroxypropylidene-l, 1bisphosphonic acid (ibandronic acid), 2- (3-pyridinyl) -1-hydroxyethylidenebisphosphonic acid (risedronic acid), 1-hydroxy-2- (imidazol-l-yl)-ethylidene-1,1-bisphosphonic acid (zoledronic acid), cycloheptylaminomethylenediphosphonic acid (cimadronic acid), 4-chlorophenylthiomethylene-l,1-bisphosphonic acid (tiludronic acid) and the derivatives thereof.
Autoimmune disorders and allergies are prevented and treated by combined use of a bisphosphonic acid or the derivatives thereof and an autoantigen which initiates the particular autoimmune disorder, such as for example in multiple sclerosis rheumatoid arthritis Hashimoto thyroiditis myasthenia gravis lupus erythematosus diabetes mellitus primary biliary cirrhosis active chronic hepatitis adrenalitis/Addison's disease polymyositis dermatomyositis autoimmune haemolytic anaemia myocarditis myopericarditis scleroderma with myelin basic protein (MBP), further extracts from nervous system tissue, with type I, II or III collagen, with thyroglobulin, with acetylcholine receptor protein, with DNA, with islet cell extracts, human insulin, with liver extracts, with liver cell extracts; with adrenal cortex extracts, with skin extracts, muscle extracts, with muscle and/or skin extracts, with haemopoetic cell line extracts, with heart extracts, with skin extracts, skin cell extracts, uveitis (phacouveitis, sympathetic ophthalmia) pemphigus vulgaris pemphigoid pernicious anaemia autoimmune atrophic gastritis Crohn's disease colitis ulcerosa or in allergies with eye lens proteins, S-antigens, S-antigen mixtures, with skin extracts, with skin extracts, with gastric cell extracts, parietal cell extracts, intrinsic factor, with gastric cell extracts, with intestinal extracts, with intestinal extracts with the allergy-specific allergens.
Combined use is also taken to include cases in which autoantigens or allergens are already present. Such cases include, for example, Crohn's disease, in which the autoantigen is already present in the intestine as a result of the disease. In this case, in the event of oral or rectal administration, only the bisphosphonic acids or the derivatives thereof need be administered. It is also unnecessary to administer the allergen if, during treatment, the affected subject is in an environment in which the allergy-specific allergen is already present (for example pollen during the pollen release season).
Combined use may proceed not only by oral administration, for example by means of tablets etc., but also, for example, by rectal, inhalatory administration, by application onto the skin or mucous membranes. Preferred administration forms are oral and inhalatory administration and application onto the skin or mucous membranes.
Of these administration forms, inhalation has proved to be particularly gentle because elevated activity is achieved with only very small quantities of autoantigen or allergen and bisphosphonic acid or the derivatives thereof and any possible side-effects of the active substances may accordingly be minimised.
The bisphosphonic acids and the derivatives thereof which are preferably used are those which are poorly resorbed, which include, for example, aminobisphosphonic acids and the derivatives thereof.
Preferred pharmaceutical compositions are tablets, sugarcoated pills, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays. Tablets, sugar-coated pills, capsules, pills and granules may contain, apart from the active substances, conventional excipients, such as fillers and extenders, for example starch, lactose, cane sugar, glucose, mannitol and silica, binders, for example carboxymethylcellulose, alginates, gelatine, polyvinylpyrrolidone, (c) humectants, for example glycerol, suspending agents, for example agar-agar, calcium carbonate and sodium carbonate, dissolution retardants, for example paraffin and resorption accelerators, for example quaternary ammonium compounds, wetting agents, for example cetyl alcohol, glycerol monostearate, (h) adsorbents, for example kaolin and bentonite and (i) lubricants, for example talcum, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances stated in to The tablets, sugar-coated pills, capsules, pills and granules may be provided with conventional coatings and shells, which optionally contain opacifying agents, and may be of a composition such that they release the active substance, optionally with a delay, solely or preferentially in a specific part of the intestinal tract, wherein polymeric substances and waxes may, for example, be used as matrix materials.
The active substance or substances, optionally together with one or more of the above-stated excipients, may also assume microencapsulated form.
Apart from the active substance or substances, suppositories may contain conventional water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C 14 alcohol with C16 fatty acid) or mixtures of these substances.
Apart from the active substance or substances, ointments, pastes, creams and gels may contain conventional O excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth gum, cellulose derivatives, -polyethylene glycols, silicones, bentonites, silica, talcum and zinc oxide or mixtures of these substances.
Apart from the active substance or substances, powders and sprays may contain conventional excipients, for example lactose, talcum, silica, aluminium hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may additionally contain conventional propellants, for example chlorofluorot carbons.
Apart from the active substance or substances, solutions and emulsions may contain conventional excipients, such as solvents, solubilising agents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, maize oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid S esters or mixtures of these substances.
Apart from the active substance or substances, suspensions may contain conventional excipients, such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth gum or mixtures of these substances.
The stated formulation forms may also contain colorants, preservatives as well as with odour- and flavourenhancing additives, for example peppermint oil and eucalyptus oil and sweeteners, for example saccharin.
Bisphosphonic acids or the derivatives thereof of the formula are suitable for simultaneous, separate or temporally staged use with the autoantigens or allergens, and these compounds should accordingly be present in the pharmaceutical preparations listed above, preferably in a concentration of approx. 0.1 to 99.5 relative to the complete mixture. The concentration of the autoantigens or allergens should be 0.1 to 99.5 wt.% in this case too.
Apart from the compounds of the formula and the autoantigen or allergen, the pharmaceutical preparations listed above may also contain further pharmaceutical active substances.
The pharmaceutical preparations listed above are produced in the conventional manner using known methods, for example by mixing the active substance or substances with the excipient or excipients.
The stated preparations may be administered to humans or animals orally, rectally, intravaginally, topically (powders, ointments, drops) and in cavities and body cavities. Suitable preparations for oral treatment which may be considered are solutions and suspensions, gels, infusion formulations, emulsions, ointments or drops.
Topical treatment may be performed using ophthalmological and dermatological formulations, .silver and other salts, ear drops, eye ointments, powders or solutions. For animals, administration may be made by 'suitable formulation with feed or drinking water. Gels, pulverulent formulations, powders, tablets, delayedrelease tablets, premixes, concentrates, granules, pellets, boli, capsules, aerosols, sprays, inhalatory preparations may also be used in humans and animals. The compounds according to the invention may furthermore be incorporated into other support materials, such as for example plastics (plastic chains for topical treatment), collagen or bone cement.
The quantities of the individual derivatives required to achieve the desired effect vary very widely. In general, it has proved advantageous in both human and veterinary medicine to administer the active substance or substances of the formula in total quantities of approx. 0.5 to approx. 2000 mg per 24 hours, optionally in the form of two or more individual doses, in order to achieve the desired results. An individual dose preferably contains the active substance or substances in quantities of approx. 0.5 to approx. 2000 mg. It may, however, be necessary to deviate from the stated dosages, specifically as a function of the species and body weight of the subject to be treated, the nature and severity of the condition, the nature of the preparation and administration of the pharmaceutical preparation and the period of time or interval within which the preparation is administered.
It may accordingly be sufficient in some cases to use less than the above-stated quantity of active substance, while in other cases the active substance must be used in a quantity greater than that stated above. The person skilled in the art will establish the optimum dosage and mode of administration of the active substances in each case on the basis of his/her expertise.
When treating animals, the compounds to be used according to the invention may be given in the conventional concentrations and preparations together with feed or with feed preparations or with drinking water.
Examples Tablets are produced in a manner known per se using a mixture of 1. 3-Amino-l-hydroxypropylidene-l,1- 600 bisphosphonate, disodium salt Bovine collagen, type II Mannitol 400 Starch Magnesium stearate 2. 4-Amino-l-hydroxybutylidene-l,1bisphosphonate (monosodium salt), 3H 2 0 Bovine collagen, type II Mannitol Starch Magnesium stearate 3. 3-Methylpentylamino-l-hydroxypropylidene-1,1-bisphosphonate, monosodium salt, 1H 2 0 Bovine collagen, type II Mannitol Starch Magnesium stearate 4. 3-Amino-l-hydroxypropylidene-l,1bisphosphonate, disodium salt Myelin basic protein (MBP) Mannitol Starch Magnesium stearate 26 mg 400 1.125 mg 400 600 8 400 4-Amino-l-hydroxybutylidene-l,1bisphosphonate (monosodium salt), 3H 2 0 Myelin basic protein (MBP) Mannitol Starch Magnesium stearate 6. 3-Methylpentylamino-l-hydroxypropylidene-1,1-bisphosphonate, monosodium salt, 1H 2 0 Myelin basic protein (MBP) Mannitol Starch Magnesium stearate 8 400 1.125 mg 8 400 Capsules are produced in a manner known per se using 7. 3-Amino-l-hydroxypropylidene-l,1- 600 bisphosphonate, disodium salt Myelin basic protein (MBP) 8 Proteolipid protein Magnesium stearate 8. 4-Amino-l-hydroxybutylidene-l,1bisphosphonate (monosodium salt), 3H 2 0 Myelin basic protein (MBP) Proteolipid protein Magnesium stearate 26 mg 9. 3-Methylpentylamino-l-hydroxypropylidene-1,1-bisphosphonate, monosodium salt, 1H 2 0 Myelin basic protein (MBP) Proteolipid protein Magnesium stearate 3-Amino-l-hydroxypropylidene-l,1bisphosphonate, disodium salt Bovine collagen, type II Magnesium stearate 11. 4-Amino-l-hydroxypropylidene-l,1bisphosphonate (monosodium salt), 3H 2 0 Bovine collagen, type II Magnesium stearate 12. 3-Methylpentylamino-l-hydroxypropylidene-1,1-bisphosphonate, monosodium salt, 1H 2 0 Bovine collagen, type II Magnesium stearate 1.125 mg 600 1.125 mg wherein the above constituents are mixed together and then introduced in conventional manner into a hard gelatine capsule.
A preparation for inhalation for a 2 ml dose is produced using: 13. 4-Amino-l-hydroxybutylidene-l,1bisphosphonate (monosodium salt), 3H 2 0 Myelin basic protein P-Cyclodextrin hydrate pH 7.2 phosphate buffer water for injection; 1.3 ma 7 0.2 7 0.2 14. 3-Amino-l-hydroxypropylidene-l,1bisphosphonate, disodium salt Myelin basic protein P-Cyclodextrin hydrate pH 7.2 phosphate buffer water for injection; 3-Methylpentylamino-l-hydroxypropylidene-1,1-bisphosphonate, monosodium salt, 1H 2 0 Myelin basic protein P-Cyclodextrin hydrate pH 7.2 phosphate buffer water for injection; 16. 4-Amino-l-hydroxybutylidene-l,1bisphosphonate (monosodium salt), 3H 2 0 Bovine collagen, type II P-Cyclodextrin hydrate pH 7.2 phosphate buffer water for injection; 0.25 mg 7 0.2 1.3 mg 10 mg 7 mg 0.2 ml 17. 3-Amino-l-hydroxypropylidene-l,1bisphosphonate, disodium salt Bovine collagen, type II P-Cyclodextrin hydrate pH 7.2 phosphate buffer water for injection; 18. 3-Methylpentylamino-l-hydroxypropylidene-1,1-bisphosphonate, monosodium salt, 1H 2 0 Bovine collagen, type II P-Cyclodextrin hydrate pH 7.2 phosphate buffer water for injection.
7 0.2 0.25 mg 7 0.2 The bisphosphonate (for example alendronate) and the autoantigen (for example MBP) are dissolved in a phosphate buffer solution and the P-cyclodextrin hydrate is dissolved therein. The solution is made up to the desired volume with water for injection, sterilised by filtration and aseptically packaged in containers suitable for inhalation by atomisation.
Claims (15)
1. Use of bisphosphonic acids and derivatives thereof for the production of pharmaceutical preparations for prevention and/or treatment of autoimmune diseases and/or allergies, wherein said bisphosphonic acids and their derivatives are of the general formula O R, O I II A 3 0-P-C-P-OA A 4 0 X OA 2 R2 (I) wherein Ai, A 2 A 3 A 4 Q. Ar X, which may be identical or different, may be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclic residue, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium, or ammonium compounds derived from ethylene-diamine or amino acids, which may also be absent, may be alkylene alkenylene or hydroxyalkylene, R1, R 2 which may be identical or different, may be H, OH, NH 2 substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heterocyclic residue and further -SR 3 Cl and -NR 3 R 4 in which R3, R 4 which may be identical or different, may mean H, OH, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclic residue, and/or their pharmaceutically compatible salts, esters thereof as well as salts of esters and/or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, wherein the bisphosphonic acids and/or their derivatives and/or the compounds which on administration form the suitable metabolites or catabolites which correspond to the above [1:\DAYLIB\LIBH]00833spec.doc:gcc 23 bisphosphonic acids and their derivatives are used in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the particular allergy, wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues and fragments thereof of the autoantigens or allergens instead of the autoantigens or allergens, provided that the mentioned substances respectively exhibit the same immunological characteristics as the corresponding whole molecules.
2. Use of bisphosphonic acids as well as their derivatives according to claim 1, wherein o0 in the general formula (I) Ai, A 2 A 3 A 4 which may be identical or different, may be hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional 15 groups, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, AI, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, which may also be absent, may be alkylene, alkenylene or hydroxyalkylene, in each case having 1 to 12 carbon atoms, 20 R1, may be H, OH, NH 2 R 2 may be H, OH, NH 2 an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may S" be substituted by functional groups, or furthermore -SR 3 Cl and NR 3 R 4 in which R 3 R 4 which may be identical or different, may be H, OH, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may be substituted by functional groups.
3. Use of bisphosphonic acids and the derivatives thereof for the production of pharmaceutical preparations for prevention and/or treatment of autoimmune diseases and/or allergies, wherein said bisphosphonic acids and their derivatives are of the general formula [IADAYLIB\LIBH]00833spec.doc:gcc 0 R 1 0 I I II A 3 0-P-C-P-OA 1 I I I A 4 0 X OA 2 R2 wherein A 1 A 2 A 3 A 4 which may be identical or different may be hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may be substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, AI, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, which may also be absent, may be (CH 2 1 amino, may be H, OH, r r r r r may be -NH 2 -N /CH 3 -N (CH 2 4 CH 3 -NH- N S 0-CI and/or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, wherein the bisphosphonic acids and/or their derivatives and/or the compounds which on administration form the suitable metabolites or catabolites which correspond to the above bisphosphonic acids and their derivatives are used in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the particular allergy, wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues and fragments thereof of the autoantigens or allergens instead of the autoantigens or allergens, provided that the mentioned substances respectively exhibit the same immunological characteristics as the corresponding whole molecules.
4. Use of bisphosphonic acids and the derivatives thereof in combination with '3 autoantigens or allergens for the production of pharmaceutical preparations for the prevention [I:\DAYLIB\LIB H100833spec.doc:gcc I_ j and/or treatment of autoimmune conditions and/or allergies according to any one of claims 1 to 3, wherein the following are used for the treatment of: multiple sclerosis myelin basic protein (MBP), further extracts from nervous system tissue, rheumatoid arthritis type I, II or III collagen, Hashimoto thyroiditis thyroglobulin, myasthenia gravis acetylcholine receptor protein, lupus erythematosus DNA, diabetes mellitus islet cell extracts, human insulin, primary biliary cirrhosis liver extracts, active chronic hepatitis liver cell extracts, adrenalitis/Addison's disease adrenal cortex extracts, polymyositis skin extracts, muscle extracts, dermatomyositis muscle and/or skin extracts, autoimmune haemolytic anaemia haemopoietic cell line extracts, Myocarditis, myopericarditis heart extracts, a a scleroderma uveitis (phacouveitis, sympathetic ophthalmia) skin extracts, skin cell extracts, eye lens proteins, S-antigens, S-antigen mixtures, pemphigus vulgaris skin extracts, pemphigoid skin extracts, pernicious anaemia gastric cell extracts, parietal cell extracts, intrinsic factor, autoimmune atrophic gastritis gastric cell extracts, Crohn's disease intestinal extracts, colitis ulcerosa intestinal extracts, allergies allergy-specific allergens.
Use of bisphosphonic acids and the derivatives thereof for the productions of pharmaceutical preparations for the prevention and/or treatment of autoimmune conditions and/or allergies according to any one of claims 1 to 3, wherein the preparations are administered in solid form, as ointments, as solutions, or as sprays.
6. A method of preventing and/or treating autoimmune diseases and/or allergies in a vertebrate comprising administering to said vertebrate a therapeutically effective amount of a bisphosphonic acid or derivative, of the general formula L\DAYLB\LIBH00833spec.doc:gcc __III~ ^IIIIW~-~i~L~- I O R, 0 II I I A 3 0-P-C-P-OAi A 4 0 X OA 2 R2(I) wherein A 1 A 2 A 3 A 4 which may be identical or different, may be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclic residue, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium, or ammonium compounds 1 0 derived from ethylene-diamine or amino acids x which may also be absent, may be alkylene alkenylene or hydroxyalkylene, S. R 1 R 2 which may be identical or different, may be H, OH, NH 2 substituted or S. unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heterocyclic residue and further -SR 3 Cl and -NR 3 R 4 in which R 3 R 4 which may be identical or different, may mean H, OH, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or 20 unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclic residue, and/or their pharmaceutically compatible salts, esters thereof as well as salts of esters and/or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, wherein the bisphosphonic acids and/or their derivatives and/or the compounds which on administration form the suitable metabolites or catabolites which correspond to the above bisphosphonic acids and their derivatives are used in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the particular allergy, [I:\DAYLIB\LIB H]00833 spec.doc:gcc wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues and fragments thereof of the autoantigens or allergens instead of the autoantigens or allergens, provided that the mentioned substances respectively exhibit the same immunological characteristics as the corresponding whole molecules.
7. The method of claim 6, wherein in the general formula Ai, A 2 A 3 A 4 which may be identical or different, may be hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional 1o groups, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, AI, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, X, which may also be absent, may be alkylene, alkenylene or hydroxyalkylene, in each case having 1 to 12 carbon atoms, 15 R 1 may be H, OH, NH 2 R2, may be H, OH, NH 2 an alkyl residue having 1 to 12 carbon atoms which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may be substituted by functional groups, or furthermore -SR 3 Cl and NR 3 R 4 in which R 3 R 4 which may be identical or different, may be H, OH, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may be substituted by functional groups.
8. A method of preventing and/or treating autoimmune diseases and/or allergies in a vertebrate comprising administering to said vertebrate a therapeutically effective amount of a bisphosphonic acid or derivative, of the general formula O R, O II I II A 3 0-P-C-P-OA, I I I A 4 0 X OA 2 R2 (I) wherein A 1 A 2 A 3 A 4 which may be identical or different may be hydrogen, an alkyl residue cA having 1 to 12 carbon atoms, which may be branched or unbranched, an [I:\DAYLIB\LIBH]00833spec.doc:gcc 28 aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may be substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, X, which may also be absent, may be (CH 2 )1- 5 amino, Ri, may be H, OH, R2, may be /CH 3 -N -NH 2 (CH 2 4 CH 3 -N -NH S CI ,-0 and/or compounds which, on administration, form the compounds to be administered g as metabolites or catabolites, wherein the bisphosphonic acids and/or their derivatives and/or the compounds which on administration form the suitable metabolites or catabolites which correspond to the above bisphosphonic acids and their derivatives are used in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the particular allergy, 20 wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues and fragments thereof of the autoantigens or allergens instead of the autoantigens or allergens, provided that the mentioned substances respectively exhibit the same immunological characteristics as the corresponding whole molecules.
9. The method of any one of claims 6 to 8 wherein the following are used for the treatment of: multiple sclerosis myelin basic protein (MBP), further extracts from nervous system tissue, rheumatoid arthritis type I, II or III collagen, Hashimoto thyroiditis thyroglobulin, myasthenia gravis acetylcholine receptor protein, lupus erythematosus DNA, diabetes mellitus islet cell extracts, human insulin, [I:\DAY LIB\L IB H]00833 spec.doc:gcc i primary biliary cirrhosis active chronic hepatitis adrenalitis/Addison's disease polymyositis dermatomyositis autoimmune haemolytic anaemia Myocarditis, myopericarditis scleroderma uveitis (phacouveitis, sympathetic ophthalmia) pemphigus vulgaris pemphigoid pernicious anaemia autoimmune atrophic gastritis Crohn's disease colitis ulcerosa allergies 29 liver extracts, liver cell extracts, adrenal cortex extracts, skin extracts, muscle extracts, muscle and/or skin extracts, haemopoietic cell line extracts, heart extracts, skin extracts, skin cell extracts, eye lens proteins, S-antigens, S-antigen mixtures, skin extracts, skin extracts, gastric cell extracts, parietal cell extracts, intrinsic factor, gastric cell extracts, intestinal extracts, intestinal extracts, allergy-specific allergens. be c cc C C.
10. The method of any one of claims 6 to 8, wherein the mode of administration is a solid form, an ointment, a solution, or a spray.
11. The method of any one of claims 6 to 10 wherein said vertebrate is a human.
12. A bisphosphonic acid or derivative in combination with a specific autoantigen and/or allergen when used for preventing and/or treating autoimmune diseases and/or allergies, wherein said bisphosphonic acid or derivative is of the general formula O R 1 0 A 3 0-P-C-P-OA, I I I A 4 0 X OA 2 R2 (1 wherein A 1 A 2 A 3 A 4 which may be identical or different, may be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclic residue, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as [:\DAYL[B\LIBHIOO833spec.doc:gcc substituted or unsubstituted ammonium, or ammonium compounds derived from ethylene-diamine or amino acids, X, which may also be absent, may be alkylene alkenylene or hydroxyalkylene, s R 1 R 2 which may be identical or different, may be H, OH, NH 2 substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heterocyclic residue and further -SR 3 Cl and -NR 3 R 4 in which 0o R 3 R 4 which may be identical or different, may mean H, OH, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclic residue, '5 and/or their pharmaceutically compatible salts, esters thereof as well as salts of esters and/or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, wherein the bisphosphonic acids and/or their derivatives and/or the compounds which on administration form the suitable metabolites or catabolites which correspond to the above 20 bisphosphonic acids and their derivatives are used in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the particular allergy, wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues and fragments thereof of the autoantigens or allergens instead of the autoantigens or allergens, provided that the mentioned substances respectively exhibit the same immunological characteristics as the corresponding whole molecules.
13. A bisphosphonic acid or derivative in combination with a specific autoantigen and/or allergen when used according to claim 12, wherein in the general formula A 1 A 2 A 3 A 4 which may be identical or different, may be hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, such as [I:\DAYLB\LIB H]00833spec.doc:gcc Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, X, which may also be absent, may be alkylene, alkenylene or hydroxyalkylene, in each case having 1 to 12 carbon atoms, R 1 may be H, OH, NH 2 R2, may be H, OH, NH 2 an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may be substituted by functional groups, or furthermore -SR 3 Cl and o1 NR 3 R 4 in which R 3 R 4 which may be identical or different, may be H, OH, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may be substituted by functional groups. 15
14. A bisphosphonic acid or derivative in combination with a specific autoantigen and/or allergen when used for preventing and/or treating autoimmune diseases and/or allergies, wherein said bisphosphonic acid or derivative is of the general formula *9 9 *999 o. 99 9 .9 9 9 o* 9 9 *99* o 9 9 9 9 0 99 99 a *e «e oeeo* 0 R 0 A 3 0-P--C-P-OA 1 A 4 0 X OA 2 R2 20 wherein A 1 A 2 A 3 A 4 X, R1, R2, which may be identical or different may be hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may be substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, AI, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, which may also be absent, may be (CH 2 )1- 5 amino, may be H, OH, maybe /CH 3 -N (CH 2 4 CH 3 N -NH 2 [I:\DAY LIB\LIB H ]0083 3 spec.doc:gcc N Z -NH-0 and/or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, wherein the bisphosphonic acids and/or their derivatives and/or the compounds which on administration form the suitable metabolites or catabolites which correspond to the above bisphosphonic acids and their derivatives are used in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the o1 particular allergy, wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues and fragments thereof of the autoantigens or allergens instead of the autoantigens or allergens, provided that the mentioned substances respectively exhibit the same immunological characteristics as the corresponding whole molecules.
15. A bisphosphonic acid or derivative in combination with a specific autoantigen and/or allergen when used for preventing and/or treating autoimmune diseases and/or allergies according to any one of claims 12 to 14, wherein the following are used for the treatment of: I 0 0090 S. 00 0 I 0500 09 S 0 S multiple sclerosis rheumatoid arthritis Hashimoto thyroiditis myasthenia gravis lupus erythematosus diabetes mellitus primary biliary cirrhosis active chronic hepatitis adrenalitis/Addison's disease polymyositis dermatomyositis autoimmune haemolytic anaemia Myocarditis, myopericarditis scleroderma uveitis (phacouveitis, sympathetic myelin basic protein (MBP), further extracts from nervous system tissue, type I, II or III collagen, thyroglobulin, acetylcholine receptor protein, DNA, islet cell extracts, human insulin, liver extracts, liver cell extracts, adrenal cortex extracts, skin extracts, muscle extracts, muscle and/or skin extracts, haemopoietic cell line extracts, heart extracts, skin extracts, skin cell extracts, eye lens proteins, S-antigens, S-antigen mixtures, [I:\DAYLIB\LIBH]00833spec.doc:gcc ophthalmia) pemphigus vulgaris pemnphigoid pernicious anaemnia autoimnmune atrophic gastritis Crohn's disease colitis ulcerosa allergies skin extracts, skin extracts, gastric cell extracts, parietal cell extracts, intrinsic factor, gastric cell extracts, intestinal extracts, intestinal extracts, allergy-specific allergens. .0 aO 0 0: 00 00 0S 0 0 .00 0 so 0: Dated 19 September, 2001 Hassan Jomnaa Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [I:\DAYLIB\LIBHOO833spec.doc:gcc
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19828450A DE19828450A1 (en) | 1998-06-26 | 1998-06-26 | Use of bisphosphonic acid compounds and autoantigens or allergens |
| DE19828450 | 1998-06-26 | ||
| PCT/DE1999/001844 WO2000000182A2 (en) | 1998-06-26 | 1999-06-24 | Medicaments containing bisphosphonic acids and derivatives thereof which are provided for preventing and treating autoimmune diseases and allergies |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU5503399A AU5503399A (en) | 2000-01-17 |
| AU740605B2 true AU740605B2 (en) | 2001-11-08 |
Family
ID=7872064
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU55033/99A Ceased AU740605B2 (en) | 1998-06-26 | 1999-06-24 | Medicaments containing bisphosphonic acids and derivatives thereof which are provided for preventing and treating autoimmune diseases and allergies |
Country Status (24)
| Country | Link |
|---|---|
| EP (1) | EP1089761B1 (en) |
| JP (1) | JP2002519319A (en) |
| KR (1) | KR20010053211A (en) |
| AT (1) | ATE224734T1 (en) |
| AU (1) | AU740605B2 (en) |
| CA (1) | CA2334711C (en) |
| DE (2) | DE19828450A1 (en) |
| DK (1) | DK1089761T3 (en) |
| EA (1) | EA200100080A1 (en) |
| EE (1) | EE200000756A (en) |
| ES (1) | ES2184496T3 (en) |
| HR (1) | HRP20000820A2 (en) |
| HU (1) | HUP0102873A3 (en) |
| ID (1) | ID27515A (en) |
| IL (1) | IL139966A0 (en) |
| IS (1) | IS5748A (en) |
| MX (1) | MXPA00012338A (en) |
| NO (1) | NO20006572L (en) |
| NZ (1) | NZ509505A (en) |
| PL (1) | PL345287A1 (en) |
| PT (1) | PT1089761E (en) |
| SK (1) | SK19602000A3 (en) |
| TR (1) | TR200003821T2 (en) |
| WO (1) | WO2000000182A2 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2356262A1 (en) | 1998-12-23 | 2000-07-06 | Jomaa Pharmaka Gmbh | Use of bisphosphonates for the prevention and treatment of infectious processes |
| WO2000038693A1 (en) * | 1998-12-25 | 2000-07-06 | Toray Industries, Inc. | Interleukin-6 production inhibitors |
| EP1392325B1 (en) * | 2001-05-02 | 2006-06-21 | Novartis AG | Method of administration of bisphosphonates by inhalation in the treatment or prevention of bone resorption and osteoporosis |
| PT1408984E (en) | 2001-07-20 | 2008-12-26 | Bioagency Ag | Organo-phosphorous compounds for activating gamma/delta t cells |
| GB0307989D0 (en) * | 2003-04-07 | 2003-05-14 | Mcewen Lab Ltd | Therapeutic composition |
| EP1713489B1 (en) * | 2004-08-23 | 2011-01-19 | Teva Pharmaceutical Industries Ltd | Crystalline form of ibandronate sodium and processes for preparation thereof |
| EP1931326A4 (en) * | 2005-09-12 | 2009-12-16 | Reddys Lab Ltd Dr | Crystalline trihydrate of zoledronic acid |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2114946T3 (en) * | 1991-09-05 | 1998-06-16 | Toray Industries | DERIVATIVE OF METHANODIPHOSPHONIC ACID, ITS PRODUCTION AND MEDICINAL USE. |
| WO1996022790A1 (en) * | 1995-01-23 | 1996-08-01 | Xenotech Incorporated | Composition to ameliorate osteolysis and metastasis |
-
1998
- 1998-06-26 DE DE19828450A patent/DE19828450A1/en not_active Withdrawn
-
1999
- 1999-06-24 AT AT99941383T patent/ATE224734T1/en active
- 1999-06-24 EP EP99941383A patent/EP1089761B1/en not_active Expired - Lifetime
- 1999-06-24 EA EA200100080A patent/EA200100080A1/en unknown
- 1999-06-24 DK DK99941383T patent/DK1089761T3/en active
- 1999-06-24 AU AU55033/99A patent/AU740605B2/en not_active Ceased
- 1999-06-24 JP JP2000556767A patent/JP2002519319A/en active Pending
- 1999-06-24 WO PCT/DE1999/001844 patent/WO2000000182A2/en not_active Application Discontinuation
- 1999-06-24 HU HU0102873A patent/HUP0102873A3/en unknown
- 1999-06-24 DE DE59902856T patent/DE59902856D1/en not_active Expired - Lifetime
- 1999-06-24 TR TR2000/03821T patent/TR200003821T2/en unknown
- 1999-06-24 EE EEP200000756A patent/EE200000756A/en unknown
- 1999-06-24 CA CA002334711A patent/CA2334711C/en not_active Expired - Fee Related
- 1999-06-24 SK SK1960-2000A patent/SK19602000A3/en unknown
- 1999-06-24 NZ NZ509505A patent/NZ509505A/en not_active IP Right Cessation
- 1999-06-24 IL IL13996699A patent/IL139966A0/en unknown
- 1999-06-24 ES ES99941383T patent/ES2184496T3/en not_active Expired - Lifetime
- 1999-06-24 MX MXPA00012338A patent/MXPA00012338A/en unknown
- 1999-06-24 ID IDW20002676A patent/ID27515A/en unknown
- 1999-06-24 PT PT99941383T patent/PT1089761E/en unknown
- 1999-06-24 KR KR1020007014813A patent/KR20010053211A/en not_active Application Discontinuation
- 1999-06-24 PL PL99345287A patent/PL345287A1/en unknown
-
2000
- 2000-11-29 HR HR20000820A patent/HRP20000820A2/en not_active Application Discontinuation
- 2000-12-01 IS IS5748A patent/IS5748A/en unknown
- 2000-12-21 NO NO20006572A patent/NO20006572L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ATE224734T1 (en) | 2002-10-15 |
| KR20010053211A (en) | 2001-06-25 |
| DE19828450A1 (en) | 1999-12-30 |
| WO2000000182A2 (en) | 2000-01-06 |
| HUP0102873A3 (en) | 2002-04-29 |
| PL345287A1 (en) | 2001-12-03 |
| TR200003821T2 (en) | 2001-06-21 |
| DK1089761T3 (en) | 2003-02-03 |
| EA200100080A1 (en) | 2001-06-25 |
| NO20006572L (en) | 2001-02-21 |
| HRP20000820A2 (en) | 2001-12-31 |
| HUP0102873A2 (en) | 2001-12-28 |
| NZ509505A (en) | 2002-11-26 |
| CA2334711A1 (en) | 2000-01-06 |
| NO20006572D0 (en) | 2000-12-21 |
| PT1089761E (en) | 2003-02-28 |
| CA2334711C (en) | 2006-12-05 |
| EP1089761B1 (en) | 2002-09-25 |
| MXPA00012338A (en) | 2003-04-25 |
| EP1089761A2 (en) | 2001-04-11 |
| DE59902856D1 (en) | 2002-10-31 |
| IL139966A0 (en) | 2002-02-10 |
| JP2002519319A (en) | 2002-07-02 |
| AU5503399A (en) | 2000-01-17 |
| SK19602000A3 (en) | 2001-07-10 |
| ID27515A (en) | 2001-04-12 |
| IS5748A (en) | 2000-12-01 |
| ES2184496T3 (en) | 2003-04-01 |
| EE200000756A (en) | 2002-04-15 |
| WO2000000182A3 (en) | 2000-03-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU615711B2 (en) | (cycloalkylamino)methylenebis(phosphonic acid) and medicines containing the same as an active ingredient | |
| CA1108622A (en) | Metronidazole phosphate and salts | |
| CA1288346C (en) | Use of n-acetylglucosamine for the therapy of degenerative joint disease and related diseases | |
| WO2003009855A2 (en) | Organo-phosphorous compounds for activating gamma/delta t cells | |
| JPH026409A (en) | Oral medicine composition of a diphosphonic acid derivative | |
| JP2859318B2 (en) | Pharmaceutical for bone disease containing inositol triphosphate | |
| AU740605B2 (en) | Medicaments containing bisphosphonic acids and derivatives thereof which are provided for preventing and treating autoimmune diseases and allergies | |
| US20170022227A1 (en) | Crystallization method and bioavailability | |
| AU754862B2 (en) | Use of bisphosphonates for the prevention and treatment of infectious processes | |
| GB2096889A (en) | Pharmaceutical composition containing 6-amino-1-hydroxyhexane-1,1-diphosphonic acid | |
| EP2438076B1 (en) | Targeted drug delivery to the bone | |
| US20060040899A1 (en) | Medicaments containing bisphosphonic acids and derivatives thereof for preventing and treating diseases and allergies | |
| NL8702297A (en) | MEDICAMENT FOR THE PROVISION OF FLUORIDE IONS FOR THE TREATMENT AND PREVENTION OF BONE-LOSS DISEASES. | |
| JPS60120995A (en) | Production of new amino acid derivative | |
| CA2112195A1 (en) | Preventive and therapeutic agent for arteriosclerosis | |
| CZ20004762A3 (en) | Bisphosphonic acids and their derivatives containing medicaments for prophylaxis and treatment of auto-immune diseases and allergies | |
| JPH0374330A (en) | Remedy of demyelinating disease | |
| CA2352511A1 (en) | Use of phosphonoformic acid derivatives for treating infections | |
| EP0408668B1 (en) | Process for increasing phosphatidylcholine in vivo | |
| RU2051674C1 (en) | Agent for bruxism treatment | |
| JPH0788304B2 (en) | Hyperammonemia treatment | |
| EP0981351A1 (en) | Use of diphosphonic acids or the physiologically acceptable salts or esters thereof in the preventive treatment of after-effects resulting from enlargement or replacement of the bladder | |
| CS209859B2 (en) | Method of making the new derivatives of the amino acids |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) | ||
| PC | Assignment registered |
Owner name: JOMAA PHARMAKA GMBH Free format text: FORMER OWNER WAS: HASSAN JOMAA |
|
| PC | Assignment registered |
Owner name: BIOAGENCY AG Free format text: FORMER OWNER WAS: JOMAA PHARMAKA GMBH |