CA1333771C - Use of imexon as an immune suppressive and pharmaceutical compositions containing them - Google Patents
Use of imexon as an immune suppressive and pharmaceutical compositions containing themInfo
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- CA1333771C CA1333771C CA000606620A CA606620A CA1333771C CA 1333771 C CA1333771 C CA 1333771C CA 000606620 A CA000606620 A CA 000606620A CA 606620 A CA606620 A CA 606620A CA 1333771 C CA1333771 C CA 1333771C
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/12—Antivirals
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- 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
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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Abstract
Imexon of formula:
Description
133377~
The present invention is concerned with the use of imexon for an immunosuppressive action, for the preparation of pharmaceutical compositions with an immunosuppressive action, and is also concerned with pharmaceutical compositions containing imexon alone or in combination with a further active material.
In particular, the present invention is concerned with the use of imexon for the treatment of autoimmune diseases, B cell and plasma cell neo-plasias, lymphoblastic lymphomas, rejection reactions after tissue and organ transplants and viral and retroviral infections, for example AIDS or ARC
(AIDS-related complex), and for the preparation of pharmaceutical compositions for such treatment. In general, imexon can be used for the treatment of diseases in which a pathophysiologically increased B-lymphocyte proliferation or B-lymphocyte activation is to be observed.
-Imexon, which has the systematic designation 4-imino-1,3-diazabicyclo-(3.1.0)-hexan-2-one, has the following structural formula:-H2C - C _ C _ NH
N
C NH
:, With regard to its structure, imexon is not comparable with any other active compounds used therapeutically. The surprisingly found preferred _3_ ~33317~
action on B-lymphocutes also has no parallel with other previously known immunosuppressively-acting compounds.
Imexon and processes for the preparation thereof are known from U.S. Patent Specification No.4,083,987.
The compound is thereby described as being a cancero-statically-active therapeutic which displays immune-stimulating properties. The cancerostatic action was demonstrated on the basis of the inhibition of the tumour growth of Walker sarcoma 256 after the adminis-tration of imexon to rats. The immune-stimulating action can be deduced from experiments in which an increase of the leukocytes, as well as an increase of the number of the antibody-forming spleen cells could be observed after the administration of imexon. The pharmacological importance of imexon is, according to this U.S. Patent Specification, to be seen in the fact that imexon so strongly impairs the growth of the rapidly dividing cancer cells that, under certain circumstances, a regression of the tumours is possible.
According to U.S. Patent Specification No. 4,083,987, the advantageous action of imexon lies in the simult-aneous strengthening of the weakened immune defence system inherent in the body which accompanies the cancerostatic action.
In general, immune suppressives as such have been known for a long time from the prior art (Pharmazie unserer Zeil, 1, 2-8/1972 and 12 , 20-29/1983). The r expression "immune suppression" used in this connection generally designates the various types of non-specific suppression of the immune response, for example with the help of antisera, ionising irradlations and special therapeutics.
The use of immune suppressive-acting chemo-therapeutics can be employed after the transplantation of tissue or organs and in the therapy of autoimmune diseases. They inhibit the proliferation of lympho-cytes by direct or indirect intervention into thesynthesis of DNA or RNA. To this class of compounds belong cyclosporins, folic acid antagonists, purine analogues, alkylating compounds, such as cyclo-phosphamide, and certain corticosteroids. However, a disadvantage of these previously used immunosuppressives is the increased extent of observed susceptibility to infection of the treated organism which weakens the whole of the body's immune system and suppresses not only the humoral but also the cellular immune response.
The previously known artificially induced immune suppression could be achieved in various ways: by the administration of antigens, administration of specific antisera or antibodies, the use of other biological reagents, for example antilymphocyte antisera, by the use of immunosuppressively-active compounds, by radiation or by the surgical removal of lymphoid tissue.
-~5~ 1 33377 1 The immunosuppressive properties of the immuno-suppressives at present known, for example cytostatics and corticosteroids, are dosage-dependent but non-selective, i.e. they act upon all immune-competent cells. These compounds inhibit not only the humoral but also the cellular immune response to a plurality of antigens and act non-specifically on T- and B-lymphocytes. Cyclosporin A, which at present is the most selective medicament, suppresses not only the proliferation of T-lymphocytes but also immune processes which are not T-cell-dependent.
Therefore, there is a great interest in immuno-suppressives which interfere specifically with patho-logically strengthened or increased immune mechanisms but without influencing the immune reactions which take ?lace normally in the body. Hitherto, such specifically-active immunosuppressive substances are not known.
The present invention seeks to provide such a new immunosuppressively-active agent.
Surprisingly, it has now been found that imexon solves this problem and can be used as an advantageous immune suppressive. It specifically suppresses the B-cell proliferation or the B-cell activation. It can be advantageously used in the treatment of all diseases in which a polyclonal activation or proliferation of B-cells is of pathophysiological, symptomatic or clinical relevance.
In this sense, the treatment of the following diseases can, for example, be considered: autoimmune diseases, for example rheumatoid arthritis, diabetes mellitus Type I, psoriasis, lupus systemicus erythematosus; rejection reactions after tissue or organ transplants, for example of skin, bone marrow and kidneys; viral or retroviral infections of any genesis, for example ARC (AIDS-related complex) and AIDS, as well as their preliminary stages; B-cell leukaemias and lymphomas, for example chronic lymphatic leukaemia, lymphoblastic lymphoma, for example Burkitt's lymphoma and the like, or B-cell/
plasma cell neoplasias, for example plasmacytoma (multiple myeloma).
As autoimmune diseases, in the literature there are generally designated those diseases in which the formation of autoantibodies have a pathogenic significance. These autoantibodies are directed against the body's own antigens and thus bring about a destruction of the body's own organs, cells or proteins. It is desired to suppress these diseased overreactions of the immune system with specifically-acting immune suppressives.
Furthermore, it has surprisingly been found that imexon inhibits the proliferation of B-lymphocytes in a dosage-dependent manner.
~7~ 1 33377 1 Imexon can be used itself directly or in the form of physiologically compatible, pharmaceutically , acceptable acid addition salts. ~ -In the meaning of the present invention, the expression "immune suppression" is, in general, to comprise all aspects of the naturally-induced immunological non-responsiveness,artificially-induced non-responsiveness and pathologically-induced tolerance to auto- and foreign antigens.
The immune suppressive action of imexon could be demonstrated on the basis of the inhibition of the proliferation of human B-lymphocytes, the prolifer-ation being induced experimentally by the B-cell growth factor (BCGF).
Furthermore, the pharmacological properties of imexon could be characterised by concanavalin A
(ConA)-induced proliferation of murine splenocytes (LTT), by phythaemagglutinin (PHA)-induced prolifer-ation of human lymphocytes, as well as by tumour growth inhibition assay (TGI).
In order to stimulate dormant B-cells to prolif-eration, two signals are necessary. The first signal is an activation signal which is brought about by an antigen or anti-~. The transmission of this activating signal finally has the result that receptors for the B-cell growth factor (BCGF) are expressed on the B-cell surface. BCGF is a soluble lymphokine secreted by I
-T-cells with a mol'ecular weight of 17,000 to 18,000 D.
The expression of BCGF receptors on the B-cells makes it possible for these to respond to the proliferatlon signal of BCGF. Normally, B-cells are converted by this two-signal process from the dormant state into the proliferative phase.
Imexon now suppresses this procedure specifically insofar as the concanavalin A (ConA)- and phyto-haemagglutinin (PHA)-induced lymphocyte proliferation, as well as the spontaneous proliferation of methyl-cholanthrene-induced fibrosarcoma cells (MethA), are not influenced or only in the case of 10 to 30 times higher concentrations.
The antiretroviral action of imexon could be demonstrated on the basis,of the Rauscher virus leukaemia model (cf. Example 5). The influence of imexon on the spontaneous formation of l~mp~om2s and the synthesis of antinuclear autoantibodies in the mouse (Example 6) pr'oves the effectiveness on an animal model for autoimmune diseases.
Imexon can also be used as a combination prepar-ation with other immune suppressives, for example cyclosporin A, ciamexon or azathioprine, 2S well as antiretrovirally-active substances, for example azidothymidine (AZT).
A combination of imexon with cytostatics is also possible, for example with cis-platinum complexes, 1 33377 ~
such as cis-diaminodichloroplatinum, or with adriamycin, cyclophosphamide, vincristin, tamoxifen, methotrexate or 5-fluorouracil and the like. In this connection, the use of such combination preparations is of especial interest subsequent to a plasmaphaeresis for the monitoring of autoimmune diseases.
In the case of the use of a combination therapy, - it is possible to administer the active materials in a so-called fixed combination, i.e. in a single pharma-ceutical formulation, in which both active materials are present simultaneously, or to use a so-called free combination in which the active materials are adminis-tered in the form of pharmaceutical formulations simultaneously or also successively in individually selectable dosage relationships.
For the preparation of pharmaceutical agents, ir,lexon is mixed in known manner with appropriate pharmaceutical carrier substances, possibly granulated and pressed, for example, into tablets or dragee cores.
A filling of the mixture into hard capsules is also possible. With the addition of appropriate adjuvants, a solution or suspension in water, an oil, for example olive oil, or a high molecular weight polymer, for example polyethylene glycol, can also be produced and administered in the form of injection solutions, soft gelatine capsules, syrups or drops.
-lo- I 33377 1 - As solid carrier materials, there can be used, for example, starches or starch derivatives, sugars, sugar alcohols, celluloses or cellulose derivatives, tensides, talc, highly dispersed silicic acids, high 5 molecular weight fatty acids or the salts thereof, gelatine, agar-agar, calcium phosphate, animal or vegetable fats or waxes and solid high molecular weight polymers (such as polyethylene glycols or poly-vinylpyrrolidones). Compositions suitable for oral administration can, if desired, contain flavouring and sweetening materials.
In this specification, it will be understood that the qualification that the salts be physio- ~
logically compatible is to be understood as extending to salts of imexon with non-toxic inorganic or organic acids which have no adverse effects to the extent that such salts would be unsuitable for administration to living bodies. The qualification that the salts be "pharmaceutically acceptable" means that the salts have the necessary physical charac-teristics, for example, stability to render themsuitable for formulation into pharmaceutical composi-tions.
~ 33377 ~
The dosage of the active material imexon depends upon the age and sex of the individual, as well as upon the nature of the indications to be treated.
In principle, the treatment can be based on the fact that 0.1 to 100 mg. of imexon per kg. body weight can be administered daily orally, intra-venously, subcutaneously or intramuscularly. However,it is preferred to use amounts of from 5 to 50 mg./kg.
body weight and especially 5 to 20 mg./kg. body weight. The dosages of the active material can be administered 1 to 3 times daily.
In particular, pharmaceutical compositions may contain imexon or an acceptable salt thereof in an amount of from 10 to 1000 mg. per unit form of administration.
The specific immunosuppressive action of imexon is demonstrated by the following Examples:
ExamPle 1 BCGF-dependent proliferation of human B-lYmphocytes.
The enrichment of peripheral human B-cells and F~
--12_ the BCGF proliferation assay were carried out as follows (Cf. Eur. J. Immun., 16, 350/1986):
Enriched human B-lymphocytes were washed twice with complete RPMI 1640 medium (streptomycin/penicillin, L-glutamine, 2-mercaptoethanol, FCS) and adjusted to 3 x 105 cells/ml. 150 ml. of this suspension were pipetted into each well of microtitre plates. As pseudoantigen, there were added thereto 10 ml. of a solution of HFC ~S-IgG (300 ~g./ml.) and, as growth factor, 20 ~1. BCGF (Cellular Products Incorporated).
To this were pipetted 20 ~1. of the compound to be tested in 10 fold concentration. The cultures were incubated for a total of 140 hours at 37C. with 5%
carbon dioxide and 95% relative atmospheric humidity.
16 hours before the conclusion of the incubation period, each culture was pulsed with 1 ~Ci of a [3H]-thymidine solution. At the end of the experiment, the cells were collected with a harvester and the incorporated radio-activity determined in a liquid scintillatio~ counter.
Example 2.
Concanavalin A (ConA)-induced proliferation of murine splenocytes.
Spleen cells (4 x 105) of CB6Fl mice were incubated for a total of 48 hours with 0.5 ~g./ml. ConA
in microtitre plates (Nunc GmbH, Wiesbaden, Federal Republic of Germany) and various concentrations of imexon in 6 fold batches. 5 hours before the _ -13- l 33377 1 termination of the incubation period, the cultures were pulsed with [3H]-thymidine and subsequently harvested on glass fibre filter platelets by means of a multi-sample harvester (Skatron A.S., Lier, Norway). The filter platelets were dried and the radioactivity was determined in a Packard scintillation spectrometer.
Example 3.
Phythaemag~lutinin (PHA)-induced proliferation of human lymphocytes.
1 ml. of human whole blood was diluted with 500 ~g. PHA solution (500 ~g./ml.) and diluted with 48 ml. DMEM medium. 200 ~1. amounts of this batch were mixed with 20 ~1. of the imexon concentration to be tested in 6 fold batches and incubated for 4 days.
After pulsing with [3H]-thymidine, incubation was continued for a further 24 hours, followed by harvest-ing and evaluation as described in Example 2.
Example 4.
Tumour growth inhibition assay (TGI).
A methylcholanthrene-induced fibrosarcoma cell line (MethA) was obtained from our own tumour cell bank and passed intraperitoneally into CB6Fl mice.
1 x 104 MethA cells were incubated with the imexon concentration to be tested in DMEM medium for 48 hours. 3 hours before the end of the incubation time, pulsing was carried out with [3H]-thymidine, followed by harvesting and evaluated as described in Example 2.
-14- 1 33377~
The values given in the following Table 1 show the results of a representative experiment. They are the results of the investigations with imexon in the TGI, LTT (ConA, PHA) as well as in the BCGF assay, i.e. the influence of imexon on the proliferation of the MethA sarcoma cell, T-lymphocytes and B-cells is shown. Imexon suppressed significantly and specifically the BCGF-induced B-cell proliferation at a concentration of 1 yg./ml., whereas the lymphocyte proliferation induced either by ConA or PHA was only significantly inhibited at concentrations of > 10 yg./ml. Further-more, the spontaneous proliferation of MethA sarcoma cells was also only significantly suppressed at > 10 yg./ml.
The results of the above experiments are summarised in the following Table 1:
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~ Example 5.
Antiretroviral action of imexon in the Rauscher virus leukaemia model.
8 to 9 week old female Balb/c mice were infected with 0.2 ml. of spleen homogenate of infected animals (diluted 1:2 in PBS). From day 0 (or day -1) up to day 13, the animals were treated intraperitoneally daily with the given dosage of the active material.
On day 7 and on day 14, animals of the individual treatment groups were sacrificed and the spleen weight determined as a measure of the viraemia.
In the following Table 2 are summarised the ' results of the investigations. Imexon controlled the virus-caused increased weight of the spleen in the same dosage range as azidothymidine.
.~ 1 33377 1~ . --- c .~ ~
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JJ 1-'~ >r-l r-l CO ~~O `D C~i ~r~ O ~ ~C~l O r~
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The present invention is concerned with the use of imexon for an immunosuppressive action, for the preparation of pharmaceutical compositions with an immunosuppressive action, and is also concerned with pharmaceutical compositions containing imexon alone or in combination with a further active material.
In particular, the present invention is concerned with the use of imexon for the treatment of autoimmune diseases, B cell and plasma cell neo-plasias, lymphoblastic lymphomas, rejection reactions after tissue and organ transplants and viral and retroviral infections, for example AIDS or ARC
(AIDS-related complex), and for the preparation of pharmaceutical compositions for such treatment. In general, imexon can be used for the treatment of diseases in which a pathophysiologically increased B-lymphocyte proliferation or B-lymphocyte activation is to be observed.
-Imexon, which has the systematic designation 4-imino-1,3-diazabicyclo-(3.1.0)-hexan-2-one, has the following structural formula:-H2C - C _ C _ NH
N
C NH
:, With regard to its structure, imexon is not comparable with any other active compounds used therapeutically. The surprisingly found preferred _3_ ~33317~
action on B-lymphocutes also has no parallel with other previously known immunosuppressively-acting compounds.
Imexon and processes for the preparation thereof are known from U.S. Patent Specification No.4,083,987.
The compound is thereby described as being a cancero-statically-active therapeutic which displays immune-stimulating properties. The cancerostatic action was demonstrated on the basis of the inhibition of the tumour growth of Walker sarcoma 256 after the adminis-tration of imexon to rats. The immune-stimulating action can be deduced from experiments in which an increase of the leukocytes, as well as an increase of the number of the antibody-forming spleen cells could be observed after the administration of imexon. The pharmacological importance of imexon is, according to this U.S. Patent Specification, to be seen in the fact that imexon so strongly impairs the growth of the rapidly dividing cancer cells that, under certain circumstances, a regression of the tumours is possible.
According to U.S. Patent Specification No. 4,083,987, the advantageous action of imexon lies in the simult-aneous strengthening of the weakened immune defence system inherent in the body which accompanies the cancerostatic action.
In general, immune suppressives as such have been known for a long time from the prior art (Pharmazie unserer Zeil, 1, 2-8/1972 and 12 , 20-29/1983). The r expression "immune suppression" used in this connection generally designates the various types of non-specific suppression of the immune response, for example with the help of antisera, ionising irradlations and special therapeutics.
The use of immune suppressive-acting chemo-therapeutics can be employed after the transplantation of tissue or organs and in the therapy of autoimmune diseases. They inhibit the proliferation of lympho-cytes by direct or indirect intervention into thesynthesis of DNA or RNA. To this class of compounds belong cyclosporins, folic acid antagonists, purine analogues, alkylating compounds, such as cyclo-phosphamide, and certain corticosteroids. However, a disadvantage of these previously used immunosuppressives is the increased extent of observed susceptibility to infection of the treated organism which weakens the whole of the body's immune system and suppresses not only the humoral but also the cellular immune response.
The previously known artificially induced immune suppression could be achieved in various ways: by the administration of antigens, administration of specific antisera or antibodies, the use of other biological reagents, for example antilymphocyte antisera, by the use of immunosuppressively-active compounds, by radiation or by the surgical removal of lymphoid tissue.
-~5~ 1 33377 1 The immunosuppressive properties of the immuno-suppressives at present known, for example cytostatics and corticosteroids, are dosage-dependent but non-selective, i.e. they act upon all immune-competent cells. These compounds inhibit not only the humoral but also the cellular immune response to a plurality of antigens and act non-specifically on T- and B-lymphocytes. Cyclosporin A, which at present is the most selective medicament, suppresses not only the proliferation of T-lymphocytes but also immune processes which are not T-cell-dependent.
Therefore, there is a great interest in immuno-suppressives which interfere specifically with patho-logically strengthened or increased immune mechanisms but without influencing the immune reactions which take ?lace normally in the body. Hitherto, such specifically-active immunosuppressive substances are not known.
The present invention seeks to provide such a new immunosuppressively-active agent.
Surprisingly, it has now been found that imexon solves this problem and can be used as an advantageous immune suppressive. It specifically suppresses the B-cell proliferation or the B-cell activation. It can be advantageously used in the treatment of all diseases in which a polyclonal activation or proliferation of B-cells is of pathophysiological, symptomatic or clinical relevance.
In this sense, the treatment of the following diseases can, for example, be considered: autoimmune diseases, for example rheumatoid arthritis, diabetes mellitus Type I, psoriasis, lupus systemicus erythematosus; rejection reactions after tissue or organ transplants, for example of skin, bone marrow and kidneys; viral or retroviral infections of any genesis, for example ARC (AIDS-related complex) and AIDS, as well as their preliminary stages; B-cell leukaemias and lymphomas, for example chronic lymphatic leukaemia, lymphoblastic lymphoma, for example Burkitt's lymphoma and the like, or B-cell/
plasma cell neoplasias, for example plasmacytoma (multiple myeloma).
As autoimmune diseases, in the literature there are generally designated those diseases in which the formation of autoantibodies have a pathogenic significance. These autoantibodies are directed against the body's own antigens and thus bring about a destruction of the body's own organs, cells or proteins. It is desired to suppress these diseased overreactions of the immune system with specifically-acting immune suppressives.
Furthermore, it has surprisingly been found that imexon inhibits the proliferation of B-lymphocytes in a dosage-dependent manner.
~7~ 1 33377 1 Imexon can be used itself directly or in the form of physiologically compatible, pharmaceutically , acceptable acid addition salts. ~ -In the meaning of the present invention, the expression "immune suppression" is, in general, to comprise all aspects of the naturally-induced immunological non-responsiveness,artificially-induced non-responsiveness and pathologically-induced tolerance to auto- and foreign antigens.
The immune suppressive action of imexon could be demonstrated on the basis of the inhibition of the proliferation of human B-lymphocytes, the prolifer-ation being induced experimentally by the B-cell growth factor (BCGF).
Furthermore, the pharmacological properties of imexon could be characterised by concanavalin A
(ConA)-induced proliferation of murine splenocytes (LTT), by phythaemagglutinin (PHA)-induced prolifer-ation of human lymphocytes, as well as by tumour growth inhibition assay (TGI).
In order to stimulate dormant B-cells to prolif-eration, two signals are necessary. The first signal is an activation signal which is brought about by an antigen or anti-~. The transmission of this activating signal finally has the result that receptors for the B-cell growth factor (BCGF) are expressed on the B-cell surface. BCGF is a soluble lymphokine secreted by I
-T-cells with a mol'ecular weight of 17,000 to 18,000 D.
The expression of BCGF receptors on the B-cells makes it possible for these to respond to the proliferatlon signal of BCGF. Normally, B-cells are converted by this two-signal process from the dormant state into the proliferative phase.
Imexon now suppresses this procedure specifically insofar as the concanavalin A (ConA)- and phyto-haemagglutinin (PHA)-induced lymphocyte proliferation, as well as the spontaneous proliferation of methyl-cholanthrene-induced fibrosarcoma cells (MethA), are not influenced or only in the case of 10 to 30 times higher concentrations.
The antiretroviral action of imexon could be demonstrated on the basis,of the Rauscher virus leukaemia model (cf. Example 5). The influence of imexon on the spontaneous formation of l~mp~om2s and the synthesis of antinuclear autoantibodies in the mouse (Example 6) pr'oves the effectiveness on an animal model for autoimmune diseases.
Imexon can also be used as a combination prepar-ation with other immune suppressives, for example cyclosporin A, ciamexon or azathioprine, 2S well as antiretrovirally-active substances, for example azidothymidine (AZT).
A combination of imexon with cytostatics is also possible, for example with cis-platinum complexes, 1 33377 ~
such as cis-diaminodichloroplatinum, or with adriamycin, cyclophosphamide, vincristin, tamoxifen, methotrexate or 5-fluorouracil and the like. In this connection, the use of such combination preparations is of especial interest subsequent to a plasmaphaeresis for the monitoring of autoimmune diseases.
In the case of the use of a combination therapy, - it is possible to administer the active materials in a so-called fixed combination, i.e. in a single pharma-ceutical formulation, in which both active materials are present simultaneously, or to use a so-called free combination in which the active materials are adminis-tered in the form of pharmaceutical formulations simultaneously or also successively in individually selectable dosage relationships.
For the preparation of pharmaceutical agents, ir,lexon is mixed in known manner with appropriate pharmaceutical carrier substances, possibly granulated and pressed, for example, into tablets or dragee cores.
A filling of the mixture into hard capsules is also possible. With the addition of appropriate adjuvants, a solution or suspension in water, an oil, for example olive oil, or a high molecular weight polymer, for example polyethylene glycol, can also be produced and administered in the form of injection solutions, soft gelatine capsules, syrups or drops.
-lo- I 33377 1 - As solid carrier materials, there can be used, for example, starches or starch derivatives, sugars, sugar alcohols, celluloses or cellulose derivatives, tensides, talc, highly dispersed silicic acids, high 5 molecular weight fatty acids or the salts thereof, gelatine, agar-agar, calcium phosphate, animal or vegetable fats or waxes and solid high molecular weight polymers (such as polyethylene glycols or poly-vinylpyrrolidones). Compositions suitable for oral administration can, if desired, contain flavouring and sweetening materials.
In this specification, it will be understood that the qualification that the salts be physio- ~
logically compatible is to be understood as extending to salts of imexon with non-toxic inorganic or organic acids which have no adverse effects to the extent that such salts would be unsuitable for administration to living bodies. The qualification that the salts be "pharmaceutically acceptable" means that the salts have the necessary physical charac-teristics, for example, stability to render themsuitable for formulation into pharmaceutical composi-tions.
~ 33377 ~
The dosage of the active material imexon depends upon the age and sex of the individual, as well as upon the nature of the indications to be treated.
In principle, the treatment can be based on the fact that 0.1 to 100 mg. of imexon per kg. body weight can be administered daily orally, intra-venously, subcutaneously or intramuscularly. However,it is preferred to use amounts of from 5 to 50 mg./kg.
body weight and especially 5 to 20 mg./kg. body weight. The dosages of the active material can be administered 1 to 3 times daily.
In particular, pharmaceutical compositions may contain imexon or an acceptable salt thereof in an amount of from 10 to 1000 mg. per unit form of administration.
The specific immunosuppressive action of imexon is demonstrated by the following Examples:
ExamPle 1 BCGF-dependent proliferation of human B-lYmphocytes.
The enrichment of peripheral human B-cells and F~
--12_ the BCGF proliferation assay were carried out as follows (Cf. Eur. J. Immun., 16, 350/1986):
Enriched human B-lymphocytes were washed twice with complete RPMI 1640 medium (streptomycin/penicillin, L-glutamine, 2-mercaptoethanol, FCS) and adjusted to 3 x 105 cells/ml. 150 ml. of this suspension were pipetted into each well of microtitre plates. As pseudoantigen, there were added thereto 10 ml. of a solution of HFC ~S-IgG (300 ~g./ml.) and, as growth factor, 20 ~1. BCGF (Cellular Products Incorporated).
To this were pipetted 20 ~1. of the compound to be tested in 10 fold concentration. The cultures were incubated for a total of 140 hours at 37C. with 5%
carbon dioxide and 95% relative atmospheric humidity.
16 hours before the conclusion of the incubation period, each culture was pulsed with 1 ~Ci of a [3H]-thymidine solution. At the end of the experiment, the cells were collected with a harvester and the incorporated radio-activity determined in a liquid scintillatio~ counter.
Example 2.
Concanavalin A (ConA)-induced proliferation of murine splenocytes.
Spleen cells (4 x 105) of CB6Fl mice were incubated for a total of 48 hours with 0.5 ~g./ml. ConA
in microtitre plates (Nunc GmbH, Wiesbaden, Federal Republic of Germany) and various concentrations of imexon in 6 fold batches. 5 hours before the _ -13- l 33377 1 termination of the incubation period, the cultures were pulsed with [3H]-thymidine and subsequently harvested on glass fibre filter platelets by means of a multi-sample harvester (Skatron A.S., Lier, Norway). The filter platelets were dried and the radioactivity was determined in a Packard scintillation spectrometer.
Example 3.
Phythaemag~lutinin (PHA)-induced proliferation of human lymphocytes.
1 ml. of human whole blood was diluted with 500 ~g. PHA solution (500 ~g./ml.) and diluted with 48 ml. DMEM medium. 200 ~1. amounts of this batch were mixed with 20 ~1. of the imexon concentration to be tested in 6 fold batches and incubated for 4 days.
After pulsing with [3H]-thymidine, incubation was continued for a further 24 hours, followed by harvest-ing and evaluation as described in Example 2.
Example 4.
Tumour growth inhibition assay (TGI).
A methylcholanthrene-induced fibrosarcoma cell line (MethA) was obtained from our own tumour cell bank and passed intraperitoneally into CB6Fl mice.
1 x 104 MethA cells were incubated with the imexon concentration to be tested in DMEM medium for 48 hours. 3 hours before the end of the incubation time, pulsing was carried out with [3H]-thymidine, followed by harvesting and evaluated as described in Example 2.
-14- 1 33377~
The values given in the following Table 1 show the results of a representative experiment. They are the results of the investigations with imexon in the TGI, LTT (ConA, PHA) as well as in the BCGF assay, i.e. the influence of imexon on the proliferation of the MethA sarcoma cell, T-lymphocytes and B-cells is shown. Imexon suppressed significantly and specifically the BCGF-induced B-cell proliferation at a concentration of 1 yg./ml., whereas the lymphocyte proliferation induced either by ConA or PHA was only significantly inhibited at concentrations of > 10 yg./ml. Further-more, the spontaneous proliferation of MethA sarcoma cells was also only significantly suppressed at > 10 yg./ml.
The results of the above experiments are summarised in the following Table 1:
-_ . _.
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I ~ 00 ~ 00 ~ C~ ~
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F J~ ~, C`~ J ~ O ~ Lr~
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~ C~ ~ 11~ u~ r~ c~
_, O ~ C ~ ~ ~
~~ ~_', _ ___ _. _ C~ ~ ~ ~' 5~ E~, I X ~ c~
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~ l ~: ~ .,~
o U~.~,.,, I ~ ~ 0~ ~ ~ I
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C~. . _ o 00 ~ C~ ~ 00 0~ o ~_~ U~ O ~ ~ I`
~ ~: ~ a ~ ~ o ~ co 00 11 C~ ~ ~ ~ C
P~ ~ ~ ~
~ ~ . . ~
~' ~ ~ u~ ~ ~ O o~ ~ G`
E~ ~ I ~C oo oo E~ c) c~ u~ u~ r~ oo ~ u~ oo ~ ~ ~ u~
it ~ -~ ~
c~ ~ ~
~ ~ ,l ~'' -'` ~~-- ~ oo C`~ o ~ ~ ~
o - - - - - - - -~ ~ c`l ~ ~ ~ ~ c~ c~
~ a o ~ ~ ~ a~ 1-- oo ~
._ ~ U~ c~
~ ~ c~
ct~ . Il _, ~ _,, . . _. . __ ,, l ~ ~ a~ o _ ~ r I~ O O ~ oo c~l I~C oo ~ u~ oo ~ ~ o r~
C~ ~ ~I ~ 00 C~it C~
O C~l ~ ~ ~ O
... _ .. ._ _____ . .
, ,~
O
~-~1 I ~ ~ ~ I I
~;
~; ~ ~
~ . ~
O ~ 0 1-- ~ ~ O ~ C~ ~
~, -~ a o ~ ~ ~ ~ ~ co ~ o o ~ u~ O ~ ~ ~ ~r~ o ~ o o C~ ~ ~ _ ._ ___ O O
E~ E~`- ~^ ~ ~ ~ ~ u~ ~ ~ ~/ \/
~C E I X ~o ~ ~ ~ ~ ~ 1-- a~
e~: ~ ~1 u~ ~ ~ ~ ~ u~
c~ ~ S::
c~
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~ ~ O
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--1~ 133377~
~ Example 5.
Antiretroviral action of imexon in the Rauscher virus leukaemia model.
8 to 9 week old female Balb/c mice were infected with 0.2 ml. of spleen homogenate of infected animals (diluted 1:2 in PBS). From day 0 (or day -1) up to day 13, the animals were treated intraperitoneally daily with the given dosage of the active material.
On day 7 and on day 14, animals of the individual treatment groups were sacrificed and the spleen weight determined as a measure of the viraemia.
In the following Table 2 are summarised the ' results of the investigations. Imexon controlled the virus-caused increased weight of the spleen in the same dosage range as azidothymidine.
.~ 1 33377 1~ . --- c .~ ~
aJ o ~ +, ~ +, C ri~D c~l riO O
JJ 1-'~ >r-l r-l CO ~~O `D C~i ~r~ O ~ ~C~l O r~
C 4~ ~~ ~ 00 P
r O P~O O ~I r~ riO O r1 r~
'1 ri ~ ____.__ O O O
tl5 ' O r-l r_l Or-~
,~ O+1--~ ~ +l--~
C :~ ,-1 +1 ,~ +Irt ri O Lr~ 1--E--ICO ~-1 0 E~r1 00 ri ~ir-~ O ) ~~1 0 r-~
E ~ _~ ¢ . . o ,_ ¢. . o -~ C~ ~ O O C~l O ~ O O C~i r1 IJ ~ ._. __ _ __ _ __ . . _ __.
~ C~ ri ri rl ~ ~O ~ ~ O _~
N t.q _~ ~~i O O ~c~i O O
~-1 ~ rtr~
r-l X +l--~ ~ X +l `--~ C p~ ~o O O r-l +l ~f) Oco ~ +l c~i :~ Xo~ ~ O v X ~'1 r~ c)~
~r~ O ~ ~ C~l O 00 C c~ Ct~ ~ O ~) ~ O ' 0~ ~ E HO O C~i r-l E H O OC~i O
_ ~ ~-r~
q ~ ~ a) __ __ .,, g~ c~ o~
a~ ~ o o hO X ~ o ,_ ,_ ~
O hi ~ ~ O O O ~ _~
C~i ~1 ~ r-l r-l ~ O O
C a) C+I~_ _, ,~ ,~
O ~ U~ O +l C +l _ a) .V 0 o X J(~ ~ XO ~'-1 +
r~ C~ C ri ~C~i O I ~ O
1 H . . r-f . E~ ~) r1 t~l ~ ~i O OC~ r-l H C~
E-~ ,~ ~.C~ 00 a) ~ _ _ ) O C~i a) _ ,_ ~
c a~ ~ _~ o o ,~ o o 0 ~1 07r-~ r-l 07 r1 r~
rl O ~ O ~+l _ _, O ~ +l-- --J-J ,C H ,n ~1 + I L~ ~1 + I ~) t~ ~ O ~1) ri r~ a.) ~i o ~-~ ~i ~ ~ o ~~ ~r--t~ ~ r- O ~ ~J
~i ~i ~i O ~ t~ ~ C~l a~ ri U O r~ + . . O r~ + . ~ ~ . X
r r~ ~~ O OC~ r~ ~~ O O r~ O O
~J
C~ 0E --- _ _ __ __ __ . 0 ,_ ,_ ,_ _~ ~ ,~ a ~-~1 o~ u~ ~n u~ u~ u~
,i E O ~ +l--~ ~ O ~ +l-- ~ ~
+l ~ ~ +lC~i a,) ,i c~ O ~1 u~ ~ C~
~1 ~ C) ~ r-l H C~i ~.) ~ ~ r~
~i :J ki r-l O. r-l ~i r-l C~ rn ~ ~ r~ I ~ O ' r~ I . . O
o ,~ ~-- o oC~ ,~ ,~-- o o C~i o C) U~ ri . . ._. _ _ _. _ __ _ _. ____ ~
ri _ _~ _ _ C~
4~ ~ ~8 bO ~ r~
O ~_ ~ _ JJ ~ ~ ~ ~ 'C
r C~ rl rl rl ~h~ ~i L~ ~ ~ ~ ~ ' ~ ~
~ r~ ~J ~ r~ ~
i . r-~ ~r~ r1 O E~
~ ~ C :~ ~ C
~ ~n ~ ~ c~ ~
. _ _ _ _ _ _ _ _ _ . _ _ _ 1 33377 ~
Example 6.
Action of imexon in the case of autoimmune diseases.
With increasing age, the mouse strain MRL lpr/lpr develops increasingly spontaneously lymphadenoma and SLE-like symptoms, for example the synthesis of anti-nuclear autoantibodies. For the investigation of the prophylactic effect of imexon on the development of these symptoms, 11 week old MRL mice were treated intraperitoneally once daily with the given dosages of imexon and cyclophosphamide. The number of lympha-denomas and the concentration of antinuclear antibodies were documented. In the case of the investigation of the therapeutic potency of imexon,- MRL mice, after each animal had developed at least one lymphadenoma (about 14 week old animals), were also treated once daily with the given dosages of imexon and cyclophosphamide.
The measurement parameters were again the number of lymphadenomas, as well as the autoantibody titre.
The results of these investigations have shown that imexon, in the case of very good compatibility, lowers the number of spontaneously arising lymphadenomas and the concentration of DNA-specific antibodies. The effectiveness of imexon was also shown in the case of therapeutic use with animals already having lymphomas.
The number of lymphadenomas decreased dependent upon the dosage, as well as the titre of the autoantibodies.
Example 7.
Preparation of a pharmaceutical formulation of imexon.
A film tablet with, for example, 100 g. of active material and which has the following composition has proved to be an appropriate pharmaceutical composition:
weight/unit/mg.
imexon 100.000 lactose monohydrate 63.000 10 poly-(0-carboxymethyl)-starch, sodium salt 7.000 poly-(l-vinyl-2-pyrrolidone) 25,000 4.000 poly-(0-carboxymethyl)-starch, 15 sodium salt 3 000 microcrystalline cellulose20.000 highly dispersed silicon dioxide 1.500 magnesium stearate 1.500 core weight 200.000 The film tablets were then produced in the usual way by the film drageeing of the imexon cores obtained.
Film tablets with, for example 10 mg., 50 mg., 200 mg. and 500 mg. of active material were produced in a corresponding manner.
In this specification the expression "such as"
means --for example-- and is not intended to be con-strued as limiting.
O ~_ ~ _ JJ ~ ~ ~ ~ 'C
r C~ rl rl rl ~h~ ~i L~ ~ ~ ~ ~ ' ~ ~
~ r~ ~J ~ r~ ~
i . r-~ ~r~ r1 O E~
~ ~ C :~ ~ C
~ ~n ~ ~ c~ ~
. _ _ _ _ _ _ _ _ _ . _ _ _ 1 33377 ~
Example 6.
Action of imexon in the case of autoimmune diseases.
With increasing age, the mouse strain MRL lpr/lpr develops increasingly spontaneously lymphadenoma and SLE-like symptoms, for example the synthesis of anti-nuclear autoantibodies. For the investigation of the prophylactic effect of imexon on the development of these symptoms, 11 week old MRL mice were treated intraperitoneally once daily with the given dosages of imexon and cyclophosphamide. The number of lympha-denomas and the concentration of antinuclear antibodies were documented. In the case of the investigation of the therapeutic potency of imexon,- MRL mice, after each animal had developed at least one lymphadenoma (about 14 week old animals), were also treated once daily with the given dosages of imexon and cyclophosphamide.
The measurement parameters were again the number of lymphadenomas, as well as the autoantibody titre.
The results of these investigations have shown that imexon, in the case of very good compatibility, lowers the number of spontaneously arising lymphadenomas and the concentration of DNA-specific antibodies. The effectiveness of imexon was also shown in the case of therapeutic use with animals already having lymphomas.
The number of lymphadenomas decreased dependent upon the dosage, as well as the titre of the autoantibodies.
Example 7.
Preparation of a pharmaceutical formulation of imexon.
A film tablet with, for example, 100 g. of active material and which has the following composition has proved to be an appropriate pharmaceutical composition:
weight/unit/mg.
imexon 100.000 lactose monohydrate 63.000 10 poly-(0-carboxymethyl)-starch, sodium salt 7.000 poly-(l-vinyl-2-pyrrolidone) 25,000 4.000 poly-(0-carboxymethyl)-starch, 15 sodium salt 3 000 microcrystalline cellulose20.000 highly dispersed silicon dioxide 1.500 magnesium stearate 1.500 core weight 200.000 The film tablets were then produced in the usual way by the film drageeing of the imexon cores obtained.
Film tablets with, for example 10 mg., 50 mg., 200 mg. and 500 mg. of active material were produced in a corresponding manner.
In this specification the expression "such as"
means --for example-- and is not intended to be con-strued as limiting.
Claims (38)
1. The use of imexon or a physiologically compatible, pharmaceutically acceptable acid addition salt thereof for the production of a pharmaceutical composition with an immunosuppressive action.
2. The use of imexon or a physiologically compatible, pharmaceutically acceptable acid addition salt thereof for the production of a pharmaceutical composition for the treatment of diseases which involve an increased B-lymphocyte activation.
3. The use according to claim 1, wherein the pharmaceutical composition is for the treatment of autoimmune diseases.
4. The use according to claim 2, wherein the pharmaceutical composition is for the treatment of autoimmune diseases.
5. The use according to claim 1, wherein the pharmaceutical composition is for the treatment of leukaemias or lymphomas.
6. The use according to claim 2, wherein the pharmaceutical composition is for the treatment of leukaemias or lymphomas.
7. The use according to claim 1, wherein the pharmaceutical composition is for the suppression of rejection reactions after tissue or organ trans-plantations.
8. The use according to claim 2, wherein the pharmaceutical composition is for the suppression of rejection reactions after tissue or organ trans-plantations.
9. The use according to claim 1, wherein the pharmaceutical composition is for the treatment or prophylaxis of viral or retroviral infections.
10. The use according to claim 2, wherein the pharmaceutical composition is for the treatment or prophylaxis of viral or retroviral infections.
11. The use according to claim 1, wherein the pharmaceutical composition is for the prophylaxis or treatment of AIDS or ARC.
12. The use according to claim 2, wherein the pharmaceutical composition is for the prophylaxis or treatment of AIDS or ARC.
13. The use according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein the pharmaceutical composition is in the form of tablets.
14. The use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein said imexon or salt thereof is in an amount of from 10 to 1000 mg. per unit form of administration of the pharmaceutical composition.
15. The use according to claim 13, wherein said imexon or salt thereof is in an amount of from 10 to 1000 mg. per unit form of administration of the pharmaceutical composition.
16. The use according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 15. wherein the pharmaceutical composition contains said imexon or salt thereof in a dosage of 0.1 to 100 mg./kg.
17. The use according to claim 13, wherein the pharmaceutical composition contains said imexon or salt thereof in a dosage of 0.1 to 100 mg./kg.
18. The use according to claim 14, wherein the pharmaceutical composition contains said imexon or salt thereof in a dosage of 0.1 to 100 mg./kg.
19. The use of imexon or a physiologically compatible, pharmaceutically acceptable acid addition salt thereof as active material for the production of pharmaceutical compositions with a cytostatic action.
20. Imexon or a physiologically compatible, pharmaceutically acceptable acid addition salt thereof for use in the treatment of diseases which involve an increased B-lymphocyte activation.
21. Imexon or a physiologically compatible, pharmaceutically acceptable acid addition salt thereof for use in the treatment of autoimmune diseases.
22. A pharmaceutical composition for the treat-ment of autoimmune diseases, B cell and plasma cell neoplasias, lymphoblastic lymphomas, rejection reactions after tissue and organ transplants, viral infections or retroviral infections, comprising an effective amount of imexon or a physiologically compatible, pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier.
23. A pharmaceutical composition according to claim 22, wherein said imexon or said salt thereof is present in an amount of from 10 to 1000 mg. per unit form of administration.
24. A pharmaceutical composition according to claim 23, in the form of tablets.
25. A pharmaceutical composition containing imexon or a physiologically compatible, pharma-ceutically acceptable acid addition salt thereof in combination with at least one further immuno-suppressive active material.
26. A pharmaceutical composition containing imexon or a physiologically compatible, pharma-ceutically acceptable acid addition salt thereof in combination with at least one anti-retroviral active material.
27. A composition according to claim 25 or 26, further including a pharmaceutically acceptable carrier.
28. A pharmaceutical composition for the treat-ment or prophylaxis of viral and retroviral infec-tions comprising an effective amount of a combination of imexon or a physiologically compatible, pharma-ceutically acceptable acid addition salt thereof with at least one further immunosuppressive active material.
29. An immunosuppressive pharmaceutical composition comprising an acceptable immunosuppressive amount of imexon or a physiologically compatible, pharmaceuti-cally acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier.
30. An antiviral or antiretroviral pharmaceutical composition comprising an acceptable antiviral or antiretroviral amount of imexon or a physiologically compatible, pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier.
31. A B-cell and plasma cell neoplasias suppressing pharmaceutical composition comprising an acceptable B-cell and plasma cell neoplasias suppressing amount of imexon or a physiologically compatible, pharmaceuti-cally acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier.
32. A lymphoblastic lymphomas suppressing pharma-ceutical composition comprising an acceptable lymphoblastic lymphomas suppressing amount of imexon or a physiologically compatible, pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier.
33. Imexon or a physiologically compatible, pharma-ceutically acceptable acid addition salt thereof for use in the treatment of B-cell and plasma cell neoplasias.
34. Imexon or a physiologically compatible, pharma-ceutically acceptable acid addition salt thereof for use in the treatment of lymphoblastic lymophomas.
35. Imexon or a physiologically compatible, pharma-ceutically acceptable acid addition salt thereof for use in the suppression of B-cell proliferation or activation caused by AIDS (acquired immunodeficiency syndrome) or ARC (AIDS-related complex).
36. Imexon or a physiologically compatible, pharma-ceutically acceptable acid addition salt thereof for use in the suppression of B-cell proliferation or activation in a B-cell lymphoma or B-cell leukemia.
37. The use of imexon or a physiologically compat-ible, pharmaceutically acceptable acid addition salt thereof for the production of a pharmaceutical compo-sition for suppression of B-cell proliferation or activation caused by AIDS (acquired immunodeficiency syndrome) or ARC (AIDS-related complex).
38. The use of imexon or a physiologically compat-ible, pharmaceutically acceptable acid addition salt thereof for the production of a pharmaceutical compo-sition for suppression of B-cell proliferation or activation in a B-cell lymphoma or B-cell leukemia.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3825667A DE3825667A1 (en) | 1988-07-28 | 1988-07-28 | USE OF IMEXON AS IMMUNOSUPPRESSIVE |
| DEP3825667.3 | 1988-07-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1333771C true CA1333771C (en) | 1995-01-03 |
Family
ID=6359767
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000606620A Expired - Fee Related CA1333771C (en) | 1988-07-28 | 1989-07-25 | Use of imexon as an immune suppressive and pharmaceutical compositions containing them |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0352652B1 (en) |
| JP (1) | JP2848634B2 (en) |
| KR (1) | KR0135757B1 (en) |
| AT (1) | ATE117551T1 (en) |
| AU (1) | AU619027B2 (en) |
| CA (1) | CA1333771C (en) |
| DE (2) | DE3825667A1 (en) |
| DK (1) | DK175199B1 (en) |
| HU (1) | HU206827B (en) |
| IE (1) | IE66680B1 (en) |
| IL (1) | IL91138A (en) |
| PH (1) | PH26684A (en) |
| PT (1) | PT91293B (en) |
| ZA (1) | ZA895710B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2548491A1 (en) * | 2003-12-08 | 2005-06-23 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Synergistic anti-cancer compositions |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2528460A1 (en) * | 1975-06-26 | 1977-01-13 | Boehringer Mannheim Gmbh | 1-Carbamoyl 2-cyano aziridine as immunostimulant - for therapy of bacterial and viral infections |
| DE2530398A1 (en) * | 1975-07-08 | 1977-01-27 | Boehringer Mannheim Gmbh | ORGANIC CONNECTION |
| DE2736296A1 (en) * | 1977-08-12 | 1979-02-22 | Boehringer Mannheim Gmbh | USE OF 2-CYAN-AZIRIDINE AND ITS DERIVATIVES FOR IMMUNESTIMULATION |
-
1988
- 1988-07-28 DE DE3825667A patent/DE3825667A1/en active Granted
-
1989
- 1989-07-21 PH PH38984A patent/PH26684A/en unknown
- 1989-07-21 DK DK198903633A patent/DK175199B1/en not_active IP Right Cessation
- 1989-07-21 EP EP89113425A patent/EP0352652B1/en not_active Expired - Lifetime
- 1989-07-21 DE DE58908926T patent/DE58908926D1/en not_active Expired - Fee Related
- 1989-07-21 AT AT89113425T patent/ATE117551T1/en not_active IP Right Cessation
- 1989-07-24 AU AU38877/89A patent/AU619027B2/en not_active Ceased
- 1989-07-25 CA CA000606620A patent/CA1333771C/en not_active Expired - Fee Related
- 1989-07-27 IE IE244889A patent/IE66680B1/en not_active IP Right Cessation
- 1989-07-27 HU HU893821A patent/HU206827B/en not_active IP Right Cessation
- 1989-07-27 PT PT91293A patent/PT91293B/en not_active IP Right Cessation
- 1989-07-27 ZA ZA895710A patent/ZA895710B/en unknown
- 1989-07-27 IL IL9113889A patent/IL91138A/en not_active IP Right Cessation
- 1989-07-28 JP JP1194417A patent/JP2848634B2/en not_active Expired - Fee Related
- 1989-07-28 KR KR1019890010705A patent/KR0135757B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR0135757B1 (en) | 1998-04-23 |
| PT91293B (en) | 1995-03-01 |
| DE3825667C2 (en) | 1991-06-27 |
| ZA895710B (en) | 1990-04-25 |
| KR900001369A (en) | 1990-02-27 |
| DK175199B1 (en) | 2004-07-05 |
| EP0352652A2 (en) | 1990-01-31 |
| IL91138A (en) | 1994-10-21 |
| HU206827B (en) | 1993-01-28 |
| IE892448L (en) | 1990-01-28 |
| PH26684A (en) | 1992-09-15 |
| EP0352652B1 (en) | 1995-01-25 |
| IE66680B1 (en) | 1996-01-24 |
| ATE117551T1 (en) | 1995-02-15 |
| DK363389D0 (en) | 1989-07-21 |
| HUT52378A (en) | 1990-07-28 |
| JP2848634B2 (en) | 1999-01-20 |
| DE58908926D1 (en) | 1995-03-09 |
| AU619027B2 (en) | 1992-01-16 |
| AU3887789A (en) | 1990-02-01 |
| JPH0288521A (en) | 1990-03-28 |
| EP0352652A3 (en) | 1991-09-04 |
| DK363389A (en) | 1990-01-29 |
| PT91293A (en) | 1990-02-08 |
| IL91138A0 (en) | 1990-03-19 |
| DE3825667A1 (en) | 1990-03-15 |
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