EP0946168A1 - Verwendung von ethylendiamindisuccinat zur herstellung eines arzneimittels mit antiviralen eigenschaften - Google Patents
Verwendung von ethylendiamindisuccinat zur herstellung eines arzneimittels mit antiviralen eigenschaftenInfo
- Publication number
- EP0946168A1 EP0946168A1 EP97921801A EP97921801A EP0946168A1 EP 0946168 A1 EP0946168 A1 EP 0946168A1 EP 97921801 A EP97921801 A EP 97921801A EP 97921801 A EP97921801 A EP 97921801A EP 0946168 A1 EP0946168 A1 EP 0946168A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- edds
- cations
- medicament
- viruses
- substance
- 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.)
- Withdrawn
Links
- 239000003814 drug Substances 0.000 title claims abstract description 12
- 229940071087 ethylenediamine disuccinate Drugs 0.000 title abstract description 14
- 230000000840 anti-viral effect Effects 0.000 title description 21
- 150000001768 cations Chemical class 0.000 claims abstract description 13
- 230000001506 immunosuppresive effect Effects 0.000 claims abstract description 9
- 208000015181 infectious disease Diseases 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 6
- -1 zinc (II) ions Chemical class 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 210000004698 lymphocyte Anatomy 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910001414 potassium ion Inorganic materials 0.000 claims description 3
- 229910001415 sodium ion Inorganic materials 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 2
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 claims description 2
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 claims description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 2
- REDXJYDRNCIFBQ-UHFFFAOYSA-N aluminium(3+) Chemical compound [Al+3] REDXJYDRNCIFBQ-UHFFFAOYSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 claims description 2
- 229910001416 lithium ion Inorganic materials 0.000 claims description 2
- 150000002892 organic cations Chemical class 0.000 claims description 2
- 229960003104 ornithine Drugs 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 claims 1
- 150000003141 primary amines Chemical class 0.000 claims 1
- 230000035755 proliferation Effects 0.000 claims 1
- 241000701022 Cytomegalovirus Species 0.000 abstract description 18
- VKZRWSNIWNFCIQ-WDSKDSINSA-N (2s)-2-[2-[[(1s)-1,2-dicarboxyethyl]amino]ethylamino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NCCN[C@H](C(O)=O)CC(O)=O VKZRWSNIWNFCIQ-WDSKDSINSA-N 0.000 abstract description 4
- 239000000126 substance Substances 0.000 description 33
- 241000700605 Viruses Species 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 10
- 238000012360 testing method Methods 0.000 description 8
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 229960002963 ganciclovir Drugs 0.000 description 5
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 5
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 4
- MPJQXAIKMSKXBI-UHFFFAOYSA-N 2,7,9,14-tetraoxa-1,8-diazabicyclo[6.6.2]hexadecane-3,6,10,13-tetrone Chemical compound C1CN2OC(=O)CCC(=O)ON1OC(=O)CCC(=O)O2 MPJQXAIKMSKXBI-UHFFFAOYSA-N 0.000 description 3
- 208000007514 Herpes zoster Diseases 0.000 description 3
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 3
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 3
- 241000700584 Simplexvirus Species 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
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- 238000000338 in vitro Methods 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229960003330 pentetic acid Drugs 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 208000009889 Herpes Simplex Diseases 0.000 description 2
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- 206010062016 Immunosuppression Diseases 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000220317 Rosa Species 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
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- 210000000987 immune system Anatomy 0.000 description 2
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- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 230000006213 negative regulation of lymphocyte proliferation Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 2
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- 230000003612 virological effect Effects 0.000 description 2
- CUGDYSSBTWBKII-LXGUWJNJSA-N (2r,3r,4r,5s)-6-(dimethylamino)hexane-1,2,3,4,5-pentol Chemical compound CN(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO CUGDYSSBTWBKII-LXGUWJNJSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000029483 Acquired immunodeficiency Diseases 0.000 description 1
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
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- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical group C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
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- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000011420 Phospholipase D Human genes 0.000 description 1
- 108090000553 Phospholipase D Proteins 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 102000000505 Ribonucleotide Reductases Human genes 0.000 description 1
- 108010041388 Ribonucleotide Reductases Proteins 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
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- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
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- 230000035584 blastogenesis Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- QQIRJGBXQREIFL-UHFFFAOYSA-N butanedioic acid;ethane-1,2-diamine Chemical compound NCCN.OC(=O)CCC(O)=O QQIRJGBXQREIFL-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
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- 230000012010 growth Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
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- 210000000265 leukocyte Anatomy 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
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- 231100000028 nontoxic concentration Toxicity 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008196 pharmacological composition Substances 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
Definitions
- the invention relates to the use of ethylenediamine disuccinate including compatible salt-forming ions and the protonated form for the manufacture of a medicament with antiviral properties which also has an immunosuppressive effect.
- (S, S) -N, N '-ethylenediamine disuccinate is described in detail in the publication by Takaaki NISHIKIORI et al. (1984), The Journal of Antibiotics, Vol. 37, No. 4: 426-427.
- (S, S) - N, N'-ethylenediamine disuccinate can be obtained from actinomycetes and can also be prepared synthetically (JA Neal and NJ rose (1968), Inorg. Chem. Vol. 7; 2405-2412). It inhibits phospholipase C and D. If (S, S) - N, N'-ethylenediamine disuccinate is administered intraperitoneally to mice, the antibody production and the DTH reaction (delayed type hypersensitivity) are suppressed.
- CMV cytomegaloviruses
- the viruses are ubiquitous. The infection of the population varies from 30% to 85%, yes 95%. The infection runs inconspicuously in adults with a functional immune system and shows at most unspecific symptoms, such as fatigue and slightly increased body temperature.
- CMV infections focus on pulmonary diseases, inflammation of the arteries and gastrointestinal disorders. In AIDS patients, CMV infections cause most deaths.
- Foscarnet is an antiviral substance with selective activity against human viruses of the herpes group, such as herpes simplex, varicella zoster, Epstein-Barr and cytomegaloviruses as well as hepatitis viruses.
- the antiviral effect is based on the inhibition of viral enzymes, such as DNA polymerases and reverse transcriptases.
- Foscarnet has a virostatic effect on cytomegaloviruses, but the viruses cannot be eliminated (Lutz Schneider (1991), Pharmaceutical Newspaper, Vol. 136, No. 46, 33-36).
- An essential problem of the cytomegalovirus infection is the necessity of the sometimes lifelong long-term treatment of the patients.
- Ganciclovir is described in the publication by Lutz Schneider (1990), Pharmazie, Vol. 135, No. 37, 2396 to 2400.
- Ganciclovir is one of the nucleoside antimetabolites derived from 2'-deoxiguanosine. It carries an acyclic side chain instead of the 2'-deoxyribose and differs from aciclovir only by an additional hydroxymethyl group in the side chain.
- Ganciclovir is approved for the treatment of life or eyesight-threatening cytomegalovirus infections in patients with acquired immunodeficiency or medicinal immunosuppression, for example after organ transplants.
- ganciclovir is also effective in other human pathogenic herpes viruses (HSV 1 and 2, Varicella zoster and Epstein-Barr), its use is prohibited because of the high rate of side effects such infections. Ganciclovir leads to neutropenia, and it has also been observed that mice develop tumors during the treatment. Another disadvantage is that the cytomegaloviruses have recently become more resistant to this substance (Stanat et al. (1991), Lancet, Vol. 337: 1292-1293).
- WO 94/22438 (DINU, filing date: December 29, 1993) describes diethylenetriaminepentaacetic acid for the treatment of herpes simplex, varicella zoster, encephalomyelitis, polyradiculomiritis, multiple sclerosis, but not of cytomegaloviruses.
- Immunosuppressants such as cyclosporin A or tacrolimus, have been used successfully in organ transplants to avoid or mitigate rejection reactions. The disadvantage of this is of course the susceptibility of the treated patients to serious complications caused by viral and bacterial infections. Infection with cytomegaloviruses is particularly worth mentioning in this context.
- the technical problem underlying the invention is to provide a compound with an antiviral effect which also has an immunosuppressive effect.
- the substance to be used according to the invention is significantly more effective in terms of its antiviral activity. Compared to the substance desferrioxamine, the substance according to the invention is more effective by a factor of 30.
- the antiviral effect of the substance according to the invention can be modulated by adding iron (II) and iron (III) ions. Antiviral activity is reduced by a factor of 2 to 3, but is not completely eliminated. Thus it becomes obvious that the formation of iron chelate has an observable effect when acting as an antiviral agent, but it is also evident that this effect alone is not sufficient to explain the antiviral effect.
- the substance according to the invention can be used very selectively against cytomegaloviruses. Concentrations of the substance according to the invention which have an antiviral effect have no effect on cell growth. The therapeutic index is therefore very high. The substance according to the invention is therefore of great clinical importance.
- cytomegaloviruses can be used against cytomegaloviruses, but has no influence on certain other viruses, such as adenoviruses (ATTC strain: GB type 3), varicella zoster viruses (ATCC strain: Maclntyre) and herpes simplex viruses (HSV -Vero) has.
- adenoviruses ATCC strain: GB type 3
- varicella zoster viruses ATCC strain: Maclntyre
- HSV -Vero herpes simplex viruses
- the invention further comprises the ethylene diamine succinate according to the invention and its salts and / or acid groups.
- the salts inevitably result from the environment and the physical state of the substance.
- (S, S) -N, N '-ethylenediamine disuccinate in which the cations from the group of magnesium (II) -, aluminum (III) -, calcium (II) -, manganese (II) -, iron (II) -, iron (III) -, cobalt (II), nickel (II) -, copper (II) -, zinc (II) - ions and further lithium, potassium and sodium ions are selected or mixtures thereof previously mentioned ions are. Lithium, manganese (II), calcium (II), potassium and sodium ions are also particularly preferred.
- the (S, S) -N, N'-ethylenediamine disuccinate is preferred, in which the salts comprise organic cations.
- (S, S) -N, N '-ethylenediamine disuccinate in which the cations from the group of the primary; secondary or tertiary amines (e.g. ethanolamine, diethanoiamine, triethanolamine, morpholine, glucamine, N, N-dimethylglucamine and N-methylglucamine), lysine, arginine or ornithine are selected or the cations are mixtures of the cations mentioned above.
- secondary or tertiary amines e.g. ethanolamine, diethanoiamine, triethanolamine, morpholine, glucamine, N, N-dimethylglucamine and N-methylglucamine
- lysine, arginine or ornithine are selected or the cations are mixtures of the cations mentioned above.
- a mixture of organic and inorganic salts is included in the invention.
- the substance (S, S) -N, N'-ethylenediamine disuccinate is preferred as a medicament if it forms a composition with pharmacologically acceptable auxiliaries and carriers.
- auxiliaries and carriers are described in Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).
- the compositions can be prepared by known methods.
- the (S, S) -N, N'-ethylenediamine disuccinate according to the invention has pharmacological properties and can therefore be used as an active pharmaceutical ingredient.
- the invention also includes a medicament containing the (S, S) -N, N '-ethylenediamine disuccinate.
- the substance (S, S) -N, N'-ethylenediamine disuccinate according to the invention has an activity against cytomegaloviruses.
- the substance according to the invention shows an antiviral inhibition (IC 50 value) at concentrations of 4 ⁇ g / ml. Higher concentrations can be used without disturbing the test system.
- the substance according to the invention can thus be used in a concentration of 0.5 to 100 ⁇ g / ml.
- test results of this in vitro test show that the substance according to the invention can be used as a medicament or for medical treatment. These test results can easily be transferred from the in vitro test system to an in vivo system, since the antiviral test system is an established test set-up which serves to detect the antiviral activity (Gerna et al., (1992) Antiviral. Res. Vol. 19: 333-345). EDDS can therefore be used according to the invention for the treatment or prevention of cytomegalovirus infections, the substance also acting as an immunosuppressant. It can be used as an inhibitor in mammals, especially humans, for the treatment of the aforementioned disease.
- the invention further provides
- a pharmacological composition for the treatment or prevention of cytomegaloviruses which comprises a substance according to the invention and at least one pharmaceutical auxiliary and / or carrier.
- Different doses are suitable for the therapeutic effect. They depend, for example, on the salts used, on the host, on the type of administration and on the type and severity of the conditions to be treated.
- the daily doses range from 1 to 500 mg per kg. Include body weight.
- a recommended daily dose is in the range from 1 to 50 mg per kg of body weight, a dose of 5 to being most preferred 30 mg per kg body weight.
- this dose is expediently administered in partial doses up to four times a day. Satisfactory results can be expected if the substance according to the invention is administered subcutaneously or intravenously. Oral administration is also possible.
- Antiviral activity cells and viruses used
- HFF Human foreskin fibroblasts
- EMEM Eagle's minimal essential medium
- the CMV laboratory strain AD169 is used.
- the viruses are propagated in EMEM culture medium with a 4% addition of fetal calf serum (maintenance medium).
- the virus titer is determined by determining what are known as immediate early antigen forming units (I.E.F.U.) which are formed in the preservation medium (Gerna et al. (1992), Antiviral. Res., Vol. 19: 333-345).
- IC 50 value represents the concentration of active ingredient which lowers the production rate of the antigen by 50%.
- the sub- punches have an IC 50 value of 4 ⁇ g / ml ⁇ 1 ⁇ g / ml.
- the cell vitality is measured in an HFF cell culture using an MTT assay.
- the result is expressed by the TC 50 value, which is the concentration at which 50% of the cells tested are still vital. It is 435 ⁇ g / ml in HFF cells for the substances according to the invention.
- the quotient TC S0 / IC 50 is formed from both values in order to determine the therapeutic index. In the substances according to the invention, this is 109 (Gerna et al. (1992) Antiviral Res. Vol. 19: 333-345).
- lymphocyte cultures were prepared in mixed lymphocyte cultures (MLC) or with 1% phytohaemaglutinin (PHA) in a total volume of 200 ⁇ l culture medium. 18 to 20 hours before the measurement, 0.1 ⁇ Ci methyl [ 3 H] thymidine (NEN, Germany) was added. Radioactively labeled DNA was harvested on filter membranes (Schleicher & Schüll, Germany). The radioactivity was quantified using a scintillation counter (Zinsser, Germany). The PBL sample affects peripheral blood lymphocytes as a control standard.
- MLC mixed lymphocyte cultures
- PHA phytohaemaglutinin
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- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19616992A DE19616992C1 (de) | 1996-04-27 | 1996-04-27 | Verwendung von Ethylendiamindisuccinat zur Behandlung von Infektionen mit Cytomegalieviren |
DE19616992 | 1996-04-27 | ||
PCT/EP1997/002175 WO1997040827A1 (de) | 1996-04-27 | 1997-04-26 | Verwendung von ethylendiamindisuccinat zur herstellung eines arzneimittels mit antiviralen eigenschaften |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0946168A1 true EP0946168A1 (de) | 1999-10-06 |
Family
ID=7792705
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97921801A Withdrawn EP0946168A1 (de) | 1996-04-27 | 1997-04-26 | Verwendung von ethylendiamindisuccinat zur herstellung eines arzneimittels mit antiviralen eigenschaften |
Country Status (6)
Country | Link |
---|---|
US (1) | US6140367A (de) |
EP (1) | EP0946168A1 (de) |
AU (1) | AU2772997A (de) |
CA (1) | CA2252779A1 (de) |
DE (1) | DE19616992C1 (de) |
WO (1) | WO1997040827A1 (de) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2333703A (en) * | 1998-01-31 | 1999-08-04 | Procter & Gamble | Complexing agents (eg N,N'-ethylenediamine disuccinic acid) in reduction of enzyme activity & hence treatment of enzymatic dermatitis, skin rash and malodour |
GB2333704A (en) * | 1998-01-31 | 1999-08-04 | Procter & Gamble | Contrasting compositions for magnetic resonance imaging comprising a complex of ethylene diamine disuccinic acid and one or more paramagnetic metal ions |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4704233A (en) * | 1986-11-10 | 1987-11-03 | The Procter & Gamble Company | Detergent compositions containing ethylenediamine-N,N'-disuccinic acid |
HUT64391A (en) * | 1990-11-14 | 1993-12-28 | Procter & Gamble | Nonphosphated dishwashing compositions with oxygen belach systems and method for producing them |
GB2288812B (en) * | 1994-04-26 | 1998-08-26 | Procter & Gamble | Cleansing compositions |
US5466867A (en) * | 1994-07-11 | 1995-11-14 | Albemarle Corporation | Method for producing [S,S]-ethylenediamine-N,N'-disuccinic acid from its calcium salt |
-
1996
- 1996-04-27 DE DE19616992A patent/DE19616992C1/de not_active Expired - Fee Related
-
1997
- 1997-04-26 CA CA002252779A patent/CA2252779A1/en not_active Abandoned
- 1997-04-26 EP EP97921801A patent/EP0946168A1/de not_active Withdrawn
- 1997-04-26 AU AU27729/97A patent/AU2772997A/en not_active Abandoned
- 1997-04-26 WO PCT/EP1997/002175 patent/WO1997040827A1/de not_active Application Discontinuation
- 1997-04-26 US US09/171,836 patent/US6140367A/en not_active Expired - Fee Related
Non-Patent Citations (1)
Title |
---|
See references of WO9740827A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2252779A1 (en) | 1997-11-06 |
US6140367A (en) | 2000-10-31 |
WO1997040827A1 (de) | 1997-11-06 |
AU2772997A (en) | 1997-11-19 |
DE19616992C1 (de) | 1997-09-11 |
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