WO1999062540A1 - Utilisation de cyclosporines pour traiter les maladies inflammatoires auto-immunes - Google Patents

Utilisation de cyclosporines pour traiter les maladies inflammatoires auto-immunes Download PDF

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WO1999062540A1
WO1999062540A1 PCT/EP1999/003770 EP9903770W WO9962540A1 WO 1999062540 A1 WO1999062540 A1 WO 1999062540A1 EP 9903770 W EP9903770 W EP 9903770W WO 9962540 A1 WO9962540 A1 WO 9962540A1
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ciclosporin
meleu
hydroxy
cyclophilin
val
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PCT/EP1999/003770
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English (en)
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Peter Hiestand
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Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft Mbh
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Priority to BR9910860-7A priority Critical patent/BR9910860A/pt
Priority to KR1020007013585A priority patent/KR20010043969A/ko
Priority to SK1814-2000A priority patent/SK18142000A3/sk
Priority to IL13958999A priority patent/IL139589A0/xx
Priority to CA002333315A priority patent/CA2333315A1/fr
Priority to JP2000551796A priority patent/JP4523154B2/ja
Application filed by Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft Mbh filed Critical Novartis Ag
Priority to AU43724/99A priority patent/AU750422B2/en
Priority to PL99344451A priority patent/PL344451A1/xx
Priority to HU0102142A priority patent/HUP0102142A3/hu
Priority to EP99926489A priority patent/EP1082130A1/fr
Publication of WO1999062540A1 publication Critical patent/WO1999062540A1/fr
Priority to NO20006113A priority patent/NO20006113L/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A—HUMAN NECESSITIES
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Definitions

  • the present invention relates to novel uses of cyclosporins, and in particular to new pharmaceutical uses of non-immunosuppressive, cyclophilin binding cyclosporins.
  • Non-immunosuppressive, cyclophilin binding cyclosporins and their use in the treatment and prevention of AIDS and AIDS -related disorders are described in European Patent no. 484281 , which includes a general description of the cyclosporin class of compounds, their nomenclature and mode of action.
  • European Patent no. 484281 includes a general description of the cyclosporin class of compounds, their nomenclature and mode of action.
  • the disclosure of EP 0,484,281 B in particular the general description referred to above and other parts of the description referred to hereinafter, is included by reference in the teaching of the present application.
  • a cyclosporin is considered as binding to cyclophilin if it binds to human recombinant cyclophilin at least one fifth as well as does Ciclosporin (also referred to as cyclosporin A) in the competitive ELISA test described by Quesniaux in Eur. J. Immunol. 1987, 17, 1359- 1365.
  • Ciclosporin also referred to as cyclosporin A
  • the cyclosporin to be tested is added during the incubation of cyclophilin with coated BSA-Ciclosporin and the concentration required to give a 50% inhibition of the control reaction without competitor is calculated (IC 50 ).
  • BR Binding Ratio
  • a cyclosporin is considered to be non-immunosuppressive when it has an activity in the Mixed Lymphocyte Reaction (MLR) of no more than 5%, preferably no more than 2%, that of Ciclosporin.
  • MLR Mixed Lymphocyte Reaction
  • the Mixed Lymphocyte Reaction is described by T. Meo in "Immunological Methods", L. Lefkovits and B. Peris, Eds., Academic Press, N.Y. pp. 227-239 (1979).
  • Spleen cells (0.5 x 10 6 ) from Balb/c mice (female, 8-10 weeks) are co-incubated for 5 days with 0.5 x 10 6 irradiated (2000 rads) or mitomycin C treated spleen cells from CBA mice (female, 8-10 weeks).
  • the irradiated allogeneic cells induce a proliferative response in the Balb c spleen cells which can be measured by labelled precursor incorporation into the DNA. Since the stimulator cells are irradiated (or mitomycin C treated) they do not respond to the Balb/c cells with proliferation but do retain their antigenicity.
  • the IC 50 found for the test compound in the MLR is compared with that found for Ciclosporin in a parallel experiment.
  • an IL-2 Reporter Gene Assay may be used, e.g. as a primary screen, for selection of non-immunosuppressive, cyclophilin-binding cyclosporin compounds for use in the invention.
  • Active Compounds The non-immunosuppressive, cyclophilin-binding cyclosporin compounds which are active as inhibitors inflammatory autoimmune conditions are hereinafter referred to as Active Compounds.
  • the Active Compounds are particularly useful for the treatment, prevention, or amelioration of autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases.
  • autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases.
  • Specific auto-immune diseases for which the Active Compounds may be employed include autoimmune haematological disorders (including e.g.
  • hemolytic anaemia aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven- ohnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn's disease), pancreatitis, endocrine ophthalmopathy, Graves disease, sarcoidosis.
  • multiple sclerosis primary biliary cirrhosis
  • diabetes e.g. juvenile diabetes (diabetes mellitus type I), uveoretinitis (Behcets disease), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g.
  • idiopathic nephro- tic syndrome or minimal change nephropathy including idiopathic nephro- tic syndrome or minimal change nephropathy
  • asthma and other inflammatory airways diseases including an autoimmune component, thyroiditis (Hashimoto Ghoto disease), encephalomyelitis, inflammatory conditions of the central nervous system, and similar autoimmune disorders.
  • EAU Experimental autoimmune uveitis
  • Female Lewis rats, 12 weeks of age (BRL, Basel) are injected in the right foot-pad with 50 ⁇ g of purified bovine retinal S-antigen.
  • the antigen is diluted with phosphate- buffered saline and emulsified 50:50 (v/v) with Freund's complete adjuvant and Bacto M Tuberculosis H37 RA (Difco).
  • the volume injected is 0.1 ml, containing 50 ⁇ l complete adjuvant and 1.14 mg Mycobacterium tuberculosis.
  • the eyes are inspected daily using a slit lamp.
  • the extent of ocular inflammation is scored in a semi-quantitative way using a scale from 0 - 4:
  • EAE Experimental autoimmune encephalomyelitis
  • OFA and Wistar rats male or female, 150g body weight
  • OFA and Wistar rats are injected i.e. at the base of the tail or in the hind paw with 0.1 ml of mineral oil containing 0.6 mg of lyophilised heat-killed Mycobacterium smegmatis.
  • treatment is started immediately after the injection of the adjuvant (days 1 - 18); in the established arthritis model treatment is started on day 14, when the secondary inflammation is well developed (days 14-20).
  • the swelling of the joints is measured by means of a micro-caliper. Prevention or inhibition of disease progression in the developing or established test models is indicative of pharmaceutical utility.
  • Rats are immunized with collagen type II administered intra-dermally around the base of the tail. 10-12 days later, onset of arthritis occurs, typified by erythema and swelling in the joints. Treatment of the animals bid p.o. with test compound, normally at two different doses is started shortly after the onset of swelling and continued for up to 10 days. Control arthritic animals and rats treated with a proprietary COX-inhibitor are included in the study. Swelling of the hind paws is assessed regularly. At the end of the study, animals are sacrificed and joints are prepared for the assessment of histological parameters. Test compounds which show good inhibition of swelling, e.g. about 50% or more of the effect of the proprietary COX-inhibitor are chosen for further study.
  • Chemotaxis in vitro e.g. using the Boyden Chamber
  • cyclophilin induced infiltration of neutrophils and similar assays may also be used.
  • One group of Active Compounds are cyclosporins in which the MeLeu group at position 4 is replaced by a different N-methylated amino acid for example ⁇ -hydroxy-MeLeu, Melle, MeVal, MeThr, Me Ala, Me Tyr or MeTyr(O-PO(OH) 2 ), or Pro.
  • Melle and MeThr the allo-forms Mealle and MeaThr may also be used.
  • the stereochemistry at the ⁇ -position has the opposite configuration to that of the natural amino acid, so that the normal form and the allo-form constitute a pair of diastereoisomers.
  • a further group of Active Compounds is that in which Val at the 5-position is replaced by an N-alkyl-, preferably N-methyl-, amino acid.
  • the amino acid which is N- alkylated is Val or Leu.
  • the hydrogen of the imino group of [Val] 5 is replaced by a non-branched C ⁇ _ 6 alkyl group, preferably methyl, ethyl or n-propyl, particularly methyl.
  • the latter preferred group of Active Compounds are all novel. Additionally or alternatively, certain Active Compounds may differ from Ciclosporin at the 1, 2, 3, and/or 6 positions.
  • Ciclosporin derivatives of formula A are Ciclosporin derivatives of formula A
  • Alk represents straight or branched chain alkylene containing from 2 to 6 carbon atoms or cycloalkylene containing from 3 to 6 carbon atoms
  • R represents a carboxy or alkyloxycarbonyl radical; a radical -NR)R 2 in which Ri and R 2 are the same or different and represent hydrogen, alkyl, C 2 . alkenyl, C 3 _ 6 cycloalkyl, phenyl (optionally substituted by halogen, alkoxy, alkoxycarbonyl, amino, alkylamino or dialkylamino) or a benzyl or saturated or unsaturated heterocyclyl radical containing 5 or 6 ring atoms and 1 to 3 heteroatoms, or in which Riand R 2 form together with the nitrogen atom to which they are attached a saturated or unsaturated heterocycle containing 4 to 6 ring atoms and optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur and optionally substituted by alkyl, phenyl or benzyl; a radical of formula
  • R 3 represents hydrogen or an alkyl radical and n is a whole number from 2 to 4, and wherein alkyl denotes straight or branched chain alkyl containing from 1 to 4 carbon atoms; C is MeLeu or or 4-hydroxy-MeLeu; and the pharmaceutically acceptable salts thereof.
  • Ciclosporin derivatives is further described in published International patent applications Nos. WO 98/28328, WO 98/28329 and WO 9828330.
  • a particularly preferred compound of this class is the compound of formula A in which B is the amino acid residue
  • CH and C is the amino acid residue 4-hydroxy-MeLeu.
  • a particularaly preferred group of Active Compounds is constituted by the compounds of Formula I:
  • W is MeBmt, dihydro-MeBmt or 8'-hydroxy-MeBmt
  • X is ⁇ Abu, Val, Thr, Nva or O-methyl threonine (MeOThr);
  • R is Sar or (D)-MeAla;
  • Y is MeLeu, ⁇ -hydroxy-MeLeu, Melle, MeVal, MeThr, MeAla, Me Tyr, MeTyr(0- PO(OH) 2 ), Mealle or MeaThr, or Pro;
  • Z is Val, Leu, N-Alk-Val or N-Alk-Leu wherein Alk represents Me or Me substituted by vinyl optionally substituted by phenyl, or an N S or O heteroaryl containing 6 ring members, or phenyl optionally substituted by halogen; and Q is MeLeu, ⁇ -hydroxy-MeLeu or MeAla and the pharmaceutically acceptable salts thereof.
  • W is preferably W' where W' is MeBmt or dihydro-MeBmt;
  • X is preferably X' where X' is ⁇ Abu or Nva, more preferably X" where X" is ⁇ Abu;
  • Y is preferably Y' where Y' is ⁇ -hydroxy-MeLeu, MeVal, MeThr, MeAla or MeTyr(O- PO(OH) 2 );
  • Z is preferably Z' where Z' is Val or MeVal; and Q is preferably Q' where Q' is MeLeu;
  • One especially preferred group of Active Compounds are the compounds of Formula I in which W is W ⁇ X is X', Y is Y ⁇ Z is Z' and Q is Q'.
  • Especially preferred Active Compounds are [Melle] 4 -Ciclosporin and [ ⁇ -hydroxy-MeLeu] 4 Ciclosporin, most especially [Melle] 4 -Ciclosporin.
  • preferred Active Compounds include, for example
  • the Active Compounds may be obtained by methods including:
  • Example 1 1 of EP 0484281 B describes measurement of the immunosuppressive and cyclophilin-binding activities of representative Active Compounds relative to Ciclosporin, and the teaching of this examples is also included within the disclosure of the present application.
  • the Active Compounds are indicated for use both for the prevention and the treatment of inflammatory autoimmune conditions and diseases in patients.
  • the invention provides use of a nonimmunosuppresive, cyclophilin-binding cyclosporin in the manufacture of a medicament for treating or preventing an inflammatory autoimmune disease or condition.
  • the invention further provides a method for the treatment or the prevention of inflammatory autoimmune conditions and diseases in a patient suffering or at risk of such a disease or condition, comprising administering to said patient an effective amount of an Active Compound of the invention.
  • the Active Compound may be administered by any conventional route, in particular enterally, e.g. orally, for example in the form of solutions for drinking, tablets or capsules or parenterally, for example in the form of injectible solutions or suspensions.
  • enterally e.g. orally
  • an indicated daily dosage may be from 1 to 20 mg/kg, preferably from 3 to 10 mg/kg
  • oral route from 1 to 50 mg/kg, preferably from 10 to 30 mg/kg.
  • the toxicity of the Active Compounds is believed to be less to that of Ciclosporin. As the Active Compounds are not immunosuppressive, certain side effects of Ciclosporin related to immunosuppression are avoided. Other side effects associated with Ciclosporin, particularly nephrotoxicity and central nervous system toxicity in long term use, are conveniently less than with Ciclosporin.
  • the Active Compounds may be used for treatment and prevention of inflammatory autoimmune diseases either alone or in combination with other therapeutic compounds, e.g. antinflammatory compounds and/or immunosuppressive compounds.
  • the Active Compounds are used in combination with Sanglifehrins, a recently identified class of immunosuppressive, cyclophilin-binding compounds which do not inhibit calcineurin activity.
  • the Sanglifehrins and methods for their preparation are described in WO 9702285 and WO 9807743 .
  • Particularly preferred Sanglifehrins for use in combination with the the Active Compounds are the Sanglifehrins A through L, especially Sanglifehrins A, B, C and D.
  • the invention provides a process for the treatment or the prevention of inflammatory autoimmune conditions and diseases in a patient suffering or at risk of such a disease or condition, comprising administering to said patient an effective amount of a combination comprising an Active Compound of the invention and a Sanglifehrin.
  • the invention also provides a pharmaceutical composition, e.g. for the treatment or prevention of an inflammatory autoimmune disease or condition, comprising an Active Compound of the invention and a Sanglifehrin.
  • compositions of the invention are coveniently in the form of a combined preparation for simultaneous, separate or sequential use in therapy.
  • the Active Compound and the Sanglifehrin may be administered together in the form of a fixed composition, or may be administered separately and at different times.
  • the compositions may be in unit dosage form comprising an effect amount of the combined preparation.
  • Preferred galenic formulations for the Active Compounds include those based on microemulsions as described in British Patent Application 2 222 770A, which include topical as well as oral forms; also oral and injectable forms obtained from solid solutions comprising a fatty acid saccharide monoester, e.g. saccharose monolaurate, as described in British Patent Application 2 209 671 A.
  • Suitable unit dosage forms for oral administration comprise e.g. from 25 to 200mg Active Compound per dosage.
  • Formulation Examples A, B, C and D of EP 0484281 B are incorporated herein by reference:
  • Active Compounds When the Active Compounds are administered together with other compounds, e.g. Sanglifehrins, similar formulations may be used, with appropriate ratios of Active Compound and other compound.
  • Active Compound and Sanglifehrin are preferably used in the weight ratio range from about 5: 1 to about 50: 1 (Active Compound po : Sanglifehrin sc) with an Acitve Compound po dose of about 10 to about 100 mg/kg.
  • Figure 1 is a graph of disease scores (y-axis) in the EAE assay for control animals (A. black bars) and [Melle] 4 -Cs treated animals (B. grey bars) from 9 to 18 days after immunisation (x-axis);
  • Figure 2 is a graph showing percentage inhibition of swelling (y-axis) in the developing adjuvant arthritis assay for groups of animals treated with A. - 30 mg/kg [Melle] 4 -Cs p.o.; B. - 1 mg/kg Sanglifehrin A s.c; and C - 30 mg/kg [Melle] 4 -Cs p.o. + 1 mg/kg Sanglifehrin A s.c, and
  • Figure 3 is a graph showing swelling of hind paws (in mm - y-axis) in the collagen induced arthritis assay for rats treated with vehicle (-_-; EtOH 10%/Corn oil /5 ml/kg p.o., 6 animals), [Melle] 4 -Cs (-( ; 2 x 12.5 mg/kg/day p.o., 7 animals), [Melle] 4 -Cs (-__- ; 2 x 25 mg/kg/day p.o., 7 animals) and a proprietary COX-inhibitor (__ ⁇ £. ; 2 x 2.5 mg/kg/day p.o., 4 animals) with immunisation on day 12 anf treatment on days 0 to 9 (x-axis) Biological Activity Assays
  • EAE Experimental autoimmune encephalomyelitis
  • a representative Active Compound of the invention, [Melle] -Ciclosporin is tested in the acute EAE assay as described above at a dose of 30 mg/kg and is found to significantly inhibit onset of the disease.
  • the results obtained are given in Figure 1 which is a graph showing severeness of disease for control animals and Active compound treated animals on days 9 to 18 following immunisation.
  • the control group animals have scores of over 0.5 on day 1 1 and scores approaching 2.0 on days 15 and 16; whereas the [Melle] 4 -Cs treated animals have no measurable score until day 12 and have maximum scores of about 0.5 on days 15 to 17, decreasing thereafter.
  • Ciclosporin and an ethanol in corn oil placebo are also tested in in the EAU assay essentially as described above. The results obtained are given in Table II below.
  • FIG. 2 is a graph for the average inhibition of swelling obtained for groups of 5 animals treated with 30 mg/kg po of [MeIle] 4 -Ciclosporin, 1 mg/kg sc of Sanglifehrin A, or the combination of 30 mg/kg po of [MeIle] 4 -Ciclosporin plus 1 mg/kg sc of Sanglifehrin A.
  • the non-immunosuppressive cyclosporin, [Me-Ile 4 ]-Ciclosporin (also referred to as NIM 81 1) is investigated in a therapeutic protocol in the rat collagen-induced arthritis model. Rats are immunized with collagen type II administered intra-dermally around the base of the tail. 10-12 days later, onset of arthritis occurs, typified by erythema and swelling in the joints. Treatment of the animals bid p.o. with [Me-Ile 4 ]-Ciclosporin (in ethanol 10% / corn oil vehicle, two different doses) is started shortly after the onset of swelling and continued for up to 10 days.
  • Control arthritic animals and rats treated with a proprietary COX-inhibitor are included in the study. Swelling of the hind paws is assessed regularly. At the end of the study, animals are sacrificed and joints are prepared for the assessment of histological parameters.
  • [Me-Ile 4 ] -Ciclosporin exerts good inhibition of swelling at both doses used ( 12.5 and 25 mg/kg bid p.o.) up to approx. 60% of the effect of the proprietary COX-inhibitor at day 9 (dosed at 2.5 mg/kg bid p.o.) ( Figure 3).
  • Comparison with data for Ciclosporin (CyA, effective ED 50 around 10-15 mg/kg p.o. - see Smith R. J. and Sly L. M., J. Pharmacol. Exp. Ther., June 1996; 277(3): 1801-1813) shows a similar potency to that of [Me-Ile 4 ]- Ciclosporin in this model of rheumatoid arthritis.

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Abstract

L'invention concerne des cyclosporines non immunosuppressives se fixant à la cyclophiline, en particulier les [MeIle]4-Cyclosporines, qui peuvent être utilisées pour prévenir et traiter les maladies inflammatoires auto-immunes, par exemple la polyarthrite rhumatoïde.
PCT/EP1999/003770 1998-06-02 1999-05-31 Utilisation de cyclosporines pour traiter les maladies inflammatoires auto-immunes WO1999062540A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
KR1020007013585A KR20010043969A (ko) 1998-06-02 1999-05-31 염증성 자기면역 질환의 치료에서 사이클로스포린의 용도
SK1814-2000A SK18142000A3 (sk) 1998-06-02 1999-05-31 Použitie cyklosporínov na liečenie zápalových autoimunitných ochorení
IL13958999A IL139589A0 (en) 1998-06-02 1999-05-31 Use of cyclosporins in the treatment of inflammatory autoimmune diseases
CA002333315A CA2333315A1 (fr) 1998-06-02 1999-05-31 Utilisation de cyclosporines pour traiter les maladies inflammatoires auto-immunes
JP2000551796A JP4523154B2 (ja) 1998-06-02 1999-05-31 炎症性自己免疫疾患の処置におけるサイクロスポリン類の使用
BR9910860-7A BR9910860A (pt) 1998-06-02 1999-05-31 Uso de ciclosporinas no tratamento de doenças auto-imunes inflamatórias
AU43724/99A AU750422B2 (en) 1998-06-02 1999-05-31 Use of cyclosporins in the treatment of inflammatory autoimmune diseases
PL99344451A PL344451A1 (en) 1998-06-02 1999-05-31 Use of cyclosporins in the treatment of inflammatory autoimmune diseases
HU0102142A HUP0102142A3 (en) 1998-06-02 1999-05-31 Use of cyclosporins in the treatment of inflammatory autoimmune diseases
EP99926489A EP1082130A1 (fr) 1998-06-02 1999-05-31 Utilisation de cyclosporines pour traiter les maladies inflammatoires auto-immunes
NO20006113A NO20006113L (no) 1998-06-02 2000-12-01 Anvendelse av cyklosporiner i behandlingen av inflammatoriske autoimmune sykdommer

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JP (2) JP4523154B2 (fr)
KR (1) KR20010043969A (fr)
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BR (1) BR9910860A (fr)
CA (1) CA2333315A1 (fr)
GB (1) GB9811854D0 (fr)
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WO2005021028A1 (fr) * 2003-09-03 2005-03-10 Novartis Ag Utilisation de cyclosporines pour le traitement des troubles lies au vhc
WO2005097164A2 (fr) * 2004-04-08 2005-10-20 Novartis Ag Nim811 utilise dansla prevention ou le traitement de l'ischemie cerebrale et de lesions cerebrales et de la moelle epiniere
WO2006071618A1 (fr) * 2004-12-23 2006-07-06 Novartis Ag Composes pour le traitement des infections virales par flaviviridae
WO2006071619A1 (fr) * 2004-12-23 2006-07-06 Novartis Ag Compositions pour le traitement du vhc
WO2006138507A1 (fr) 2005-06-17 2006-12-28 Novartis Ag Utilisation de sangliféhrine dans le virus de l'hépatite c
US7419670B2 (en) * 2000-09-29 2008-09-02 Viron Therapeutics, Inc. Method of treating arthritis with SERP-1 and an immunosuppressant
US7514405B2 (en) 1999-10-27 2009-04-07 Viron Therapeutics Inc. Methods for treating transplant rejection
WO2009148615A1 (fr) * 2008-06-06 2009-12-10 Scynexis, Inc. Analogues de la cyclosporine et leur utilisation dans le traitement d'infections par le vhc
WO2010002428A2 (fr) * 2008-06-06 2010-01-07 Scynexis, Inc. Nouveaux peptides macrocycliques
US7671017B2 (en) 2004-07-14 2010-03-02 Novartis Ag Use of a combination of cyclosporine and pegylated interferon for treating hepatitis C (HCV)
US7745396B2 (en) 2004-10-21 2010-06-29 Viron Therapeutics Inc. Use of SERP-1 as an antiplatelet agent
WO2011070364A1 (fr) * 2009-12-09 2011-06-16 Scynexis, Inc. Nouveaux peptides cycliques
US8536114B2 (en) 2008-12-31 2013-09-17 Scynexis, Inc. Macrocycles
US9072696B2 (en) 2012-09-29 2015-07-07 Novartis Ag Cyclic peptides and use as medicines

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NZ554412A (en) * 2004-10-01 2011-01-28 Debiopharm Sa Use of [D-MeAla]3-[EtVal]4-cyclosporin for the treatment of hepatitis C infection and pharmaceutical composition comprising said [D-MeAla]3-[EtVal]4-cyclosporin
JP2007112775A (ja) * 2005-10-24 2007-05-10 Hamamatsu Univ School Of Medicine サイトメガロウイルス感染の処置におけるシクロスポリン類の使用
EP2908841A4 (fr) * 2012-10-19 2016-05-25 Scynexis Inc Nouveaux macrocycles antiviraux

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CZ288631B6 (cs) * 1996-01-18 2001-08-15 Galena, A. S. Léčivé přípravky s obsahem cyklosporinu
CZ288739B6 (cs) * 1996-08-01 2001-08-15 Galena, A. S. Cyklosporin obsahující léčivé přípravky

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WO1998007743A1 (fr) * 1996-08-22 1998-02-26 Novartis Ag Macrolides

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7906483B2 (en) 1999-10-27 2011-03-15 Viron Therapeutics Inc. Method for treating transplant rejection
US7514405B2 (en) 1999-10-27 2009-04-07 Viron Therapeutics Inc. Methods for treating transplant rejection
US7419670B2 (en) * 2000-09-29 2008-09-02 Viron Therapeutics, Inc. Method of treating arthritis with SERP-1 and an immunosuppressant
WO2005021028A1 (fr) * 2003-09-03 2005-03-10 Novartis Ag Utilisation de cyclosporines pour le traitement des troubles lies au vhc
EP1797892A1 (fr) * 2003-09-03 2007-06-20 Novartis AG Utilisation de cyclosporines modifiées pour le traitement de maladies liées au virus de l'hépatite C (HCV)
US7968518B2 (en) 2003-09-03 2011-06-28 Novartis Ag Use of modified cyclosporins for the treatment of HCV disorders
AU2008203031B2 (en) * 2003-09-03 2011-04-07 Novartis Ag Use of modified cyclosporins for the treatment of HCV disorders
WO2005097164A3 (fr) * 2004-04-08 2006-06-01 Novartis Ag Nim811 utilise dansla prevention ou le traitement de l'ischemie cerebrale et de lesions cerebrales et de la moelle epiniere
WO2005097164A2 (fr) * 2004-04-08 2005-10-20 Novartis Ag Nim811 utilise dansla prevention ou le traitement de l'ischemie cerebrale et de lesions cerebrales et de la moelle epiniere
US7671017B2 (en) 2004-07-14 2010-03-02 Novartis Ag Use of a combination of cyclosporine and pegylated interferon for treating hepatitis C (HCV)
US7745396B2 (en) 2004-10-21 2010-06-29 Viron Therapeutics Inc. Use of SERP-1 as an antiplatelet agent
WO2006071619A1 (fr) * 2004-12-23 2006-07-06 Novartis Ag Compositions pour le traitement du vhc
WO2006071618A1 (fr) * 2004-12-23 2006-07-06 Novartis Ag Composes pour le traitement des infections virales par flaviviridae
US7897565B2 (en) 2004-12-23 2011-03-01 Novartis Ag Compositions for HCV treatment
WO2006138507A1 (fr) 2005-06-17 2006-12-28 Novartis Ag Utilisation de sangliféhrine dans le virus de l'hépatite c
AU2006259348B2 (en) * 2005-06-17 2010-07-22 Novartis Ag Use of sanglifehrin in HCV
WO2010002428A3 (fr) * 2008-06-06 2010-03-11 Scynexis, Inc. Nouveaux peptides macrocycliques
WO2010002428A2 (fr) * 2008-06-06 2010-01-07 Scynexis, Inc. Nouveaux peptides macrocycliques
WO2009148615A1 (fr) * 2008-06-06 2009-12-10 Scynexis, Inc. Analogues de la cyclosporine et leur utilisation dans le traitement d'infections par le vhc
US9090671B2 (en) 2008-06-06 2015-07-28 Scynexis, Inc. Macrocyclic peptides
US8536114B2 (en) 2008-12-31 2013-09-17 Scynexis, Inc. Macrocycles
WO2011070364A1 (fr) * 2009-12-09 2011-06-16 Scynexis, Inc. Nouveaux peptides cycliques
US9072696B2 (en) 2012-09-29 2015-07-07 Novartis Ag Cyclic peptides and use as medicines
US9566312B2 (en) 2012-09-29 2017-02-14 Novartis Ag Cyclic peptides and use as medicines

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HUP0102142A2 (hu) 2001-11-28
PL344451A1 (en) 2001-11-05
NO20006113L (no) 2001-01-25
KR20010043969A (ko) 2001-05-25
AU4372499A (en) 1999-12-20
IL139589A0 (en) 2002-02-10
TWI250022B (en) 2006-03-01
CA2333315A1 (fr) 1999-12-09
JP2010059177A (ja) 2010-03-18
AU750422B2 (en) 2002-07-18
TW200522975A (en) 2005-07-16
ID27576A (id) 2001-04-12
HUP0102142A3 (en) 2001-12-28
JP4523154B2 (ja) 2010-08-11
BR9910860A (pt) 2001-03-06
SK18142000A3 (sk) 2001-06-11
JP2002516873A (ja) 2002-06-11
ZA200006464B (en) 2002-03-11
TWI250021B (en) 2006-03-01
EP1082130A1 (fr) 2001-03-14
NO20006113D0 (no) 2000-12-01
CN1304315A (zh) 2001-07-18
GB9811854D0 (en) 1998-07-29

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