|Publication number||USRE40987 E1|
|Application number||US 12/123,601|
|Publication date||Nov 17, 2009|
|Filing date||Jun 30, 1999|
|Priority date||Jul 1, 1998|
|Also published as||CA2335903A1, CA2335903C, CN1218958C, CN1308635A, DE69928938D1, DE69928938T2, EP1091975A1, EP1091975B1, US6927208, WO2000001715A1|
|Publication number||12123601, 123601, PCT/1999/1232, PCT/IB/1999/001232, PCT/IB/1999/01232, PCT/IB/99/001232, PCT/IB/99/01232, PCT/IB1999/001232, PCT/IB1999/01232, PCT/IB1999001232, PCT/IB199901232, PCT/IB99/001232, PCT/IB99/01232, PCT/IB99001232, PCT/IB9901232, US RE40987 E1, US RE40987E1, US-E1-RE40987, USRE40987 E1, USRE40987E1|
|Inventors||Roland M. Wenger, Manfred Mutter, Thomas Rückle|
|Original Assignee||Debiopharm S.A.|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (30), Non-Patent Citations (64), Referenced by (1), Classifications (12), Legal Events (1)|
|External Links: USPTO, USPTO Assignment, Espacenet|
The present invention relates to a novel cyclosporin (Cs), the pharmaceutical use thereof and to a pharmaceutical composition containing it.
Cyclosporins are a class of cyclic poly-N-methylated undecapeptides having several pharmacological activities; in particular, they are immunosuppressants, anti-inflammatories, anti-parasitic agents, drug resistance suppressors (anti-MDR) and anti-viral agents. The first cyclosporin isolated from a fungal culture is cyclosporin A which is found in the natural state and which is represented by the following formula:
The amino acids described according to their conventional abbreviation have the configuration L unless otherwise specified.
Since this fist cyclosporin was discovered, a large number of other varieties have been isolated and identified, as have non-natural varieties obtained by synthetic or semi-synthetic methods, or even by the application of modified culture techniques. The production of cyclosporin A is described by [Kobel et al. European Journal of Applied Microbiology and Biotechnology 14, 237-240 (1982)]. The production of artificial cyclosporins produced by a purely synthetic method developed by R. Wenger is also described—see Traber et al. 1, Traber et al. 2 and Kobel et al., U.S. Pat. Nos. 4,108,985; 4,210,581; 4,220,641; 4,288,431; 4,554,351 and 4,396,542; EP 34 567 and 54 782; WO 86/02080; Wenger 1, Transpl. Proc. 15, Suppl. 1:2230 (1983); Wenger 2, Angew. Chem.Int. Ed., 24,77 (1985); and Wenger 3, Progress in the Chemistry of Organic Natural Products 50, 123 (1986).
Cyclosporin A (CsA) isolated 20 years ago from Tolypocladium inflatum has considerable immunosuppressive activity. It has revolutionised organ transplantation and is commonly used in the treatment of autoimmune diseases. For a recent review of the use of CsA and its mechanisms of action, see Wenger et al; Cyclosporine Chemistry, Structure-activity relationships and Mode of Action, Progress in Clinical Biochemistry and Medicine, Vol. 2, 176 (1986).
The therapeutic effect of CsA results mainly in the selective suppression of the activation of T lymphocytes. This immunosuppressive activity is explained by the fact that CsA binds to an intracellular proteic receptor cyclophilin A (CyP), forming a CyP-CsA complex which interacts with calcineurin (CaN) and thus inhibits its phosphatase activity. Thus, the transcription of families of genes exhibiting precocious activation will be blocked (cf. O'Keefe, S. J; Tamura, J; Nature 1992, 357, 692-694).
The present invention provides the production of a novel cyclosporin with considerable HIV-1 (human immunodeficiency virus) inhibitory activity and not having the immunosuppressive activity of CsA.
The mode of infection of HIV type 1 is unique amongst the retroviruses because it requires the specific incorporation into its virion of the cellular protein CyP which interacts with the polyprotein Gag (cf. Eltaly Kara Franke, Bi-Xing Chem. Journal of Virology, September 1995, vol. 69 no. 9). It is well known that CyP binds to CsA and CaN in a ternary complex. However, the native function of CyP is to catalyse the isomerisation of peptidyl-prolyl bonds, a limiting and important step in the process allowing proteins to acquire a definitive three-dimensional structure. CyP also protects cells from thermal shocks or acts as a chaperone protein. Unlike CsA, the product of the Gag gene of HIV-1 prohibits the formation of a ternary complex with CyP and CaN. In fact, the HIV virus needs CyP in order to bind to the product of the Gag gene so as to form its own virions (cf. Franke, E. K; 1994 Nature 372, 359-362). In the presence of CsA, there is direct competition with the polyprotein derived from the Gag gene of HIV-1 to bind the CyP. This CsA acts at two levels on the replication of the viral cycle. Firstly, at the level of translocation towards the core of the pre-integrated complex, then in the production of infectious viral particles.
U.S. Pat. No. 4,814,323 already describes anti-HIV activity of CsA, but the latter also has considerable immunosuppressive activity which is undesirable for the treatment of patients infected with the HIV virus. Recently, another type of cyclosporin has been developed, namely derivatives in position 4 such as MeIle4Cs, MeVal4Cs, or (4-OH)MeLeu4-Cs to mention only the most anti-HIV and the least immunosuppressive substances. The derivative [(4-OH) MeLeu4Cs] is synthesised by oxidation of cyclosporin A using a microorganism. Another patent WO 97/04005 uses the method of preparation of the patent EP 484 281 and the method developed by Seebach EP 194972 in order to produce derivatives in position 3 such as, for example, (D)-MeSer3-(4-OH)MeLeu4 cyclosporin. This substance has a better affinity for CyP but only has limited anti-HIV activity compared with the reference derivative MeIle4-Cs (NIM 811). The more hydrophilic nature of this substance prevents it penetrating the cells and the organism. This is reflected directly in the reduced anti-HIV activity of this substance (cf. Cristos Papageorgiou, J. J. Sanglier and RenéTraber—Bioorganic & Medicinal Chemistry Letters, Vol. 6, No. 1, pp. 23-26, 1996).
Table I shows affinity results of Cs derivatives for cyclophilin A in a competitive ELISA test;
Table II shows the percentage protection during HIV infection of a CEM-SS cell line; and
TABLE III shows examples of cyclosporins with different groups R1, R2, R3 and R4.
The substances described in this invention have the dual advantage of retaining the same affinity for CyP as that observed with [(4-OH)MeLeu4]-Cs or cyclosporin A whilst having anti-HIV activity which is identical to or greater than that of the reference derivatives (MeVal4-Cs or MeIle4-Cs) and appreciably greater than the anti-HIV activity of cyclosporin A or of (4-OH)MeLeu4-Cs. The object of the invention is to provide a novel cyclosporin which does not have the immunosuppressive activity of CsA and has an improved profile of activity. This new family of Cs is characterised by the formula (I):
Thus by replacing the natural MeLeu group in position 4 by an N-(alkyl)aa group (where alkyl>CH3), the anti-HIV 1 activity of this derivative is improved.
The new cyclosporin molecule thus obtained offers the unexpected and surprising advantage of having much better stability towards metabolisation than all the other cyclosporins known hitherto.
This new molecule is much more resistant to the phenomena of oxidation and degradation which take place in the cell. Consequently, the “in vivo” life of this new N-alkyl as Cs is particularly prolonged.
Moreover, this new N-alkyl aa4 cyclosporin has high affinity for CyP and has anti-HIV activity which is equal to or greater than the best existing cyclosporins.
This novel cyclosporin is thus characterised principally by the presence, in position 4, of a residue with R>CH3 and R<C10 H21. The substituent of nitrogen used will be, for example, ethyl, propyl, butyl or pentyl, but these examples are not limiting. This novel cyclosporin is particularly active if the residue in position 4 is an N-ethylated amino acid (see drawings 2 and 3).
The invention also claims the pharmaceutical composition of the substance as described by formula (I). This may be combined with a pharmaceutically acceptable solution. The pharmaceutical formulation thus produced makes it possible to increase the solubility in water or to keep the composition in the form of microemulsions in suspension in water. The object of the present invention is also to provide a new medicinal product which may be used, for example, in the treatment and prevention of AIDS (acquired immunodeficiency syndrome). The cyclosporin modified in position 4 by a residue Z, namely N-ethyl-valine will be used in particular for the production of a medicinal product intended for the treatment and prevention of AIDS. The application for the prevention of AIDS is not limiting. This substance may also be used, for example, for its anti-inflammatory properties.
With regard to the process for the production of this novel cyclosporin, we used conventional techniques described in the literature and certain specific methods developed in the laboratory.
The process for the synthesis of CsA is described in: R. Wenger (Helv. Chim. Acta Vol. 67, p. 502-525 (1984)). The process for opening protected cyclosporin A (OAc) is described in Peptides 1996. The CsA molecule is treated with Meerwein's reagent (CH3)3OBF4 then cleaved by treatment with acid in methanol or hydrolysed by water in order to convert it to a linear peptide of 11 amino acid residues: H-MeLeu-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal-MeBmt(OAc)-Abu-Sar-OCH3. This process was presented at the international conference of the European Society of Peptides (EPS-24) in Edinburgh 8-13 Sep. 1996 and published in Peptides 1996 by R. Wenger. This linear peptide is then treated according to the conventional Edman process in order to cleave its last amino acid residue (MeLeu) and to provide our starting product: the decapeptide H-Val-MeLeu-Ala-(D)Ala-MeLeu-MeVal-MeBmt (OAc)-Abu-Sar-OMe. This product is then used in the following steps:
Preparation of (1) (protection):
Boc-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeValMeBmt (OAc)-Abu-Sar-OMe (1)
0.72 ml (4.18 mmoles) of a solution of diisopropylethylamine and 0.65 g (2.95 mmoles) of Boc anhydride in 50 ml of dioxane are added to a solution of 2.83 g (2.46 mmoles) of the decapeptide H-Val MeLeu-Ala-(D)Ala-MeLeu-MeVal-MeBmt(OAc)-Abu-Sar-OMe in 120 ml of dioxane. 17 ml of water are added to the solution which is mixed for 2 hours at ambient temperature. The solvent is then evaporated and the resulting reaction mixture is dissolved in 300 ml of ethyl acetate then washed 3× with a 5% solution of citric acid, 3× with a saturated solution of NaHCO3 and finally 3× with a solution of NaCl. The organic phases are dried with anhydrous Na2SO4, filtered, and the solvent is finally evaporated under vacuum. 3 g (98%) of the protected decapeptide (Boc-decapeptide methyl ester) are thus obtained.
The product is then used for the following synthesis routes without an additional purification step. This substance is hydrolysed then activated and condensed with 1 corresponding amino acid in order to produce a new peptide with 11 residues, the starting product for the cyclisation and production of a novel cyclosporin with the desired properties.
Preparation of (2) (hydrolysis of the ester):
Boc-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeValMeBmt (OAc)-Abu-Sar-OH (2)
192 mg (4.56 mmoles) of LiOH/H2O dissolved in 36 ml of water are added dropwise (at 15° C.) to 4.08 g (3.26 mmoles) of the previous compound (1) in 146 ml of tetrahydrofuran. The whole mixture is stirred at 15° C. The reaction is complete after 120 hours after the successive addition of 5 portions respectively of 1.4 equivalents of LiOH/H2O each. The solution obtained is neutralised with 0.1 N HCl and the solvent is then evaporated. The solid product recovered is then dissolved in 500 ml of ethyl acetate and washed 2× with a 5% solution of citric acid and 2× with a brine solution. The aqueous phases are extracted 4× with 50 ml of ethyl acetate and the combined organic phases are then dried with anhydrous Na2SO4, filtered and evaporated. 3.84 g (95%) of compound (2) are thus obtained. The product is then used without additional purification.
Preparation of (3) (addition of a new amino acid):
6.18 g (5 mmoles) of compound (2) are dissolved in 250 ml of anhydrous dichloromethane under argon. The solution is then cooled and 3.9 ml of N-methylmorpholine (10 mmoles; pH 8.5) and 1.1 ml (10 mmoles) of isobutylchloroformate are then added slowly under argon. The solution is stirred for 15 minutes at −15° C. A solution of 2.4 g (12 mmoles) of H-NEt Val-OtBu dissolved in 40 ml of anhydrous dichloromethane is then added within a period of 20 minutes. The mixture is then stirred for 1 hour at −15° C., then for 1 hour at 0° C. and finally overnight at ambient temperature. 400 ml of dichloromethane are then added, then 3 extractions are carried out with a 5% solution of citric acid followed by 3 extractions with a saturated solution of NaHCO3 and finally 3 final extractions with a saturated solution of NaCl. The organic phases are dried with anhydrous Na2SO4 then filtered and finally the solvent is evaporated. After chromatography, 4.42 g (62%) of pure undecapeptide are recovered.
Preparation of (4) (deprotection):
H-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal-MeBmt (OAc)-Abu-Sar-EtVal-OH (4)
830 mg (0.58 mmole) of protected undecapeptide (4) are dissolved in 15 ml of pure dichloromethane. 3.2 ml of trifluoroacetic acid are added to this solution within a period of 3 minutes at ambient temperature. The reaction is monitored by HPLC which proves to be complete after 1 h 30. The solvent is evaporated and the remaining trifluoroacetic acid is evaporated 2× in the presence of ethyl acetate.
The crude product (900 mg) is purified by chromatography [150 g of silica gel (0.4-0.63)], use of dichloromethane/methanol/triethylamine (17:3:0.05) as eluants) to eluate 700 mg (95%) of pure, deprotected undecapeptide (4).
Preparation of (5) (cyclisation):
275 mg of TFFH (1.04 mmoles) are dissolved under argon in 3.45 l of anhydrous dichloromethane. The deprotected undecapeptide (4) [438 mg (0.347 mmole)] is then dissolved in 40 ml of anhydrous dichloromethane, and 0.52 ml (3.82 mmoles) of collidine are added thereto. This slightly basic peptide solution is added dropwise to the solution of TFFH within a period of 20 minutes under argon and with vigorous stirring. After 1 h 30 all the starting material is cyclised. In order to trap the excess TFFH, 5 ml of water are added, then the solution is evaporated. 200 ml of dichloromethane are added then the whole mixture is washed respectively 3× with a 0.1 N solution of aqueous HCl, 3× with a brine solution then dried with Na2SO4, filtered, and the solvent is evaporated. 360 mg of a yellowish oil are obtained. The crude product is purified by chromatography on silica gel using 100 g of silica gel (0.04-0.063 mm) and 1% of methanol in ethyl acetate as eluant. 230 mg (54%) of the pure derivative (5) are thus produced.
Cleavage of the MeBmt (OAc)-EtVal4-Cs (5) acetate group and production of EtVal4-Cs (6):
1.44 ml of a 0.45 molar solution of NaOCH3 in MeOH (0.647 mmole) are added dropwise, under argon, to a solution of 700 mg (0.562 mmole) of the derivative of Cs (5) in 28 ml of MeOH. [The solution of NaOCH3 in methanol is prepared by adding sodium to pure MeOH.] The reaction is complete after 48 h with stirring at ambient temperature. The mixture is adjusted to pH 5 by adding 50% acetic acid in water. The solvents are removed under vacuum. The crude product is dissolved in 200 ml of ethyl acetate and extracted 2× with water. The aqueous phase is re-extracted with 50 ml of ethyl acetate then the combined organic phases are washed 2× with a brine solution, dried with Na2SO4, filtered and the solvent is evaporated.
The product obtained (750 g) is chromatographed on 180 g of silica gel (0.04-0.063 mm) using a solution of acetone/hexane 1:1 (20 ml fractions). 550 mg (82%) of (EtVal4)Cs (6) are thus produced.
Preparation of H-EtVal-Ot-Bu:
4.1 ml (23.83 mmoles) of diisopropylethylamine are added, under argon, to a suspension of 5 g (23.8 mmoles) of II-ValOtBuxHCl in 1 l of trimethyloxoformate. At the end of 10 minutes the suspension becomes clear. 13.5 ml (0.24 mmole) of acetaldehyde dissolved in 30 ml of trimethyloxoformate are added dropwise to this solution under anhydrous conditions. The reaction mixture is stirred for 45 minutes under argon at ambient temperature.
Using a low vacuum, the excess acetaldehyde is removed by evaporation for 1 h 30. 25 g (0.112 mmole) of solid NaBH(OAc)3 are added, under argon, to this solution. After 15 minutes, the solution is cooled to 0° C. and 500 ml of a 2% aqueous solution of HCl are added slowly.
The trimethyloxoformate is evaporated under vacuum and the remainder of the aqueous solution is diluted in 300 ml of water. This solution is then extracted 2× with 100 ml of diethylether. The organic phase is then re-extracted 3× with a 0.1 N aqueous solution of HCl. The combined aqueous phases are cooled to 0° C. then the pH is adjusted to 9 using (2N)NaOH. The solution then becomes cloudy. The aqueous suspension is extracted 4× with 100 ml of diethylether. The combined organic phases are then dried with Na2SO4, filtered and the solvent is finally evaporated.
4.2 g of a yellowish oil resulting from this step are purified by chromatography using 900 g of silica gel (0.04-0.063 mm) and a mixture of hexane/ethyl acetate 8:2 as eluant. Finally, 3.13 g (65%) of pure H-EtLeu-OtBu are obtained.
The results of Table 1 show the affinity of the derivatives of Cs for cyclophilin A in a competitive ELISA test described by Quesniaux in Eur. J. Immunology 1987, 17, 1359-1365. In this test, during incubation with cyclophilin, Cs bound to BSA (serum albumin) is added to the Cs to be tested. The concentration required to obtain 50% inhibition (IC50) of the reference reaction in the absence of competitor is then calculated. The results are expressed by the binding index BI which is the ratio of the IC50 of the derivative and the IC50 of CsA. A binding index (BI) of 1.0 indicates that the compound tested binds as well as CsA. A value lower than 1.0 indicates that the derivative binds better than CsA, and a value greater than 1.0 means that the derivative binds less well to CyP than CsA.
Cs is regarded as being immunosuppressive if its activity in the mixed lymphocyte reaction (MLR) is greater than 5%. The reaction (MLR) is described by T. Meo in “Immunological Methods”, L. Lefkovits and B. Devis, Eds, Académie Prev. N.Y. pp: 227-239 (1979).
Spleen cells (0.5.106) originating from Balb/c mice (female, 8 to 10 weeks) are co-incubated for 5 days in the presence of treated spleen cells originating from CBA mice (females, 8 to 10 weeks). These cells were treated with mitomycin C or were irradiated at 2000 rads. The non-irradiated allogenic spleen cells exhibit a proliferative response in Balb/c cells which can be measured by incorporating a labelled precursor in the DNA. If the stimulator cells are irradiated (or treated with mitomycin C), the Balb/c cells no longer exhibit a proliferative response but retain their antigenicity. The IC50 calculated in the MLR test is compared with the IC50 corresponding to CsA in a parallel experiment. The IR index is thus found, this being the ratio of the IC50 of the MLR test of the derivatives over the IC50 of cyclosporin A.
As with the binding index (BI) above, a value of 1.0 for the IR means an activity similar to CsA. Similarly, a lower value means better activity and a value greater than 1.0 shows that the activity of the compound is lower than that of CsA.
An IR value of >20 shows that the substance is not immunosuppressive. The immunosuppression values of the derivatives are given in Table I.
Table II describes the percentage protection during infection with HIV of a CEM-SS cell line. The protection of this line in the presence of a Cs derivative is compared with the infection of a line cultivated in the absence of Cs (reference control). A mean value is established at a concentration of the derivative of 2×10−6 molar. This anti-HIV activity was measured by the NCI (National Cancer Institute) in Washington in the USA.
Percentage HIV Substance Structure Protection UNIL 002 MeVal4-Cs 66.4 UNIL 004 EtVal4-Cs 74.0 UNIL 007 MeIle4-Cs 68.5
A better percentage of protection against HIV infection obtained with the compound EtVal4-Cs (compared with the two other references known to be 10× better than CsA) shows the advantage of substitution by N-ethyl in position 4. This remark is even more pertinent if one compares the affinity for CyP of each substance. An affinity for CyP similar to that of CsA (BI=1.0) is obtained for the EtVal4-Cs derivative, whereas the derivatives MeVal4-Cs and MeIle4-Cs exhibit greater affinity for CyP (BI=0.6 and 0.5 respectively). A greater anti-HIV activity corresponds to a lower affinity for CyP of EtVal4-Cs. This clearly shows the value of this novel derivative.
c = 0.07, MeOH −177
c = 0.05, MeOH −204
c = 0.24, MeOH −159
c = 0.06, MeOH −134
c = 0.07, MeOH −95
c = 0.12, MeOH −145
c = 0.06, MeOH −138
c = 0.05, MeOH −136
c = 0.15, MeOH −160
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US4108985||Oct 27, 1976||Aug 22, 1978||Sandoz Ltd.||Dihydrocyclosporin c|
|US4210581||Jun 9, 1978||Jul 1, 1980||Sandoz Ltd.||Organic compounds|
|US4220641||May 4, 1978||Sep 2, 1980||Sandoz Ltd.||Organic compounds|
|US4288431||Oct 12, 1979||Sep 8, 1981||Sandoz Ltd.||Cyclosporin derivatives, their production and pharmaceutical compositions containing them|
|US4396542||Sep 3, 1981||Aug 2, 1983||Sandoz Ltd.||Method for the total synthesis of cyclosporins, novel cyclosporins and novel intermediates and methods for their production|
|US4441644 *||Dec 1, 1981||Apr 10, 1984||Karl M. Reich Maschinenfabrik Gmbh||Buffer system for fastener driving devices|
|US4554351||May 5, 1983||Nov 19, 1985||Sandoz Ltd.||Method for the total synthesis of cyclosporins, novel cyclosporins and novel intermediates and methods for their production|
|US4814323||Mar 25, 1986||Mar 21, 1989||Andrieu J M||Process for the treatment and the prevention of AIDS and other disorders induced by the LAV/HTLV III virus|
|US5525590||Nov 10, 1994||Jun 11, 1996||Sandoz Ltd.||Cyclosporins and their use as pharmaceuticals|
|US5639724||Dec 6, 1993||Jun 17, 1997||Sandoz Ltd.||Cyclosporin galenic forms|
|US5767069||Apr 24, 1995||Jun 16, 1998||Novartis Ag||Cyclosporins|
|US5948884||Jul 17, 1996||Sep 7, 1999||C-Chem Ag||Cyclosporin derivatives with anti-HIV effect|
|US5981479||May 26, 1998||Nov 9, 1999||Novartis Ag||Cyclosporins|
|US6255100||Sep 9, 1999||Jul 3, 2001||Novartis Ag||Cyclosporin fermentation process|
|US6444643||May 28, 1999||Sep 3, 2002||Guilford Pharmaceuticals Inc.||Methods of using inhibitors of cyclophilin rotamase activity to affect neurological activity|
|US6927208||Jun 30, 1999||Aug 9, 2005||Debiopharm S.A.||Cyclosporin with improved activity profile|
|US7439277||May 19, 2005||Oct 21, 2008||Fina Technology, Inc.||In-situ preparation of hydroperoxide functionalized rubber|
|EP0034567B1||Feb 13, 1981||Nov 7, 1984||Sandoz Ag||A method for the total synthesis of cyclosporins and novel cyclosporins|
|EP0056782B1||Jan 6, 1982||Aug 1, 1984||Sandoz Ag||Novel cyclosporins|
|EP0194972B1||Mar 4, 1986||Jul 29, 1992||Sandoz Ag||Novel cyclosporins|
|EP0484281A2||Oct 30, 1991||May 6, 1992||Sandoz Ltd.||Cyclosporins|
|GB2222770A||Title not available|
|WO1986002080A1||Sep 27, 1985||Apr 10, 1986||Sandoz Ag||Monoclonal antibodies to cyclosporings|
|WO1997004005A2||Jul 17, 1996||Feb 6, 1997||C-Chem Ag||Cyclosporin derivatives with anti-hiv effect|
|WO1997018828A1||Nov 15, 1996||May 29, 1997||Guilford Pharmaceuticals Inc.||Inhibitors of cyclophilin rotamase activity|
|WO1998028328A1||Dec 23, 1997||Jul 2, 1998||Rhone-Poulenc Rorer S.A.||Cyclosporin derivative, its preparation and pharmaceutical compositions containing same|
|WO1998028329A1||Dec 23, 1997||Jul 2, 1998||Rhone-Poulenc Rorer S.A.||Cyclosporin derivatives, their preparation and pharmaceutical compositions containing them|
|WO1998028330A1||Dec 23, 1997||Jul 2, 1998||Rhone-Poulenc Rorer S.A.||Novel cyclosporin derivatives, method of preparation and pharmaceutical compositions containing them|
|WO2000001715A1||Jun 30, 1999||Jan 13, 2000||Debiopharm S.A.||Novel cyclosporin with improved activity profile|
|WO2005021028A1||Sep 2, 2004||Mar 10, 2005||Novartis Ag||Use of modified cyclosporins for the treatment of hcv disorders|
|1||Amendment filed in U.S. Appl. No. 11/406,800 on Nov. 26, 2007, 5 pages.|
|2||Amendment filed Jun. 4, 2008 in U.S. Appl. No. 11/406,800, 10 pages.|
|3||Application No. PCT/IB2004/003205, filed Apr. 12, 2006, as U.S. Appl. No. 11/406,800, 31 pages.|
|4||Balogh-nair, V., et al., "Synthesis activity and toxicity of novel macrocyclic ligands against HIV-1 in Jurkat CEM-SS cell lines," Cellular and Molecular Biology, 1995, pp. S9-S14, vol. 41 (Suppl. 1).|
|5||Bartz, S. R., et al., Inhibitition of human immunodeficiency virus replication by nonimmunosuppressinve analogs of cyclosporin A, Proc. Natl. Acad. Sci. USA, vol. 92, pp. 5381-5385, Jun. 1995.|
|6||Baumann, G., et al., "Cyclosporine and its Analogue SDZ IMM 125 Mediate Very Similar Effects on T-Cell Activation-A Comparative Analysis In Vitro," Transplantation Proceedings, Aug. 1992, pp. 43-48, vol. 24, No. 4, Suppl. 2.|
|7||Baumann, G., et al., "Molecular Mechanisms of Immunosuppression," Journal of Autoimmunity, (1992) 5 (Supplement A), pp. 67-72.|
|8||Billich, A., et al., "Mode of Action of SDZ NIM 811, a Nonimmunosuppressive Cyclosporin A Analog with Activity against Human Immunodeficiency Virus (HIV) Type 1: Interference with HIV Protein-Cyclophilin A Interactions," Journal of Virology, Apr. 1995, pp. 2451-2461, vol. 69, No. 4.|
|9||Borel, J. F., et al., "Immunopharmacological Properties of Cyclosporine (Sandimmune(R)) and (Val2)-Dihydrocyclosporine and Their Prospect in Chronic Inflammation," advances in Inflammation Research, 1986, pp. 277-291, vol. 11.|
|10||Borel, J. F., et al., "In Vivo Pharmacological Effects of Ciclosporin and Some Analogues," Advances in Pharmacology, 1996, pp. 115-246, vol. 35.|
|11||Borel, J. F., et al., "The Cyclosporins," Transplantation Proceedings, Feb. 1989, pp. 810-815, vol. 21, No. 1.|
|12||Cebrat, M., et al., "Immunosuppressive Activity of Hymenistatin I," Peptides, 1996, pp. 191-196, vol. 17, No. 2.|
|13||Dorfman, T., et al., "Active-Site Residues of Cyclophillin A Are Crucial for Its Incorporation into Human Immunodeficiency Virus Type 1 Virions," Journal of Virology, Sep. 1997, pp. 7110-7113, vol. 71, No. 9.|
|14||Fesik, S. W. et al., "NMR Studies of (U-13C)Cyclosporin A Bound to Cyclophillin: Bound Conformation and Portions of Cyclosporin Involved in Binding," Biochemistry, 1991, pp. 6574-6583, vol. 30, No. 26.|
|15||Final Office Action for U.S. Appl. No. 11/406,800 mailed on Feb. 28, 2008, 14 pages.|
|16||Fliri, H. G., et al., "Cyclosporine: Synthetic Studies. Structure-Activity Relationships, Biosysthesis and Mode of Action," Biochemistry of Peptide Antibiotics, Walter de Gruyter: New York, 1990, pp. 245-287, Chapter 10.|
|17||Fliri, H., et al., "Cyclosporins: Structure-Activity Relationships," Anals of the New York Academy of Sciences, Nov. 30, 1993, pp. 47-53, vol. 696.|
|18||Franke, E. K, et al., "Inhibition of HIV-1 Replication by Cyclosporin A or Related Compound Correlates with the Ability to Disrupt the Gag-Cyclophillin A Interaction," Virology, 1996, pp. 279-282, vol. 222, Article No. 0421.|
|19||Franke, E. K., et al., "Cyclophillin Binding to the Human Immunodeficiency Virus Type 1 Gag Polyprotein is Mimicked by an Anti-Cyclosporine Antibody," Journal of Virology, Sep. 1995, pp. 5821-5823, vol. 69, No. 9.|
|20||Franke, E.K., et al., "Specific Incorporation of cyclophillin A into HIV-1 virions," Nature, Nov. 24, 1994, pp. 359-362, vol. 372.|
|21||Hansson, M. J., et al., "The Nonimmunosuppressive Cyclosporin Analogs NIM811 and UNIL025 Display Nanomolar Potencies on Permeability Transition in Brain-Derived Mitochondria," Journal of Bioenergetics and Biomembranes, Aug. 2004, pp. 407-413, vol. 36, No. 4.|
|22||Heguy, A., "Inhibition of the HIV REV Transactivator: A New Target for Therapeutic Intervention," Frontiers in Bioscience, Jun. 1, 1997, pp. 283-297, vol. 2.|
|23||Holmes, K. K., et al., "Report of the NIH Aids Research Program Evaluation Natural History, Epidemiology, and Prevention Research Area Review Panel Findings and Recommendations of the Office of AIDS Research Advisory Council," Jun. 7, 1996, pp. 1-40.|
|24||Hubler, F., et al., "Synthetic routes to NetXaa4-cyclosporin A derivates as potential anti-HIV 1 drugs," Institute of Organic Chemistry, University of Lausanne, Tetrahedron Letters, 2000, pp. 7193-7196, vol. 41.|
|25||Inoue, K., et al., "Combined interferon alpha2b and cyclosporin A in the treatment of chronic hepatitis C controlled trial," Journal of Gastroenterology, 2003; pp. 567-572, vol. 38.|
|26||Inque, K., et al., "Interferon Combined With Cyclosporine Treatment as an Effective Countemeasure Against Hepatitis C Virus Recurrence in Liver Transplant Patients With End-Stage Hepatitis C Virus Related Disease," Transplantation Proceedings, 2005, pp. 1233-1234, vol. 37.|
|27||Ko, S. Y., et al., "Solid-Phase Total Synthesis of Cyclosporine Analogues," Helvetica Chimica Acta-1997, pp. 695-705, vol. 80.|
|28||Kobel, H., et al., "Directed Biosynthesis of Cyclosporins," European Journal of Applied Microbiology and Biotechnology, 1982, pp. 237-240, vol. 14.|
|29||Levine, A., et al., "Report of the NIH AIDS Research Program Evaluation Working Group of the Office of Aids Research Advisory Council," pp. 1-57, Mar. 13, 1996-Final.|
|30||Meo, T., "The MLR Test in the Mouse," Immunological Methods, 1979, pp. 227-239.|
|31||Mlynar, E., et al., "The non-immunosuppressive cyclosporin A analogue SDZ NIM 811 inhibits cyclophilin A incorporation into virions and virus replication in human immunodeficency virus type 1-infected primary and growth-arrested T-cells," Journal of General Virology, 1997, pp. 825-835, vol. 78.|
|32||Nakagawa, M., et al., "Specific inhibition of hepatitis C virus replication by cyclosporin A," Biochemical and Biophysical Research Communications, 2004, pp. 42-47, vol. 313.|
|33||Nicolli, A., et al., "Interactions of Cyclophillin with the Mitochondrial Inner Membrane and Regulation of the Premeability Transition Pore, a Cyclosporin A-sensitive Channel," The Journal of Biological Chemistry, Jan. 26, 1996, pp. 2185-2192, vol. 271, No. 4.|
|34||Notice of Allowance and Examiner's Amendment for U.S. Appl. No. 11/406,800 mailed on Aug. 29, 2008, 24 pages.|
|35||Office Action for U.S. Appl. No. 11/406,800 mailed on Sep. 25, 2007, 10 pages.|
|36||O'Keefe, S. J., et al., "FK-506 and CsA-sensitive activation of the interleukin-2 promoter by calcineurin," Nature, Jun. 25, 1992, pp. 692-694, vol. 357.|
|37||Papageorgiou, C. et al. , "Anti-HIV-1 Activity of a Hydrophilic Cyclosporin Derivative with Improved Binding Affinity To Cyclophillin A," Bioorganic & Medicinal Chemistry Letters, 1996, pp. 23-26, vol. 6, No. 1.|
|38||Papageorgiou, C., et al., "Calcineurin Has A Very Tight-Binding Pocket For The Side Chain of Residue 4 Of Cyclosporin," Bioorganic & Medicinal Chemistry Letters, 1994, pp. 267-272, vol. 4, No. 2.|
|39||Papageorgiou, C., et al., "Improved Binding Affinity for Cyclophilin A by a Cyclosporin Derivitative Singly Modified at Its Effector Domain," J. Med. Chem. 1994, pp. 3674-3676, vol. 37.|
|40||Payne, T. G., et al., "Interpretation of Peptide Drug-Receptor Interactions Using Intrinsic Binding Energers Cyclosporin As An Example," QSAR in Design of Bioactive Compounds, J. R. Prous Science Publishers, S.A., pp. 347-359, 1992.|
|41||Preliminary Amendment to Replace Specification in Compliance with 37 CFR 1.52, 1.121 (b)(3), 1.125, filed May 31, 2006 in U.S. Appl. No. 11/406,800, 64 pages.|
|42||Preliminary Amendment, filed Apr. 12, 2006 in U.S. Appl. No. 11/406,800, 6 pages.|
|43||Quesniaux, V. F. J., et al., "Cyclophilin binds to the region of cyclosporine involved in its immunosuppressive activity," Eur. J. Immunol., 1987, pp. 1359-1365, vol. 17.|
|44||Quesniaux, V. F. J., et al., "Cyclosporine-Cyclophilin Interaction," Transplanation Proceedings, Apr. 1988, pp. 58-62, vol. XX, No. 2, Suppl. 2.|
|45||Quesniaux, V. F. J., et al., "Fine Specificity and Cross-Reactivity of Monoclonal Antibodies to Cyclosporine," Molecular Immunology, 1987, pp. 1159-1168, vol. 24, No. 11.|
|46||Rauffer, N., et al., "Structure-Activity Relationships For The Interaction Between Cyclosporin A Derivates and the Fab Fragment of a Monoclonal Antibody," Molecular Immunology, 1994, 913-922, vol. 31, No. 12.|
|47||Rosenwirth, B., et al., "Inhibition of Human Immunodeficiency Virus Type 1 Repliby SDZ NIM 811, a Nonimmunosuppresive Cyclosporine Analog," Antimicrobial Agents and Chemotherapy, Aug. 1994, pp. 1763-1772, vol. 38, No. 8.|
|48||Seebach, D., et al., "Modification of Cyclosporin A (CS)'): Generation of an Enolate at the Sarosine Residue and Reactions with Electrophiles ," Helevtica Chimica Acta, 1993, pp. 1564-1590, vol. 76.|
|49||Sigal, N. H., et al., "Is Cyclophilin Involved in the Immunosuppressive and Nephrotoxic Mechanism of Action of Cyclosporin A?, " Journal of Experimental Medicine, Mar. 1991, pp. 619-628, vol. 173.|
|50||Steinkasserer, A., et al., "Mode of Action of SDZ NIM 811, a Nonimmunosuppressive Cyclosporin A Analog with Activity against Human Immunodeficiency Virus Type 1 (HIV-1): Interference with Early and Late Events in HIV-1 Replication, Journal of Virology, " Feb. 1995, pp. 814-824, vol. 69, No. 2.|
|51||Thali, M., et al., "Functional association of cyclophillin A with HIV-1-virions, " Nature, Nov. 24, 1994, pp. 363-365, vol. 372.|
|52||Traber, R., et al., "[Melie]Cyclosporin, a novel natural cyclosporin with anti-HIV activity: structural elucidation biosynthesis and biological properties," Antiviral Chemistry & Chemotherapy, 1994, pp. 331-339, vol. 5, No. 5.|
|53||Watashi, K., et al., "Cyclosporin A Suppresses Replication of Hepatitis C Virus Genome in Cultured Hepatocytes," Hepatology, 2003, pp. 1282-1288, vol. 38. No. 5.|
|54||Wenger, R. M. et al., "Cyclosporine: Intrinsic Binding Energies to Interpret Structure-Activity Relationships," Quatitative Structure-Activity Relationships in Drug Design (QSAR), 1989, pp. 301-305.|
|55||Wenger, R. M., "Cyclosporine and Analogues-Isolation and Synthesis-Mechanism of Action and Structural Requirements for Pharmological Activity," Progress in the Chemistry of Organic Natural Products, 1986, pp. 123-168, vol. 50.|
|56||Wenger, R. M., "Structures of Cyclosporine and Its Metabolities," Transplantation Proceedings, Jun. 1990, pp. 1104-1108, vol. 22, No. 3.|
|57||Wenger, R. M., "Synthesis of Cyclosporine and Analogues: Structural Requirements for Immunosuppressive Activity," Angew. Chem. Int. Ed. Engl., Feb. 1985, pp. 77-85, vol. 24, No. 2.|
|58||Wenger, R. M., "Synthesis of Cyclosporine, Total Synthesis of 'Cyclosporin A' and 'Cyclosporin H', Two Fungal Methabolites Isolated from the Species," Tolypocladium Inflatum GAMS, Helvetica Chimica Acta, 1984, pp. 502-525, vol. 67, Fasc. 2, Nr. 60.|
|59||Wenger, R. M., et al., "Cyclosporine: Chemistry, Structure-Activity Relationships and Mode of Action," Progress in Clinical Biochemistry and Medicine, 1986, pp. 157-191, vol. 3.|
|60||Wenger, R., "Synthesis of Cyclosporine and Analogues: Structure, Activity, Relationships of New Cycloporine Derivates, " Transplantation Proceedings, Dec. 1983, pp. 2230-2241, vol. XV, No. 4, Suppl. 1.|
|61||Wenger, R.M., "The Chemistry of Cyclosporine," Peptides, 1996, pp. 173-178.|
|62||Wenger, R.M., et al., "Structure of Cyclosporine and Its Metabolities: Total Synthesis of Cyclosporine Metabolities Formed by Oxidation at Positions 4 and 9 of Cyclospine. Preparation of Leucine-4-cyclosporine, gamma-Hydroxy)-N-methyl-leucine-9-cyclosporine and Leucine-4-(gamma-hydroxy)N-methyl-leucine-9-cyclosporine," Chimia, 1992, pp. 314-322, vol. 46.|
|63||Xia, W.L., et al., "Inhibitory effect of cyclosporine A on hepatitis B virus replication in vitro and its possible mechanisms," Hepatobiliary & Pancreatic Diseases International, Feb. 15, 2005, pp. 18-22, vol. 4, No. 1.|
|64||Zenke, G., et al., "Molecular Mechanisms of Immunosuppression by Cyclosporins," Anals of the New York Academy of Sciences, 1993, pp. 330-335, vol. 685.|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US20130267460 *||Sep 16, 2011||Oct 10, 2013||The Johns Hopkins University||Methods of Inhibiting Alphavirus Replication and Treating Alphavirus Infection|
|U.S. Classification||514/1.1, 530/402, 530/317, 424/278.1|
|International Classification||C07K7/64, A61K38/00, A61P31/18, A61P37/04, A61K38/12|
|Cooperative Classification||C07K7/645, A61K38/00|