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WO1993017039A1 - Sels d'iso-cyclosporine - Google Patents

Sels d'iso-cyclosporine Download PDF

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Publication number
WO1993017039A1
WO1993017039A1 PCT/EP1993/000407 EP9300407W WO9317039A1 WO 1993017039 A1 WO1993017039 A1 WO 1993017039A1 EP 9300407 W EP9300407 W EP 9300407W WO 9317039 A1 WO9317039 A1 WO 9317039A1
Authority
WO
WIPO (PCT)
Prior art keywords
iso
mebmt
ciclosporin
cyclosporin
sar
Prior art date
Application number
PCT/EP1993/000407
Other languages
English (en)
Inventor
Roland Wenger
Original Assignee
Sandoz Ltd.
Sandoz-Patent-Gmbh
Sandoz-Erfindungen Verwaltungsgesellschaft M.B.H.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sandoz Ltd., Sandoz-Patent-Gmbh, Sandoz-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Sandoz Ltd.
Publication of WO1993017039A1 publication Critical patent/WO1993017039A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C07K7/645—Cyclosporins; Related peptides
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to novel iso-cyclosporin acid addition salts and iso-cyclosporins, their use as pharmaceuticals and pharmaceutical conpositions comprising them, as well as to processes for their production.
  • the cyclosporins comprise a class of structurally distinctive, cy ⁇ restart, poly-N-methylated undecapeptides, commonly possessing pharmacolo ⁇ gical, in particular immunosuppressive, anti-inflammatory and/or anti- parasitic activity.
  • the first of the cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyclosporine, also known as cyclosporin A and commercially available under the Registered Trademark SANDM-IUN or SANDIMMUNE R .
  • Ciclosporin is the cyclosporin of formula I
  • MeBmt represents the N-methyl- (4R) -4-but-2E-en-l-yl-4- methyl-(L)threonyl residue of formula II
  • Ciclosporin Since the original discovery of Ciclosporin, a wide variety of naturally occurring cyclosporins have been isolated and identified and many further non-natural cyclosporins have been prepared by total- or semi-synthetic means or by the application of modified culture techni ⁇ ques.
  • the class comprised by the cyclosporins is thus now substantial and includes, for example, the naturally occurring cyclosporins A through Z [cf. Traber et al, 1, Helv. Chim. Acta, _60, 1247-1255 (1977; Traber et al, 2, Helv Chim.
  • Iso-cyclosporins are those cyclosporins in which the linkage of the residue MeBmt at the 1- ⁇ osition to the residue at the 11-position is via the 3'-0-atom rather than the ⁇ -N-atom such that the MeBmt residue at position 1 has the structure of formula III:
  • cyclosporins Also included in the class are derivatised cyclosporins; cyclo ⁇ sporins in which the MeBmt residue is present in isomeric form (e.g. in which the configuration across positions 6' and 7' of the MeBmt residue is cis rather than trans) ; and cyclosporins wherein variant amino acids are incorporated at specific positions within the peptide sequence employing e.g. the total synthetic method for the production of cyclosporins developed by R enger - see e.g. Traber et al 1, Traber et al, 2 and Kobel et al, loc.
  • the class comprised by the cyclosporins is thus now very large in ⁇ deed and includes, for example, [Thr] 2 -, [Val] 2 -, [Nva] 2 - and [Nva] 2 - [Nva] 5 -Ciclosporin (also known as cyclosporins C, D, G and M respective ⁇ ly), [Dihydro-MeBmt] 1 -[Val] 2 -Ciclosporin (also known as dihydro-cyclo- sporin D), [ (D)Ser] 8 -Ciclos ⁇ orin, [Melle] 11 -Ciclosporin, [ (D)MeVal] 11 - Ciclosporin (also known as cyclosporin H) , [MeAla] 6 -Ciclosporin, [ (D)Pro] 3 -Ciclosporin and so on.
  • cyclosporins In accordance with conventional nomenclature for cyclosporins, these are defined throughout the present specification and claims by reference to the structure of Ciclosporin (i.e. Cyclosporin A) . This is done by first indicating those residues in the molecule which differ from those present in Ciclosporin and then applying the term "Ciclosporin” to characterise the remaining residues which are identical to those present in Ciclosporin. At the same time the.prefix "dihydro" is employed to designate cyclosporins wherein the MeBmt residue is hydrogenated (dihydro-MeBmt) i.e. wherein -x-y- in formula II is -CH 2 -CH 2 -.
  • the prefix "iso” is employed to designate cyclosporins where the residue at the 1-position is a residue of formula III, above (iso-MeBmt) and the prefix "iso-dihydro” is used to designate cyclosporins in which the residue at the 1-position is a residue of formula III above wherein -x-y- is -CH 2 -CH 2 - (iso-dihydro-MeBmt) .
  • [Thr] 2 -Ciclosporin is the cyclosporin having the sequence shown in Formula I but in which ⁇ Abu at the 2- ⁇ osition is replaced by Thr
  • [dihydro-MeBmt] 1 -[Val] 2 -Ci ⁇ closporin is the cyclosporin having the sequence shown in Formula I but in which the MeBmt residue at position 1 is hydrogenated and ⁇ Abu at the 2-position is replaced by Val.
  • [Iso-dihydro-MeBmt] 1 -[Val] 2 -Ciclosporin is the cyclosporin having the sequence shown in formula I, but in which the residue at the 1-position is a residue of formula III wherein -x-y- is -CH 2 -CH 2 - and ⁇ Abu at the 2-position is replaced by Val.
  • amino acid residues referred to by abbreviation e.g. Ala, MeVal, ⁇ Abu etc. are, in accordance with conventional practice, to be understood as having the (L)-configuration unless otherwise indicated, e.g. as in the case of "(D)Ala”.
  • Individual residues of the cyclosporin molecule are numbered, as in the art, clockwise and starting with the residue MeBmt or dih dro- MeBmt in position 1. The same numerical sequence is employed throughout the present specification and claims.
  • iso-cyclosporins e.g., iso-cyclosporin A and certain 2-position derivatives (iso-cyclosporins B, D, and G)
  • iso-cyclosporins B, D, and G 2-position derivatives
  • iso-cyclosporins acid addition salts of the invention present an improved pharmacokinetic profile over cyclosporins, particularly for oral administration.
  • One difficulty with cyclosporins is that following oral administration, the blood concentration level rapidly reaches a high peak, which is followed by a rapid drop to a low trough.
  • absorbtion is somewhat variable, depending on the individual and on his activity and eating patterns.
  • oral administration of effective amounts of the cyclosporin i.e., amounts sufficient to obtain an effective concentration at the trough level, may lead to transient but dangerously high concentrations of cyclosporin in the blood at the peak level, resulting in various undesirable side effects, particularly kidney and liver damage.
  • iso-cyclosporins salts of the present invention exhibit lower toxicity. It is hypothesized that the reason for this lower toxicity is that iso-cyclosporins are absorbed from the gut in the iso-form, which is relatively inactive and nontoxic, and are then subsequently converted to the pharmacologically active cyclosporin form, thus reducing the peak concentrations in the blood following administration to safer levels while maintaining a relatively constant level of active cyclosporin in the blood.
  • the present invention thus provides a pharmaceutically acceptable acid addition salt of an iso-cyclosporin in solid form.
  • the invention also provides pharmaceutical compositions comprising an acid addition salt of an iso-cyclosporin in association with a pharmacologically acceptable diluent or carrier.
  • Such compositions may comprise the acid addition salt in solid form or as a solution or suspension in a pharmaceutically acceptable solvent or diluent.
  • the acid addition salts of the invention are to be understood as being products in which salt formation occurs at the ⁇ -N atom of the residue at the * l-position.
  • the term iso-cyclosporin as applied herein to the compounds of the invention is to be understood as including both regular iso-cyclosporins e.g.
  • the iso-cyclosporin acid addition salts of the invention are sometimes identified herein by giving the name of the iso-cyclosporin base, followed by the formula of the associated acid.
  • [iso-MeBmt]-Ciclosporin-HC1 is the hydrochloric acid addition s-alt of iso-cyclosporin A.
  • the molar ratio of acid to base present in the salt is 1:1.
  • a particularly preferred embodiment is an iso-cyclosporin acid addition salt in solid form wherein the residue at the 1-position is a residue of formula IV:
  • Especially preferred iso-cyclosporin acid addition salts in accor ⁇ dance with the present invention are those of formula V ⁇ X-Y— Z—MeLeu-W-MeLeu-Ala-Q-MeLeu-MeLeu— R 1 2 3 4 5 6 7 8 9 10 11 (V)
  • Y is ⁇ Abu, Thr, Val or Nva
  • Z is Sar, or is an ⁇ -N-methyl-(D) - ⁇ -amino acid residue, e.g., (D)MeAla, (D)MeLeu, or ⁇ -(methylthio) -(D)Sar,
  • W is Val or, when Y is Nva, also optionally Nva,
  • Q is (D)Ala, a ⁇ -hydroxy-(D)- ⁇ -amino acid residue or an ether or ester derivative of a ⁇ -hydroxy- (D) - ⁇ -amino acid residue;
  • R is (D)MeVal or MeVal
  • A is a pharmaceutically acceptable anion of valency b.
  • b may be 1 or 2, preferably 1.
  • A may be any pharmaceutically acceptable anion, such as, for example, Cl ⁇ , CH 3 S0 3 ", HS0 ⁇ , H 2 P0 4 " , hydrogen maleate or pyruvate.
  • the anion is the anion of an acid which has a pK value of ⁇ 3.
  • HS0 ", H 2 P0 " , and especially Cl" are particularly preferred anions.
  • Suitable ⁇ -hydroxy-(D)- ⁇ -amino acid residues as Q are, for example, (D)Ser or (D)Thr. Cyclosporins of this type are described and claimed in European Patent No. 056 782. Suitable ethers of ⁇ -hydroxy- (D) - ⁇ -amino acid residues include 0-(2-hydroxyethyl) -(D) Ser, described and claimed in European Patent Application 414 632. Suitable esters of ⁇ -hydroxy-(D)- ⁇ -amino acid residues are described and claimed in British Patent 2 155 936. Suitable ⁇ -N-methyl-(D) - ⁇ -amino acid residues as Z include those described in European Patent 194 972.
  • the present invention also provides a process for the production of a pharmaceutically acceptable acid addition salt of an iso-cyclosporin in solid form, which comprises salifying an iso-cyclosporin, e.g. wherein the residue at the 1- ⁇ osition is iso-MeBmt or iso-dihydro-MeBmt, e.g. an iso-cyclosporin of formula V as illustrated above.
  • the above process step may be carried out according to conventional salification procedures, e.g. by contacting the desired iso-cyclosporin base with an appropriate acid in the presence of an inert solvent or diluent, followed by isolation of the salt in solid form-
  • the acid is a strong acid, e.g. hydrochloric acid.
  • the reaction is suitably performed at temperatures of from 0° to 40°C, preferably -from 15° to 25°C.
  • Isolation of the solid form may for example be by precipitation followed by separation from the liquid phase by filtration, centri- fugation, etc., or by evaporation of the liquid phase, or by a combination of these methods, e.g. first concentrating the solution by evaporation, then filtering off the liquid phase.
  • trifluoroacetic acid methane sulphonic acid or p-toluenesulphonic acid (of which trifluoroacetic acid is preferred)
  • a solvent such as toluene, methanol, chloroform or dioxane followed by isolation of the pure base iso-cyclosporin.
  • Reaction is suitably performed at from room temperature to 60°C, preferably at room temperature (approx. 20°C) .
  • the iso-cyclosporin salts of the invention are characterized by proton NMR spectra showing a series of sharply defined singlet peaks in the region between 2.5 and 3.5 ppm. This indicates that they have a single well defined conformation in which the N-methylammonium group in the [iso-MeBmt] 1 residue is bridged with the carbonyl group of the [MeLeu] 10 residue.
  • the NMR spectra for the iso-cyclosporin free bases is less sharply defined, with and more numerous peaks, suggesting a mixture of conformations.
  • the conformation of the salt form is highly stable over time and at elevated temperatures.
  • experiments measuring conversion from the iso-cyclosporin form to the cyclosporin form as shown by HPLC analysis following storage over time show that iso-cyclosporin salt forms are stable in ethanol solution indefinitely, whereas the iso-cyclosporin free base forms convert to the cyclosporin form at room temperature in ethanol solution (approximately 10% conversion after 60 hours, >50% conversion after several weeks) .
  • the iso-cyclosporin salts of the invention are stable in ethanol solution at elevated temperatures (e.g. 50°C), whereas there is substantial conversion of the free base iso-cyclosporin to cyclosporin upon mild heating in ethanol solution (e.g., approximately 70% conversion after 2 hours at 50°C) .
  • elevated temperatures e.g. 50°C
  • ethanol solution e.g., approximately 70% conversion after 2 hours at 50°C
  • X is iso-MeBmt or iso-dihydro-MeBmt
  • Y is ⁇ Abu, Thr, Val or Nva
  • Z is Sar, or an ⁇ -N-methyl- (D) - ⁇ -amino acid residue, e.g.,
  • Q is (D)Ala or a ⁇ -hydroxy-(D)- ⁇ -amino acid residue or an ether or ester derivative thereof, e.g. (D)Ser, (D)Thr, or 0-(2-hydroxyethyl) -(D)Ser; and
  • R is MeVal or (D)MeVal;
  • iso-cyclosporins have pharmaceutical utility, e.g. as immuno- suppressive and anti-inflammatory agents, e.g. as may be evidenced by activity in the test methods hereinafter described, and are thus useful as pharmaceutical agents in their own right, as well as as intermediates for the production of the acid addition salts of iso-cyclosporins of the invention.
  • the title compound is produced by analogy with Example 2, using iso-cyclosporin A as starting material.
  • the free base form of the title compound is prepared by analogy to example 4a using [dihydroMeBmt] 1 -[Val] 2 -[ ⁇ -(methylthio) (D)Sar] 3 - Ciclosporin (prepared, e.g., as described in European patent 0 194 972, example 21) as the starting material.
  • the free base form of the title compound is prepared by analogy to example 4a using [dihydroMeBmt] 1 -[ ⁇ -(methylthio) (D) Sar] 3 - Ciclosporin (prepared, e.g., as described in European patent 0 194 972, example 23) as the starting material.
  • the title compound as hydrochloric acid addition salt is prepared by analogy to example 2 using iso-cyclosporin D as starting material.
  • the iso-cyclosporin acid addition salts of the present invention possess pharmaceutical utility.
  • Their activity in vitro is in part a function of the length of the test; in shorter tests, such as the cyclophilin binding assay, they appear less active, but in longer in vitro tests for im unosuppression in cell cultures, such as the mixed lymphocyte reaction, when the compounds are exposed to physiologic conditions for substantial period of time, the compounds exemplified herein exhibit activity on the same order of magnitude as cyclosporin A.
  • this slow conversion from the inactive form to the active form is a high advantage as it can be shown to decrease the peak concentration of active cyclosporin in the blood and to provide a sustained release over time, thereby reducing toxic peak concentration levels while nevertheless maintaining pharmacologically active concentrations in the blood.
  • Spleen cells (1 x 10 7 ) from 6 week old female Wistar/Furth (WF) rats are injected subcutaneously on day 0 into the left hind-paw of female (F344 x WF)F ⁇ rats weighing about lOOg. Animals are treated for 4 con ⁇ secutive days and the popliteal lymph nodes are removed and weighed on day 7. The difference in weight between the two lymph nodes is taken as the parameter for evaluating the reaction.
  • Product Iso-cyclosporins are active in the above test method at dosages of, e.g. 25 mg/kg to 35 mg/kg p.o. and 10 mg/kg to 15 mg/kg s.c. 2) Kidney Allograft Reaction in Rat
  • kidney from a female fisher 344 rat is transplanted onto the renal vessel of a unilateral!** " (left side) nephrectomised WF recipient rat using an end-to-end anastomosis. Ureteric anastamosis is also end- to-end.
  • Treatment commences on the day of transplantation and is con ⁇ tinued for 14 days.
  • a contralateral nephrectomy is done seven days after transplantation, leaving the recipient relying on the performance of the donor kidney. Survival of the graft is taken as the parameter for a functional graft.
  • Product Iso-cyclosporins are active in the above test method at dosages of e.g. 5 mg/kg to 7.5 mg/kg p.o.
  • OFA and Wistar rats male or female, 150g body weight
  • treatment is started immediate ⁇ ly after the injection of the adjuvant (days 1 - 18) ; in the established arthritis model treatment is started on day 14, when the secondary in ⁇ flammation is well developed (days 14-20) .
  • the swelling of the joints is measured by means of a micro- caliper.
  • ED 50 is the oral dose in mg/kg which reduces the swelling (pri ary or secondary) to half of that of the controls.
  • Product Iso-cyclosporins are active in the above test method at dosages of, e.g. 15 to 25 mg/kg p.o.
  • Product Iso-cyclosporins are therefore useful as pharmaceuticals, e.g. as immunosuppressive as well as anti-inflammatory agents.
  • Iso-cyclosporins are particularly useful for the prevention of organ or tissue transplant rejection, e.g. for the treatment of recipients of e.g. heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or corneal transplants. They are also indicated for the prevention of graft-versus-host disease, such as following bone marrow transplantation.
  • Iso-cyclosporins are also useful for the treatment of autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune compo ⁇ nent such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases.
  • autoimmune diseases for which the cyclosporins of the invention may be employed include, autoimmune haematological disorders (including e.g.
  • haemolytic anaemia aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopaenia
  • systemic lupus erythematosus polychon- dritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g.
  • ulcerative colitis and Crohn's disease endocrine ophthalmopathy
  • Graves disease sarcoidosis, multiple sclerosis, primary billiary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephro- tic syndrome or minimal change nephropathy) and juvenile dermatomyosi ⁇ tis.
  • Product Iso-cyclosporins are further indicated for use in the treatment of other diseases or conditions for which cyclosporins, e.g. Ciclosporin, therapy is practised or proposed, for example, for the treatment of alopecia/the promotion of hair growth and for the treatment of asthma, e.g. on administration by inhalation. They are also indica ⁇ ted for use as anti-parasitic agents, in particular for the treatment of parasitic, e.g. protozoal, fungal or vermicular infection or invasion, for example in the treatment of filariasis, schistosomiasis, coccidio- mycosis-or plasmoidal infection, e.g. malaria. They are yet further indicated for use in the reversal of resistance of malignancies or infections to other chemotherapy (multidrug resistance) , as well as the enhancement of wound healing.
  • cyclosporins e.g. Ciclosporin
  • therapy is practised or proposed, for example, for the treatment of alopecia
  • the appropriate dosage will, of course, vary depending upon, for example the Product Iso-cyclosporin employed, the host, the mode of administration and the nature and severity of the condition being treated. With organ transplant, for example, the dosage will vary during the course of the treatment. However, in general, satisfactory results are indicated to be obtained at daily dosages of from about 2.5 to 15 mg/kg, preferably from about 2.5 to 7.5 mg/kg conveniently administered in divided doses of from, e.g. 800 mg prefer ⁇ ably 400 mg or in sustained release form.
  • the Product Iso-cyclosporins may be administered by any conventional route, in particular enterally, e.g. in the form of solutions for drinking, or in tablet or capsule form, or parenterally e.g.
  • the iso-cyclosporin salts of the invention are characterised by im ⁇ proved stability as compared with known iso-cyclosporins, which enables them to be more readily incorporated into stable solid galenic forms. They also possess modified solubility characteristics.
  • the enhanced solubility and stability properties of the iso-cyclosporin salts of the invention permit provision of solid dosage forms such as powders, granu ⁇ lates and tablets, which contain the product cyclosporins in concentra ⁇ tions sufficiently high to permit convenient use and yet also meet the required criteria in terms of bioavailability, e.g. enabling effective resorption from the stomach or gut lumen and achievement of consistent and appropriately high blood/blood serum levels.
  • a suitable tablet formulation for the iso-cyclosporin salts of the invention comprises the following excipients: a) iso-cyclosporin salt as active ingredient b) a saccharide or fatty acid saccharide monoester c) a solid, e.g. polymeric carrier d) a water swellable or water soluble component; and e) a binder or lubricant.
  • formulation A More specifically, an example of the ingredients for the tablet formulation is formulation A:
  • An alternative and preferred tablet formulation B contains the following ingredients:
  • formulation B the drug and hydroxypropyl- methyl cellulose are dissolved in a mixture of absolute ethanol and acetone.
  • the solvents are evaporated in a rotovapor, and the solid dispersion is milled in a ball mill, then mixed with the other components and compressed into tablets-
  • a method of effecting immunosuppression in a subject in need of such treatment which method comprises administering to said subject an effec ⁇ tive amount of a Product Iso-cyclosporin.
  • B A method:
  • organ transplant rejection for example for the treatment of recipients of organ transplants of any of the particular types hereinbefore set forth, or graft-vs-host disease;
  • a Product Iso-cyclosporin for use as a pharmaceutical e.g. for use as an immunosuppressant or for use in the treatment of any disease or condition as set forth under B above.
  • a pharmaceutical composition comprising a Product Iso-cyclosporin together with a pharmaceutically acceptable diluent or carrier therefor.

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Abstract

Il s'avère que les sels d'addition d'acide d'iso-cyclosporines présentent des caractéristiques galéniques améliorées de manière surprenante, par exemple une solubilité et une stabilité améliorées, ainsi qu'un profil pharmacologique amélioré par rapport à celui de cyclosporines, ce qui les rend utilisables comme produits pharmaceutiques, par exemple comme immunodépresseurs et notamment comme précurseurs de médicament pour les cyclosporines. L'invention concerne également de nouvelles iso-cyclosporines utiles, par exemple, dans la fabrication des sels d'addition d'acide d'iso-cyclosporines précités, ainsi que les procédés de fabrication, les formulations pharmaceutiques, et les applications thérapeutiques de ces composés.
PCT/EP1993/000407 1992-02-24 1993-02-20 Sels d'iso-cyclosporine WO1993017039A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929203886A GB9203886D0 (en) 1992-02-24 1992-02-24 Improvements in or relating to organic compounds
GB9203886.8 1992-02-24

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WO1993017039A1 true WO1993017039A1 (fr) 1993-09-02

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100439467B1 (ko) * 2002-11-13 2004-07-09 주식회사 엘지생활건강 모발 성장 효과를 갖는 사이클로스포린 3 위치 유도체를유효성분으로 하는 모발 성장 촉진제
US6762164B2 (en) 2001-05-11 2004-07-13 Lg Household & Health Care Ltd. Use of 3-position cyclosporin derivatives for hair growth
KR100512019B1 (ko) * 2002-07-25 2005-09-02 신득용 사이클로스포린 ａ 또는 이의 유도체를 이용한 세포의노화를 억제하는 방법 및 배양배지
US6987090B2 (en) 2002-05-09 2006-01-17 Lg Household & Health Care Ltd. Use of 3-position cyclosporin derivatives for hair growth
US7060672B2 (en) 2001-10-19 2006-06-13 Isotechnika, Inc. Cyclosporin analog formulations
KR100865211B1 (ko) * 2001-10-26 2008-10-23 주식회사 엘지생활건강 비면역 [감마 히드록시 엔-메틸 엘-루신4] 사이클로스포린 유도체를 유효성분으로 하는 항암 화학요법 기인 탈모증상 억제제
JPWO2020122182A1 (ja) * 2018-12-12 2021-10-28 中外製薬株式会社 分子内水素結合可能な官能基を有するアミノ酸とそれらのアミノ酸を含むペプチド化合物、およびそれらの製造方法
IT202100032651A1 (it) * 2021-12-24 2023-06-24 Isoxa S R L Metodo di preparazione di un sale di isociclosporina a
IT202100032648A1 (it) * 2021-12-24 2023-06-24 Isoxa S R L Metodo di preparazione di un sale di isociclosporina a
EP4201398A1 (fr) 2021-12-24 2023-06-28 Isoxa S.r.l. Isocyclosporin de pour le traitement topique de maladies oculaires

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GB2033398A (en) * 1978-10-18 1980-05-21 Sandoz Ltd L compositions containing them cyclosporin derivatives their production and pharmaceutica
CH641356A5 (en) * 1979-02-27 1984-02-29 Sandoz Ag Pharmaceutical compositions containing cyclosporin

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US6762164B2 (en) 2001-05-11 2004-07-13 Lg Household & Health Care Ltd. Use of 3-position cyclosporin derivatives for hair growth
US6790830B2 (en) 2001-05-11 2004-09-14 Lg Household & Health Care Ltd. Use of 3-position cyclosporin derivatives for hair growth
KR100465012B1 (ko) * 2001-05-11 2005-01-13 주식회사 엘지생활건강 모발 성장 효과를 갖는 사이클로스포린 3 위치 유도체를유효성분으로 하는 모발 성장 촉진제
US7429562B2 (en) 2001-10-19 2008-09-30 Isotechnika Inc. Cyclosporin analog formulations
US7060672B2 (en) 2001-10-19 2006-06-13 Isotechnika, Inc. Cyclosporin analog formulations
KR100865211B1 (ko) * 2001-10-26 2008-10-23 주식회사 엘지생활건강 비면역 [감마 히드록시 엔-메틸 엘-루신4] 사이클로스포린 유도체를 유효성분으로 하는 항암 화학요법 기인 탈모증상 억제제
US6987090B2 (en) 2002-05-09 2006-01-17 Lg Household & Health Care Ltd. Use of 3-position cyclosporin derivatives for hair growth
KR100512019B1 (ko) * 2002-07-25 2005-09-02 신득용 사이클로스포린 ａ 또는 이의 유도체를 이용한 세포의노화를 억제하는 방법 및 배양배지
KR100439467B1 (ko) * 2002-11-13 2004-07-09 주식회사 엘지생활건강 모발 성장 효과를 갖는 사이클로스포린 3 위치 유도체를유효성분으로 하는 모발 성장 촉진제
JPWO2020122182A1 (ja) * 2018-12-12 2021-10-28 中外製薬株式会社 分子内水素結合可能な官能基を有するアミノ酸とそれらのアミノ酸を含むペプチド化合物、およびそれらの製造方法
IT202100032651A1 (it) * 2021-12-24 2023-06-24 Isoxa S R L Metodo di preparazione di un sale di isociclosporina a
IT202100032648A1 (it) * 2021-12-24 2023-06-24 Isoxa S R L Metodo di preparazione di un sale di isociclosporina a
EP4201398A1 (fr) 2021-12-24 2023-06-28 Isoxa S.r.l. Isocyclosporin de pour le traitement topique de maladies oculaires
WO2023119172A1 (fr) * 2021-12-24 2023-06-29 Isoxa S.R.L. Procédé de préparation d'un sel d'isocyclosporine a
WO2023118487A1 (fr) 2021-12-24 2023-06-29 Isoxa S.R.L. Isocyclosporine a destinée au traitement topique de maladies oculaires
WO2023119173A1 (fr) * 2021-12-24 2023-06-29 Isoxa S.R.L. Procédé de préparation d'un sel d'isociclosporine a
US20250082719A1 (en) * 2021-12-24 2025-03-13 Dompe' Farmaceutici S.P.A. Isocyclosporin a for topical treatment of ocular diseases
EP4559529A2 (fr) 2021-12-24 2025-05-28 Dompé farmaceutici S.p.A. Isocyclosporine a pour le traitement topique de maladies oculaires
EP4559529A3 (fr) * 2021-12-24 2025-08-20 Dompé farmaceutici S.p.A. Isocyclosporine a pour le traitement topique de maladies oculaires

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