WO2000051558A1 - Methode de traitement de la chute des cheveux au moyen de composes non immunosuppresseurs - Google Patents

Methode de traitement de la chute des cheveux au moyen de composes non immunosuppresseurs Download PDF

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Publication number
WO2000051558A1
WO2000051558A1 PCT/US2000/005300 US0005300W WO0051558A1 WO 2000051558 A1 WO2000051558 A1 WO 2000051558A1 US 0005300 W US0005300 W US 0005300W WO 0051558 A1 WO0051558 A1 WO 0051558A1
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Prior art keywords
methyl
group
propenyl
hydrogen
ethyl
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PCT/US2000/005300
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English (en)
Inventor
Andrew Wayne Fulmer
Jay Patrick Tiesman
Charles Raymond Degenhardt
David Joseph Eickhoff
John Mcmillan Mciver
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The University Of Texas Southwestern Medical Center
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Priority to EP00917685A priority Critical patent/EP1161222A1/fr
Priority to AU38619/00A priority patent/AU3861900A/en
Priority to JP2000602029A priority patent/JP2002538092A/ja
Priority to CA002366312A priority patent/CA2366312A1/fr
Publication of WO2000051558A1 publication Critical patent/WO2000051558A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • the present invention relates to methods for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth.
  • Hair loss is a common problem which occurs, for example, through natural processes or is often chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often such hair loss is accompanied by lack of hair regrowth which causes partial or full baldness.
  • hair growth occurs by a cycle of activity which involves alternating periods of growth and rest
  • This cycle is often divided into three main stages which are known as anagen, catagen, and telogen.
  • Anagen is the growth phase of the cycle and may be characterized by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair.
  • the next phase is catagen, which is a transitional stage marked by the cessation of cell division, and du ⁇ ng which the hair follicle regresses through the dermis and hair growth is ceased.
  • the next phase, telogen is often characterized as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells.
  • cyclospo ⁇ n A is known to invoke a prominent hair induction side effect.
  • cyclospo ⁇ n A is not practical for use as a hair growth agent due to its strongly immunosuppressive activity. See Yamamoto et al., "Hair Growth-Stimulating Effects of Cyclosporm A and FK506, Potent Immunosuppressants", Journal of Dermatological Science, Vol. 7 (suppl.), pp. S47 - S54 (1994); Maurer et al, "Hair Growth Modulation by Topical Immunophilm Ligands", American Journal of Pathology, Vol. 150, No. 4, pp. 1433 - 1441 (1997); Paus et al..
  • the present invention relates to methods for treating hair loss comprising administering to a mammal a non-immunosuppressive compound which has been found by the present inventors to be particularly useful for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth.
  • the compounds utilized m the present method have the structure:
  • R_, R , Ri" R 2 , R 3 , R4, R 5 , R 5 ', Re, R 7 , and R 8 are as defined herein.
  • the present invention relates to methods of using compounds and compositions which are particularly useful for treating hair loss in mammals, preferably humans, including arresting and / or reversing hair loss and promoting hair growth.
  • the present inventors have also surprisingly discovered that lmmunosuppression is not required for hair growth stimulation.
  • the present inventors have further discovered compounds that are useful for treating hair loss but are surprisingly non-immunosuppressive.
  • the compounds useful in the method of the present invention are therefore, as defined herein, non-immunosuppressive.
  • salt is a cationic salt formed at any acidic (e g , carboxyl) group, or an anionic salt formed at any basic (e.g , amino) group
  • Preferred cationic salts include the alkali metal salts (such as, for example, sodium and potassium), alkaline earth metal salts (such as, for example, magnesium and calcium), and organic salts
  • Preferred anionic salts include the hahdes (such as, for example, chloride salts) Such acceptable salts must, when administered, be appropriate for mammalian use.
  • alkenyl is an unsaturated hydrocarbon chain radical Alkenyls have at least one double bond. Unless otherwise specified, alkenyls have from 2 to about 15 carbon atoms (C 2 - C 15 ); preferably from 2 to about 10 carbon atoms (C 2 - C 10 ); more preferably from 2 to about 8 carbon atoms (C 2 - C 8 ), and most preferably from 2 to about 6 carbon atoms (C 2 - C 6 )
  • Non-limitmg examples of alkenyls include vinyl, allyl, and butenyl.
  • alkoxy is an oxygen radical having an alkyl, alkenyl, or alkynyl, preferably an alkyl or alkenyl, and most preferably an alkyl substituent.
  • alkoxy radicals include -O-methyl and -O-ethyl.
  • alkyl is a saturated hydrocarbon chain radical Unless otherwise specified, alkyls have from 1 to about 15 carbon atoms (C, - C 15 ); preferably from 1 to about 10 carbon atoms (C, - C 10 ); more preferably from 1 to about 6 carbon atoms ( - C 6 ), and most preferably from 1 to about 4 carbon atoms (C, - C 4 )
  • Preferred alkyls include, for example, methyl, ethyl, propyl, .jO-propyl, and butyl
  • alkynyl is an unsaturated hydrocarbon chain radical. Alkynyls have at least one triple bond Unless otherwise specified, alkynyls have from 2 to about 15 carbon atoms (C 2 - C 15 ); preferably from 2 to about 10 carbon atoms (C 2 - C 10 ); more preferably from 2 to about 8 carbon atoms (C 2 - C 8 ), and most preferably from 2 to about 6 carbon atoms (C 2 - C 6 ).
  • biohydrolyzable amides are amides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
  • biohydrolyzable esters are esters of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound
  • biohydrolyzable lmides are lmides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound
  • a “lower” moiety is a moiety having 1 to about 6, preferably 1 to about 4, carbon atoms
  • pharmaceutically acceptable means suitable for use in a human or other mammal.
  • safe and effective amount of a compound means an amount that is effective to exhibit biological activity, preferably wherein the biological activity is arresting and / or reversing hair loss or promoting hair growth, at the s ⁇ te(s) of activity in a mammalian subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit / risk ratio when used in the manner of this invention.
  • substituent groups may themselves be substituted. Such substitution may be with one or more substituents.
  • substituents include those listed m C Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979).
  • substituted in reference to a group, moiety, or the like, preferably means having one or more substituent groups each independently selected from hydrogen, alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, ammo, alkylammo, cyano, halo, carboxy, alkoxyacyl (e g , carboethyoxy), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g , pipe ⁇ dmyl, morphohnyl, pyrrolidinyl), imino, thioxo, hydroxyalkyl, aryloxy, and arylalkyl, more preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, ammo, alkylammo, halo, thiol, and aryloxy, even more preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy, o
  • variable, moiety, group, or the like occurs more than one time in any variable or structure, its definition at each occurrence is independent of its definition at every other occurrence.
  • the present invention relates to methods of treating hair loss comprising administering to a mammal a composition comprising a compound having the structure:
  • R ⁇ is selected from the group consisting of 1-propenyl, propyl, 3 -hydroxy- 1-propenyl, -O-methyl, -0- >-benzoyl benzyl, and hydroxy;
  • Ri' is selected from hydroxy, oxo, and acyloxy
  • R_" is selected from hydrogen and methyl
  • R 2 is selected from ethyl, «-butyl, 2-hydroxypropyl, 2-methoxypropyl, 1- methylpropyl, and 2-acyloxy-propyl;
  • R 3 is selected from hydrogen, methyl, benzyl, 1-propenyl, and 2-methyl-3-hydroxy- propyl;
  • R_ t is substituted or unsubstituted C, - C 9 straight or branched alkyl
  • R 5 is substituted or unsubstituted Ci - C 6 straight or branched alkyl
  • R 5 ' is selected from hydrogen, methyl, benzyl, / fluorobenzyl, 1-propenyl, and 1- phenyl- 1 -propenyl;
  • R 6 is selected from 2-methylpropyl, 2-methyl-3-hydroxypropyl, methyl, and ethyl;
  • (j) 7 is selected from methyl and phenyl; and
  • (k) R 8 is selected from methyl and hydroxymethyl.
  • Rj is selected from 1-propenyl, propyl, 3 -hydroxy- 1-propenyl, -O-methyl, -O- /?-benzoyl benzyl, and hydroxy. More preferably, Rj is selected from 1-propenyl, propyl, and 3- hydroxy- 1-propenyl, most preferably Rj is 1-propenyl.
  • the Ri' Moiety is selected from hydroxy, oxo, and acyloxy.
  • oxo means a doubly bonded oxygen radical.
  • Rj moiety is selected from hydrogen and methyl. Most preferably, Ri" is hydrogen.
  • R R]', and R] moieties are further described in, for example, U.S. Patent No. 5,767,069, Ko et al.. assigned to Novartis, issued June 16, 1998; WO 97/18828, Sterner et al.. assigned to Guilford Pharmaceuticals, Inc., published May 29, 1997; and Bartz et al.. "Inhibition of Human Immunodeficiency Virus Replication by Nonimmunosuppressive Analogs of Cyclosporm A", Proceedings of the National Academy of Sciences U.S.A., Vol. 92, pp. 5381 - 5385 (1995).
  • the R 2 moiety is selected from ethyl, «-butyl, 2-hydroxypropyl, 2-methoxypropyl, 1- methylpropyl, and 2-acyloxy-propyl.
  • acyloxy is an oxygen radical having an acyl substituent.
  • 2-acyloxy-propyl is exemplified by:
  • X is any substituent but preferably selected from alkyl, alkenyl, alkynyl, and aryl, most preferably alkyl.
  • R 2 is preferably selected from ethyl, w-butyl, 2-hydroxypropyl, and 2-methoxypropyl. Most preferably, R 2 is ethyl. These R 2 moieties are further described m, for example, U.S. Patent No. 5,767,069, Ko et ah, assigned to Novartis, issued June 16, 1998; and WO 97/18828, Sterner et al.. assigned to Guilford Pharmaceuticals, Inc., published May 29, 1997.
  • R 3 moiety is selected from hydrogen, methyl, benzyl, 1-propenyl, and 2-methyl-3- hydroxy-propyl.
  • R 3 is selected from hydrogen, methyl and benzyl,. Most preferably R 3 is hydrogen or benzyl.
  • R 3 moieties are further described m, for example, U.S. Patent No. 5,767,069, Ko et al., assigned to Novartis, issued June 16, 1998; WO 97/18828, Sterner et al.. assigned to Guilford Pharmaceuticals, Inc., published May 29, 1997; and Hu et al.. "Cyclosporm Analogs Modified m the 3,7,8-Pos ⁇ t ⁇ ons- Substituent Effects on Peptidylprolyl Isomerase Inhibition and Immunosuppressive Activity Are Nonadditive", Journal of Medicinal Chemistry, Vol. 38, pp 4164 - 4170 (1995).
  • the R 3 moiety may be in the L or D configuration, but is preferably in the D configuration.
  • the R 4 moiety is substituted or unsubstituted Ci - C 9 straight or branched alkyl, preferably substituted or unsubstituted - C 6 straight or branched alkyl, and more preferably substituted or unsubstituted Cj - C straight or branched alkyl.
  • R 4 is selected from 2-methylpropyl, 2-methyl-3-hydroxypropyl, 2- methylbutyl, is ⁇ -propyl, 2-hydroxypropyl, and methyl. Most preferably, R, is 2-methylpropyl.
  • R_ ⁇ moieties are further described m, for example, U.S. Patent No. 5,767,069, Ko et ah, assigned to Novartis, issued June 16, 1998; WO 97/18828, Sterner et al.. assigned to Guilford Pharmaceuticals, Inc., published May 29, 1997; and Bartz et al.. "Inhibition of Human Immunodeficiency Virus Replication by Nonimmunosuppressive Analogs of Cyclosporm A", Proceedings of the National Academy of Sciences U.SA , Vol. 92, pp. 5381 - 5385 (1995).
  • the R 5 moiety is substituted or unsubstituted - C 6 straight or branched alkyl, and more preferably substituted or unsubstituted C] - G» straight or branched alkyl.
  • R 5 is selected from 2-methylpropyl, «-butyl and z_? ⁇ -propyl. Most preferably, R 5 is «o-propyl.
  • R 5 moieties are further described in, for example, U.S. Patent No. 5,767,069, Ko et al, assigned to Novartis, issued June 16, 1998; and WO 97/18828, Sterner et al. assigned to Guilford Pharmaceuticals, Inc., published May 29, 1997.
  • R 5 ' moiety is selected from hydrogen, methyl, benzyl, /?-fluorobenzyl, 1-propenyl, and 1 -phenyl- 1-propenyl.
  • 1-propenyl is exemplified as:
  • R 5 ' is selected from hydrogen, methyl, and 1-propenyl, more preferably hydrogen and 1-propenyl Most preferably, R 5 ' is hydrogen.
  • the Re moiety is selected from 2-methylpropyl, 2-methyl-3-hydroxypropyl, methyl, and ethyl, more preferably, 2-methylpropyl and 2-methyl-3-hydroxypropyl Most preferably, R 6 is 2- methylpropyl
  • R 6 moieties are further described in, for example, U S. Patent No 5,767,069, Ko et al. assigned to Novartis, issued June 16, 1998, and WO 97/18828, Sterner et al. assigned to Guilford PharmaceuUcals, Inc., published May 29, 1997
  • R 7 is selected from methyl and phenyl.
  • R 7 is methyl
  • R 7 moieties are further described in, for example, WO 97/18828, Sterner et al. assigned to Guilford Pharmaceuticals, Inc., published May 29, 1997 and Hu et al. "Cyclosporm Analogs Modified in the 3,7,8-Positions: Substituent Effects on Peptidylprolyl Isomerase Inhibition and Immunosuppressive Activity Are Nonadditive", Journal of Medicinal Chemistry, Vol. 38, pp. 4164 - 4170 (1995).
  • R 8 is selected from methyl and hydroxymethyl
  • R 8 is methyl
  • R 8 moieties are further described in, for example, WO 97/18828, Sterner et al. assigned to Guilford Pharmaceuticals, Inc., published May 29, 1997 and Hu et al. "Cyclospo ⁇ n Analogs Modified m the 3,7,8-Positions: Substituent Effects on Peptidylprolyl Isomerase Inhibition and Immunosuppressive Activity Are Nonadditive", Journal of Medicinal Chemistry, Vol. 38, pp. 4164 - 4170 (1995).
  • the present invention relates to methods of treating hair loss m mammals by administering to a mammal a non-immunosuppressive compound having a structure as described herein.
  • Compounds test compounds
  • test compounds may be tested for their ability to induce anagen and their immunosuppressive activity (or lack thereof) using the following methods.
  • other methods well-known m the art may be used (but with the term "non-immunosuppressive" being defined according to the method disclosed herein below)
  • the Telogen Conversion Assay measures the potential of a test compound to convert mice in the resting stage of the hair growth cycle ("telogen”), to the growth stage of the hair growth cycle (“anagen”)
  • telogen there are three principal phases of the hair growth cycle: anagen, catagen, and telogen It is believed that there is a longer telogen period m C3H mice (Harlan Sprague Dawley, Inc , Indianapolis, IN) from approximately 40 days of age until about 75 days of age, when hair growth is synchronized. It is believed that after 75 days of age, hair growth is no longer synchronized Wherein about 40 day-old mice with dark fur (brown or black) are used m hair growth experiments, melanogenesis occurs along with hair (fur) growth wherein the topical application of hair growth mducers are evaluated.
  • the Telogen Conversion Assay herein below is used to screen compounds for potential hair growth by measuring melanogenesis.
  • a vehicle control group Three groups of 44 day-old C3H mice are utilized: a vehicle control group, a positive control group, and a test compound group, wherein the test compound group is administered a compound used in the method of the present invention.
  • the length of the assay is at least 19 days with 15 treatment days (wherein the treatment days occur Mondays through Fridays). Day 1 is the first day of treatment. Most studies will end on Day 19, but a few may be carried out to Day 24 if the melanogenesis response looks positive, but occurs slowly.
  • a typical study design is shown in Table 1 below:
  • the vehicle is 60% ethanol, 20% propylene glycol, and 20% dimethyl isosorbide (commercially available from Sigma Chemical Co., St. Louis, MO).
  • mice are treated topically Monday through Friday on their lower back (base of tail to the lower rib).
  • a pipettor and tip are used to deliver 400 ⁇ L to each mouse's back.
  • the 400 ⁇ L application is applied slowly while moving hair on the mouse to allow the application to reach the
  • the immunosuppression assay herein predicts the immunosuppressive activity (or nonimmunosuppressive activity) of a compound used in the method of the present invention.
  • the assay is performed as follows:
  • Spleens are excised from euthanized (CO, asphyxiation) adult male C3H mice ranging in age from seven to sixteen weeks old (live mice commercially available from Harlan Sprague Dawley, Inc., Indianapolis, IN)
  • the spleens are placed immediately in cold Hanks Balanced Salt Solution (HBSS, commercially available from Gibco-BRL, Gaithersburg, MD).
  • HBSS Hanks Balanced Salt Solution
  • the spleens are then ground up between frosted glass slides and filtered through a sterile screen to remove tissue debris.
  • the resulting cell suspension is underlayed with an equal volume of Ficoll-Paque Plus (commercially available from Pharmacia Biotech, Piscataway, NJ) and cent ⁇ fuged at 400 x g for approximately forty minutes at 20 °C m order to collect the splenocytes.
  • the splenocytes are collected from the interface using a disposable pipet and are washed twice with HBSS, followed by cent ⁇ fugation at 100 x g for ten minutes at 20 °C.
  • Splenocytes are resuspended in five to ten mL of cell culture media consisting of phenol red- free RPMI 1640 (culture media commercially available from Gibco-BRL) containing 10% heat-mactivated fetal bovine serum (Gibco-BRL), penicillin (50 U/mL), streptomycin (100 ⁇ g/mL), L-glutamme (2 mM), 2-mercaptoethanol (10 "5 M), and N-2-hydroxyethylp ⁇ perazme-N'-2-ethanesulfon ⁇ c acid (HEPES) (10 mM). The cells are counted and checked for viability using, for example, trypan blue.
  • Test compounds are made up as stock solutions in methyl sulfoxide (DMSO), then diluted m medium and 50 ⁇ L/well added, such that the final concentration of DMSO in the assay is below 0.05%
  • DMSO methyl sulfoxide
  • the plates are incubated at 37 °C with 5% C0 2 for 48 hours. After 48 hours, the cells are pulsed with 1 ⁇ Ci/well of methyl- 3 H- thymidine (commercially available from Amersham, Buckinghamshire, England) and incubated an additional 24 hours.
  • the cells are harvested onto GF/C filter plates (commercially available from Packard, Downers Grove, IL), solubilized in Microscmt 20 (Packard), and counted on a TopCount microplate scintillation and luminescence plate counter (Packard). Activity is measured as a percentage of control activity in the absence of test compound and plotted versus test compound concentration. The data are fit to a 4-parameter curve fit (Sigmaplot) and IC50 values are calculated.
  • GF/C filter plates commercially available from Packard, Downers Grove, IL
  • Microscmt 20 Packard
  • Activity is measured as a percentage of control activity in the absence of test compound and plotted versus test compound concentration.
  • the data are fit to a 4-parameter curve fit (Sigmaplot) and IC50 values are calculated.
  • test compounds are considered non-immunosuppressive if, by using this method, the ratio of (cyclospo ⁇ n A IC 5 Jtest compound IC 50 ) x 100 is less than or equal to 0.02, 1 e , as defined herein, a non-immunosuppressive test compound has ⁇ 2% of the immunosuppressive activity of cyclosporm A.
  • MTT 3-[4,5-d ⁇ methyl-th ⁇ azoyl-2-yl]2,5-d ⁇ phenyl- tetrazohum bromide
  • MTT 3-[4,5-d ⁇ methyl-th ⁇ azoyl-2-yl]2,5-d ⁇ phenyl- tetrazohum bromide
  • the assay is carried out in serum-free, phenol red-free RPMI 1640 and the dye is solubilized m 100 ⁇ L/well DMSO and read at an OD of 540 nm with a background correction at 650 nm on a SpectraMax Plus microplate reader (Molecular Devices, Menlo Park, CA).
  • the compounds used in the methods of the present invention are prepared according to procedures which are well-known to those skilled in the art.
  • the starting materials used in preparing the compounds are known, made by known methods, or are commercially available as a starting mate ⁇ al
  • the compounds of the present invention may have one or more chiral centers.
  • one optical isomer including diastereomers and enantiomers
  • another optical starting materials for example by chiral starting materials, catalysts or solvents
  • both stereoisomers or both optical isomers including diastereomers and enantiomers at once (a racemic mixture).
  • the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, may be separated using known methods, such as through the use of, for example, chiral salts and chiral chromatography.
  • one optical isomer including a diastereomer and enantiomer, or a stereoisomer
  • both optical isomers including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
  • the mixture is stirred at 5 °C for 1 hour followed by addition of a solution of sodium thiosulfate (5.53 g, 35 mmol), sodium bicarbonate (5.03 g, 60 mmol) and water (100 mL).
  • the resulting mixture is stirred rapidly for 20 minutes while warming from 5 °C to ambient temperature.
  • the mixture is extracted with dichloromethane (3 x 75 mL), then the combined organic extracts are dried (MgS0 4 ), filtered, and concentrated under reduced pressure
  • the resulting residue is purified via preparative chromatography (silica gel; water saturated ethyl acetate) to afford the desired (3'-keto)cyclospo ⁇ n A.
  • Cyclosporm A (N 5 - 1-propenyl) Cyclosporm A: Cyclosporm A (2 g, 1.66 mmol; commercially available from Alexis Corporation, San Diego, CA) is dissolved in tetrahydrofuran (40 mL) at ambient temperature under inert atmosphere. The reaction solution is cooled to -78 °C and IN phosphazene base P4-t-butyl solution (8.4 mL, 8.32 mmol; commercially available from Fluka Chemika AG, Buchs, Switzerland) is added dropwise over 5 minutes. The solution is stirred an additional 5 minutes at -78 °C followed by the dropwise addition of allyl bromide (1.16 mL, 13.3 mmol) over 1 minute.
  • the methods of the present invention are performed by administration of a compound having a structure as described herein and, preferably, a pharmaceutically-acceptable or cosmetically-acceptable carrier
  • the compounds herein may be used for the treatment of such conditions as treating hair loss m mammals, including arresting and / or reversing hair loss and promoting hair growth. Such conditions may manifest themselves in, for example, alopecia, including male pattern baldness and female pattern baldness
  • the compounds of the present invention are, as defined herein, non-immunosuppressive.
  • the compounds are formulated into pharmaceutical or cosmetic compositions for use in treatment or prophylaxis of conditions such as the foregoing Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, PA (1990).
  • a compound having a structure as described herein is administered per day for systemic administration
  • these dosage ranges are by way of example only, and that daily administration can be adjusted depending on various factors.
  • the specific dosage of the compound to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic are interdependent.
  • the dosage and treatment regimen will also depend upon such factors as the specific compound used, the treatment indication, the efficacy of the compound, the personal attributes of the subject (such as, for example, weight, age, sex, and medical condition of the subject), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment.
  • the subject compounds are co-admmistered with a pharmaceutically-acceptable or cosmetically-acceptable carrier (herein collectively described as “carrier”).
  • carrier means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a mammal.
  • compatible means that the components of the composition are capable of being commingled with a compound of the present invention, and with each other, in a manner such that there is no interaction which would substantially reduce the efficacy of the composition under ordinary use situations
  • Carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal, preferably mammal (most preferably human), bemg treated.
  • the carrier can itself be inert or it can possess pharmaceutical and / or cosmetic benefits of its own.
  • compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration.
  • topical and / or oral administration are especially prefe ⁇ ed with topical being most prefe ⁇ ed.
  • carriers well- known in the art may be used These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active or cosmetically-active materials may be included which do not substantially interfere with the activity of the compound of the present invention The amount of earner employed m conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • substances which can serve as carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch, cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; algmic acid; emulsifiers, such as the TWEENS, wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tabletmg agents, stabilizers; antioxidants; preservatives; pyrogen-free water; lsototol
  • a carrier to be used in conjunction with the subject compound is typically determined by the way the compound is to be administered.
  • carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, lsotomc saline, and pyrogen-free water.
  • Prefe ⁇ ed ca ⁇ iers for parenteral administration include propylene glycol, ethyl oleate, py ⁇ ohdone, ethanol, and sesame oil.
  • the ca ⁇ ier, in compositions for parenteral administration comprises at least about 90% by weight of the total composition.
  • oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of a compound used in the present invention Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- mducmg agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • the ca ⁇ iers suitable for the preparation of unit dosage forms for oral administration are well-known m the art Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; dismtegrants such as starch, algmic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc Ghdants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance.
  • inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose
  • binders such as starch, gelatin and sucrose
  • dismtegrants such as starch, algmic acid and croscarmelose
  • lubricants such as magnesium ste
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets
  • Capsules typically comprise one or more solid diluents disclosed above. The selection of ca ⁇ ier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art.
  • compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like.
  • the ca ⁇ iers suitable for preparation of such compositions are well known m the art.
  • Typical components of ca ⁇ iers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released m the gastrointestinal tract m the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvmylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • compositions useful for attaining systemic delivery of the subject compounds include subhngual, buccal and nasal dosage forms
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalhne cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose Ghdants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • the compounds of the present invention may also be topically administered.
  • the ca ⁇ ier of the topical composition preferably aids penetration of the present compounds into the skm to reach the environment of the hair follicle.
  • Topical compositions of the present invention may be in any form including, for example, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skm patches, and the like.
  • Topical compositions containing the active compound can be admixed with a variety of ca ⁇ ier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantom, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 my ⁇ styl propionate, and the like. 24
  • compositions suitable for use in topical ca ⁇ iers include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows:
  • Emollients such as stearyl alcohol, glyceryl mono ⁇ cinoleate, glyceryl monostearate, propane- 1,2-d ⁇ ol, butane- 1, 3 -diol, mink oil, cetyl alcohol, zs ⁇ -propyl isostearate, stearic acid, iso- butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-w-butyl sebacate, iso- propyl my ⁇ state, zso-propyl palmitate, wo-propyl stearate, butyl stearate, polythylene glycol, t ⁇ ethylene glycol, lanolm, sesame oil, coconut oil, arachis oil, cast
  • the compounds used in the present invention may also be administered in the form of posome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phosphohpids, such as cholesterol, stearylamme or phosphatidylcholines.
  • a prefe ⁇ ed formulation for topical delivery of the present compounds utilizes liposomes such as described m Dowton et al, "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporm A I. An in vitro Study Using Hairless Mouse Skin", S.T P. Pharma Sciences. Vol.
  • the compounds of the present invention may also be administered by iontophoresis. See, e.g.. internet site www.unipr ⁇ t/a ⁇ a/d ⁇ pfarm erasmus/erasml4.html, Banga et al, "Hydrogel- based Iontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protem Drugs", Pharm. Res., Vol. 10 (5), pp. 697-702 (1993); Ferry. "Theoretical Model of Iontophoresis Utilized m Transdermal Drug Delivery", Pharmaceutical Ada Helvetiae, Vol 70, pp. 279-287 (1995); Gangarosa et al.
  • compositions of the present invention may also optionally comprise an activity enhancer.
  • the activity enhancer can be chosen from a wide variety of molecules which can function in different ways to enhance hair growth effects of a compound of the present invention.
  • Particular classes of activity enhancers include other hair growth stimulants and penetration enhancers.
  • Additional hair growth stimulants can be chosen from a wide variety of molecules which can function in different ways to enhance the hair growth effects of a compound of the present invention. These optional other hair growth stimulants, when present, are typically employed in the compositions herein at a level ranging from about 0.01% to about 15%, preferably from about 0.1% to about 10%, most preferably from about 0.5% to about 5% by weight of the composition.
  • Vasodilators such as potassium channel agonists including, for example, mmoxidil and mmoxidil derivatives such as aminexil and such as those described m U.S. Patent 3,382,247, U.S. Patent 5,756,092, issued May 26, 1998, U.S. Patent 5,772,990, issued June 30, 1998, U.S. Patent 5,760,043, issued June 2, 1998, U S. Patent 328,914, issued July 12, 1994, U.S. Patent 5,466,694, issued November 14, 1995, 5,438,058, issued August 1, 1995, and U.S. Patent 4,973,474, issued November 27, 1990, (all of which are herein incorporated by reference), and cromakalm and diazoxide can be used as an additional hair growth stimulant in the compositions herein.
  • antiandrogens include, but are not limited 5- ⁇ -reductase inhibitors such as fmasteride and those described in U.S. Patent 5,516,779, issued May 14, 1996 (herein incorporated by reference) and in Nane et al, Cancer Research 58. "Effects of Some Novel Inhibitors of 07,20-Lyase and 5 ⁇ -Reductase in vitro and in vivo and Their Potential Role in the Treatment of Prostate Cancer ' as well as cyproterone acetate, azelaic acid and its derivatives and those compounds described in U.S.
  • FK506 analogs such as those described in Mclver et al. U.S. Patent Application Serial No. 09/400,681, filed September 21, 1999; Mclver et al. U.S. Patent Application Serial No. 09/400,682, filed September 21, 1999; Mclver et al. U.S. Patent Application Serial No. 09/400,679, filed September 21, 1999; Tiesman et al. U.S. Patent Application Serial No. 09/400,021, filed September 21, 1999; Fulmer et al. U.S. Patent Application Serial No. 09/400,425, filed September 21, 1999; U.S. Provisional Patent Application No.
  • Another suitable class of optional hair growth stimulants are antimicrobials such as selenium sulfide, ketoconazole, t ⁇ clocarbon, t ⁇ closan, zmc py ⁇ thione, ltraconazole, asiatic acid, hmokitiol, mipirocm and those described in EPA 0,680,745 (herein incorporated by reference), clmacycm hydrochlo ⁇ de, benzoyl peroxide, benzyl peroxide and minocyclm
  • antimicrobials such as selenium sulfide, ketoconazole, t ⁇ clocarbon, t ⁇ closan, zmc py ⁇ thione, ltraconazole, asiatic acid, hmokitiol, mipirocm and those described in EPA 0,680,745 (herein incorporated by reference), clmacycm hydrochlo ⁇ de, benzoyl peroxide, benzyl peroxid
  • Anti-inflammato ⁇ es can also be incorporated into the compositions herein as an optional hair growth stimulant
  • suitable anti-mflammato ⁇ es may include glucocorticoids such as hydrocortisone, mometasone furoate and predmsolone, nonsteroidal anti-mflammato ⁇ es including cyclooxygenase or hpoxygenase inhibitors such as those described in U S Patent 5,756,092, and benzydamine, salicylic acid, and those compounds described in EPA 0,770,399, published May 2, 1997, WO 94/06434, published March 31, 1994, and FR 2,268,523, published November 21, 1975, all of which are herein incorporated by reference.
  • thyroid hormones and derivatives and analogs thereof are thyroid hormones and derivatives and analogs thereof.
  • suitable thyroid hormones for use herein may include t ⁇ iodothy ⁇ onme.
  • suitable thyroid hormone analogs which may be suitable for use herein include those described in U.S. Provisional Patent Application No. 60/136,996, Zhang et al, filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,024, Zhang et al, filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,022, Zhang et al, filed June 1, 1999, U S. Provisional Patent Application No. 60/137,023, Zhang et al, filed June 1, 1999, U.S. Provisional Patent Application No.
  • Prostaglandm agonists or antagonists can also be used as optional hair growth stimulants m the compositions herein.
  • suitable prostaglandms agonists or antagonists include latanoprost and those desc ⁇ bed in WO 98/33497, Johnstone, published August 6, 1998, WO 95/11003, Stjernschantz, published April 27, 1995, JP 97-100091, Ueno and JP 96-134242, Nakamura.
  • Suitable retmoids may include isotretmoin, acitretm, and tazarotene.
  • t ⁇ terpenes such as, for example, those disclosed m Bradbury et al, U.S. Patent Application Serial No. 09/353,408, “Method for Regulating Hair Growth", filed July 15, 1999 and Bradbury et al, U.S. Patent Application Serial No. 09/353,409, “Compositions Which Contain T ⁇ terpenes for Regulating Hair Growth", filed July 15, 1999, each incorporated by reference in their entirety.
  • optional hair growth stimulants for use herein include flavmoids, ascomyc derivatives and analogs, histamme antagonists such as d phenhydramme hydrochloride, other t ⁇ terpenes such as oleanohc acid and ursolic acid and those described m U.S. Patent 5,529,769, JP 10017431, WO 95/35103, U.S Patent 5,468,888, JP 09067253, WO 92/09262, JP 62093215, U.S. Patent 5,631,282, U.S.
  • Patent 5,679,705, JP 08193094, saponms such as those described in EP 0,558,509 to Bonte et al, published September 8, 1993 and WO 97/01346 to Bonte et al, published January 16, 1997 (both of which are herein incorporated by reference in their entirety), proteoglycanase or glycosam oglycanase inhibitors such as those described in U.S. Patents 5,015,470, issued May 14, 1991, U.S. Patent 5,300,284, issued April 5, 1994 and U.S.
  • Non-hmitmg examples of penetration enhancers which may be used in the compositions herein include, for example, 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-d ⁇ ol, POE(2) ethyl ether, d ⁇ (2-hydroxypropyl) ether, pentan-2,4-d ⁇ ol, acetone, POE(2) methyl ether, 2-hydroxyprop ⁇ on ⁇ c acid, 2-hydroxyoctano ⁇ c acid, propan-1-ol, 1,4-d ⁇ oxane, tetrahydrofuran, butan-l,4-d ⁇ ol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropy
  • the compounds of the invention can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.
  • composition Administration do not limit the invention, but provide guidance to the skilled artisan to perform the methods of the present invention.
  • a compound other than the one mentioned may be substituted by another having a structure as described herein.
  • Example A composition for topical administration comprising:
  • a human male subject suffering from male pattern baldness is treated by a method of this invention. Specifically, for 6 weeks, the above composition is daily administered topically to the subject.
  • a composition for topical administration is made according to the method of Dowton et al, "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporm A: I. An in vitro Study Using Hairless Mouse Skm", S.T.P. Pharma Sciences, Vol. 3, pp. 404 - 407 (1993), using the compound of Example 1 in lieu of cyclosporm A and using the Novasome 1 for the non-ionic liposomal formulation.
  • a human male subject suffering from male pattern baldness is treated each day with the above composition. Specifically, for 6 weeks, the above composition is administered topically to the subject.
  • the above shampoo is used daily by the subject.

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Abstract

La présente invention concerne des méthodes de traitement de la chute des cheveux chez les mammifères, lesquelles méthodes permettent de stopper et/ou de contrecarrer la chute des cheveux et de favoriser la pousse des cheveux. Lesdites méthodes consistent à administrer un composé non immunosuppresseur dont la structure figure dans le descriptif, ainsi qu'un vecteur pharmaceutiquement acceptable.
PCT/US2000/005300 1999-03-05 2000-02-29 Methode de traitement de la chute des cheveux au moyen de composes non immunosuppresseurs WO2000051558A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP00917685A EP1161222A1 (fr) 1999-03-05 2000-02-29 Methode de traitement de la chute des cheveux au moyen de composes non immunosuppresseurs
AU38619/00A AU3861900A (en) 1999-03-05 2000-02-29 Method of treating hair loss using non-immunosuppressive compounds
JP2000602029A JP2002538092A (ja) 1999-03-05 2000-02-29 非免疫抑制剤を使用した抜け毛の治療方法
CA002366312A CA2366312A1 (fr) 1999-03-05 2000-02-29 Methode de traitement de la chute des cheveux au moyen de composes non immunosuppresseurs

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US60/122,925 1999-03-05

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1339378A1 (fr) * 2000-11-22 2003-09-03 LG Household & Health Care Ltd. Utilisation de derives de cyclosporine a 7-thioamide pour stimuler la croissance des cheveux
EP1339377A1 (fr) * 2000-11-22 2003-09-03 LG Household & Health Care Ltd. Utilisation du derive 7-thioamide de la cyclosporine pour la croissance capillaire
EP1361850A1 (fr) * 2001-02-14 2003-11-19 LG Household & Health Care Ltd. Utilisation de (gamma-hydroxy-n-methyl-l-leucine9) cyclosporine a pour la croissance des cheveux
EP1387660A1 (fr) * 2001-05-11 2004-02-11 LG Household & Health Care Ltd. Utilisation de derives de la cyclosporine substitue en position 3 pour favoriser la croissance du cheveu
US6987090B2 (en) 2002-05-09 2006-01-17 Lg Household & Health Care Ltd. Use of 3-position cyclosporin derivatives for hair growth
US9072696B2 (en) 2012-09-29 2015-07-07 Novartis Ag Cyclic peptides and use as medicines

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5807820A (en) * 1988-05-13 1998-09-15 Novartis Ag Cyclosporin compositions for topical application

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5807820A (en) * 1988-05-13 1998-09-15 Novartis Ag Cyclosporin compositions for topical application

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1339378A1 (fr) * 2000-11-22 2003-09-03 LG Household & Health Care Ltd. Utilisation de derives de cyclosporine a 7-thioamide pour stimuler la croissance des cheveux
EP1339377A1 (fr) * 2000-11-22 2003-09-03 LG Household & Health Care Ltd. Utilisation du derive 7-thioamide de la cyclosporine pour la croissance capillaire
EP1339378A4 (fr) * 2000-11-22 2004-05-12 Lg Household & Health Care Ltd Utilisation de derives de cyclosporine a 7-thioamide pour stimuler la croissance des cheveux
EP1339377A4 (fr) * 2000-11-22 2004-05-19 Lg Household & Health Care Ltd Utilisation du derive 7-thioamide de la cyclosporine pour la croissance capillaire
EP1361850A1 (fr) * 2001-02-14 2003-11-19 LG Household & Health Care Ltd. Utilisation de (gamma-hydroxy-n-methyl-l-leucine9) cyclosporine a pour la croissance des cheveux
EP1361850A4 (fr) * 2001-02-14 2004-08-04 Lg Household & Health Care Ltd Utilisation de (gamma-hydroxy-n-methyl-l-leucine9) cyclosporine a pour la croissance des cheveux
US6762164B2 (en) 2001-05-11 2004-07-13 Lg Household & Health Care Ltd. Use of 3-position cyclosporin derivatives for hair growth
EP1387660A1 (fr) * 2001-05-11 2004-02-11 LG Household & Health Care Ltd. Utilisation de derives de la cyclosporine substitue en position 3 pour favoriser la croissance du cheveu
US6790830B2 (en) 2001-05-11 2004-09-14 Lg Household & Health Care Ltd. Use of 3-position cyclosporin derivatives for hair growth
EP1387660A4 (fr) * 2001-05-11 2006-05-17 Lg Household & Health Care Ltd Utilisation de derives de la cyclosporine substitue en position 3 pour favoriser la croissance du cheveu
US6987090B2 (en) 2002-05-09 2006-01-17 Lg Household & Health Care Ltd. Use of 3-position cyclosporin derivatives for hair growth
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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