WO2000018361A2 - Procede de traitement de la chute de cheveux par administration de sulfonamides - Google Patents

Procede de traitement de la chute de cheveux par administration de sulfonamides Download PDF

Info

Publication number
WO2000018361A2
WO2000018361A2 PCT/US1999/022214 US9922214W WO0018361A2 WO 2000018361 A2 WO2000018361 A2 WO 2000018361A2 US 9922214 W US9922214 W US 9922214W WO 0018361 A2 WO0018361 A2 WO 0018361A2
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
alkyl
group
alkenyl
hydrogen
Prior art date
Application number
PCT/US1999/022214
Other languages
English (en)
Other versions
WO2000018361A3 (fr
Inventor
Jay Patrick Tiesman
Andrew Wayne Fulmer
John Mcmillan Mciver
Charles Raymond Degenhardt
David Joseph Eickhoff
Original Assignee
The Procter & Gamble Company
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 The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to EP99969667A priority Critical patent/EP1117372A2/fr
Priority to BR9914196-5A priority patent/BR9914196A/pt
Priority to JP2000571883A priority patent/JP2002525305A/ja
Priority to AU60601/99A priority patent/AU6060199A/en
Publication of WO2000018361A2 publication Critical patent/WO2000018361A2/fr
Publication of WO2000018361A3 publication Critical patent/WO2000018361A3/fr

Links

Classifications

    • 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
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • 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
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • 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 m 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. Such baldness is cosmetically unappealing, and is particularly distressing to the person expe ⁇ encmg the hair loss.
  • 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 charactenzed by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair.
  • catagen is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased.
  • telogen is often characterized as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells.
  • the initiation of a new anagen phase is caused by rapid cell proliferation in the germ, expansion of the dermal papilla, and elaboration of basement membrane components. This cycle is repeated throughout hair growth. Wherein hair growth ceases, most of the hair follicles reside in telogen and anagen is not engaged, thus causing the onset of full or partial baldness.
  • Propecia ® may be more effective than Rogaine ®
  • patients using Propecia ® are experiencing limited hair growth.
  • potential side effects of Propecia ® are serious.
  • Propecia ® may cause impotence, decreased sexual drive, decreased volume of ejaculate, breast tenderness and enlargement, and hypersensitivity reactions, including lip swelling and skin rash.
  • Propecia ® is not indicated for women and children. In fact, women who are pregnant or potentially pregnant should not even handle crushed or broken tablets containing the drug. See Physician's Desk Reference ® . 52 th Ed. (1998), p. 1737 and The New England Journal of Medicine, Vol. 338, No.
  • FK506 is a complex, macrocyclic molecule having the following structure:
  • WO 96/36630 assigned to Vertex Pharmaceuticals, Inc., published November 21, 1996; Armistead et a , WO 97/36869, assigned to Vertex Pharmaceuticals, Inc., published October 9, 1997; Zelle et ah, WO 96/15101, assigned to Vertex Pharmaceuticals, Inc., published May 23, 1996; Armistead et al.. WO 92/19593, assigned to Vertex Pharmaceuticals, Inc., published November 12, 1992; Armistead et al.. WO 94/07858, assigned to Vertex Pharmaceuticals, Inc., published April 14, 1994; Zelle et al.. WO 95/26337, assigned to Vertex Pharmaceuticals, Inc., published October 5, 1995; Duffy et al..
  • the present inventors have discovered a class of compounds which arrest and / or reverse hair loss or promote hair growth but do not share the complex, macrocyclic structure of FK506.
  • the present inventors have further discovered compounds among this class which invoke hair growth yet are surprisingly non-immunosuppressive or are nominally immunosuppressive.
  • the minimized and / or absent immunosuppressive activity of these hypertrichotic compounds are distinct advantages as compared to the immunosuppressive compounds cyclosporin A and FK506.
  • the present inventors therefore provide methods of treating hair loss by administering compositions comprising the compounds described herein.
  • the present invention relates to methods for treating hair loss comprising administering compounds which have 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 in the present method have the structure:
  • the present invention relates to methods of using compounds and compositions which are particularly useful for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth.
  • the present inventors have also surprisingly discovered that immunosuppression 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.
  • Preferred compounds useful in the method of the present invention are therefore, as defined herein, non- immunosuppressive .
  • Publications and patents are referred to throughout this disclosure. All references cited herein are hereby incorporated by reference.
  • 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 halides (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 olef ⁇ nic double bond. Unless otherwise specified, alkenyls have from 2 to about 15 carbon atoms (C, - 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 about 2 to about 6 carbon atoms (C 2 - C 6 ).
  • Non-limiting 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. Examples of alkoxy radicals include -O-alkyl and -O-alkenyl..
  • alkyl is a saturated hydrocarbon chain radical. Unless otherwise specified, alkyls have from 1 to about 15 carbon atoms ( - C 15 ); preferably from 1 to about 10 carbon atoms (C, - C, 0 ); more preferably from 1 to about 6 carbon atoms ( - C 6 ); and most preferably from 1 to about 4 carbon atoms (C, - C 4 ).
  • alkyls include, for example, methyl, ethyl, propyl, is ⁇ -propyl, and butyl.
  • alkylene refers to an alkyl, alkenyl, or alkynyl which is a diradical.
  • methylene is -CH2-.
  • 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 about 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 imides are imides 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.
  • “carbocyclic ring”, “carbocycle”, or the like is a hydrocarbon ring radical.
  • Carbocyclic rings are monocyclic or are fused, bridged, or spiro polycyclic rings. Unless otherwise specified, monocyclic rings contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms.
  • Polycyclic rings contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms.
  • cycloalkyl is a saturated carbocyclic or heterocyclic ring radical.
  • Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and cyclohexyl.
  • heteroalkenyl is an alkenyl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen.
  • heteroalkyl is an alkyl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen.
  • heterocyclic ring is a ring radical comprised of carbon atoms and one or more heteroatoms in the ring wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen.
  • Heterocycles are monocyclic or are fused, bridged, or spiro polycyclic rings.
  • monocycles contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms.
  • Polycycles contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms.
  • Heterocyclic rings may be substituted or unsubstituted.
  • a “lower” moiety is 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 site(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.
  • any 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.
  • Methods of the Present Invention relates to methods of treating hair loss comprising administering a composition comprising: (a) a compound having the structure:
  • Q is a first heteroatom, wherein the first heteroatom is nitrogen;
  • G is selected from - C 6 alkyl, - C 6 alkenyl, C 5 - C 7 cycloalkyl, C 5 - C 7 cycloalkenyl substituted with C] - C 4 alkyl, C 5 - C 7 cycloalkenyl substituted with C 2 - C 4 alkenyl, Ar substituted with alkyl, Ar substituted with alkenyl, and Ar;
  • Ar is selected from phenyl, 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl,
  • J is selected from hydrogen, - C 2 alkyl, and benzyl
  • K is selected from the group consisting of C] - C 4 alkyl, benzyl, and cyclohexylmethyl; or J and K may be bonded together to form a 5-, 6-, or 7-membered heterocyclic ring wherein the ring may optionally contain an additional heteroatom selected from the group consisting of O, S, S(O), and S(0) 2
  • A is selected from CH 2 , O, and NRi, wherein R] is selected from hydrogen and Ci - C 4 alkyl
  • B and D are each, independently, selected from hydrogen, Ar, d - C 6 alkyl,
  • Z is selected from hydrogen, Ci - C 6 alkyl, and C 2 - C 6 alkenyl
  • T is selected from Ar and 5-, 6-, or 7-membered cycloalkyl substituted with at least one substituent selected from hydrogen, hydroxyl, - C 4 alkoxy, and oxo; wherein at least one of B and D is not hydrogen; and (vii) m is an integer from 0 to 3; and (b) a pharmaceutically-acceptable carrier.
  • G moiety is directly attached to the sulfonamide moiety as shown herein.
  • Preferred G moieties include substituted or unsubstituted phenyl, 4-methylphenyl, 2-thienyl, 2,4,6- triisopropylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, methyl, 1-napthyl, 8-quinolyl, l-(5-N,N-dimethylamino)napthyl, 4- methoxyphenyl, 4-iodophenyl, 2,4,6-trimethylphenyl, benzyl, 2-napthyl, 4-nitrophenyl, 3- nitrophenyl, 4-chlorophenyl, and E-styrenyl.
  • the most preferred G moiety is 3,4,5- trimethoxyphenyl .
  • the J and K moieties may be independent of each other having the above described structures or, as stated, may be bonded together to form a 5-, 6-, or 7-membered heterocyclic ring optionally containing an additional heteroatom selected from O, S, S(O), and S(0) 2 .
  • J and K are bonded together to form a 5-, 6-, or 7-membered heterocyclic ring optionally containing an additional heteroatom selected from O, S, S(O), and S(0) 2 .
  • the ring is preferably 5- or 6-membered.
  • the ring preferably does not contain any additional heteroatoms other than the Q nitrogen required at the 1 -position of the cycle as shown herein.
  • A is selected from CH 2 , O, and NR b wherein R, is selected from hydrogen and Ci - C 4 alkyl.
  • R is selected from hydrogen and Ci - C 4 alkyl.
  • A is selected from O and NR].
  • B and D are side chains which are selected from a variety of moieties described herein above.
  • Preferred B moieties are selected from hydrogen, - C 6 alkyl, C] - C 6 alkenyl, 3-(2- pyridyl)propyl, 3-phenylpropyl, 2-phenoxyphenyl, 3-phenoxyphenyl, phenyl, benzyl, 2-(3- pyridyl)ethyl, E-3-[trans-(4-hydroxycyclohexyl)]-2-methyl-prop-2-enyl, E-3-[trans-(4- hydroxycyclohexyl)]-2-methyl-eth-2-enyl, 3-(3-pyridyl)propyl, 2-phenylethyl, 2-(4- methoxyphenyl)ethyl, 3-(N-benzimidazolyl)propyl, 3-(4-methoxyphenyl)propyl, 3-[N-(7- azaindolyl)propyl, 3-(N-purinyl)propyl, 3-(
  • Preferred D moieties are selected from nil, hydrogen, 3-phenylpropyl, 2-phenoxyphenyl, 3-(3-indolyl)-propyl, 2-phenylethyl, 4-phenylbutyl, 3,5-bis(benzyloxy)phenyl, Ci - C 6 alkyl, C] - C 6 alkenyl, phenyl, and 3-(4-methoxyphenyl)propyl.
  • the integer m is from 0 to 3, preferably from 0 to 1.
  • the present invention relates to methods of treating hair loss by administering a compound having a structure as described herein.
  • the preferred compounds are non-immunosuppressive.
  • 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 in 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 in 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 in hair growth experiments, melanogenesis occurs along with hair (fur) growth wherein the topical application of hair growth promoters 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 5 below:
  • 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 skin.
  • the immunosuppression assay herein predicts the immunosuppressive activity of a compound used in the method of the present invention.
  • the assay is performed as follows:
  • Spleens are excised from euthanized (C0 2 asphyxiation) adult male C3H mice ranging m 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). The spleens are then ground up between frosted glass slides and filtered through a sterile screen to remove tissue debris.
  • HBSS Hanks Balanced Salt Solution
  • 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 mm at 20 °C.
  • Splenocytes are resuspended m 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 bovme serum (Gibco-BRL), penicillin (50 U/mL), streptomycin (100 ⁇ g/mL), L-glutamme (2 mM), 2-mercaptoethanol (10 5 M), and N-2-hydroxyethylp ⁇ peraz ⁇ ne-N'-2-ethanesulfon ⁇ c acid (HEPES) (10 mM). The cells are counted and checked for viability using, for example, trypan blue.
  • DMSO methyl sulfoxide
  • the cells are harvested onto GF/C filter plates (commercially available from Packard, Downers Grove, IL), solubilized in Microscint 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
  • Microscint 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 (cyclosporin A IC 50 /test compound IC 50 ) x 100 is less than or equal to 0.02, i.e., a non-immunosuppressive test compound has ⁇ 2% of the immunosuppressive activity of cyclosporin A.
  • MTT 3-[4,5-dimethyl-thiazoyl-2-yl]2,5-diphenyl- tetrazolium bromide
  • MTT 3-[4,5-dimethyl-thiazoyl-2-yl]2,5-diphenyl- tetrazolium bromide
  • the assay is carried out in serum-free, phenol red-free RPMI 1640 and the dye is solubilized in 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 methods 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 material.
  • the compounds of the present invention may have one or more chiral center. As a result, one may selectively prepare one optical isomer, including diastereomers and enantiomers, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers 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 acidic aqueous layer is washed with 100 mL of 4:1 ethe ⁇ ethyl acetate, is basified by the addition of 8 mL of 30% NH 4 OH, and is extracted into ethyl acetate.
  • the combined organic extracts are washed with brine, dried over MgSO 4 , and concentrated to give the free amine.
  • (S)-Boc-Prpecolyl-l,7-d ⁇ phenyl-4-heptanyl ester To a solution of (S)-Boc-L-p ⁇ pecohc acid (164 mg, 0.72 mmol) in 5 mL of dichloromethane at room temperature is added the alcohol 2c (174 mg, 0.65 mmol), EDAC (140 mg, 0.72 mmol), and a catalytic amount of N,N- dimethylaminopyridine. The reaction mixture is stirred at room temperature for 0.5 hours and is then applied directly to a silica gel column. Elution provides the desired ester.
  • Butoxycarbonyl)-pipecolic acid (4.0 g, 17.7 mmol) is dissolved in 160 mL of DMF. 1,7- Diphenyl-4-aminoheptane (4.30 g, 16.1 mmol) and N,N-diisopropylethylamine (4.16 g, 32.2 mmol) are added followed by PyBOP (8.80 g, 16.9 mmol). The reaction is stirred for 18.5 hours at room temperature, then poured onto ice-cold 0.1N HCl (600 mL) and extracted with ethyl acetate (600 mL).
  • the concentrate is poured onto ethyl acetate (300 mL) and washed successively with 0.1 M HCl (100 mL), saturated sodium bicarbonate solution (100 mL), and brine (50 mL).
  • the organic solution is dried over MgS0 4 , filtered, and concentrated in vacuo. Purification of the crude product by preparative chromatography on silica gel affords the desired sulfonamide 3c.
  • the reaction is stirred for 20.5 hours at room temperature, then poured onto ice-cold 0.1N HCl (600 mL) and extracted with ethyl acetate (600 mL). The layers are separated and the organic layer washed successively with brine (100 mL), saturated NaHC0 3 solution (300 mL), and brine (2 x 200 mL). The organic solution is dried over MgS0 4 , filtered, and concentrated under reduced pressure. Purification of the product on silica gel affords the desired amide 4a.
  • pyrrolidine-2(S)-carboxylic acid l,7-diphenyl-4-heptylamide The amide 4a (7.4 g, 16.5 mmol) is taken up in 160 mL of anhydrous dichloromethane. Trifluoroacetic acid (130 mL) is added dropwise over a 5 minute period. After 45 minutes the mixture is cooled in an ice-bath and saturated K 2 CO 3 solution is added until the pH is approximately 8. The mixture is transferred to a separatory funnel containing dichloromethane (300 mL) and water (300 mL) and shaken. The organic layer is washed with water (100 mL) before drying over MgS0 4 . The mixture is filtered and concentrated under reduced pressure to afford the desired amine 4b.
  • N-(3',4'-Dimethoxyphenylsulfonyl)-pyrrolidine-2(S)-carboxylic acid l,7-diphenyl-4- heptylamide The amine 4b (4.38 g, 12.0 mmol) is taken up in anhydrous dichloromethane (100 mL) at room temperature. N,N-diisopropylethylamine (2.6 mL, 15 mmol) is added and the solution is cooled to 5 °C. 3',4'-Dimethoxyphenylsulfonyl chloride (3.5 g, 15 mmol) is added in one portion.
  • 5b. l,7-Diphenyl-4-aminoheptane The reaction mixture of 5a is diluted with methanol (3.2 L) using an addition funnel. Sodium borohydride (83.4 g, 2.2 mol) is added in portions. Upon complete addition the reaction is stirred at room temperature for six hours. The reaction mixture is quenched by a slow addition of water (3.2 L). The mixture is diluted with ether (3.2 L) and water (1.6 L). The ether layer is separated and the aqueous layer is extracted twice with ether (3.2 L x 2). The combined ether extracts are washed once with sodium chloride solution, dried, filtered, and concentrated in vacuo to give the crude product.
  • This product is diluted in ether (1.2 L) and acidified by slow addition of 1M HCl (1.2 L). The mixture stirs for one hour and is concentrated in vacuo. The resulting precipitate is diluted with acetoni rile and is stirred for 16 hours. The desired l,7-Diphenyl-4-aminoheptane 5b is collected by filtration.
  • the method of the present invention is performed by administration of a compound having a structure herein and a pharmaceutically-acceptable carrier.
  • the compounds herein may be used for the treatment of such conditions as treating hair loss in 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 preferred compounds of the present invention are, as defined herein, non-immunosuppressive.
  • the compounds are formulated into pharmaceutical 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. It is understood that 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-administered with a pharmaceutically-acceptable carrier ("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, being treated.
  • the carrier can itself be inert or it can possess pharmaceutical benefits of its own.
  • the 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. Of these, topical or oral administration is especially preferred.
  • a variety of pharmaceutically-acceptable 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 materials may be included, which do not substantially interfere with the activity of the compound of the present invention.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics. Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms. 2 nd Ed., (1976).
  • substances which can serve as pharmaceutically-acceptable 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; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water;
  • 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 of 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-inducing 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 pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for oral administration are well-known in 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
  • 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 carrier 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.
  • Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like.
  • the pharmaceutically-acceptable earners suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers 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 algmate; 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 in the gastrointestinal tract in 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 sub ngual, 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, microcrystallme cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Ghdants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • Topical compositions of the present invention may be m any form including, for example, solutions, creams, ointments, gels, lotions, shampoos, leave- on and nnse-out hair conditioners, milks, cleansers, moistunzers, sprays, skm patches, and the like.
  • Topical compositions containing the active compound can be admixed with a variety of carrier matenals well known m the art, such as, for example, water, alcohols, aloe vera gel, allantom, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 mynstyl propionate, and the like.
  • carrier matenals well known m the art, such as, for example, water, alcohols, aloe vera gel, allantom, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 mynstyl propionate, and the like.
  • мем ⁇ ран ⁇ мм suitable for use m topical carriers include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of matenals, which can be used singly or as mixtures of one or more materials, are as follows:
  • Emollients such as stearyl alcohol, glyceryl mono ⁇ cmoleate, glyceryl monostearate, propane- 1,2-d ⁇ ol, butane- 1,3-d ⁇ ol, mink oil, cetyl alcohol, zs ⁇ -propyl isostearate, steanc acid, iso- butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, iso- propyl myristate, zs ⁇ -propyl palmitate, zso-propyl stearate, butyl stearate, polythylene glycol, tnethylene glycol, lanolin, sesame oil, coconut oil, arachis oil
  • the compounds used in the present invention may also be administered in the form of hposome delivery systems, such as small umlamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • a preferred formulation for topical delivery of the present compounds utilizes liposomes such as described in Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skin", S.T.P. Pharma Sciences. Vol. 3, pp.
  • the compounds of the present invention may also be administered by iontophoresis. See. e.g.. www.unipr.it/arpa/dipfarm/erasmus/erasml4.html, Banga et al., "Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protein Drugs", Pharm. Res.. Vol. 10 (5), pp. 697-702 (1993), Ferry L.L., "Theoretical Model of Iontophoresis Utilized in Transdermal Drug Delivery", Pharmaceutical Acta Helvetiae. Vol 70, pp.
  • 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, minoxidil and minoxidil derivatives such as aminexil and such as those described in 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 4,973,474, issued November 27, 1990 (all of which are herein incorporated by reference), and cromakalin 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 finasteride 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 C17,20-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.
  • Another suitable class of optional hair growth stimulants are immunosuppressants or non-immunosuppressants such as 1) cyclosporin and cyclosporin analogs including those described in U.S. Provisional Patent Application No. 60/122,925, Fulmer et al.. filed March 5, 1999, herein incorporated by reference, and 2) FK506 analogs such as those described in U.S. Provisional Patent Application No. 60/147,279, Degenhardt et al.. filed August 5, 1999; U.S. Provisional Patent Application No. 60/147,313, Degenhardt et al.. filed August 5, 1999; U.S. Provisional Patent Application No. 60/147,280, Degenhardt et al.. filed August 5, 1999; U.S.
  • Another suitable class of optional hair growth stimulants are antimicrobials such as selenium sulfide, ketoconazole, triclocarbon, triclosan, zinc pyrithione, itraconazole, asiatic acid, hinokitiol, mipirocin and those described in EPA 0,680,745 (herein incorporated by reference), clinacycin hydrochloride, benzoyl peroxide, benzyl peroxide and minocyclin.
  • antimicrobials such as selenium sulfide, ketoconazole, triclocarbon, triclosan, zinc pyrithione, itraconazole, asiatic acid, hinokitiol, mipirocin and those described in EPA 0,680,745 (herein incorporated by reference), clinacycin hydrochloride, benzoyl peroxide, benzyl peroxide and minocyclin.
  • Anti-inflammatories can also be incorporated into the compositions herein as an optional hair growth stimulant.
  • suitable anti-inflammatories may include glucocorticoids such as hydrocortisone, mometasone furoate and prednisolone, nonsteroidal anti-inflammatories including cyclooxygenase or lipoxygenase 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 triiodothyrionine.
  • 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.
  • Prostaglandin agonists or antagonists can also be used as optional hair growth stimulants in the compositions herein.
  • suitable prostaglandins agonists or antagonists include latanoprost and those described in WO 98/33497, Johnstone, published August 6, 1998, WO 95/11003, Stjemschantz, published April 27, 1995, JP 97-100091, Ueno and JP 96-134242, Nakamura.
  • Suitable retinoids may include isotretinoin, acitretin, and tazarotene.
  • triterpenes such as, for example, those disclosed in 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 Triterpenes for Regulating Hair Growth", filed July 15, 1999, each incorporated by reference in their entirety.
  • optional hair growth stimulants for use herein include flavinoids, ascomycin derivatives and analogs, histamine antagonists such as diphenhydramine hydrochloride, other triterpenes such as oleanolic acid and ursolic acid and those described in 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, saponins 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 glycosaminoglycanase 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.
  • Patent 5,714,515 issued February 3, 1998, EPA 0,319,991, published June 14, 1989, EPA 0,357,630, published October 6, 1988, EPA 0,573,253, published December 8, 1993, JP 61- 260010, published November 18, 1986, U.S. Patent 5,772,990, issued June 30, 1998, U.S. Patent 5,053, 410, issued October 1, 1991, and U.S. Patent 4,761,401, issued August 2, 1988, all of which are herein incorporated by reference.
  • Non-limiting 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-diol, POE(2) ethyl ether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone, POE(2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran, butan-l,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-
  • the compounds used in the present method can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.
  • 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.
  • Example B A composition for topical administration is made according to the method of Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skin", S.T.P. Pharma Sciences. Vol. 3, pp. 404 - 407 (1993), using the compound of Example 1 in lieu of cyclosporin 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne des procédés de traitement de la chute de cheveux chez les mammifères, visant notamment à freiner et/ou stopper la chute de cheveux et à activer leur croissance. Ces procédés reposent sur l'administration d'un composé de structure particulière renfermant un excipient pharmaceutiquement acceptable.
PCT/US1999/022214 1998-09-30 1999-09-24 Procede de traitement de la chute de cheveux par administration de sulfonamides WO2000018361A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP99969667A EP1117372A2 (fr) 1998-09-30 1999-09-24 Procede de traitement de la chute de cheveux par administration de sulfonamides
BR9914196-5A BR9914196A (pt) 1998-09-30 1999-09-24 Processo de tratamento da perda de cabelo
JP2000571883A JP2002525305A (ja) 1998-09-30 1999-09-24 スルホンアミドを用いた脱毛治療の方法
AU60601/99A AU6060199A (en) 1998-09-30 1999-09-24 Method of treating hair loss using sulfonamides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10243798P 1998-09-30 1998-09-30
US60/102,437 1998-09-30

Publications (2)

Publication Number Publication Date
WO2000018361A2 true WO2000018361A2 (fr) 2000-04-06
WO2000018361A3 WO2000018361A3 (fr) 2000-05-25

Family

ID=22289839

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/022214 WO2000018361A2 (fr) 1998-09-30 1999-09-24 Procede de traitement de la chute de cheveux par administration de sulfonamides

Country Status (6)

Country Link
EP (1) EP1117372A2 (fr)
JP (1) JP2002525305A (fr)
CN (1) CN1320028A (fr)
AU (1) AU6060199A (fr)
BR (1) BR9914196A (fr)
WO (1) WO2000018361A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001010837A1 (fr) * 1999-08-05 2001-02-15 The Procter & Gamble Company Sulfonamides multivalents
WO2001010838A1 (fr) * 1999-08-05 2001-02-15 The Procter & Gamble Company Composes multivalents
US6909019B1 (en) 2004-05-25 2005-06-21 Eastman Chemical Company Process for preparing aldehydes

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5815774B2 (ja) * 2014-02-27 2015-11-17 一般社団法人グリーンエバー サルファ剤およびキトサン剤を含む、発毛および／または育毛促進組成物

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006031A1 (fr) * 1993-08-23 1995-03-02 Immunex Corporation Inhibiteurs de la secretion de facteur alpha de necrose tumorale
WO1997020824A1 (fr) * 1995-12-08 1997-06-12 Agouron Pharmaceuticals, Inc. Inhibiteurs de metalloproteinases, compositions pharmaceutiques contenant ces inhibiteurs et leurs utilisations pharmaceutiques, et procedes et intermediaires servant a leur preparation
WO1998008815A1 (fr) * 1996-08-28 1998-03-05 The Procter & Gamble Company Inhibiteurs de metalloproteases a cycle amino substitue
WO1998022432A1 (fr) * 1996-11-18 1998-05-28 Yamanouchi Pharmaceutical Co., Ltd. Derives d'acylanilide a substitution acylamino ou composition comprenant ces derives
WO1998025580A1 (fr) * 1996-12-13 1998-06-18 Handelman, Joseph, H. Moderation de la pousse pileuse
WO1998027069A1 (fr) * 1996-12-17 1998-06-25 Fujisawa Pharmaceutical Co., Ltd. Composes de piperazine inhibiteurs de metalloprotease matricielle (mmp) ou de tnf
WO1998050348A1 (fr) * 1997-05-09 1998-11-12 Agouron Pharmaceuticals, Inc. Inhibiteurs de metalloproteases, compositions pharmaceutiques les contenant et leurs utilisations pharmaceutiques
WO1999006340A2 (fr) * 1997-07-31 1999-02-11 The Procter & Gamble Company Inhibiteurs de metalloprotease acycliques
WO1999062490A1 (fr) * 1998-06-03 1999-12-09 Gpi Nil Holdings, Inc. Compositions pour la croissance des cheveux a base de petites molecules de sulfonamides et utilisation de ces compositions

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006031A1 (fr) * 1993-08-23 1995-03-02 Immunex Corporation Inhibiteurs de la secretion de facteur alpha de necrose tumorale
WO1997020824A1 (fr) * 1995-12-08 1997-06-12 Agouron Pharmaceuticals, Inc. Inhibiteurs de metalloproteinases, compositions pharmaceutiques contenant ces inhibiteurs et leurs utilisations pharmaceutiques, et procedes et intermediaires servant a leur preparation
WO1998008815A1 (fr) * 1996-08-28 1998-03-05 The Procter & Gamble Company Inhibiteurs de metalloproteases a cycle amino substitue
WO1998022432A1 (fr) * 1996-11-18 1998-05-28 Yamanouchi Pharmaceutical Co., Ltd. Derives d'acylanilide a substitution acylamino ou composition comprenant ces derives
WO1998025580A1 (fr) * 1996-12-13 1998-06-18 Handelman, Joseph, H. Moderation de la pousse pileuse
WO1998027069A1 (fr) * 1996-12-17 1998-06-25 Fujisawa Pharmaceutical Co., Ltd. Composes de piperazine inhibiteurs de metalloprotease matricielle (mmp) ou de tnf
WO1998050348A1 (fr) * 1997-05-09 1998-11-12 Agouron Pharmaceuticals, Inc. Inhibiteurs de metalloproteases, compositions pharmaceutiques les contenant et leurs utilisations pharmaceutiques
WO1999006340A2 (fr) * 1997-07-31 1999-02-11 The Procter & Gamble Company Inhibiteurs de metalloprotease acycliques
WO1999062490A1 (fr) * 1998-06-03 1999-12-09 Gpi Nil Holdings, Inc. Compositions pour la croissance des cheveux a base de petites molecules de sulfonamides et utilisation de ces compositions

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001010837A1 (fr) * 1999-08-05 2001-02-15 The Procter & Gamble Company Sulfonamides multivalents
WO2001010838A1 (fr) * 1999-08-05 2001-02-15 The Procter & Gamble Company Composes multivalents
US6909019B1 (en) 2004-05-25 2005-06-21 Eastman Chemical Company Process for preparing aldehydes

Also Published As

Publication number Publication date
EP1117372A2 (fr) 2001-07-25
BR9914196A (pt) 2001-06-19
CN1320028A (zh) 2001-10-31
AU6060199A (en) 2000-04-17
WO2000018361A3 (fr) 2000-05-25
JP2002525305A (ja) 2002-08-13

Similar Documents

Publication Publication Date Title
US6307049B1 (en) Heterocyclic 2-substituted ketoamides
US6525094B1 (en) Method of treating hair loss using diphenylether derivatives
WO2000018725A1 (fr) Cetoamides 2-substitues
US6300341B1 (en) 2-substituted heterocyclic sulfonamides
WO2000018361A2 (fr) Procede de traitement de la chute de cheveux par administration de sulfonamides
MXPA01012496A (es) Compuestos de biarilo.
US6646005B1 (en) Method of treating hair loss using sulfonyl thyromimetic compounds
US6723717B1 (en) Sulfur-containing thyroxane derivatives and their use as hair growth promotors
MXPA01012492A (es) Metodo para tratar la perdida capilar.
EP1161222A1 (fr) Methode de traitement de la chute des cheveux au moyen de composes non immunosuppresseurs
EP1117371A2 (fr) Methode de traitement de la chute des cheveux au moyen de cetoamides
EP1223809A1 (fr) Methodes de traitement de la chute des cheveux comprenant l'administration d'un compose d'indoline
MXPA01012497A (es) Derivados de tiroxano que contienen azufre y su uso como promotores de crecimiento capilar.
MXPA01003327A (en) Method of treating hair loss using sulfonamides
MXPA01003326A (en) Method of treating hair loss using ketoamides
WO2001010821A1 (fr) Composes diceto exocycliques multivalents
WO2001010838A1 (fr) Composes multivalents
WO2001010839A2 (fr) Cetoamides et amides substitues multivalents
MXPA01003330A (en) 2-substituted ketoamides
MXPA01003329A (en) 2-substituted heterocyclic sulfonamides
WO2001010837A1 (fr) Sulfonamides multivalents
MXPA01003331A (en) Heterocyclic 2-substituted ketoamides useful for treating hair loss in mammals
WO2001010836A1 (fr) Procede de traitement de la perte de cheveux a l'aide de cetoamides et d'amides multivalents

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 99811573.8

Country of ref document: CN

AK Designated states

Kind code of ref document: A2

Designated state(s): AU BR CA CN JP MX

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

AK Designated states

Kind code of ref document: A3

Designated state(s): AU BR CA CN JP MX

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase in:

Ref document number: 2000 571883

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/2001/003327

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 1999969667

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1999969667

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1999969667

Country of ref document: EP