WO1999062483A1 - Compositions pour la croissance des cheveux a base de derives d'acide pipecolique et utilisation de ces compositions - Google Patents

Compositions pour la croissance des cheveux a base de derives d'acide pipecolique et utilisation de ces compositions Download PDF

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Publication number
WO1999062483A1
WO1999062483A1 PCT/US1998/011242 US9811242W WO9962483A1 WO 1999062483 A1 WO1999062483 A1 WO 1999062483A1 US 9811242 W US9811242 W US 9811242W WO 9962483 A1 WO9962483 A1 WO 9962483A1
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WO
WIPO (PCT)
Prior art keywords
piperidinecarboxylate
dimethyl
oxopentanoyl
oxoacetyl
ethyl
Prior art date
Application number
PCT/US1998/011242
Other languages
English (en)
Inventor
Gregory S. Hamilton
Joseph P. Steiner
Original Assignee
Gpi Nil Holdings, Inc.
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 Gpi Nil Holdings, Inc. filed Critical Gpi Nil Holdings, Inc.
Priority to PCT/US1998/011242 priority Critical patent/WO1999062483A1/fr
Priority to CA002333698A priority patent/CA2333698A1/fr
Priority to JP2000551739A priority patent/JP2002516839A/ja
Priority to EP98925152A priority patent/EP1083872A1/fr
Priority to AU77167/98A priority patent/AU761083B2/en
Publication of WO1999062483A1 publication Critical patent/WO1999062483A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using pipecolic acid derivatives.
  • Hair loss occurs in a variety of situations. These situations include male pattern alopecia, alopecia senilis, alopecia areata, diseases accompanied by basic skin lesions or tumors, and systematic disorders such as nutritional disorders and internal secretion disorders.
  • the mechanisms causing hair loss are very complicated, but in some instances can be attributed to aging, genetic disposition, the activation of male hormones, the loss of blood supply to hair follicles, and scalp abnormalities.
  • the immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell specific immunosuppressants, and are effective against graft rejection after organ transplantation. It has been reported that topical, but not oral, application of FK506 (Yamamoto et al . , J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al . , J. Invest. Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al . , J. Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth in a dose-dependent manner.
  • alopecia areata One form of hair loss, alopecia areata, is known to be associated with autoimmune activities; hence, topically administered immunomodulatory compounds are expected to demonstrate efficacy for treating that type of hair loss.
  • the hair growth stimulating effects of FK506 have been the subject of an international patent filing covering FK506 and structures related thereto for hair growth stimulation (Honbo et al . , EP 0 423 714 A2) .
  • Honbo et al discloses the use of relatively large tricyclic compounds, known for their immunosuppressive effects, as hair revitalizing agents.
  • FK50 and related agents are disclosed in many U.S. patents (Goulet et al . , U.S. Patent No. 5,258,389; uly et al . , U.S. Patent No. 5,457,111; Goulet et al . , U.S. Patent No. 5,532,248; Goulet et al . , U.S. Patent No. 5,189,042; and Ok et al . , U.S. Patent No. 5,208,241; Rupprecht et al . , U.S. Patent No. 5,284,840; Organ et al . , U.S. Patent No. 5,284,877).
  • immunosuppressive compounds by definition suppress the immune system and also exhibit other toxic side effects. Accordingly, there is a need for non-immunosuppressant , small molecule compounds which are useful as hair revitalizing compounds .
  • the present invention relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a pipecolic acid derivative.
  • the present invention further relates to a pharmaceutical composition which comprises : (i) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition which comprises : (i) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
  • the pipecolic acid derivatives used in the inventive methods and pharmaceutical compositions include immunosuppressive and non-immunosuppressive compounds having an affinity for FKBP-type immunophilins, particularly FKBP12.
  • Non- immunosuppressive compounds as their name suggests, do not exert any significant immunosuppressive activity.
  • FIG. 1 is a photograph of mice treated with a vehicle after six weeks.
  • FIG. 1 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered.
  • FIG. 2 is a photograph of mice treated with 10 ⁇ M of a pipecolic acid derivative, GPI 1116, after six weeks.
  • FIG. 2 shows that 90% of the shaved area is covered with new hair growth when GPI 1116 is administered.
  • FIG. 3 is a photograph of mice treated with 3 ⁇ M of a pipecolic acid derivative, GPI 1102, after six weeks.
  • FIG. 3 shows that 90% of the shaved area is covered with new hair growth when GPI 1102 is administered.
  • FIG. 4 is a bar graph plotting the hair growth scores of unshaven animals and shaven animals treated with a vehicle, GPI 1116 (1 ⁇ M and 10 ⁇ M) , GPI 1102 (1 ⁇ M and 3 ⁇ M) , and a related pipecolic acid derivative neuroimmunophilin FKBP ligand, GPI 1044 (1 ⁇ M, 3 ⁇ M and 10 ⁇ M) .
  • FIG. 5 is a bar graph depicting the relative hair growth indices for C57 Black 6 mice treated with a vehicle, FK506, related neuroimmunophilin FKBP ligand GPI 1206, and GPI 1116, 14 days after treatment with each identified compound.
  • Figure 5 demonstrates the remarkable early hair growth promoted by neuroimmunophilin FKBP ligands. DETAILED DESCRIPTION OF THE INVENTION Definitions
  • Alopecia refers to deficient hair growth and partial or complete loss of hair, including without limitation androgenic alopecia (male pattern baldness) , toxic alopecia, alopecia senilis, alopecia areata, alopecia pelada and trichotillomania .
  • Alopecia results when the pilar cycle is disturbed. The most frequent phenomenon is a shortening of the hair growth or anagen phase due to cessation of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles are detached from the dermal papillae, and the hairs fall out.
  • Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental stresses, hormonal problems, and secondary effects of drugs.
  • B is 3 -Phenylpropyl
  • D is 3 -Phenylpropyl
  • L is Phenyl .
  • GPI 1102 refers to Compound 98, 4 -phenyl -1- (3 - phenylpropyl) butyl 1- (3 , 3 -dimethyl - 2 -oxopentanoyl) -2- piperidinecarboxylate .
  • GPI 1116 refers to Compound 103, l-phenethyl-3- phenylpropyl 1- (3 , 3 -dimethyl-2 -oxopentanoyl) -2- piperidinecarboxylate .
  • GPI 1206 refers to a compound of formula
  • “Isomers” refer to different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. "Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. “Diastereoisomers” are stereoisomers which are not mirror images of each other. “Racemic mixture” means a mixture containing equal parts of individual enantiomers. “Non-racemic mixture” is a mixture containing unequal parts of individual enantiomers or stereoisomers.
  • “Pharmaceutically acceptable salt, ester, or solvate” refers to a salt, ester, or solvate of a subject compound which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable.
  • a salt, ester, or solvate can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, c amphor sul f ona t e , cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulf onate , lac
  • base salts, esters, or solvates include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts; N-methyl-D-glucamine; and salts with amino acids, such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups can be quarternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl , and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides; and others. Water or oil-soluble or dispersible products are thereby obtained.
  • "Pilar cycle” refers to the life cycle of hair follicles, and includes three phases:
  • the catagen phase the period when growth stops and the follicle atrophies which, insofar as scalp hair is concerned, lasts about one to two weeks ; and (3) the telogen phase, the rest period when hair progressively separates and finally falls out which, insofar as scalp hair is concerned, lasts about three to four months.
  • telogen phase hair is uniform in diameter with a slightly bulbous, non-pigmented root.
  • anagen phase hair has a large colored bulb at its root.
  • “Promoting hair growth” refers to maintaining, inducing, stimulating, accelerating, or revitalizing the germination of hair.
  • Treating alopecia refers to: (i) preventing alopecia in an animal which may be predisposed to alopecia; and/or
  • Terminal hair is coarse, pigmented, long hair in which the bulb of the hair follicle is seated deep in the dermis .
  • Vellus hair is fine, thin, non-pigmented short hair in which the hair bulb is located superficially in the dermis. As alopecia progresses, the hairs change from the terminal to the vellus type.
  • the present invention relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a pipecolic acid derivative.
  • the inventive method is particularly useful for treating male pattern alopecia, alopecia senilis, alopecia areata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapy such as chemotherapy and radiation, and alopecia resulting from systematic disorders such as nutritional disorders and internal secretion disorders.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: (i) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
  • the pipecolic acid derivatives used in the methods and pharmaceutical compositions of the present invention have an affinity for FKBP-type immunophilins, such as FKBP12.
  • FKBP-type immunophilins such as FKBP12.
  • a pipecolic acid derivative binds to an FKBP-type immunophilin, it has been found to inhibit the prolyl-peptidyl cis- trans isomerase, or rotamase, activity of the binding protein.
  • the compounds have also been found to stimulate hair growth.
  • These rotamase inhibiting compounds may be immunosuppressive or non- immunosuppressive . Examples of useful compounds are set forth below.
  • R 2 Phe-o- tert-butyl
  • R 3 Val-O- ert-butyl
  • R 3 Leu-O- tert-butyl
  • R 3 hexahydro-Phe-O- ert- butyl
  • R 3 allylalanine-O- tert- butyl
  • R 3 CH 2 OMe
  • COMPOUNDS 89-110 Additional exemplary pipecolic acid derivatives are represented by Formulas XXI -XXV and Tables XXI- XXV.
  • Formulas I -XXV are used in the pharmeceutical compositions and methods of the present invention.
  • FKBP12 Affinity for FKBP12
  • the compounds used in the inventive methods and pharmaceutical compositions have an affinity for the FK506 binding protein, particularly FKBP12.
  • the inhibition of the prolyl peptidyl cis - trans isomerase activity of FKBP may be measured as an indicator of this affinity.
  • the cis- trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe- p-nitroanilide is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases para- nitroanilide from the trans form of the substrate.
  • the inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change in first-order rate constant as a function of inhibitor concentration to yield the apparent K ⁇ values.
  • a plastic cuvette In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCI) , 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCI, 1 mM dithiothreitol) , 25 mL of chymotrypsin (50 mg/ml in 1 mM HCl) and 10 mL of test compound at various concentrations in dimethyl sulfoxide.
  • the reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL in 2.35 mM LiCl in trifluoroethanol) .
  • the compounds used in the inventive methods and pharmaceutical compositions must readily affect the targeted areas.
  • the compounds are preferably administered topically to the skin.
  • the compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Dosage levels on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg.
  • the specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration.
  • vi tro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art.
  • the compounds can be administered with other hair revitalizing agents. Specific dose levels for the other hair revitalizing agents will depend upon the factors previously stated and the effectiveness of the drug combination.
  • C57 black 6 mice were used to demonstrate the hair revitalizing properties of pipecolic acid derivatives GPI 1116 and GPI 1102, as well as related pipecolic acid derivative neuroimmunophilin FKBP ligand GPI 1044.
  • C57 black 6 mice approximately 7 weeks old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlaying dermal layers.
  • the animals were in anagen growth phase, as indicated by the pinkish color of the skin.
  • four animals were treated by topical administration with 20% propylene glycol vehicle (FIG. 1)
  • seven animals per group were treated by topical administration with 10 ⁇ M GPI 1116 (FIG. 2)
  • 3 ⁇ M GPI 1102 FIG. 3
  • the animals were treated with vehicle, GPI 1116, or GPI 1102 every 48 hours (3 applications total over the course of 5 days) and the hair growth was allowed to proceed for 6 weeks. Hair growth was quantitated by the percent of shaved area covered by new hair growth during this time period.
  • FIG. 1 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth.
  • FIGS. 2 and 3 show that animals treated with 10 ⁇ M GPI 1116 and 3 ⁇ M GPI 1102 exhibited dramatic hair growth, covering as much as 50% of the shaved area in some animals.
  • FIG. 1 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth.
  • FIGS. 2 and 3 show that animals treated with 10 ⁇ M GPI 1116 and 3 ⁇ M GPI 1102 exhibited dramatic hair growth, covering as much as 50% of the shaved area in some animals.
  • FIG. 1 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth.
  • FIGS. 2 and 3 show that animals treated with 10 ⁇ M
  • the animals were in a anagen growth phase when shaved.
  • Five animals per group were treated by topical administration with a vehicle, FK506, or a neuroimmunophilin FKBP ligand (GPI 1116 or 1206) at a concentration of one micromole per milliliter to the shaved area.
  • the animals were treated three times per week, and hair growth was evaluated 14 days after initiation of treatment. Hair growth was quantitated by the percent of shaved area covered by new hair growth, as scored by a blinded observer, on a scale of 0 (no growth) to five (complete hair regrowth in shaved area) .
  • Figure 5 shows that after 14 days, the animals treated with vehicle exhibited the beginning of growth in small tufts. In contrast, animals treated with one of the neuroimmunophilin FKBP ligands exhibited dramatic hair growth.
  • a lotion comprising the following composition may be prepared.
  • a pipecolic acid derivative Into 95% ethanol are added a pipecolic acid derivative, ⁇ -tocopherol acetate, ethylene oxide (40 mole) adducts of hardened castor oil, perfume and a dye. The resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain a transparent liquid lotion. 5 ml of the lotion may be applied once or twice per day to a site having marked baldness or alopecia.
  • a lotion comprising the following composition shown may be prepared.
  • the resulting mixture is stirred, and purified water is added to the mixture to obtain a transparent liquid lotion.
  • the lotion may be applied by spraying once to 4 times per day to a site having marked baldness or alopecia .
  • An emulsion may be prepared from A phase and B phase having the following compositions.
  • the A phase and the B phase are respectively heated and melted and maintained at 80°c. Both phases are then mixed and cooled under stirring to normal temperature to obtain an emulsion.
  • the emulsion may be applied by spraying once to four times per day to a site having marked baldness or alopecia .
  • a cream may be prepared from A phase and B phase having the following compositions.
  • the A phase is heated and melted, and maintained at 70°c.
  • the B phase is added into the A phase and the mixture is stirred to obtain an emulsion.
  • the emulsion is then cooled to obtain a cream.
  • the cream may be applied once to 4 times per day to a site having marked baldness or alopecia.
  • Example 6
  • a liquid comprising the following composition may be prepared.
  • a shampoo comprising the following composition may be prepared .
  • the shampoo may be used on the scalp once or twice per day.
  • a patient is suffering from alopecia senilis.
  • a pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from male pattern alopecia.
  • a pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from alopecia areata.
  • a pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from hair loss caused by skin lesions.
  • a pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from hair loss caused by tumors.
  • a pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from hair loss caused by a systematic disorder, such as a nutritional disorder or an internal secretion disorder.
  • a systematic disorder such as a nutritional disorder or an internal secretion disorder.
  • a pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from hair loss caused by chemotherapy.
  • a pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient .
  • Increased hair growth is expected to occur following treatment.
  • a patient is suffering from hair loss caused by radiation.
  • a pipecolic acid derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

Abstract

Cette invention concerne des compositions pharmaceutiques et des procédés qui permettent de traiter l'alopécie et de favoriser la croissance des cheveux à l'aide de dérivés d'acide pipécolique.
PCT/US1998/011242 1998-06-03 1998-06-03 Compositions pour la croissance des cheveux a base de derives d'acide pipecolique et utilisation de ces compositions WO1999062483A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/US1998/011242 WO1999062483A1 (fr) 1998-06-03 1998-06-03 Compositions pour la croissance des cheveux a base de derives d'acide pipecolique et utilisation de ces compositions
CA002333698A CA2333698A1 (fr) 1998-06-03 1998-06-03 Compositions pour la croissance des cheveux a base de derives d'acide pipecolique et utilisation de ces compositions
JP2000551739A JP2002516839A (ja) 1998-06-03 1998-06-03 ピペコリン酸誘導体毛髪成長組成物およびその使用
EP98925152A EP1083872A1 (fr) 1998-06-03 1998-06-03 Compositions pour la croissance des cheveux a base de derives d'acide pipecolique et utilisation de ces compositions
AU77167/98A AU761083B2 (en) 1998-06-03 1998-06-03 Pipecolic acid derivative hair growth compositions and uses

Applications Claiming Priority (1)

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US7273874B2 (en) 2004-12-20 2007-09-25 Wyeth Rapamycin derivatives and the uses thereof in the treatment of neurological disorders
US7276498B2 (en) 2004-12-20 2007-10-02 Wyeth Rapamycin analogues and uses thereof in the treatment of neurological disorders
US7598278B2 (en) 2002-04-11 2009-10-06 L'oreal Administration of pyridinedicarboxylic acid compounds for stimulating or inducing the growth of human keratinous fibers and/or arresting their loss
US10835468B2 (en) 2014-12-22 2020-11-17 L'oreal Particular pyridinedicarboxylic acid derivative/antioxidant combination

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US5385908A (en) * 1993-11-22 1995-01-31 American Home Products Corporation Hindered esters of rapamycin
WO1996011943A1 (fr) * 1994-10-14 1996-04-25 Astra Aktiebolag Nouveaux peptides a effets immunodulateurs
US5620971A (en) * 1991-05-09 1997-04-15 Vertex Pharmaceuticals Incorporated Biologically active acylated amino acid derivatives
WO1998013343A1 (fr) * 1996-09-25 1998-04-02 Guilford Pharmaceuticals Inc. Thioesters et cetones heterocycliques

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EP0423714A2 (fr) * 1989-10-16 1991-04-24 Fujisawa Pharmaceutical Co., Ltd. Agent vitalisateur des cheveux
US5620971A (en) * 1991-05-09 1997-04-15 Vertex Pharmaceuticals Incorporated Biologically active acylated amino acid derivatives
US5252579A (en) * 1993-02-16 1993-10-12 American Home Products Corporation Macrocyclic immunomodulators
US5385908A (en) * 1993-11-22 1995-01-31 American Home Products Corporation Hindered esters of rapamycin
WO1996011943A1 (fr) * 1994-10-14 1996-04-25 Astra Aktiebolag Nouveaux peptides a effets immunodulateurs
WO1998013343A1 (fr) * 1996-09-25 1998-04-02 Guilford Pharmaceuticals Inc. Thioesters et cetones heterocycliques

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7598278B2 (en) 2002-04-11 2009-10-06 L'oreal Administration of pyridinedicarboxylic acid compounds for stimulating or inducing the growth of human keratinous fibers and/or arresting their loss
US9107847B2 (en) 2002-04-11 2015-08-18 Societe L'oreal S.A. Administration of pyridinedicarboxylic acid compounds for stimulating or inducing the growth of human keratinous fibers and/or arresting their loss
US7273874B2 (en) 2004-12-20 2007-09-25 Wyeth Rapamycin derivatives and the uses thereof in the treatment of neurological disorders
US7276498B2 (en) 2004-12-20 2007-10-02 Wyeth Rapamycin analogues and uses thereof in the treatment of neurological disorders
US7470682B2 (en) 2004-12-20 2008-12-30 Wyeth Rapamycin analogues and the uses thereof in the treatment of neurological disorders
US7476678B2 (en) 2004-12-20 2009-01-13 Wyeth Rapamycin derivatives and the uses thereof in the treatment of neurological disorders
US7560457B2 (en) 2004-12-20 2009-07-14 Wyeth Rapamycin analogues and the uses thereof in the treatment of neurological, proliferative, and inflammatory disorders
US7795252B2 (en) 2004-12-20 2010-09-14 Pfizer Inc. Rapamycin analogues and the uses thereof in the treatment of neurological, proliferative, and inflammatory disorders
US10835468B2 (en) 2014-12-22 2020-11-17 L'oreal Particular pyridinedicarboxylic acid derivative/antioxidant combination

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JP2002516839A (ja) 2002-06-11
AU7716798A (en) 1999-12-20
AU761083B2 (en) 2003-05-29
CA2333698A1 (fr) 1999-12-09
EP1083872A1 (fr) 2001-03-21

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