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WO1999062484A1 - Compositions pour la croissance des cheveux a base de petites molecules de carbamates ou d'urees et utilisation de ces compositions - Google Patents

Compositions pour la croissance des cheveux a base de petites molecules de carbamates ou d'urees et utilisation de ces compositions Download PDF

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Publication number
WO1999062484A1
WO1999062484A1 PCT/US1998/011243 US9811243W WO9962484A1 WO 1999062484 A1 WO1999062484 A1 WO 1999062484A1 US 9811243 W US9811243 W US 9811243W WO 9962484 A1 WO9962484 A1 WO 9962484A1
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Prior art keywords
straight
branched chain
group
chain alkyl
chain alkenyl
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PCT/US1998/011243
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English (en)
Inventor
Gregory S. Hamilton
Joseph P. Steiner
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GPI Nil Holdings Inc
Eisai Corp of North America
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Guilford Pharmaceuticals Inc
GPI Nil Holdings Inc
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Application filed by Guilford Pharmaceuticals Inc, GPI Nil Holdings Inc filed Critical Guilford Pharmaceuticals Inc
Priority to AU78077/98A priority Critical patent/AU764032B2/en
Priority to PCT/US1998/011243 priority patent/WO1999062484A1/fr
Priority to JP2000551740A priority patent/JP2002516840A/ja
Priority to EP98926180A priority patent/EP1083875A1/fr
Priority to CA002333679A priority patent/CA2333679A1/fr
Publication of WO1999062484A1 publication Critical patent/WO1999062484A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K31/453—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
    • A61K31/44—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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/70—Biological properties of the composition as a whole

Definitions

  • This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using low molecular weight, small molecule carbamates and ureas.
  • 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.
  • FK506 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 small molecule carbamate or urea.
  • the present invention further relates to a pharmaceutical composition which comprises:
  • a small molecule carbamate or urea for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
  • the small molecule carbamates and ureas used in the inventive methods and pharmaceutical compositions may be immunosuppressive, but are preferably 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 related neuroimmunophilin FKBP ligand, GPI 1044, after six weeks.
  • FIG. 2 shows that 90% of the shaved area is covered with new hair growth when GPI 1044 is administered.
  • FIG. 3 is a photograph of mice treated with 10 ⁇ M of a related neuroimmunophilin FKBP ligand, GPI 1116, after six weeks.
  • FIG. 3 shows thac 90% of the shaved area is covered with new hair growth when GPI 1116 is administered.
  • FIG. 4 is a photograph of mice treated with 3 ⁇ M of a related neuroimmunophilin FKBP ligand, 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. 5 is a bar graph plotting the hair growth scores of unshaven animals and shaven animals treated with a vehicle, GPI 1044 (1 ⁇ M, 3 ⁇ M and 10 ⁇ M) , GPI 1116 (1 ⁇ M and 10 ⁇ M) , and GPI 1102 (1 ⁇ M and 3 ⁇ M) .
  • FIG. 6 is a bar graph depicting the relative hair growth indices for C57 Black 6 mice created with a vehicle, FK506, related neuroimmunophilin FKBP ligand GPI 1116, and GPI 1206 14 days after treatment with each identified compound.
  • Figure 6 demonstrates the remarkable early hair growth promoted by neuroimmunophilin FKBP ligands.
  • 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 s Phenyl
  • GPI 1102 refers to 4-phenyl-l- (3-phenylpropyl) butyl 1- (3 , 3-dimethyl-2-oxopentanoyl) - 2 - piperidinecarboxylate .
  • GPI 1116 refers to 1-phenethyl-3-phenylpropyl 1 - ( 3 , 3 -dimethyl -2 -oxopentanoyl ) - 2 - piperidinecarboxylate .
  • “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. “Diastereoiso ers” 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, camphor sul fonat e , cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesul fonat e , lactate
  • 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, ly ⁇ ine, and so forch.
  • 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 scearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides; and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl , and butyl chlorides, bromides, and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl , and diamyl s
  • Palm cycle refers to the life cycle of hair follicles, and includes three phases:
  • the anagen phase the period of active hair growth which, insofar as scalp hair is concerned, lasts about three to five years ;
  • 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.
  • 80 to 90 percent of the follicles are in the anagen phase, less than 1 percent being in the catagen phase, and the rest being in the telogen phase.
  • hair is uniform in diameter with a slightly bulbous, non-pigmented root.
  • 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:
  • 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 promocing hair growth in an animal, which comprises administering to said animal an effective amount of a small molecule carbamate or urea .
  • 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:
  • an effective amount of a small molecule carbamate or urea for treating alopecia or promoting hair growth in an animal (i) an effective amount of a small molecule carbamate or urea for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
  • the carbamates and ureas used in the methods and pharmaceutical compositions of the present invention are low molecular weight, small molecule compounds having an affinity for FKBP-type immunophilins , such as FKBP12.
  • FKBP-type immunophilins such as FKBP12.
  • FKBP-12 FKBP-12
  • rotamase inhibiting compounds may be immunosuppressive, but preferably are non- imrnunosuppressive . Examples of useful compounds are set forth below.
  • An exemplary small molecule carbamate or urea is a compound of Formula I
  • A is CH 2 , O, NH or N- (C x -C 4 alkyl);
  • B and D are independently Ar, hydrogen, C ⁇ C g straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl or alkynyl, C 5 -C 7 cycloalkyl substituted straight or branched chain alkyl or C 3 -C 6 straight or branched chain alkenyl or alkynyl, C 5 -C 7 cycloalkenyl substituted straight or branched chain alkyl or C 3 -C 6 straight or branched chain alkenyl or alkynyl, Ar substituted Ci-Cg straight or branched chain alkyl, or Ar substituted C 3 -C 6 straight or branched chain alkenyl or alkynyl; wherein any carbon atom of said alkyl is optionally replaced by a heteroatom selected from the group consisting of O, S, SO, S0 2 , and NR
  • J is selected from the group consisting of hydrogen, straight or branched chain alkyl, C 3 -C 6 straight or branched chain alkenyl, and -CH 2 Ar
  • K is selected from the group consisting of C x -C 4 straight or branched chain alkyl, -CH 2 Ar, and cyclohexylmethyl ; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with 0, S, SO, or S0 2 ;
  • Z is 0 or S
  • Y is 0 or N, provided that when Y is 0, then R ⁇ is a lone pair of electrons and R 2 is selected from the group consisting of Ar, straight or branched chain alkyl, and C 3 -C 6 straight or branched chain alkenyl or alkynyl; and when Y is N, then R x and R 2 are independently selected from the group consisting of Ar, straight or branched chain alkyl, and C 3 -C 6 straight or branched chain alkenyl or alkynyl ; or R L and ?_ 2 are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine;
  • Ar is a carbocyclic aromatic group selected from the group consisting of phenyl , 1-naphthyl, 2- naphthyl, indenyl , azulenyl, fluorenyl, and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2- thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl , thiazolyl, imidazolyl , pyraxolyl , 2 -pyrazolinyl , pyrazol idinyl , isoxazolyl, isotriazolyl, 1 , 2 , 3-oxadiazolyl , 1, 2 , 3 -triazolyl , 1, 3 , -thiadiazolyl, pyridazinyl, pyrimidinyl,
  • (C 3 -C 4 straight or branched chain alkenyl), 0-benzyl, O-phenyl, 1 , 2 -methylenedioxy, -NR 3 R 4 , carboxyl , N- (C ⁇ C s straight or branched chain alkyl or C 3 -C 5 straight or branched chain alkenyl) carboxamides , N,N-di- (C ⁇ C s straight or branched chain alkyl or C 3 -C 5 straight or branched chain alkenyl) carboxamides, morpholinyl, piperidinyl, O-X, CH 2 - (CH 2 ) q -X, 0-(CH 2 ) q -X, (CH 2 ) q -0-X, and CH CH-X;
  • R 3 and R 4 are independently selected from the group consisting of Ci-Cg straight or branched chain alkyl, C 3 -C 6 straight or branched chain alkenyl, hydrogen, and benzyl; or R 3 and R 4 are taken together to form a 5-6 membered heterocyclic ring;
  • X is selected from the group consisting of 4- methoxyphenyl , 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl , 3 , 5-dimethylisoxazoyl , isoxazoyl,
  • J and K are taken together to form a 5-7 membered ring.
  • At least one of said B and D is/are independently represented by the formula - (CH 2 ) r - (X) - (CH 2 ) S -Ar, wherein: r is 1 -4 ; s is 0 - 1 ;
  • Ar is as defined above in Formula I; and each X is independently selected from the group consisting of CH 2 , 0, S, SO, S0 2 , and NR, wherein R is selected from the group consisting of hydrogen, C x -C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, and C ⁇ d bridging alkyl wherein a bridge is formed between the nitrogen atom and Ar.
  • Ar is selected from the group consisting of phenyl , 2- pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl , 1 , 2 , 3 , 4-tetrahydroiso- quinolinyl, and 1, 2 , 3 , 4-tetrahydroquinolinyl , wherein said Ar is unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of hydrogen, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl, 0- (C x -C 6 straight or branched chain alkyl), halogen, S0 3 H, and NR 3 R 4 ; and R 3 and R 4 are independently selected from the group consisting of straight or branched chain alkyl, C 3 -C 6 straight or branched chain alkenyl, hydrogen,
  • Another exemplary small molecule carbamate or urea is a compound of Formula II or III
  • Ar is as defined above in Formula I;
  • J is hydrogen, C ⁇ C g straight or branched chain alkyl, or C 3 -C 6 straight or branched chain alkenyl; and w is 1 or 2.
  • a further exemplary small molecule carbamate or urea is a compound of Formula IV or V
  • Ar is as defined above in Formula I; J is hydrogen, straight or branched chain alkyl, or C 3 -C 6 straight or branched chain alkenyl; and w is 1 or 2.
  • a further exemplary small molecule carbamate or urea is a compound of Formula VI
  • V is C, N, or S;
  • R is either C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 9 cycloalkyl, C 3 -C 7 cycloalkenyl , or Ar 1# wherein R is either unsubstituted of substituted with one or more substituent (s) independently selected from the group consisting of halo, haloalkyl, carbonyl , carboxy, hydroxy, nitro, trifluoromethyl , C ⁇ C g straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 1 alkoxy,
  • Ar x and Ar 2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S;
  • A, B, D, R l; R 2 , Y, Z, and n are as defined in Formula I above.
  • Representative compounds of Formulas I -VI are presented in Table I .
  • All the compounds of Formulas I -VI possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual R- and S- stereoisomers .
  • the individual stereoisomers may be obtained by using an optically active starting material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving the compounds of Formulas I -VI. It is understood that the compounds of Formulas I -VI encompass individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers.
  • S-stereoisomers are used in the pharmaceutical compositions and methods of the present invention.
  • Isocyanates (R x NC0) or isothiocyanates (R X NCS) 4 may be conveniently prepared from the corresponding readily available amines by reaction with phosgene or thiophosgene, as depicted in Scheme II.
  • 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 Co yield the apparent K x 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 NaCl) , 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCl , 1 mM dithiothreitol) , 25 mL of chymotrypsin (50 mg/ml in 1 mM HC1) 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 absorbance at 390 nm versus time is monitored for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance versus time data files.
  • 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.
  • mice were used to demonstrate the hair revitalizing properties of related neuro-immunophilin FKBP ligands GPI 1044, GPI 1116 and GPI 1102.
  • C57 black 6 mice approximately 7 weeks old, had an area of about 2 inches by 2 in.'T.e ⁇ 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 che pinkish color of the skin. Referring now to FIGS. 1, 2, 3 and 4, four animals were treated by topical administration with 20% propylene glycol vehicle (FIG.
  • 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. 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.
  • FIG. 5 compares the hair growth score of unshaven animals with the hair growth scores of shaven animals treated with a vehicle, GPI 1044 (1 ⁇ M, 3 M and 10 ⁇ M) , GPI 1116 (1 ⁇ M and 10 ⁇ M) , and GPI 1102 (1 ⁇ M and 3 ⁇ M) .
  • Experiment B C57 Black 6 mice were used to demonstrate the hair revitalizing properties of neuroimmunophilin FKBP ligands, including GPI 1206.
  • GPI 1206 neuroimmunophilin FKBP ligand
  • 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 6 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, GPI 1206, exhibited dramatic hair growth.
  • a lotion comprising the following composition may be prepared.
  • 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 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 scirred Co 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.
  • a liquid comprising the following composition may be prepared.
  • the liquid may be applied once to 4 times per day to a site having marked baldness or alopecia.
  • 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 small molecule carbamate or urea 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 small molecule carbamate or urea 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.
  • Example 15 A patient is suffering from alopecia areata.
  • a small molecule carbamate or urea as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected co occur following treatment.
  • a patient is suffering from hair loss caused by skin lesions.
  • a small molecule carbamate or urea 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.
  • Example 17 A patient is suffering from hair loss caused by tumors.
  • a small molecule carbamate or urea 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 small molecule carbamate or urea 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.
  • Example 19 A patient is suffering from hair loss caused by chemotherapy.
  • a small molecule carbamate or urea 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.
  • Example 20
  • a patient is suffering from hair loss caused by radiation.
  • a small molecule carbamate or urea 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.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Birds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Cosmetics (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyrrole Compounds (AREA)

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 petites molécules de carbamates et d'urées.
PCT/US1998/011243 1998-06-03 1998-06-03 Compositions pour la croissance des cheveux a base de petites molecules de carbamates ou d'urees et utilisation de ces compositions Ceased WO1999062484A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU78077/98A AU764032B2 (en) 1998-06-03 1998-06-03 Small molecule carbamate or urea hair growth compositions and uses
PCT/US1998/011243 WO1999062484A1 (fr) 1998-06-03 1998-06-03 Compositions pour la croissance des cheveux a base de petites molecules de carbamates ou d'urees et utilisation de ces compositions
JP2000551740A JP2002516840A (ja) 1998-06-03 1998-06-03 小分子カルバメートまたは尿素発毛組成物および使用
EP98926180A EP1083875A1 (fr) 1998-06-03 1998-06-03 Compositions pour la croissance des cheveux a base de petites molecules de carbamates ou d'urees et utilisation de ces compositions
CA002333679A CA2333679A1 (fr) 1998-06-03 1998-06-03 Compositions pour la croissance des cheveux a base de petites molecules de carbamates ou d'urees et utilisation de ces compositions

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1998/011243 WO1999062484A1 (fr) 1998-06-03 1998-06-03 Compositions pour la croissance des cheveux a base de petites molecules de carbamates ou d'urees et utilisation de ces compositions

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JP (1) JP2002516840A (fr)
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WO (1) WO1999062484A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018358A3 (fr) * 1998-09-30 2000-07-27 Procter & Gamble Methode de traitement de la chute des cheveux au moyen de cetoamides
US6300341B1 (en) 1998-09-30 2001-10-09 The Procter & Gamble Co. 2-substituted heterocyclic sulfonamides
US6307049B1 (en) 1998-09-30 2001-10-23 The Procter & Gamble Co. Heterocyclic 2-substituted ketoamides
US9085555B2 (en) 2011-01-04 2015-07-21 Novartis Ag Complement pathway modulators and uses thereof
US9388199B2 (en) 2012-06-28 2016-07-12 Novartis Ag Pyrrolidine derivatives and their use as complement pathway modulators
US9464081B2 (en) 2012-06-28 2016-10-11 Novartis Ag Pyrrolidine derivatives and their use as complement pathway modulators
US9468661B2 (en) 2012-06-28 2016-10-18 Novartis Ag Pyrrolidine derivatives and their use as complement pathway modulators
US9487483B2 (en) 2012-06-28 2016-11-08 Novartis Ag Complement pathway modulators and uses thereof
US9550755B2 (en) 2012-07-12 2017-01-24 Novartis Ag Complement pathway modulators and uses thereof
US9815819B2 (en) 2012-06-28 2017-11-14 Novartis Ag Complement pathway modulators and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2505114A1 (de) * 1975-02-07 1976-08-19 Koehler Valentin Kopfhautpflegemittel und dessen verwendung
WO1985004577A1 (fr) * 1984-04-06 1985-10-24 Gail Sansone Bazzano Compositions stimulant la croissance des cheveux
WO1996015101A1 (fr) * 1994-11-16 1996-05-23 Vertex Pharmaceuticals Incorporated Nouveaux derives d'acides amines presentant une meilleure activite contre la resistance a plusieurs medicaments
EP0823419A2 (fr) * 1996-08-09 1998-02-11 Takeda Chemical Industries, Ltd. Composés de diméthylpropanediol

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2505114A1 (de) * 1975-02-07 1976-08-19 Koehler Valentin Kopfhautpflegemittel und dessen verwendung
WO1985004577A1 (fr) * 1984-04-06 1985-10-24 Gail Sansone Bazzano Compositions stimulant la croissance des cheveux
WO1996015101A1 (fr) * 1994-11-16 1996-05-23 Vertex Pharmaceuticals Incorporated Nouveaux derives d'acides amines presentant une meilleure activite contre la resistance a plusieurs medicaments
EP0823419A2 (fr) * 1996-08-09 1998-02-11 Takeda Chemical Industries, Ltd. Composés de diméthylpropanediol

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018358A3 (fr) * 1998-09-30 2000-07-27 Procter & Gamble Methode de traitement de la chute des cheveux au moyen de cetoamides
US6300341B1 (en) 1998-09-30 2001-10-09 The Procter & Gamble Co. 2-substituted heterocyclic sulfonamides
US6307049B1 (en) 1998-09-30 2001-10-23 The Procter & Gamble Co. Heterocyclic 2-substituted ketoamides
US9085555B2 (en) 2011-01-04 2015-07-21 Novartis Ag Complement pathway modulators and uses thereof
US9388199B2 (en) 2012-06-28 2016-07-12 Novartis Ag Pyrrolidine derivatives and their use as complement pathway modulators
US9464081B2 (en) 2012-06-28 2016-10-11 Novartis Ag Pyrrolidine derivatives and their use as complement pathway modulators
US9468661B2 (en) 2012-06-28 2016-10-18 Novartis Ag Pyrrolidine derivatives and their use as complement pathway modulators
US9487483B2 (en) 2012-06-28 2016-11-08 Novartis Ag Complement pathway modulators and uses thereof
US9815819B2 (en) 2012-06-28 2017-11-14 Novartis Ag Complement pathway modulators and uses thereof
US9550755B2 (en) 2012-07-12 2017-01-24 Novartis Ag Complement pathway modulators and uses thereof

Also Published As

Publication number Publication date
EP1083875A1 (fr) 2001-03-21
CA2333679A1 (fr) 1999-12-09
JP2002516840A (ja) 2002-06-11
AU764032B2 (en) 2003-08-07
AU7807798A (en) 1999-12-20

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