Classifications

• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
• • 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
  • 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 N-oxides of heterocyclic esters, amides, thioesters, or ketones .
• 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.
• 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 an N-oxide of a heterocyclic ester, amide, thioester, or ketone .
• the present invention further relates to a pharmaceutical composition which comprises:
• a pharmaceutically acceptable carrier (ii) a pharmaceutically acceptable carrier.
• the N-oxides of heterocyclic esters, amides, thioesters, or ketones used in the inventive methods and pharmaceutical compositions have an affinity for FKBP-type immunophilins and do not exert any significant immunosuppressive activity.
• FIG. 1 is a photograph of C57 Black 6 mice before being shaved for the hair regeneration experiment.
• FIG. 2 is a photograph of mice treated with a vehicle after six weeks.
• FIG. 2 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered.
• FIG. 3 is a photograph of mice treated with 10 ⁇ M of GPI 1046, a related non-immunosuppressive neuro- immunophilin FKBP ligand, after six weeks.
• FIG. 3 shows the remarkable effects of neuro-immunophilin FKBP ligands, wherein 90% of the shaved area is covered with new hair growth.
• FIG. 4 is a photograph of mice treated with 30 ⁇ M of GPI 1046, a related non- immunosuppressive neuroimmunophilin FKBP ligand, after six weeks.
• FIG. 4 shows the remarkable ability of these compounds to achieve, essentially, complete hair regrowth in the shaved are .
• FIG. 5 is a bar graph depicting the relative hair growth indices for C57 Black 6 mice treated with a vehicle, FK506, and various non-immunosuppressive neuroimmunophilin FKBP ligands 14 days after treatment with each identified compound.
• Figure 5 demonstrates the remarkable early hair growth promoted by a wide variety of non-immunosuppressive neuroimmunophilin FKBP ligands. DETAILED DESCRIPTION OF THE INVENTION
• 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 prolifera ion. This results m 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.
• “GPI 1605" refers to a compound of formula
• GPI 1046 refers to 3- (3 -pyridyl) -1-propyl (2s) 1- (3 , 3 -dimethyl -l , 2 -dioxopentyl) -2 pyrrolidinecarboxylate, a compound of formula
• 'GPI 1234" 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 su 1 f ona t e , cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide , hydroiodide, 2- hydroxye thanesul fonate ,
• 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.
• lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
• dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates
• 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 catagen phase the period when growth stops and the follicle atrophies which, insofar as scalp hair is concerned, lasts about one to two weeks
• 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 m which tne 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 m an animal, which comprises administering to said animal an effective amount of an N-oxide of a heterocyclic ester, amide, thioester, or ketone.
• 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: d) an effective amount of an N-oxide of a heterocyclic ester, amide, thioester, or ketone for treating alopecia or promoting hair growth in an animal ; and (ii) a pharmaceutically acceptable carrier.
• the N-oxides of heterocyclic esters, amides, thioesters, and ketones 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.
• N-oxide of a heterocyclic ester, amide, thioester, or ketone may be a compound of formula I
• a and B are taken together, with the nitrogen and carbon atoms to which they are respectively attached, to form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH, CH 2 , 0, S, SO, S0 2 , N, NH and R lf - W is 0, S, CH 2 , or H 2 ;
• R is straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, or Ar x , which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C x - C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, and Ar 2 ;
• Ax ⁇ and Ar 2 are independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl , C- L -Cg straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino;
• X is 0, NH, NR 1; S, CH, CR ⁇ or CR ⁇ ;
• Y is a direct bond, straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C ⁇ C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C x -C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR 2 , S,
• R 2 is selected from the group consisting of hydrogen, C 1 -C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, and C__ - C 4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group ;
• Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is selected from the group consisting of pyridyl , pyrimidyl , quinolinyl, or isoquinolinyl , which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl , C ⁇ C g straight or branched chain alky
• Ar is selected from the group consisting of pyrrolidinyl, pyridyl , pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl ;
• R ⁇ and R 3 are independently hydrogen, C x -C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, or Y-Z.
• N-oxide of a heterocyclic ester, amide, thioester, or ketone may be a compound of formula II
• E, F, G and J are independently CH 2 , O, S, SO,
• W is O, S, CH 2 , or H 2 ;
• R is Cj-Cg straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, or Ar 1( which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C 1 - C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, and Ax ⁇ ;
• Ar x is selected from the group consisting of 1- napthyl, 2-napthyl, 1- indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl, and phenyl, having one or more substituent (s) independently selected from the group consisting of
• alkyl C 2 -C 4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR 2 , S, SO, or S0 2 ;
• R 2 is selected from the group consisting of hydrogen, C ⁇ d straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyi, and C-, - C 4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group ;
• Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine is pyridyl, pyrimidyl , quinolinyl, and isoquinolinyl , which is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl , C j -Cg straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR 4 R 5 R 6 , wherein R 4 , R 5 , and R 6 are independently selected from the group consisting of Ci-Cg straight or branched chain alkyl and C 2 -C 6 straight or branched chain alkenyl; wherein said
• Ar is selected from the group consisting of pyrrolidinyl , pyridyl, pyrimidyl, pyrazyl, pyridazyl , quinolinyl, and isoquinolinyl ;
• Ri and R 3 are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl , or Y-Z.
• N-oxide of a heterocyclic ester, amide, thioester, or ketone may further be a compound of formula III
• E, F, and G are independently CH 2 , O, S, SO, S0 2 , NH or NR 1; -
• W is O, S, CH 2 , or H 2 ;
• R is straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, or Ar lf which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C 1 - C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, and Ar l -
• Ax ⁇ is selected from the group consisting of 1- napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl , straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino;
• X is O, NH, NR X , S, CH, CR lf or CR ⁇ ;
• Y is a direct bond, C 1 -C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C x - C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C x -C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0,
• R 6 are independently selected from the group consisting of Ci-Cg straight or branched chain alkyl and C 2 -C 6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of -Cg straight or branched chain alkyl,
• Ar is selected from the group consisting of pyrrolidinyl , pyridyl, pyrimidyl, pyrazyl, pyridazyl , quinolinyl, and isoquinolinyl; and R x and R 3 are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, or Y-Z.
• N-oxide of a heterocyclic ester, amide, thioester, or ketone may be a compound of formula IV
• n 1, 2, or 3, forming a 5-7 member heterocyclic ring
• W is 0, S, CH 2 , or H 2 ;
• R is C j -C 8 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl,
• C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, and Ar 1# - Ax ⁇ is selected from the group consisting of 1- # napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl , straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino;
• X is 0, NH.
• Y is a direct bond, straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of C X - C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C x -C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR 2
• R s are independently selected from the group consisting of -C 8 straight or branched chain alkyl and C 2 -C 6 straight or branched chain alkenyl ; wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C 3 ,-C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR
• Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl;
• R- L and R 3 hydrogen, C 1 -C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl , or Y-Z.
• N-oxide of a heterocyclic ester, amide, thioester, or ketone may further be a compound of formula V
• V is C, N, or S;
• R 7 is either straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 9 cycloalkyl, C 5 -C 7 cycloalkenyl, or Ar 3 , wherein R 7 is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl , straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C,-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthi
• Ar 3 and Ar 4 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 O, N, and S ; and
• R, W, X, Y, and Z are as defined in Formula I above .
• All the compounds of Formulas I-V 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
• 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 alanme-prolme bond m a model substrate, N-succmyl-Ala-Ala-Pro-Phe- p-nicroanilide is monitored speccrophotometrically 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 firs -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 Duffer (25 mM HEPES, pH 7.8, 100 mM NaCl) , 10 mL of FKBP (2.5 mM m 10 mM T ⁇ s-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/ml m 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 (succmyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL m 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. Typically, in 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.
• the crude material was triturated with several portions of ether, and the ether portions were filtered through Celite to remove solids and concentrated in vacuo.
• the concentrated filtrate was purified on a flash column (gradient elution, 25% ethyl acetate in hexane to pure ethyl acetate) to obtain 5.47 g (80%) of GPI 1046 as a colorless oil (partial hydrate) .
• mice were used to demonstrate the hair revitalizing properties of a low molecular weight, small molecule, non-immunosuppressive neuroimmunophilin FKBP ligand, GPI 1046, which is related to N-oxides of heterocylic esters, amides, thioesters, and ketones.
• GPI 1046 non-immunosuppressive neuroimmunophilin FKBP ligand
• FIGS. 1 and 2 of the drawings 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. Referring now to FIGS.
• FIG. 2 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. 3 shows that animals treated with 10 ⁇ M GPI 1046 exhibited dramatic hair growth, covering greater than 90% of the shaved area in all animals.
• FIG. 4 shows that mice treated with 30 ⁇ M GPI 1046 exhibited essentially complete hair regrowth and their shaved areas were indistinguishable from unshaven C57 black 6 mice.
• Experiment B C57 Black 6 mice were used to demonstrate the hair revitalizing properties of various low molecular weight, small molecule, non- immunosuppressive neuroimmunophilin FKBP ligands.
• mice per group Five animals per group were treated by topical administration with a vehicle, FK506, or one of the low molecular weight, small molecule, non- immunosuppressive neuroimmunophilin FKBP ligands (GPI 1605, 1046, 1312, 1572, 1389, 1511, and 1234) 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 any one of the low molecular weight, small molecule, non-immunosuppressive neuroimmunophilin FKBP ligands exhibited dramatic hair growth.
• a lotion comprising the following composition may be prepared.
• a lotion comprising the following composition 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 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 7
• a liquid comprising the following composition may be prepared.
• polyoxypropylene butyl ether Into ethanol are added polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, an N-oxide of a heterocylic ester, amide, thioester, or kecone, and perfume.
• the resulcing mixture is stirred, and purified water is added to the mixture to obtain a liquid.
• 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.
• Example 9
• a patient is suffering from alopecia senilis.
• An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 10 A patient is suffering from male pattern alopecia.
• An N-oxide of a heterocylic ester, amide, thioester, or ketone 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.
• An N-oxide of a heterocylic ester, amide, thioester, or ketone 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.
• An N-oxide of a heterocylic ester, amide, thioester, or ketone 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.
• An N-oxide of a heterocylic ester, amide, thioester, or ketone 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.
• An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 patienc is suffering from hair loss caused by chemotherapy.
• An N-oxide of a heterocylic ester, amide, thioester, or ketone 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 16 A patient is suffering from hair loss caused by radiation.
• An N-oxide of a heterocylic ester, amide, thioester, or ketone 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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• 1998
  • 1998-06-03 CA CA002334032A patent/CA2334032A1/en not_active Abandoned
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  • 1998-06-03 WO PCT/US1998/011245 patent/WO1999062486A1/en active IP Right Grant
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