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MXPA00011941A - N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses - Google Patents

N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses

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Publication number
MXPA00011941A
MXPA00011941A MXPA/A/2000/011941A MXPA00011941A MXPA00011941A MX PA00011941 A MXPA00011941 A MX PA00011941A MX PA00011941 A MXPA00011941 A MX PA00011941A MX PA00011941 A MXPA00011941 A MX PA00011941A
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Mexico
Prior art keywords
alkyl
alkenyl
long
group
branched chain
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MXPA/A/2000/011941A
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Spanish (es)
Inventor
S Hamilton Gregory
P Steiner Joseph
Original Assignee
Guilford Pharmaceuticals Inc
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Application filed by Guilford Pharmaceuticals Inc filed Critical Guilford Pharmaceuticals Inc
Publication of MXPA00011941A publication Critical patent/MXPA00011941A/en

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Abstract

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using N-oxides of heterocyclic esters, amides, thioesters, or ketones.

Description

COMPOSITIONS FOR THE GROWTH OF HAIR CONTAINING N-OXIDES OF HETEROCYCLIC ESTERS. THIOESTERS. AMIDAS. O CETONAS BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using small molecules of low molecular weight N-oxides of heterocyclic esters, thioester amides or ketones.
PREVIOUS ART Hair loss occurs in a variety of situations. These situations include male pattern alopecia, senile alopecia, alopecia areata, diseases accompanied by basic skin lesions or tumors and systematic diseases such as nutritional diseases and internal secretion diseases. The mechanisms that cause hair loss are very complicated, but in some cases can be attributed to aging, genetic disposition, the activation of male hormones, loss of blood supply to the hair follicles and abnormalities of the scalp. The immunosuppressive drugs FK506, rapamicin and cyclosporin are well known as potent specific immunosuppressants of the T cell and are effective against graft rejection after organ transplantation. It has been reported that the topical but non-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 growth in a dose-dependent manner. A form of hair loss, alopecia areata, is known to be associated with autoimmune activities, therefore, immunomodulatory compounds administered topically are expected to demonstrate efficacy in the treatment of that type of hair loss. The stimulating effects of hair growth of FK506 has been the subject of an international patent filed covering the FK506 and related structures for the stimulation of hair growth (Honbo et al., EP 0 423 714 A2). Honbo et al. describes the use of relatively large tricyclic compounds, known for their immunosuppressive effects as hair revitalizing agents. The revitalizing and hair growth effects of FK506 and related agents are described in many US patents. (Goulet et al., U.S. Patent No. 5,258,389, Luly 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). These patents claim the compounds related to FK506. Although they do not claim hair revitalization methods, they describe the known use of FK506 to effect hair growth. Similar to FK506 (and the variations claimed in the Honbo et al patent), the compounds claimed in these patents are relatively large. In addition, the cited patents related to immunomodulatory compounds for use in related autoimmune diseases, for which the efficacy of FK506 is well known. Other patents of E.U.A. describe the use of cyclosporin and related compounds for hair revitalization (Hauer et al., U.S. Patent No. 5,342,625, Eberle, U.S. Patent No. 5,284,826, Hewitt et al., U.S. Patent No. 4,996,193). These patents also relate to compounds useful for the treatment of autoimmune diseases and cite the known use of cyclosporin and the related immunosuppressant compounds for hair growth. However, immunosuppressive compounds by definition suppress the immune system and also exhibit other toxic side effects. Accordingly, there is a need for small molecule, non-immunosuppressive compounds that are useful as hair revitalizing compounds. Hamilton and Steiner describe in the U.S. Patent. No. 5, 614,547 novel pyrrolidine carboxylate compounds that bind to FKBP12 immunophilin and stimulate nerve growth, but that grow of immunosuppressive effects. Unexpectedly, it has been discovered that these non-immunosuppressive compounds promote hair growth with efficacy similar to that of FK506. Still their novel small molecular structure and their immunosuppressive properties differentiate them from FK506 and the related immunosuppressive compounds are found in the prior art.
SUMMARY OF THE INVENTION The present invention relates to a method for treating alopecia or to promote hair growth in an animal, comprising administering to said animal an effective amount of an N-oxide of a heterocyclic ester, amide, thioester or ketone. The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of an N-oxide of a heterocyclic ester, thioester amide or ketone for the treatment of alopecia or to promote hair growth in an animal and (i?) a pharmaceutically acceptable carrier.
The heterocyclic esters, amides, thioesters or ketones used in the methods of the inventive and the pharmaceutical compositions have an affinity for imunofilins of the FKBP type and do not exert any significant immunosuppressive activity.
BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a photograph of Black C57 mice 6 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 less than 3% of the area that is covered with the growth of the new hair when the vehicle (control) is administered. Fig. 3 is a photograph of mice treated with 10 μg of GPI 1046, a neuro-immunophilin non-immunosuppressant related FKBP ligand, after six weeks. Fig. 3 shows the remarkable effects of the neuro-immunophilin FKBP ligands, where 90% of the shaved area is covered with the growth of new hair. Fig. 4 is a photograph of mice treated with 30 μM of GPI 1046, a ligand FKBP neuro-immunofilin non-immunosuppressant related. Fig. 4 shows the remarkable ability of these compounds to achieve, essentially, complete the regrowth of the hair in the shaved area. FIG. 5 is a bar graph depicting relative hair growth rates for C57 Black 6 mice treated with one vehicle, FK506 and several non-immunosuppressive neuroimmunophilin FKBP ligands 14 days after treatment with each identified compound. Figure 5 demonstrates the clearly remarkable hair growth promoted by a wide variety of non-immunosuppressive FKBP neuroinmunophilin ligands, wherein: A = Hair growth (relative index) 0 = no growth 1 = growth on small tufts 2 = growth of the hair hair covering less < 25% shaved area 3 = hair growth covering more > 25% but less than 50% shaved area 4 = hair growth covering more > 50% but less than 75% of the shaved area 5 = complete hair growth of the shaved area DETAILED DESCRIPTION OF THE INVENTION Definitions "Alopecia" refers to deficient hair growth and complete or partial loss of hair, including androgenic alopecia without limitation (baldness), toxic alopecia, senile alopecia, alopecia areata, peeled alopecia and trichotillomania. Alopecia results when the pillar cycle deteriorates. The most frequent phenomenon is a reduction in hair growth or anagen phase due to the cessation of cell proliferation. This results in the premature onset of the catagen phase and consequently a large number of hair in the telogen phase during which the follicles separate from the dermal papillo and the hair falls out. Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental stress, hormonal problems and side 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-1,2-dioxopentyl) -2-pyrrolodinecarboxylate, a compound of formula "GP1 1312" refers to a compound of formula "GP1 1572" refers to a compound of formula "GP1 1389" refers to a compound of formula "GP1 1511" refers to a compound of formula ° GPI 1234"refers to a compound of formula "Isomers" refers to different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way atoms arrange themselves in space. The "enantiomers" are a pair of stereoisomers that are mirror images not superimposed on one another. "Diastereomers" are stereoisomers that are not mirror images of one another. "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" is a mixture containing equal parts of individual enantiomers or stereoisomers. "Pharmaceutically acceptable salt, ester or solvate" refers to a salt, ester or solvate of an object compound that possesses the desired pharmacological activity and that is biologically or otherwise undesired. A salt, ester or solvate can be formed with organic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camforate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate , hemyl sulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples of basic salts, esters or solvates include ammonium salts, alkali metal salts, such as sodium and potassium salts; alkaline salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexlamine salts; H-methyl-D-glucamine and salts with amino acids, such as arginine, lysine and so on. Also, basic groups containing nitrogen can be made quaternary compounds with said agents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates such as diethyl, dibutyl and diamyl sulfates; long halide chains, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides, such as phenethyl and benzyl bromides and others. The products dispersible or soluble in oil or water are thus obtained. "Pillar cycle" refers to the life cycle of the hair follicles and includes three phases: (1) the anagen phase, the period of active growth of the hair, insofar as it refers to the hair of the scalp, lasts approximately three to five years; (2) the catagen phase, the period when growth stops and in which the follicle atrophies, as it refers to the hair of the scalp, lasts approximately one to two weeks and (3) the telogen phase, the rest of the period when the hair progressively separates and finally falls, as it refers to the hair of the scalp, lasts approximately three to four months. Normally 80 to 90 percent of the follicles are in the anagen phase, less than 1 percent is in the catagen phase and the rest is in the telogen phase. In the telogen phase, the hair is uniform in diameter with a slightly bulbous and non-pigmented root. On the contrary, in the anagen phase, the hair has a large bulb colored at its root. "Promotion of hair growth" refers to maintaining, inducing, stimulating, accelerating or revitalizing hair germination. Treating alopecia "refers to: (i) preventing alopecia in an animal that may be predisposed to alopecia and / or (ii) inhibiting, retarding or reducing alopecia and / or (iii) promoting hair growth and / or or (iv) prolong the anagen phase of the hair cycle and / or (v) convert hair to hair to grow terminal hair.The terminal hair is long, rough, pigmented, in which the bulb of the hair follicle sits The hair on the other hand is fine, thin, non-pigmented hair, in which the hair bulb is located superficially in the dermis, and as the hair progresses, the hair changes from the type of hair to the hair. terminal type.
Methods of the Present Invention The present invention relates to a method for treating alopecia or promoting hair growth in an animal, comprising administering to said animal an effective amount of an N-oxide of a heterocyclic ester, amide, thioester or ketone. The method of inventiveness is particularly useful for treating male pattern alopecia, senile alopecia, alopecia areata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapies such as radiation and chemotherapy. and alopecia resulting from systemic diseases such as nutritional diseases and internal secretion diseases.
Pharmaceutical Compositions of the Present Invention The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of N-oxide of a heterocyclic ester, amide, thioester or ketone to treat alopecia or to promote hair growth in an animal and (ii) a pharmaceutically acceptable carrier.
N-OXIDES OF HETEROCICLES ESTERS. AMIDAS. TIOESTERES Y CETONAS The N-oxides of heterocyclic esters, amides, thioesters and ketones used in the methods and pharmaceutical compositions of the present invention are small molecule and low molecular weight compounds that have an affinity for immunofilins of the FKBP type, such as FKBP12. When an N-oxide of a heterocyclic ester, amide, thioester or ketone is linked to an immunophilin of the FKBP type, it has been found to inhibit the propyl-peptidyl cis-trans isomerase or rotamase, activity of the binding protein.
Unexpectedly, it has also been found that these compounds stimulate hair growth. The compounds are devoid of any significant immunosuppressive activity.
FORMULA I The N-oxide of a heterocyclic ester, amide, thioester or ketone can be a compound of Formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B are taken together with the nitrogen and the carbon atoms to which they are respectively attached to form an unsaturated or saturated heterocyclic ring of 5 to 7 members containing any combination of CH, CH2, O, S, SO, SO2, N, NH and NR; W is O, S, CH2 or H2; R is long or branched chain alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ar ^ which is optionally substituted with one or more substituents independently selected from the group consisting of CC alkyl, C2-C alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar2; Ari and Ar2 are independently selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-ynolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl and phenyl, having one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, long or branched chain C 1 -C alkyl, long chain C 2 -C 2 alkenyl or branched, C2-C4 alkenoxy) phenoxy, benzyloxy and amino; X is O, NH, NR1 f S, CH, CR! or C ^ RZ Y is a direct bond, long chain or branched C? -C6 alkyl or C2-C6 long or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consists of long chain or branched CrC6 alkyl, C2-C6 long chain or branched alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with C 1 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 O, NH, NR2, S, SO or SO2; R2 is selected from the group consisting of hydrogen, long chain or branched CC alkyl, C3-C4 alkenyl or long chain or branched alkynyl and C4 alkyl bridging 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 a group Ar; 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 substituted or unsubstituted with one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, long-chain alkyl or branched, C2-C6 long chain or branched alkenyl C? -C alkoxy, C2-C alkenyloxy, phenoxy, benzyloxy and amino; said tertiary amine is NRfRsRβ, wherein R4, R5 and R6 are independently selected from the group consisting of long or branched chain C C? C6 alkyl or long or branched chain C2-C6 alkenyl optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain d-Cβ alkyl, C2-C6 long chain or branched alkenyl, C3-C8 cycloalkyl) Cs-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with CrC4 alkyl) C2-C alkenyl, hydroxy or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR1f S, SO or SO2; Ar is selected from the group which of the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl and so-quinolinyl and R-Í and R3 are independently hydrogen, long or branched chain dC alkyl, C3-C chain alkenyl long or branched or alkynyl or YZ.
FORMULA II Additionally, the N-oxide of a heterocyclic ester, amide, thioester or ketone can be a compound of formula II II or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, G and J are independently CH2, O, S, SO, SO2, NH or NR ^ W is O, S, CH2 or H2; R is long chain or branched CrC6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ar1 (which is optionally substituted with one or more substituents independently selected from the group consisting of alkyl C? -C, C2-C alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and An; Ar1 is selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2- furil, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl long or branched chain C6 alkyl, C2-C6 long chain or branched alkenyl, C2-C4 alkenyloxy phenoxy, benzyloxy and amino; X is O, NH, N ^, S, CH, CR, or CR? R3; Y is a direct bond, long or branched chain C1-C6 alkyl or long chain or branched C2-C6 alkenyl, wherein said alkyl or alkenyl is substituted optionally with one or more substituents independently selected from the group consisting of long chain or branched CrC6 alkyl, long chain or branched C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar1; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C 1 -C 4 alkyl, C 2 -C alkenyl, hydroxy or oxygen carbonyl; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR2, S, SO or SO2; R 2 is selected from the group consisting of hydrogen, long or branched chain C 1 -C 4 alkyl, long or branched chain C 3 -C alkenyl or alkynyl and C 4 C bridging alkyl wherein the bridge is formed between the nitrogen and a carbon 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 unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, long or branched chain C6 alkyl, C2- alkenyl C6 of long or branched chain; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain C6 alkyl or long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with 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 O, NH, NRi, S, SO or SO2; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl and isoquinolinyl and Ri and R3 are independently hydrogen, long chain or branched CC, branched or long chain C3-C4 alkenyl or alkynyl or YZ .
FORMULA III The N-oxide of a heterocyclic ester, amide, thioester or ketone can also be a compound of the formula III. or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F and G are independently CH2, O, S, SO, SO2l NH or NR ^ W is O, S, CH2 or H2; R is long chain or branched C6 alkyl, long and branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or A ?, which is optionally substituted with one or more substituents independently selected from the group consisting of d-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C8 cycloalkyl, cycloalkenyl Ar is selected from the group consisting of of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, long or branched chain C 6 alkyl, long chain and branched C 2 -C 6 alkenyl, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy and amino; X is O, NH, NRi, S, CH, CR! O CR ^; Y is a direct bond, long or branched chain C6 alkyl, or long chain and branched C2-C6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain CrC6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy , carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C 4 alkyl, C 2 -C alkenyl, hydroxy or oxygen carbonyl; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR2, S, SO or SO2; R 2 is selected from the group consisting of hydrogen, long chain or branched CC alkyl, long or branched chain C 3 -C 4 alkenyl or alkynyl and C 4 C 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 or isoquinolinyl, which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, long or branched chain C 1 -C 6 alkyl, alkenyl Long chain or branched C 2 -C 6, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy and amino; said tertiary amine is wherein R f, R 5 and R 6 are independently selected from the group consisting of long or branched chain C 6 alkyl and long chain or branched C 2 -C 6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long chain or branched CrC6 alkyl, long or branched chain C2-C2 alkenyl, C3-C8 cycloalkyl) C5-C7 cycloalkenyl, hydroxy , carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C 1 alkyl, C 2 -C alkenyl, hydroxy or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR ,, S, SO or SO2; Ar is selected from the group consisting of the group of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl and isoquinolinyl, and Ri and R3 are independently hydrogen, long chain or branched C? -C alkyl, long chain C3-C alkenyl or branched or alkynyl or YZ.
FORMULA IV On the other hand, the N-oxide of a heterocyclic ester, amide, thioester or ketone can be a compound of formula IV or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: n is 1, 2 or 3, forming a 5-7 membered heterocyclic ring; W is O, S, CH2 or H2; R is long chain or branched CrC6 alkyl, long or branched chain C2-C2 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Art, which is optionally substituted with one or more substituents independently selected from the group consisting of CC alkyl , C2-C alkenyl, hydroxy, C3-C8 cycloalkyl, Cs-C7 cycloalkenyl and Ar ,; Ap is selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one to more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, long or branched chain C6 alkyl, long or branched chain C2-C6 alkenyl, C2- alkenyl loxy C4, phenoxy, benzyloxy and amino; X is O, NH, NR1 (S, CH, CR, or CR1R3; Y is a direct bond, long or branched chain C6 alkyl, C2-C6 long chain and branched alkenyl, wherein said alkyl or alkenyl is substituted optionally with one or more substituents independently selected from the group consisting of long or branched chain C6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with CrC alkyl, C2-C6 alkenyl, hydroxy or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O , NH, NR2, S, SO or SO2; R2 is selected from the group consisting of hydrogen, long or branched chain CrC alkyl, long or branched chain C3-C4 alkenyl or alkynyl and CrC4 bridging alkyl, wherein a bridge is way between the nit 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 pyrridyl, pyrimidyl, quinolinyl or isoquinolinyl which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, long or branched chain C -C6 alkyl, C2- alkenyl C6 of long and branched chain, C 1 -C 4 alkoxy, C 2 -C 4 alkenyl, phenoxy, benzyloxy and amino; said tertiary amine is NR1R5R6, wherein Rt, R5 and R6 are selected from the group consisting of long or branched chain C6 alkyl and long chain or branched C2-C3 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain CrC6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy , carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with Crd, hydroxy or carbonyl oxygen alkyl, wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR ^ S, SO or SO2; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl and isoquinolinyl and Hydrogen Rt and R3l long chain or branched C3 alkyl or C3-C4 alkenyl long or branched chain or alkynyl or YZ. Examples of the compounds of formula IV when W is O are presented in Table I.
No. n XYR 1 IO (CH2) 3 3-Pyrldyl N-oxide 1,1-dimethylpropyl 2 IO (CH2) 3 2-Pyridyl N-oxide 1,1-dimethylpropyl 3 IO (CH2) 3 4-Pyridyl N-oxide 1, 1-dimethylpropyl 4 IO (CH 2) 3 2-Quinolinyl N-oxide 1,1-dimethylpropyl 5 IO (CH 2) 3 3-Quinolinyl N-oxide 1,1-dimethylpropyl 6 IO (CH 2) 3 4-Quinolinyl N- 1, 1-dimethylpropyl oxide Preferred compounds of the formula IV can be selected from the group consisting of: 3- (2-pyridyl) -1-propyl (2S) -1- (1,1-dimethyl-1,2-dioxopentyl) -2- pyrrolidinecarboxylate, N-oxide; 3- (3-Pyridyl) -1-propyl (2S) -1- (1,1-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate; N-oxide; 3- (4-Pir? DTI) -1-propyl (2S) -1 - (1,1-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (2-Quinolyl) -1-propyl (2S) -1- (1,1-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (3-Quinolyl) -1-propyl (2S) -1- (1,1-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (4-Quinoll) -1-propyl (2S) -1- (1,1-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide; pharmaceutically acceptable salts, esters and solvates thereof.
FORMULA V The N-oxide of a heterocyclic ester, amide, thioester or ketone can also be a compound of the formula V or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N or S; A and B, taken together with V and the carbon atom to which they are respectively added, form a saturated and unsaturated 5-7 membered heterocyclic ring containing, in addition to V, one or more heteroatoms independently selected from the group consisting of of O, S, SO, SO2, N, NH and NR7; R7 is long or branched chain C1-C9 alkyl or C2-C9 long or branched chain alkenyl, C3-C9 cycloalkyl, Cs-C7 cycloalkenyl or Ar3, wherein R is unsubstituted or substituted by one or more substituents independently selected from a group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, tridluoromethyl, long or branched chain C 6 alkyl, long chain or branched C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy , thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl and Ar4; Ar3 and Ar4 are independently alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the size of the individual ring is 5-8 members; wherein said heterocyclic ring contains from 1-6 heteroatoms 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 compounds of Formulas I-V possess asymmetric centers and therefore can be produced as mixtures of stereoisomers or as individual stereoisomers R- and S-. Individual stereoisomers can be obtained by using an optically active starting material by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stages of the synthesis or by resolving the compounds of Formulas I-V. It is understood that the compounds of Formulas I-V include individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers. Preferably, the S-stereoisomers are used in the pharmaceutical compositions and methods of the present invention.
Affinity for FKBP12 The compounds used in the inventive methods and the pharmaceutical compositions have an affinity for the FK506 binding protein, particularly FKBP12. Inhibition of the prolyl peptidyl cis-trans isomerase activity of FKBP can be measured as an indicator of this affinity.
Kt Test Procedure The inhibition of peptidyl prolyl isomerase (rotamase) activity of the compounds used in the methods of the inventive and the pharmaceutical compositions can be evaluated by known methods described in the literature (Harding et al., Nature, 1989, 341: 758-760; Holt et al., J. Am. Chem. Soc, 115: 9923-9938). These values are obtained as apparent K, s and are presented for the representative compounds in Table II. The cis-trans isomerization of an alanine-proline bond in a substrate model, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, was monitored spectrophotometrically in a coupled chymotrypsin 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 the inhibitor was determined and the data analyzed as a change in the constant of the first order ratio as a function of the concentration of the inhibitor to produce the K values, apparent. In a plastic bowl, 950 ml of an ice-cold test stabilizer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 ml of FKBP (2.5 mM in 10 mM Tris-CI pH 7.5, 100 mM NaCl, 1 mM were added. of dithiothreitol), 25 ml of chymotrypsin (50 mg / ml in 1 mM HCl) and 10 ml of the test compound in various concentrations in dimethyl sulfoxide. The reaction was initiated by the addition of 5 ml of the 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 was monitored for 90 seconds using a spectrophotometer and the absorbance rate constants were determined against the time data fields. The data are presented in Table II for 3- (3-pyridyl) -1-propyl (2S) -1- (1,1-Dimethyl-1,2-dioxopentyl) -2-pyrrolidine-carboxylate, N-oxide ( compound 1) and its origin (non-oxidized) compound.
Table II Results of the In Vitro Test - Formulas I to V Compound K¿ (nM) Origin 7.5 1 225 Route of Administration To effectively treat alopecia or promote hair growth, the compounds used in the inventive methods and pharmaceutical compositions should rapidly affect the target areas. For these purposes, the compounds are preferably administered topically on the skin. For topical application to the skin, the compounds may be formulated in appropriate ointments containing the suspended or dissolved compounds, 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. Alternatively, the compounds may be formulated in appropriate lotions or creams containing the suspended or dissolved active compound, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol , 2-ododecanol, benzyl alcohol and water. Other routes of administration known in the pharmaceutical art are also contemplated by this invention.
Dosage Dosage levels in the order of about 0.1 mg to about 10,000 mg of the compound of the active ingredient 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 on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex and the patient's diet; the time of administration, the rate of excretion, the combination of the drug; the severity of the particular disease that is being treated and the form of administration. Typically, the results of the in vitro dose effect provide useful guidance at the appropriate doses for administration to the patient. Studies in animal models are also useful. Considerations for determining appropriate dose levels are well known in the art. The compounds can be administered with other hair revitalizing agents. The specific dose levels for other revitalizing agents will depend on the previously established factors and the effectiveness of the combination of the drug.
EXAMPLES The following examples are illustrative of the present invention and are not limiting. Unless indicated otherwise, all percentages are based on 100% by weight of the final composition.
Example 1 Synthesis of 3- (3-pyridyl) -1-propyl (2S) -1- (3,3-Dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate. N-oxide (1) Methyl (2S) -1-p2-d-oxo-2-methoxyethyl) -2-pyrrolidinecarboxylate A solution of methyl ester L-proline hydrochloride (3.08 g, 18.60 mmol) in dry methylene chloride was cooled at 0 ° C and treated with triethylamine (3.92 g, 38.74 mmol, 2.1 eq). After stirring the suspension formed under a nitrogen atmosphere for 15 minutes, a solution of oxalyl methyl chloride (45 ml) was added dropwise. The resulting mixture was stirred at 0 ° C for 1.5 hours. After filtering to remove the solids, the organic phase was washed with water, dried under MgSO and concentrated. The crude residue was purified on a column of silica gel, eluted with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; the data for the given trans rotamer. 1 H NMR (CDCl 3): "1.93 (dm, 2H), 2.17 (m, 2H), 3.62 (m, 2H), 3.71 (s, 3H), 3.79, 3.84 (s, 3H total), 4.86 (dd, 1 H, J = 8.4, 3.3).
Methyl (2S1-1 - (1 ^ dioxo-3 3-dimethylpentyl) -2-pyrrolidinecarboxylate A solution of methyl (2S) -1- (1,2-dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g; 10.90 nmol) in 30 ml of tetrahydrofuran (THF) was cooled to -78 ° C and treated with 14.2 ml of a 1.0 M chloride solution of 1 ml., 1-dimethylpropylmagnesium in THF. After stirring the resulting homogeneous mixture at -78 ° C for three hours, the mixture was poured into saturated ammonium chloride (100 ml) and extracted into ethyl acetate. The organic phase was washed with water, dried and concentrated and the crude material obtained after the removal of the solvent was purified on a column of silica gel, eluted with 25% ethyl acetate in hexane to obtain 2.10 g (75%). ) of the oxamate as a colorless oil. 1 H NMR (CDCl 3): 6? 0.88 (t, 3H); 1.22, 1.26 (s, every 3H); 1.75 (dm, 2H); 1.87-2.10 (m, 3H), 2.23 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); 4.52 (dm, 1 H, J = 8.4, 3.4). (2S) -1- (1,2-D-Oxo-3,3-dimethylpentyl) -2-pyrrolidinecarboxylic acid A mixture of methyl (2S) -1- (1,2-dioxo-3,3-dimethylpentyl-2-pyrrolidine) Carboxylate (2.10 g, 8.23 mmol), 1 N LiOH (15 ml) and methanol (50 ml) were stirred at 0 ° C for 30 minutes and at room temperature overnight, the mixture was acidified to pH 1 with 1 N HCl, diluted with water and extracted into 100 ml of methylene chloride, the organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of a white solid that did not require further purification. CDCI3): d 0.87 (t, 3H), 1.22, 1.25 (s, every 3H), 1.77 (dm, 2H), 2.02 (m, 2H), 2.17 (m, 1 H), 2.25 (m, 1 H) 3.53 (dd, 2H, J = 10.4, 7.3), 4.55 (dd, 1H, J = 8.6, 4.1). 3- (3-Pyridyl) -1-propyl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate A mixture of (2S) -1- (1,2-dioxo-3,3) acid -dimethylpentyl) -2-pyrrolidinecarboxylic acid (4.58 g, 19 mmol), 3-pyridinopropanol (3.91 g, 28.5 mmol), dicyclohexylcarboimide (6.27 g, 30.4 mmol), camphorsulfonic acid (1.47 g, 6.33 mmol) and 4-dimethyl aminopyridine ( 773 mg; 6. 33 mmol) in methylene chloride (100 ml) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through celite to remove solids and concentrated in vacuo. The crude material was triturated with several portions of ether and the portions of ether were filtered through Celite to remove the solids and concentrated in vacuo. The concentrated filtrate was purified on a flash column (elution gradient, 25% ethyl acetate in hexane to pure ethyl acetate) to obtain 5.47 g (80%) of GPI 1046 as a colorless oil (partial hydrate). H NMR (CDCl 3, 300 MHz): 0.85 (t, 3H); 1.23, 1.26 (s, every 3H); 1.63-1.89 (m, 2H); 1.90-2.30 (m, 4H); 2.30-2.50 (m, 1 H); 2.72 (t, 2H); 3.53 (m, 2H); 4.19 (m, 2H); 4.53 (m, 1 H); 7.22 (m, 1 H); 7.53 (dd, 1 H); 8.45. Analysis calculated for C20H28NO4 - 0.25 H2O: C, 65.82; H, 7.87; N, 7.68. Found: C, 66.01; H; 7.85; N, 7.64. 3-f3-Pyridyl) -1-propyl (2S) -1- (3,3-dimethyl-1,2-d-oxopentyl) -2-pyrrolidinecarboxylate. N-oxide (1) A solution of 3- (3-pyridyl) -1-propyl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate (190 mg, 0.52 mmol) and m-chloroperbenzoic acid (160 mg 57% -86% material, 0.53 mmol) was stirred in methylene chloride (20 ml) at room temperature for 3 hours. The reaction mixture was diluted with methylene chloride and washed twice with 1N NaOH. The organic extract was dried and concentrated and the crude material was chromatographed, eluting with 10% methanol in ethyl acetate to obtain 130 mg of the Compound 1 of Example 1. 1 H NMR (CDCl 3, 300 MHz): 6? 0.83 (t, 3H); 1.21 (s, 3H); 1.25 (s, 3H); 1.75-2.23 (m, 8H); 2.69 (t, 2H, J = 7.5); 3.52 (t, 2H, J = 6.3); 4.17 (dd, 2H, J = 6.3); 4.51 (m, 1 H); 7.16-7.22 (m, 2H); 8.06-8.11 (m, 2H). Analysis calculated for C20H28N2O5- 0.75 H2O: C, 61.60; H, 7.63; N, 7.18. Found: C, 61.79; H, 7.58; N, 7.23.
Example 2 In vivo Live Hair Generation Tests with C57 Black 6 Mice Experiment A: C57 black 6 mice were used to demonstrate the revitalizing properties of low molecular weight hair, small molecule, non-immunosuppressive neurokinmunophilin FKBP ligand, GPI 1046, which is relates to N-oxides of heterocyclic esters, amides, thioesters and ketones. With reference to Figures 1 and 2, the C57 black 6 mice, approximately 7 weeks old, had an area of approximately 5.08 cm in their shaved hindquarters to remove all existing hair. Care was taken not to scratch or cause abrasion on the underlying dermal layers. The animals were in the anagen growth phase, as indicated by the pink color of the skin. With reference to Figures 2, 3 and 4, four animals per group were treated by topical administration with 20% propylene glycol vehicle (Fig. 2), 10 μM GPI 1046 (Fig. 3) or 30 μM GPI 1046 (Fig. 4). ) dissolved in the vehicle. The animals are treated with the vehicle or GPI 1046 every 48 hours (3 applications in total in the course of 5 days) and hair growth was allowed to proceed for 6 weeks. Hair growth was quantified by the percentage of the shaved area covered with the growth of the new hair during this period of time. Fig. 2 shows that the animals with the vehicle exhibited only a small amount of hair growth in patches or tufts with less than 3% of the shaved area covered with the new growth. By contrast, Fig. 3 shows that animals treated with 10 μM of GPI 1046 exhibited dramatic hair growth, covering more than 90% of the shaved area in all animals. In addition, Fig. 4 shows that mice treated with 30 μM of GPI 1046 exhibited essentially complete hair regrowth and their shaved areas were indistinguishable from the non-shaved areas of C57 black mice.
Experiment B: C57 black 6 mice were used to demonstrate the hair revitalizing properties of several FKBP neuroinmunofilin non-immunosuppressive small molecule and low molecular weight ligands. C57 black 6 mice, 55 to 75 days old, had an area of approximately 5.08 cm by 2.08 cm in their shaved hindquarters to remove all existing hair. Care was taken not to scratch or cause abrasion on the underlying dermal layers. The animals were in the anagen growth phase when they were shaved. Five animals per group were treated by topical administration with a vehicle, FK506 or one of the FKBP neuroimmunophilin non-immunosuppressive ligands of small molecule and low molecular weight (GPI 1605, 1046, 1312, 1572, 1389, 1511 and 1234) in a concentration of one micromol per milliliter in the shaved area. The animals were treated three times a week and the hair growth was evaluated for 14 days after starting treatment. Hair growth was quantified by the percentage of the shaved area covered by the growth of the new hair, as recorded by an autonomous observer, on a scale from o (no growth) to five (full regrowth of the hair in the shaved area). Figure 5 shows that after 14 days, the animals were treated with the vehicle exhibiting the start of growth in small tufts. In contrast, animals treated with any of the non-immunosuppressive small molecule, low molecular weight FKBP neuroinmunophilin ligands exhibited dramatic hair growth.
Example 3 A lotion comprising the following composition can be prepared.
In 95% ethanol, an N-oxide of a heterocyclic ester, amide, thioester or ketone, a-tocopherol acetate, ethylene oxide adducts (40 moles) of hardened castor oil, perfume and a blotter was added. The resulting mixture was stirred and dissolved and the purified water was added to the mixture to obtain a clear liquid lotion. 5 ml of the lotion can be applied once or twice a day in a site that has marked baldness or alopecia.
Example 4 A lotion comprising the following composition can be prepared.
In 95% ethanol, an N-oxide of a heterocyclic ester, amide, thioester or ketone, hinokitol, ethylene oxide (40 mole) adducts of hardened castor oil, perfume and a blotter was added. The resulting mixture was stirred and purified water was added to the mixture to obtain a clear liquid lotion. The lotion can be applied by spraying one to four times a day in a place that has marked baldness or alopecia.
Example 5 An emulsion of phase A and B having the following compositions can be prepared.
Phase A and phase B respectively are heated, mixed and maintained at 80 ° C. Both phases are then mixed and cooled under agitation to maintain them at normal temperature to obtain an emulsion. The emulsion can be applied by spray one to four times a day to a site that has marked baldness or alopecia.
Example 6 A cream can be prepared from phase A and phase B having the following compositions.
Phase A was heated, mixed and maintained at 70 ° O Phase B was added in phase A and the mixture was stirred to obtain an emulsion. The emulsion was subsequently cooled to obtain a cream. The cream can be applied one to four times a day in a site that has marked baldness or alopecia.
Example 7 A liquid comprising the following composition can be prepared.
(%) Butyl polyoxyethylene 20.0 ether Ethanol 50.0 An N-oxide of a heterocyclic ester, amide, thioester or ketone as defined above 0.001 Propylene glycol 5.0 Polyoxyethylene derived from hardened castor oil (0.4 ethylene oxide adducts 80 moles) Perfume q.s.
Purified water q.s.
In ethanol was added butyl polyoxypropylene ether, propylene glycol, polyoxyethylene hardened castor oil, an N-oxide of a heterocyclic ester, amide, thioester or ketone and perfume. The resulting mixture was stirred and purified water was added to the mixture to obtain a liquid. The liquid can be applied one to four times a day in a site that has marked baldness or alopecia.
Example 8 A shampoo comprising the following composition can be prepared.
Purified water 69.7 In 69.7 of purified water was added 5.0 g of sodium laurisulfate, 5.0 g of triethanolamine lauryl sulfate, 6.0 g of betaine lauryl dimethyl-aminoacetate. Subsequently, a mixture was obtained by adding 5.0 g of an N-oxide of a heterocyclic ester, amide, thioester or ketone, 5.0 g of polyethylene glycol and 2.0 g of ethylene glycol distearate to 2.0 g of ethanol, followed by stirring and adding successfully 0.3 g of perfume. The resulting mixture was heated and subsequently cooled to obtain a shampoo. The shampoo can be used on the scalp once or twice a day.
Example 9 A patient suffering from senile alopecia. An N-oxide of a heterocyclic ester, amide, thioester or ketone as identified above or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.
Example 10 A patient suffering from male pattern alopecia. An N-oxide of a heterocyclic ester, amide, thioester or ketone as identified above or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.
Example 11 A patient suffering from alopecia areata. An N-oxide of a heterocyclic ester, amide, thioester or ketone as identified above or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.
Example 12 A patient suffering from hair loss caused by skin lesions. An N-oxide of a heterocyclic ester, amide, thioester or ketone as identified above or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.
Example 13 A patient suffering from hair loss caused by tumors. An N-oxide of a heterocyclic ester, amide, thioester or ketone as identified above or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.
Example 14 A patient suffering from hair loss caused by a systemic disease such as a nutritional disease or an internally secreted disease. An N-oxide of a heterocyclic ester, amide, thioester or ketone as identified above or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.
Example 15 A patient suffering from hair loss caused by chemotherapy. An N-oxide of a heterocyclic ester, amide, thioester or ketone as identified above or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.
Example 16 A patient suffering from hair loss caused by radiation. An N-oxide of a heterocyclic ester, amide, thioester or ketone as identified above or a pharmaceutical composition comprising the same, can be administered to the patient. Increased hair growth is expected after treatment.
The invention described, it is obvious that it can vary in many ways. Said variations are not considered to depart from the spirit and scope of the invention and said modifications will be included within the scope of the following claims.

Claims (20)

1. A method for the treatment of alopecia or to promote hair growth in an animal, comprising administering to said animal an effective amount of an N-oxide of a heterocyclic ester, amide, thioester or ketone.
2. The method according to claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone is non-immunosuppressant.
3. The method according to claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone has an affinity for an immunophilin of the FKBP type.
4. The method according to claim 3, wherein the N-oxide of a thioester, amide, or ketone heterocyclic ester is FKBP-12.
5. The method according to claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone is a compound of Formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B are taken together with the nitrogen and the carbon atoms to which they are respectively attached to form an unsaturated or saturated heterocyclic ring of 5 to 7 members containing any combination of CH, CH2, O, S, SO, SO2, N, NH and NR; W is O, S, CH2 or H2; R is long or branched chain Ci-Cß alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ar ^ which is optionally substituted with one or more substituents independently selected from the group consisting of CrC alkyl, C2-C4 alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C cycloalkenyl and Ar2; Ari and Ar2 are independently selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienl, 3-thienyl, 2-pyridyl, 3-pyridyl , 4-pyridyl and phenyl, having one to more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, long or branched chain C 1 -C 6 alkyl, long chain C 2 -C 6 alkenyl or branched, C2-C4 alkenyloxy, phenoxy, benzyloxy and amino; X is O, NH, NRL S, CH, CR, or CR ^; Y is a direct bond, long chain or branched C 6 alkyl or long or branched chain C 2 -C 6 alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C 6 alkyl of long or branched chain, C2-C6 long chain or branched alkenyl, C3-C8 cycloalkyl, C-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with C 4 alkyl, C 2 -C alkenyl, hydroxy or oxygen carbonyl; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR2, S, SO or SO2; R2 is selected from the group consisting of hydrogen, long chain or branched CC alkyl, long chain or branched C3-C4 alkenyl or alkynyl and C4 alkyl bridging 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 substituted or unsubstituted with one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, long chain CrC6 alkyl or branched, long or branched chain C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, C 2 -C alkenyloxy, phenoxy, benzyloxy and amino; said tertiary amine is N iRsRβ, wherein Rf, R5 and R6 are independently selected from the group consisting of long or branched chain d-C6 alkyl and C2-C6 long chain or branched alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain d-C6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl , hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C 4 alkyl, C 2 -C alkenyl, hydroxy or oxygen carbonyl; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR ,, S, SO or SO2; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl and isoquinolinyl and Ri and R3 are independently hydrogen, long chain or branched C4 alkyl, long or branched chain C3-C4 alkenyl or alkynyl or AND Z.
6. The method according to claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone is a compound of Formula II can be a compound of formula II or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, G and J are independently CH 2, O, S, SO, SO 2, NH or NR; W is O, S, CH2 or H2; R is long chain or branched C6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or A ?, which is optionally substituted with one or more substituents independently selected from the group consisting of of C1-C4 alkyl, C2-C alkenyl, hydroxy, C3-C8 cycloalkyl, cycloalkenyl Cs-Cr- and A; Ar, is selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, pyridyl and phenyl, which has one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, long or branched chain C 1 -C 6 alkyl, long chain or branched C 2 -C 6 alkenyl, C 2 alkenyloxy -C phenoxy, benzyloxy and amino; X is O, NH, NRL S, CH, CR, or CR ^; Y is a direct bond, long chain or branched CrC6 alkyl or long or branched chain C2-C6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain C6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with CrC alkyl, C2-C alkenyl, hydroxy or oxygen carbonyl; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR2) S, SO or SO2; R 2 is selected from the group consisting of hydrogen, long or branched chain C 4 alkyl, long chain or branched C 3 -C 4 alkenyl or alkynyl and C 4 alkyl bridging wherein the 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 unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, long or branched chain CrC6 alkyl, C2-C6 alkenyl long or branched chain, CrC4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy and amino; said tertiary amine is wherein R, R5 and Re are independently selected from the group consisting of long chain or branched CrC6 alkyl and long chain or branched C2-C8 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain C6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C 1 -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 O, NH, NRi, S, SO or SO2; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazil, quinolinyl and isoquinolinyl and Ri and R3 are independently hydrogen, long chain or branched CrC4 alkyl, long chain or branched C3-C alkenyl or alkynyl or YZ .
7. The method according to claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone is a compound of the formula III or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F and G are independently CH 2, O, S, SO, SO 2, NH or NR; W is O, S, CH2 or H2; R is long or branched chain CrCß alkyl, long chain and branched C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ar, which is optionally substituted with one or more substituents independently selected from the group consisting of alkyl C C4, C2-C alkenyl, hydroxy, C3-C8 cycloalkyl, cycloalkenyl Cg-Cr and Ar !; Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, long or branched chain C 1 -C 6 alkyl, long and branched chain C 2 -C 6 alkenyl, alkenyloxy C2-C, phenoxy, benzyloxy and amino; X is O, NH, NR ,, S, CH, CR, or CR ^; Y is a direct bond, long or branched chain C6 alkyl or long chain and branched C2-C6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain C6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C4 alkyl, C2-C4 alkenyl, hydroxy or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR2, S, SO or SO2; R 2 is selected from the group consisting of hydrogen, long or branched chain C 1 -C 4 alkyl, long chain or branched C 3 -C 4 alkenyl or alkynyl and d-C 4 bridging alkyl wherein a bridge is formed between nitrogen and an atom carbon 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 or isoquinolinyl, which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, long or branched chain C -Cß alkyl, C2- alkenyl Long chain or branched C6, C2-C4 alkenyloxy CrC4 alkoxy, phenoxy, benzyloxy and amino; said tertiary amine is NRtRsRβ, wherein Rt, R5 and Re are independently selected from the group consisting of long or branched chain C?-C6 alkyl and long or branched chain C 2 -C β alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain C6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C 4 alkyl, C 2 -C alkenyl, hydroxy or oxygen carbonyl; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR ^ S, SO or SO2; Ar is selected from the group consisting of the group of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl and isoquinolinyl and R, and R 3 are independently hydrogen, long or branched chain C 4 alkyl, long or branched chain C 3 -C 4 alkenyl or alkynyl or YZ.
8. The method according to claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone is a compound of formula IV or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: n is 1, 2 or 3, forming a 5-7 membered heterocyclic ring; W is O, S, CH2 or H2; R is long chain or branched C6 alkyl, long or branched chain C2-C2 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ar, which is optionally substituted with one or more substituents independently selected from the group consisting of CC alkyl, C2-C alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar ,; Ari is selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one to more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, long or branched chain C 6 alkyl, long or branched chain C 2 -C 6 alkenyl, C 2- alkenyloxy C4, phenoxy, benzyloxy and amino; X is O, NH, NR ?, S, CH, CR, or CR, R3; Y is a direct bond, long or branched chain C6 alkyl, long or branched chain C2-C6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain C 1 -C 6 alkyl, long or branched chain C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, cycloalkenyl C5-C7, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C 1 -C 4 alkyl, C 2 -C 6 alkenyl, hydroxy or oxygen carbonyl; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR2, S, SO or SO2; R 2 is selected from the group consisting of hydrogen, long or branched chain C 1 -C 4 alkyl, long chain or branched C 3 -C alkenyl or alkynyl, and CC bridging alkyl, wherein a bridge is formed between the nitrogen and a carbon 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 pyrridyl, pyrimidyl, quinolinyl or isoquinolinyl which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, long or branched chain C6 alkyl, C2-C6 alkenyl long and branched chain, C, -C, C2-C alkenyloxy, phenoxy, benzyloxy and amino alkoxy; said tertiary amine is NRtRsRβ, wherein R ,, R5 and R8 are independently selected from the group consisting of long or branched chain C, -C6 alkyl and long or branched chain C2-C2 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain C -Cß alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C, -C, C2-C alkenyl, hydroxy or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is it optionally replaces with O, NH, NR ,, S, SO or SO2; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl and isoquinolinyl and R 1 and R 3 independently are hydrogen, long or branched chain CC alkyl or long chain or branched C 3 -C 4 alkenyl or alkynyl or YZ .
9. The method according to claim 8, wherein the compound is selected from the group consisting of: 3- (2-pyridyl) -1-propyl (2S) -1- (1,1-dimethyl-1,2-dioxo) -pentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (3-Pyridyl) -1-propyl (2S) -1 - (1,1-dimethyl-1,2-dioxo-pentyl) -2-pyrrolidinecarboxylate; N-oxide; 3- (4-Pyridyl) -1-propyl (2S) -1 - (1,1-dimethyl-1,2-dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (2-Quinoll) -1-propyl (2S) -1- (1,1-dimethyl-1,2-dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (3-QuinolI) -1-propyl (2S) -1- (1,1-dimethyl-1,2-dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (4-Quinol? I) -1-propyl (2S) -1 - (1,1-dimethyl-1,2-dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide and pharmaceutically acceptable salts, esters and solvates thereof.
10. The method according to claim 1, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone is a compound of the formula V or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N or S; A and B, taken together with V and the carbon atom to which they are respectively added, form a saturated and unsaturated 5-7 membered heterocyclic ring containing, in addition to V, one or more heteroatoms independently selected from the group consisting of of O, S, SO, SO2, N, NH and NR7; R7 is long or branched chain C1-C9 alkyl or C2-C9 long or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl or Ar3, wherein R7 is unsubstituted or substituted by one or more substituents independently selected from a group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, tridluoromethyl, long or branched chain C 1 -C 6 alkyl, long chain or branched C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl and Ar4; Ar3 and Ar4 are independently alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the size of the individual ring is 5-8 members; wherein said heterocyclic ring contains from 1-6 heteroatoms independently selected from the group consisting of O, N and S and R, W, X, Y and Z are as defined in claim 5 above.
11. A pharmaceutical composition comprising: (i) an effective amount of an N-oxide of a heterocyclic ester, amide, thioester or ketone to treat alopecia or to promote hair growth in an animal and (i) a pharmaceutically acceptable carrier .
12. The pharmaceutical composition according to claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone is non-immunosuppressant.
13. The pharmaceutical composition according to claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone has an affinity for an immunophlyin of the FKBP type.
14. The pharmaceutical composition according to claim 13, wherein the immunophilin of the FKBP type is FKBP-12.
15. The pharmaceutical composition according to claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone is a compound of the formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B are taken together with the nitrogen and the carbon atoms to which they are respectively attached to form an unsaturated or saturated heterocyclic ring of 5 to 7 members containing any combination of CH, CH2, O, S, SO, SO2, N, NH and NR; W is O, S, CH2 or H2; R is long chain or branched C 6 alkyl, C 2 -C 6 long chain or branched alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl or Ap, which is optionally substituted with one or more substituents independently selected from the group consisting of of alkyl C, -C, C2-C4 alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar2; Ar, and Ar2 are independently selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indoIyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl and phenyl, having one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, long or branched chain C6 alkyl, long chain or branched C2-C6 alkenyl , C2-C alkenyloxy, phenoxy, benzyloxy and amino; X is O, NH, NR ,, S, CH, CR, or CR, R3; Y is a direct bond, long or branched chain C 6 alkyl or long or branched chain C 2 -C 6 alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C, - alkyl Long or branched chain C6, long chain or branched C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with C 1 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 O, NH, NR2, S, SO or SO2; R 2 is selected from the group consisting of hydrogen, long or branched chain CrC 4 alkyl, long chain or branched C 3 -C 4 alkenyl or alkynyl and CC alkyl alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said chain of alkyl or alkenyl 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 substituted or unsubstituted with one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C, -C6 alkyl, long or branched chain, C2-C6 long chain or branched alkoxy C, -C, C2-C alkenyloxy, phenoxy, benzyloxy and amino; said tertiary amine is NRtRsRe, wherein R ,, R5 and R6 are independently selected from the group consisting of long or branched chain C6-C6 alkyl and long or branched chain C2-C6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain Ci-Cß alkyl, long or branched chain C2-C8 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl , hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C 1 -C alkyl, C 2 -C 4 alkenyl, hydroxy or oxygen carbonyl; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR ,, S, SO or SO2; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl and soquinolinyl and R, and R3 are independently hydrogen, long or branched chain C-C4 alkyl, long or branched chain C3-C4 alkenyl or alkynyl or YZ.
16. The pharmaceutical composition according to claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone is a compound of the formula or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, G and J are independently CH 2, O, S, SO, SO 2, NH or NR; W is O, S, CH2 or H2; R is long or branched chain C 1 -C 6 alkyl, long chain or branched C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl or An, which is optionally substituted with one or more substituents independently selected from the group consists of CrC4 alkyl, C2-C alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar ,; Ar, is selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, pyridyl and phenyl, which has one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, long or branched chain C-C6 alkyl, long or branched chain C2-C6 alkenyl, C2- alkenyloxy C4 phenoxy, benzyloxy and amino; X is O, NH, NR ,, S, CH, CR, or CR, R3; Y is a direct bond, long or branched chain C, -C6 alkyl or long chain or branched C2-C6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain C-C6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl , hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C 1 -C 4 alkyl, C 2 -C 4 alkenyl, hydroxy or oxygen carbonyl; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR2, S, SO or SO2; R 2 is selected from the group consisting of hydrogen, long or branched chain C, -C 4 alkyl, long chain or branched C 3 -C alkenyl or alkynyl and C 1 -C 4 bridging alkyl wherein the 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 unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, long or branched chain C-C6 alkyl, C2 alkenyl -C6 long or branched chain, C, -C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy and amino; said tertiary amine is NR4R5R6, wherein} , R5 and R6 are independently selected from the group consisting of long or branched chain C6 alkyl and long or branched chain C2-C6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain C, -C6 alkyl, long chain or branched C2-C6 alkenyl, C3-C8 cycloalkyl, cycloalkenyl Cs- C7, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with CrC4 alkyl, C2-C4 alkenyl, hydroxy or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR ,, S, SO or SO2; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl and R, and R 3 are independently hydrogen, long or branched chain C, -C 4 alkyl, long chain or branched C 3 -C alkenyl. or alkynyl or YZ.
17. The pharmaceutical composition according to claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone is a compound of the formula III or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F and G are independently CH 2, O, S, SO, SO 2, NH or NR; W is O, S, CH2 or H2; R is long or branched chain C, -C6 alkyl, long and branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ap, which is optionally substituted with one or more substituents independently selected from the group consisting of C-C4 alkyl, C2-C alkenyl, hydroxy, C3-C8 cycloalkyl, cycloalkenyl C5-C7 and Ar ,; Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indoyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, pyridyl and phenyl having one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, long or branched chain C 1 -C 6 alkyl, long and branched chain C 2 -C 6 alkenyl, C 2 alkenyloxy -C4, phenoxy, benzyloxy and amino; X is O, NH, NR ,, S, CH, CR, or CR, R3; Y is a direct bond, long or branched chain C6 alkyl or long chain and branched C2-C6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain C6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C, -C4, C2-C4 alkenyl, hydroxy or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR2, S, SO or SO2; R 2 is selected from the group consisting of hydrogen, long or branched chain CC alkyl, long chain or branched C 3 -C 4 alkenyl or alkynyl and C 1 -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 or isoquinolinyl, which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, long or branched chain C-C6 alkyl, C2 alkenyl Long chain or branched C 6, C 1 -C 4 alkoxy, C 2 -C alkenyloxy, phenoxy, benzyloxy and amino; said tertiary amine is NR4R5R6, wherein R, R5 and R6 are independently selected from the group consisting of long or branched chain C, -C6 alkyl and long chain or branched C2-C6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain C6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with C 1 -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 O, NH, NR ,, S, SO or SO2; Ar is selected from the group consisting of the group of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl and isoquinolinyl and R, and R 3 are independently hydrogen, long or branched chain C 4 alkyl, long or branched chain C 3 -C alkenyl or alzulnil or YZ.
18. The pharmaceutical composition according to claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone is a compound of the formula IV or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: n is 1, 2 or 3, forming a 5-7 membered heterocyclic ring; W is O, S, CH2 or H2; R is long or branched chain C, -C6 alkyl, C2-C2 long chain or branched alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ar, which is optionally substituted with one or more substituents independently selected from the group consists of C, -C4, C2-C4 alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Ar alkyl; Ari is selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl and phenyl, having one to more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, long or branched chain C-C6 alkyl, long or branched chain C2-C6 alkenyl, C2 alkenyloxy -C > phenoxy, benzyloxy and amino; X is O, NH, NR ,, S, CH, CR, or CR, R3; Y is a direct bond, long or branched chain C, -C6 alkyl, long chain or branched C2-C6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long chain or branched C? -C alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, cycloalkenyl C5- C7, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with CrC4 alkyl, C2-C6 alkenyl, hydroxy or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NR2, S, SO or SO2; R 2 is selected from the group consisting of hydrogen, long or branched chain CrC 4 alkyl, long chain or branched C 3 -C 4 alkenyl or alkynyl and C 1 -C 4 alkyl bridging, wherein a bridge is formed between the nitrogen and a carbon 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 pyrridyl, pyrimidyl, quinolinyl or isoquinolinyl which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, long or branched chain C6 alkyl, C2-C6 alkenyl long and branched chain, C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy and amino; said tertiary amine is wherein Ri, R5 and R6 are independently selected from the group consisting of long or branched chain C6-C6 alkyl and long or branched chain C2-C6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of long or branched chain C6 alkyl, long or branched chain C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with CrC4 alkyl, C2-C4 alkenyl, hydroxy or carbonyl oxygen, wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally replaced with O, NH, NRi, S, SO or SO2; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl and isoquinolinyl and R, and R 3 independently is hydrogen, long or branched chain C 1 -C 4 alkyl or long chain or branched C 3 -C 4 alkenyl group or alkynyl or YZ.
19. The pharmaceutical composition according to claim 18, wherein the compound is selected from the group consisting of: 3- (2-Pyridyl) -1-propyl (2S) -1- (1,1-Dimeti-1, 2-dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (3-Pyridyl) -1-propyr (2S) -1 - (1,1 -Dimethyl-1 ^ -dioxo-penti ^ -pyrrolidinecarboxylate, N-oxide; 3- (4-pyridyl) -1- propyl (2S) -1 - (1,1-dimethyl-1,2-d-oxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (2-Chloroyl) -1-propyl (2S) -1- (1,1-dimethyl-1,2-dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (3-QuinolI) -1-propyl (2S) -1- (1,1-Dimethyl-1,2-dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (4-Quinolyl) -1-propyl (2S) -1- (1,1-dimethyl-1,2-dioxo-pentyl) -2-pyrrolidinecarboxylate, N-oxide and pharmaceutically acceptable salts, esters and solvates of the same.
20. The pharmaceutical composition according to claim 11, wherein the N-oxide of a heterocyclic ester, amide, thioester or ketone is a compound of the formula V or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N or S; A and B, taken together with V and the carbon atom to which they are respectively added, form a saturated and unsaturated 5-7 membered heterocyclic ring containing, in addition to V, one or more heteroatoms independently selected from the group consisting of of O, S, SO, SO2, N, NH and NR7; R7 is C, -C9 long chain or branched alkyl or C2-Cg long chain or branched alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl or Ar3, wherein R7 is unsubstituted or substituted by one or more independently selected substituents of the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, tridluoromethyl, C-C6 long chain or branched alkyl, C2-C6 long chain or branched alkenyl, C, -C, C2-C4 alkenyloxy , phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl and Ar 4; Ar3 and Ar are independently alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the size of the individual ring is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S and R, W, X, Y and Z are as defined in claim 15 above.
MXPA/A/2000/011941A 2000-11-30 N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses MXPA00011941A (en)

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