MXPA00011912A - Heterocyclic ester and amide hair growth compositions and uses - Google Patents
Heterocyclic ester and amide hair growth compositions and usesInfo
- Publication number
- MXPA00011912A MXPA00011912A MXPA/A/2000/011912A MXPA00011912A MXPA00011912A MX PA00011912 A MXPA00011912 A MX PA00011912A MX PA00011912 A MXPA00011912 A MX PA00011912A MX PA00011912 A MXPA00011912 A MX PA00011912A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- straight
- branched chain
- group
- chain alkyl
- Prior art date
Links
- 230000003698 anagen phase Effects 0.000 title claims abstract description 52
- 150000001408 amides Chemical class 0.000 title claims abstract description 43
- 230000003779 hair growth Effects 0.000 title claims abstract description 43
- -1 Heterocyclic ester Chemical class 0.000 title claims description 83
- 239000000203 mixture Substances 0.000 title description 32
- 201000004384 alopecia Diseases 0.000 claims abstract description 48
- 231100000360 alopecia Toxicity 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 31
- 230000001737 promoting Effects 0.000 claims abstract description 3
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 149
- 150000001875 compounds Chemical class 0.000 claims description 62
- 125000003342 alkenyl group Chemical group 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 49
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 239000011780 sodium chloride Substances 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000005842 heteroatoms Chemical group 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- 108010027179 Tacrolimus Binding Proteins Proteins 0.000 claims description 18
- 102000018679 Tacrolimus Binding Proteins Human genes 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 18
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 239000012453 solvate Substances 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 125000002723 alicyclic group Chemical group 0.000 claims description 12
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- OBKXEAXTFZPCHS-UHFFFAOYSA-M 4-phenylbutyrate Chemical compound [O-]C(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-M 0.000 claims description 6
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 102100014139 FKBP1A Human genes 0.000 claims description 5
- 125000004429 atoms Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 150000007942 carboxylates Chemical class 0.000 claims description 5
- 230000001861 immunosuppresant Effects 0.000 claims description 5
- 239000003018 immunosuppressive agent Substances 0.000 claims description 5
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 108010006877 Tacrolimus Binding Protein 1A Proteins 0.000 claims description 4
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 3
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000005467 butylenyl group Chemical group 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000005356 cycloalkylalkenyl group Chemical class 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000004001 thioalkyl group Chemical group 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
- 125000002619 bicyclic group Chemical group 0.000 claims 2
- 125000002950 monocyclic group Chemical group 0.000 claims 2
- 125000000837 carbohydrate group Chemical group 0.000 claims 1
- 210000004209 Hair Anatomy 0.000 description 30
- 230000001506 immunosuppresive Effects 0.000 description 17
- 230000003676 hair loss Effects 0.000 description 15
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- 201000010099 disease Diseases 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000027455 binding Effects 0.000 description 9
- 239000003446 ligand Substances 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000006210 lotion Substances 0.000 description 7
- 230000012010 growth Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000000765 neuroimmunophilin Substances 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 208000004631 Alopecia Areata Diseases 0.000 description 5
- 210000004761 Scalp Anatomy 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- PMATZTZNYRCHOR-CGLBZJNRSA-N (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17 Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 4
- 108010036949 Cyclosporine Proteins 0.000 description 4
- 229960001265 ciclosporin Drugs 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000002304 perfume Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
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- 101700067048 CDC13 Proteins 0.000 description 3
- OQAHHWOPVDDWHD-INIZCTEOSA-N Gpi-1046 Chemical compound CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)OCCCC1=CC=CN=C1 OQAHHWOPVDDWHD-INIZCTEOSA-N 0.000 description 3
- 210000003780 Hair Follicle Anatomy 0.000 description 3
- 210000003491 Skin Anatomy 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
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- 239000002453 shampoo Substances 0.000 description 3
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- 239000000758 substrate Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 206010068168 Androgenetic alopecia Diseases 0.000 description 2
- 108090000317 Chymotrypsin Proteins 0.000 description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 206010029098 Neoplasm skin Diseases 0.000 description 2
- 108060002058 PPIL1 Proteins 0.000 description 2
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- 238000005299 abrasion Methods 0.000 description 2
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- 150000003863 ammonium salts Chemical class 0.000 description 2
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- 102000024070 binding proteins Human genes 0.000 description 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
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- 150000004694 iodide salts Chemical class 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N 2,2,2-trifluoroethyl alcohol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- SWGDHTSWHSSMLE-UHFFFAOYSA-N 3,3-dimethylpentane-2,4-dione Chemical compound CC(=O)C(C)(C)C(C)=O SWGDHTSWHSSMLE-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-M 3-cyclopentylpropanoate Chemical compound [O-]C(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-M 0.000 description 1
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- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
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- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl-oxo-[1-[6-(trifluoromethyl)pyridin-3-yl]ethyl]-$l^{6}-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
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- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
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- 201000002996 androgenic alopecia Diseases 0.000 description 1
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- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
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- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- 230000036770 blood supply Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
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- 229940081733 cetearyl alcohol Drugs 0.000 description 1
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- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007697 cis-trans-isomerization reaction Methods 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- JZKFHQMONDVVNF-UHFFFAOYSA-N dodecyl sulfate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCCCCCCOS(O)(=O)=O JZKFHQMONDVVNF-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
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- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000035784 germination Effects 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 231100001007 hair change Toxicity 0.000 description 1
- 230000031774 hair cycle Effects 0.000 description 1
- 230000003663 hair growth cycle Effects 0.000 description 1
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- 150000004820 halides Chemical class 0.000 description 1
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- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 1
- 230000003054 hormonal Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-M isethionate Chemical compound OCCS([O-])(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-M 0.000 description 1
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 230000003902 lesions Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- ZXUQEPZWVQIOJE-UHFFFAOYSA-N methyl 2-chloro-2-oxoacetate Chemical compound COC(=O)C(Cl)=O ZXUQEPZWVQIOJE-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- SOWBFZRMHSNYGE-UHFFFAOYSA-M oxamate Chemical compound NC(=O)C([O-])=O SOWBFZRMHSNYGE-UHFFFAOYSA-M 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-M pyrrolidine-1-carboxylate Chemical class [O-]C(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-M 0.000 description 1
- 230000001603 reducing Effects 0.000 description 1
- 230000000979 retarding Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000004936 stimulating Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000224 toxic side effect Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Abstract
This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using heterocyclic esters or amides.
Description
HETEROCICLES ESTER AND AMID COMPOSITIONS FOR HAIR GROWTH AND USES
This request is a partial continuation of the
U.S. Patent Application Number 08 / 869,426, filed June 4, 1997, the entire contents of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION Field of the Invention This invention relates to pharmaceutical compositions and methods for the treatment of alopecia, and to promote hair growth using low molecular weight, small molecule heterocyclic esters or amides.
2. Description of Related Art 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 systemic disorders, such as nutritional disorders and internal secretion disorders. The mechanisms that cause hair loss are very complicated, but in some cases, they can be attributed to aging, to the disposition
| * «S ^^^^^ i ^ U genetic, to the activation of male hormones, to the loss of blood supply to the hair follicles, and to abnormalities of the scalp. The immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell-specific immunosuppressants, and are effective against graft rejection after organ transplantation. It has been reported that topical, but not oral, application of FK506 (Yamamoto et al., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J. Invest. Dermatol., 1995, 104, 523- 525) and cyclosporin (Iwabuchi et al., J. Dermatol, Sci., 1995, 9, 64-69) stimulates hair growth in a dose-dependent manner. It is known that a form of hair loss, alopecia areata, is associated with autoimmune activities; therefore, it is expected that topically administered immunomodulatory compounds demonstrate efficacy for the treatment of that type of hair loss. The stimulating effects of hair growth of FK506 have been the subject of an international patent presentation covering FK506 and structures related thereto for the stimulation of hair growth (Honbo et al., European Patent Number EP 0423 714 A2). Honbo et al. Report the use of relatively large tricyclic compounds, known for their immunosuppressive effects, as hair revitalizing agents.
The effects of hair growth and revitalization of FK506, and related agents, are disclosed in many United States patents. North America (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. United States of America Number 5,189,042; and Ok et al., United States Patent 5,208,241; Rupprecht et al., United States Patent Number 5,284,840; Organ et al., United States Patent Number 5,284,877) . These patents claim compounds related to FK506. Although they do not claim methods for hair revitalization, they do disclose 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. Furthermore, the patents cited refer to immunomodulatory compounds for use in diseases related to autoimmunity, for which the efficacy of FK506 is well known. Other patents from the United States of America disclose the use of cyclosporin and related compounds
* - «* < & amp; amp; jii ^^^^^^ i ^? ^ & * »for the revitalization of hair (Hauer et al., U.S. Patent 5,342,625; Eberle, U.S. Patent Number 5,284,826; Hewitt et al., United States Patent Number 4,996,193). These patents also refer to compounds useful for the treatment of autoimmune diseases, and cite the known use of cyclosporin and related immunosuppressant compounds for hair growth. However, immunosuppressive compounds, by definition, suppress the immune system, and also exhibit other toxic side effects. According to the above, there is a need for small molecule compounds that are not immunosuppressive, which are useful as compounds for revitalizing the hair. Hamilton and Steiner disclose, in U.S. Patent No. 5,614,547, novel pyrrolidine carboxylate compounds, which bind to the immunophilin FKBP12, and stimulate nerve growth, but which lack immunosuppressive effects. In an unexpected way, it has been discovered that these compounds, which are not immunosuppressive, promote hair growth with an effectiveness similar to that of FK506. However, their novel structure of small molecules, and their non-immunosuppressive properties, differentiate them from FK506 and related immunosuppressive compounds found in the prior art.
COMPENDIUM OF THE INVENTION The present invention relates to a method for the treatment of alopecia, or to promote hair growth in an animal, which comprises administering to this animal an effective amount of a heterocyclic ester or amide. The present invention further relates to a pharmaceutical composition comprising: (i) an effective amount of a heterocyclic ester or amide, for the treatment of alopecia or to promote hair growth in an animal; and (ii) a pharmaceutically acceptable carrier. The heterocyclic esters and amides used in the methods of the invention, and the pharmaceutical compositions, have an affinity for the FKBP type immunophilins, and do not exert any significant immunosuppressive activity.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a photograph of C57 Black 6 mice before being shaved for the hair regeneration experiment. Figure 2 is a photograph of mice treated with a vehicle after six weeks. Figure 2 shows that less than 3 percent of the shaved area is covered with new hair growth when the vehicle is administered (control). Figure 3 is a photograph of mice treated with 10 μM of GPI 1046, a ligand of neuroimmunophilin FKBP, non-immunosuppressive related, after six weeks. The figure
3 shows the notorious effects of FKBP neuroimmunophilin ligands, where 90 percent of the shaved area is covered with new hair growth. Figure 4 is a photograph of mice treated with
μM of GPI 1046, a non-immunosuppressive related neuroimmunophilin ligand FKBP, after six weeks. The figure
4 shows the remarkable ability of the FKBP neuroimmunophilin ligands to achieve essentially complete re-growth of the hair in the shaved area. Figure 5 is a bar graph illustrating the relative hair growth rates for C57 Black 6 treated mice with one vehicle, FK506, and different non-immunosuppressive FKBP neuroimmunophilin ligands, including GPI 1572, 14 days after treatment with each compound identified. Figure 5 demonstrates the notorious early hair growth promoted by a wide variety of non-immunosuppressive FKBP neuroinmunophilin ligands.
DETAILED DESCRIPTION OF THE INVENTION Definitions "Alopecia" refers to poor hair growth, and a partial or complete loss of hair, including, without limitation, androgenic alopecia (male pattern baldness), toxic alopecia, alopecia senilis, alopecia areata, peeling alopecia and trichotillomania. Alopecia results when the pillar cycle is interrupted. The most frequent phenomenon is a shortening of hair growth or anagen phase, due to the cessation of cell proliferation. This results in an early establishment of the catagen phase, and consequently, a large number of hairs in the telogen phase during which the follicles of the dermal papillae separate, and the hair falls out. Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental tensions, hormonal problems, and side effects of drugs. "GPI 1605" refers to a compound of the formula:
"GPI 1046" refers to (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidine-carboxylate of 3- (3-pyridyl) -1-propyl, a compound of the formula :
GPl 1312"refers to a compound of the formula:
GPl 1572"refers to a compound of the formula:
GP 1389"refers to a compound of the formula:
"GPl 1511" refers to a compound of the formula:
GPl 1234"refers to a compound of the formula:
"Isomers" refers to different compounds that have the same molecular formula. "Stereoisomers" are the isomers that differ only in the way that atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are mirror images that can not be superimposed on one another. "Diastereoisomers" are stereoisomers that 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 portions of individual enantiomers or stereoisomers.
< - .. < -, ... x .-- ,, .. -y * sy.h. .
"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 not biologically or otherwise undesirable. A salt, ester, or solvate can be formed with inorganic acids, such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorrate, camphorsulfonate, cyclopentanpropionate, digluconate, dodecylisulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, iodhydrate, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthalene sulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples of the salts, esters, or base 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, etc. Also, groups containing basic nitrogen can be quaternized with agents such 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 chlorides,
t ^^ j¡Í £ ^^^^^^ & ^^^^^^^^^^^^^^^^^^^^^^ jiJi * ^^ K * ¡& z ^^ bromides and iodides of decyl, lauryl, myristyl and stearyl; aralkyl halides, such as benzyl and phenethyl bromides, and others. In this way soluble or dispersible products are obtained in water or oil. "Pillar cycle" refers to the life cycle of hair follicles, and includes three phases: (1) The anagen phase, the period of active growth of the hair that, up to where it refers to the hair of the scalp, lasts approximately three at five years, - (2) the catagen phase, the period when growth stops, and the follicle atrophies, which, as far as the hair of the scalp is concerned, lasts approximately one to two weeks; and (3) the telogen phase, the remaining period when the hair progressively separates and finally falls, which, as far as the hair of the scalp is concerned, lasts for approximately three to four months. Normally 80 to 90 percent of the follicles are in the anagen phase, less than 1 percent in the catagen phase, and the rest in the telogen phase. In the telogen phase, the hair is of a uniform diameter with a slightly bulbous, non-pigmented root. In contrast, in the anagen phase, the hair has a large colored bulb at its root. "Promotion of hair growth" refers to
... i.
maintain, induce, stimulate, accelerate, or revitalize hair germination. "Alopecia treatment" 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) promote hair growth; and / or (iv) prolonging the anagen phase of the hair cycle; and / or (v) convert hair to grow as terminal hair. The terminal hair is thick, pigmented, long hair, where the bulb of the hair follicle sits deep in the dermis. The hair, on the other hand, is fine, thin, short and non-pigmented hair, where the hair bulb is located superficially in the dermis. As the alopecia progresses, the hair changes from the terminal type to the hairy type.
Methods of the Present Invention The present invention relates to a method for the treatment of alopecia or to promote hair growth in an animal, which comprises administering to this animal an effective amount of a heterocyclic ester or amide. The method of the invention is particularly useful
; -. *. xtt ^ ^ - ix a .¿ --.- yj * »*.
for the treatment of male pattern alopecia, senile alopecia, alopecia areata, alopecia resulting from lesions or skin tumors, alopecia resulting from cancer therapy, such as chemotherapy and radiation, and alopecia resulting from systemic disorders, such as nutritional disorders and disorders of internal secretion.
Pharmaceutical Compositions of the Present Invention The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of a heterocyclic ester or amide, for the treatment of alopecia or for promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
STERES AND HETEROCICLIC AMIDES The heterocyclic esters and amides used in the methods and pharmaceutical compositions of the present invention are low molecular weight small molecule compounds, which have an affinity for an FKBP type immunophilin, such as FKB12. When a heterocyclic ester or amide is attached to an immunophilin of the FKBP type, it has been found to inhibit the cis-trans isomerase of prolyl-peptidyl, or rotamase, the activity of the binding protein. In an unexpected way, it has also been found that the compounds stimulate the
.J.
Hair growth. The compounds are free from any significant immunosuppressive activity.
FORMULA I The heterocyclic ester or amide may be a compound of Formula I:
or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, together with the nitrogen and carbon atoms with which they are respectively attached, form a saturated or unsaturated 5- to 7-membered heterocyclic ring containing, in addition to the nitrogen atom, one or more additional heteroatoms O, S, SO, S02, N, NH or NRX; X is 0 or S; Z is 0, NH or NR ?; and Y are independently 0, S, CH or H2; RL is straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms, which is substituted with one or more substituents independently selected from the group consisting of (Ar - straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Ar1) n, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with cycloalkyl of 3 to 8 carbon atoms, Y Ar2; n is 1 or 2; straight or branched chain of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Ar1; alkyl, alkenyl, cycloalkyl or cycloalkenyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl branched or straight-chain 1 to 4 carbon atoms, branched alkenyl or straight-chain 2 to 4 carbon atoms, and hydroxy; and Ar-L and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen , hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 atoms carbon, phenoxy, benzyloxy and amino, wherein the size of the individual ring is from 5 to 6 members; and wherein the heterocyclic ring contains from 1 to 6 heteroatoms independently selected from the group consisting of 0, N and S. Suitable carbo- and heterocyclic rings include, without limitation, naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl and phenyl.
FORMULA II Additionally, the heterocyclic ester or amide may be a compound of Formula II:
or a pharmaceutically acceptable salt, ester or solvent thereof, wherein:
^^^ ft A, B and C are independently CH2, 0, S, SO, S02,
NH Ó NR ?; R is straight or branched chain alkyl of 1 to 5 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms, which is substituted with one or more substituents independently selected from the group consisting of (Ar ^ -, and straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with { - r-) n; n is 1 or 2; R2 is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or A1 (- and Arx is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy, phenoxy, benzyloxy and amino; wherein the size of the individual ring is from 5 to 6 members, and wherein the heterocyclic ring contains from 1 to 6 heteroatoms independently selected from the group consisting of O, N and S. In a preferred embodiment of the of the formula II, the heterocyclic ester or amide is the compound GPl 1572, of the formula:
In a particularly preferred embodiment of Formula II, compounds wherein: A is CH2, B is CH2 or S; C is CH2 or NH; R- is selected from the group consisting of 3-phenylpropyl and 3- (3-pyridyl) propyl; and R2 is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl and tertiary butyl. The specific examples of this modality are presented in Table I.
TABLE I
FORMULA III The heterocyclic ester or amide may also be a compound of Formula III:
or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A, B, C and D are independently CH2, 0, S, SO, S02, NH or NR ?;
J ^^ z R? is straight or branched chain alkyl of 1 to 5 carbon atoms, or straight or branched chain alkenyl of 2 to 5 carbon atoms, which is substituted with one or more substituents independently selected from the group consisting of (Ar. and straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Arx) n; n is 1 or 2, R2 is straight chain alkyl or branched from 1 to
9 carbon atoms, straight chain or branched alkenyl of
2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or r ^ - and Ar-L is an alicyclic or aromatic ring, mono-, bi-or tricyclic, carbo- or heterocyclic, wherein the ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, chain alkenyl straight or branched of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; wherein the size of the individual ring is from 5 to 6 members; and wherein the heterocyclic ring contains from 1 to 6 heteroatoms independently selected from the group that
- ** a ^ ~ ,. '.X -m $ ¿? - > . x &r¿. ± - yy consists of O, N and S. In a particularly preferred embodiment of Formula III, compounds wherein: A is CH2; B is CH2; C is S, O or NH; D is CH2; R-L is selected from the group consisting of 3-phenylpropyl and (3,4,5-trimethoxy) phenylpropyl; and R, is selected from the group consisting of
1,1-dimethylpropyl, cyclohexyl, tertiary butyl, phenyl and 3,4,5-trimethoxyphenyl. The specific examples of this modality are presented in Table II.
TABLE II
FORMULA IV
The heterocyclic ester or amide may also be a compound of Formula IV:
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 with which they are respectively attached, form a saturated or unsaturated 5- to 7-membered heterocyclic ring containing, in addition to V, one or more heteroatoms independently selected from the group consisting of 0, S, S02, N, NH and NR R is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 9 atoms of carbon, cycloalkenyl of 5 to 7 carbon atoms, or Ar 3, wherein R is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, haloalkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, n-oxoxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar4; Ar3 and Ar4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the size of the individual ring is from 5 to 8 member; wherein the heterocyclic ring contains from 1 to 6 heteroatoms independently selected from the group consisting of O, N and S; and Rl; R2, X, Y and Z are as defined in Formula I above. All compounds of Formulas I-IV possess asymmetric centers and, therefore, can be produced as mixtures of stereoisomers, or as the individual R and S stereoisomers. Individual stereoisomers can be obtained by using an optically active starting material, by resolution of a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of compounds of Formulas I-IV . It is understood that the compounds of Formulas I-IV encompass the individual stereoisomers, as well as the mixtures (racemic and non-racemic) of the stereoisomers. Preferably S stereoisomers are used in the pharmaceutical compositions and methods of the present invention.
Affinity for FKBP12 The compounds used in the methods and pharmaceutical compositions of the invention have an affinity for the binding protein of FKB506, particularly FKBP12. Inhibition of the prolyl-peptidyl cis-trans isomerase activity of FKBP can be measured from an indicator of this affinity.
Test procedure K The inhibition of the peptidyl-prolyl isomerase activity (rotamase) of the compounds used in the methods and pharmaceutical compositions of the invention can be evaluated by known ones described in the literature (Harding et al., Nature 1989, 341: 758-760; Holt et al., J. Am. Soc., 115: 9923-9938). These values are obtained as the apparent Kx, and are presented for the representative compounds in Table III. The cis-trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-
Item.
nitroanilide, is monitored spectrophotometrically in an assay coupled with chymotrypsin, 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 are analyzed as a change in the first order index constant as a function of the concentration of the inhibitor to produce the apparent K-values. 950 milliliters of frozen test regulator (25 mM HEPES) are added to a plastic cuvette, pH 7.8, 100 mM NaCl), 10 milliliters of FKBP (2.5 nM in 10 mM Tris-Cl, pH 7.5, 100 mM NaCl, 1 mM dithioerythritol), 25 milliliters of chymotrypsin (50 milligrams / milliliter in 1 mM HCl. ), and 10 milliliters of the test compound in different concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 milliliters of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 milligrams / milliliter in 2.35 mM LiCl in trifluoroethanol). The absorbance is monitored at 390 nanometers against time for 90 seconds using a spectrophotometer, and the index constants are determined from the absorbance data files against time.
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Route of Administration To effectively treat alopecia, or to promote hair growth, the compounds used in the methods and pharmaceutical compositions of the invention, should easily affect the targeted areas. For these purposes, the compounds are preferably topically administered to the skin. For topical application to the skin, the compounds may be formulated in suitable ointments containing the suspended or dissolved compounds in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, compound of polyoxyethylene-polyoxypropylene, emulsifying wax and water. Alternatively, the compounds can be formulated in 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, wax ethyl ester, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The present invention also contemplates other routes of administration known in the pharmaceutical art.
Dosage Dosage levels in the range of about 0.1 milligrams to about 10,000 milligrams of the active ingredient compound are useful in the treatment of the above conditions, with levels of about 0.1 milligrams to about 1,000 milligrams being preferred. 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 drugs; the severity of the particular disease being treated; and the form of administration. Normally, dosing-effect results provide a useful guide on the appropriate doses to be administered 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 agents to revitalize the hair. The specific dose levels for the other hair revitalizing agents will depend on the previously mentioned factors, and on the effectiveness of the drug combination.
EXAMPLES The following examples are illustrative of the present invention, and are not intended to be limitations thereon. Unless stated otherwise, all percentages are based on 100 percent by weight of the final composition.
Example 1 Synthesis of (2S) -1- (3, 3-dimethyl-1,2-dioxopentyl) -2- thiazolidin) 3-phenyl-1-propyl (1) 2- (4-thiazolidin) -carboxylate 1- (1,2-dioxo-methoxyethyl) carboxylate A solution of L-thioproline (1.51 grams, 11.34 mmol) in 40 milliliters of dry methylene chloride was cooled to 0 ° C, and treated with 3.3 milliliters (2.41 grams, 23.81 millimoles) of triethylamine. After stirring this mixture for 30 minutes, a solution of methyloxalyl chloride (1.81 grams, 14.74 mmol) was added dropwise. The resulting mixture was stirred at 0 ° C for 1.5 hours, filtered through Celite to remove solids, dried and concentrated. The crude material was purified on a column of silica gel, eluting with 10 percent MeOH in methylene chloride, to obtain 2.0 grams of the oxamate as an orange-yellow solid. (2S) -1- (1,2-dioxo-2-methoxyethyl) -2- (4-thiazolin) carboxylate of 3-phenyl-1-propyl. 2- (4-thiazolidin) -carboxylic acid 1- (1,2-dioxo-2-methoxyethyl) (500 milligrams, 2.25 mmol), 3-phenyl-1-propanol (465 milligrams, 3.42 mmol), dicyclohexylcarbodiimide (750 milligrams, 3.65 millimoles), 4-dimethylaminopyridine
(95 milligrams, 0.75 millimoles), and camphor sulfonic acid (175 milligrams); 0.75 mmol) in 30 milliliters of methylene chloride were stirred together overnight. The mixture was filtered through Celite to remove the solids, and passed through chromatography (25 percent ethyl acetate / hexane) to obtain 690 milligrams of the material. 1 H NMR (CDC13, 300 MHz): dl.92-2.01 (m, 2H); 2.61-2.69 (m, 2H); 3.34 (m, ÍH); 4.11-4.25 (m, 2H); 4.73 (m, ÍH); 5.34 (m, ÍH); 7.12 (m, 3H); 7.23 (m, 2H). (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2- (4-thiaxolidine) 3-phenyl-1-propyl carboxylate (1) A solution of (2S) -1- (1) , 3-phenyl-1-propyl 2-dioxo-2-methoxyethyl) -2- (4-thiazolidin) carboxylate (670 milligrams, 1.98 millimoles) in tetrahydrofuran (10 milliliters), cooled to -78 ° C, and treated with 2.3 milliliters of a 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in ether. After stirring the mixture for 3 hours, it was poured into saturated ammonium coloruro, extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated. The crude material was purified on a column of silica gel, eluting with 25 percent ethyl acetate in hexane, to obtain 380 milligrams of the title compound of Example 1 as a yellow oil. 1 H NMR (CDC13, 300 MHz): d 0.86 (t, 3H); 1.21
(?, 3H); 1.26 (s, 3H); 1.62-1.91 (m, 3H); 2.01 (m, 2H); 2.71
(m, 2H); 3.26-3.33 (m, 2H); 4.19 (m, 2H); 4.58 (m, ÍH); 7.19
(m, 3H); 7 30 (m, 2H). Analysis calculated for C20H27NO4S: C,
63 63; H, 7 2. 3; N, 3 71 Found: C, 64. 29; H, 7 39; N, 3 46 Example 2 Synthesis of (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2- (4- iazolidin) carboxylate of 3- (3-pyril) -1-propyl (2) The compound of Example 2 was prepared according to the procedure of Example 1, using 3- (3-pyridyl) -1-propanol in the final step, to give (2) -1- (3, 3-dimethyl-2, 2- dioxopentyl) -2- (4-thiazolidin) carboxylic acid 3- (3-pyril-1-propyl) -1H NMR (CDC13, 300 MHz): d? .89 (t, 3H, J = 7.3); 1.25 (S, 3H ), 1.28 (s, 3H), 1.77 (q, 2H, J = 7.3), 2.03 (tt, 2H, J = 6.4, 7.5), 2.72 (t, 2H, J = 7.5), 3.20 (dd, ÍH, J = 4.0, 11.8), 3.23 (dd, ÍH, J = 7.0, 11.8), 4.23 (t, 2H, J = 6.4), 4.55 (d, 2H, J = 8.9), 5.08 (dd, ÍH, J = 4.0, 7.0), 7.24 (m, HH), 8.48 (m, 2H), calculated analysis for C19H26N204S - 0.5 H20: C, 58.89; H, 7.02, N, 7.23 Found: C, 58.83; H, 7.05; N , 7.19.
Example 3 Live Hair Generation Tests with C57 Black 6 Mice Experiment A: C57 Black 6 mice were used to demonstrate the hair revitalization properties of a non-immunosuppressive, small molecule, low molecular weight FKBP neuroinmunophilin ligand, GPl 1046, which is related to the heterocyclic esters and amides. Referring now to Figures 1 and 2 of the drawings, the C57 Black 6 mice, approximately 7 weeks old, had an area of approximately 5 centimeters by 5 centimeters of their shaved hindquarters to remove all existing hair. Care was taken not to pinch or cause abrasion to the underlying dermal layers. The animals were in the anagen growth phase, as indicated by the pink color of the skin. Referring now to Figures 2, 3 and 4, four animals were treated per group by topical administration with 20 percent propylene glycol vehicle (Figure 2), 10 μM GPl 1046 (Figure 3), or 30 μM GPl 1046 (Figure 2). 4) dissolved in the vehicle. The animals were treated with vehicle or GPl 1046 every 48 hours (3 applications in total during the course of five days), and hair growth was allowed to proceed for 6 weeks. Hair growth was quantified by the percentage of the shaved area covered by new hair growth during this period of time.
Figure 2 shows that the vehicle-treated animals exhibited only a small amount of hair growth in patches or tufts, with less than 3 percent of the shaved area covered by the new growth. In contrast, Figure 3 shows that animals treated with 10 μM GPl 1046 exhibited dramatic hair growth, covering more than 90 percent of the shaved area in all animals. In addition, Figure 4 shows that mice treated with 30 μM GPl 1046 exhibited an essentially complete re-growth of hair, and their shaved areas were indistinguishable from those of non-shaved C57 Black 6 mice. Experiment B: C57 Black 6 mice were used to demonstrate the hair revitalization properties of a variety of non-immunosuppressive, small molecule, low molecular weight FKBP neuroimmunophilin ligands, including GPl 1572. C57 Black 6 mice, 55 75 days old, they had an area of approximately 5 centimeters by five centimeters of their shaved hindquarters, to remove all existing hair. Care was taken not to pinch or cause abrasion to 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 vehicle, FK506, or one of the non-immunosuppressive, small molecule, low molecular weight FKBP neuroinmunophilin ligands (GPl 1605, 1046,
US x j > .
1312, 1572, 1389, 1511 and 1234), in a concentration of one micromole per milliliter to the shaved area. The animals were treated three times a week, and hair growth was evaluated 14 days after the start of treatment. Hair growth was quantified by the percentage of shaved area covered by the new hair growth, qualified by a blind observer, on a scale of 0 (no growth) to five (a re-growth of full hair in the shaved area) . Figure 5 shows that after 14 days, the animals treated with vehicle exhibited the start of growth in small tufts. In contrast, animals treated with one of the non-immunosuppressive small molecule, low molecular weight FKBP neuroinmunophilin ligands, including GPl 1572, exhibited dramatic hair growth.
Example 4 A lotion comprising the following composition can be prepared.
In 95 percent ethanol, a heterocyclic ester or amide, o-α-tocopherol acetate, ethylene oxide (40 mole) adducts of hardened castor oil, perfume and a dye were added. The resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain a clear liquid lotion. You can apply 5 milliliters of the lotion once or twice a day to a site that has a noticeable baldness or alopecia.
Example 5
A lotion comprising the following composition shown can be prepared.
In 95 percent ethanol, a heterocyclic ester or amide, hinokitol, ethylene oxide (40 moles) adducts of hardened castor oil, perfume and a dye are added.
The resulting mixture is stirred, and purified water is added to the mixture to obtain a clear liquid lotion. The lotion can be applied by spraying one to four times a day to a site that has notorious baldness or alopecia.
Example 6 An emulsion can be prepared from phase A and phase B, having the following compositions.
Phase A and phase B are heated and melted respectively, and maintained at 80 ° C. Then both phases are mixed and cooled with stirring at normal temperature to obtain an emulsion. The emulsion can be applied by spraying one to four times a day to a site that has a noticeable baldness or alopecia.
Example 7
A cream can be prepared from Phase A and Phase B having the following compositions.
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Phase A is heated and melted, and maintained at 70 ° C.
Phase B is added in phase A, and the mixture is stirred to obtain an emulsion. Then the emulsion is cooled to obtain a cream. The cream can be applied one to four times
days to a site that has notorious baldness or alopecia.
Example 8 A liquid comprising the following composition can be prepared. 25
^ .- ^ ¿s ^ Jx k.
In ethanol, polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, a heterocyclic ester or amide, and perfume are added. The resulting mixture is stirred, and purified water is added to the mixture to obtain a liquid. The fluid can be applied one to four times a day to a site that has notorious baldness or alopecia.
Example 9 A shampoo comprising the following composition can be prepared.
--1 *
In 69.7 grams of purified water, 5.0 grams of sodium laurisulfate, 5.0 grams of triethanolamine lauryl sulfate, 6.0 grams of betaine lauryl dimethylaminoacetate are added. Then a mixture obtained is successively added by the addition of 5.0 grams of a heterocyclic ester or amide, 5.0 grams of polyethylene glycol, and 2.0 grams of ethylene glycol distearate to 2.0 grams of ethanol, followed by stirring, and 0.3 grams of perfume. The resulting mixture is heated, and subsequently cooled to obtain a shampoo. The shampoo can be used on the scalp once or twice a day.
. - j Example 10 A patient suffers from alopecia senilis. A heterocyclic ester or amide may be administered as identified above, or a pharmaceutical composition comprising them, to the patient. It is expected that more hair growth will occur next to the treatment.
Example 11 A patient suffers from male pattern alopecia. The heterocyclic ester or amide may be administered to the patient as identified above, or a pharmaceutical composition comprising them. It is expected that more hair growth will occur next to the treatment.
Example 12 A patient suffers from alopecia areata. The heterocyclic ester or amide may be administered to the patient as identified above, or a pharmaceutical composition comprising them. It is expected that more hair growth will occur next to the treatment.
Example 13 A patient suffers from hair loss caused by skin lesions. A heterocyclic ester or amide can be administered to the patient as identified
I, above, or a pharmaceutical composition comprising them. It is expected that more hair growth will occur next to the treatment.
Example 14 A patient suffers from hair loss caused by tumors. The heterocyclic ester or amide may be administered to the patient as identified above, or a pharmaceutical composition comprising them. It is expected that more hair growth will occur next to the treatment.
Example 15 A patient suffers from hair loss caused by a systemic disorder, such as a nutritional disorder or an internal secretion disorder. The heterocyclic ester or amide may be administered to the patient as identified above, or a pharmaceutical composition comprising them. It is expected that more hair growth will occur next to the treatment.
Example 16 A patient suffers from hair loss caused by chemotherapy. The heterocyclic ester or amide may be administered to the patient as identified above, or a pharmaceutical composition comprising them. It is expected that more hair growth will occur next to the treatment.
Example 17 A patient suffers from hair loss caused by radiation. The heterocyclic ester or amide may be administered to the patient as identified above, or a pharmaceutical composition comprising them. It is expected that more hair growth will occur next to the treatment.
Having thus described the invention it will be obvious that it can be varied in many ways. These variations should not be considered as a departure from the spirit and scope of the invention, and it is intended that all of these modifications be included within the scope of the following claims.
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Claims (32)
1. A method for the treatment of alopecia or to promote hair growth in an animal, which comprises administering to this animal an effective amount of a heterocyclic ester or amide.
2. The method of claim 1, wherein the heterocyclic ester or amide is non-immunosuppressant.
3. The method of claim 1, wherein the heterocyclic ester or amide has an affinity for an immunophilin of the FKBP type.
4. The method of claim 3, wherein the FBKP and FKBP-12 type immunophilin.
The method of claim 1, wherein the heterocyclic ester or amide is a compound of Formula I: or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, together with the nitrogen and carbon atoms with which they are respectively attached, form a saturated or unsaturated 5- to 7-membered heterocyclic ring containing, in addition to the nitrogen atom, one or more additional 0, S, SO, S02, N, NH or NRX heteroatoms; X is 0 or S; Z is 0, NH or NR ?; W and Y are independently 0, S, CH2 or H2; R-- is straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms, which is substituted with one or more substituents independently selected from the group consisting of (Ar.,.) -, straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Ar ^, cycloalkyl of 3 to 8 carbon atoms) carbon, straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with cycloalkyl of 3 to 8 carbon atoms, and Ar2; n is 1 or 2; R2 is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl from 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Ar ^ wherein this alkyl, alkenyl, cycloalkyl or cycloalkenyl is unsubstituted or substituted with one or more independently selected substituents from the group consisting of straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbon atoms, and hydroxyl; and Ar2 and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl , nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms , phenoxy, benzyloxy and amino, wherein the size of the individual ring is from 5 to 6 members; and wherein the heterocyclic ring contains from 1 to 6 heteroatoms independently selected from the group consisting of O, N and S.
The method of claim 5, wherein the mono- or bicyclic, carbo- or heterocyclic ring, is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, «A ^ ¿. > 4 -. x? fluorenyl and phenyl.
The method of claim 5, wherein one or more additional heteroatoms in the saturated or unsaturated 5-7 membered heterocyclic ring is NH or NRX.
The method of claim 1, wherein the heterocyclic ester or amide is a compound of Formula II: or a pharmaceutically acceptable salt, ester or solvent thereof, wherein: A, B and C are independently CH2, 0, S, SO, S02, NH or NRX; R? is straight or branched chain alkyl of 1 to 5 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms, which is substituted with one or more substituents independently selected from the group consisting of (AG- L) .-, and straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Ar ^ j; n is 1 or 2; R2 is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or A1 # - and Arx is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy, phenoxy, benzyloxy and amino; wherein the size of the individual ring is from 5 to 6 members; and wherein the heterocyclic ring contains from 1 to 6 heteroatoms independently selected from the group consisting of O, N and S.
The method of claim 8, wherein: A is CH2, B is CH2 or S; C is CH2 or NH; R-L is selected from the group consisting of 3-phenylpropyl and 3- (3-pyridyl) propyl; and R2 is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl and tertiary butyl. ? ÍHH¿jB¿ xx - ¿wig »A. í fc * *
10. The method of claim 9, wherein: B is CH2; C is NH; and Ri is 3-phenylpropyl.
The method of claim 9, wherein: B is S; and C is CH2.
The method of claim 8, wherein the compound is selected from the group consisting of: (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2- (4-thiazolidine) 3-phenyl-1-propyl carboxylate; (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2- (4-thiazolidin) carboxylate of 3- (3-pyridyl) -1-propyl; and pharmaceutically acceptable salts, esters and solvates thereof.
The method of claim 1, wherein the heterocyclic ester or amide is a compound of Formula III: or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A, B, C and D are independently CH2, 0, S, SO, S02, NH or NRX; R- is straight or branched chain alkyl of 1 to 5 carbon atoms, or straight or branched chain alkenyl of 2 to 5 carbon atoms, which is substituted with one or more substituents independently selected from the group consisting of ( Ar1) r ?, and straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Ar1) n; n is 1 or 2; R2 is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Ar1 # - and Rx is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl , nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy from 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; wherein the size of the individual ring is from 5 to 6 members; and wherein the heterocyclic ring contains from 1 to 6 heteroatoms independently selected from the group consisting of O, N and S.
The method of claim 13, wherein: A is CH2; B is CH2; C is S, 0 or NH; D is CH2; R1 is selected from the group consisting of 3-phenylpropyl and (3,4,5-trimethoxy) phenylpropyl; and R2 is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl, tertiary butyl, phenyl and 3,4,5-trimethoxyphenyl.
15. The compound of claim 14, wherein: C is NH; and R 2 is 1,1-dimethylpropyl or phenyl.
16. The method of claim 1, wherein the heterocyclic ester or amide is a compound of Formula IV: B .-. ? 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 with which they are respectively attached, form a saturated or unsaturated 5- to 7-membered heterocyclic ring containing, in addition to V, one or more heteroatoms independently selected from the group consisting of 0, S, S02, N, NH and NR R is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 9 atoms of carbon, cycloalkenyl of 5 to 7 carbon atoms, or Ar 3, wherein R is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, haloalkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, b encyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 4; Ar3 and Ar4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbohydrate ring. heterocyclic; wherein the size of the individual ring is from 5 to 8 member; wherein the heterocyclic ring contains from 1 to 6 heteroatoms independently selected from the group consisting of 0, N and S; and R1; R2, X, Y and Z are as defined in claim 5 above.
17. A pharmaceutical composition comprising: (i) an effective amount of a heterocyclic ester or amide, for the treatment of alopecia or for promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
18. The pharmaceutical composition of claim 17, wherein the heterocyclic ester or amide is non-immunosuppressant.
19. The pharmaceutical composition of claim 17, wherein the heterocyclic ester or amide has an affinity for an immunophilin of the FKBP type.
20. The pharmaceutical composition of claim 19, wherein the FKBP type immunophilin is FKBP-12.
21. The pharmaceutical composition of claim 17, wherein the heterocyclic ester or amide is a compound of Formula I: -. or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, together with the nitrogen and carbon atoms with which they are respectively attached, form a saturated or unsaturated 5- to 7-membered heterocyclic ring containing, in addition to the nitrogen atom, one or more additional 0, S, SO, S02, N, NH or NR1 heteroatoms; X is 0 or S; Z is 0, NH or NR ?; and Y are independently 0, S, CH2 or H2; RL is straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms, which is substituted with one or more substituents independently selected from the group consisting of (Ar) ) n, straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Ar-L) n, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with 3 to 3 cycloalkyl 8 carbon atoms, and Ar2; n is 1 or 2; R2 is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl TO .. from 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Arx, wherein this alkyl, alkenyl, cycloalkyl or cycloalkenyl is unsubstituted or substituted with one or more independently selected substituents from the group consisting of straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbon atoms, and hydroxyl; and Arx and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl , nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms , phenoxy, benzyloxy and amino, wherein the size of the individual ring is from 5 to 6 members; and wherein the heterocyclic ring contains from 1 to 6 heteroatoms independently selected from the group consisting of O, N and S.
The pharmaceutical composition of claim 21, wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl and phenyl.
23. The pharmaceutical composition of claim 21, wherein one or more additional heteroatoms in the saturated or unsaturated 5-7 membered heterocyclic ring is NH or NRX.
The pharmaceutical composition of claim 17, wherein the heterocyclic ester or amide is a compound of Formula II: or a pharmaceutically acceptable salt, ester or solvent thereof, wherein: A, B and C are independently CH2, O, S, SO, S02, NH or NR-L; RL is straight or branched chain alkyl of 1 to 5 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms, which is substituted with one or more substituents independently selected from the group consisting of (AG -L) .., and straight or branched chain alkyl of 1 to 6 carbon atoms, or chain alkenyl ----- straight or branched of 2 to 6 carbon atoms substituted with (Ar?) n; n is 1 or 2; R2 is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or A; and Ar-L is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy, phenoxy, benzyloxy and amino; wherein the size of the individual ring is from 5 to 6 members; and wherein the heterocyclic ring contains from 1 to 6 heteroatoms independently selected from the group consisting of 0, N and S.
25. The pharmaceutical composition of the claim 24, wherein: A is CH2, B is CH2 or S; C is CH2 or NH; R-L is selected from the group that A consists of 3-phenylpropyl and 3- (3-pyridyl) propyl; and R2 is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl and tertiary butyl.
26. The pharmaceutical composition of claim 24, wherein: B is CH2; C is NH; and Ri is 3-phenylpropyl.
27. The pharmaceutical composition of the claim 25, where: B is S; and
28. The pharmaceutical composition of claim 24, wherein the compound is selected from the group consisting of: (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2- (4- thiazolidin) 3-phenyl-1-propyl carboxylate; (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2- (4-thiazolidin) carboxylate of 3- (3-pyridyl) -1-propyl; and pharmaceutically acceptable salts, esters and solvates thereof.
29. The pharmaceutical composition of claim 17, wherein the heterocyclic ester or amide is a compound of Formula III: b & amp; amp; amp; amp; & amp; amp; amp; amp; or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A, B, C and D are independently CH2, O, S, SO, S02, NH or NR-L; RL is straight or branched chain alkyl of 1 to 5 carbon atoms, or straight or branched chain alkenyl of 2 to 5 carbon atoms, which is substituted with one or more substituents independently selected from the group consisting of (Ar -L) n, and straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Ar 1) n; n is 1 or 2; R2 is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Ar1; and 'Ar! is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, Straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and not me; where the size of the individual ring is from 5 to 6 members; and wherein the heterocyclic ring contains from 1 to 6 heteroatoms independently selected from the group consisting of O, N and S.
The pharmaceutical composition of claim 29, wherein: A is CH2; B is CH2; C is S, 0 or NH; D is CH2; R- is selected from the group consisting of 3-phenylpropyl and (3,4,5-trimethoxy) phenylpropyl; and R2 is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl, tertiary butyl, phenyl and 3,4,5-trimethoxyphenyl.
31. The compound of claim 30, wherein: C is NH; Y R2 is 1,1-dimethylpropyl or phenyl.
32. The pharmaceutical composition of claim 17, wherein the heterocyclic ester or amide is a compound of Formula IV: B 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 with which they are respectively attached, form a saturated or unsaturated 5- to 7-membered heterocyclic ring containing, in addition to V, one or more heteroatoms independently selected from the group consisting of O, S, S02, N, NH and NR R is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 9 atoms of carbon, cycloalkenyl of 5 to 7 carbon atoms, or Ar3, wherein R is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, haloalkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, b encyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 4; Ar3 and Ar4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the size of the individual ring is from 5 to 8 member; wherein the heterocyclic ring contains from 1 to 6 heteroatoms independently selected from the group consisting of 0, N and S; and R1 # R2, W, X, Y and Z are as defined in claim 21 above.
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00011912A true MXPA00011912A (en) | 2002-05-09 |
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