JP5815552B2 - 眼疾患を治療する化合物および方法 - Google Patents
眼疾患を治療する化合物および方法 Download PDFInfo
- Publication number
- JP5815552B2 JP5815552B2 JP2012543237A JP2012543237A JP5815552B2 JP 5815552 B2 JP5815552 B2 JP 5815552B2 JP 2012543237 A JP2012543237 A JP 2012543237A JP 2012543237 A JP2012543237 A JP 2012543237A JP 5815552 B2 JP5815552 B2 JP 5815552B2
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- JP
- Japan
- Prior art keywords
- aminomethyl
- methyl
- acid
- hexanoic acid
- phenoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 150000001875 compounds Chemical class 0.000 title description 100
- 238000000034 method Methods 0.000 title description 42
- 208000030533 eye disease Diseases 0.000 title description 5
- -1 primary amine compound Chemical class 0.000 claims description 156
- 239000003814 drug Substances 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 49
- 229940124597 therapeutic agent Drugs 0.000 claims description 43
- 208000017442 Retinal disease Diseases 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000004432 carbon atom Chemical group C* 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 25
- AYXYPKUFHZROOJ-SSDOTTSWSA-N pregabalin Chemical compound CC(C)C[C@@H](CN)CC(O)=O AYXYPKUFHZROOJ-SSDOTTSWSA-N 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 17
- 208000002780 macular degeneration Diseases 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 11
- 208000027073 Stargardt disease Diseases 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 238000012360 testing method Methods 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 238000011200 topical administration Methods 0.000 claims description 7
- 208000007014 Retinitis pigmentosa Diseases 0.000 claims description 5
- FEWJHICLKRAPHS-OCCSQVGLSA-N (3s,5r)-3-(aminomethyl)-5-methyl-7-phenylheptanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CCC1=CC=CC=C1 FEWJHICLKRAPHS-OCCSQVGLSA-N 0.000 claims description 4
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 4
- AYXYPKUFHZROOJ-UHFFFAOYSA-N 3-(azaniumylmethyl)-5-methylhexanoate Chemical compound CC(C)CC(CN)CC(O)=O AYXYPKUFHZROOJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000007910 systemic administration Methods 0.000 claims description 4
- SWBXHLVRIGSWFW-KGLIPLIRSA-N (2S,4R)-2-ethyl-6-(4-methoxyphenyl)-4-methylhexan-1-amine Chemical compound NC[C@@H](CC)C[C@@H](CCC1=CC=C(C=C1)OC)C SWBXHLVRIGSWFW-KGLIPLIRSA-N 0.000 claims description 3
- IASDTUBNBCYCJG-SFYZADRCSA-N (3r,4r)-3-(azaniumylmethyl)-4,5-dimethylhexanoate Chemical compound CC(C)[C@@H](C)[C@H](CN)CC(O)=O IASDTUBNBCYCJG-SFYZADRCSA-N 0.000 claims description 3
- IASDTUBNBCYCJG-YUMQZZPRSA-N (3r,4s)-3-(azaniumylmethyl)-4,5-dimethylhexanoate Chemical compound CC(C)[C@H](C)[C@H](CN)CC(O)=O IASDTUBNBCYCJG-YUMQZZPRSA-N 0.000 claims description 3
- BGQCKHBIIZKBJU-ZJUUUORDSA-N (3s,5r)-3-(aminomethyl)-5,7-dimethyloctanoic acid Chemical compound CC(C)C[C@@H](C)C[C@H](CN)CC(O)=O BGQCKHBIIZKBJU-ZJUUUORDSA-N 0.000 claims description 3
- CRENPLBKNGOMEN-MNOVXSKESA-N (3s,5r)-3-(aminomethyl)-5,8-dimethylnonanoic acid Chemical compound CC(C)CC[C@@H](C)C[C@H](CN)CC(O)=O CRENPLBKNGOMEN-MNOVXSKESA-N 0.000 claims description 3
- ADANSFWHWWMFDU-NEPJUHHUSA-N (3s,5r)-3-(aminomethyl)-5,9-dimethyldecanoic acid Chemical compound CC(C)CCC[C@@H](C)C[C@H](CN)CC(O)=O ADANSFWHWWMFDU-NEPJUHHUSA-N 0.000 claims description 3
- XKLLXPMHSPFOQW-HIFRSBDPSA-N (3s,5r)-3-(aminomethyl)-5-methyl-8-phenyloctanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CCCC1=CC=CC=C1 XKLLXPMHSPFOQW-HIFRSBDPSA-N 0.000 claims description 3
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- LFUPHGVCYOENSK-ZJUUUORDSA-N (3s,5r)-3-(aminomethyl)-5-methylnon-8-enoic acid Chemical compound C=CCC[C@@H](C)C[C@H](CN)CC(O)=O LFUPHGVCYOENSK-ZJUUUORDSA-N 0.000 claims description 3
- KUSIIZRBOLFILF-ZJUUUORDSA-N (3s,5r)-3-(aminomethyl)-5-methylnonanoic acid Chemical compound CCCC[C@@H](C)C[C@H](CN)CC(O)=O KUSIIZRBOLFILF-ZJUUUORDSA-N 0.000 claims description 3
- YAMOPJPIJYQIGY-BDAKNGLRSA-N (3s,5r)-3-(aminomethyl)-5-methyloct-7-enoic acid Chemical compound C=CC[C@@H](C)C[C@H](CN)CC(O)=O YAMOPJPIJYQIGY-BDAKNGLRSA-N 0.000 claims description 3
- HLRPRVFNTZZSHY-NEPJUHHUSA-N (3s,5r)-3-(aminomethyl)-5-methylundecanoic acid Chemical compound CCCCCC[C@@H](C)C[C@H](CN)CC(O)=O HLRPRVFNTZZSHY-NEPJUHHUSA-N 0.000 claims description 3
- SHMPJXGCBKABBT-KOLCDFICSA-N (3s,5r)-3-(aminomethyl)-6-cyclobutyl-5-methylhexanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CC1CCC1 SHMPJXGCBKABBT-KOLCDFICSA-N 0.000 claims description 3
- LUHAQNAPMJQCNM-YPMHNXCESA-N (3s,5r)-3-(aminomethyl)-6-cyclohexyl-5-methylhexanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CC1CCCCC1 LUHAQNAPMJQCNM-YPMHNXCESA-N 0.000 claims description 3
- SSFYNNBUYYSXPA-PWSUYJOCSA-N (3s,5r)-3-(aminomethyl)-6-cyclopentyl-5-methylhexanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CC1CCCC1 SSFYNNBUYYSXPA-PWSUYJOCSA-N 0.000 claims description 3
- NOTGKXLKLLOOEU-SCZZXKLOSA-N (3s,5r)-3-(aminomethyl)-6-cyclopropyl-5-methylhexanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CC1CC1 NOTGKXLKLLOOEU-SCZZXKLOSA-N 0.000 claims description 3
- SMNXTMSRSMKVKF-NEPJUHHUSA-N (3s,5r)-3-(aminomethyl)-7-(2-chlorophenyl)-5-methylheptanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CCC1=CC=CC=C1Cl SMNXTMSRSMKVKF-NEPJUHHUSA-N 0.000 claims description 3
- UHGGXBVJHJAACY-NEPJUHHUSA-N (3s,5r)-3-(aminomethyl)-7-(2-fluorophenyl)-5-methylheptanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CCC1=CC=CC=C1F UHGGXBVJHJAACY-NEPJUHHUSA-N 0.000 claims description 3
- VLOKSFBDWGOMMO-OLZOCXBDSA-N (3s,5r)-3-(aminomethyl)-7-(2-methoxyphenyl)-5-methylheptanoic acid Chemical compound COC1=CC=CC=C1CC[C@@H](C)C[C@H](CN)CC(O)=O VLOKSFBDWGOMMO-OLZOCXBDSA-N 0.000 claims description 3
- BCUGWHAHZHUTBT-YPMHNXCESA-N (3s,5r)-3-(aminomethyl)-7-(3-chlorophenyl)-5-methylheptanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CCC1=CC=CC(Cl)=C1 BCUGWHAHZHUTBT-YPMHNXCESA-N 0.000 claims description 3
- NIOLEXIXWFZQHF-YPMHNXCESA-N (3s,5r)-3-(aminomethyl)-7-(3-fluorophenyl)-5-methylheptanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CCC1=CC=CC(F)=C1 NIOLEXIXWFZQHF-YPMHNXCESA-N 0.000 claims description 3
- SNRGQBQIBPMKAD-OCCSQVGLSA-N (3s,5r)-3-(aminomethyl)-7-(3-methoxyphenyl)-5-methylheptanoic acid Chemical compound COC1=CC=CC(CC[C@@H](C)C[C@H](CN)CC(O)=O)=C1 SNRGQBQIBPMKAD-OCCSQVGLSA-N 0.000 claims description 3
- PEJUAJWTYKBIOI-YPMHNXCESA-N (3s,5r)-3-(aminomethyl)-7-(4-chlorophenyl)-5-methylheptanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CCC1=CC=C(Cl)C=C1 PEJUAJWTYKBIOI-YPMHNXCESA-N 0.000 claims description 3
- PMLSDYKLDFLDFE-PWSUYJOCSA-N (3s,5r)-3-(aminomethyl)-7-cyclobutyl-5-methylheptanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CCC1CCC1 PMLSDYKLDFLDFE-PWSUYJOCSA-N 0.000 claims description 3
- MUDLFVXEGNVOKP-OCCSQVGLSA-N (3s,5r)-3-(aminomethyl)-7-cyclohexyl-5-methylheptanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CCC1CCCCC1 MUDLFVXEGNVOKP-OCCSQVGLSA-N 0.000 claims description 3
- YBMHFGVRIJZSSK-YPMHNXCESA-N (3s,5r)-3-(aminomethyl)-7-cyclopentyl-5-methylheptanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CCC1CCCC1 YBMHFGVRIJZSSK-YPMHNXCESA-N 0.000 claims description 3
- HOFQYLXJJCNSDJ-SFYZADRCSA-N (3s,5r)-3-(aminomethyl)-8,8,8-trifluoro-5-methyloctanoic acid Chemical compound FC(F)(F)CC[C@@H](C)C[C@H](CN)CC(O)=O HOFQYLXJJCNSDJ-SFYZADRCSA-N 0.000 claims description 3
- NMURPDGMDUUFIQ-OCCSQVGLSA-N (3s,5r)-3-(aminomethyl)-8-cyclopentyl-5-methyloctanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CCCC1CCCC1 NMURPDGMDUUFIQ-OCCSQVGLSA-N 0.000 claims description 3
- LGPVGEYDVBVKIW-BDAKNGLRSA-N (3s,5r)-3-(aminomethyl)-8-fluoro-5-methyloctanoic acid Chemical compound FCCC[C@@H](C)C[C@H](CN)CC(O)=O LGPVGEYDVBVKIW-BDAKNGLRSA-N 0.000 claims description 3
- LYHACJSMVUYWEN-IUCAKERBSA-N (3s,5s)-3-(aminomethyl)-5,6,6-trimethylheptanoic acid Chemical compound CC(C)(C)[C@@H](C)C[C@H](CN)CC(O)=O LYHACJSMVUYWEN-IUCAKERBSA-N 0.000 claims description 3
- WFZVNCOAWKCUAL-UWVGGRQHSA-N (3s,5s)-3-(aminomethyl)-5-(2-chlorophenoxy)hexanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)OC1=CC=CC=C1Cl WFZVNCOAWKCUAL-UWVGGRQHSA-N 0.000 claims description 3
- MYHCDXIFXKZNNJ-YUMQZZPRSA-N (3s,5s)-3-(aminomethyl)-5-(2-fluoroethoxy)hexanoic acid Chemical compound FCCO[C@@H](C)C[C@H](CN)CC(O)=O MYHCDXIFXKZNNJ-YUMQZZPRSA-N 0.000 claims description 3
- BNDAKBMXSSJUEC-QWRGUYRKSA-N (3s,5s)-3-(aminomethyl)-5-(2-methoxyphenoxy)hexanoic acid Chemical compound COC1=CC=CC=C1O[C@@H](C)C[C@H](CN)CC(O)=O BNDAKBMXSSJUEC-QWRGUYRKSA-N 0.000 claims description 3
- XFVKCZVIDAAGDL-UWVGGRQHSA-N (3s,5s)-3-(aminomethyl)-5-(2-nitrophenoxy)hexanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)OC1=CC=CC=C1[N+]([O-])=O XFVKCZVIDAAGDL-UWVGGRQHSA-N 0.000 claims description 3
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- LCTKKGWISDWDSR-QWRGUYRKSA-N (3s,5s)-3-(aminomethyl)-5-(3-methoxyphenoxy)hexanoic acid Chemical compound COC1=CC=CC(O[C@@H](C)C[C@H](CN)CC(O)=O)=C1 LCTKKGWISDWDSR-QWRGUYRKSA-N 0.000 claims description 3
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- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
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- TZHVYFBSLOMRCU-UHFFFAOYSA-N tert-butyl 2-aminopropanoate Chemical compound CC(N)C(=O)OC(C)(C)C TZHVYFBSLOMRCU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
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- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
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- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
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- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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Description
本出願は、主題が本明細書に参照として組み込まれている、2009年12月8日に出願された米国仮特許出願第61/267,645号から優先権を主張する。
本発明は、国立衛生研究所により与えられた助成金交付番号EY09339の下で政府支援によりなされた。米国政府は本発明に一定の権利を有する。
本出願は、網膜における異常なオールトランスレチナールクリアランスに関連する眼および/または網膜疾患を治療する化合物および方法、ならびにより具体的には、第一級アミン化合物を用いて網膜変性および/または網膜疾患を治療する化合物および方法に関する。
R3は、1〜8個の炭素原子の直鎖もしくは分枝の非置換もしくは置換アルキル、2〜8個の炭素原子の直鎖もしくは分枝アルケニル、3〜7個の炭素原子のシクロアルキル、1〜6個の炭素原子のアルコキシ、−アルキルシクロアルキル、−アルキルアルコキシ、−アルキル、OH、−アルキルフェニル、−アルキルフェノキシ、−フェニルまたは置換フェニルであり、
R4は、水素、または(C1−C6)直鎖もしくは分枝の非置換もしくは置換アルキル、またはカルボキシルであり、
Arは、非置換または1〜5個のR7で置換されたフェニルであり、ここで、R7は、
(1)ハロゲン、
(2)直鎖または分枝であり、非置換または1〜5個のハロゲンで置換されたC1−6アルキル、
(3)直鎖または分枝であり、非置換または1〜5個のハロゲンで置換されたOC1−6アルキル、および
(4)CN
からなる群より独立して選択され、
X1は、
(1)N、および
(2)CR6
からなる群より選択され、
R5およびR6は、
(1)水素
(2)CN、
(3)直鎖もしくは分枝であり、非置換もしくは1〜5個のハロゲンで置換されたC1−10アルキル、または非置換もしくはハロゲン、CN、OH、R8、OR8、NHSO2R8、SO2R8、CO2H、およびCO2C1−6アルキルから独立して選択される1〜5個の置換基で置換されたフェニル(ここで、CO2C1−6アルキルは直鎖または分枝である)、
(4)非置換またはハロゲン、CN、OH、R8、OR8、NHSO2R8、SO2R8、CO2H、およびCO2C1−6アルキルから独立して選択される1〜5個の置換基で置換されたフェニル(ここで、CO2C1−6アルキルは直鎖または分枝である)、ならびに
(5)N、SおよびOから独立して選択される1〜4個のヘテロ原子を含む、飽和であっても、不飽和であってもよい5員または6員複素環であり、当該複素環は、非置換またはオキソ、OH、ハロゲン、C1−6アルキル、およびOC1−6アルキルから独立して選択される1〜3個の置換基で置換される(ここで、C1−6アルキル、およびOC1−6アルキルは、直鎖または分枝であり、必要に応じて1〜5個のハロゲンで置換されてもよい)、複素環、
からなる群より独立して選択され、
R8は、直鎖または分枝であり、非置換またはハロゲン、CO2H、およびCO2C1−6アルキルから独立して選択される1〜5個の基で置換されたC1−6アルキルであり(ここで、CO2C1−6アルキルは直鎖または分枝である)、
R9およびR10は、同じであっても、異なっていてもよく、水素、1〜6個の炭素原子の直鎖または分枝アルキル、低級アルキルアリール、低級アルケニル、フェニル、CF3、ヒドロキシ、低級アルコキシ、低級アルキルチオ、低級アルキルスルホニル、CF3O、6位におけるハロゲン、ニトロ、カルボキシ、低級アルコキシカルボニル、NR11R12CO、NR11R12、R11CONR12、CN、NR11R12SO2であり(ここで、R11およびR12は、同じであっても、異なっていてもよく、水素、低級アルキル、またはアリールである);R9およびR10は、一緒に炭素環またはメチレンジオキシ環を形成してもよく、
R14は、シアノ、シアノメチル、メトキシメチル、またはエトキシメチルであり、
X2は、O、N(H)、またはSであり、hetは、5員もしくは6員複素環であり、nは、0、1、2、または3であり、各々のDは、非分枝低級アルキル基であり、
Uは、ハロゲン原子;シアノ;低級アルキル(ここで、低級アルキル基上の1つ以上の水素原子は、必要に応じて、ハロゲン原子、ヒドロキシル、カルバモイル、アミノ、アリール、ならびに窒素、酸素、および硫黄原子から選択される1つ以上のヘテロ原子を含有する単環または二環式複素環基から選択される基により置換される);低級アルキルチオ(ここで、アルキル基上の1つ以上の水素原子は、必要に応じて、ハロゲン原子、ヒドロキシル、カルバモイル、アミノ、およびアリールから選択される基により置換される);低級アルキルスルホニル(ここで、アルキル基上の1つ以上の水素原子は、必要に応じて、ハロゲン原子、ヒドロキシル、カルバモイル、アミノ、およびアリールから選択される基により置換される);ヒドロキシル;低級アルコキシ;ホルミル;低級アルキルカルボニル;アリールカルボニル;カルボキシル;低級アルコキシカルボニル;カルバモイル;N−低級アルキルカルバモイル;N,N−ジ−低級アルキルアミノカルボニル;アミノ;N−低級アルキルアミノ;N,N−ジ−低級アルキルアミノ;ホルミルアミノ;低級アルキルカルボニルアミノ;アミノスルホニルアミノ;(N−低級アルキルアミノ)スルホニルアミノ;(N,N−ジ−低級アルキルアミノ)スルホニルアミノ;必要に応じて、ハロゲン原子、ヒドロキシル、カルバモイル、アリールおよびアミノから選択される基により置換されるアリール;ならびに窒素、酸素、および硫黄原子から選択される1つ以上のヘテロ原子を含有する単環もしくは二環式複素環基から選択される置換基であり、
Q、T、およびVは各々、独立して、N、S、O CUまたはCHであり、
W、X、Y、およびZのうちの少なくとも1つはNであるように、W、X、Y、およびZは各々、独立して、N、S、O CUまたはCHであり、
Aは、
Dは、非分枝低級アルキルであり、
R15およびR16は各々、独立して、置換もしくは非置換C1、C2、C3、C4、C5、C6、C7、もしくはC8、直鎖アルキル、または置換もしくは非置換C3、C4、C5、C6、C7、もしくはC8、分枝鎖アルキルであり、
Lは、単結合またはCH2であり、
mは、0、1、または2であり、
nは、0、1、2、3、または4であり、
Y1は、−(CH2)2−、−(CH2)3−、−CH2CH(CH3)−、または−CH2C(CH3)2−であり、
R17は、アリールまたはヘテロアリールであり、
R18およびR19は各々、独立して、C1−4アルキルまたは2−メトキシエチルであり、
R20は、水素、C1−C4アルキル、2−(C1−C4アルコキシ)エチル、シクロプロピルメチル、ベンジル、または−(CH2)m1COR21であり(ここで、m1は、1、2または3であり、R21は、ヒドロキシ、C1−C4アルコキシまたは−NR22である(ここで、R22は、水素またはC1−C4アルキルである))、
R23およびR24は、同じであっても、異なっていてもよく、水素、メチル、またはエチルである)
およびその薬学的に許容可能な塩を含み得る。
を有し得る。
R3は、1〜8個の炭素原子の直鎖または分枝の非置換または置換アルキル、2〜8個の炭素原子の直鎖または分枝アルケニル、3〜7個の炭素原子のシクロアルキル、1〜6個の炭素原子のアルコキシ、−アルキルシクロアルキル、−アルキルアルコキシ、−アルキル、OH、−アルキルフェニル、−アルキルフェノキシ、−フェニルまたは置換フェニルであり、
R4は、水素、または(C1−C6)直鎖もしくは分枝の非置換もしくは置換アルキル、またはカルボキシである)
およびその薬学的に許容可能な塩である。
R3は、1〜8個の炭素原子の直鎖もしくは分枝アルキル、2〜8個の炭素原子の直鎖もしくは分枝アルケニル、3〜7個の炭素原子のシクロアルキル、1〜6個の炭素原子のアルコキシ、−アルキルシクロアルキル、−アルキルアルコキシ、−アルキルOH、−アルキルフェニル、−アルキルフェノキシ、−フェニルまたは置換フェニルであり、
R4は、水素であり、かつ、R3がメチルである場合、R2は、1〜6個の炭素原子の直鎖もしくは分枝アルキルまたはフェニルである)
またはその薬学的に許容可能な塩である。
またはその薬学的に許容可能な塩であり得る。
3−アミノメチル−5−メチルヘキサン酸;3−アミノメチル−5−メチルヘプタン酸;3−アミノメチル−5−メチル−オクタン酸;3−アミノメチル−5−メチル−ノナン酸;3−アミノメチル−5−メチル−デカン酸;3−アミノメチル−5−メチル−ウンデカン酸;3−アミノメチル−5−メチル−ドデカン酸;3−アミノメチル−5−メチル−トリデカン酸;3−アミノメチル−5−シクロプロピル−ヘキサン酸;3−アミノメチル−5−シクロブチル−ヘキサン酸;3−アミノメチル−5−シクロペンチル−ヘキサン酸;3−アミノメチル−5−シクロヘキシル−ヘキサン酸;3−アミノメチル−5−トリフルオロメチル−ヘキサン酸;3−アミノメチル−5−フェニル−ヘキサン酸;3−アミノメチル−5−(2−クロロフェニル)−ヘキサン酸;3−アミノメチル−5−(3−クロロフェニル)−ヘキサン酸;3−アミノメチル−5−(4−クロロフェニル)−ヘキサン酸;3−アミノメチル−5−(2−メトキシフェニル)−ヘキサン酸;3−アミノメチル−5−(3−メトキシフェニル)−ヘキサン酸;3−アミノメチル−5−(4−メトキシフェニル)−ヘキサン酸;3−アミノメチル−5−(フェニルメチル)−ヘキサン酸;(S)−3−(アミノメチル)−5−メチルヘキサン酸;(R)−3−(アミノメチル)−5−メチルヘキサン酸;(3R,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸;3−アミノメチル−4,5−ジメチル−ヘキサン酸;(3R,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸MP;(3S,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸;(3R,4R)−3−アミノメチル−4,5−ジメチル−ヘキサン酸MP;3−アミノメチル−4−イソプロピル−ヘキサン酸;3−アミノメチル−4−イソプロピル−ヘプタン酸;3−アミノメチル−4−イソプロピル−オクタン酸;3−アミノメチル−4−イソプロピル−ノナン酸;3−アミノメチル−4−イソプロピル−デカン酸;3−アミノメチル−4−フェニル−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メトキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−エトキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−プロポキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−イソプロポキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−tert−ブトキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−フルオロメトキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−フルオロ−エトキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3,3,3−トリフルオロ−プロポキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−フェノキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(4−クロロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3−クロロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−クロロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(4−フルオロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3−フルオロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−フルオロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(4−メトキシ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3−メトキシ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−メトキシ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(4−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−6−ヒドロキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−メトキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−エトキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル−6−プロポキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−6−イソプロポキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−tert−ブトキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−フルオロメトキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−フルオロ−エトキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル−6−(3,3,3−トリフルオロ−プロポキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル−6−フェノキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−クロロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−クロロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−クロロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−フルオロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−フルオロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−フルオロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−メトキシ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−メトキシ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−メトキシ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(4−トリフルオロメチル−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(3−トリフルオロメチル−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(2−トリフルオロメチル−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(4−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(3−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(2−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−6−ベンジルオキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−7−ヒドロキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−メトキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−エトキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−プロポキシ−ヘプタン酸;(3S,5S)−3−アミノメチル−7−イソプロポキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−tert−ブトキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−フルオロメトキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(2−フルオロ−エトキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(3,3,3−トリフルオロ−プロポキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−7−ベンジルオキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−フェノキシ−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(4−クロロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(3−クロロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(2−クロロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(4−フルオロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(3−フルオロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(2−フルオロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(4−メトキシ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(3−メトキシ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(2−メトキシ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(4−トリフルオロメチル−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(3−トリフルオロメチル−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(2−トリフルオロメチル−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(4−ニトロ−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(3−ニトロ−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(2−ニトロ−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−6−フェニル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−クロロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−クロロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−クロロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−メトキシ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−メトキシ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−メトキシ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−フルオロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−フルオロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−フルオロ−フェニル)−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−5−メチル−7−フェニル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(4−クロロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(3−クロロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(2−クロロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(4−メトキシ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(3−メトキシ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(2−メトキシ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(4−フルオロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(3−フルオロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(2−フルオロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−5−メチル−オクト−7−エン酸;(3S,5R)−3−アミノメチル−5−メチル−ノナ−8−エン酸;(E)−(3S,5S)−3−アミノメチル−5−メチル−オクト−6−エン酸;(Z)−(3S,5S)−3−アミノメチル−5−メチル−オクト−6−エン酸;(Z)−(3S,5S)−3−アミノメチル−5−メチル−ノナ−6−エン酸;(E)−(3S,5S)−3−アミノメチル−5−メチル−ノナ−6−エン酸;(E)−(3S,5R)−3−アミノメチル−5−メチル−ノナ−7−エン酸;(Z)−(3S,5R)−3−アミノメチル−5−メチル−ノナ−7−エン酸;(Z)−(3S,5R)−3−アミノメチル−5−メチル−デカ−7−エン酸;
(E)−(3S,5R)−3−アミノメチル−5−メチル−ウンデカ−7−エン酸;(3S,5S)−3−アミノメチル−5,6,6−トリメチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5,6−ジメチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−シクロプロピル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−シクロブチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−シクロペンチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−シクロヘキシル−ヘキサン酸;(3S,5R)−3−アミノメチル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−5−メチル−ノナン酸;(3S,5R)−3−アミノメチル−5−メチル−デカン酸;(3S,5R)−3−アミノメチル−5−メチル−ウンデカン酸;(3S,5R)−3−アミノメチル−5−メチル−ドデカン酸;(3S,5R)−3−アミノメチル−5,9−ジメチル−デカン酸;(3S,5R)−3−アミノメチル−5,7−ジメチル−オクタン酸;(3S,5R)−3−アミノメチル−5,8−ジメチル−ノナン酸;(3S,5R)−3−アミノメチル−6−シクロプロピル−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−6−シクロブチル−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−6−シクロペンチル−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−6−シクロヘキシル−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−7−シクロプロピル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−シクロブチル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−シクロペンチル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−シクロヘキシル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−8−シクロプロピル−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−8−シクロブチル−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−8−シクロペンチル−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−8−シクロヘキシル−5−メチル−オクタン酸;(3S,5S)−3−アミノメチル−6−フルオロ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−7−フルオロ−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−8−フルオロ−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−9−フルオロ−5−メチル−ノナン酸;(3S,5S)−3−アミノメチル−7,7,7−トリフルオロ−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−8,8,8−トリフルオロ−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−5−メチル−8−フェニル−オクタン酸;(3S,5S)−3−アミノメチル−5−メチル−6−フェニル−ヘキサン酸;(3S,5R)−3−アミノメチル−5−メチル−7−フェニル−ヘプタン酸;およびそれらの薬学的に許容可能な塩。上記の化合物を合成する方法は、国際公開第00/76958号に記載されており、その全体は本明細書に参照として組み込まれる。
およびその薬学的に許容可能な塩である。上記の構造式を有する化合物およびそのような化合物を生成する方法は、その全体が本明細書に参照として組み込まれる、米国特許第4,024,175号明細書に記載されている。
を有し得る。上記の化合物を合成する方法は、その全体が本明細書に参照として組み込まれている、米国特許第4,085,225号明細書に記載されている。
を有し得る。上記の化合物を合成する方法は、その全体が本明細書に参照として組み込まれている、米国特許第4,572,909号明細書に記載されている。
を有し得る。
エチル2−[[2−[2−[[2−アミノ−3−(4−ヒドロキシフェニル)プロパノイル]アミノ]プロパノイルアミノ]アセチル]アミノ]アセテート、2−アミノ−5−クロロ−N−(4−ピリジルメチル)ベンズアミド、8−ニトロナフタレン−1−アミン、2−アミノ−3−シクロプロピル−プロパン酸、2−(2−イソプロピル−5−メチル−フェノキシ)エタンアミン、2−アミノ−N−[(E)−1−(2−ヒドロキシフェニル)エチリデンアミノ]ベンズアミド、(2R)−2−アミノ−3−ベンズヒドリルスルファニル−プロパン酸、tert−ブチル2−アミノプロパノエート、2−[4−(1−エチルプロピル)フェノキシ]−5−(トリフルオロメチル)アニリン、N1−メチルベンゼン−1,3−ジアミン、1−(4−アミノフェニル)スルファニル−3−(ジエチルアミノ)プロパン−2−オール、N−(4−アミノフェニル)−2,2−ジメチル−プロパンアミド、2−アミノ−3−(4−ニトロフェニル)ブタン酸、2−(2−アミノ−5−ブロモ−フェニル)−4−メチル−ベンゾ[g]キノキサリン−3−オン、N−[3−[(2−アミノフェニル)メチルアミノ]−1−メチル−3−オキソ−プロピル]−2−フェニル−キノリン−4−カルボキサミド、N−[2−[(2−アミノフェニル)メチルアミノ]−2−オキソ−1−フェニル−エチル]−2−フェニル−キノリン−4−カルボキサミド、(5S)−5−(4−アミノブチル)−3−[4−(o−トリル)フェニル]イミダゾリジン−2,4−ジオン、(5S)−5−(4−アミノブチル)−3−[4−(ベンゾチオフェン−2−イル)−1−ナフチル]−2−チオキソ−イミダゾリジン−4−オン、2−アミノ−4,6−ジtert−ブチル−フェノール、5−(アミノメチル)−2,4−ジメチル−ピリジン−3−アミン、3−アミノ−N−[5−ヒドロキシ−1−(2,4,6−トリクロロフェニル)ピラゾール−3−イル]ベンズアミド、(2R)−2−アミノ−3−(4−フルオロフェニル)−N−[4−グアニジノ−1−(1−ピペリジルメチル)ブチル]プロパンアミド、3−[[2−[2−(3−アミノプロピルカルバモイル)フェニル]ベンゾイル]−[(2,5−ジフルオロフェニル)メチル]アミノ]プロパン酸、N−[(4−アセトアミドフェニル)メチル]−N−(3−アミノ−2,2−ジメチルプロピル)−2−(4−エチルフェニル)ピリジン−4−カルボキサミド、N−(3−アミノプロピル)−2−(4−エチルフェニル)−N−[(3,4,5−トリメトキシフェニル)メチル]ピリジン−4−カルボキサミド、N−(2−アミノエチル)−5−(4−フルオロフェニル)−N−(2−ピリジルメチル)ピリジン−3−カルボキサミド、N−[[4−(アミノメチル)フェニル]メチル]−5−(1−ナフチル)−N−(2−ピリジルメチル)ピリジン−3−カルボキサミド、2−(3−アセチルフェニル)−N−(3−アミノプロピル)−N−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イルメチル)ピリジン−4−カルボキサミド、2−[(4S,5R)−2−[(1R)−1−アミノ−2−(4−フルオロフェニル)エチル]−5−(2−ナフチル)テトラヒドロピラン−4−イル]アセトニトリル、(2R)−2−アミノ−1−[(2S,4R)−4−ベンジルオキシ−2−[2−(1,2,4−トリアゾール−4−イル)エチル]ピロリジン−1−イル]−3−(4−フルオロフェニル)プロパン−1−オン、(2R)−2−アミノ−3−フェニル−1−[4−フェニル−4−(1,2,4−トリアゾール−1−イルメチル)−1−ピペリジル]プロパン−1−オン、N’−シクロドデシルエタン−1,2−ジアミン、7−[2−[(2−アミノ−2−メチル−プロピル)アミノ]ピリミジン−4−イル]−6−(4−フルオロフェニル)−2,3−ジヒドロ−1H−ピラゾロ[1,2−a]ピラゾール−5−オン、2,3,4,5−テトラヒドロ−1−ベンゾチエピン−5−アミン、5−[(2R,3R,4S)−3−アミノ−4−(メトキシカルボニルアミノ)テトラヒドロチオフェン−2−イル]ペンタン酸、3−(2−アミノフェニル)スルファニル−3−(3,4−ジクロロフェニル)−1−フェニル−プロパン−1−オン、およびそれらの薬学的に許容可能な塩からなる群より選択される。
(レチナールと選択されたアミンとの間のシッフ塩基の形成)
本発明者らは、眼の生理学的条件下でオールトランスRALのアルデヒド基と反応して、コンジュゲート(シッフ塩基)を形成するかどうかを決定するために、第一級アミノ基を含有する5つのFDAに承認された薬物を試験した。その5つのFDAに承認された薬物には、ポタバ(Potaba)、ペーサー(Paser)、セロマイシン(Seromycin)、カプリミン(Cuprimine)、およびリリカ(Lyrica)が含まれた。
本発明者らは、オールトランスRALのアルデヒド基と反応して、光に対する曝露後の眼においてその毒性レベルを減少させ、その毒性コンジュゲートへの縮合を防ぐかどうかを決定するために、第一級アミノ基を含有する20のFDAに承認された薬物を試験した。FDAに承認された薬物には、フルマジン(Flumadine)、ナメダ(Nameda)、ポタバ、ダプソン(Dapsone)、ペーサー、ルボックス(Luvox)、セロマイシン、アミノ馬尿酸ナトリウム、カプリミン、ジャヌビア(Januvia)、プリマキシンI.M.(Primaxin I.M.)、プリニビル(Prinivil)、サルファマイロン(Sulfamylon)、エックスフォージ(Exforge)、スタレボ(Stalevo)、ジウリルナトリウム(Sodium Diuril)、リリカ、アサコール(Asacol)、タミフル(Tamiflu)、またはリルテック(Rilutek)が含まれた。これらの実験に関して、本発明者らは、シュタルガルト疾患およびAMDについてのモデルとしてABCA4−/−/RDH8−/−マウスを使用した。本発明者らは、レチノイドおよび組織切片を分析するためのHPLC/MS/MS、ならびにレチナール病変を評価するためのOCTを含む、候補薬物の薬力学および薬物動態を決定するための分析方法を利用した。レチノイドおよびそれらの組成の相対量は、網膜の健康状態と強く相関する。FDAに承認された薬物は、ABCA4−/−/RDH8−/−マウスに投与された場合、そのマウスが少なくとも約2.5の光コヒーレンストモグラフィースコアを示し、その薬物は、未処置の対照動物と比べて、11−シス−レチナール量を少なくとも約30%増加させることより、網膜変性を治療するのに有効であると決定した。ABCA4−/−/RDH8−/−マウスで分析を実施するための方法を以下に記載する。
Rdh8−/−マウスを、J.Biol.Chem.280,188−18832(2005)に以前に記載されているように産生し、遺伝子型分類した。Abca4−/−マウスもまた、標準的な手順(Ingenious Targeting,Inc.,Stony Brook,NY)により産生した。標的ベクターを、エキソン1を、Cell,98 13−23(1999)に記載されているようにneoカセットに置換することにより構築した。ABCA4に対する免疫反応は、免疫細胞化学または免疫ブロット法によってこれらのマウス由来の眼の抽出物において検出されなかった。Abca4−/−マウスは、色素性129Sv/EvまたはC57BL/6混合型バックグラウンドのいずれかで維持され、それらの子孫を大部分の実験に使用した。Rdh8−/−Abca4−/−マウスは、Abca4−/−マウスとRdh8−/−マウスとを交配することによって確立した。マウスの遺伝子型決定は、野生型(WT)(619bp)についてABCR1(5’−gcccagtggtcgatctgtctagc−3’)dABCR2(5’−cacaaaggccgctaggaccacg−3’)ならびに標的欠失(455bp)についてA0(5’−ccacagcacacatcagcatttctcc−3’)およびN1(5’−tgcgaggccagaggccacttgtgtagc−3’)のプライマーを用いてPCRにより実施した。PCR産物をクローニングし、それらの同一性を検証するためにシークエンスした。Rdh8−/−Abca4−/−マウスは繁殖性があり、明白な発生学的異常は示されなかった。
解剖したマウスの眼からのレチノイドの抽出、誘導体化、および分離に関連する全ての実験手順は、暗赤色灯下で実施した。2つの完全なマウスの眼を、50%エタノールおよび10mM NH2OHを含有する、1mlの50mMリン酸緩衝液、pH7.0中でホモジナイズした。室温(RT)でのインキュベーションの20分後に氷冷したメタノール(1ml)をホモジネートに加え、非極性レチノイドを4mlのヘキサンで2回抽出した。有機相を回収し、SpeedVac中でドライダウンし、0.3mlのヘキサン中に再懸濁した。レチノイドの3つの主なクラス(レチニルエステル、レチナールオキシム、およびレチノール)、およびそれらの幾何異性体を、Agilent Si、5μm、4.5×250mmカラムおよび1.4ml/分の流速におけるヘキサン中の酢酸エチルの段階的勾配(15分間、0.5%、および60分まで6%)を用いることによって、順相HPLCによる単一の実施により分離した(図6)。ダイオードアレイ検出器を用いて、レチノイドを325nm(レチニルエステルおよびレチノール)および350nm(レチニルオキシム)にて検出した。対象のものを、HP Chemstation A.03.03ソフトウェアを用いて計算したそれらのピーク下面積に基づいて定量し、標準曲線としてプロットした既知の量の合成標準物に基づいて計算した面積と比較した。
補足的技術、質量分析を使用して、眼組織におけるレチノイドおよびそれらの誘導体を検出、同定、および定量した。レチノイドのコンジュゲートしたポリエン鎖は、UVおよび可視波長における比較的強い光吸収に起因する。したがって、吸光度スペクトルにより、コンジュゲートした二重結合の数についての情報が与えられた。さらに、最大吸収の波長およびスペクトルの形状のわずかな差はレチノイド異性体の正確な識別を可能にした。しかしながら、この方法の制限は、そのUV−V吸光度の低い選択性であり、クロマトグラフ条件および分析される化合物の正確な識別が注意深く設計されることを要求する。低い存在度(3pmol/眼未満)でレチノイドの複数の幾何異性体または識別されていない化合物が存在する場合、この分析は特に困難になり得る。したがって、本発明者らは、この問題を取り扱うために、代替の技術である、高速液体クロマトグラフィー(LC−MS)と合わせて質量分析を使用した。レチノイドの質量スペクトルは、Agilent 1100HPLCシステムと連結し、大気圧化学イオン化(APCI)源とインターフェースで接続した、LXQ高スループット線形イオントラップ質量分析計(Thermo Scientific,Waltham,MA)を用いることによって獲得した。そのワイドダイナミックレンジおよびHPLCレチノイド分離に必要とされる高い流速で作動する能力のために、陽イオン化モードにおけるAPCI源をLC−MS法について選択する。LC−MSの最も大きな利点は、それぞれ、10〜50fmolおよび20〜200fmol範囲のレチノイド検出および定量化の限界に達するその感受性である。さらに、このLXQ機器は、決定的な構造識別を与えるMSn分析を実施する能力を有する。
第一級アミンを含有する化合物で処置したマウスの眼を、50%メタノール中のトリス/HCl緩衝液、pH9.0中でホモジナイズし、極性に応じてヘキサンまたは酢酸エチルで抽出し、ドライダウンし、アセトニトリル中に再懸濁した。遠心分離後、上清中の抽出化合物を、1.5ml/分の一定の流速で20分間、アセトニトリル中の水の線形勾配(50〜100%)を用いる逆相HPLCクロマトグラフィー(Agilent Zorbax Eclipse XBD C18、5μm、4.6×150mmカラム)により分離した。レチナールコンジュゲートを、APCI源を備えたLXQ質量分析計で検出し、識別した。各々の個々の化合物についてのMS走査をSIMモードで記録した(図7M3)。検出した付加物の識別はそれらのMS2スペクトルに基づいて確認する。レチナール−アミンコンジュゲートの量は、抽出前に添加した同位体標識した合成標準物を用いて定量する。
分析的および組織学的方法は網膜の包括的な特徴付けを提供するが、それらはインビボで実施できない。屠殺する動物の数および分析に必要とされる時間を減少させるために、Bioptigen(Research Triangle Park,NC)のSD−OCTを、マウス網膜のインビボでのイメージングのために利用した。BioptigenのOCTシステムは、通常のOCTシステムより高い解像度(2.0μm)で網膜の構造を調べるために広帯域幅光源からの狭シングルモードビームを利用する。100mMのNaClを含有する10mMのリン酸ナトリウム、pH7.2で希釈した20μg/g bwの6mg/mlケタミンおよび0.44mg/mlのキシラジンの腹腔内(IP)注射によりマウスに麻酔をかけた。1%トロピカミドを用いて瞳孔を拡張させた。インビボで、SD−OCTイメージを両眼から得た。B走査モードで獲得した4つの写真を、最終的な平均画像を構築するために使用した(図8)。本発明者らは、SD−OCT画像化により、網膜における初期の病的変化を識別でき、網膜の断面を利用する現在の病理組織法により得られたものと匹敵する解像度にて同じ生存動物において種々の治療レジメン下で病変の進行または改善/予防を定量的に観察できた。
インビボで、Rdh8−/−Abca4−/−マウスの網膜構造を、4週齢にて30分間の10,000ルクス照射の7日後にSD−OCTにより画像化する。図9は、照射しないRdh8−/−Abca4−/−マウスが健康な網膜を示したが、30分間の10,000ルクスでの照射が重度の網膜変性を引き起こしたことを示す(左のパネル)。網膜形態における化合物の予防効果をOCTスコアとして示す(右のパネル)。
スコア5:網膜変性なし
スコア4:局所的網膜変性(1000μm幅未満)
スコア3:ELMの反転を有する広範囲に観察される網膜変性(1000μm幅超)
スコア2:ELMの反転を有さない広範囲に観察される網膜変性(1000μm幅超)
スコア1:光受容体および光に曝露したRdh8−/−Abca4−/−マウスからの反転を有さない重度の網膜変性(左のパネルを参照)。
以下の表は、フルマジン、ナメダ、ポタバ、ダプソン、ペーサー、ルボックス、セロマイシン、アミノ馬尿酸ナトリウム、カプリミン、ジャヌビア、プリマキシンI.M.、プリニビル、サルファマイロン、エックスフォージ、スタレボ、ジウリルナトリウム、リリカ、アサコール、タミフル、またはリルテックで処置したABCA4−/−/RDH8−/−のOCTスコアおよび11−シス−レチナール面積を記載する。表に示したように、フルマジン、ダプソン、ペーサー、ルボックス、セロマイシン、ジャヌビア、サルファマイロン、エックスフォージ、ジウリルナトリウム、リリカ、アサコール、またはリルテックのいずれかで処置したABCA4−/−/RDH8−/−マウスは、少なくとも約2.5の光コヒーレンストモグラフィースコアを有し、それらの薬物は、未処置の対照動物と比較して、11−シス−レチナール量を少なくとも約30%増加させ、マウスにおける網膜変性を治療するのに有効であった。実施例1において、疑似生理学的条件下でオールトランスRALとシッフ塩基を容易に形成した3つのFDAにより承認された薬物は、少なくとも約2.5の光コヒーレンストモグラフィースコアを有し、未処置の対照動物と比較して、11−シス−レチナール量を少なくとも約30%増加させ、マウスにおける網膜変性を治療するのに効果的であった。対照的に、実施例1において、疑似生理学的条件下でオールトランスRALとシッフ塩基を容易に形成しなかった2つのFDAにより承認された薬物は、2.5以下の光コヒーレンストモグラフィースコアを有し、未処置の対照動物と比較して、11−シス−レチナール量を少なくとも約30%増加させず、マウスにおける網膜変性を治療するのに効果がなかった。
Claims (22)
- 網膜疾患を治療するための治療剤であって、
以下の式を含む治療有効量の第一級アミン化合物:
R2は、水素または(C1−C6)直鎖もしくは分枝非置換もしくは置換アルキルであり、
R3は、1〜8個の炭素原子の直鎖もしくは分枝非置換もしくは置換アルキル、2〜8個の炭素原子の直鎖もしくは分枝アルケニル、3〜7個の炭素原子のシクロアルキル、1〜6個の炭素原子のアルコキシ、−アルキルシクロアルキル、−アルキルアルコキシ、−アルキル、OH、−アルキルフェニル、−アルキルフェノキシ、−フェニルまたは置換フェニルであり、
R4は、水素または(C1−C6)直鎖もしくは分枝非置換もしくは置換アルキル、またはカルボキシルである)
およびその薬学的に許容可能な塩を含む治療剤。 - 前記第一級アミン化合物が、
3−アミノメチル−5−メチルヘキサン酸;3−アミノメチル−5−メチルヘプタン酸;3−アミノメチル−5−メチル−オクタン酸;3−アミノメチル−5−メチル−ノナン酸;3−アミノメチル−5−メチル−デカン酸;3−アミノメチル−5−メチル−ウンデカン酸;3−アミノメチル−5−メチル−ドデカン酸;3−アミノメチル−5−メチル−トリデカン酸;3−アミノメチル−5−シクロプロピル−ヘキサン酸;3−アミノメチル−5−シクロブチル−ヘキサン酸;3−アミノメチル−5−シクロペンチル−ヘキサン酸;3−アミノメチル−5−シクロヘキシル−ヘキサン酸;3−アミノメチル−5−トリフルオロメチル−ヘキサン酸;3−アミノメチル−5−フェニル−ヘキサン酸;3−アミノメチル−5−(2−クロロフェニル)−ヘキサン酸;3−アミノメチル−5−(3−クロロフェニル)−ヘキサン酸;3−アミノメチル−5−(4−クロロフェニル)−ヘキサン酸;3−アミノメチル−5−(2−メトキシフェニル)−ヘキサン酸;3−アミノメチル−5−(3−メトキシフェニル)−ヘキサン酸;3−アミノメチル−5−(4−メトキシフェニル)−ヘキサン酸;3−アミノメチル−5−(フェニルメチル)−ヘキサン酸;(S)−3−(アミノメチル)−5−メチルヘキサン酸;(R)−3−(アミノメチル)−5−メチルヘキサン酸;(3R,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸;3−アミノメチル−4,5−ジメチル−ヘキサン酸;(3R,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸MP;(3S,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸;(3R,4R)−3−アミノメチル−4,5−ジメチル−ヘキサン酸MP;3−アミノメチル−4−イソプロピル−ヘキサン酸;3−アミノメチル−4−イソプロピル−ヘプタン酸;3−アミノメチル−4−イソプロピル−オクタン酸;3−アミノメチル−4−イソプロピル−ノナン酸;3−アミノメチル−4−イソプロピル−デカン酸;3−アミノメチル−4−フェニル−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メトキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−エトキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−プロポキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−イソプロポキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−tert−ブトキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−フルオロメトキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−フルオロ−エトキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3,3,3−トリフルオロ−プロポキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−フェノキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(4−クロロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3−クロロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−クロロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(4−フルオロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3−フルオロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−フルオロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(4−メトキシ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3−メトキシ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−メトキシ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(4−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−6−ヒドロキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−メトキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−エトキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル−6−プロポキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−6−イソプロポキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−tert−ブトキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−フルオロメトキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−フルオロ−エトキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル−6−(3,3,3−トリフルオロ−プロポキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル−6−フェノキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−クロロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−クロロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−クロロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−フルオロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−フルオロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−フルオロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−メトキシ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−メトキシ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−メトキシ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(4−トリフルオロメチル−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(3−トリフルオロメチル−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(2−トリフルオロメチル−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(4−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(3−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(2−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−6−ベンジルオキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−7−ヒドロキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−メトキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−エトキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−プロポキシ−ヘプタン酸;(3S,5S)−3−アミノメチル−7−イソプロポキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−tert−ブトキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−フルオロメトキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(2−フルオロ−エトキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(3,3,3−トリフルオロ−プロポキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−7−ベンジルオキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−フェノキシ−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(4−クロロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(3−クロロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(2−クロロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(4−フルオロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(3−フルオロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(2−フルオロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(4−メトキシ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(3−メトキシ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(2−メトキシ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(4−トリフルオロメチル−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(3−トリフルオロメチル−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(2−トリフルオロメチル−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(4−ニトロ−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(3−ニトロ−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(2−ニトロ−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−6−フェニル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−クロロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−クロロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−クロロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−メトキシ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−メトキシ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−メトキシ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−フルオロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−フルオロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−フルオロ−フェニル)−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−5−メチル−7−フェニル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(4−クロロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(3−クロロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(2−クロロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(4−メトキシ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(3−メトキシ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(2−メトキシ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(4−フルオロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(3−フルオロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(2−フルオロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−5−メチル−オクト−7−エン酸;(3S,5R)−3−アミノメチル−5−メチル−ノナ−8−エン酸;(E)−(3S,5S)−3−アミノメチル−5−メチル−オクト−6−エン酸;(Z)−(3S,5S)−3−アミノメチル−5−メチル−オクト−6−エン酸;(Z)−(3S,5S)−3−アミノメチル−5−メチル−ノナ−6−エン酸;(E)−(3S,5S)−3−アミノメチル−5−メチル−ノナ−6−エン酸;(E)−(3S,5R)−3−アミノメチル−5−メチル−ノナ−7−エン酸;(Z)−(3S,5R)−3−アミノメチル−5−メチル−ノナ−7−エン酸;(Z)−(3S,5R)−3−アミノメチル−5−メチル−デカ−7−エン酸;(
E)−(3S,5R)−3−アミノメチル−5−メチル−ウンデカ−7−エン酸;(3S,5S)−3−アミノメチル−5,6,6−トリメチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5,6−ジメチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−シクロプロピル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−シクロブチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−シクロペンチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−シクロヘキシル−ヘキサン酸;(3S,5R)−3−アミノメチル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−5−メチル−ノナン酸;(3S,5R)−3−アミノメチル−5−メチル−デカン酸;(3S,5R)−3−アミノメチル−5−メチル−ウンデカン酸;(3S,5R)−3−アミノメチル−5−メチル−ドデカン酸;(3S,5R)−3−アミノメチル−5,9−ジメチル−デカン酸;(3S,5R)−3−アミノメチル−5,7−ジメチル−オクタン酸;(3S,5R)−3−アミノメチル−5,8−ジメチル−ノナン酸;(3S,5R)−3−アミノメチル−6−シクロプロピル−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−6−シクロブチル−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−6−シクロペンチル−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−6−シクロヘキシル−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−7−シクロプロピル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−シクロブチル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−シクロペンチル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−シクロヘキシル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−8−シクロプロピル−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−8−シクロブチル−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−8−シクロペンチル−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−8−シクロヘキシル−5−メチル−オクタン酸;(3S,5S)−3−アミノメチル−6−フルオロ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−7−フルオロ−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−8−フルオロ−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−9−フルオロ−5−メチル−ノナン酸;(3S,5S)−3−アミノメチル−7,7,7−トリフルオロ−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−8,8,8−トリフルオロ−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−5−メチル−8−フェニル−オクタン酸;(3S,5S)−3−アミノメチル−5−メチル−6−フェニル−ヘキサン酸;(3S,5R)−3−アミノメチル−5−メチル−7−フェニル−ヘプタン酸;およびそれらの薬学的に許容可能な塩からなる群より選択される、請求項1に記載の網膜疾患を治療するための治療剤。 - 前記第一級アミン化合物が、(R)−3−(アミノメチル)−5−メチルヘキサン酸、および(S)−3−(アミノメチル)−5−メチルヘキサン酸と(R)−3−(アミノメチル)−5−メチルヘキサン酸とのラセミ混合物からなる群から選択される、請求項1に記載の網膜疾患を治療するための治療剤。
- 前記第一級アミン化合物が、1、10、または25重量%未満の(S)−3−(アミノメチル)−5−メチルヘキサン酸および99、90、または75重量%超の(R)−3−(アミノメチル)−5−メチルヘキサン酸を含む、請求項1に記載の網膜疾患を治療するための治療剤。
- 前記第一級アミン化合物が、(R)−3−(アミノメチル)−5−メチルヘキサン酸から実質的になる、請求項1に記載の網膜疾患を治療するための治療剤。
- 前記第一級アミン化合物が、(R)−3−(アミノメチル)−5−メチルヘキサン酸である、請求項1に記載の網膜疾患を治療するための治療剤。
- 前記第一級アミン化合物は、局所投与、全身投与、硝子体内注射、および眼内送達のうちの少なくとも1つにより被験体に送達される、請求項1から6の何れか1項に記載の網膜疾患を治療するための治療剤。
- 前記網膜疾患が、黄斑変性症、シュタルガルト疾患、および網膜色素変性症からなる群より選択される、請求項1−7の何れか1項に記載の網膜疾患を治療するための治療剤。
- 網膜疾患を治療するための治療剤であって、
以下の式を含む治療有効量の第一級アミン化合物:
R2は、水素、1〜6個の炭素原子の直鎖もしくは分枝アルキル、またはフェニルであり、
R3は、1〜8個の炭素原子の直鎖もしくは分枝アルキル、2〜8個の炭素原子の直鎖もしくは分枝アルケニル、3〜7個の炭素原子のシクロアルキル、1〜6個の炭素原子のアルコキシ、−アルキルシクロアルキル、−アルキルアルコキシ、−アルキル、OH、−アルキルフェニル、−アルキルフェノキシ、−フェニルまたは置換フェニルであり、
R4は、水素であり、かつ、R3がメチルである場合、R2は、1〜6個の炭素原子の直鎖もしくは分枝アルキルまたはフェニルである)
またはその薬学的に許容可能な塩を含む治療剤。 - 前記第一級アミン化合物が、
3−アミノメチル−5−メチルヘキサン酸;3−アミノメチル−5−メチルヘプタン酸;3−アミノメチル−5−メチル−オクタン酸;3−アミノメチル−5−メチル−ノナン酸;3−アミノメチル−5−メチル−デカン酸;3−アミノメチル−5−メチル−ウンデカン酸;3−アミノメチル−5−メチル−ドデカン酸;3−アミノメチル−5−メチル−トリデカン酸;3−アミノメチル−5−シクロプロピル−ヘキサン酸;3−アミノメチル−5−シクロブチル−ヘキサン酸;3−アミノメチル−5−シクロペンチル−ヘキサン酸;3−アミノメチル−5−シクロヘキシル−ヘキサン酸;3−アミノメチル−5−トリフルオロメチル−ヘキサン酸;3−アミノメチル−5−フェニル−ヘキサン酸;3−アミノメチル−5−(2−クロロフェニル)−ヘキサン酸;3−アミノメチル−5−(3−クロロフェニル)−ヘキサン酸;3−アミノメチル−5−(4−クロロフェニル)−ヘキサン酸;3−アミノメチル−5−(2−メトキシフェニル)−ヘキサン酸;3−アミノメチル−5−(3−メトキシフェニル)−ヘキサン酸;3−アミノメチル−5−(4−メトキシフェニル)−ヘキサン酸;3−アミノメチル−5−(フェニルメチル)−ヘキサン酸;(S)−3−(アミノメチル)−5−メチルヘキサン酸;(R)−3−(アミノメチル)−5−メチルヘキサン酸;(3R,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸;3−アミノメチル−4,5−ジメチル−ヘキサン酸;(3R,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸MP;(3S,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸;(3R,4R)−3−アミノメチル−4,5−ジメチル−ヘキサン酸MP;3−アミノメチル−4−イソプロピル−ヘキサン酸;3−アミノメチル−4−イソプロピル−ヘプタン酸;3−アミノメチル−4−イソプロピル−オクタン酸;3−アミノメチル−4−イソプロピル−ノナン酸;3−アミノメチル−4−イソプロピル−デカン酸;3−アミノメチル−4−フェニル−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メトキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−エトキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−プロポキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−イソプロポキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−tert−ブトキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−フルオロメトキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−フルオロ−エトキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3,3,3−トリフルオロ−プロポキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−フェノキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(4−クロロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3−クロロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−クロロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(4−フルオロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3−フルオロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−フルオロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(4−メトキシ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3−メトキシ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−メトキシ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(4−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(3−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−(2−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−6−ヒドロキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−メトキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−エトキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル−6−プロポキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−6−イソプロポキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−tert−ブトキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−フルオロメトキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−フルオロ−エトキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル−6−(3,3,3−トリフルオロ−プロポキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル−6−フェノキシ−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−クロロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−クロロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−クロロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−フルオロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−フルオロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−フルオロ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−メトキシ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−メトキシ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−メトキシ−フェノキシ)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(4−トリフルオロメチル−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(3−トリフルオロメチル−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(2−トリフルオロメチル−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(4−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(3−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−5−メチル6−(2−ニトロ−フェノキシ)−ヘキサン酸;(3S,5S)−3−アミノメチル−6−ベンジルオキシ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−7−ヒドロキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−メトキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−エトキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−プロポキシ−ヘプタン酸;(3S,5S)−3−アミノメチル−7−イソプロポキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−tert−ブトキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−フルオロメトキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(2−フルオロ−エトキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(3,3,3−トリフルオロ−プロポキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−7−ベンジルオキシ−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−フェノキシ−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(4−クロロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(3−クロロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(2−クロロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(4−フルオロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(3−フルオロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(2−フルオロ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(4−メトキシ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(3−メトキシ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−7−(2−メトキシ−フェノキシ)−5−メチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(4−トリフルオロメチル−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(3−トリフルオロメチル−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(2−トリフルオロメチル−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(4−ニトロ−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(3−ニトロ−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−7−(2−ニトロ−フェノキシ)−ヘプタン酸;(3S,5S)−3−アミノメチル−5−メチル−6−フェニル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−クロロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−クロロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−クロロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−メトキシ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−メトキシ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−メトキシ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(4−フルオロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(3−フルオロ−フェニル)−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−6−(2−フルオロ−フェニル)−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−5−メチル−7−フェニル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(4−クロロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(3−クロロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(2−クロロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(4−メトキシ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(3−メトキシ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(2−メトキシ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(4−フルオロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(3−フルオロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−(2−フルオロ−フェニル)−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−5−メチル−オクト−7−エン酸;(3S,5R)−3−アミノメチル−5−メチル−ノナ−8−エン酸;(E)−(3S,5S)−3−アミノメチル−5−メチル−オクト−6−エン酸;(Z)−(3S,5S)−3−アミノメチル−5−メチル−オクト−6−エン酸;(Z)−(3S,5S)−3−アミノメチル−5−メチル−ノナ−6−エン酸;(E)−(3S,5S)−3−アミノメチル−5−メチル−ノナ−6−エン酸;(E)−(3S,5R)−3−アミノメチル−5−メチル−ノナ−7−エン酸;(Z)−(3S,5R)−3−アミノメチル−5−メチル−ノナ−7−エン酸;(Z)−(3S,5R)−3−アミノメチル−5−メチル−デカ−7−エン酸;(
E)−(3S,5R)−3−アミノメチル−5−メチル−ウンデカ−7−エン酸;(3S,5S)−3−アミノメチル−5,6,6−トリメチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5,6−ジメチル−ヘプタン酸;(3S,5S)−3−アミノメチル−5−シクロプロピル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−シクロブチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−シクロペンチル−ヘキサン酸;(3S,5S)−3−アミノメチル−5−シクロヘキシル−ヘキサン酸;(3S,5R)−3−アミノメチル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−5−メチル−ノナン酸;(3S,5R)−3−アミノメチル−5−メチル−デカン酸;(3S,5R)−3−アミノメチル−5−メチル−ウンデカン酸;(3S,5R)−3−アミノメチル−5−メチル−ドデカン酸;(3S,5R)−3−アミノメチル−5,9−ジメチル−デカン酸;(3S,5R)−3−アミノメチル−5,7−ジメチル−オクタン酸;(3S,5R)−3−アミノメチル−5,8−ジメチル−ノナン酸;(3S,5R)−3−アミノメチル−6−シクロプロピル−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−6−シクロブチル−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−6−シクロペンチル−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−6−シクロヘキシル−5−メチル−ヘキサン酸;(3S,5R)−3−アミノメチル−7−シクロプロピル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−シクロブチル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−シクロペンチル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−7−シクロヘキシル−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−8−シクロプロピル−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−8−シクロブチル−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−8−シクロペンチル−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−8−シクロヘキシル−5−メチル−オクタン酸;(3S,5S)−3−アミノメチル−6−フルオロ−5−メチル−ヘキサン酸;(3S,5S)−3−アミノメチル−7−フルオロ−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−8−フルオロ−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−9−フルオロ−5−メチル−ノナン酸;(3S,5S)−3−アミノメチル−7,7,7−トリフルオロ−5−メチル−ヘプタン酸;(3S,5R)−3−アミノメチル−8,8,8−トリフルオロ−5−メチル−オクタン酸;(3S,5R)−3−アミノメチル−5−メチル−8−フェニル−オクタン酸;(3S,5S)−3−アミノメチル−5−メチル−6−フェニル−ヘキサン酸;(3S,5R)−3−アミノメチル−5−メチル−7−フェニル−ヘプタン酸;およびそれらの薬学的に許容可能な塩からなる群より選択される、請求項9に記載の網膜疾患を治療するための治療剤。 - 前記第一級アミン化合物が、(R)−3−(アミノメチル)−5−メチルヘキサン酸、および(S)−3−(アミノメチル)−5−メチルヘキサン酸と(R)−3−(アミノメチル)−5−メチルヘキサン酸とのラセミ混合物からなる群から選択される、請求項9に記載の網膜疾患を治療するための治療剤。
- 前記第一級アミン化合物が、1、10または75重量%未満の(S)−3−(アミノメチル)−5−メチルヘキサン酸および99、90、または25重量%超の(R)−3−(アミノメチル)−5−メチルヘキサン酸を含む、請求項9に記載の網膜疾患を治療するための治療剤。
- 前記第一級アミン化合物が、(R)−3−(アミノメチル)−5−メチルヘキサン酸から実質的になる、請求項9に記載の網膜疾患を治療するための治療剤。
- 前記第一級アミン化合物が、(R)−3−(アミノメチル)−5−メチルヘキサン酸である、請求項1に記載の網膜疾患を治療するための治療剤。
- 前記第一級アミン化合物は、局所投与、全身投与、硝子体内注射、および眼内送達のうちの少なくとも1つにより被験体に送達される、請求項9−14の何れか1項に記載の網膜疾患を治療するための治療剤。
- 前記網膜疾患が、黄斑変性症、シュタルガルト疾患、および網膜色素変性症からなる群より選択される、請求項9−15の何れか1項に記載の網膜疾患を治療するための治療剤。
- (R)−3−(アミノメチル)−5−メチルヘキサン酸、および(S)−3−(アミノメチル)−5−メチルヘキサン酸と(R)−3−(アミノメチル)−5−メチルヘキサン酸とのラセミ混合物からなる群から選択される治療有効量の第一級アミン化合物を含有する網膜疾患を治療するための治療剤。
- 前記ラセミ混合物が、1,10、または25重量%未満の(S)−3−(アミノメチル)−5−メチルヘキサン酸および99,90、または75重量%超の(R)−3−(アミノメチル)−5−メチルヘキサン酸を含む、請求項17に記載の網膜疾患を治療するための治療剤。
- 前記第一級アミン化合物が、(R)−3−(アミノメチル)−5−メチルヘキサン酸から実質的になる、請求項17に記載の網膜疾患を治療するための治療剤。
- 前記第一級アミン化合物が、(R)−3−(アミノメチル)−5−メチルヘキサン酸である、請求項17に記載の網膜疾患を治療するための治療剤。
- 前記第一級アミン化合物は、局所投与、全身投与、硝子体内注射、および眼内送達のうちの少なくとも1つにより被験体に送達される、請求項17−20の何れか1項に記載の網膜疾患を治療するための治療剤。
- 前記網膜疾患が、黄斑変性症、シュタルガルト疾患、および網膜色素変性症からなる群より選択される、請求項17−21の何れか1項に記載の網膜疾患を治療するための治療剤。
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US20140235604A1 (en) | 2014-08-21 |
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