NZ615880B2 - Prodrugs of d-isoglutamyl-[d/l]-tryptophan - Google Patents
Prodrugs of d-isoglutamyl-[d/l]-tryptophan Download PDFInfo
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- NZ615880B2 NZ615880B2 NZ615880A NZ61588012A NZ615880B2 NZ 615880 B2 NZ615880 B2 NZ 615880B2 NZ 615880 A NZ615880 A NZ 615880A NZ 61588012 A NZ61588012 A NZ 61588012A NZ 615880 B2 NZ615880 B2 NZ 615880B2
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- New Zealand
- Prior art keywords
- compound
- trp
- glu
- mmol
- ncf3
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- 239000000651 prodrug Substances 0.000 title abstract description 26
- 229940002612 prodrugs Drugs 0.000 title abstract description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 50
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 190
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 claims description 37
- 239000011780 sodium chloride Substances 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- -1 Cg-CB cycloaikyl Chemical group 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- 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 5
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 3
- 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 239000000546 pharmaceutic aid Substances 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 241000269799 Perca fluviatilis Species 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 88
- 201000010099 disease Diseases 0.000 abstract description 6
- KSOCSOONUPBQDP-DGCLKSJQSA-N (2R)-2-[[(4R)-4,5-diamino-5-oxopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound C1=CC=C2C(C[C@@H](NC(=O)CC[C@@H](N)C(N)=O)C(O)=O)=CNC2=C1 KSOCSOONUPBQDP-DGCLKSJQSA-N 0.000 abstract description 4
- 210000000987 Immune System Anatomy 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 180
- 238000002360 preparation method Methods 0.000 description 79
- 238000005160 1H NMR spectroscopy Methods 0.000 description 74
- 235000019439 ethyl acetate Nutrition 0.000 description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 68
- 239000000243 solution Substances 0.000 description 59
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
- 239000007787 solid Substances 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 36
- 238000000034 method Methods 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
- 239000000706 filtrate Substances 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000012267 brine Substances 0.000 description 22
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 21
- 239000008079 hexane Substances 0.000 description 21
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 21
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 210000004369 Blood Anatomy 0.000 description 18
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M Sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 18
- 239000012458 free base Substances 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 239000008280 blood Substances 0.000 description 17
- 239000005457 ice water Substances 0.000 description 17
- 210000003494 Hepatocytes Anatomy 0.000 description 16
- 239000001257 hydrogen Substances 0.000 description 16
- 238000002390 rotary evaporation Methods 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 description 13
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 13
- 238000000967 suction filtration Methods 0.000 description 13
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- CATMPQFFVNKDEY-DGCLKSJQSA-N (2R)-2-amino-5-[[(1R)-1-carboxy-2-(1H-indol-3-yl)ethyl]amino]-5-oxopentanoic acid Chemical compound C1=CC=C2C(C[C@@H](NC(=O)CC[C@@H](N)C(O)=O)C(O)=O)=CNC2=C1 CATMPQFFVNKDEY-DGCLKSJQSA-N 0.000 description 11
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-hydroxy-Succinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 11
- 241000700159 Rattus Species 0.000 description 11
- 239000003480 eluent Substances 0.000 description 11
- 238000005984 hydrogenation reaction Methods 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 10
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- 239000001184 potassium carbonate Substances 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- 239000007789 gas Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 150000002500 ions Chemical class 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 230000035536 Oral bioavailability Effects 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 229940079593 drugs Drugs 0.000 description 8
- 150000003840 hydrochlorides Chemical class 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 230000036220 oral bioavailability Effects 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 229950007856 Mofetil Drugs 0.000 description 7
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- 238000004458 analytical method Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
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- 238000003786 synthesis reaction Methods 0.000 description 7
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 6
- 229940083599 Sodium Iodide Drugs 0.000 description 6
- 229940035295 Ting Drugs 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000006260 foam Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 235000009518 sodium iodide Nutrition 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000002194 synthesizing Effects 0.000 description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 108010025174 thymodepressin Proteins 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 235000012970 cakes Nutrition 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical class [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 239000011877 solvent mixture Substances 0.000 description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 4
- KKFDCBRMNNSAAW-UHFFFAOYSA-N 2-(morpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1 KKFDCBRMNNSAAW-UHFFFAOYSA-N 0.000 description 4
- 230000035533 AUC Effects 0.000 description 4
- 230000036983 biotransformation Effects 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- BOXZXICVMMSYPE-UHFFFAOYSA-N chloromethyl benzoate Chemical compound ClCOC(=O)C1=CC=CC=C1 BOXZXICVMMSYPE-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000001225 therapeutic Effects 0.000 description 4
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- NFVNYBJCJGKVQK-CYBMUJFWSA-N (2R)-3-(1H-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound C1=CC=C2C(C[C@@H](NC(=O)OC(C)(C)C)C(O)=O)=CNC2=C1 NFVNYBJCJGKVQK-CYBMUJFWSA-N 0.000 description 3
- 108010016626 Dipeptides Proteins 0.000 description 3
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 description 3
- 210000004072 Lung Anatomy 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
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- 206010047461 Viral infection Diseases 0.000 description 3
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000017613 viral reproduction Effects 0.000 description 3
- YVRGKFXJZCTTRB-UHFFFAOYSA-N 1-chloroethyl ethyl carbonate Chemical compound CCOC(=O)OC(C)Cl YVRGKFXJZCTTRB-UHFFFAOYSA-N 0.000 description 2
- SCQZHPMTSDVGKB-UHFFFAOYSA-N 2-morpholin-4-ylethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN1CCOCC1 SCQZHPMTSDVGKB-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
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- 230000036499 Half live Effects 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- JJTUDXZGHPGLLC-UHFFFAOYSA-N dilactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 2
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- 125000005842 heteroatoms Chemical group 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 230000001665 lethal Effects 0.000 description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
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- NFVNYBJCJGKVQK-ZDUSSCGKSA-N (2S)-3-(1H-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound C1=CC=C2C(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)=CNC2=C1 NFVNYBJCJGKVQK-ZDUSSCGKSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical group C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N 1-butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- ONZWFHWHTYZZLM-UHFFFAOYSA-N 1-chloroethyl cyclohexyl carbonate Chemical compound CC(Cl)OC(=O)OC1CCCCC1 ONZWFHWHTYZZLM-UHFFFAOYSA-N 0.000 description 1
- XPTPAIJDVFQPJT-UHFFFAOYSA-N 1-chloroethyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OC(C)Cl XPTPAIJDVFQPJT-UHFFFAOYSA-N 0.000 description 1
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 1
- BLXSFCHWMBESKV-UHFFFAOYSA-N 1-iodopentane Chemical compound CCCCCI BLXSFCHWMBESKV-UHFFFAOYSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
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- 125000000725 trifluoropropyl group Chemical group [H]C([H])(*)C([H])([H])C(F)(F)F 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
Abstract
Provided are prodrugs of D-isoglutamyl-[D/L]-tryptophan of formula (I), where the variables are as defined in the specification. Examples of the prodrugs include H-D-Glu(D-Trp-OH)-OCH2CH2CF3 and H-D-Glu(D-Trp-O-CH(CH3)-O-CO-O-cyclohexyl)-OH. Further provided is the use of the pro-drugs in pharmaceutical compositions. D-isoglutamyl-D-tryptophan and D-isoglutamyl-L-tryptophan may be useful in the treatment of various diseases, particularly those that are immune system related. ical compositions. D-isoglutamyl-D-tryptophan and D-isoglutamyl-L-tryptophan may be useful in the treatment of various diseases, particularly those that are immune system related.
Description
TECHNICAL FIELD
This invention relates to the field of pharmaceutical sciences and more
particularly to prodrugs of D-isoglutamyl-D-tryptophan and prodrugs of
D-isoglutamyl—L—tryptophan.
BACKGROUND
A prodrug is a compound that is ed in the body after its
administration to provide an active drug. Depending on the therapeutic use and
mode of stration, a prodrug may be used orally, for ion, intranasally,
or in an inhaler formulation directed at lung tissues (Rautio et al. Nature s
Drug Discovery 7, 255—270 (February 2008). The use of prodrug compounds in
an inhaler formulation directed at the lung tissue has been reviewed
(Proceedings Of The American Thoracic Society Vol 1 2004, How the Lung
Handles Drugs, Pharmacokinetics and Pharmacodynamics of Inhaled
Corticosteroids, Julia Winkler, Guenther Hochhaus, and Hartmut Derendorf 356-
363; H. Derendorf et al., Eur Respir J 2006; 28: 1042—1050).
For r and intranasal means of administration, the minimization of
oral bioavailability and systemic side effects by rapid clearance of absorbed
active drug may be part of the design considerations. A prodrug designed for
oral administration may prefer an improvement to oral bioavailability upon oral
administration to animals, and appropriate al stability in simulated
digestive fluids at pH 1.2 (also known as simulated gastric fluids) or pH 5.8 or 6.8
(also known as the simulated intestinal fluids). For prodrugs that are used in
injection, the s solubility of the compound is an important consideration.
The screening criteria for prodrugs depend on its mode of administration.
However, a g that can be readily hydrolyzed to the active drug in a human
blood is a positive e upon administration. Human blood has esterases that
are capable of biotransforming some ester derivatives to the active drug (Derek
r and Phyllis Godby Croft, Biood Esterases, Biochem J. 1942 December;
VIA510127NZI’R
30313-8046
36(10—12): 746—757; Williams FM. Clinical significance of esterases in man. Clin
Pharmacokinet. i985 Sep-Oct;10(5):392-403). ln on, prodrugs can be
bioconverted in a human liver to the active drug (Baba et a/., The
pharmacoklnetics of enalapril in patients with compensated liver sis Br J
Clin Pharmacol. 1990 Jun;29(6):766~9). Thus, regardless of the mode of
administration, human hepatocyte and blood nsformation results may be
used to evaluate ester prodrugs.
D—lsoglutamyl-D-tryptophan (also known as H~D-Glu(D-Trp-OH)-OH or
Apo805) is a synthetic hemoregulatory dipeptide developed for the treatment of
autoimmune diseases including psoriasis (Sapuntsova, S. G., et al. (May 2002),
Bulletin of Experimental Biology and Medicine, 133(5), 488—490). The sodium
salt of H-D-Glu(D-Trp—OH)-OH (thymodepressin) is considered an effective
treatment for sis (US 5,736,519), and is avaitable as an injection ampoule
in Russia.
D-lsoglutamyI-L-tryptophan (also known as H-D-Glu(L—Trp-OH)~OH or
) is reported as useful for modulating the immune system of a patient (US
452), and useful for treating lung cancer (A1),
tuberculosis (WO 13572 A1), genital viral infections (),
melanoma (WC 2007/123847), hemorrhagic viral infections (),
respiratory viral infections (WC 2005/1 , hepatitis C (),
and injury or damage due to e of mucosa (). SCV~07 is
also reported as a vaccine enhancer ().
SUMMARY
The present invention is based, in part, on the elucidation of prodrugs of
D-isoglutamyl—D-tryptophan (H-D-Glu(D-Trp-OH)-OH) and prodrugs of
D-isoglutamyI-L-tryptophan (H-D-Glu(L-Trp-OH)—OH).
VIA510127N21'R
303134046
iliustrative embodiments of the present invention provide a nd of
(3‘ o HN
O Q
(R) O O T
Formula I: H2N (I) or a pharmaceutically acceptable salt
thereof, wherein G is selected from the group consisting of: H,
2-morpholinoethyl, (CH2)nCF3, 01-08 alkyl, benzyl and A5 — A10 aryl; T is selected
from the group consisting of: H, C1-C3 alkyl, 2-morpholinoethyl, (CH2)nCF3,
P{(om/R2
CHZCONR4R5,CHZCH2NR4R5,Cg—Cecycloalkyl,A5—A10aryl, R‘ O and
“Wrote
R1 O ; n is 1, 2, 3 or 4; R‘ is H or 01-08 aikyl; R2 is 01-08 aikyl, 03-c6
cycloalkyl, or phenyi; R3 is 01-03 alkyl, Cg~Ce cycloalkyl, or phenyi; and R4 and
R5 are either separate groups or together form a single group with the N to which
they are bonded; when R4 and R5 are separate groups, R4 and R5 are
independently selected from the group consisting of: Cq-Cfi alkyl; when R4 and
R5 together with the N to which they are bonded form the single group, the single
group is selected from the group ting of: morphotinyl, N-(C1-C4
alkyI)—piperazinyi and piperidinyl; provided that if T is H, then G is
2-morpholinoethyl, (CH2)nCF3, C1-C8 alkyl or benzyl; if T is CHZCONR4R5,
CH20H2NR4R5, or 03-06 cycloalkyi, then G is H; and ifT is 01-08 alkyl, then G is
holinoethyl, CF3, or A5 — A10 aryl.
Illustrative embodiments of the present invention provide a compound
described herein wherein if G is H, then T is ed from the group consisting
of: 2-morpholinoethyl, (CH2)nCF3, R4R5, CH20H2NR4R5, cg-ce
cycloalkyl, R1 0 and R1 0
V1A510127NZPR
303134046
Illustrative embodiments of the present invention provide a compound
described herein wherein if G is H, then T is selected from the group ting
a/OYRz
of: 2-morpholinoethyl, (CH2)nCF3, CHZCHZNR4R5, 03-06 cycloalkyl, R1 0
and R1 0
rative embodiments of the present ion provide a compound
described herein wherein if G is H, then T is selected from the group consisting
from? Wire‘s
of: 2-morpholinoethyl,(CH2)nCF3,CH2CH2NR4R5, R1 0 and R1 O
rative embodiments of the present invention provide a compound
described herein wherein a chiral carbon of a tryptophan moiety is in the
D-configuration.
Illustrative embodiments of the present invention provide a compound
described herein wherein a chiral carbon of a tryptophan moiety is in the
L-configuration.
rative embodiments of the present invention provide a compound
bed herein wherein G is H and T is A5 to A10 aryl.
rative embodiments of the present ion provide a compound
S/OWRZ
described herein n T is R1 0
Illustrative embodiments of the present invention provide a compound
doro‘rr
described herein wherein T is R1 0
Illustrative embodiments of the present invention provide a compound
described herein wherein T is (CH2)nCF3.
Illustrative embodiments of the present invention provide a compound
described herein wherein T is 2-morpholinoethyl.
VIA510127NZPR
303134046
Illustrative embodiments of the present invention provide a compound
described herein wherein G is 2-morpholinoethyl, (CH2)nCF3, or 01-08 alkyl; and
sort screw
T is 2-morpholinoethyl, (CH2)nCF3, A5 to A10 aryi, R1 0 or R1 0
Illustrative embodiments of the t invention provide a compound
described herein wherein T is C1-CB alkyl.
Illustrative embodiments of the present invention e a compound
described herein wherein G is A5 to A10 aryi.
Illustrative ments of the present invention provide a compound
described herein wherein T is isoamyl, G is indanyl.
Illustrative embodiments of the present invention e a compound
described herein wherein T is H.
Illustrative embodiments of the present invention provide a compound
described herein wherein G is H.
Illustrative embodiments of the present invention provide a compound
described herein wherein T is H and G is ethyl.
iilustrative embodiments of the t invention provide a compound
described herein wherein T is H and G is benzyl.
Illustrative ments of the present invention provide a compound
described herein wherein T is H and G is methyl.
rative embodiments of the present invention e a compound
described herein wherein T is H and G is isoamyl.
Illustrative embodiments of the present invention e a nd
described herein wherein T is H and G is isopropyl.
rative embodiments of the present invention provide a compound
described herein wherein T is H, G is (CH2)nCF3 and n is 1.
Illustrative embodiments of the present invention provide a compound
described herein wherein T is H, G is CF3 and n is 2.
illustrative embodiments of the present invention provide a compound
described herein T is H and G is 2-morpholinoethyl.
VlA510127NZI’R
303134046
Illustrative embodiments of the present ion provide a compound
PiKOirO‘Ri
described herein wherein T is R‘ 0 R1 is methyi, R3 is cyciohexyl and G
is H.
Illustrative embodiments of the present invention provide a compound
described herein wherein T is 2-morpholinoethyl and G is H.
illustrative embodiments of the t invention provide a compound
described herein wherein T is cyclohexyl and G is H.
Illustrative embodiments of the t invention provide a compound
”droirO‘Ri
described herein wherein T is R‘ 0 R1 is methyl, R3 is cyclohexyl and G
is H.
Illustrative embodiments of the present invention provide a compound
described herein n T is (CH2)nCF3, n is 2 and G is H.
Illustrative embodiments of the present invention provide a nd
described herein wherein T is R1 0
, R1 is methyl, R3 is ethyl and G is H.
Illustrative embodiments of the present invention provide a compound
WOW/R2
described herein wherein T is R‘ 0 R1 is H, R2 is pent—Z-yl and G is H.
Illustrative embodiments of the present invention provide a compound
Wire‘s
described herein wherein T is R1 0 R1 is methyl, R3 is isopropyl and G
is H.
rative embodiments of the present invention provide a nd
described herein wherein T is CHZCONR4R5, R4 is CH3, R5 is CH3 and G is H.
Illustrative embodiments of the t invention provide a compound
described herein n T is CH2CONR4R5, R4 is CH3, R5 is CH3 and G is H.
VIASIOIZ'INZPR
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liiustrative ments of the present invention provide a compound
PdroTRZ
described herein wherein T is R‘ 0 R1 is H, R2 is C(CH3)2-CHZCHZCH3
and G is H.
Illustrative embodiments of the present invention provide a compound
described herein wherein T is (CH2)nCF3, n is 1 and G is H.
rative embodiments of the present invention provide a compound
described herein wherein T is (CH2)nCF3, n is 1 and G is H.
illustrative embodiments of the present invention provide a compound
described herein wherein T is l and G is H.
Illustrative embodiments of the present invention provide a compound
described herein wherein T is 2-methoxyphenyl and G is H.
Illustrative embodiments of the present invention provide a compound
Fifi/om}?
bed herein wherein T is R1 0 R1 is H, R2 is t—butyl and G is H.
Illustrative embodiments of the present invention provide a compound
P{row/R2
described herein wherein T is R‘ 0 R1 is H, R2 is phenyl and c
, is H.
Illustrative embodiments of the present invention provide a compound
bed herein wherein T is (CH2)nCF3, n is 2, G is (CH2)nCF3 and n is 2.
Illustrative embodiments of the present invention provide a compound
described herein n T is holinoethyl and G is ethyl.
illustrative embodiments of the present invention provide a compound
PirhrO‘Ri’
described herein wherein T is R‘ 0 R1 is methyl, R3 is ethyl and G is
ethyl.
Illustrative embodiments of the present invention provide a nd
described herein wherein T is holinoethyi and G is 2~morpholinoethyL
rative embodiments of the present ion provide a compound
described herein wherein T is benzyl and G is 2—morpholinoethyl.
VIA5‘10127NZI’R
303134046
Illustrative embodiments of the present invention provide a compound
described herein wherein T is indanyl and G is 2-morpholinoethyl.
Illustrative embodiments of the present invention provide a compound
described herein wherein T is 2-morpholinoethyl, G is (CH2)nCF3 and n is 2.
Illustrative embodiments of the present ion provide a compound
described herein n T is 2-morpholinoethyl and G is isoamyl.
illustrative embodiments of the present invention e a nd
described herein wherein T is (CH2)nCF3, n is 1, G is (CH2)nCF3 and n is 1.
Illustrative embodiments of the present invention provide a pharmaceutical
formulation comprising a compound described herein and a pharmaceutically
acceptable excipient.
Illustrative embodiments of the present invention provide a pharmaceutical
ition described herein wherein the formulation is adapted for inhalation.
Other aspects and es of the t invention will become apparent
to those ordinarily skilled in the art upon review of the following description of
specific embodiments of the ion in conjunction with the accompanying
figures.
BRIEF DESCRIPTION OF THE GS
Figure 1 shows the average (n=5) concentration of H-D-GIu(D-Trp~OH)—OH
(Ap0805) in plasma after oral dosing of H—D—G|u(D~Trp-O-CH2-O-CO-t-Bu)-OH (Apo839)
and H-D-Glu(D-Trp-OH)-OH monopotassium salt (Ap0805K1) (5 mg/kg) to rats
demonstrating similar oral bioavailability of the prodrug.
Figure 2 shows the average (n=5) concentration of H-D-G|u(D-Trp-OH)-OH
(Apo805) in plasma after oral dosing of H-D-Glu(D-Trp-O-CH(CH3)~O—CO~O~cyclohexyl)-
OH (Ap0843) and H-D-GIu(D-Trp-OH)-OH monopotassium salt (Ap0805K1) (5 mg/kg) to
rats demonstrating reduced oral bioavailability of the prodrug. The minimization of oral
bioavailability is one e to be considered for prodrugs designed for an inhaler mode
of administration.
VIA510327NZPR
303134046
DETAILED PTION
The present invention is based, in part, on the ation of prodrugs of
D-isoglutamyi—D-tryptophan and prodrugs of D-isoglutamyI-L-tryptophan.
As used herein, the symboi “11” indicates the point at which the
displayed moiety is attached to the remainder of the molecule. For e,
propyl or CH3-CH2-CH2- may be shown asW Another exampie is
CH3-CH2-CH—CH2-CH3 (a pent-S-yi moiety) may be shown as 29.
As used herein, the term “alkyl” means a branched or ched
ted arbon chain. Non-limiting, illustrative examples of aikyl moieties
include, methyl, ethyl, , isopropyi, n-propyl, butyl, sec-butyl, yl, n-
pentyl, hexyl, octyl and the like. When the terminology “OX—Cy”, where x and y
are integers, is used with respect to alkyl moieties, the ‘C’ relates to the number
of carbon atoms the alkyt moiety. For example, methyl may be described as a C1
alkyl and isobutyl may be described as a C4 alkyl. 01-04 alkyl means methyl (a
C1 alkyl), ethyl (a C2 alkyl), propyl or isopropyi (a 03 alkyl), butyl or sec-butyl or
isobutyl or tert-butyl ( a C4 alkyl). All specific integers and ranges of integers
within each range are specifically disciosed by the broad range. For example,
01—08, specifically includes the following: C1, Cg, C3, C4, C5, 05, C7, Ca, 01-02,
C1-C3. C1-C4, 01-05, 01'06: C1-C7, 01-08. 02-03, C2-04. Cz~C5. 02-06, Cz-C7.
Cz-Cs. C3-04, C3'05: C3-C6! C3-07. C3'08: C4435, C4‘C6: C4-C7, 04-08, 05-06.
C5-C7, C5-C8, Cs-C7, C6-Cg, and 07-03. Another example is Cs-Cg specifically
includes C5, 05, C7, C8, Cs-Cs, C5-C7, C5-Cg, Cs-C7, Ce-Cg, and C7-C8.
As used herein the term “aryl" means any moiety which has at least a
portion of the moiety that conforms to i's rule. This includes moieties that
are hydrocarbons and moieties that include heteroatoms. For clarity, an aryl
moiety as a whole does not need to conform to Huckel's rule as long as some
portion of the aryl moiety, when considered in the absence of the remainder of
VIA310127NZI’R
303134046
the moiety, does conform to Hiickel's rule. Non-limiting, illustrative examples of
aryl moieties include phenyl, benzyl, l, 2-methoxyphenyl, 3-methoxyphenyl
and 2-fluorophenyl. When the ology “AX-Ay” where x and y are integers,
is used with respect to aryl moieties, the ‘A’ relates to the total number of carbon
and heteroatoms in the aryl moiety. For example, 1-fluorophenyi may be
described as an A7 aryl group and 2-methoxyiphenyl may be described as an A8
aryl group. Furan is an example of an A5 aryl group. All specific integers and
ranges of integers within each range are specifically disclosed by the broad
range. For example, A5-A10, specifically includes the following: A5, A6, A7, A3,
A9. A10, A5-A6. A5-A7, As-A8,A5-A9,A5-A1o. Act—A7, Ae-As. Ara—Ag. . A7'A8:
A7-A9. A7-A1o, Ass-Ag. Aer/5x10 and A9~A10.
As used herein, the term “mofetil” means a morphoiinoethyl radical having
0 HZ—
the structure: \—/
. Mofetil is often referred to by the lUPAC name
2~morpholinoethyl.
The following acronyms and/or and on are also used .
Acron m and/or Shorthand Ex-lanation of Acron m and/or Shorthand
1-ethyl-3—(3-dimethylaminopropyl)
carbodiimide h drochioride
diisoprop Ieth lamine
dimethylformamide
dimeth lsulfoxide
room tem oerature
h drox succinimide
Boc—D-GIu(O-le)—OH
Boc-D-GIu-O-isoamyi
-1 1-
VIA510127NZPR
303134046
Acron m and/or Shorthand Ex-lanation of Acronym and/or Shorthand
H ||
Boc—D-GIu-OBZI >f firm \/0 \\\ Cx
0” ‘OCHzPh
Boc-D—Glu(O-le)«O-isoamyl
Cbz—D—Glu-O-le
_-_H-D-Glu OH ~OH Du-amma-Iutam I-D-tr ootohan
H—D-Glu L—Trp-OH)—OH D-oamma-giutam I-L-tr ptohan
0 HM
u(Trp-OH)-OH 0% q (R) O O H
(D-gamma-giutamyI-tryptophan)
(wherein the stereochemistry in the tryptophan
unit is not defined
A i HN
Boc-D—Glu(D—Trp—O-Bzi)-O- o NH
isoamyl 07?" H
w ,/\n/ ”j;\\
0 O
O OCHZPh
Boc-D-Glu( D-Trp-OH)-O-
isoamyl
-1 2..
VIA510127NZI’R
303134046
Acron m and/or Shorthand Explanation of Acron m and/or Shorthand
H-D-Glu(D-Trp-OH)-O-isoamy¥
Boc-D-Glu(D—Trp—O—le)—OEt
OCHzPh
Boc—D-Glu(D-Trp-OH)-0Et
H-D-G|u(D-Trp-OH)-0Et
Boc-D-Glu(D-Trp-O-le)—O-iPr
GIu(D-Trp-OH)-O-iPr
H-D—Glu(D-Trp-OH)—O—iPr
VIA510127NZPR
303134046
Acron m and/or Shorthand Ex- Ianation of Acron m and/or Shorthand
Boc—D-GIu(D-Trp-OH)—
OCHzCHgCFa
H-D-G3U(D-Trp-OH)-
OCHzCHgCFa
Boc-D-GIu(D-Trp-OH)-O-Bzi
u(D-Trp—OH)-O-le
H-D-Glu(D-Trp—OH)—OCH;CF3
Cbz—D-Giu(D-Trp-OH )-O-Bz|
\71A5101Z7NZI’R
303134046
Acron m andlor and Explanation of Acron m and/or Shorthand
Cbz—D—G|u(D-Trp—O-CH(CH3)—
O-CO-O-cyciohexyi)—O—le
wherein the stereochemistry at the * position is
not defined
H-D—Giu(D—Trp~O—CH(CH3)—O— Hofiyw H
yciohexyl)—OH
0 W01 i Q O
O O *OAO
wherein the stereochemistry at the * position is
not defined
Cbz-D~G|u(D-Trp-O-CH(CH3)-
O-CO-O-Et)-O-le
wherein the stereochemistry at the * position is
not defined
H-D-Glu(D—Trp—O-CH(CH3)-OCO-O-Et
)-OH
wherein the stereochemistry at the * position is
notdefined
-1 5 _
VIA510127NZI’R
303134046
Acron m and/or Shorthand Ex- on of Acron m and/or Shorthand
O HN
Glu(D-Trp-O-CH(CH3)- OVOANH \
O-CO—O-i-Pr)-O—le o7])”I,/\[r(R) H
o 02:LOiiL(R)
wherein the stereochemisotry at theo" positionIs
not defined
H-D-Glu(D-Trp-O-CH(CH3)-O—
CO-O-i—Pr)—OH Hog”,”/WN0010ioo
wherein the stereochemistory at9the"Oposition is
not defined
Cbz-D-Glu(D-Trp-O-CH200-
N(CH3)2)~O~Bz|
H-D-G|u(D-Trp-O-CH2CO-
N(CH3)2)'OH
Cbz—D-G|u(D-Trp-O-mofetil)-O—
VIA310127NZI’R
Acron m and/or Shorthand Explanation of Acron m and/or Shorthand
H~D—Glu(D-Trp-O-mofeti|)—OH
Cbz-D-GIu(D-Trp-OCH20-CO-
Ph)—O-th
H-D-Glu(D-Trp-OCH20-CO-
Ph)—OH
H~D—G!u(D-Trp-OCH20-CO-
[pentyl])-OH
H-D-Glu(D-Trp-OCH20-CO-
C(CH3)g-CH20H2CH3)—OH
H-D-G|u(D-Trp-OCHZCHgCF3)—
V1A510127NZI’R
303134046
Acron m and/or Shorthand
Boc-D-G1u(D-Trp-O-mofetil)-O-
mofetii
H-D—Glu(D-Trp~O—mofeti|)-O-
mofetil
H-D-G|U(D-Trp-O-CH20H2CF3)“
HzCFa
Cbz-D—GIu(D—Trp~OH)-0Et
Cbz—D~G|u(D—Trp—O-CH(CH3)-
O-CO—O-cyclohexyI)-0Et
VIAS 10127NZPR
303134046
Acron m and/or Shorthand Ex-lanation of Acron m and/or Shorthand
H-D-G|u(D-Trp-O-CH(CH3)-O-
CO-O-cyclohexyl)-0Et
Glu(D—Trp~O-CH(CH3)-
O-CO-OEt)-0Et
H—D-Glu(D-Trp-O-CH(CH3)-O-
CO-OEt)-OEt
Cbz—D-G|u(D-Trp-O-mofeti|)-
H-D-Glu(D-Trp-O-mofeti|)-0Et
H—D-Glu(D-Trp-O-mofeti|)-O-
CHZCHZCFs
VIASI DIZYNZPR
303134046
Acron m and/or Shorthand Explanation of Acron m and/or Shorthand
H-D-G|u(D-Trp-O—mofetiI)-O—
isoamyl
u(D-Trp-OindanyI)-O-
mofetil
H-D-Glu(D-Trp-OH)-O-mofeti¥
H~D~G|u(D-Trp-O-le)—O-mofeti|
H-D-G|U(D-Trp-OCHzo-CO-
C(CH3)3)'OH
Compounds of the present invention may be described by Formula I:
-20..
VIASlOIZ'INZPR
303134046
H2N (1)-
In Formula I:
G is selected from the group consisting of: H, 2—morpholinoethyl,
(CH2)nCF3, C-g-Cg alkyl, and A5-A1o aryl; and
T is selected from the group ting of: H, C1-Ca alkyl,
2-morpholinoethyl, (CH2)nCF3, CH2CONR4R5, CH2CH2NR4R5, Cg-Ce cycloalkyl,
$8sz PirOtrO‘Rs
A5—A1o aryl, R1 0 and R1 0
In the (CH2)nCF3 moiety, n is 1,2, 3 or 4.
In those moieties in which R1 appears, R1 is H or C1-C3 alkyl.
In the moiety in which R2 appears, R2 is 01-03 alkyl, 03-06 cycloalkyi, or
phenyl.
In the moiety in which R3 appears, R3 is 01-08 alkyl, 03-06 cycloalkyi, or
phenyl.
In those es in which R4 and R5 appear, R4 and R5 are either
separate groups or together form a single group with the N to which they are
bonded. When R4 and R5 are separate groups, R4 and R5 are independentiy
selected from the group consisting of: C1-C6 alkyl. When R4 and R5 together
with the N to which they are bonded form the single group, the single group is
selected from the group consisting of: linyl, N~(Cq-C4 alkyi)—piperaziny|
and dinyl.
Compounds of Formula l are limited to compounds in which if T is H, then
G is 2-morpholinoethyl, (CH2)nCF3, C1-C3 alkyl or benzyl (benzyl is a particular
VIA51 01 27NZPR
303134046
A5-A10 aryl) and ifT is CHZCONR4R5, CH20H2NR4R5, or 03-06 lkyl, then G
is H and if T is 01-08 alkyl, G is 2—morpholinoethyl, (CH2)nCF3, or A5-A1o aryl.
In particular ments, compounds of Formuia I may be r limited
to compounds in which when G is H, T is ed from the group ting of:
2-morpholinoethyl, (CH2)nCF3, CHZCONR4R5, CHZCHgNR4R5, 03—06 cycloalkyi,
in particular embodiments, compounds of Formula I may be further d
to compounds in which when G is H, T is selected from the group consisting of:
rN),\ro\n,R2
2-morpholinoethyl,(CH2)nCF3,CHgCH2NR4R5,03-08 cycloalkyl, R1 0 and
drown
R1 o
in particular embodiments, compounds of Formula I may be further limited
to compounds in which when G is H, T is selected from the group consisting of:
W we
2-morpholinoethyi, (CH2)nCF3, CH20H2NR4R5, R1 0 and R1 0
in particular embodiments, compounds of Formula | specificaliy exclude
compounds in which T is A5-A10 aryi and G is H.
In particular embodiments, compounds of Formula i specifically exclude
compounds in which G is 01—08 alkyi and T is H.
In particular embodiments, compounds of Formula I specifically e
compound in which T is H and G is H.
In particular embodiments, compounds of Formula I specifically exclude
compounds in which G is 01-08 alkyl and T is 01-03 alkyl.
In particular embodiments, compounds of Formula l are also compounds
of Formula lA:
127N21’R
303134046
2:]:
H\ 0 HM
0% q (R) 0 0 T
(IA).
In a IA, T is selected from the group consisting of: 2-
WOW/R2
morpholinoethyl; R1 0 wherein R1 is H or 01-03 alkyl, and R2 is 01-03 alkyl,
PJrOwro‘Ra
C3-C5 cycloalkyl, or phenyl; R1 0 wherein R1 is H or 01-03 alkyl, and R3
is (31-05; alkyl, , or 03-05 cycloalkyl; and ~(CH2)nCF3 wherein n is 1 to 4.
In particular embodiments, compounds of Formula I are also compounds
of Formula IE:
G 0 HM
O O
(R) O O H
H2N (lB).
In Formula lB, G is selected the group consisting of: 2-morpholinoethyl;
and (CH2)nCF3 wherein n is 1 to 4.
In particular embodiments, compounds of Formula I are also compounds
of Formula IC:
In Formula IC:
-23_
VIASI 0127NZPR
303134046
G is selected from the group consisting of: 01-08 alkyi, 2-
morpholinoethyl, ~(CH2)nCF3 wherein n is 1 to 4, and A5 — A10 aryl; and
T is selected from the group ting of: 2-morpholinoethyl;
firm0O R2
wherein R‘ is H or 01-03 alkyl, and R2 is 01-08 aikyl, 03-06 cycloalkyl,
Wire‘s
or phenyl; R1 0 wherein R1 is H or C1-C3 alkyl, and R3 is C1-C8 alkyl,
phenyl, or 03—05 cycloalkyl; and -(CH2)nCF3 wherein n is 1 to 4.
Compounds of Formulas |, IA, IB and IC comprise a tryptophan moiety.
The tryptophan moiety may be considered as the following moiety:
0 By
Of ular interest in the tryptophan moiety is a chiral carbon, which is
denoted above by the “*”. The chiral carbon of the tryptophan moiety may be in
either the L-configuration or the D-configuration. In some embodiments, the
compounds of Formula I, IA, IB and/or lC comprise a chiral carbon of the
tryptophan moiety in the D—configuration. In other embodiments, the compounds
of Formula |, IA, IB and/or 10 comprise a chiral carbon of the tryptophan moiety in
the iguration. In still other embodiments, compositions of compounds
comprising compounds of as l, IA, IB and/or IC may comprise some
compounds in which the chiral carbon of the tryptophan moiety is in the
L-configuration and other compounds in which the chiral carbon of the tryptophan
moiety is in the D-configuration.
Compounds of the present invention may also be provided in the form of a
salt or a pharmaceutically able salt. An e of a pharmaceuticaliy
acceptable salt of this ion is ApoQOO, H~D~Giu(D-Trp-O-mofeti|)—O-Et.2HCl,
(ethyl (2R)—2—amino({(2R)—3—(1H—indol—3—yl)[2-(morpho|inyl)ethoxy]
VIASI DiZYNZl’R
303134046
oxopropanyl}amino)—5—oxopentanoate dihydrochloride), which may be
diagrammaticalty represented by the ing structure:
0 O C!“
Aowfiw H
Owfivfi
NH3+cr o be
Compounds of the present invention may be pharmaceutically acceptable
salts and include salts of acidic or basic groups present in compounds described
herein. Pharmaceutically acceptable acid addition salts include, but are not
limited to, hydrochloride, hydrobromide, hydroiodide, e, sulfate, ate,
phosphate, acid phosphate, otinate, acetate, lactate, salicylate, citrate,
tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, inate,
fumarate, gluccnate, glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzensutfonate, p-toluenesulfonate and
pamoate (i.e., 1,1'-methylene-bis-(2—hydroxy—3—naphthoate)) salts. Suitable base
salts include, but are not limited to, aluminum, calcium, lithium, magnesium,
potassium, , zinc, and diethanoiamine salts. For a review on
pharmaceutically able salts see Berge et al., 66 J. Pharm. Sci. 1—19
(1977).
Syntheses of compounds of Formula l are outlined below in Schemes 1, 2
and 3.
VIA510127NZI’R
H—D-Glu(L—TrpT)-OH (IA). D, L diastereomer
CBZ-D-Glu(L-Trp-O-T)—OCH2Ph
1 (i)
CBz-D—G1u(L-TrprH)-OCH2PI1
G = CHzph
CBz-D-Glu-O-G
(*0 (c) (e)
G = CHzPh G = B G = CHzph
CBZ—D-Glu(D-Trp-O-T)-OCH2Ph Glu(D-TrpT)-0Bt CBz—D—Glu(D-Trp-OH)-OCH2Ph
(b) l (d) l l (f)
H-D—Glu(D-Trp-O—T)—OH H-D-Glu(D-Trp-O-T)-0Et GIu(D-Trp-O—T)-OCHZPh
(IA); D,D diastereomer (16). DD diastereomer
1 (g)
H-D—Glu(D~Trp-O-T)—OH
(IA); D,D diastereomer
SCHEME 1
Process A: (a) EDCI/HOBt/DIEA, D-Trp-O-T.HC!, CHzClz; (b) H2, 10% Pd/C, EtOH.
Process B: (c) EDCI/HOBt/DIEA, D-Trp-O-THCI, CHzClz; (d) H2, 10% Pd/C, EtOH.
Process C: (e) EDCI/HOBt/DIEA, then D~Trp~OH, CHszz; (f) T-i or T-Cl, K2003, DMF;
(g) H2, 10% Pd/C, EtOH.
Process D: (h) EDCI/HOBt/DIEA, then L-Trp-OH, CHQCIQ; (i) T—l or T-Cl, K2003, DMF; (j)
H2, 10% Pd/C, EtOH.
—26—
VIASIOi27NZPR
303134046
Process A describes synthesis of a compound of Formula IA wherein the
ide is u(D-Trp-O-T)-OH is used as an illustrative example. The
process may be readily adapted to make other compounds of Formula l.
In s A step (a), Cbz—D-GIu-OCHzPh is coupled with D—Trp-O-T.HCI
ester wherein T is C3-Cs cycloalkyl, or an A5 — A10 aryl to give the compound
Cbz—D-Glu(D~Trp—O-T)-OCH2Ph using EDCI, HOBt, DIEA propylethylamine)
in CHgClz. In step (b), hydrogenation of the Cbz—D-Glu(D-Trp-O-T)—OCH2Ph give
the compound of formula ( 1 A) as shown above.
Process B describes synthesis of a compound of Formuia IC wherein the
dipeptide is H-D-GIu(D—Trp-O-T)-O-G is used as an illustrative example. The
process may be readily adapted to make other compounds of a I.
In process B step (c), Cbz-D-Giu-OEt is coupled with D-Trp-O-THCI ester
wherein T is 03-05 cycloalkyl, or an A5 —— A10 aryl to give the compound Cbz-D-
Glu(D—Trp-O-T)-0Et using EDCI, HOBt, DIEA in Cchig. In step (d),
hydrogenation of the Cbz—D-Glu(D~Trp~O-T)-0Et give the nd of formula
(IC) wherein G is ethyl, T is 03-03 cycloalkyl, or an A5 — A10 aryl.
Process C describes synthesis of nds of Formula IA wherein T is
fi/OWRZ
N-morpholinylethyl; R1 0 wherein R1 is H or 01-03 alkyl, and R2 is 01-03
alkyl, c3-c6 cycloalkyl, or phenyl; R1 0 wherein R1 is H or cr-c3 aikyl,
and R3 is 01-03 alkyl, phenyl, or 03-05 cycloalkyl; or (CH2),,CF3 wherein n is 1 to
4. The process may be readily adapted to make other nds of Formula I.
In process C step (e), Cbz-D—GIu-OCHgPh is coupled with D—Trp-OH to
give the compound Cbz—D-GIu(D-Trp-OH)—OCH2Ph using EDCI, HOBt, DIEA in
CH2CI2. In step (1‘), Cbz~D-GIu(D-Trp-OH)—OCH2Ph is reacted with potassium
carbonate and T-CI or T~I wherein T is defined above under the compound of
formula (IA) in process C to give the dipeptide Cbz-D-GIu(D-Trp-O-T)-OCH2Ph.
In step (9), hydrogenation of the Cbz-D—GIu(D-Trp-O-T)-OCH2Ph gives the
e i-I-D-GIu(D-Trp-O-T)—OH, a nd of formula (IA) wherein T is
defined above under process C.
VlA510127NZI‘R
Process D describes synthesis of compounds of Formula IA wherein T is
$0762
N-morpholinyiethyl; R1 0 wherein R1 is H or ctr-ca alkyl, and R2 is 01-08
alkyl, C3-Cs cycloalkyl, or phenyl; R1 0 wherein R1 is H or 01-03 alkyl,
and R3 is 01—08 alkyl, phenyl, or 03—06 cycioalkyi; or (CH2)nCF3 wherein n is 1 to
4. The process may be readily adapted to make other compounds of Formula I.
Process D is identical to process C, with the exception that L-Trp~OH is
used instead of D-Trp-OH in the process. As an illustrative example, by
replacing the D-Trp-OH in step (e) with L—Trp-OH, Ap0894 (D,L), a compound of
a 1A wherein T = CH200N(CH3)2 can be made. The procedure is further
exemplified in a ular embodiment in Example 16.
Boc-D-GIu~O—G > Glu(D-Trp-OCHzPh)-O-G
j a)
u(D-Trp-OH)—O-G (m)
+—"'—"‘ Boc-D-Glu(D—Trp-OH)—O-G
(13)
SCHEME 2
Process E: (k) EDCI/HOBt/DIEA, CHgClz, D-Trp—OCHgPh; (I) H2, 10% Pd/C, EtOH; (m)
HCI, EtOAC.
Process E describes synthesis of a compound of Formula IB. The process may
be y adapted to make other compounds of Formula I.
in process E step (k), Boc—D-Glu-O-G wherein G is C1-Ca alkyl,
trifluoropropyl is coupled to the D-Trp-OCHzPhHCI with EDCl/HOBt/DElA in
Cchig to give Boc-D-Glu(D—Trp-OCH2Ph)-O-G. In step (I), hydrogenation over
Pd/C in ethanol gives Boc-D-GIu(D-Trp-OH)-O-G. in step (m), de-Boc of Boc-D-
GIu(D-Trp—OH)—O—G using HCI in EtOAc s the compound of Formula (IB).
VlA510127NZPR
303134046
Boc-D~Glu(D~Trp-OH)-OH ---—> Boc-D-GIu(D-Trp-O-T)-O-G
l (m)
H-D~Glu(D—Trp—O~T)~O-G
(1C)
SCHEME 3
Process F: (p) T = G in this reaction, T-l, K2003, DMF; (m) HCI, EtOAc.
Process F bes synthesis of a nd wherein G = T = N-
morpholinylethyl. The process may be readily adapted to make other
compounds of Formula I.
In process F step (p), Boc-D-Glu(D-Trp-OH)-OH is d with T—I,
K2003, DMF to give Boc~D~G|u(D~Trp-O-T)-O-G wherein G = T, and G is N-
morpholinylethyl. In step (m), treatment of Boc-D-GIu(D-Trp-O-T)—O-G gives the
compound (IC) wherein G = 'i'.
In a similar manner, compounds of Formuia | with the gamma-D-glutamyl
and L-tryptophanyt moiety may be prepared using the ation as described in
processes A to F adapted to suit the ulars of the desired product.
Compounds of Formula I that exist in free base form may be converted to
their pharmaceutically acceptable salts by treatment with the appropriate
nic or organic acid. Salts of the compounds of Formula I may be
converted to the free base form or to another salt.
Compounds of the present invention or salts thereof may be formulated
into a pharmaceutical formulation. Many nds of this invention are
generally water soluble and may be formed as salts. In such cases,
pharmaceutical compositions in accordance with this invention may comprise a
salt of such a compound, preferably a physiologically acceptable salt, which are
known in the art. Pharmaceutical ations will typically comprise one or
more carriers acceptable for the mode of administration of the preparation, be it
by injection, inhalation, topical administration, lavage, or other modes suitable for
VIA510127NZPR
303134046
the selected treatment. Suitable carriers are those known in the art for use in
such modes of administration.
Suitable pharmaceutical compositions may be formulated by means
known in the art and their mode of administration and dose determined by the
skilled practitioner. For parenteral administration, a compound may be dissolved
in sterile water or saline or a pharmaceutically able vehicle used for
administration of non-water soluble compounds such as those used for vitamin K.
For enteral stration, the compound may be administered in a tablet,
capsule or ved in liquid form. The tablet or capsule may be enteric coated,
or in a formulation for sustained release. Many suitable ations are known,
including, polymeric or protein microparticles encapsulating a compound to be
released, nts, pastes, gels, hydrogels, or solutions which can be used
topically or locally to administer a compound. A sustained release patch or
implant may be ed to provide release over a prolonged period of time.
Many techniques known to one of skill in the art are described in Remington: the
Science & Practice of Pharmacy by Alfonso o, 20th ed., Lippencott
ms & s, (2000). Formulations for parenteral administration may, for
example, contain excipients, polyaikylene glycols such as polyethylene glycol,
oils of vegetable origin, or hydrogenated naphthalenes. patible,
biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-
polyoxypropylene copolymers may be used to control the release of the
compounds. Other potentially useful parenteral delivery systems for modulatory
compounds e ethylene-vinyl e copolymer particles, osmotic pumps,
implantable infusion s, and liposomes. Formulations for inhalation may
n excipients, for example, lactose, or may be aqueous ons containing,
for example, polyoxyethylene~9~lauryl ether, glycocholate and deoxycholate, or
may be oily solutions for administration in the form of nasal drops, or as a gel.
Compounds or pharmaceutical compositions in accordance with this
invention or for use in this invention may be administered by means of a medical
device or appliance such as an implant, graft, prosthesis, stent, etc. Also,
implants may be devised which are intended to contain and release such
Vll\510127NZI’R
303134046
nds or compositions. An example would be an implant made of a
polymeric material adapted to release the compound over a period of time.
An “effective amount” of a pharmaceutical composition according to the
invention includes a therapeutically effective amount or a prophylactically effective
amount. A “therapeuticaiiy effective amount" refers to an amount effective, at
dosages and for periods of time necessary, to achieve the desired therapeutic
result, such as improved PASI score. A therapeutically effective amount of a
compound may vary according to factors such as the disease state, age, sex, and
weight of the subject, and the ability of the compound to elicit a d response in
the subject. Dosage regimens may be adjusted to provide the optimum eutic
response. A therapeutically effective amount is also one in which any toxic or
detrimental s of the compound are outweighed by the therapeutically
beneficial effects. A "prophylactically effective amount” refers to an amount
effective, at dosages and for periods of time necessary, to e the desired
prophyiactic result, such as a desireable PASI score. lly, a lactic dose
is used in subjects prior to or at an earlier stage of disease, so that a
lacticaily effective amount may be less than a therapeutically effective
amount.
it is to be noted that dosage values may vary with the severity of the
condition to be alleviated. For any particular subject, specific dosage regimens
may be adjusted over time according to the dual need and the professional
ent of the person administering or supervising the administration of the
compositions. Dosage ranges set forth herein are exemplary only and do not
limit the dosage ranges that may be selected by medical practitioners. The
amount of active compound(s) in the ition may vary according to factors
such as the disease state, age, sex, and weight of the t. Dosage regimens
may be adjusted to provide the optimum therapeutic response. For example, a
single bolus may be administered, several divided doses may be administered
over time or the dose may be proportionally reduced or increased as indicated by
the exigencies of the therapeutic situation. it may be advantageous to formulate
V11\510127NZPR
303134046
parenteral compositions in dosage unit form for ease of administration and
uniformity of .
In general, compounds of the invention should be used without causing
substantial toxicity. Toxicity of the compounds of the invention can be
determined using standard techniques, for example, by testing in cell cultures or
experimental animals and ining the therapeutic index, i.e., the ratio
between the LD50 (the dose lethal to 50% of the population) and the LDtOO (the
dose lethal to 100% of the population). In some circumstances however. such as
in severe e conditions, it may be necessary to administer substantial
excesses of the compositions.
As used herein, a “subject” may be a human, non-human primate, rat,
mouse, cow, horse, pig, sheep, goat, dog, cat, etc. The subject may be
ted of having or at risk for having psoriasis and/or atopic itis and/or
a medical condition wherein an agent is used in modulating the immune system.
Diagnostic methods for psoriasis, atopic dermatitis and various disorders for
which immune modulating compounds are used and the clinical delineation of
those conditions’ diagnoses are known to those of ordinary skill in the art.
Examples
The following examples are illustrative of some of the ments of the
invention described herein. These examples do not iimit the spirit or scope of the
invention in any way.
e 1:
Preparation of H-D-Glu(D-Trp-OH)-OCH2CH2CF3, Apo878
Ni—I2
/\/O (R) 'I,’ N “0
F3C \n) W01H
0 00 OH
A. ation of Boc~D~Glu(OH)-OCH2CH20F3
VlASlOlZ'INZI’R
303134046
To a solution of Boc-D-G|u(O-le)-OH (7.00 g, 20.7 mmol) in DMF (50 mL)
was added N-hydroxysuccinimide (HOSu, 2.63 g, 22.8 mmol) followed by
C| (4.38 g, 22.8 mmol). After stirring for 1h, 3,3,3—trifluoropropano| (3.2
mL, 36.3 mmol) and DIPEA (4.0 mL, 22.8 mmol) were added and the resulting
mixture was stirred at RT for ght. The on mixture was quenched with
de—ionized water and extracted with EtOAc. The organic fraction was washed
with brine, dried over anhydrous Na2804, filtered and then evaporated to s
under reduced pressure. A mixture of the crude G|u(O-le)—OCH2CH20F3
and 1.6 g of wet 10% Pd-C in EtOH (100 mL) was then hydrogenated under 45
psi of hydrogen gas pressure in a Parr apparatus for 1.5 h. The e was
filtered, and the filtrate was concentrated in vacuo to afford Boc-D—GIu(OH)—
OCHzCHgCFa (crude yield = 81%), which was used without further purification.
B. ation of Boc—D-G|u(D-Trp-O-BzI)-OCH20HZCF3
The Boc-D-Glu(OH)-OCHZCH2CF3 from section A was dissolved in DMF
(70 mL). N-Hydroxysuccinimide (2.63 g, 22.8 mmol), EDC|.HCl (4.38 g, 22.8
mmol), H-D-Trp-OBZIHCI (7.5 g, 22.8 mmol) and DIPEA (4.0 mL, 22.8 mmol)
were successively added. The resulting solution was stirred at RT for overnight.
The reaction mixture was quenched with de-ionized water and then extracted
with EtOAc. The organic layer was washed with brine and dried over anhydrous
Na2804, filtered and concentrated to dryness. The residue was purified by flash
column chromatography using a mixture of EtOAc and hexanes (1/1, v/v) as
eluent, thereby affording Boc-D~G|u(D—Trp-O—le)—OCH2CHZCF3 (3.74 g. Y =
29%); MS—ESI (m/z): 620 [M+1]+.
C. ation of Boc—D—Giu(D-Trp—OH)-OCH20H20F3
A mixture of Boc-D-GIu(D-Trp-O-BzI)-OCH20H2CF3 from Section B above
(3.7 g, 6.0 mmol) and 1.5 g of wet 10% Pd-C in EtOH (150 mL) was
hydrogenated under 45 psi of hydrogen gas pressure in a Parr apparatus for
3O 2.5h. The reaction mixture was filtered, and the filtrate was concentrated to
s to give the crude Boc—D-Giu(D-Trp-OH)-OCH2CH2CF3.
-33..
VIA510127NZI’R
3031 34046
D. Preparation of H-D-Glu(D-Trp-OH)-OCH20H20F3, Ap0878
The Boc—D-Glu(D—Trp—OH)~OCHzCH20F3 from section C above was
dissolved in E1220 (15mL), and then a 2M HCl in EtZO solution (25mL) was added.
The mixture was stirred at RT for overnight. The reaction mixture was
concentrated to dryness. The residue was dissolved in de—ionized water (10 mL),
and then adjusted to pH 6 using a conc. %) NH4OH solution at ice-water
bath temperature. The itated solid was collected by suction filtration and
dried under vacuum to afford u(D~Trp-OH)-OCHZCH20F3, (Ap0878, 1.499)
as a light purple solid. Yield = 58%; 1H NMR (DMSO-D6 + D20, 400 MHz) 5
(ppm): 7.51 (d, J: 5.1 Hz, 1H), 7.31 (dd, J: 8.1, 3.0 Hz, 1H), 7.10 (br. s, 1H),
7.04 (t, J = 5.6 Hz, 1H), 6.89 - 7.01 (m, 1H), 4.18 - 4.44 (m, 3H), 3.41 - 3.55 (m,
1H), 3.13 - 3.29 (m, 1H), 2.89 - 3.04 (m, 1H), 2.56 - 2.76 (m, 2H), 2.07-2.18 (m,
2H), 1.78 - 1.94 (m, 1H), 1.64- 1.79 (m, 1H); MS-ESl (m/z): 430 [M+1]+.
Example 2
General procedure for the preparation of Boc-D-Glu(0H)—O-alkyl
A. Preparation of Glu(OH)-O-isoamyl
To a suspension of Boc-D-G|u(O-le)-0H (5.48 g, 16.2 mmol), potassium
carbonate (4.48 g, 32.5 mmol) and DMF (30 ml.) at room temperature was added 1-
iodomethylbutane(6.43 g, 32.5 mmol). After the reaction mixture was stirred at room
temperature for overnight, the solid was filtered off and washed with ethyi acetate. The
filtrate was concentrated by rotary evaporation and the residue was mixed with water.
The resulting solid was taken up in hexanes, and the organic solution was washed with
water (2x), dried over magnesium sulphate, then filtered. The filtrate was trated
by rotary evaporation to give Boc-D—Glu(O-le)-O-isoamyl as a white solid (6.64 g) in
quantitative yield. 1H NMR (CDCla, 90 MHz) 6 ppm: 7.03 - 7.56 (m, 5H), 5.12 (s, 3H),
3.87 - 4.50 (m, 3H), 2.25 - 2.63 (m, 2H), 1.83 - 2.20 (m, 2H), 1.23 ~ 1.75 (m, 12H), 0.91
(d, J = 5.85 Hz, 6H).
Boc—D-Glu(O-le)-O-isoamyl (6.20 g, 15.2 mmol) from above and 10 %
Pd/C (wet, 0.62 g) were mixed in ethyl acetate (80 mL), The reaction mixture was
hydrogenated under a hydrogen gas here using a Parr apparatus at 40
VIASI 0127NZPR
303134046
psi hydrogen pressure for 4.5 h. The mixture was filtered through TM and
the cake was thoroughly washed with ethyl acetate. The filtrate was concentrated
by rotary ation to give the title compound Boc-D-Glu(OH)—O-isoamyl as a
sticky clear oil in quantitative yield (5.50 g). 1H NMR (00013, 400 MHz) 5 ppm:
.18 (d, J = 7.1 Hz, 1H), 4.35 (br. s, 1H), 4.18 (t, J = 7.1 Hz, 2H), 2.38 — 2.54 (m,
2H), 2.12 - 2.27 (m, 1H), 1.84 - 2.04 (m, 1H), 1.63 -1.81 (m, 1H), 1.50 - 1.63 (m,
2H), 1.45 (s, 9H), 0.93 (d, J: 6.1 Hz, 6H).
B. In a similar manner, by replacing 1-iodomethylbutane with other alkyl s
l iodide, ethyl iodide, propane), the following compounds are prepared:
Boc—D-G|u(OH)—O-Me
Boc-D-Glu(OH)—O-Et
Boc-D-Glu(OH)-O-i—Pr
Example 3
Preparation of H-D-Glu(D-Trp-OH)-O-isoamyl (Ap0844)
0%.!” H
YV /\n/ (iN 9“
O O
O OH
A. Preparation of Boc—D-Glu(D—Trp~O-le)-O-isoamyl
To a solution of Boc—D-G|u(OH)-O~isoamyl (1.94 g, 6.1 mmol) in MN-
dimethylformamide (15 mL) were added EDCI. HCI (1.17 g, 6.1 mmol), HOBt
hydrate (0.93 g, 6.1 mmol) and H—D—Trp-OBZIHCI (2.02 g, 6.1mmol), followed by
DIPEA (1 .18g, 9.1 mmoL). The reaction mixture was stirred at RT for overnight.
The reaction mixture was quenched with a 0.5N HCI solution then extracted with
ethyl acetate. The organic layer was successively washed with water, a 0.5M
sodium carbonate on, water and brine, dried over magnesium sulphate and
filtered. The filtrate was concentrated in vacuo and the crude product was
purified by column tography using a solvent gradient consisting of a
mixture of ethyl acetate/(iichloromethane/hexanes (2/1/7 to 311/6, v/v/v) as
VIA510127NZPR
303134046
eluant. Thus Boc-D-G|u(D-Trp-O-le)-O—isoamyt was obtained (2.24 g) as a pale
yellow solid. Yield = 62%; MS-ESI (m/z): 594 [M+1]+.
B. Preparation of Boc—D-G|u(D-Trp-OH)-O~isoamyl
Boc—D-Glu(D-Trp-O-le)-O-isoamyl from Section A above (2.09 g, 3.5
mmol) and 10 % Pd/C (wet, 0.28 g) was mixed in ethyl acetate (50 mL). The
reaction mixture was hydrogenated in a Parr apparatus at 10 psi (instrument
meter reading) of en gas pressure for 2.5 h. The e was filtered
through CeilteTM and the cake was washed with ethyl acetate. The filtrate was
trated by rotary evaporation under d pressure. The residue was
triturated with hexanes to give Boc—D-Glu(D-Trp-OH)-O-isoamyl (1.49 g) as a
pale-pink solid. Yield = 84%; MS (m/z): 504 [M+1]+.
C. H-D-Glu(D-Trp-OH)—O~isoamyl (Ap0844)
Boc-D-Glu(D-Trp—OH)-O-isoamyl ed in Section B above (987 mg,
2.0 mmol) was mixed with a 2M HCI in ether solution (30 mL) at RT and stirred
for 22.5 h. The reaction mixture was diluted with dichloromethane and
concentrated under vacuum by rotary evaporation. The residue was dissolved in
water (20 mL) and decolorized with charcoal (1 Q), then filtered through CeliteTM.
The filtrate was neutralized with a 1M sodium hydroxide solution to pH 6. The
precipitate was filtered, washed with water to give u(D-Trp-OH)-O-isoamy|
(Apo844, 652 mg) as off-white solid. Yield = 82%; 1H NMR ( DMSO-D5+D20, 400
MHz) 6 ppm: 7.50 (d, J: 8.1 Hz, 1H), 7.30 (d, J: 8.1 Hz, 1H), 7.10 (s, 1 H), 7.03
(t, J z 7.1 Hz, 1H), 6.86 - 6.99 (m, 1H), 4.27 - 4.39 (m, 1H), 4.05 (t, J = 6.1 Hz,
2H), 3.23 ~ 3.31 (m, 1H), 3.17 (dd, J = 14.2, 5.1 Hz, 1H), 2.96 (dd, J = 14.2,
8.1Hz, 1H), 2.14 (t, J= 7.1 Hz, 2 H), 1.70 - 1.85 (m, 1H), 1.51 - 1.68 (m, 2H),
1.38 - 1.50 (m, 2H), 0.86 (d, J = 6.1 Hz, 6 H); MS—ESI (m/z): 404 [M+1]+.
—36—
VIA510127NZPR
303l34046
Exam pie 4
Preparation of H-D-Glu(D-Trp-OH)-0—Et hydrochloride salt (Ap0836.HCl)
.HCI HN
voj‘?’ H
“HiN 0 00 OH
A. Preparation of Boc—D-Glu(D-Trp-O-le)-O~Et
Proceeding in a similar manner as described under Example 3A, Boc-D-
GIu(D—Trp-O-le)—O—Et was prepared in 87% yield. 1H NMR( DMSO-Ds, 400
MHz) 5 ppm: 10.87, (s, 1H), 8.35 (d, J: 7.2 Hz, 1H), 7.48 (d, J: 7.8 Hz, 1H),
7.35 (d, J = 7.9 Hz, 1H), 7.29-7.33 (m, 3H), 7.23 (d, J: 7.7 Hz, 1H), .22
(m, 3H), 7.08 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 7.7 Hz, 1H), 4.98 - 5.06 (m, 2H),
4.55 (apparent q, J = 7.3 Hz, 1H), 4.04 — 4.11 (m, 2H), 3.90 - 3.95 (m, 1H), 3.04
—3.19(m, 2H), 2.18— 2.23 (m, 2H), 1.84 - 1.89 (m, 1H), 1.70 - 1.77 (m, 1H), 1.38
(s, 9H), 1.16 (t, J: 7.1 Hz, 3H); MS-ESi (m/z): 552 .
B. Preparation of Boc—D-Glu(D-Trp-OH)-O-Et
Proceeding in a r manner as described under e 38, Boo-D-
Glu(D-Trp-0H)—O-Et was prepared in quantitative yield. 1H NMR ( s, 400
MHz) 5 ppm: 12.62 (br. 1H), 10.82, (s, 1H), 8.10 (d, J3 7.7 Hz, 1H), 7.52 (d, J =
7.8 Hz, 1H), 7.33 (d, J: 8.0 Hz, 1H), 7.23 (d, J: 7.5 Hz, 1H), 7.12 (s, 1H), 7.06
(t, J = 7.3 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 4.45 (apparent q, J = 7.7 Hz, 1H),
4.03 — 4.11 (m, 2H), 3.87 - 3.92 (m, 1H), 3.13 — 3.18 (m, 1H), 2.96 — 3.03 (m,
1H), 2.13 —2.20 (m, 2H), 1.82 - 1.88 (m, 1H), 1.69-1.75 (m, 1H), 1.38 (s, 9H),
1.17 (t, J = 7.1 Hz, 3H); MS-ESI (m/z): 462 [M+1]*.
C. Preparation of H-D-GIu(D-Trp-OH)-O~Et.HCI (Ap0836.HCl)
To an ice-cooled solution of Boc—D-Glu(D-Trp—OH)-O-Et (4.55 g, 9.8
mmol) obtained in Section 8 above in dichloromethane (100 mL) was bubbled
HCI gas for 15 min. The reaction mixture was concentrated under vacuum by
rotary evaporation to give H-D-G|u(D—Trp~OH)-O-Et hydrochloride (Apo836.HC|,
VIAS 10|27N ZI’R
303134046
4.0 g) as a foamy solid.1H NMR( DMSO—De, 400 MHz) 6 ppm: 12.68 (br. s, 1H),
.90, (s, 1H), 8.66 (br, s, 3H), 8.33 (d, J: 7.8 Hz, 1H), 7.52 (d, J: 7.8 Hz, 1H),
7.33 (d, J = 8.0 Hz, 1H), 7.12 (d, J3 1.5 Hz, 1H), 7.06 (t, J: 7.2 Hz, 1H), 6.98 (t,
J = 7.2 Hz, 1H), 4.47 (apparent q, J = 4.8 Hz, 1H), 4.13 — 4.19 (m, 2H), 3.90 (br,
1H), 3.16 — 3.20 (m, 1H), 2.98 _. 3.04 (m, 1H), 2.29 — 2.33 (m, 2H), 1.94 - 1.98
(m, 2H), 1.20 (t, J = 7.1 Hz, 3H); MS—ESI (m/z): 362 [M+1]+ (free base).
Example 5
Preparation of H-D-Glu(D-Trp-OH)—O-i—Pr, Ap0846
II/\n/ (iN _‘\\
O O
O OH
A. Preparation of Boc—D-Glu(D-Trp-O-le)-O-i-Pr
The Boc-D-Glu(OH)-O~i—Pr was dissolved in DMF (60 mL), and then N-
hydroxysuccinimide (2.87 g, 24.9 mmol), EDCl.HC| (4.77 g, 24.9 mmol) and DIPEA (4.3
mL, 24.9 mmol) were successively added. After stirring at RT for 3.5h, H-D-Trp-
Ole.HC| (7.55 g, 22.8 mmol) was added ed by DIPEA (4.3 mL, 24.9 mmol). The
mixture was stirred for overnight. The reaction mixture was quenched with de-ionized
water and then extracted with EtOAc. The EtOAc layer was washed with brine, dried
over anhydrous Na2804, ed and concentrated to s to give crude Boo-D-
G!u(D-Trp-O-le)~O~i~Pr.
B. Preparation of Boc-D-Glu(D~Trp—OH)-O-i—Pr
The crude t from section A above was dissolved in isopropanol (100 mL),
and 0.7 g of wet 10% Pd—C was added. The mixture was hydrogenated under 40 psi
hydrogen gas pressure in a Parr apparatus for 2h. The mixture was filtered, and the
filtrate was evaporated to dryness to give crude Boc-D-Glu(D—Trp~0H)-O-i-Pr.
C. Preparation of H—D~Glu(D-Trp—OH)—O-i-Pr, Ap0846
The residue from section 8 above was dissolved in EtZO (20mL), and a 2M HCl
in EtZO on (15m L) was added. The mixture was stirred at RT for overnight. The
VIA510127NZPR
303134046
on mixture was concentrated to dryness. The residue was dissolved in de-ionized
water (6 mL), and the pH of the mixture was adjusted to about 5.5 using 8 SN NaOH
solution at ice-water bath temperature to afford a crude product. The crude material was
purified using the Biotage instrument with reverse C18 column to afford the u(D~
Trp-OH)-O-i-Pr (Ap0846, 1.06 g) as white solid. Yield : 14%; 1H NMR (DMSO-De +D20,
400 MHz) 5 ppm: 7.52 (d, J: 7.1 Hz, 1H), 7.31 (d, J: 8.1 Hz, 1H), 7.10 (s, 1H), 7.04 (t,
J = 7.6 Hz, 1H), 6.93 - 6.99 (m, 1H), 4.90 (quin, J = 6.1 Hz, 1H), 4.35 (dd, J = 8.6, 4.5
Hz, 1H), 3.35 (dd, J = 8.1, 5.1 Hz, 1H), 3.18 (dd, J = 14.7, 4.5 Hz, 1H), 2.96 (dd, J =
14.7, 8.6 Hz, 1H), 2.16 (t, J: 7.6 Hz,2H), 1.73 - 1.85 (m, 1H), 1.59 - 1.72 (m, 1H), 1.18
(m, 6H); MS-ESI (m/z): 376 {M+1]+.
Example 6
Preparation of H-D-GIu(D-Trp—OH)—0-le, Ap0829
O (R)
'I El \\
le/ "/\[f (i
O O
O OH
A. Preparation of Boc~D~Glu(D-Trp-OH)-O-le
Boc-D-GIu-OBZI (11.24 g, 33.3 mmol) was mixed with HOSu (3.83 g, 33.3
mmol) and EDCi hydrochloride (6.38 g, 33.3 mmol) in DMF (80 mL) at room
temperature and d for overnight. D-Trp-OH (10.2 g, 50 mmol) was added ail
at once and the reaction mixture was stirred at room temperature for another 6 h.
The mixture was then quenched with a 0.5N HCI solution (250 mL) as a sticky
solid formed. The liquid fraction was decanted and the residual sticky solid was
dissolved in ethyl acetate (200 mL). The ethyl acetate layer was washed with a
0.5 N HCl solution (100 mL x 2), water (100 mL x 2) and brine, dried over M9804
and filtered. The filtrate was concentrated in vacuo by rotary evaporation and the
residue was triturated with ether to give Boc-D-Glu(D-Trp-OH)-O~le as a white
solid (6.60 g). The mother liquid was concentrated and triturated with 10 % ethyl
acetate in hexanes to give a second crop of product as off-white solid (7.23 9).
ed yield = 13.829 (79%); 1H NMR (DMSO-Ds, 400MHz) 5 (ppm): 10.82
(br. s, 1H), 8.09 (d, J = 7.1 Hz, 1H), 7.51 (d, J: 7.1 Hz, 1H), 7.27 - 7.41 (m, 7H),
VIA510127NZI’R
30313-1046
7.11 (s, 1H), 7.05 (t, J: 7.1 Hz, 1H), 6.92 — 7.00 (m, 1H), 5.01 - 5.21 (m, 2H),
4.39 - 4.51 (m, 1H), 3.94 - 4.06 (m, 1H), 3.08 - 3.19 (m, 1H), 2.93 - 3.06 (m, 1H),
2.05 - 2.26 (m, 2H), 1.32 - 1.93 (m, 1H), 1.67 - 1.79 (m, 1H), 1.37 (s, 9H); MS
(m/z) 524 [M+1]+.
B. Preparation of H-D—Glu(D-Trp-OH)-O-le hydrochloride salt, Ap0829.HCl
Boc—D-GIu(D-Trp-OH)-O-Bz| ( 6.60 g, 12.6 mmol) was mixed with 4M HCI
in dioxane (30 mL) and ethyl acetate (30 mL) at room temperature. After stirring
for 50 min, an additional 4M HCI in dioxane (10 mL) was added. The reaction
mixture was d for another 140 min, then concentrated in vacuo by rotary
evaporation. The e was triturated with ethyl acetate and the mixture was
stirred for overnight. The resulting sticky solid was then triturated with a 10 %
ethyl acetate in hexanes mixture to give H~D-G|u(D-Trp-OH)—O-le hydrochloride
salt as an off-white solid (5.15 9). Yield = 88 %; 1H NMR (400 MHz, DMSO-De) 8
ppm: 10.88 (br. s, 1H), 8.53 (br. s, 3H), 8.31 (d, J= 8.1 Hz, 1H), 7.51 (d, J: 8.1
Hz, 1H), 7.29 - 7.43 (m, 6H), 7.14 (s, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.97 (m, 1H),
.24 (d, J = 12.4 Hz, 1H), 5.16 (d, J= 12.4 Hz, 1H), 4.41 - 4.52 (m, 1H), 3.96 -
4.13 (m, 2H), 3.16 (dd, J: 14.2, 5.1 Hz, 1H), 3.01 (dd, J: 14.7, 8.6 Hz, 1H),
2.26 - 2.36 (m, 2H), 1.92-2.03 (m, 2H). In a ate experiment, the desired HCI
product (5.95 g) was obtained in 94% from the deprotection reaction of Boc—D-
Glu(D—Trp-OH)-O—le with 4M HCI in dioxane (40 mL).
C. Preparation of H—D~G|u(D-Trp-OH)-O-le, Ap0829
The combined products ed in Step B above (11.0 g) was dissolved
in water (75 mL) and filtered. The ice-water cooled filtrate was then neutralized
with a 6N NaOH solution to pH about 6. The resulting precipitate was ed,
washed with water to afford H-D-G|u(D-Trp-OH)-O—le (Ap0829). The wet
product was triturated with ether (100 mL) for an hour, and was then collected via
suction filtration. Analysis by HPLC indicated an AUC purity of 96.7 %.Further
purification was carried out. Thus, the product was mixed with ethyl acetate (20
mL) and 4M HCI in e (20 mL) to form a clear on. The solution was
Vl2\510127NZI’R
303134046
concentrated and the residue was triturated with ethyl acetate and s. The
solid was dissolved in water (300 mL) and cooled in an ice—water bath, then
neutralized with a BN NaOH on to pH about 6. The precipitated fine solid
was collected by suction filtration, washed with water and ether to give H—D-
G|u(D-Trp-OH)-O-le, Ap0829 (6.05 9). Yield = 60 %; HPLC purity (AUC) = 98.8
%;1H NMR (400 MHz, DMSO—Ds) 5 ppm: 10.51 (br. s, 1H), 8.05 (d, J: 8.1 Hz,
1H), 7.51 (d, J = 6.1 Hz, 1H). 7.27 — 7.41 (m, 6H), 7.12 (s. 1H), 7.04 (t, J m 7.6
Hz, 1H), 6.91 — 6.99 (m, 1H), 5.10 (s, 2H), 4.35 — 4.46 (m, 1H), 3.30 — 3.36 (m,
1H), 3.16 (dd, J a 14.7, 4.6 Hz, 1H), 2.97 (dd, J = 14.7, 6.6 Hz, 1H), 2.12 — 2.24
(m, 2H), 1.74— 1.67 (m, 1H), 1.59 (dd, J: 14.2, 7.1 Hz, 1H); MS~ESl (m/z) 424
[M+1}*.
D. Proceeding in a similar manner as above, H-D-Glu(D-Trp-OH)-OCH2CF3,
Ap0865 was prepared.
0W2“
O OH
Yield = 8.39 (49%); 1H NMR (DMSO-De +020, ) 5 (ppm): 7.50 (d,
J = 6.8 Hz, 1H), 7.32 (d, J = 7.0 Hz, 1H), 7.10 (s, 1H), 7.03 - 7.09 (m, 1H), 6.94 -
7.03 (m, 1H), 4.70-4.75 (m, 2H), 4.38-4.41 (m, 1H),3.49-3.51 (m, 1H), 3.14-3.19
(m, 1H), 2.93-2.99 (m, 1H), 2.17 - 2.24 (m, 2H), 1.80 -1.86 (m, 1H), 1.60-1.68 (m
1H); MS—ESI (m/z): 416 {M+1]+..
Example 7
Preparation of H-D-Glu(D-TrpCH(CH3)-O-CO-O-cyciohexyl)-0H (Ap0843).
V11\5‘10§27N ZI’R
A. Preparation of Cbz—D-Giu(D-Trp-OH)-O-Bz|.
Cbz—D-Glu(OH)-O-Bzi (18.57 g, 50 mmol), HOSu (5.76 g, 50 mmol) and
EDCl.HCI (9.59 g, 50 mmol) were mixed in DMF (100 mL) at ice-water bath
temperature. The reaction mixture was allowed to warm to RT then d at RT
for overnight. The reaction mixture was cooled again in an ice-water bath and D—
Trp-OH (10.21 g, 50 mmol) was added. The mixture was then d at RT for 6
h. The mixture was poured into a beaker containing a mixture of 0.5M HCl (200
mL) and ice chunks. The mixture was extracted with ethyl acetate twice (200 mL
+ 100 mL). The organic layers were combined and washed with water (100 mL
x3) and brine (100 mL), dried over magnesium te and filtered. The filtrate
was concentrated by rotary evaporation under reduced pressure and the
resulting solid was triturated with a mixture of ether and hexanes. Cbz~D~Giu(D—
Trp-OH)—O—le (24.5 g) was obtained as a white solid after suction filtration. Yield
= 88%; 1H NMR (DMSO-De, 400 MHz) 5 ppm: 12.55 (br. s, 1H), 10.81 (s, 1H),
8.11 (d, J: 8.1 Hz, 1H), 7.78 (d, J= 8.1 Hz, 1H), 7.51 (d, J: 7.1 Hz, 1H), 7.19 —
7.45 (m, 11 H), 7.11 (s, 1 H), 7.05 (t, J= 7.6 Hz, 1H), 6.96 (t, J: 7.6 Hz, 1H),
4.92 — 5.22 (m, 4H), 4.37 —- 4.55 (m, 1H), 3.99 — 4.17 (m, 1H), 3.14 (dd, J,=,14.7,
.6 Hz, 1H), 2.92 -— 3.07 (m, 1 H), 2.08 — 2.33 (m, 2H), 1.85 — 2.07 (m, 1H), 1.64
— 1.85 (m, 1H); MS-ESl (m/z): 558 [M+1]+.
B. Preparation of Cbz—D~Glu(D-Trp-O—CH(CH3)-O-CO-O-cyciohexyl)-O-le
To a mixture of Cbz—D-Glu(D-Trp—OH)-O-le (6.00 g, 10.8 mmol),
potassium carbonate (5.94 g, 43.0 mmol) and sodium iodide (28.50 g , 190.1
mmol) in N,N~dimethylformamide (40 mL) was added 1-chioroethyi-cyclohexyl
carbonate (8.90 g, 43.0 mmol) at RT. After stirring at 30°C for overnight, the
reaction mixture was diluted with ethyl acetate. The mixture was then washed
with water (x3) and brine. The residue was subjected to purification by column
chromatography on silica gel using a solvent gradient ting of a mixture of
ethyl acetate in hexanes (20 to 40%) as . Fractions rich in product were
combined, and volatiles were removed in vacuo. Thus, the alkylated product
Glu(D-Trp-O—CH(CH3)—O—CO~O~cyclohexyi)-O-le (3.77 g) was obtained
VlASlDl27NZPR
as a pale—yellow foam. Yield = 48%; 1H NMR (DMSO—De, 400 MHz) 8 ppm: 10.86
(s, 1H), 8.35 (dd, J = 17.7, 7.6 Hz, 1H), 7.78 (t, J: 7.6 Hz, 1H), 7.46 (t, J = 8.1
Hz, 1H), 7.34 (br. s, 11H), 7.14 (d, J: 3.0 Hz, 1H), 7.06 (t, J: 7.6 Hz, 1H), 6.94 -
7.00 (m, 1H), 6.62 (q, J: 5.1 Hz, 0.5H), 6.51 (Q, J: 5.1 Hz, 0.5H), 5.12 (d, J:
3.0 Hz, 2H), 4.97 - 5.09 (m, 2H), 4.40 - 4.59 (m, 2H), 4.05 - 4.15 (m, 1H), 2.93 -
3.18 (m, 2H), 2.15 —2.27 (m, 2H), 1.91 — 1.97 (m, 1H), 1.71 - 1.86 (m, 3H), 1.57-
1.68 (m, 2H), 1.13 - 1.49 (m, 9H); MS—ESl (m/z): 728 [M+1]“.
C. Preparation of H-D—Glu(D-Trp-O-CO-O—cyclohexyl)-OH (A90843)
Cbz—D-Glu(D-Trp-O-CH(CH3)—O-CO-O-cyclohexyl)—O-le obtained in
Section B above (3.67 g, 5.0 mmol) and 10 % Pd—C (wet, 1.16 g) was mixed in
ethanol (100 mL). The mixture was hydrogenated in a Parr apparatus under a
blanket of hydrogen at 15-25 psi of en pressure for 3 h. The mixture was
d through CeilteTM and the cake was washed with ethanol. The filtrate was
concentrated by rotary evaporation under reduced pressure and the residue was
triturated with ether to give the title compound H-D-Glu(D-Trp—O-CH(CH3)-O-CO-
O-cyclohexyl)—OH (Ap0843, 2.00 g) as a white solid. Yield = 78%; 1H NMR
(DMSO-D6+D20, 400 MHz,) 6 ppm: 7.46 (t, J = 9.1 Hz, 1H), 7.34 (d, J = 8.1 Hz,
1H), 7.17 (s, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.90 - 7.03 (m, 1H), 6.58 - 6.68 (m,
0.5H), 6.42 - 6.57 (m, 0.5H), 4.49 - 4.61 (m, 1H), 4.32 — 4.49 (m, 1H), 3.20 - 3.30
(m, 1H), 2.89 - 3.20 (m, 2H), 2.09 - 2.38 (m, 2H), 1.75 — 1.92 (m, 4H), 1.62 (br. s,
2H), 1.12 - 1.54 (m, 9H); MS-ESI (m/z): 504 [M+1}+.
Preparation of H-D-Glu(D-Trp-O—CH(CH3)-O-COEt)-OH, Ap0888
140%..”/\n/NH o
O O
O O/LOAOA
Proceeding in a similar manner as described under example 7B, Cbz—D—
Glu(D—Trp—O—CH(CH3)-O-CO-O-Et)-O-le (1.65 9, yield = 61%) was prepared
127NZPR
303134046
from the reaction of Cbz-D-Glu(D-Trp-OH)-O-Bzi from example 7A (2.24 g, 4.0
mmol) with 1—chloroethyl ethyl carbonate (1.22 g, 8.0 mmol) in the presence of
potassium carbonate (1.10 g, 8.0 mmol) and sodium iodide (2.40g, 16.0 mmol) in
N,N-dimethylformamide (20 mL) at 50°C for overnight. 1H NMR , 400
MHz) 8 ppm: 10.86 (br. s, 1H), 8.24 - 8.47 (m, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.40 -
7.52 (m, 1H), 7.24 - 7.42 (m, 11H), 7.14 (d, J: 5.1 Hz, 1H), 7.06 (t, J: 7.6 Hz,
1H), 6.93 - 7.02 (m, 1H), 6.57 - 6.67 (m, 0.5H), 6.44 - 6.56 (m, 0.5H), 5.12 (d,
J=3.0 Hz, 2H), 4.97 — 5.09 (m, 2H), 4.41 — 4.49 (m, 1H), 4.05 - 4.18 (m, 3H), 2.95
- 3.17 (m, 2H), 2.13 - 2.29 (m, 2H), 1.88 - 1.98 (m, 1H), 1.76 (dd, J = 14.1, 8.1
Hz, 1H), 1.42 (d, J: 6.1 Hz, 1.5H), 1.13 - 1.25 (m, 45H); MS-ESI (m/z): 674
[M+1]+.
ding in a similar manner as described under example 7C, H-D-
Glu(D-Trp-O-CH(CH3)-O-CO-O-Et)-OH, Apo888, (623 mg, yield = 56%) was
prepared from the deprotection of Cbz—D-Giu(D—Trp~O-CH(CH3)-O-CO-O-Et)-O-
le (1.65, 2.5 mmol) via hydrogenation with 10 % Pd/C (wet, 0.5 g) in ethanol
(100 mL) under a blanket of en. 1H NMR (DMSO-De, 400 MHz) 8 ppm:
.96 (br. s, 1H), 8.76 (br. s, 1H), 7.41 - 7.52 (m, 1H), 7.34 (d, J= 8.1 Hz, 1H),
7.20 (br. s, 1H), 7.02 ~ 7.14 (m, 1H), 6.90 - 7.02 (m, 1H), 6.57 - 6.69 (m, 0.5H),
6.44 - 6.57 (m, 0.5H), 4.36 - 4.49 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 2.93 - 3.17
(m, 3H), 2.18 - 2.37 (m, 2H), 1.71 - 1.99 (m, 2H), 1.45 (d, J: 5.1 Hz, 1.5H), 1.17
- 1.27 (m, 4.5H). MS m/z: 450 [M+1]+.
Example 9
Preparation of H-D—Glu(D-TrpCH(CH3)-O-COi-Pr)-OH (Ap0891)
W‘fliii
O O OiO/k
Proceeding in a similar manner as described under example 78, Cbz-D-
GIu(D-Trp—O-CH(CH3)—O-CO—O—i—Pr)-O-Bz| (1.54 g, yield = 56%) was prepared
from the reaction of Cbz—D-Giu(D-Trp-OH)-O—le from Example 7A above (2.24
V]/\510]27NZPR
303134046
9, 4.0 mmol) with 1-chloroethyl isopropyl carbonate (1.33 g, 8.0 mmol) in
presence of potassium carbonate (1.10 g, 8.0 mmol) and sodium iodide (2.40 g ,
16.0 mmol) in N,N—dimethyiformamide (20 mL) at 50°C for overnight. 1H NMR
(CDaOD, 400 MHz) 5 ppm: 7.43 - 7.55 (m, 1H), 7.31 (br. s, 11H), 7.03 - 7.12 (m,
2H), 6.92 - 7.04 (m, 1H), 6.6”.7 - 6.78 (m, 0.5H), 6.53 - 6.67 (m, 0.5H), 5.00 — 5.18
(m, 4H), 4.76 - 4.85 (m, 1H), 4.63 - 4.76 (m, 1H), 4.12 — 4.23 (m, 1H), 3.20 - 3.25
(m, 1H), 3.05 — 3.19 (m, 1H), 2.18 - 2.31 (m, 2H), 2.01 - 2.13 (m, 1H), 1.77 - 1.93
(m, 1H), 1.45 (d, J: 5.1 Hz, 1.5H), 1.18 — 1.31 (m, 7.5H); MS—ESI (m/z): 688
[M+1]+.
Proceeding in a similar manner as described under example 70, HD-
G|u(D—Trp-O—CH(CH3)-O-CO-O-i-Pr)-OH, Ap0891, (0.36 9, yield = 36%) was
ed from the enation of Cbz—D-Glu(D-Trp-O-CH(CH3)-O-CO—O-i—Pr)—
O-Bzi (1.50, 2.2 mmol) with 10 % Pd/C (wet, 0.56 g) in ethanol (50 mL).1H NMR
(CD30D, 400 MHz) 6 ppm: 7.47 - 7.55 (m, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.05 ~
7.15 (m, 2H), 6.97 - 7.05 (m, 1H), 6.70 - 6.78 (m, 0.5H), 6.58 - 6.66 (m, 0.5H),
4.80 - 4.86 (m, 1H), 4.66 » 4.74 (m, 1H), 3.58 - 3.65 (m, 1H), 3.24-3.37 (m. 1H),
3.04 - 3.21 (m, 1H), 2.32 - 2.50 (m, 2H), 1.93 - 2.11 (m, 2H), 1.49 (d, J = 5.1 Hz,
1.5H), 1.21 - 1.32 (m, 7.5H); MS-ESl(m/z):464[M+1]+.
Example 10
Preparation of H-D-Glu(D-Trp-O-CH2CO-N(CH3)2)-0H, Ap0893
0 o 0
”Own“. O\/U\N/
NH2 0 '
Proceeding in a similar manner as described under example 78, Cbz—D-
Trp-O~CH2CO-N(CH3)2)—O—le (1.11 g, yield = 43%) was prepared from
the reaction of Cbz—D—Glu(D—Trp-OH)—O—le from Example 7A above (2.24 g, 4.0
mmol) with 2-chloro-N,N-dimethyiacetamide (0.73 g, 6.0 mmol) in the ce
of potassium carbonate (1.10 g, 8.0 mmol) in N,N—dimethylformamide (20 mL).
0127NZPR
303134046
1H NMR (DMSO-Ds, 400 MHZ) 8 ppm: 10.84 (br. s, 1H), 8.31 (d, J = 7.1 Hz, 1H),
7.78 (d, J: 8.1 Hz, 1H), 7.49 (d, J: 8.1 Hz, 1H), 7.22 - 7.44 (m, 11H), 7.17 (s,
1H), 7.02 - 7.15 (m, 1H), 6.98 (d, J = 7.1 Hz, 1H), 4.94 - 5.18 (m, 4H), 4.85 (d, J
=14.8 Hz, 1H), 4.75 (d, J: 14.8 Hz, 1H), 4.48 - 4.60 (m, 1H), 3.99 - 4.14 (m
1H), 3.28 - 3.32 (m, 1H), 2.95 - 3.07 (m, 1H), 2.89 (s, 3H), 2.82 (s, 3H), 2.07 -
2.27 (m, 2H), 1.82 — 1.98 (m, 1H), 1.64 - 1.80 (m, 1H); MS-ESI (m/z): 643 [M+1]+.
Proceeding in a similar manner as described under Example 70, H-D-
GIu(D—Trp~O—CH2CO-N(CH3)2)-OH, , (0.54 9, yield = 75 %) was prepared
from the deprotection of Cbz-D—GIu(D-Trp-O-CH2CO-N(CH3)2)-O-le (1.10 g, 1.7
mmol) via hydrogenation with 10 % Pd/C (wet, 0.62 g) in ethanol (100 mL) under
a blanket of hydrogen. 1H NMR (DMSO-Ds, 400 MHz) 5 ppm: 10.98 (br. s, 1H),
8.82 (d, J: 7.1 Hz, 1H), 7.51 (d, J: 8.1 Hz, 1H), 7.34 (d, J: 8.1 Hz, 1H), 7.22
(s, 1H), 7.02 - 7.13 (m, 1H), 6.94 — 7.02 (m, 1H), 4.89 (d, J== 14.8 Hz, 1H), 4.78
(d, J = 14.8 Hz, 1H), 4.46 - 4.58 (m, 1H), 3.26 - 3.37 (m, 2H), 2.95 — 3.08 (m, 1H),
2.90 (s, 3H), 2.83 (s, 3H), 2.24 - 2.36 (m, 1H), 2.11 - 2.24 (m, 1H), 1.72 - 1.89 (m,
2H); MS—ESI (m/z): 419 [M+1]+.
Example 11
Preparation of H-D-GEu(D-Trp-O-mofetil)-OH.HC! salt (Ap0849.HCl)
«of,“iii“
OHCI
Proceeding in a similar manner as described under example 78, Cbz-D-
Glu(D-Trp-O-mofetiI)-O-le hydrochloride (4.53 9, yield = 64%) was prepared
from the reaction of Cbz-D-Glu(D-Trp-OH)-O-le (2.24 g, 4.0 mmol) with 2—
morpholinoethyl methanesulfonate, which was prepared from 2-
morpholinoethanol , 15.0 mmol) and methanesulfonyl chloride (1.72 g,
.0 mmol), in the presence of potassium carbonate (1.10 g, 8.0 mmol) in MN—
ylformamide (15 mL). 1H NMR (DMSO-De, 400 MHZ) d ppm: 10.91 (br. s,
VIA510127NZI’R
303134046
2H), 8.49 (d, J: 7.1 Hz, 1H), 7.81 (d, J= 8.1 Hz, 1H), 7.49 (d, J: 8.1 Hz,1H),
7.35 (d, J = 3.0 Hz, 11H), 7.17 (s, 1H), 7.07 (t, J: 7.6 Hz, 1H), 6.93 - 7.03 (m,
1H), 5.12 (br. s, 2H), 4.98 - 5.10 (m, 2H), 4.53 (q, J = 7.1 Hz, 1H), 4.22 - 4.41 (m,
2H), 4.06 - 4.15 (m, 1H), 3.61 — 3.89 (m, 4H), 3.01 ~ 3.34 (m, 6H), 2.86 - 3.01 (m,
2H), 2.21 - 2.30 (m, 2H), 1.89 - 2.03 (m, 1H), 1.69 - 1.83 (m, 1H); MS-ESI (m/z):
671 [M+1]*.
ding in a similar manner as described under example 7C, H-D-
Glu(D-Trp-O-mofetil)-OH hydrochloride salt, Ap0849.HC|, (1.01 9, yield = 74%)
was prepared from the hydrogenation of Cbz—D-Giu(D—Trp—O—mofetil)-O-le
hydrochloride (2.00 g, 2.8 mmol) with 10 % Pd-C (wet, 1.00 g) in methanol (100
mL).1H NMR (DMSO—Ds, 400 MHz) 8 ppm: 11.20 (br. s, 1H), 8.87 (d, J: 7.1 Hz,
1H), 7.74 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.44 (s, 1H), 7.32 (t, J:
7.1 Hz, 1H), 7.24 (t, J: 7.6 Hz, 1H), 4.75 (q, J: 7.1 Hz, 1H), 4.35 - 4.50 (m, 2H),
3.96 - 4.06 (m, 1H), 3.88 (br. s, 4H), 3.41 (dd, J: 14.1, 6.1 Hz, 1H), 3.31 (dd, J:
14.1, 8.1 Hz, 1H), 2.91 - 3.08 (m, 2H), 2.85 (br. s, 4H), 2.45 - 2.66 (m, 2H), 2.12 -
2.28 (m, 2H); MS-ESI (m/z): 447 [M+1]+ (free base).
Example 12
Preparation of u(D-Trp-OCH20-CO-Ph)-OH, Ap0883
Hogan H
/\il’ N J O
O o I
OAOJKQ
Proceeding in a similar manner as described under example 78 above,
Cbz-D~Glu(D—Trp-OCH20-CO-Ph)-O-le (2.45 g) was obtained after work-up
from the reaction of a mixture of chloromethyl benzoate (1.04 g, 6.1 mmol),
sodium iodide (4.6 g, 30.7 mmol) and Cbz-D-G|u(D-Trp-OH)-O-Bz| (2.29 g, 4.1
mmol) in presence of DIPEA (0.82 mL, 4.7 mmol) in e (80mL). Yield =
86%; 1H NMR (DMSO-De, 400 MHz) 6 ppm: 10.86 (br. s, 1H), 8.40 (d, J = 7.1 Hz,
1H), 7.94 (d, J = 7.1 Hz, 2H), 7.78 (d, J: 8.1 Hz, 1H), 7.70 (t, J: 7.6 Hz, 1H),
VIA510127NZPR
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7.51 - 7.61 (m, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.24 - 7.42 (m, 11H), 7.14 (d, J =
2.0 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.89 - 7.00 (m, 1H), 5.90 — 6.00 (m, 2H),
4.97 - 5.18 (m, 4H), 4.47 - 4.59 (m, 1H), 4.05 - 4.11 (m, 1H), 3.11 - 3.21 (m, 1H),
3.00 - 3.11 (m, 1H), 2.12 - 2.31 (m,2H), 1.87 - 2.02 (m, 1H), 1.67 - 1.83 (m, 1H);
MS-ES! (m/z): 692 [M+1}*.
Proceeding in a similar manner as bed under example 70, the
hydrogenolysis of Cbz—D-Glu(D-Trp-OCHzo-CO-Ph)-O-le (2.2 g, 3.2 mmol)
obtained above with 2.2 g of wet 10% Pd-C in MeOH (150 mL) under 45 psi
hydrogen pressure in a Parr apparatus for 5.5 h afforded crude u(D-Trp-
CO-Ph)-OH. Purification of the crude product (1.2 g) by flash column
chromatography on silica gel using a mixture of i—PrOH and H20 (85/15, v/v) as
eluent afforded the title compound u(D-Trp-OCH20-CO-Ph)—OH (Ap0883,
410mg). Yield = 28%; 1H NMR (DMSO~D5+ 020, 400 MHz): 6 ppm: 7.91 (d, J =
8.1 Hz, 2H), 7.65 - 7.74 (m, 1H), 7.54 (t, J: 7.6 Hz, 2H), 7.44 (d, J: 8.1 Hz, 1H),
7.31 (d, J: 8.1 Hz, 1H), 7.13 (s, 1H), 7.04 (t, J= 7.6 Hz, 1H), 6.90 - 6.98 (m,
1H), 5.86 - 5.97 (m, 2H), 4.45 — 4.55 (m, 1H), 3.30 (t, J = 6.1 Hz, 1H), 2.97 - 3.19
(m, 2H), 2.24 (t, J = 7.6 Hz, 2H), 1.75 - 1.93 (m, 2H); MS-ESI (m/z): 468 [M+1]+.
Example 13
Preparation of H-D-Glu(D-Trp-OCHZO-CO-[pentyl])-OH, Ap0889
HO?-W H
/\ii’N _. O
O O I
O OAOJ\(\
in a similar manner as described under Example 12, by replacing
chloromethyl benzoate with chloromethyl 2—ethylbutanoate, H-D-GIu(D-Trp-
OCHZO-CO-[pent-3~yl])-OH (Apo889) was prepared. 1H NMR (DMSO—DB + 020,
400 MHz) 6 ppm: 7.46 (d, J = 7.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.18 (s, 1H),
7.04 - 7.12 (m, 1H), 6.96 — 7.03 (m, 1H), 5.74 - 5.82 (m, 1H), 5.67 - 5.74 (m, 1H),
4.45 (dd, J: 9.1, 5.1 Hz, 1H), 3.27 (t, J: 6.6 Hz, 1H), 3.06 - 3.17 (m, 1H), 2.99
Vl1\5l0127NZPR
303134046
(dd, J: 14.7, 9.6 Hz, 1H), 2.14 - 2.32 (m, 3H),1.72 - 1.91 (m, 2H), 1.38 - 1.58
(m, 4H), 0.74 - 0.87 (m, 6H); MS~ES| (m/z): 462[M+1]+.
Example 14
Preparation of H-D-Glu(D-Trp-OCH20-CO-C(CH3)2-CH2CH2CH3)-0H, Ap0895
HO (R) N
o Oooo’HA//\
Proceeding in a similar manner as bed in Example 12, by replacing
chloromethyl benzoate with chloromethyl 2,2-dimethylpentanoate, H—D—Glu(DTrp-OCHzo-CO-C
(CH3)2-CHZCH2CH3)-OH (Ap0895) was prepared. 1H NMR
(DMSO-De + D20, 400 MHz) 5 ppm: 7.44 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.1 Hz,
1H), 7.17 (s, 1H), 7.04 - 7.14 (m, 1H), 6.93 - 7.04 (m, 1H), 5.61 - 5.83 (m, 2H),
4.36 - 4.53 (m, 1H), 3.20 ~ 3.38 (m, 1H), 3.06 - 3.21 (m, 1H), 2.91 - 3.06 (m, 1H),
2.14 - 2.36 (m, 2H), 1.72 - 1.94 (m, 2H), 1.25 - 1.52 (m, 2H), 0.91 - 1.26 (m, 8H),
0.68 - 0.88 (m, 3H); MS—ESI (m/z): 476 [M+1]".
Example 15
ation of u(D-Trp-OCHZCHZCF3)-OH, Ap0877
no?” H
,/\[r(fl.\N o o
o O/\/CF3
In a similar manner as described under example 12, by replacing
chloromethyl benzoate with CF30HZCH2l, GIu(D—Trp—OCHZCH20F3)-O-le
(2.0 9, yield = 86%) was obtained after purification by flash column
chromatography on silica gel. Hydrogenolysis of Cbz—D~Glu(D-Trp-
OCHZCH2CF3)—O~le (2.0 g, 3.1 mmol) with 1 g of wet 10% Pd-C in EtOH (150
mL) under 45 psi hydrogen pressure in a Parr apparatus for 1.5 h afforded the
VlA510l27NZI’R
30313-1046
title compound H-D-Giu(D-Trp-OCH2CHZCF3)-OH (Ap0877, 1.2 g) as a white
solid after work up and purification. Yield = 91%; 1H NMR Ds + D20, 400
MHz) 5 ppm: 7.47 (d, J: 8.1 Hz, 1H), 7.35 (d, J: 8.1 Hz, 1H), 7.18 (s, 1H), 7.08
(t, J = 7.1 Hz, 1H), 6.95 - 7.04 (m, 1H), 4.43 (dd, J: 9.1, 5.1 Hz, 1H), 4.21 (qt, J
= 11.7, 5.7 Hz, 2H), 3.30 (t, J = 6.6 Hz, 1H), 3.10 - 3.21 (m, 1H), 2.96 - 3.08 (m,
1H), 2.41 — 2.64 (m, 2H), 2.17 - 2.36 (m, 2H), 1.76 - 1.96 (m, 2H); MS-ESI (m/z):
430 [M+1]+.
Example 16
Preparation of H-D-Glu(L-Trp-OCHg-CO-N(CH3)2)-OH, Ap0894
\ NHo
o o
HOWN (S) O\)kN/ H
NH2 o I
Cbz—D-GIu(OH)—Ole (18.57 g, 50.0 mmol), HOSu (6.04 g, 52.5 mmol)
and EDCI hydrochloride (10.55 g, 55.0 mmol) were mixed in DMF (75 mL) and
stirred for 2.5 h. L-Trp—OH (12.25 g, 55.0 mmol) was then added to the reaction
mixture. After stirring at RT for overnight, the mixture was diluted with ethyl
acetate, then washed with a 0.5N HCI solution (x2), water and brine, dried over
M9804 and filtered. The fiitrate was trated by rotary evaporation to give
Cbz—D-GIu(L—Trp-OH)—OBZI (27.5 g) as a white solid. Yield = 98%. 1H NMR
Ds, 400 MHz) d ppm: 12.55 (br. s, 1H), 10.83 (br. s, 1H), 8.14 (d, J z 8.1
Hz, 1H), 7.78 (d, J: 8.1 Hz, 1H), 7.51 (d, J: 7.1 Hz, 1H), 7.28 - 7.44 (m, 11H),
7.12 (s, 1H), 7.02 — 7.10 (m, 1H), 6.90 - 7.01 (m, 1H), 5.12 (s, 2H), 4.97 - 5.08 (m,
2H), 4.35 - 4.50 (m, 1H), 4.04 - 4.15 (m, 1H), 3.14 (dd, J = 14.7, 4.5 Hz, 1H), 2.98
(dd, J = 14.7, 8.6 Hz, 1H), 2.12 - 2.27 (m, 2H), 1.87 - 2.00 (m, 1H), 1.64 - 1.81
(m, 1H).
To a mixture of Cbz—D-GIu(L-Trp-OH)-Ole (2.24 g, 4.08 mmol) with
potassium carbonate (1.11 g, 8.0 mmol) in N,N-dimethyiformamide (20 mL)
warmed under a 45°C temperature oil bath was added 2-chloro—N,N—
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303134046
dimethylacetamide (0.73 g, 6.0 mmol). After stirring for 3h, the reaction mixture
was diluted with water and extracted with ethyl e. The organic layer was
washed with water (x3) then brine. The product was purified by column
chromatography on silica gel using a solvent e of ethyl acetate/hexanes
(8/2, v/v) to give the desired aikylated compound Cbz—D-Glu(L-Trp-OCH2-CO—
N(CH3)2)—Ole (1.79 g) as a white foam. Yield = 69%; 1H NMR (DMSO-Ds, 300
MHz) 5 ppm: 10.85 (br. s, 1H), 8.34 (d, J: 7.5 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H),
7.50 (d, J: 7.5 Hz, 1H), 7.34 (br. s, 11H), 7.19 (s, 1H), 7.03 - 7.13 (m, 1H), 6.93 -
7.02 (m, 1H), 5.12 (s, 2H), 4.96 - 5.09 (m, 2H), 4.81 (q, J = 15.1 Hz, 2H), 4.49 -
4.62 (m, 1H), 4.02 - 4.15 (m, 1H), 3.27 ~ 3.33 (m, 1H), 3.01 (dd, J: 14.3, 9.8 Hz,
1H), 2.90 (s, 3H), 2.83 (s, 3H), 2.12 - 2.30 (m, 2H), 1.87 — 1.98 (m, 1H), 1.64 -
1.80 (m, 1H); MS (m/z): 643 [M+1]+.
Cbz—D-Glu(L-Trp-OCH2-CO-N(CH3)2)-OBz[ (1.65 g, 2.6 mmol) and 10 %
Pd-C (wet, 0.36 g) was mixed in ethanol (100 mL). The reaction mixture was
hydrogenated in a Parr apparatus for 1.5 h under an atmosphere of hydrogen.
The mixture was ed through CeilteTM. The filtrate was concentrated by rotary
evaporation under d pressure and the e was triturated with
acetonitrile. The title compound H-D-Glu(L-Trp—OCH2-CO-N(CH3)2)-OH (Ap0894,
1.00 g) was collected by suction filtration as a white solid. Yietd = 92%; 1H NMR
(DMSO-D6+ D20, 300 MHz) d ppm: 7.49 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 7.5 Hz,
1H), 7.18 (br. s, 1H), 6.90 - 7.12 (m, 2H), 4.79 (q, J: 15.1 Hz, 2H), 4.47 - 4.61
(m, 1H), 3.26 - 3.39 (m, 1H), 3.19 (t, J = 5.7 Hz, 1H), 2.94— 3.12 (m, 1H), 2.88 (br.
s, 3H), 2.81 (br. s, 3H), 2.11 — 2.33 (m, 2H), 1.68 - 1.93 (m, 2H).
Example 17
Preparation of H-D-Glu(D-Trp-O-mofetil)-O-mofetiL3HC|, Ap0903.3HC|
V1A510127NZPR
Preparation of Boc—D-Glu(D—Trp—O—mofetil)—O~mofetil
To a solution of 2-morpholinoethanol (3.94 g, 30.0 mmol) with
triethylamine (5.06 g, 50 mmol) in dichloromethane (40 mL) cooled in an ice-
water bath, methanesulfonyl chloride (3.44 g, 30.0 mmol) was carefully added.
After stirring for 10 min, the reaction mixture was concentrated under reduced
pressure by rotary evaporation. The residue was mixed with potassium
ate (4.15 g, 30.0 mmol) and Boc—D—Glu(D~Trp-OH)~OH (4.33 g, 10.0
mmol) in DMF (30 mL) with ice-water bath cooling. The mixture was then heated
to 40°C and stirred for overnight. The mixture was d to cool to RT and
diluted with ethyl acetate. The inorganic salt was removed by suction filtration
and the filtrate was washed with water (x3) and brine. The ethyl e layer
was concentrated with silica gel and the crude mixture was purified by column
chromatography with a solvent mixture of acetone and ethyl acetate (gradient,
1/9 to 4/6 ratio, v/v) to give Boc-D-Glu(D-Trp-O-mofetil)-O-mofetil (3.13 g) as a
white foam. Yield = 47%; 1H NMR (DMSO-De, 400 MHz) 5 ppm: 10.86 (br. s, 1H),
8.26 (d, J = 7.1 Hz, 1H), 7.47 (d, J: 8.1 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.25
(d, J: 8.1 Hz, 1H), 7.15 (s, 1H), 7.06 (t, J: 7.1 Hz,1H),6.95 - 7.01 (m, 1H),
4.46 (q, J = 7.1 Hz, 1H), 4.17 — 4.27 (m, 1H), 3.97 - 4.12 (m, 3H), 3.88 - 3.97 (m,
1H), 3.43 - 3.57 (m, 8H), 3.13 (dd, J: 14.7, 6.6 Hz, 1H), 3.01 (dd, J: 14.7, 7.6
Hz, 1H), 2.20 - 2.55 (m, 14H), 1.80 - 1.94 (m, 1H), 1.65 - 1.78 (m, 1H), 1.38 (s,
9H); MS-ESI (m/z): 660 [M+1}+.
Proceeding in a similar manner as described under e 6B, the title
compound u(D-Trp-O-mofetii)—O-mofetil.3HCI (Ap0903.3HC|, 590 mg,
yield = 88%) was obtained from deprodection of Boc—D—Glu(D~Trp—O-mofetil)-O-
mofetil (660 mg, 1.0 mmol) in 4M HCI in dioxane (4mL) and ethyl acetate (20
mL); 1H NMR (DMSO—De, 400 MHz) 5 ppm: 11.21 (br. s, 2H), 10.94 (br. s, 1H),
8.70 (m, 4H), 7.51 (d, J: 7.1 Hz, 1H), 7.35 (d, J: 8.1 Hz, 1H), 7.21 (s, 1H), 7.08
(t, J = 7.1 Hz, 1H), 6.95 - 7.04 (m, 1H), 4.28 — 4.62 (m, 5H), 4.02 - 4.13 (m, 1H),
3.71 - 3.99 (m, 9H), 2.85 - 3.47 (m, 13H), 2.29 - 2.44 (m, 2H), 1.98 — 2.06 (m,
2H); MS MS—ESI (m/z): 560 [M+1]+ (free base).
_52-
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e 18
Preparation of H-D-Glu(D-Trp-O-CHZCHZCF3)CH2CH2CF3 hydrochloride
(Ap0879.HCI)
\ H-C]
v- 0 F
NH2 0 F
To a suspension of H-D-Giu(D-Trp-OH)-OH (2.0 g, 6.0 mmol) in 3,3,3-
oropropan—1—ol (8.5 mL, 96.4 mmol) was bubbled HCl (gas) at ice—water bath
temperature. The resulting mixture was allowed to warm to RT and then stirred
for overnight. The reaction mixture was concentrated to dryness in vacuo. The
residue was purified by flash column chromatography on silica gel using a
solvent mixture of [PA and CH2CI2 (from 1/9 to 2/8, v/v) as eluent. Fractions rich
in product were pooled together and trated in vacuo. The residue was
stirred in 2M H01 in Etgo (10 mL), then concentrated to dryness and dried under
vacuum to afford the title compound (1.8 g). Y = 53.4%; 1H NMR (DMSO-De, 400
MHz) 5 ppm: 11.00 (br. s, 1H), 8.73 (br. s, 3H), 8.58 (d, J: 7.1 Hz, 1H), 7.48 (d,
J: 8.1 Hz, 1H), 7.36 (d, J: 8.1 Hz, 1H), 7.22 (s, 1H), 7.04 - 7.13 (m, 1H), 6.96 -
7.04 (m, 1H), 4.43 - 4.53 (m, 1H), 4.29 - 4.43 (m, 2H), 4.14 - 4.29 (m, 2H), 3.95
(t, J = 6.1 Hz, 1H), 3.12 - 3.24 (m, 1H), 3.01 - 3.12 (m, 1H), 2.64 - 2.81 (m, 2H),
2.47 — 2.64 (m, 2H), 2.23 - 2.45 (m, 2H), 1.91 — 2.06 (m, 2H); MS—ESl (m/z): 526
[M+1]*.
-53..
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Example 19
Preparation of H—D-Glu(D-Trp-O-CH(CH3)CO-O-cyclohexyI)-O-Et
hydrochloride salt, Ap0854.HCI
O O H~Cl
/\WH o o o
r r U
Cbz—D-Glu(OH)—O-Et (12.1 g, 39.1 mmol), HOSu (4.60 g, 40.0 mmol) and
EDC|.HCI (7.67 g, 40.0 mmol) were mixed in DMF (100 mL) under ice-water bath
temperature. The reaction mixture was allowed to warm to RT then stirred for
overnight. The reaction mixture was cooled again in an ter bath and D-Trp-
OH (8.17 g, 40.0 mmol) was added. The mixture was stirred at room temperature
for overnight. The mixture was poured into a beaker containing 0.5N HCI (200
mL) and ice s. The mixture was extracted with ethyl acetate (2x200 ml. +
1x100 mL). The organic layers were combined and washed with a 0.5N HCl
solution (100 mL), water (2x100 mL) and brine (100 mL), dried over MgSO4, then
filtered. The filtrate was concentrated via rotary evaporation under reduced
pressure and the resulting solid Cbz—D—Glu(D-Trp—OH)-O-Et was triturated with
% ethyl e in hexanes. The itated white solid was collected via
suction filtration (17.6 g). Yield = 90 %; 1H NMR (DMSO-De, 400 MHz) 5 ppm:
12.58 (br. s, 1H), 10.82 (s, 1H), 8.12 (d, J: 8.1 Hz, 1H), 7.71 (d, J: 8.1 Hz,1H),
7.52 (d, J: 8.1 Hz, 1H), 7.23 - 7.42 (m, 6H), 7.12 (s, 1H), 7.06 (t, J: 7.6 Hz,
1H), 6.97 (t, J = 7.6 Hz, 1H), 4.97 - 5.10 (m, 2H), 4.41 - 4.51 (m, 1H), 3.95 - 4.15
(rn, 3H), 3.15 (dd, J: 14.1, 5.1 Hz, 1H), 2.99 (dd, J: 15.2, 8.1 Hz, 1H), 2.09 -
2.26 (m, 2H), 1.83 - 1.96 (m, 1H), 1.65 - 1.81 (m, 1H), 1.16 (t, J3 7.1 Hz, 3H);
MS—ESI (m/z): 496 [M+1]+.
To a mixture of Cbz-D-Glu(D-Trp-OH)-O—Et (4.95 g, 10.0 mmol) with
potassium ate (4.15 g, 30.0 mmol) and sodium iodide (6.00 g, 40.0 mmol)
in N,N-dimethylformamide (30 mL) at room temperature, 1-chloroethylcyclohexyl
carbonate (6.20 g, 30.0 mmot) was added. After being stirred at room
VIA510127NZI’R
303134046
temperature for overnight, additional N,N-dimethylformamide (30 mL) was added
and the reaction mixture was stirred at 40°C for overnight. The reaction mixture
was diluted with ethyl acetate then washed with water (3x) then with brine. The
crude product Cbz—D-Glu(D-Trp-O—CH(CH3)—O-CO—O~cyc|ohexyl)-O-Et was
purified by column chromatography on silica get using a solvent gradient of a
mixture of ethyl e in hexanes (20 to 40%) as eluant. Fractions rich in
product were combined together and evaporated to dryness. Thus, the desired
compound Cbz—D-Glu(D-Trp-O-CH(CH3)—O-CO-O-cyclohexyl)-O-Et (4.43 g) was
obtained as a pale-yellow foam. Yield = 66 %;1H NMR (DMSO-Ds, 400 MHz) 8
ppm: 10.86 (br. s, 1H), 8.36 (dd, J: 17.2, 7.1 Hz, 1H), 7.66 - 7.77 (m, 1H), 7.46
(t, J: 8.0 Hz., 1H), 7.22 — 7.42 (m, 6H), 7.10 - 7.20 (m, 1H), 7.02 - 7.10 (m, 1H),
6.90 — 7.02 (m, 1H), 6.58 - 6.70 (m, 0.5H), 6.46 - 6.58 (m, 0.5H), 5.04 (br. s, 2H),
4.38 - 4.61 (m, 2H), 3.93 - 4.15 (m, 3H), 2.90 - 3.17 (m, 2H), 2.20 (br. s, 2H),
1.54 - 1.96 (m, 6H), 1.02 - 1.53 (m, 12H); MS-ESI (m/z): 666 .
Cbz—D-Glu(D-Trp-O-CH(CH3)~O-CO-O-cyclohexyl)—O-Et (2.0 g, 3.0 mmol)
and 10 % Pd/C (wet, 0.6 g) was mixed in ethanol (50 mL) and 2M HCl in ether
(1.7 mL, 3.4 mmol). The reaction mixture was hydrogenated in a Parr apparatus
at 20-25 psi of en pressure for an hour. The mixture was filtered through
CeliteTM and the cake was washed with ethanol. The filtrate was concentrated by
rotary evaporation and the residue was triturated with a mixture of ether and
s. Thus, H-D-G|u(D-Trp-O-CH(CH3)-O-CO-O-cyciohexyl)-O-Et
hydrochloride salt (Ap0854.HCI, 0.80 g) was obtained as a pink solid foam. Yield
= 47%; 1H NMR (DMSO-De, 400 MHz) 5 ppm: 10.94 (br. s, 1H), 8.57 (br. s, 4H),
7.47 (t, J: 8.1 Hz, 1H), 7.34 (d, J: 8.1 Hz, 1H), 7.19 (s, 1H), 7.07 (t, J: 7.6 Hz,
1H), 6.88 ~ 7.03 (m, 1H), 6.58 - 6.72 (q, J = 5.1 Hz, 0.5H), 6.53 (q, J = 5.1 Hz,
0.5H), 4.39 - 4.63 (m, 2H), 4.00 - 4.26 (m, 2H), 3.78 - 4.00 (m, 1H), 2.93 - 3.18
(m, 2H), 2.18 - 2.41 (m, 2H), 1.88 - 2.02 (m, 2H), 1.82 (br. s, 2H), 1.63 (br. s, 2H),
1.13 - 1.53 (m, 12H); MS-ESI (m/z): 532 {M+1]‘“ (free base).
VIA510127NZPR
303 1340-16
Example 20
Preparation of u(D-Trp-O-CH(CH3)-O-CO-O-Et)-O-Et hydrochloride,
Ap0901.HC|
\ H—Cl
O O
/\W O O o\/
o T If
Proceeding in a similar manner as described in Example 19 above, Cbz—
D-Glu(D-Trp-O-CH(CH3)—O-CO-O~Et)-O—Et (1.64 9, yield 53 %) was prepared
from the reaction of CBz-D-GIu(D-Trp—OH)-O—Et (2.48 g, 5.00 mmol) with 1-
chloroethyl ethyl carbonate (1.53 g, 10.0 mmol) in presence of potassium
carbonate (1.38 g, 10.0 mmol) and sodium iodide (3.00 g, 20.0 mmol) in MN-
dimethylformamide (30 mL) at 50 °C overnight. 1H NMR (DMSO-Ds .400 MHz) 6
ppm: 10.87 (br. s, 1H), 8.24 - 8.48 (m, 1H), 7.72 (t, J = 7.1 Hz, 1H), 7.42 - 7.55
(m, 1H), 7.22 - 7.42 (m, 6H), 7.14 (d, J = 5.1 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H),
6.91 - 7.02 (m, 1H), 6.63 (q, J== 5.1 Hz, 0.5H), 6.51 (q, J = 5.1 Hz, 0.5H), 4.97 -
.13 (m, 2H), 4.37 - 4.51 (m, 1H), 3.88 - 4.23 (m, 5H), 2.92 - 3.20 (m, 2H), 2.10 -
2.28 (m, 2H), 1.80 - 1.96 (m, 1H), 1.73 (m, 1H), 1.43 (d, J= 5.1 Hz, 1.5H), 1.12 -
1.29 (m, 7.5H).
H-D-Giu(D-Trp—O-CH(CH3)-O-CO-O-Et)~0-Et hydrochloride 1.HCI,
0.97 g) was obtained from the hydrogenation of Cbz—D-Glu(D-Trp-O-CH(CH3)—O—
COO-Et)—O-Et (1.60, 2.60 mmol) with 10 % Pd/C (wet, 1.00 g) in ethanol (75 mL)
and 4M HCI in dioxane (0.8 mL) in a Parr apparatus under a en
atmosphere. Yield = 72 %; 1H NMR (DMSO-Ds, 400 MHz) 6 ppm: 11.04 (br. s,
1H), 8.56 - 8.89 (m, 4H), 7.42 - 7.53 (m, 1H), 7.35 (d, J = 7.1 Hz, 1H), 7.22 (s,
1H), 7.06 (t, J: 7.1 Hz, 1H), 6.91 — 7.01 (m, 1H), 6.64 (m, 0.5H), 6.54 (m, 0.5H),
4.39 — 4.57 (m, 1H), 4.05 - 4.27 (m, 4H), 3.80 - 3.97 (m, 1H), 2.97 - 3.24 (m, 2H),
2.20 - 2.45 (m, 2H), 1.92 - 2.07 (m, 2H), 1.45 (d, J = 5.1 Hz, 1.5H), 1.12 - 1.30
(m, 7.5H); MS-ESI (m/z): 478 [MM]+ (free base).
Vh\510127NZPR
303‘] 340-16
Exam pie 21
Preparation of H-D-Giu(D-Trpmofeti|)Et.2HCI, Ap0900.2HCI
0 o .2HCi
/\WO O\/\
NHZ O N/E
Proceeding in a simiiar manner as described in Example 19 above, Cbz—
D-G|u(D-Trp-O-mofeti|)-O-Et hydrochloride salt (2.21 9, yield 34 %) was prepared
from the reaction of Cbz-D-G|u(D-Trp-OH)—O-Et (4.96 g, 10.0 mmol) with 2-
morpholinoethyl methanesulfonate, which was made from 2-morpholinoethanol
(1.97 g, 15.0 mmol) with methanesulfonyl chloride (1.72 g, 15.0 mmol), in
presence of potassium carbonate (2.76 g, 20.0 mmol) in N,N~dimethylformamide
(30 mL). 1H NMR (DMSO-De, 400 MHz) 8 ppm: 11.07 (br. s, 1H), 10.90 (br. s,
1H), 8.48 (d, J = 7.1 Hz, 1H), 7.73 (d, J: 8.1 Hz, 1H), 7.50 (d, J: 7.1 ,
7.27 - 7.43 (m, 6H), 7.17 (s, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.93 - 7.04 (m, 1H),
4.98 - 5.11 (m, 2H), 4.54 (q, J = 7.1 Hz, 1H), 4.25 - 4.44 (m, 2H), 3.96 - 4.14 (m,
3H), 3.67 ~ 3.91 (m, 4H), 3.04 - 3.33 (m, 6H), 2.85 - 3.04 (m, 2H), 2.19 - 2.30 (m,
2H), 1.85 - 1.97 (m, 1H), 1.68 - 1.82 (m, 1H), 1.17 (t, J: 7.1 Hz, 3H); MS-ESl
(m/z): 609 [MM]+ (free base).
H-D-Glu(D-Trp-O-mofetil)-O-Et dihydrochloride salt (1.22 g, 65 %) was
prepared from the enation of Cbz—D—GIu(D-Trp—O-mofetil)-O-Et
hydrochloride (2.21, 3.40 mmol) with 10 % Pd/C (wet, 1.4 g) in ethanol (100 ml.)
and 2M HCI in ether (2.5 mi.) in a Parr tus under a hydrogen atmosphere.
1H NMR (DMSO-De, 400 MHz) 8 ppm: 11.80 (br. s, 1H), 11.02 (br. s, 1H), 8.66 -
8.85 (m, 4H), 7.51 (d, J: 8.1 Hz, 1H), 7.35 (d, J: 8.1 Hz, 1H), 7.23 (br. s, 1H),
7.06 (t, J = 7.1 Hz, 1H), 6.94 — 7.02 (m, 1H), 4.56 (q, J = 7.1 Hz, 1H), 4.33 ~ 4.45
(m, 2H), 4.06 - 4.23 (m, 2H), 3.86 (br. s, 5H), 2.90 - 3.37 (m, 8H), 2.26 - 2.46 (m,
2H), 1.91 - 2.03 (m, 2H), 1.20 (t, J: 6.6 Hz, 3H); MS—ESI (m/z): 475 [M+1]+ (free
base).
VIA510127NZI’R
303134046
Example 22
Preparation of H-D-Glu(D-Trp-Oindanyl)-0H, Ap0851
HO 0 \
(R) Q
o o
A. Preparation of H-D-Trp-Oindanyl hloride
Boc—D-Trp-OH (3.04 g, 10.0 mmol), 5-indanol (5.41 g, 40.0 mmol),
EDC|.HC| (2.30 g, 12.0 mmol), HOBt hydrate (1.68 g, 11.0 mmol) and N-
methylmorpholine (1.21 g, 12.0 mmol) were mixed in dichloromethane (10 mL).
The on mixture was stirred at room temperature for overnight and then
diluted with ethyl acetate. The mixture was washed with water (2x) and brine,
then dried over magnesium sulphate. The product was purified by column
chromatography on silica gel using a solvent gradient consisting of a mixture of
ethyl acetate (5 to 20%) in hexanes as eluent to give Boc-D—Trp-O-S-indanyl
(3.26 g) as a colorless foam. Yield: 77 %; 1H NMR (CD300, 90 MHz) 5 ppm:
7.60 (d, J = 7.0 Hz, 1H), 7.27 - 7.47 (m, 1H), 6.88 - 7.27 (m, 4H), 6.48 - 6.82 (m,
2H), 4.63 (t, J = 6.9 Hz, 1H) 4.10 (q, 68 Hz, 1H) 2.63 — 3.05 (m, 4H), 1.87 - 2.31
(m, 3H) 1.09 - 1.65 (m, 11H); MS-ESI (m/z) 421 .
Boc—D-Trp-O-S-indanyl (3.25 g, 7.70 mmol) was mixed with 2M HCI in
ether (20 mL) at room temperature and stirred for 20 h. Additional 2M HCI in
ether (10 mL) was added and the e was kept stirring for another 3.5 h. The
precipitate was ted by suction filtration, thoroughly washed with ether to
give H-D-Trp—O-S-indanyl hydrochloride as off-white solid (2.01 9). Yield: 72 %;
1H NMR (DMSO-Ds, 400 MHz) 6 ppm: 7.57 (d, J= 8.1 Hz, 1H), 7.40 (d, J = 8.1
Hz, 1H), 7.31 (s, 1H), 7.08 - 7.20 (m, 2H), 6.97 - 7.06 (m, 1H), 6.51 - 6.62 (m,
2H), 4.45 (t, J = 6.6 Hz, 1H), 3.30 - 3.49 (m, 2H), 2.70 - 2.84 (m, 4H), 1.91 - 2.05
(m, 2H); MS m/z: 321 [M+1]+ (free base).
B. Preparation of Cbz-D-Glu(D—Trp~O—5—indanyl)-O-le
~58—
Vl!\510127NZPR
30313-1046
H-D-Trp-O-S-indanyl hloride (1.00 g, 2.8 mmol), Cbz—D-Glu-O-le
(1.04 g. 2.80 mmol), EDCl .HCI (0.64 g, 3.30 mmol), HOBt hydrate (0.47 g, 3.10
mmol) and N-methylmorpholine (0.57 g, 5.60 mmol) were mixed in
dichloromethane (10 mL). The reaction e was stirred at room ature
for overnight and then diluted with ethyl acetate. The mixture was washed with
water, a saturated sodium bicarbonate solution, water, 0.5N HCI solution and
brine, then dried with magnesium sulphate. The organic solution was
concentrated by rotary evaporation and the residue was triturated with ether to
give Cbz—D-GIu(D-Trp-Oindanyl)—O-le (1.63 g) as a white soiid. Yield 87 %;
1H NMR (DMSO-Ds, 400 MHZ) 6 ppm: 10.92 (br. s, 1H), 8.52 (d, J = 6.1 Hz, 1H),
7.82 (d, J: 8.1 Hz, 1H), 7.54 (d, J: 7.1 Hz, 1H), 7.19 - 7.41 (m, 12H), 7.04 —
7.18 (m, 2H), 6.94 - 7.04 (m, 1H), 6.60 (s, 1H), 6.57 (d, J: 8.1 Hz, 1H), 5.13 (s,
2H), 4.99 - 5.09 (m, 2H), 4.55 - 4.70 (m, 1H), 4.08 - 4.21 (m, 1H), 3.12 - 3.28 (m,
2H), 2.70 - 2.86 (m, 4H), 2.29 (br. s, 2H), 1.92 - 2.08 (m, 3H), 1.69 - 1.90 (m, 1H);
MS—ESI (m/z): 674 .
C. Preparation of H-D-Giu(D-Trp-O-5—indanyI)-OH, Apo851
Cbz—D-Glu(D-Trp-O-5~indanyl)-O-Bzi (1.62 g, 2.4 mmol) and 10 % Pd/C
(wet, 0.60 g) were mixed in ethanol (180 mL). The reaction mixture was
hydrogenated under a hydrogen atmosphere using a balloon for 4h. The mixture
was filtered through CeliteTM and the cake was washed with ethanol. The filtrate
was concentrated by rotary evaporation and the residue was triturated with
acetonitrile to give H-D-GIu(D-Trp~O-5~indany|)-OH 1, 0.95 g) as a white
solid. Yield = 80 %;1H NMR (DMSO—De, 400 MHz) 6 ppm: 10.99 (br. s, 1H), 9.02
(d, J: 7.1 Hz, 1H), 7.55 (d, J: 8.1 Hz, 1H), 7.37 (d, J: 8.1 Hz, 1H), 7.28 (s,
1H), 7.15 (d, J = 8.1 Hz,1H),7.04 - 7.12 (m, 1H), 6.92 - 7.04 (m, 1H), 6.64 (s,
1H), 6.59 (d, J: 8.1 Hz, 1H), 4.60 (Q, J: 7.1 Hz, 1H), 3.11 — 3.43 (m, 4H), 2.71 -
2.87 (m, 4H), 2.23 - 2.42 (m, 2H), 1.94 - 2.11 (m, 2H), 1.71 - 1.93 (m, 2H); M8-
E81 (m/z): 450 [M+1]+.
VIA510127NZPR
303134046
Example 23
ation of H-D-Glu(D-Trp-O-(2—methoxyphenyl))—OH, Ap0852
HO O \
(R) H
“it Q
A. Preparation of H-D-Trp-O-(2-methoxyphenyl) hydrochloride
Proceeding in a similar manner as described in Example 22A above, Boc—
D—Trp-O-(2-methoxyphenyl) (5.85 9, yield = 70 %) was prepared from Trp-
OH (6.08 g, 20.0 mmol), EDC|.HC| (4.60 g, 24.0 mmol), HOBt hydrate (3.36 g,
22.0 mmol), N—methylmorpholine (2.42 g, 24.0 mmol) and 2-methoxyphenoi (10.3
g, 80.0 mmol) in dichloromethane (20 mL) at room temperature. 1H NMR
(DMSO-Ds, 400 MHz) 6 ppm: 10.89 (br. s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.42 (d,
J: 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.20 - 7.31 (m, 2H), 7.11 - 7.16 (m, 1H),
7.09 (t, J = 7.6 Hz, 1H), 6.92 - 7.03 (m, 3H), 4.36 - 4.51 (m, 1H), 3.76 (s, 3H),
3.31 - 3.38 (m, 1H), 3.09 - 3.20 (m, 1H), 1.35 (s, 7.5H), 1.28 (s, 15H).
H-D-Trp-O-(Z-methoxyphenyl) hydrochloride (4.55 9, yield = 96%) was
prepared from the reaction of Trp-O-(Z-methoxyphenyl) (5.64 g, 13.6
mmol) with 2M H0] in ether (40 mL) at room temperature.
B. Preparation of Cbz—D-Glu(D-Trp~O-(2-methoxyphenyl))-O-le
Proceeding in a similar manner as described in Example 22B above,
Cbz—D-GIu(D-Trp-O-(2-methoxyphenyl))-O—le (2.25 9, yield = 47%) was
prepared from p—O-(Z-methoxyphenyl) hydrochloride (2.50 g, 7.2 mmol),
EDCl.HCl (1.66 g, 8.6 mmol), HOBt hydrate (1.21 g, 7.9 mmol), N-
methylmorpholine (1.53 g, 15.1 mmol) and Cbz-D-Glu-O-le (2.68 g, 7.2 mmol)
in dichloromethane (20 mL) at room temperature. 1H NMR (DMSO-Ds, 400 MHz)
6 ppm: 10.90 (br. s, 1H), 8.50 (d, J: 8.1 Hz, 1H), 7.81 (d, J= 7.1 Hz, 1H), 7.56
(d, J: 8.1 Hz, 1H), 7.19 - 7.40 (m, 13H), 7.05 - 7.15 (m, 2H), 6.96 - 7.03 (m, 1H),
6.87 - 6.96 (m, 2H), 5.12 (s, 2H), 4.98 - 5.09 (m, 2H), 4.69 - 4.79 (m, 1H), 4.05 -
VI/\510127NZPR
303134046
4.16 (m, 1H), 3.73 (s, 3H), 3.32-3.41(m, 1H), 3.15 (dd, J = 14.7, 8.6 Hz, 1H), 2.15
- 2.35 (m, 2H), 1.88 - 2.03 (m, 1H), 1.70
— 1.86 (m, 1H); MS—ESI (m/z): 664
[M+1]*.
C. Preparation of H-D-Glu(D—Trp-O—(2-methoxyphenyi))—OH, Apo852
Proceeding in a similar manner as described in Example 22C above, H-
D-Glu(D-Trp-O-(2-methoxyphenyl))—OH, Ap0852 (1.11 9, yield = 84%) was
prepared from the hydrogenation of Cbz—D—Glu(D—Trp-O-(2-methoxyphenyl))-O-
le (2.00 g, 3.0 mmol) with 10 % Pd/C (wet, 0.75 g) in ethanol (200 mL) under an
atmosphere of hydrogen using a balloon. 1H NMR (CD30D, 400 MHz) 6 ppm:
7.60 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.17 — 7.26 (m, 2H), 6.99 - 7.14
(m, 3H), 6.88 - 6.95 (m, 2H), 4.99 (dd, J: 9.1, 5.1 Hz, 1H), 3.78 (s, 3H), 3.60 (t, J
= 6.1 Hz, 1H), 3.54 (dd, J: 14.1, 5.1 Hz, 1H), 3.21
- 3.30 (m, 1H), 2.35 — 2.57 (m
2H), 1.98 - 2.11 (m, 2H); MS—ESI (m/z): 440 [M+1]+.
Example 24
Preparation of H-D-Glu(D-Trp-O-mofetil)-O-CH20H2CF3 dihydrochloride
(Ap0913.2HCl)
O O
.2HCI (R)lo/VNQ
A. Preparation of Boc—D-Trp-O-mofetilO
A solution of Boc-D-Trp-OH (30.4 9, 100.0 mmol), 2—morpholinoethanol
(13.2 9, 100.0 mmol), EDCI.HC| (19.2 9, 100.0 mmol), HOBt hydrate (15.3 9,
100.0 mmol) in romethane (300 mL) was d at room temperature. After
two days the reaction mixture was trated in vacuo. The residue was
diluted with ethyl acetate. The resulting solution was sively washed with a
saturated sodium bicarbonate solution (2x), water (2x) and brine, then dried over
magnesium sulphate. After filtration, the organic fraction was trated in
vacuo to give crude Boc-D~Trp-O—mofetil (37.6 g) as a pale-brown oil. The
product was used in the next step reaction without further purification. 1H NMR
—61—
VIASIOIZ’JNZPR
(C003, 400 MHz) 5 (ppm): 8.37 (br. s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.34 (d, J =
8.1 Hz, 1H), 7.18 (t, J = 7.6 Hz,1H),7.06 - 7.14 (m, 1H), 7.03 (s, 1H), 5.12 (d, J
= 8.1 Hz, 1H), 4.58 - 4.71 (m, 1H), 4.10 - 4.20 (m, 2H), 3.58 - 3.73 (m, 4H), 3.19
3.35 (m, 2H), 2.43 - 2.56 (m, 2H), 2.29 - 2.42 (m, 4H), 1.43 (s, 9H).
B. Preparation of H-D-Trp-O-mofetil dihydrochloride
To a solution of Boc-D-Trp-O-mofetil (37.0 g, 89.0 mmol) in ethyl acetate
(250 mL) was slowly bubbled HCI gas for 3 h. The resulting precipitate was
collected via suction filtration and ghly washed with ethyl acetate to give H-
D-Trp-O-mofetil dihydrochtoride (30.6 g) as an off-white solid. Yield = 88%; 1H
NMR (DMSO-Ds, 400MHz) 8 (ppm): 11.35 (br. s, 1H), 11.11 (br. s, 1H), 8.77 (br.
s, 3H), 7.56 (d, J = 8.1 Hz, 1H), 7.38 (d, J: 8.1 Hz, 1H), 7.29 (s, 1H), 7.10 (t, J=
7.6 Hz, 1H), 6.93 - 7.06 (m, 1H), 4.33 - 4.57 (m, 2H), 4.22 - 4.31 (m, 1H), 3.85
(br. s, 4H), 2.82 - 3.48 (m, 8H); MS-ESI (m/z): 318 [M+1]* (free base).
C. Preparation of Boc—D-Glu-(OBn)-O-CH20H20F3
A e of Glu-(OBn)-OH (6.75 g, 20.0 mmol), 3,3,3-
trifluoropropanol (2.28 g, 20.0 mmol), EDClJ—ICI (3.84 g, 20.0 mmol) and HOBt
hydrate (3.06 g, 20.0 mmol) in dichloromethane (100 mL) was stirred at room
temperature for overnight. The reaction mixture was concentrated in vacuo, and
the residue was diluted with ethyl acetate. The resulting solution was
successively washed with a 1N HCI solution (2x), a saturated sodium
bicarbonate solution (2x), water (2x) and brine, then dried over magnesium
sulphate. After filtration, the filtrate was evaporated to dryness and then triturated
with ether to afford a first cr0p of Boc-D-Glu-(OBn)—O-CH2CH20F3 (3.69 g) as a
white solid. The mother liquid was concentrated to give a second crop (1.09 g).
Total 2 4.78 g, 1H NMR (CDCI3, 400 MHz) 8 (ppm): 7.35 (br. s, 5H), 4.93 - 5.29
(m, 3H), 4.26 - 4.50 (m, 2H), 2.34 - 2.67 (m, 4H), 2.09 - 2.34 (m, 1H), 1.90 - 2.04
(m, 1H), 1.35 - 1.49 (m, 9H).
D. ation of Boc-D-Giu-O—CchHgCF3
-62—
V11\510127NZPR
303134046
A mixture of Boc-D-Glu-(OBn)-O-CH20H20F3 (4.71 g, 10.8 mmol) and
% Pd-C (wet, 1.22 g) in ethyl acetate (100 mL) was stirred under a hydrogen
atmosphere using a bailoon at RT for 2 h. The mixture was filtered through
CeliteTM and the filtrate was trated in vacuo. The residue was triturated
with hexanes to give Boc—D-Glu—O—CHgCHzCFs (3.43 g) as a white solid, which
was used without further purification in the next step.
E. Preparation of Boc~D~Glu—(D—Trp—O—mofetil)—O—CHgCHZCF3
To a mixture H—D—Trp-O—mofetil diHCl (1.26 g, 3.2 mmol), Boc-D-GIu-O-
CHZCHZCFg (1.00 g, 2.94 mmoi) and EDCIHCI (0.62 g, 3.23 mmol) in
dichloromethane (75 mL), triethylamine (0.98 g, 9.7 mmol) was added. The
reaction mixture was stirred at room ature for overnight and then
concentrated in vacuo. The residue was diluted with ethyl acetate and the
resuiting solution was successively washed with water, a ted sodium
bicarbonate solution and brine, then dried over ium sulphate, fiitered, and
concentrated with silica gel. The product was purified by column tograpy
with ethyl acetate as eluent to give Boc—D-Glu—(D-Trp-O-mofeti|)-O-CHzCHgCF3
(0.944 g) as a white foam. Yield = 45%. 1H NMR (CDCla, 400MHz) 5 (ppm): 8.21
(br. s, 1H), 7.53 (d, J: 7.1 Hz, 1H), 7.35 (d, J: 8.1 Hz, 1H), 7.19 (t, J: 7.6 Hz,
1H), 7.00 - 7.15 (m, 2H), 6.37 (br. s, 1H), 5.32 (br. s, 1H), 4.80 - 5.05 (m, 1H),
4.06 - 4.48 (m, 5H), 3.58 — 3.85 (m, 4H), 3.19 - 3.46 (m, 2H), 2.08 - 2.69 (m,
10H), 1.80 - 2.01 (m, 2H), 1.43 (s, 9H); MS—ESI (m/z): 643 [M+1]+.
F. Preparation of H~D~G|u—(D—Trp-O—mofetil)—O-CH2CHZCFg dihydrochioride
Proceeding In a similar manner as bed under example 68, the title
compound H-D-GIu(D-Trp-O-mofeti|)-O-CH2CH20F3.2HCI (Ap0913.2HCI, 737
mg, yield = 86%) was obtained from the ection of Boc-D-Glu(D-Trp-O-
mofeti|)-O-CH20HZCF3 (890 mg, 1.4 mmol) in 4M H01 in dioxane (3.45 mL) and
ethyl acetate (3.0 mL). 1H NMR (DMSO-Ds, 400MHz) 6 (ppm): 11.41 (br. s, 1H),
10.95 (br. s, 1H), 8.68 (d, J: 7.1 Hz, 1H), 8.61 (br. s, 3H), 7.51 (d, J: 8.1 Hz,
1H), 7.35 (d, J = 8.1 Hz, 1H), 7.20 (s, 1H), 7.04 — 7.11 (m, 1H), 6.95 - 7.03 (m,
-63—
VIA510127NZPR
303134046
1H), 4.57 (q, J = 7.1 Hz, 1H), 4.27 - 4.45 (m, 4H), 3.96 - 4.07 (m, 1H), 3.85 (br. s,
4H), 2.83 — 3.37 (m, 8H), 2.63 - 2.81 (m, 2H), 2.25 - 2.45 (m, 2H), 1.91 ~ 2.06 (m,
2H); MS~ES| (m/z): 543 [(M+1]+ (free base).
e 25
Preparation of H-D~Glu(D-Trp-O-mofetil)-O-isoamyl dihydrochloride
(Ap091 7.2HCl)
HN(HZN.2HCl :3:O/\/N\J
A. Preparation of Boc-D-Glu(D-Trp-O~mofeti|)-O-isoamyl
Proceeding in a similar manner as described in Example 24E above, Boc-
D-G|u(D~Trp~O-mofetil)-O-isoamyl (2.22 9, yield = 57%) was prepared from the
reaction of Boc-D-Glu~0»isoamyl (Example 2, 2.00 g, 6.3 mmol) and H-D-Trp-O-
mofetil hydrochloride le 24B, 2.46 g, 6.3 mmol) with HOBt hydrate (1.06
g, 6.9 mmol), EDCl hloride (1.38 g, 7.2 mmol) and N—methylmorpholine
(0.64 g, 6.3 mmol) in dichloromethane (20 mL) at room temperature for
overnight. 1H NMR (DMSO~D6, 400MHz) 6 (ppm): 10.86 (br. s, 1H), 8.29 (d, J:
7.1 Hz, 1H), 7.47 (d, J: 8.1 Hz, 1H), 7.33 (d, J= 8.1 Hz, 1H), 7.23 (d, J: 7.1 Hz,
1H), 7.15 (s, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.93 - 7.02 (m, 1H), 4.46 (q, J = 7.1
Hz, 1H), 3.96 - 4.16 (m, 4H), 3.84 - 3.97 (m, 1H), 3.43 - 3.57 (m, 4H), 3.08 - 3.21
(m, 1H), 2.93 - 3.08 (m, 1H), 2.09 ~ 2.45 (m, 8H), 1.79-1.94 (m, 1H), 1.56 - 1.79
(m, 2H), 1.24 - 1.55 (m, 11H), 0.87 (d, J: 6.1 Hz, 6H); MS~ESI (m/z): 617
[M+1]".
B. Preparation of H-D-Glu(D~Trp—O-mofetil)-O-isoamyl dihydrochloride
Proceeding In a similar manner as described under example 6B, the title
compound H-D-Glu(D-Trp-O-mofeti|)-O-isoamyl ochloride (0.81 9, yield 2
40%) was obtained from the deprotection of Boc—D-Glu(D—Trp-O-mofeti|)-O-
isoamyl (2.13 g, 1.4 mmol) in 4M HCl in dioxane (15 mL) and ethyl acetate (20
—64-
VII\510I27NZPR
303134046
mL). 1H NMR (DMSO-De, 400MHz) 5 (ppm): 11.75 (br. s, 1H), 11.01 (br. s, 1H),
8.72 (br. s, 4H), 7.52 (d, .1 = 8.1 Hz, 1H), 7.35 (d, J = 7.1 Hz, 1H), 7.22 (s, 1H),
7.04 - 7.12 (m, 1H), 6.92 - 7.02 (m, 1H), 4.49 - 4.64 (m, 1H), 4.39 (br. s, 2H),
4.14 (br. s, 2H), 3.70 - 3.97 (m, 5H), 2.80 - 3.46 (m, 8H), 2.19 — 2.46 (m, 2H),
1.87 - 2.11 (m,2H), 1.55 — 1.72 (m, 1H), 1.49 (d, J: 7.1 Hz, 2H), 0.87 (d, J: 7.1
Hz, 6H); MS—ESI (m/z): 517 [M+1]+ (free base).
Example 26
Preparation of H-D-Glu(D-Trp-O-Bn)-O-mofetil dihydrochloride
(Ap0904.2HC|)
(\N/VO O \
od @1112;o(R) N
.2HCI 0 0/\©
A. Preparation of Boc-D-Glu-(OBn)-O-mofeti|
Proceeding in a similar manner as described in Example 240 above, Boc-
D-GIu-(OBn)-O-mofetil (8.70 9, yield = 96 %) was ed from the reaction of
Boc—D-Glu-(OBn)-OH (6.75 g, 20.0 mmol), holinoethanot (2.62 g, 20.0
mmol), HOBt e (3.06 g, 20.0 mmol) and EDCi hydrochloride (3.84 g, 20.0
mmol) in dichloromethane (100 mL) at room temperature for overnight. 1H NMR
(DMSO-De, 400MHz) 6 (ppm): 7.16 — 7.61 (m, 5H), 5.77 (s, 1H), 5.10 (s, 2H),
4.18 — 4.42 (m, 1H), 3.88 - 4.18 (m, 2H), 3.52 (br..s, 4H), 2.51 (br. s, 4H), 2.23-
2.46(m,4H), 1.71 - 2.12 (m, 2H), 1.20 - 1.57 (m, 9H).
B. Preparation of Boc-D—Glu-(OH)—O-mofeti|
Proceeding in a similar manner as described in Example 24D above, Boc-
D—Giu-(OH)~O-mofeti| (6.58 9, yield = 94 %) was prepared from the
hydrogenation of Glu-(OBn)-O-mofetil (8.70 g, 19.3 mmol) with 10 % Pd-C
(wet, 2.5 g) in ethyl acetate (100 mL) under a hydrogen atmosphere using a Parr
instrument. MS—ESI (m/z): 361 [M+1]+.
~65-
VIA510127N21’R
303134046
C. Preparation of Boc-D-Glu-(D-Trp-O-Bn)—O-mofetil
Proceeding in a similar manner as described in Example 24E above, Boc-
D-Glu-(D-Trp-O-Bn)-O-mofetil (1.72 9, yield = 54 %) was prepared from the
reaction of Boc-D-Glu-O—mofetil (1.80 g, 5.0 mmol) and H~D—Trp-0Bn
hydrochloride (1.65 g, 5.0 mmol) with EDCI hloride (0,96 9, 5.0 mmol) in
dichloromethane (50 mL) at room temperature for ght. MS-ESI (m/z): 637
[M+1}+.
D. Preparation of H-D-Glu-(D-Trp-O-Bn)-O-mofeti| dihydrochloride
Proceeding in a simiiar manner as described under example 6B, the title
nd H-D-Giu-(D-Trp-O-Bn)—O-mofetil dihydrochloride (Ap0904.2HCl, 1.26
9, yield = 77%) was obtained from the deprotection of Boc—D-GIu-(D-Trp-O—Bn)~
O-mofetil (1.70 g, 2.67 mmol) with 4M HCI in dioxane (8 mL) and ethyl acetate
(20 mL).1H NMR (DMSO—De, 400MHz) 6 (ppm): 11.12 (br. s, 1H), 10.91 (s, 1H),
8.68 (br. s, 3H), 8.56 (d, J: 7.1 Hz, 1H), 7.48 (d, J: 8.1 Hz, 1H), 7.25 - 7.39 (m,
4H), 7.09-7.20 (m., 3H), 7.08 (t, J = 7.6 Hz, 1H), 6.95 - 7.03 (m, 1H), 4.93 - 5.10
(m, 2H), 4.38 - 4.63 (m, 3H), 4.00 ~ 4.16 (m, 1H), 3.85-4.00 (m, 4H), 3.00 - 3.52
(m, 8H), 2.27 - 2.42 (m, 2H), 1.95 - 2.16 (m, 2H). MS-ESI (m/z): 537 [M+1]+ (free
base).
Example 27
Preparation of H-D-Giu(D-Trp-OH)-O-mofeti| dihydrochloride (Ap0905.2HCI)
Proceeding in a r manner as described in Example 22C above, H-D-
Trp-OH)—O-mofeti| dihydrochloride (Ap0905.2HC|, 580 mg, yield = 75%)
was prepared from the hydrogenation of H—D—GIu-(D-Trp-O-Bn)-O-mofetil
dihydrochloride (900 mg, 1.48 mmol) with 10 % Pd/C (wet, 450mg) in ethanol (50
ViA510127NZPR
303134046
mL) under an atmosphere of hydrogen using a balloon. 1H NMR (DMSO-De,
400MHz) 6 (ppm): 11.28 (br. s, 1H), 10.89 (br. s, 1H), 8.73 (br. s, 3H), 8.34 (d, J
= 8.1 Hz, 1H), 7.52 (d, J: 8.1 Hz, 1H), 7.34 (d, J: 8.1 Hz, 1H), 7.17 (s, 1H),
7.06 (t, J = 7.6 Hz, 1H), 6.90 - 7.01 (m, 1H), 4.38 - 4.63 (m, 3H), 4.03 (br. s, 1H),
3.92 (br. 3., 4H), 3.07 - 3.60 (m, 7H), 3.01 (dd, J: 14.7, 8.6 Hz, 1H), 2.27 - 2.39
(m, 2H), 1.91 — 2.06 (m, 2H); MS—ESI (m/z): 447 [M+1]*.
e 28
Preparation of H-D-Glu(D-Trp-Oindanyl)-O-mofetil dihydrochloride
(Ap0906.2HCl)
NH l
NH +cr3
//\crNi
O\// H
ation of Boc-D-Glu(D-Trp-Oindanyl)-O-mofetil
Proceeding in a similar manner as described in Example 24E above, Boc~
D-Giu(D—Trp—O-S-indanyi)—O—mofetil (499 mg, yield = 75%) was prepared from
the reaction of Boc-D-Glu-O—mofetil (2.00 g, 6.3 mmol), H-D—Trp-O—5-indanyl
hydrochloride (Example 22A, 2.46 g, 6.3 mmol) with HOBt hydrate (1.06 g, 6.9
mmol), EDCI hydrochloride (1.38 g, 7.2 mmol) and N—methylmorpholine (0.64 g,
6.3 mmoi) in dichloromethane (20 mL) at room ature for overnight. 1H
NMR (CDCIs, 400MHz) 5 (ppm): 8.79 (br. s, 1H), 7.61 (d, J: 8.1 Hz, 1H), 7.35
(d, J: 8.1 Hz, 1H), 7.08 - 7.24 (m, 4H), 6.81 (s, 1H), 6.70—6.77 (m, 2H), 5.14 -
.26 (m, 2H), 4.17 - 4.32 (m, 2H), 4.04 ~ 4.14 (m, 1H), 3.63 - 3.74 (m, 4H), 3.42 ~
3.57 (m, 2H), 2.88 (t, J: 7.1 Hz, 4H), 2.61 (t, J: 5.1 Hz, 2H), 2.51 (br. s, 4H),
2.24 - 2.32 (m, 2H), 2.03 — 2.18 (m, 3H), 1.81 - 1.96 (m, 1H), 1.44 (br. s, 9H);
MS—ESI (m/z): 663 [M+1]”.
-67—
VlA510127NZl’R
303134046
Preparation of H~D~Glu(D-Trp-Oindanyl)-O-mofetil dihydrochloride
Proceeding in a similar manner as described under e 68, the title
compound H-D—Glu(D-Trp-Oindanyl)-O-mofetil dihydrochloride (Ap0906.2HC],
85 mg, yield = 62%) was obtained from the deprotection of Boc-D-Glu(D-Trp-O-
-indanyl)—O-mofetil (142 mg, 0.214 mmol) in 4M HCI in dioxane solution (3 mL)
and ethyl acetate (3 mL). 1H NMR (DMSO-De, 400MHz) 6 (ppm): 11.05 (br. s,
1H), 10.97 (br. s, 1H), 8.51 - 8.91 (m, 4H), 7.54 (d, J: 8.1 Hz, 1H), 7.37 (d, J:
8.1 Hz, 1H), 7.28 (s, 1H), 7.16 (d, J: 8.1 Hz, 1H), 7.09 (t, J: 7.6 Hz, 1H), 6.95 ~
7.05 (m, 1H), 6.55 - 6.67 (m, 2H), 4.38 - 4.73 (m, 3H), 4.01-4.15 (m, 1H), 3.76 —
4.01 (m, 4H), 2.98 - 3.50 (m, 8H), 2.79 (m, 4H), 2.29 - 2.48 (m, 2H), 1.88 - 2.17
(m, 4H); MS-ES! (m/z): 563 [M+1]+ (free base).
Example 29
Preparation of H-D-Glu(D-Trp-O-cyclohexyl)-0H (Ap0850)
HOWN“(R) .
NH2 0 00
A. Preparation of p-O-cyclohexyl hloride salt
To a suspension of Boc-D-Trp—OH (15.0 g, 49.4 mmol) in CH2012 was
added EDC.HCI (14.2 g, 74.1 mmol) at RT. To the resulting clear solution was
added cyclohexanol (26.1 mL, 247 mmol) followed by DMAP (0.6 g, 4.9 mmol) at
RT. The resulting mixture was stirred for 4 days. The reaction e was
partitioned between a 1N HCI solution (200 mL) and EtOAc (120 mL). The
aqueous layer was extracted once again with EtOAc (150 mL). The combined
organic fractions was washed with 1N HCI (100 mL) followed by water (100 mL),
then dried over sodium sulfate, filtered and evaporated to dryness. The residue
was purified by flash column chromatography on silica gel (100% hexanes and
% EtOAc in hexanes as eluent) to afford Trp-O—cyclohexyl as a
ish solid (15.4 9). Yield = 81%; MS—ESI (m/z): 387 [M+1]+.
VIA510127NZPR
303‘1 340-16
To a solution of Boc—D—Trp—O—cyclohexyl (13.8 9, 35.8 mmol) in CHZClz
cooled to 5-10°C was bubbled HCI gas for 30 min. The resulting solid suspension
was collected by suction filtration, washed with CH2CI2 (2 x 100 mL), then dried in
a vacuum oven at 42°C for 6h. Thus, H-D-Trp—O—cyclohexyl hloride salt
was obtained (6.4 g) as a solid. 1H NMR (DMSO-De, 400 MHz) 6 ppm: 11.12 (br.
s, 1H), 8.68 (br.s, 3H), 7.55 (d, J: 7.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.24 (s,
1H), 7.07 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 4.64 (apparent br. t, 1H),
4.13 (apparent br. t, 1H), 3.30 - 3.35 (m, 1H), 3.22 — 3.28 (m, 1H), 1.44 — 1.50 (m,
1H), 1.35 ~ 1.65 (m, 4H), 1.10 - 1.30 (m, 5H); MS-ESi (m/z): 287 [MM]+ (free
base).
B. Preparation of Cbz—D-Glu(D-Trp-O-cyclohexyl)-O»le.
To a solution of Cbz-D—Glu-O-le (2.89, 7.6 mmol), EDC.HCI (2.29, 11.4
mmol), HOBt hydrate (1.59, 11.4 mmol) and DlPEA (3.3 mL, 19.0 mmol) was
added p-O—cyclohexyl hydrochloride salt (3.2 9, 9.9 mmol) at RT. The
mixture was stirred under a t of nitrogen for overnight. The e was
evaporated to dryness in vacuo and the e was partitioned between a 5%
sodium carbonate solution (150 mL) and EtOAc (150 mL). The aqueous layer
was extracted once again with EtOAc (150 mL). The combined organic fractions
was successively washed with a 5% sodium carbonate solution (100 mL), a 1N
HCI solution (2x100 mL) and water (100mL), then dried over sodium sulfate,
filtered and trated in vacuo. Purification of the residue by cotumn
chromatography on silica gel (20 to 40% EtOAc in hexanes then 10% MeOH in
EtOAc as eluent) afforded Cbz-D-Glu(D—Trp—O-cyclohexyl)—O—le.in quantitative
yield. 1H NMR (DMSO-Ds, 400 MHz) 5 ppm: 10.88 (br. s, 1H), 8.35 (d, J = 7.0 Hz,
1H), 7.82 (d, J = 7.0 Hz, 1H), 7.49 (d, J: 7.0 Hz, 1H), 7.25 — 7.40 (m, 11H), 7.18
(s, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 5.13 (s, 2H), 5.02 — 5.10
(m, 2H), 4.56 — 4.62 (m, 1H), 4.48 (apparent q, J = 7.2 Hz, 1H), 4.05 — 4.12 (m,
1H), 3.04 - 3.12 (m, 1H), 2.98 — 3.06 (m, 1H), 2.15 - 2.25 (m, 2H), 1.90 — 2.00 (m,
1H), 0.90 — 1.80 (m, 11H); MS-ESI (m/z): 640 [M+1]“.
VIA510127NZPR
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C. Preparation of H~D-Glu(D-Trp-O—cyolohexy|)-OH (Ap0850).
A solution of G|u(D—Trp-O—cyclohexyl)-O-Bz| (2.89 g, 4.52 mmol)
and 10% wet Pd/C (387 mg) in EtOH (180 mL) was subjected t hydrogenolysis
under a hydrogen pressure of 15 psi for 2.75h. The mixture was filtered over a
pad of CeliteTM and the filtrate was ated to dryness. ation of the
residue by column chromatography on silica gel (5 to 20% MeOH in CHZCIZ)
ed H-D-Glu(D-Trp-O-cyclohexyl)—OH (Ap0850, 1.409) as a white solid.
Yield = 75%;1H NMR (DMSO-De, 400 MHz) 5 ppm: 11.01 (br. s, 1H), 8.78 (d, J =
7.2 Hz, 1H), 7.50 — 8.20 (br above baseline hump), 7.49 (d, J = 7.8 Hz, 1H), 7.34
(d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.06 (t, J2 7.2 Hz, 1H), 6.98 (t, J= 7.5 Hz, 1H),
4.60 (br apparent t, 1H), 4.48 (apparent q, J = 6.9 Hz, 1H), 3.20 — 3.60 (br above
baseline hump), 3.30 (t, J = 6.3 Hz, 2H), 3.10 - 3.18 (m, 1H), 2.98 — 3.06 (m, 1H),
2.24 - 2.32 (m, 2H), 1.83 - 1.87 (m, 2H), 1.50 — 1.70 (m, 4H), 1.15 - 1.45 (m, 6H);
MS-ESI (m/z): 416 [M+1]+.
Example 30
Preparation of H-D-Glu(D-Trp-OCH20-CO-C(CH3)3)-0H, Ap0839
HO1% W01(R) N
O O
O GAO/“\K
Proceeding in a similar manner as described in Example 12, by replacing
chloromethyl te with chloromethyl pivaiate, H—D-Glu(D-Trp—OCH20-CO-
C(CH3)3)—OH (Ap0839) was prepared. 1H NMR (DMSO~D6, 400 MHz) 5 ppm:
11.09 (br. 1H), 8.83 (d, J = 7.1 Hz, 1H), 7.50 -— 8.20 (br above baseline hump),
7.47 (d, J: 7.8 Hz, 1H), 7.34 (d, J: 8.0 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.06 (t,
J = 7.1 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 5.68 — 5.76 (m, 2H), 4.42 - 4.48 (m, 1H),
3.40 — 3.70 (br. above baseline hump), 3.29 (t, J = 6.5 Hz, 1H), 3.12 — 3,15 (m,
1H), 3.00 - 3.08 (m, 1H), 2.26 — 2.30 (m, 2H), 1.46 - 1.52 (m, 2H), 1.12 (s, 9H);
MS—ESl (m/z): 448 [M+1]+.
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Example 31
Preparation of H-D-Glu(D-Trp-0H)-0Me (Ap0841)
\OWW(R) 0H
NH2 o
A mixture of Boc—D-Glu(D-Trp-OH)—OBZI (Example GA, 2.10 g, 4.00 mmol)
and sodium methoxide (0.55 g, 10.0 mmol) in methanol (60 mL) was d at
RT for 25 min. The reaction e was quenched with acetic acid (0.6 mL, 10.5
mmol), then evaporated to dryness in vacuo to afford crude Boc—D-Glu(D—Trp-
OH)-OMe as an oil.
The al oil was taken up in CH2Cl2 (180 mL), then washed with a
mixture of de-ionized water (50 mL) and acetic acid (0.3 mL). The organic
solution was dried over Na2804, filtered, and the volume of the filtrate was
reduced to about 80 mL via rotary ation. The organic layer was cooled in
an ice-water bath, as HC] gas was bubbled in slowly. The progress of the
reaction was monitored by HPLC. The upper liquid was decanted, and the sticky
solid was triturated with more CH2CI2. The sticky solid was then dissolved in
water (30 mL) and the pH of the on was adjusted to about 5.5 by with a BN
NaOH solution (0.5 mL, 3 mmol). Acetonitrile (100 mL) was then added, and the
mixture was evaporated to dryness in vacuo to give an oil. Upon trituration with
ethyl acetate a solid formed. The solid was collected via suction filtration,
thoroughly washed with water and dried to afford H-D—GIu(D-Trp-OH)-0Me
(Apo822, 0.49 9). Yield = 35 %; HPLC (AUC) purity at 280 nm = 98.1%; 1H NMR
(DMSO-Ds) 8 ppm: 10.82 (s, 1H), 8.07 (d, J: 7.8 Hz, 1H), 7.52 (d, J: 7.8 Hz,
1H), 7.32 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.05 (t, J: 7.4 Hz, 1H), 6.97 (t, J = 7.4
Hz, 1H), 4.39-4.45 (m, 1H), 3.60 (s, 3H), 3.28-3.31 (m, 1H), 3.14-3.19 (m, 1H),
2.95-3.01 (m, 1H), 2.15-2.19 (m, 2H), 1.73-1.82 (m, 1H), 1.54-1.63 (m, 1H); MS-
ESl (m/z): 348 [M+1]“.
-71..
ViA510127NZI’R
303134046
Example 32
Preparation of a mixture of D-Glu(D-Trp-OCH2CF3)-OH and D-Glu(L-Trp-
OCHgCF3)-OH, Apo860
(R) O:HNlF3 (R)
H2N (R) “W (8)
00A ACFS—- 7: 3 mixture
A. Preparation of Cbz-D-Glu(D-Trp-OH)-OBn.
To an ice—water cooled solution of GIu—OBZI (20.0 g, 53.9 mmol) in
DMF (100 mL) was added N-hydroxysuccinimide (6.82 g, 59.2 mmol), followed
by EDC|.HC| (11.4 g, 59.2 mmol), and the mixture was stirred at RT for
overnight. The e was then cooled in an ice—water bath, and p-OH
(12.1 g, 59.2 mmol) was added, followed by DIPEA (10 mL). The mixture was
stirred for ght. The reaction mixture was quenched with a 0.5N HCI,
solution and then extracted with EtOAc. The EtOAc layer was washed with a
% citric acid on and brine, dried over anhydrous Na2804, filtered and
trated to dryness. The residue was triturated with Etgo, and the solid was
collected via filtration to afford Cbz-D-Glu(D-Trp-OH)—OBn (26.1 9). Yield = 87%;
MS—ESI (m/z): 558 [Mi-11+.
B. Preparation of a mixture of D—GIu(D-Trp-OCH20F3)-OH and D-GIu(L—Trp-
OCHZCF3)—OH, Ap0860
To an ice-water cooled solution of Cbz-D-Glu(D~Trp—OH)—OBZI (3.5 g, 6.3
mmol) in DMF (50 mL) was added N-hydroxysuccinimide (0.8 g, 6.9 mmol),
followed by EDCl.HCl (1.32 g, 6.9 mmol), and the mixture was stirred at RT for
overnight. The mixture was then cooled in an ice-water bath and DIPEA (1.23
mL, 6.9 mmol) was added, followed by 2.2.2-trifluoroethanol (1.8 mL, 25.1
mmol).The e was stirred at RT for 5 h. The reaction mixture was then
partitioned between water and EtOAc. The EtOAc layer was collected and
washed with brine, dried over anhydrous Na2804, filtered and concentrated to
VIA510127NZPR
dryness. The residue was triturated with hexanes. The hexanes layer was
discarded. The crude residue was mixed with 0.95 g of wet 10% Pd-C in EtOH
(100 mL), and was hydrogenated under a blanket of hydrogen at 45 psi hydrogen
pressure in a Parr apparatus for 3 h. The mixture was filtered, and the filtrate was
concentrated to dryness in vacuo. The e was triturated with a mixture of
acetone, EtOAc and hexanes. The solid was collected via filtration, and was
further ed by flash column chromatography on silica gel using a solvent
mixture of IPA/H20 (85/15 ratio, v/v) as eluent to afford D-G|u(D—Trp—OCH2CF3)-
OH (1.16 9). Yield = 44%; 1H NMR De +D20, 400MHz): 8 (ppm) 7.47 (d,
J=8.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.17 (s, 1H), 7.04 - 7.12 (m, 1H), 6.96 -
7.04 (m, 1H), 4.57 - 4.75 (m, 2H), 4.45 - 4.57 (m, 1H), 3.29 (t, J=6.1 Hz, 0.7H),
3.23 (t, J=6.1 Hz, 0.3H), 3.18 (d, J=6.1 Hz, 0.3H), 3.15 (d, J=6.1 Hz, 0.7H), 3.01 -
3.12 (m, 1H), 2.14 - 2.39 (m, 2H), 1.68 - 1.97 (m, 2H). MS-ESI (m/z): 416 [M+1]+.
The 1H NMR data indicates the presence of about 30% of D-Giu(L-Trp-
OCH20F3)-OH
Example 33
Preparation of H-D-Glu(D~Trp-OCH2CF3)-OCH2CF3 hydrochloride salt,
Ap0868.HCl
F3CVO o Hw\
HZN (R)
o o/\Ci=3
A. Preparation of Boc-D-Giu (D-Trp-OCH2CF3)-OCH20F3
To an ice—water cooled solution of Boc-D-Glu(D-Trp-OH)-OH (6.0 g, 13.8
mmol) in DMF (50 mL) was sively added N-hydroxysuccinimide (3.5 g,
.5 mmol), EDC|.HCl (5.8 g, 30.5 mmol), 2.2.2-trifluoroethanol (6 mL, 83.1
mmol) and DIPEA (5.3 mL, 30.5 mmol). The resulting solution was then stirred at
RT for overnight. The on mixture was quenched with water, and then
extracted with EtOAc. The EtOAc layer was washed with a 10% citric acid
solution and brine, and then dried over anhydrous Na2804, filtered and
-73..
VIA510127N21’R
3031 340-16
concentrated to dryness under reduced pressure. The residue was purified by
flash column chromatography on silica gel using a mixture of EtOAc and
Hexanes (1/1 ratio, v/v) as eluent to afford Boc-D-Glu (D-Trp-OCHZCF3)-
OCHZCFa (6.1 9). Yield =74%); MS—ESI (m/z): 598 .
B. ation of H-D-Glu (D-Trp-OCH20F3)-OCH20F3 hydrochloride salt,
Ap0868.HCl
To an ice-water cooled solution of Boc—D~Glu (D-Trp-OCH20F3)-OCH2CF3
(6.0 g, 10.0 mmol) in EtOAc was bubbled HCI gas for 35 min. The reaction
mixture was concentrated to dryness to give a crude product (5.4 g). A portion of
the crude material (1.0 g) was purified by flash column chromatography on silica
gel using a mixture of EtOAc and MeCN (gradient from 10/0 to 1/1 ratio, v/v) as
eluent to afford H-D-Glu (D-Trp-OCHZCF3)-OCH2CF3 hydrochtoride salt (625 mg).
1H NMR (DMSO-De, 400MHz): 6 (ppm) 10.95 (s, 1H), 8.66»8.72 (m, 4H), 7.48 (d,
J=7.8 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.19 (s, 1H), 7.06 - 7.09 (m, 1H), 6.98 -
7.01 (m, 1H), 4.86 - 4.92 (m, 2H), 4.69 - 4.77 (m, 2H), 4.52-4.56 (m, 1H), 4.18-
4.20 (m, 1H), 3.07-3.20 (m, 2H), 2.30-2.41 (m, 2H), 1.97 —2.01 (m, 2H); MS-ESI
(m/z): 498 .
Example 34
Preparation of (R)-2,3-dihydro-1H-indenyl 5-((S)(1H-indolyl)
(isopentyloxy)oxopropan-Z-ylamino)-2—aminooxopentanoate
hydrochloride or u(L—Trp-O-isoamyl)-O- 2,3-dihydro-1H—inden
yl.HC| or (Ap0928.HCl)
O 0 \
HZN (S)
HCI 0
o O/Vk
A. Preparation of Boc-L-Trp-O-isoamyl
VIASiUl27NZl’R
303134046
Boc—L-Trp—O-isoamyi was prepared from the reaction of Boc—L-Trp—OH (10.0 g,
32.8 mmol), 3—methyI—1-butanol (7.1 mL, 65.7 mmol) with HOBt (5.3 g, 39.4
mmol), DlPEA (7.4 mL, 42.7 mmol) and EDCI (8.2 g, 42.7 mmol) in DMF (100
mL). The resulting mixture was stirred at room ature for overnight. The
reaction mixture was poured into a beaker of cold water (100 mL) with stirring,
and the resulting suspension was stirred at 5°C (ice bath) for 20 min. Suction
filtration afforded Boc-L-Trp-O-isoamyl as a white solid, which was air—dried for
ght (10.8 9). Yield = 88 %;1H NMR (DMSO-de, 400 MHz) 5 ppm: 10.86 (br.
s., 1H), 7.48 (d, J= 8.1 Hz, 1H), 7.34 (d, J: 8.1 Hz, 1H), 7.22 (d, J: 7.1 Hz,1H),
7.16 (s, 1H), 7.07 (t, J = 7.1 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 4.12 - 4.24 (m, 1H),
3.93 - 4.09 (m, 2H), 3.05 - 3.15 (m, 1H), 2.95 - 3.05 (m, 1H), 1.48 - 1.59 (m, 1H),
1.31 — 1.41 (m, 11H), 0.82 (t, J= 6.6 Hz, 6H); MS-ESI (m/z) 375 [M+1]+.
B. ation of p-O-isoamyl hloride
HCl gas was bubbled into a suspension of Boc-L-Trp-O-isoamyl (10.52 g, 28.1
mmol) in 150 ml EtOAc for 1.5 h. The suspension was stirred at 5 °C (ice-bath)
for 20 min. The solid product was collected by suction filtration, and washed with
EtOAc (3 x 15 mL) to afford H-L-Trp-O-isoamyl hydrochloride as white solid (7.83
g). Yield: 90 %;1H NMR (DMSO-de, 400MHz) 8 ppm: 11.13 (br. s., 1 H), 8.66 (br.
s., 2 H), 7.52 (d. J= 8.1 Hz, 1 H), 7.38 (d, J: 8.1 Hz, 1 H), 7.25 (s, 1 H), 7.09 (t,
J = 7.6 Hz,1_ H), 7.01 (t, J = 7.6 Hz, 1 H), 4.19 (t, J = 6.6 Hz, 1 H), 3.94 - 4.08 (m,
2 H), 3.33 (d, J: 5.1 Hz, 1 H), 3.20 - 3.29 (m, 1 H), 1.36 - 1.48 (m, 1 H), 1.23 -
1.33 (m, 2 H), 0.78 (d, J: 5.1 Hz, 6 H); MS-ESI (m/z) 275 [M+1]+ (free base).
C. Preparation of Glu(L-Trp-O—isoamyl)-O-bzl
Boc~D-Glu(L-Trp-O—isoamyl)—O—bzl was prepared from the reaction of H-L-Trp—O-
isoamyl hydrochloride (7.65 g, 24.6 mmol), Boc-D-GIu-O-bzl (8.3 g, 24.6 mmol),
EDCI (5.67 g 29.5 mmoL), HOBt (3.5 g, 25.8 mmol) and DiPEA (8.6 mL, 49.2
mmol) in DMF (100 mL). The resulting mixture was stirred at room temperature
for overnight. The reaction mixture was poured into a beaker of cold water (250
mL) with stirring. The mixture was extracted with ethyl acetate (100 mL x 3). The
VIA510127NZPR
303134046
combined organic layers was successively washed with a 10% citric acid solution
(30 mL), a saturated NaHC03 (50 mL) and brine (50 mL), and was then dried
over M9804. After solvent was removed in vacuo, Boc-D-Glu(L—Trp-O—isoamyl)—
O-bzl was obtained as light yellowish oil (13.5 g). Yieid = 93 %; 1H NMR (DMSO-
d6 ,400MHz) 8 ppm: 10.87 (br. s., 1 H), 8.30 (d, J: 7.1 Hz, 1 H), 7.48 (d, J: 8.1
Hz, 1 H), 7.27 - 7.40 (m, 7 H), 7.15 (br. s., 1 H), 7.07 (t, J: 7.6 Hz, 1 H), 6.91 -
7.03 (m, 1 H), 5.04 - 5.19 (m, 2 H), 4.48 (d, J: 6.1 Hz, 1 H), 3.97 (t, J = 6.1 Hz, 3
H), 3.12 (dd, J: 14.1, 6.1 Hz, 1 H), 3.02 (dd, J: 14.1, 8.1 Hz, 1 H), 2.14-2.29
(m, 2 H), 1.93 (d, J: 8.1 Hz, 1 H), 1.67 — 1.83 (m, 1 H), 1.41 - 1.55 (m, 2 H),
1.28-1.38 (m, 10 H), 0.80 (t, J = 6.1 Hz, 6 H); MS-ESI (m/z) 594 [M+1]+.
D Preparation of Boc—D—Glu(L—Trp-O-isoamyl)-OH
A mixture of Glu(L-Trp-O-isoamy|)-O-benzyl (12.35 g, 20.8 mmol) and 1.5
g of 10% Pd on activated carbon (wet) in ethanol (250 ml) was shaken in a Parr
tus under a hydrogen atmosphere at a pressure of 45 psi at room
temperature for 2 h. The Pd catalyst was filtered through CeliteTM and the filtrate
was evaporated under reduced pressure to give a pink oil, which was dried under
vacuum to afford Boc-D—Glu(L-Trp-O-isoamyl)nOH (9.1 g) as a pink foamy solid.
Yield= 87%; 1H NMR ds ,400MHz) 5 ppm: 10.87 (s, 1 H), 8.30 (d, J= 7.1
Hz, 1 H), 7.48 (d, J: 7.1 Hz, 1 H), 7.34 (d, J: 8.1 Hz, 1 H), 7.15 (s, 1 H), 7.03 -
7.12 (m, 2 H), 6.93 ~ 7.03 (m, 1 H), 4.41 ~ 4.54 (m, 1 H), 3.98 (t, J = 6.6 Hz, 2 H),
3.82 - 3.92 (m, 1 H), 3.39 — 3.50 (m, 2 H), 3.07 - 3.18 (m, 1 H), 2.97 - 3.07 (m, 1
H), 2.18 (t, J = 7.6 Hz, 2 H), 1.90 (d, J: 8.1 Hz, 1 H), 1.70 (dd, J = 13.6, 7.6 Hz,
1 H), 1.47 (dq, J= 13.3, 6.7 Hz, 1 H), 1.26 -1.41 (m, 9 H), 1.07 (t, J= 6.6 Hz, 1
H), 0.75 - 0.84 (m, 6 H); MS-ESl (m/z) 504 .
E. Preparation of Boc-D-Glu(L-Trp-O-isoamyi)-O-2,3-dihydro—1H-inden-S-yl
-lndanol (0.43 g, 3.23 mmoi) was added to a solution of Boc-D-GIu(L-Trp-O—
isoamyl)—OH (1.25 g, 2.48 mmol) in DMF (35 mL) followed by EDCl (0.62 g , 3.23
mmol), HOBt (0.40 g, 2.98 mmol) and DIPEA (0.62 mL, 3.48 mmol). The
ing mixture was stirred at room temperature for overnight. The reaction
~76—
VIA510127NZPR
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mixture was poured into a beaker of cold water (100 mL) with ng. The
mixture was extracted with ethyl acetate (50 mL x 3). The combined organic
layers was successively washed with a 10% citric acid solution (20 mL), a
saturated NaHCOs solution (25 mL) and brine (40 mL). The organic fraction was
dried over MgSO4. After t was removed in vacuo, the crude product was
obtained as light ish oil. The oil was further purification by flash
chromatography on silica gel using a solvent mixture of EtOAc and Hexanes (1/1
ratio, v/v) as eluent to give Boc—D-Glu(L-Trp-O-isoamyl)-O~2,3—dihydro-1H-inden-
~yl as a light yellowish foamy solid (1.36 9). Yield: 91 %; 1H NMR (DMSO-de,
400MHz) 5 ppm: 10.87 (s, 1H), 8.37 (d, J: 7.1 Hz, 1H), 7.48 (d, J: 8.1 Hz, 2H),
7.34 (d, J: 8.1 Hz, 1H), 7.21 - 7.27 (m, J: 8.1 Hz, 1H), 7.15 (s, 1H), 7.07 (t, J=
7.1 Hz, 1H), 6.98 (t, J= 7.1 Hz, 1H), 6.92 (s, 1H), 6.76 - 6.84 (m, J: 8.1 Hz, 1H),
4.43 - 4.55 (m, 1H), 4.07 - 4.19 (m, 1H), 3.98 (t, J = 6.6 Hz, 2H), 3.13 (dd, J =
6.1, 14.2 Hz, 1H), 3.03 (dd, J = 8.1, 14.2 Hz, 1H), 2.80 - 2.90 (m, 4H), 2.24 — 2.34
(m, 2H), 1.98 - 2.10 (m, 3H), 1.82 - 1.95 (m, 1H), 1.46 (dd, J: 6.6, 13.6 Hz, 1H),
1.41 (s, 8H), 1.27 - 1.36 (m, 2H), 0.80 (t, J = 6.6 Hz, 6H); MS-ESI (m/z) 620
{M+1]+.
F. Preparation of H-D-GIu(L-Trp-O-isoamyl)-O-2,3-dihydro-1H~indenyl
hydrochloride 8.HCI)
HCI gas was bubbled into a solution of Boc-D-GIu(L-Trp-O~isoamyI)-O-2,3—
dihydro-1H—indenyl (0.72 g, 1.16 mmoL) in 35 mL dichloromethane for 3.5 h.
The reaction mixture was evaporated to dryness and the crude product was
further purified by flash chromatography on silica gel using a solvent mixture of
isopropyl alcohol and dichloromethane (1/1 ratio, v/v) as eluant to give the sticky
foamy solid. The foamy solid was then dissolved in a 2M HCl EtQO solution, and
d at room temperature for 15 min. After evaporation of volatiles in vacuo of
H—D-Glu(L-Trp-O-isoamyl)—O-2,3—dihydro-1H—inden—5-yl hydrochloride
(Ap0928.HCI) was obtained as a brown foamy solid (0.34 9). Yield: 52 %; 1H
NMR ds, 400 MHz,) 5 ppm: 10.93 (s, 1H), 8.79 (br. s., 2H), 8.62 (d, J =
7.1 Hz,1H),7.48(d,J= 8.1 Hz, 1H), 7.34 (d, J: 8.1 Hz, 1H), 7.28 (d, J = 8.1 Hz,
VIA5 10127NZI’R
30313-1046
1H), 7.17 (s, 1H), 7.02 - 7.10 (m, 2H), 6.92 — 7.01 (m, 2H), 4.50 (q, J = 7.1 Hz,
1H), 4.27 (br. s., 1H), 3.97 (t, J = 6.6 Hz, 2H), 3.10 - 3.18 (m, 1H), 3.01 - 3.10 (m,
1H), 2.87 (q, J = 7.1 Hz, 4H), 2.45 - 2.50 (m, 1H), 2.33 - 2.45 (m, 1H), 2.10 - 2.20
(m, 2H), 1.99 - 2.10 (m, 2H), 1.46 (dt, J: 6.6, 13.1 Hz, 1H), 1.26 - 1.36 (m, 2H),
0.80 (t, J = 6.6 Hz, 6H); MS—ESI (m/z) 520[M+1]+ (free base).
e 35
A. Biotransformation studies of a compound of formula I in human
hepatocytes
General Procedure:
LiverPoo|® cryopreserved human hepatocytes (pooled from 10 male
donors) was obtained from Ceisis in Vitro Technologies. The hepatocytes were
stored in liquid nitrogen until used. Just before the assay, the hepatocytes were
quickly thawed at 37°C and centrifuged at 100 x g for 10 min. The media was
removed and cells were re-suspended in PBS at a density of 4 x 106 celis/mL.
The compound of formula I (100 pM) was incubated with 0.1 x 105 hepatocytes in
50 pl. . After 10, 20, 60, 120 and 240 min of incubation, the reaction was
quenched by adding an equal volume of 5 % (w/v) TCA. The “time 0” sample was
generated by adding TCA before the test compound. After brief vortexing and 10-
min incubation on ice, sampies were centrifuged 0 x g, 10 min) and the
supernatants were analyzed by HPLC with UV detection.
HPLC analysis of pro-drugs in SGF, SIF, plasma and hepatocytes
HPLC analysis was done using an Agiient 1100 series HPLC system
consisting of a programmable channel pump, auto—injector, vacuum
degasser and HP detector controlled by Agilent HPLCZ18 Chem Station
Rev.A.09.03 re for data acquisition and analysis. A gradient method was
used for the ination of all pro-drugs and their hydrolysis products including
Ap0805 on an Agilent Eclipse XDB, C18 column (part # 963967-902, 150 X 4.6
mm, 3.5 pm) with the following chromatographic conditions:
Temperature: Ambient
-78—
VIAS 10127NZPR
303134046
Mobile phase: A = Aqueous phase: 10 mM Tris-HCI, 2
mM EDTA, pH 7.4 B = Organic phase:
Acetonitrile
Gradient method: Time: 0 min 5%B, 25 min 50%B, 35 min
80%B, 45 min 5%B. 50 min 5%B.
Mobile phase flow rate: 1.0 mL/min
injection volume: 50 pL
Data acquisition time: 30 min
Detection wavelength: 280 nm; 4 nm bandwidth, ref. 360 nm.
4 nm dth
The tograms at A = 280 nm were analyzed. Peak area (mAU*s) was used
for quantitation of pro-drugs, intermediates and epressin (Apo805).
B. Stability in human blood
Blood was collected from healthy volunteers, both male and female, in
Becton Dickinson ACD vacutainerTM ning ACD solution A (22.0 g/L
trisodium citrate, 8.0 g/L citric acid, 24.5 g/L dextrose). Blood from the
vacutainers was pooled in a 50 mi. Falcon TM tube, kept on ice, and used in the
assay within 2 hours of collection. To determine rate of hydrolysis, each prodrug
(100 uM) was incubated in pooled human blood at 37°C. immediately after test
compound addition and after 0.5, 1, 2, 4, 6 and 24 hour incubation, blood aliquots
(500 pL) were removed and fuged at 1500 x g, for 10 min at 4°C. An aliquot
of plasma (150 uL) was transferred to an eppendorf tube and the plasma ns
were precipitated by adding an equal volume of 5 % TCA (w/v). After 10-min
incubation on ice, samples were centrifuged (16,000 x g, 10 min) and the
supernatants were analyzed by HPLC.
The biotransformation data of a compound of formula l in human blood
and human hepatocytes are shown in Tables 1 to 3 below:
~79_
VIA510127N21‘R
303134046
Table 1: In vitro bioconversion of H-D-Glu(Trp-O-T)-0H to Ap0805 in human
hepatocytes and blood.
Compound Stereochemistry T Half-life for version to Ap0805*
ID (*0
Human Human blood
hepatocytes
Apo835 _ethyl >2.o (11% in 2 h) >24
Ap0839 m CHZO-CO—tBu 0.4
Apo843 CH(Me)-O~CO—O- 0.2 Pr‘ mo:
cyclohexyl
N \1
O O) V.“B—s
—-lil- A .p.
_—lil-N) - (D .0" x:
>6.0 (19% in 6 h) >24
Apo888 CH(Me)—O~CO-O- 1.1 _x 0'1
CH20H3
Ap0891 _ -OmCO-O—I'~ _\ 00
_CH2—CO-N(CH3)2 >60 (15% in 6 h) >24
Apo895 CH2-O-CO-C(Me)2— 0.7 [‘3 .—3.
CHZCHZCHa
Selected compounds of formula I with the formula H-D-GIu(D-Trp-OR2)-
OR1 show better he in its biotransformation in human hepatocytes and human
blood to thymodepressin (Ap0805, H—D~G|u(D-Trp—OH)—OH than the monoethyl
ester Ap0835 H-D-Glu(D-Trp-OEt)—OH, while the e amide Ap0893 is not
readily converted to thymodepressin in human hepatocytes.
VIA510127NZPR
303134046
Table 2. In vitro bioconversion of H—Glu(Trp-OH)-O-G to Apo805 in human
hepatocytes and blood.
ife for bioconversion to Ap0805* (h)
Human Human blood
hepatocytes
>2. 0 (21%In 2 h)
>2. 0 (12%In 2 h)
>3. 0 (25%In 3 h)
*For s for which bioconversion halflife was not measured, valuesIn
parentheses indicate t conversion to Apo805 within indicated time.
When compared to the monoalkyl ester derivatives H-D~G|u(D-Trp-OH)—O-
R3 such as Ap0829, Ap0836, Ap0841 and Ap0846, the fluoroalkyl derivatives H-
D-GIu(D-Trp-OH)-O~(CH2)nCF3 show a faster rate of biotransformation to Ap0805
in human hepatocytes.
Table 3. In vitro bioconversion of H-Glu(Trp-O-T)-O-G to Ap0805 in human
hepatocytes and blood.
Compound Stereochemistry Bioconversion to Ap0805
ID after 4 h
Human Human
4 CH(Me)-o-co
-cyclohexyl
—81—
VIA510127NZPR
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Example 36
Pharmacokinetic studies of a compound of formula I in rats
General Procedure for Animal dosing
Groups of five male Sprague-Dawley rats weighing 250 to 300 g were
utilized per dosing goup. One day prior to dosing, venous and al catheters
(made of 20 cm long polyurethane coiled tubing, and filled with 100 units/mL
heparinized saline) were implanted into the jugular vein and carotid artery of each
rat. Rats were fasted overnight prior to oral dosing and fed approximately 2 hours
post-dosing. All dosing and blood ng was performed on fully conscious rats.
Tested nds were administered either by oral gavage as solutions in water,
or by intravenous injection (Apo805K‘l only) as solution in 0.9% sodium chloride,
final pH 7.0, at doses equivalent to 5 mg/kg (per Ap0805 content). Blood (0.3 mL)
was sampled from each animal from the carotid artery for up to 30 hours post-
dosing, each sampling followed by an equivalent blood replacement. The
blood sample was immediately centrifuged (4300 x g for 5 minutes at 4°C), and
frozen at -80°C until LC/MS/MS analysis.
General Procedure for LC-MS/MS analysis of plasma drug concentration
Methanol (200 pL) was added to plasma samples (50 pL) to precipitate
plasma proteins. After brief vortexing and centrifugation, the supernatant (200 uL)
was removed and dried at 40°C under a stream if nitrogen. The sample was
reconstituted in water (300 pi.) and 25 pL was ed for analysis.
A Sciex APi 365 LC/MS/MS spectrophotometer equipped with Ionics EP10+
and HSID, was used. A chiral column (Supelco-Astec CHIROBIOTICTM TAG), 100
x 2.1 mm, 5 pm was used at ambient temperature. The mobile phase consisted of
0.1 % formic acid in water (A) and 0.1% formic acid in itrile (B) in a ratio of
88:12(A:B; v/v) and the flow rate was 0.6 mL/min. Positive ion electrospray
tion (ESI+) in MRM mode was used for analysis. Samples were analysed for
the concentration of Ap0805 (thymodepressin).
-82..
V1A510l27NZl’R
303134046
PK analysis
Non-compartmental analysis was med using WinNonIin 5.2
software, on individual animal data. ilability was calculated as a ratio of
AUCINF_D after oral dosing of test compound to AUC[NF_D after N dosing of
Ap0805K1.
Oral bioavailability of Apo839 and Ap0843 in rats
Absolute oral bioavailability of pro-drugs Ap0839 and Ap0843 was
ed to that of Apo805K1 (potassium salt of thymodepressin) in male
e-Dawley rats. Adult animals, five per group, were dosed orally with 5
mg/kg Ap0805K1. Ap0839, or Ap0843 and intravenously with 5 mg/kg
Ap0805K1. Fig 1 shows the plasma concentration of Ap0805 after oral dosing of
Ap0839 or Ap0805K1. Fig 2 shows the plasma concentration of Ap0805 after oral
dosing of Ap0843 or Ap0805K1. Ap0839 and Ap0843 show oral bioavailability
and are transformed to thymodepressin (Ap0805) in rats.
Although various ments of the invention are sed herein,
many adaptations and modifications may be made within the scope of the
invention in accordance with the common general knowledge of those skilled in
this art. Such modifications include the substitution of known equivalents for any
aspect of the invention in order to achieve the same result in ntially the
same way. c ranges are inclusive of the numbers defining the range.
Furthermore, numeric ranges are ed so that the range of values is recited
in addition to the individual values within the recited range being specifically
recited in the absence of the range. The word "comprising" is used herein as an
open-ended term, substantially equivalent to the phrase "including, but not limited
to", and the word "comprises" has a corresponding meaning. As used herein, the
singular forms "a", "an" and "the" include plural references unless the context
clearly dictates otherwise. Thus, for example, reference to "a thing" includes
more than one such thing. Citation of references herein is not an admission that
-83—
V1A510127NZPR
303134046
such references are prior art to the present invention. Furthermore, material
appearing in the background section of the specification is not an admission that
such material is prior art to the invention. Any priority document(s) are
incorporated herein by reference as if each individual priority document were
ically and individually indicated to be incorporated by nce herein and
as though fully set forth . The invention includes all embodiments and
variations substantially as hereinbefore described and with reference to the
examples and drawings.
Vl/\510127N7.1‘R
303134046
Claims (52)
1. A compound of Formula I: G O HN ‘0 Q (R) O O T HZN (i) or a ceutically acceptable salt thereof, wherein G is ed from the group consisting of: H, 2-morphoiinoethyl, (CH2)nCF3, C1-C8 alkyl, benzyl and A5 - A10 aryi; T is selected from the group consisting of: H, C1-C8 alkyl, 2-morph0linoethyl, (CH2)nCF3, CHZCONR4R5, CHZCHQNRA'RE’, 03-06 cycloalkyl, benzyl, A5 — A10 aryl, R1 0 and R1 0 ; n is 1, 2, 3or4; R1 is H or 01-08 alkyl; R2 is C1-C8 alkyl, Cg—CB cycloaikyl, or phenyl; R3 is 01-08 alkyl, 03-06 cycloalkyl, or phenyl; and R4 and R5 are either separate groups or together form a singie group with the N to which they are bonded; when R4 and R5 are te groups, R4 and R5 are independentiy selected from the group consisting of: 01-06 alkyl; when R4 and R5 together with the N to which they are bonded form the single group, the single group is selected from the group consisting of: morphoiinyl, N-(C1-C4 alkyl)~piperazinyl and piperidinyl; provided that ifT is H, then G is 2—morpholinoethyl, (CH2)nCF3, 01-08 alkyl or benzyl; if T is R4R5, CHZCHZNR4R5, or 03-06 cycloaikyl, then G is H; and if T is 01-08 alkyl, then G is 2-morpholinoethyl, (CH2)nCF3, or A5 — A10 aryl. ~85- VIASQOIZ7NZPR 303134046
2. The compound of ciaim 1 wherein if G is H, then T is selected from the group consisting of: 2-morpholinoethyl, (CH2)nCF3, CHZCONR4R5, $01112 WOYO‘RS CHgCHgNR4R5, 03-06 cycloalkyl, R1
3. The compound of claim 1 wherein if G is H, then T is selected from the group consisting of: holinoethyl, (CH2)nCF3, CHZCHZNR4R5, 03-06 flog/R2 #OYQRS cycloalkyl, R1 and R1 0
4. The compound of claim 1 wherein if G is H, then T is selected from the group consisting of: 2-morpholinoethyl, (CH2)nCF3, CH20H2NR4R5, WormR1 and R1 0
5. The compound of any one of claims 1 to 4 wherein a chiral carbon of a phan moiety is in the iguration.
6. The compound of any one of claims 1 to 4 wherein a chiral carbon of a tryptophan moiety is in the L~configuration.
7. The compound of claim 1 wherein a chiral carbon of a tryptophan moiety is in the guration or L-configuration and wherein G is H and T is A5 to A10 aryl. Fir ro R2
8. The compound of claim 5 or 6 wherein T is R1 o _86- V1A510127NZI’R 303134046 eR11;00
9. The compound of claim 5 or 6 wherein T is
10. The compound of claim 5 or 6 n T is (CH2)nCF3.
11. The compound of claim 5 or 6 wherein T is 2-morpholinoethyl.
12. The compound of claim 5 or 6 wherein G is 2-morpholinoethyl, (CH2)nCF3, Perch/R?- or 01-08 alkyl; and T is 2~morpholinoethyl, (CH2)nCF3, A5 to A10 aryl, R1 O Wolf’s or R1 0
13. The compound of claim 5 or 6 wherein T is C1-Ca alkyl.
14. The compound of claim 13 wherein G is A5 to A10 aryl.
15. The compound of claim 14 wherein T is isoamyl, G is indanyl.
16. The nd of claim 5 or 6 wherein T is H.
17. The compound of claim 5 or 6 wherein G is H.
18. The nd of claim 5 wherein T is H and G is ethyl.
19. The compound of claim 5 wherein T is H and G is benzyl.
20. The compound of claim 5 wherein T is H and G is methyl.
21. The compound of claim 5 n T is H and G is isoamyi. VIA510127NZPR 303134046
22. The compound of claim 5 wherein T is H and G is isopropyl.
23. The compound of claim 5 wherein T is H, G is (CH2)nCF3 and n is 1.
24. The compound of claim 5 wherein T is H, G is (CH2)nCF3 and n is 2.
25. The compound of claim 5 wherein T is H and G is 2-morpholinoethyl. FTQTQW
26. The nd of claim 5 wherein T is R1 O R1 is methyl, R3 is cyclohexyl and G is H.
27. The compound of claim 5 wherein T is 2-morpholinoethyl and G is H.
28. The compound of any one of claims 1 to 3 wherein a chiral carbon of a tryptophan moiety is in the D—configuration and n T is cyclohexyl and G is
29. The compound of claim 5 wherein T is (CH2),,CF3, n is 2 and G is H. FTQTQW
30. The compound of claim 5 wherein T is R1 0 R1 is methyl, R3 is ethyl and G is H.
31. The compound of claim 5 wherein T is R‘ 0 R1 is H, R2 , is pent-Z-yl and G is H. V1A510127NZPR 303134046 crowd‘s
32. The compound of claim 5 wherein T is R1 O R1 is methyl, R3 is isopropyl and G is H.
33. The compound of claim 1 or 2 wherein a chiral carbon of a tryptophan moiety is in the D-configuration and wherein T is CH200NR4R5, R4 is CH3, R5 is CH3 and G is H.
34. The compound of claim 1 or 2 n a chiral carbon of a tryptophan moiety is in the L-configuration and n T is CHZCON R4R5, R4 is CH3, R5 is CH3 and G is H. WOW/R2
35. The compound of claim 5 wherein T is R1 0 R1 , is H, R2 is 2-CHZCHZCH3 and G is H.
36. The compound of claim 5 wherein T is (CH2)nCF3, n is 1 and G is H.
37. The compound of claim 6 wherein T is (CH2)nCF3, n is 1 and G is H.
38. The nd of claim 1 wherein a chiral carbon of a tryptophan moiety is in the D—configuration and wherein T is indanyl and G is H.
39. The compound of claim 1 wherein a chiral carbon of a tryptophan moiety is in the D-configuration and wherein T is 2-methoxyphenyl and G is H. fi/OYRZ
40. The compound of claim 5 wherein T is R1 0 R1 is H, R2 , is t-butyl and G is H. VIA510127NZPR 303134046 VJ‘YOYRZ
41. The compound of claim 5 wherein T is R1 0 R1 is H, R2 is phenyl and G is H.
42. The compound of claim 5 wherein T is (CH2)nCF3, n is 2, G is (CH2)nCF3 and n is 2.
43. The compound of claim 5 wherein T is 2-morpholinoethyl and G is ethyl. dorms
44. The compound of claim 5 n T is R1 O R1 is methyl, R3 is ethyl and G is ethyl.
45. The compound of claim 5 wherein T is 2-morpholinoethyl and G is 2— morpholinoethyi.
46. The compound of claim 5 n T is benzyl and G is 2-morpholinoethyl.
47. The compound of claim 5 wherein T is indanyl and G is 2-morpholinoethyl.
48. The compound of claim 5 wherein T is holinoethyl, G is (CH2)nCF3 and n is 2.
49. The compound of claim 5 wherein T is 2—morpholinoethyl and G is isoamyl.
50. The compound of claim 5 wherein T is (CH2)nCF3, n is 1, G is (CH2)nCF3 andnisl. VII\5]0127NZPR 303134046
51. A pharmaceutical formulation comprising the compound of any one of claims 1 to 50 and a pharmaceutically acceptable excipient.
52. The pharmaceutical formulation of claim 51 wherein the ation is adapted for inhalation.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161470467P | 2011-03-31 | 2011-03-31 | |
US61/470,467 | 2011-03-31 | ||
PCT/CA2012/000304 WO2012129671A1 (en) | 2011-03-31 | 2012-03-30 | Prodrugs of d-isoglutamyl-[d/l]-tryptophan |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ615880A NZ615880A (en) | 2015-05-29 |
NZ615880B2 true NZ615880B2 (en) | 2015-09-01 |
Family
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