NO803640L - N-adamantan-substituerte tetrapeptidamider. - Google Patents

N-adamantan-substituerte tetrapeptidamider.

Info

Publication number: NO803640L
Authority: NO; Norway
Prior art keywords: methyl; formula; solution; phenylalanyl; amino
Prior art date: 1979-12-03

Application number

NO803640A

Other languages

English (en)

Norwegian (no)

Inventor

Robert Henry Mazur

Original Assignee

Searle & Co

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1979-12-03

Filing date

1980-12-02

Publication date

1981-06-04

1980-12-02 Application filed by Searle & Co filed Critical Searle & Co

1981-06-04 Publication of NO803640L publication Critical patent/NO803640L/no

Links

125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 98
150000001875 compounds Chemical class 0.000 claims description 61
-1 6,6-dimethyltyrosine Chemical compound 0.000 claims description 41
229910052739 hydrogen Inorganic materials 0.000 claims description 30
239000001257 hydrogen Substances 0.000 claims description 30
PAJPWUMXBYXFCZ-UHFFFAOYSA-N 1-aminocyclopropanecarboxylic acid Chemical compound OC(=O)C1(N)CC1 PAJPWUMXBYXFCZ-UHFFFAOYSA-N 0.000 claims description 20
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 20
150000003839 salts Chemical class 0.000 claims description 19
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
125000000217 alkyl group Chemical group 0.000 claims description 15
125000000539 amino acid group Chemical group 0.000 claims description 15
150000002431 hydrogen Chemical group 0.000 claims description 15
125000004432 carbon atom Chemical group C* 0.000 claims description 12
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 12
OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 11
229930182817 methionine Natural products 0.000 claims description 11
125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims description 11
COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 11
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 11
ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 10
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 10
QEFRNWWLZKMPFJ-ZXPFJRLXSA-N L-methionine (R)-S-oxide Chemical group C[S@@](=O)CC[C@H]([NH3+])C([O-])=O QEFRNWWLZKMPFJ-ZXPFJRLXSA-N 0.000 claims description 10
QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Chemical group CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-N 0.000 claims description 10
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 10
235000004279 alanine Nutrition 0.000 claims description 10
LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 claims description 9
229910052736 halogen Chemical group 0.000 claims description 9
150000002367 halogens Chemical group 0.000 claims description 9
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 8
KFHRMMHGGBCRIV-UHFFFAOYSA-N 2-azaniumyl-4-methoxybutanoate Chemical compound COCCC(N)C(O)=O KFHRMMHGGBCRIV-UHFFFAOYSA-N 0.000 claims description 7
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 claims description 6
YWIQQKOKNPPGDO-VURMDHGXSA-N phenyldehydroalanine Chemical compound OC(=O)C(/N)=C/C1=CC=CC=C1 YWIQQKOKNPPGDO-VURMDHGXSA-N 0.000 claims description 6
239000000126 substance Substances 0.000 claims description 5
AXDLCFOOGCNDST-UHFFFAOYSA-N N-Methyltyrosine Chemical compound CNC(C(O)=O)CC1=CC=C(O)C=C1 AXDLCFOOGCNDST-UHFFFAOYSA-N 0.000 claims 8
125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims 7
LSNDLIKCFHLFKO-JTQLQIEISA-N (2s)-2-azaniumyl-3-(4-hydroxy-2,6-dimethylphenyl)propanoate Chemical compound CC1=CC(O)=CC(C)=C1C[C@H](N)C(O)=O LSNDLIKCFHLFKO-JTQLQIEISA-N 0.000 claims 4
GTVVZTAFGPQSPC-UHFFFAOYSA-N 4-nitrophenylalanine Chemical compound OC(=O)C(N)CC1=CC=C([N+]([O-])=O)C=C1 GTVVZTAFGPQSPC-UHFFFAOYSA-N 0.000 claims 4
SCIFESDRCALIIM-UHFFFAOYSA-N N-Me-Phenylalanine Natural products CNC(C(O)=O)CC1=CC=CC=C1 SCIFESDRCALIIM-UHFFFAOYSA-N 0.000 claims 4
SCIFESDRCALIIM-VIFPVBQESA-N N-methyl-L-phenylalanine Chemical compound C[NH2+][C@H](C([O-])=O)CC1=CC=CC=C1 SCIFESDRCALIIM-VIFPVBQESA-N 0.000 claims 4
239000000243 solution Substances 0.000 description 223
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 189
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 127
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 120
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 114
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 91
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 84
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 80
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 79
239000002904 solvent Substances 0.000 description 79
239000011541 reaction mixture Substances 0.000 description 75
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 72
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 60
239000000047 product Substances 0.000 description 51
239000000203 mixture Substances 0.000 description 46
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 40
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
238000000034 method Methods 0.000 description 33
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
229910052943 magnesium sulfate Inorganic materials 0.000 description 30
235000019341 magnesium sulphate Nutrition 0.000 description 30
229960000583 acetic acid Drugs 0.000 description 28
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
238000004587 chromatography analysis Methods 0.000 description 26
229910000343 potassium bisulfate Inorganic materials 0.000 description 26
JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 25
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 25
229910000041 hydrogen chloride Inorganic materials 0.000 description 25
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 24
YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 23
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 23
235000011054 acetic acid Nutrition 0.000 description 22
229910052938 sodium sulfate Inorganic materials 0.000 description 22
235000011152 sodium sulphate Nutrition 0.000 description 22
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
239000010410 layer Substances 0.000 description 16
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 15
238000003756 stirring Methods 0.000 description 15
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
235000015497 potassium bicarbonate Nutrition 0.000 description 14
229910000028 potassium bicarbonate Inorganic materials 0.000 description 14
239000011736 potassium bicarbonate Substances 0.000 description 14
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
239000007787 solid Substances 0.000 description 14
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
239000000499 gel Substances 0.000 description 13
229910052757 nitrogen Inorganic materials 0.000 description 13
239000000377 silicon dioxide Substances 0.000 description 13
235000012239 silicon dioxide Nutrition 0.000 description 13
238000006243 chemical reaction Methods 0.000 description 12
239000002244 precipitate Substances 0.000 description 12
239000000741 silica gel Substances 0.000 description 12
229910002027 silica gel Inorganic materials 0.000 description 12
150000008064 anhydrides Chemical class 0.000 description 11
239000012299 nitrogen atmosphere Substances 0.000 description 11
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
229940024606 amino acid Drugs 0.000 description 8
235000001014 amino acid Nutrition 0.000 description 8
238000001816 cooling Methods 0.000 description 8
239000000706 filtrate Substances 0.000 description 8
239000002808 molecular sieve Substances 0.000 description 8
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 8
WVQZGBLUHZHMHD-ZZKWDYDOSA-N (2s)-2-amino-1-(1-amino-2-adamantyl)-3-phenylpropan-1-one Chemical compound C([C@H](N)C(=O)C1C2(N)CC3CC(C2)CC1C3)C1=CC=CC=C1 WVQZGBLUHZHMHD-ZZKWDYDOSA-N 0.000 description 7
239000003480 eluent Substances 0.000 description 7
150000002148 esters Chemical class 0.000 description 7
229960005190 phenylalanine Drugs 0.000 description 7
229910000027 potassium carbonate Inorganic materials 0.000 description 7
235000011181 potassium carbonates Nutrition 0.000 description 7
239000000843 powder Substances 0.000 description 7
108090000765 processed proteins & peptides Proteins 0.000 description 7
238000003786 synthesis reaction Methods 0.000 description 7
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
239000002253 acid Substances 0.000 description 6
150000001413 amino acids Chemical group 0.000 description 6
239000007864 aqueous solution Substances 0.000 description 6
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
239000000872 buffer Substances 0.000 description 6
239000012362 glacial acetic acid Substances 0.000 description 6
238000012360 testing method Methods 0.000 description 6
CNBUSIJNWNXLQQ-NSHDSACASA-N (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CNBUSIJNWNXLQQ-NSHDSACASA-N 0.000 description 5
DIMZBANHWJFXDX-CVEARBPZSA-N 2-[[(2r)-2-[[(2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-4-methylsulfanylbutanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@@H](NC(=O)OC(C)(C)C)CC1=CC=C(O)C=C1 DIMZBANHWJFXDX-CVEARBPZSA-N 0.000 description 5
ZBPOKYGSYKBAAW-UHFFFAOYSA-N 3-aminoadamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC1(N)CC2(C(O)=O)C3 ZBPOKYGSYKBAAW-UHFFFAOYSA-N 0.000 description 5
ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 5
150000001408 amides Chemical class 0.000 description 5
GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 5
238000001914 filtration Methods 0.000 description 5
238000002844 melting Methods 0.000 description 5
230000008018 melting Effects 0.000 description 5
KSXLWBWCVXHRAL-NSHDSACASA-N (2,3,4,5,6-pentachlorophenyl) (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C([C@H](NC(=O)OC(C)(C)C)C(=O)OC=1C(=C(Cl)C(Cl)=C(Cl)C=1Cl)Cl)C1=CC=C(O)C=C1 KSXLWBWCVXHRAL-NSHDSACASA-N 0.000 description 4
QVHJQCGUWFKTSE-RXMQYKEDSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-RXMQYKEDSA-N 0.000 description 4
ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 4
QSKQZXRPUXGSLR-UHFFFAOYSA-N 3-(4-hydroxy-2,6-dimethylphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC1=CC(O)=CC(C)=C1CC(NC(=O)OC(C)(C)C)C(O)=O QSKQZXRPUXGSLR-UHFFFAOYSA-N 0.000 description 4
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
239000003810 Jones reagent Substances 0.000 description 4
URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical class C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 4
230000027455 binding Effects 0.000 description 4
230000015572 biosynthetic process Effects 0.000 description 4
210000004556 brain Anatomy 0.000 description 4
239000002026 chloroform extract Substances 0.000 description 4
239000012043 crude product Substances 0.000 description 4
239000000284 extract Substances 0.000 description 4
239000012458 free base Substances 0.000 description 4
NDSPMPPVZWXGJK-WEGQEKBOSA-N methyl 3-amino-2-[(2s)-2-amino-3-phenylpropanoyl]adamantane-1-carboxylate;hydrochloride Chemical compound Cl.C([C@H](N)C(=O)C1C2(N)CC3CC(C2)CC1(C3)C(=O)OC)C1=CC=CC=C1 NDSPMPPVZWXGJK-WEGQEKBOSA-N 0.000 description 4
GMXYKQPNBFHSEJ-UHFFFAOYSA-N methyl 3-aminoadamantane-1-carboxylate;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2(N)CC1(C(=O)OC)C3 GMXYKQPNBFHSEJ-UHFFFAOYSA-N 0.000 description 4
238000012986 modification Methods 0.000 description 4
230000004048 modification Effects 0.000 description 4
BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
239000012044 organic layer Substances 0.000 description 4
238000000746 purification Methods 0.000 description 4
125000001424 substituent group Chemical group 0.000 description 4
IMUSLIHRIYOHEV-SSDOTTSWSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-methylsulfanylbutanoic acid Chemical compound CSCC[C@H](C(O)=O)NC(=O)OC(C)(C)C IMUSLIHRIYOHEV-SSDOTTSWSA-N 0.000 description 3
RRONHWAVOYADJL-HNNXBMFYSA-N (2s)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 RRONHWAVOYADJL-HNNXBMFYSA-N 0.000 description 3
VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 3
DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 3
108010092674 Enkephalins Proteins 0.000 description 3
239000004471 Glycine Substances 0.000 description 3
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
241000699670 Mus sp. Species 0.000 description 3
102000003840 Opioid Receptors Human genes 0.000 description 3
108090000137 Opioid Receptors Proteins 0.000 description 3
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
239000000556 agonist Substances 0.000 description 3
229910021529 ammonia Inorganic materials 0.000 description 3
230000037396 body weight Effects 0.000 description 3
210000004027 cell Anatomy 0.000 description 3
OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 3
WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
238000004821 distillation Methods 0.000 description 3
239000002024 ethyl acetate extract Substances 0.000 description 3
VLTIIVOWJQDNHG-SSDOTTSWSA-N methyl 2-[[(2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]acetate Chemical compound COC(=O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C VLTIIVOWJQDNHG-SSDOTTSWSA-N 0.000 description 3
YGWYFNTWOXAHRL-LYRYOMJLSA-N methyl 2-amino-2-[(2s)-2-amino-3-phenylpropanoyl]adamantane-1-carboxylate Chemical compound C([C@H](N)C(=O)C1(N)C2CC3CC(C2)CC1(C3)C(=O)OC)C1=CC=CC=C1 YGWYFNTWOXAHRL-LYRYOMJLSA-N 0.000 description 3
KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 3
229960004127 naloxone Drugs 0.000 description 3
229940124641 pain reliever Drugs 0.000 description 3
230000000144 pharmacologic effect Effects 0.000 description 3
238000002360 preparation method Methods 0.000 description 3
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
125000006239 protecting group Chemical group 0.000 description 3
239000011734 sodium Substances 0.000 description 3
229910052708 sodium Inorganic materials 0.000 description 3
229910001415 sodium ion Inorganic materials 0.000 description 3
238000004809 thin layer chromatography Methods 0.000 description 3
238000005406 washing Methods 0.000 description 3
GTRCBFGLFHVUIZ-TZHYSIJRSA-N (2r)-2-[[3-(4-hydroxy-2,6-dimethylphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound CSCC[C@H](C(O)=O)NC(=O)C(NC(=O)OC(C)(C)C)CC1=C(C)C=C(O)C=C1C GTRCBFGLFHVUIZ-TZHYSIJRSA-N 0.000 description 2
AXETXFRELLKMHV-XDMWVRHESA-N (2s)-2-amino-1-[1-(aminomethyl)-2-adamantyl]-3-phenylpropan-1-one Chemical compound C([C@H](N)C(=O)C1C2CC3CC(C2)CC1(C3)CN)C1=CC=CC=C1 AXETXFRELLKMHV-XDMWVRHESA-N 0.000 description 2
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 2
ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
QMPFWODKYNJMMX-UHFFFAOYSA-N 1-aminoadamantane-2-carboxylic acid Chemical compound C1C(C2)CC3CC2C(C(O)=O)C1(N)C3 QMPFWODKYNJMMX-UHFFFAOYSA-N 0.000 description 2
IEJPPSMHUUQABK-UHFFFAOYSA-N 2,4-diphenyl-4h-1,3-oxazol-5-one Chemical class O=C1OC(C=2C=CC=CC=2)=NC1C1=CC=CC=C1 IEJPPSMHUUQABK-UHFFFAOYSA-N 0.000 description 2
FRJZUNWIKSHRKV-PGMHMLKASA-N 2-[[(2r)-2-(methylamino)propanoyl]amino]acetic acid;hydrochloride Chemical compound Cl.CN[C@H](C)C(=O)NCC(O)=O FRJZUNWIKSHRKV-PGMHMLKASA-N 0.000 description 2
QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
KNDWUKJAYRIVHS-UHFFFAOYSA-N 2-aminoadamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC1C(N)C2(C(O)=O)C3 KNDWUKJAYRIVHS-UHFFFAOYSA-N 0.000 description 2
WQMQRNCPZFUGID-UHFFFAOYSA-N 2-azaniumyladamantane-2-carboxylate Chemical compound C1C(C2)CC3CC1C(C(O)=O)(N)C2C3 WQMQRNCPZFUGID-UHFFFAOYSA-N 0.000 description 2
MLQKIAIXKYMHBU-UHFFFAOYSA-N 2-o-tert-butyl 1-o-methyl 1-aminocyclopropane-1,2-dicarboxylate Chemical compound COC(=O)C1(N)CC1C(=O)OC(C)(C)C MLQKIAIXKYMHBU-UHFFFAOYSA-N 0.000 description 2
VZKFGHWXBWYJAH-UHFFFAOYSA-N 2-oxoadamantane-1-carboxamide Chemical compound C1C(C2)CC3CC2C(=O)C1(C(=O)N)C3 VZKFGHWXBWYJAH-UHFFFAOYSA-N 0.000 description 2
CREOOLZKVAFMCX-UHFFFAOYSA-N 2-oxoadamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2C(=O)C1(C(=O)O)C3 CREOOLZKVAFMCX-UHFFFAOYSA-N 0.000 description 2
RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 2
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
125000000296 D-methionine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C([H])([H])C([H])([H])SC([H])([H])[H] 0.000 description 2
108010016626 Dipeptides Proteins 0.000 description 2
ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Chemical group CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
238000005481 NMR spectroscopy Methods 0.000 description 2
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
125000003545 alkoxy group Chemical group 0.000 description 2
125000003277 amino group Chemical group 0.000 description 2
235000011114 ammonium hydroxide Nutrition 0.000 description 2
230000000202 analgesic effect Effects 0.000 description 2
229940040526 anhydrous sodium acetate Drugs 0.000 description 2
239000008346 aqueous phase Substances 0.000 description 2
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
238000009835 boiling Methods 0.000 description 2
UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
239000003054 catalyst Substances 0.000 description 2
239000002038 ethyl acetate fraction Substances 0.000 description 2
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
229940071870 hydroiodic acid Drugs 0.000 description 2
WVKIFIROCHIWAY-UHFFFAOYSA-N hydron;2-(methylamino)acetic acid;chloride Chemical compound Cl.CNCC(O)=O WVKIFIROCHIWAY-UHFFFAOYSA-N 0.000 description 2
239000000543 intermediate Substances 0.000 description 2
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
KDWBXERRHHGBST-UHFFFAOYSA-N methyl 2-aminoadamantane-1-carboxylate;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2C(N)C1(C(=O)OC)C3 KDWBXERRHHGBST-UHFFFAOYSA-N 0.000 description 2
WIWRHVZLCWGIET-OTXHLKQPSA-N methyl 3-amino-2-[(2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]adamantane-1-carboxylate Chemical compound C([C@@H](C(=O)C1C2(N)CC3CC(C2)CC1(C3)C(=O)OC)NC(=O)OC(C)(C)C)C1=CC=CC=C1 WIWRHVZLCWGIET-OTXHLKQPSA-N 0.000 description 2
RQDAQWMPUFEJAA-WEGQEKBOSA-N methyl 3-amino-2-[(2s)-2-amino-3-phenylpropanoyl]adamantane-1-carboxylate;hydrobromide Chemical compound Br.C([C@H](N)C(=O)C1C2(N)CC3CC(C2)CC1(C3)C(=O)OC)C1=CC=CC=C1 RQDAQWMPUFEJAA-WEGQEKBOSA-N 0.000 description 2
229960005181 morphine Drugs 0.000 description 2
DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 2
DNADEDKIQXROFJ-UHFFFAOYSA-N n-(4-oxo-1-adamantyl)acetamide Chemical compound C1C(C2)CC3CC1(NC(=O)C)CC2C3=O DNADEDKIQXROFJ-UHFFFAOYSA-N 0.000 description 2
230000007935 neutral effect Effects 0.000 description 2
239000003921 oil Substances 0.000 description 2
MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
239000012071 phase Substances 0.000 description 2
229910003446 platinum oxide Inorganic materials 0.000 description 2
102000005962 receptors Human genes 0.000 description 2
108020003175 receptors Proteins 0.000 description 2
238000010992 reflux Methods 0.000 description 2
YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
210000000813 small intestine Anatomy 0.000 description 2
235000017557 sodium bicarbonate Nutrition 0.000 description 2
229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
239000007790 solid phase Substances 0.000 description 2
239000000725 suspension Substances 0.000 description 2
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
229960004441 tyrosine Drugs 0.000 description 2
238000005303 weighing Methods 0.000 description 2
JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
ZQEBQGAAWMOMAI-SSDOTTSWSA-N (2r)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H]1C(O)=O ZQEBQGAAWMOMAI-SSDOTTSWSA-N 0.000 description 1
ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 1
IMUSLIHRIYOHEV-ZETCQYMHSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-methylsulfanylbutanoic acid Chemical compound CSCC[C@@H](C(O)=O)NC(=O)OC(C)(C)C IMUSLIHRIYOHEV-ZETCQYMHSA-N 0.000 description 1
AJGJINVEYVTDNH-LBPRGKRZSA-N (2s)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N(C)[C@H](C(O)=O)CC1=CC=CC=C1 AJGJINVEYVTDNH-LBPRGKRZSA-N 0.000 description 1
JGXPMXYKONHGBA-ZZKWDYDOSA-N (2s)-2-amino-1-(2-amino-1-adamantyl)-3-phenylpropan-1-one Chemical compound C([C@H](N)C(=O)C12C(C3CC(CC(C3)C1)C2)N)C1=CC=CC=C1 JGXPMXYKONHGBA-ZZKWDYDOSA-N 0.000 description 1
QTZFUXUPWWWXCU-WDKYEDHGSA-N (2s)-2-amino-1-[1-amino-3-(hydroxymethyl)-2-adamantyl]-3-phenylpropan-1-one;hydrochloride Chemical compound Cl.C([C@H](N)C(=O)C1C2(CO)CC3CC(C2)CC1(N)C3)C1=CC=CC=C1 QTZFUXUPWWWXCU-WDKYEDHGSA-N 0.000 description 1
GTVVZTAFGPQSPC-QMMMGPOBSA-N (2s)-2-azaniumyl-3-(4-nitrophenyl)propanoate Chemical compound OC(=O)[C@@H](N)CC1=CC=C([N+]([O-])=O)C=C1 GTVVZTAFGPQSPC-QMMMGPOBSA-N 0.000 description 1
ZAQXSMCYFQJRCQ-ZQMDXNIRSA-N (2s)-3-(1-adamantyl)-2-aminopropanoic acid Chemical compound C1C(C2)CC3CC2CC1(C[C@H](N)C(O)=O)C3 ZAQXSMCYFQJRCQ-ZQMDXNIRSA-N 0.000 description 1
APVBZIOLJVJCLT-LBPRGKRZSA-N (2s)-3-(4-hydroxyphenyl)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid Chemical compound CC(C)(C)OC(=O)N(C)[C@H](C(O)=O)CC1=CC=C(O)C=C1 APVBZIOLJVJCLT-LBPRGKRZSA-N 0.000 description 1
ZPHFSHWJMOHIAK-UHFFFAOYSA-N (3-amino-1-adamantyl)methanol Chemical compound C1C(C2)CC3CC1(N)CC2(CO)C3 ZPHFSHWJMOHIAK-UHFFFAOYSA-N 0.000 description 1
WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
XSOHXMFFSKTSIT-UHFFFAOYSA-N 1-adamantylmethanamine Chemical compound C1C(C2)CC3CC2CC1(CN)C3 XSOHXMFFSKTSIT-UHFFFAOYSA-N 0.000 description 1
OAMFERZVSCXNPO-UHFFFAOYSA-N 1-hydroxypyrrolidine-2,5-dione;2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound ON1C(=O)CCC1=O.CC(C)(C)OC(=O)NCC(O)=O OAMFERZVSCXNPO-UHFFFAOYSA-N 0.000 description 1
TYELHMHEAVPFGU-UHFFFAOYSA-N 2,2,2-trifluoro-1-(2-hydroxy-1-adamantyl)ethanone Chemical compound C1C(C2)CC3CC1C(O)C2(C(=O)C(F)(F)F)C3 TYELHMHEAVPFGU-UHFFFAOYSA-N 0.000 description 1
HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
UZKCPNFSGFGLGV-RISCZKNCSA-N 2-[[(2r)-2-[[(2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]propanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)CC1=CC=C(O)C=C1 UZKCPNFSGFGLGV-RISCZKNCSA-N 0.000 description 1
RTLTUTVUVPPPCE-UHFFFAOYSA-N 2-adamantyl 2,2,2-trifluoroacetate Chemical compound C1C(C2)CC3CC1C(OC(=O)C(F)(F)F)C2C3 RTLTUTVUVPPPCE-UHFFFAOYSA-N 0.000 description 1
QBEMWLMHTDRJGK-UHFFFAOYSA-N 2-hydroxyadamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC1C(O)C2(C(O)=O)C3 QBEMWLMHTDRJGK-UHFFFAOYSA-N 0.000 description 1
WUTRNVWTFZWDPM-UHFFFAOYSA-N 2H-tetrazol-5-yl nitrate Chemical compound [N+](=O)([O-])OC1=NN=NN1 WUTRNVWTFZWDPM-UHFFFAOYSA-N 0.000 description 1
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
KWCJYAGXRBWFOV-UHFFFAOYSA-N 4-aminoadamantane-2-carboxylic acid Chemical compound C1C(C2)CC3CC1C(N)C2C3C(O)=O KWCJYAGXRBWFOV-UHFFFAOYSA-N 0.000 description 1
HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
QBIZJUSCCUELJR-UHFFFAOYSA-N 4-oxoadamantane-2-carboxylic acid Chemical compound C1C(C2)CC3CC1C(C(=O)O)C2C3=O QBIZJUSCCUELJR-UHFFFAOYSA-N 0.000 description 1
TXEWIOREYPSNRR-UHFFFAOYSA-N 5-bromoadamantan-2-one Chemical compound C1C(C2)CC3CC1(Br)CC2C3=O TXEWIOREYPSNRR-UHFFFAOYSA-N 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
206010002091 Anaesthesia Diseases 0.000 description 1
239000005711 Benzoic acid Substances 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
241000700199 Cavia porcellus Species 0.000 description 1
WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
SEWXSBRMPFAZGJ-HHCNIIBISA-N Cl.C([C@H](N)C(=O)N[C@H](CCSC)C(=O)NCC(=O)C1(N)C2(CC3CC(C2)CC1C3)C(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=C(O)C=C1 Chemical compound Cl.C([C@H](N)C(=O)N[C@H](CCSC)C(=O)NCC(=O)C1(N)C2(CC3CC(C2)CC1C3)C(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=C(O)C=C1 SEWXSBRMPFAZGJ-HHCNIIBISA-N 0.000 description 1
PRNXMKOBNKWPBD-UJOXJYRUSA-N Cl.N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@H](CCSC)C(=O)NCC(=O)C1(C2(CC3CC(C(C1C3)N)C2)C([C@@H](N)CC2=CC=CC=C2)=O)C(=O)OC Chemical compound Cl.N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@H](CCSC)C(=O)NCC(=O)C1(C2(CC3CC(C(C1C3)N)C2)C([C@@H](N)CC2=CC=CC=C2)=O)C(=O)OC PRNXMKOBNKWPBD-UJOXJYRUSA-N 0.000 description 1
206010010774 Constipation Diseases 0.000 description 1
RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
LRQKBLKVPFOOQJ-RXMQYKEDSA-N D-norleucine Chemical compound CCCC[C@@H](N)C(O)=O LRQKBLKVPFOOQJ-RXMQYKEDSA-N 0.000 description 1
239000012848 Dextrorphan Substances 0.000 description 1
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
206010012735 Diarrhoea Diseases 0.000 description 1
RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
NIGWMJHCCYYCSF-UHFFFAOYSA-N Fenclonine Chemical compound OC(=O)C(N)CC1=CC=C(Cl)C=C1 NIGWMJHCCYYCSF-UHFFFAOYSA-N 0.000 description 1
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
125000003290 L-leucino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 1
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical group CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
JAQUASYNZVUNQP-USXIJHARSA-N Levorphanol Chemical compound C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 JAQUASYNZVUNQP-USXIJHARSA-N 0.000 description 1
241000699666 Mus <mouse, genus> Species 0.000 description 1
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
235000011613 Pinus brutia Nutrition 0.000 description 1
241000018646 Pinus brutia Species 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
229930006000 Sucrose Natural products 0.000 description 1
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
239000007983 Tris buffer Substances 0.000 description 1
CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
125000002252 acyl group Chemical group 0.000 description 1
QZWNXXINFABALM-UHFFFAOYSA-N adamantan-2-amine Chemical compound C1C(C2)CC3CC1C(N)C2C3 QZWNXXINFABALM-UHFFFAOYSA-N 0.000 description 1
FOWDOWQYRZXQDP-UHFFFAOYSA-N adamantan-2-ol Chemical compound C1C(C2)CC3CC1C(O)C2C3 FOWDOWQYRZXQDP-UHFFFAOYSA-N 0.000 description 1
125000001931 aliphatic group Chemical group 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
229940124277 aminobutyric acid Drugs 0.000 description 1
MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 1
230000037005 anaesthesia Effects 0.000 description 1
239000005557 antagonist Substances 0.000 description 1
239000006286 aqueous extract Substances 0.000 description 1
235000010323 ascorbic acid Nutrition 0.000 description 1
239000011668 ascorbic acid Substances 0.000 description 1
229960005070 ascorbic acid Drugs 0.000 description 1
238000003556 assay Methods 0.000 description 1
235000010233 benzoic acid Nutrition 0.000 description 1
229960004365 benzoic acid Drugs 0.000 description 1
HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
239000004305 biphenyl Substances 0.000 description 1
235000010290 biphenyl Nutrition 0.000 description 1
125000006267 biphenyl group Chemical group 0.000 description 1
229910000085 borane Inorganic materials 0.000 description 1
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
229910052794 bromium Inorganic materials 0.000 description 1
KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
229910000019 calcium carbonate Inorganic materials 0.000 description 1
150000003857 carboxamides Chemical class 0.000 description 1
150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
210000001638 cerebellum Anatomy 0.000 description 1
239000002036 chloroform fraction Substances 0.000 description 1
238000013375 chromatographic separation Methods 0.000 description 1
235000013985 cinnamic acid Nutrition 0.000 description 1
229930016911 cinnamic acid Natural products 0.000 description 1
230000002596 correlated effect Effects 0.000 description 1
230000000875 corresponding effect Effects 0.000 description 1
238000010168 coupling process Methods 0.000 description 1
239000013078 crystal Substances 0.000 description 1
239000002178 crystalline material Substances 0.000 description 1
239000012024 dehydrating agents‎ Substances 0.000 description 1
JAQUASYNZVUNQP-PVAVHDDUSA-N dextrorphan Chemical compound C1C2=CC=C(O)C=C2[C@@]23CCN(C)[C@@H]1[C@H]2CCCC3 JAQUASYNZVUNQP-PVAVHDDUSA-N 0.000 description 1
229950006878 dextrorphan Drugs 0.000 description 1
ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
238000001035 drying Methods 0.000 description 1
230000000694 effects Effects 0.000 description 1
150000002081 enamines Chemical class 0.000 description 1
150000002170 ethers Chemical class 0.000 description 1
VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical class OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
239000012530 fluid Substances 0.000 description 1
239000006260 foam Substances 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
239000011521 glass Substances 0.000 description 1
239000003365 glass fiber Substances 0.000 description 1
239000000174 gluconic acid Substances 0.000 description 1
235000012208 gluconic acid Nutrition 0.000 description 1
229950006191 gluconic acid Drugs 0.000 description 1
125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
229940093915 gynecological organic acid Drugs 0.000 description 1
238000007327 hydrogenolysis reaction Methods 0.000 description 1
BTJRKNUKPQBLAL-UHFFFAOYSA-N hydron;4-methylmorpholine;chloride Chemical compound Cl.CN1CCOCC1 BTJRKNUKPQBLAL-UHFFFAOYSA-N 0.000 description 1
238000000338 in vitro Methods 0.000 description 1
238000001727 in vivo Methods 0.000 description 1
238000011534 incubation Methods 0.000 description 1
239000012442 inert solvent Substances 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
238000005342 ion exchange Methods 0.000 description 1
239000003456 ion exchange resin Substances 0.000 description 1
229920003303 ion-exchange polymer Polymers 0.000 description 1
239000004310 lactic acid Substances 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
229960003406 levorphanol Drugs 0.000 description 1
239000007788 liquid Substances 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Substances 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
239000000463 material Substances 0.000 description 1
238000005259 measurement Methods 0.000 description 1
239000012528 membrane Substances 0.000 description 1
SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 1
FMMOVZRXLNVNBI-FYZOBXCZSA-N methyl (2r)-2-aminohexanoate;hydrochloride Chemical compound Cl.CCCC[C@@H](N)C(=O)OC FMMOVZRXLNVNBI-FYZOBXCZSA-N 0.000 description 1
TVHCXXXXQNWQLP-DMTCNVIQSA-N methyl (2s,3r)-2-amino-3-hydroxybutanoate Chemical compound COC(=O)[C@@H](N)[C@@H](C)O TVHCXXXXQNWQLP-DMTCNVIQSA-N 0.000 description 1
LXGRNNZUKDXTIV-UHFFFAOYSA-N methyl 1-aminocyclopropane-1-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.COC(=O)C1(N)CC1 LXGRNNZUKDXTIV-UHFFFAOYSA-N 0.000 description 1
MCNJPKDIMSOGTM-SECBINFHSA-N methyl 2-[[(2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-methylsulfanylbutanoyl]amino]acetate Chemical compound COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C MCNJPKDIMSOGTM-SECBINFHSA-N 0.000 description 1
WEDVCOYLZSUYNE-WANKRKOJSA-N methyl 2-amino-1-[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylsulfanylbutanoyl]amino]acetyl]-3-[(2S)-2-amino-3-phenylpropanoyl]adamantane-2-carboxylate hydrochloride Chemical compound Cl.N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@H](CCSC)C(=O)NCC(=O)C12C(C3(CC(CC(C1)C3)C2)C([C@@H](N)CC2=CC=CC=C2)=O)(C(=O)OC)N WEDVCOYLZSUYNE-WANKRKOJSA-N 0.000 description 1
BMCTUOOXHFSRDB-UHFFFAOYSA-N methyl 2-aminoadamantane-1-carboxylate Chemical compound C1C(C2)CC3CC2C(N)C1(C(=O)OC)C3 BMCTUOOXHFSRDB-UHFFFAOYSA-N 0.000 description 1
YCDFPJJVFUVJJF-UHFFFAOYSA-N methyl 3-aminoadamantane-1-carboxylate Chemical compound C1C(C2)CC3CC2(N)CC1(C(=O)OC)C3 YCDFPJJVFUVJJF-UHFFFAOYSA-N 0.000 description 1
WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
125000000896 monocarboxylic acid group Chemical group 0.000 description 1
LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
QPJSUIGXIBEQAC-UHFFFAOYSA-N n-(2,4-dichloro-5-propan-2-yloxyphenyl)acetamide Chemical compound CC(C)OC1=CC(NC(C)=O)=C(Cl)C=C1Cl QPJSUIGXIBEQAC-UHFFFAOYSA-N 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
150000002825 nitriles Chemical class 0.000 description 1
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
235000006408 oxalic acid Nutrition 0.000 description 1
ORTFAQDWJHRMNX-UHFFFAOYSA-M oxidooxomethyl Chemical compound [O-][C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-M 0.000 description 1
125000004043 oxo group Chemical group O=* 0.000 description 1
125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
230000020477 pH reduction Effects 0.000 description 1
FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
239000008188 pellet Substances 0.000 description 1
210000004197 pelvis Anatomy 0.000 description 1
238000010647 peptide synthesis reaction Methods 0.000 description 1
239000008024 pharmaceutical diluent Substances 0.000 description 1
ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
229920000642 polymer Polymers 0.000 description 1
229920000307 polymer substrate Polymers 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
102000004196 processed proteins & peptides Human genes 0.000 description 1
229960002429 proline Drugs 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
229940107700 pyruvic acid Drugs 0.000 description 1
239000002287 radioligand Substances 0.000 description 1
238000011160 research Methods 0.000 description 1
239000011347 resin Substances 0.000 description 1
229920005989 resin Polymers 0.000 description 1
MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
229960004889 salicylic acid Drugs 0.000 description 1
239000012453 solvate Substances 0.000 description 1
230000009870 specific binding Effects 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
239000007858 starting material Substances 0.000 description 1
238000003860 storage Methods 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
239000006228 supernatant Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
WMOYQBLSYREFRU-OAQYLSRUSA-N tert-butyl (2r)-2-amino-2-[(4-benzylidene-5-oxo-1,3-oxazol-2-yl)methylcarbamoyl]-4-methylsulfanylbutanoate Chemical compound O=C1OC(CNC(=O)[C@](N)(CCSC)C(=O)OC(C)(C)C)=NC1=CC1=CC=CC=C1 WMOYQBLSYREFRU-OAQYLSRUSA-N 0.000 description 1
LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
NQCHDDLNCFAKRO-JTFNFDHSSA-N tert-butyl n-[(2s)-1-[[(2r)-1-[[2-[[(2s)-1-(1-amino-2-adamantyl)-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]carbamate Chemical compound C([C@@H](C(=O)N[C@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)C1C2(N)CC3CC(C2)CC1C3)NC(=O)OC(C)(C)C)C1=CC=C(O)C=C1 NQCHDDLNCFAKRO-JTFNFDHSSA-N 0.000 description 1
150000003512 tertiary amines Chemical class 0.000 description 1
CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
150000003566 thiocarboxylic acids Chemical class 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
238000001665 trituration Methods 0.000 description 1
125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
238000010792 warming Methods 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1
235000005074 zinc chloride Nutrition 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
- 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
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Medicinal Chemistry (AREA)
Biochemistry (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Molecular Biology (AREA)
Genetics & Genomics (AREA)
Biophysics (AREA)
Crystallography & Structural Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Neurology (AREA)
Pain & Pain Management (AREA)
Animal Behavior & Ethology (AREA)
Biomedical Technology (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Engineering & Computer Science (AREA)
Neurosurgery (AREA)
Pharmacology & Pharmacy (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Bioinformatics & Cheminformatics (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Peptides Or Proteins (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)

NO803640A 1979-12-03 1980-12-02 N-adamantan-substituerte tetrapeptidamider. NO803640L (no)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US06/099,765 US4273704A (en)	1979-12-03	1979-12-03	N-Adamantane-substituted tetrapeptide amides

Publications (1)

Publication Number	Publication Date
NO803640L true NO803640L (no)	1981-06-04

Family

ID=22276513

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
NO803640A NO803640L (no)	1979-12-03	1980-12-02	N-adamantan-substituerte tetrapeptidamider.

Country Status (16)

Country	Link
US (1)	US4273704A (it)
JP (1)	JPS5692847A (it)
AU (1)	AU6499080A (it)
BE (1)	BE886472A (it)
CA (1)	CA1151642A (it)
DE (1)	DE3044793A1 (it)
DK (1)	DK513480A (it)
ES (2)	ES8205753A1 (it)
FR (1)	FR2476073A1 (it)
GB (1)	GB2066262B (it)
IT (1)	IT1127930B (it)
NL (1)	NL8006586A (it)
NO (1)	NO803640L (it)
PT (1)	PT72141B (it)
SE (1)	SE8008428L (it)
ZA (1)	ZA807513B (it)

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4404135A (en) *	1981-07-20	1983-09-13	G. D. Searle & Co.	Enkephalin derivatives
US4407746A (en) *	1981-12-14	1983-10-04	G. D. Searle & Co.	Cyclohexyl and phenyl substituted enkephalins
CS231221B1 (en) *	1982-06-29	1984-10-15	Martin Flegel	L-alanyl-d-isoglutamine adamantylamide
DE3485587D1 (de) *	1983-08-16	1992-04-23	Univ Georgia Res Found	Herstellung von aminocyclopropancarbonsaeuren und von peptiden.
US4629784A (en) *	1983-08-16	1986-12-16	The University Of Georgia Research Foundation, Inc.	Synthesis of cyclopropane amino acids
US4510085A (en) *	1984-04-12	1985-04-09	G.D. Searle & Co.	Antihypertensive tetrapeptide amides
US4514332A (en) *	1984-04-16	1985-04-30	G. D. Searle & Co.	Tetrapeptide adamantyl amides
FR2572399B1 (fr) *	1984-10-31	1987-01-16	Panmedica Sa	Nouveaux derives de l'adamantanamine, leurs procedes de preparation et medicaments les contenant
US4880829A (en) *	1985-08-14	1989-11-14	G. D. Searle And Company	Substituted dipeptide amides #3
US4822775A (en) *	1986-02-14	1989-04-18	G. D. Searle & Co.	Phenyl substituted dipeptide amides
US4758675A (en) *	1986-07-14	1988-07-19	G. D. Searle & Co.	3-thiophene-substituted tyrosyl dipeptide amides
US5652335A (en) *	1990-02-28	1997-07-29	Teikoku Seiyaku Kabushiki Kaisha	Physiologically active substance well capable of permeating biomembrane
DE69130489T2 (de) *	1990-02-28	1999-05-12	Teikoku Seiyaku K.K., Kagawa	Physiologisch aktive Substanz die fähig ist Biomembran zu permeieren
EP1574495A1 (en)	1997-01-14	2005-09-14	Daicel Chemical Industries, Ltd.	Adamantane derivatives
US7795468B2 (en) *	2001-01-19	2010-09-14	Chevron U.S.A. Inc.	Functionalized higher diamondoids
US20050245534A1 (en) *	2004-04-29	2005-11-03	Link James T	Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
US20100222316A1 (en)	2004-04-29	2010-09-02	Abbott Laboratories	Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8415354B2 (en) *	2004-04-29	2013-04-09	Abbott Laboratories	Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US20050261302A1 (en) *	2004-04-29	2005-11-24	Hoff Ethan D	Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme and their therapeutic application
US7880001B2 (en) *	2004-04-29	2011-02-01	Abbott Laboratories	Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
WO2006010362A1 (de) *	2004-07-23	2006-02-02	Justus-Liebig-Universität Giessen	Aminoadamantan-derivate, verfahren zu ihrer herstellung und ihre verwendung
EP1812407A2 (en) *	2004-11-02	2007-08-01	Pfizer, Inc.	Novel compounds of substituted and unsubstituted adamantyl amides
KR101496190B1 (ko)	2005-01-05	2015-02-26	애브비 인코포레이티드	11-베타-하이드록시스테로이드 데하이드로게나제 타입 1 효소의 억제제로서의 아다만틸 유도체
US8198331B2 (en) *	2005-01-05	2012-06-12	Abbott Laboratories	Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US20090192198A1 (en)	2005-01-05	2009-07-30	Abbott Laboratories	Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
HRP20050242B1 (en) *	2005-03-15	2010-09-30	Institut Ruđer Bošković	Synthetic peptides containing unnatural adamantane related amino acids for use as antitumour drugs
JP5736098B2 (ja) *	2007-08-21	2015-06-17	アッヴィ・インコーポレイテッド	中枢神経系障害を治療するための医薬組成物
EP2399926A1 (en) *	2010-06-22	2011-12-28	Justus-Liebig-Universität Giessen	Peptides incorporating 3-aminoadamantane carboxylic acids enhance synaptic plasticity and act as neurogenic agents
CN112552374B (zh) *	2019-09-10	2024-06-04	西藏海思科制药有限公司	一种肽酰胺类化合物及其中间体的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DE2732451A1 (de) *	1976-07-27	1978-02-02	Reckitt & Colmann Prod Ltd	Peptidverbindungen, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneipraeparate

1979
- 1979-12-03 US US06/099,765 patent/US4273704A/en not_active Expired - Lifetime
1980
- 1980-11-28 DE DE19803044793 patent/DE3044793A1/de not_active Withdrawn
- 1980-12-02 AU AU64990/80A patent/AU6499080A/en not_active Withdrawn
- 1980-12-02 NO NO803640A patent/NO803640L/no unknown
- 1980-12-02 SE SE8008428A patent/SE8008428L/ not_active Application Discontinuation
- 1980-12-02 ES ES497353A patent/ES8205753A1/es not_active Expired
- 1980-12-02 CA CA000365903A patent/CA1151642A/en not_active Expired
- 1980-12-02 IT IT50294/80A patent/IT1127930B/it active
- 1980-12-02 DK DK513480A patent/DK513480A/da not_active Application Discontinuation
- 1980-12-02 ZA ZA00807513A patent/ZA807513B/xx unknown
- 1980-12-03 JP JP17078580A patent/JPS5692847A/ja active Pending
- 1980-12-03 PT PT72141A patent/PT72141B/pt unknown
- 1980-12-03 GB GB8038684A patent/GB2066262B/en not_active Expired
- 1980-12-03 BE BE0/203025A patent/BE886472A/fr unknown
- 1980-12-03 NL NL8006586A patent/NL8006586A/nl not_active Application Discontinuation
- 1980-12-03 FR FR8025696A patent/FR2476073A1/fr not_active Withdrawn
1981
- 1981-12-16 ES ES508060A patent/ES508060A0/es active Granted

Also Published As

Publication number	Publication date
ES8300087A1 (es)	1982-10-01
IT1127930B (it)	1986-05-28
FR2476073A1 (fr)	1981-08-21
ES497353A0 (es)	1982-06-16
PT72141A (en)	1981-01-01
GB2066262A (en)	1981-07-08
DE3044793A1 (de)	1981-06-19
IT8050294A0 (it)	1980-12-02
GB2066262B (en)	1983-05-11
JPS5692847A (en)	1981-07-27
AU6499080A (en)	1981-06-11
NL8006586A (nl)	1981-07-01
ZA807513B (en)	1982-07-28
SE8008428L (sv)	1981-06-04
CA1151642A (en)	1983-08-09
ES508060A0 (es)	1982-10-01
ES8205753A1 (es)	1982-06-16
US4273704A (en)	1981-06-16
PT72141B (en)	1981-10-28
BE886472A (fr)	1981-06-03
DK513480A (da)	1981-07-09

Publication	Publication Date	Title
US4273704A (en)	1981-06-16	N-Adamantane-substituted tetrapeptide amides
Lipkowski et al.	1982	Double-enkephalins—synthesis, activity on guinea-pig ileum, and analgesic effect
US5317014A (en)	1994-05-31	Peptides and pseudopeptides derived from tachykinin
Salvadori et al.	1982	Synthesis and pharmacological activity of dermorphin and its N‐terminal sequences
KR0161972B1 (ko)	1998-11-16	크기가 감소된 lhrh 동족체
US5723575A (en)	1998-03-03	Process for the preparation of backbone cyclic peptides
US4684620A (en)	1987-08-04	Cyclic polypeptides having mu-receptor specificity
US4518711A (en)	1985-05-21	Conformationally constrained cyclic enkephalin analogs with delta receptor specificity
Grieco et al.	2002	Design and synthesis of highly potent and selective melanotropin analogues of SHU9119 modified at position 6
Gacel et al.	1988	Development of conformationally constrained linear peptides exhibiting a high affinity and pronounced selectivity for. delta. opioid receptors
IE902740A1 (en)	1991-02-27	Lhrh analogs
DK148904B (da)	1985-11-11	Analogifremgangsmaade til fremstilling af analgetisk virksomme enkephalin-analoge pentapeptidamider eller farmaceutisk acceptable, ikke-toxiske syreadditionssalte deraf
HU182866B (en)	1984-03-28	Process for preparing new tetrapeptide derivatives
US4407746A (en)	1983-10-04	Cyclohexyl and phenyl substituted enkephalins
HU185320B (en)	1985-01-28	Process for producing biologically active encephaline analogous compounds
Marastoni et al.	1987	Synthesis and activity profiles of new dermorphin-(1-4) peptide analogs
GB1577115A (en)	1980-10-22	Container closure units
Bower et al.	1976	Enkephalin. Synthesis of two pentapeptides isolated from porcine brain with receptor-mediated opiate agonist activity
JPS59101451A (ja)	1984-06-12	薬理学的に活性なペプチド
Fichna et al.	2011	Effect of 2′, 6′-dimethyl-L-tyrosine (Dmt) on pharmacological activity of cyclic endomorphin-2 and morphiceptin analogs
Salvadori et al.	1985	Synthesis and pharmacological activity of partially modified retro-inverso dermorphin tetrapeptides
Hiskey et al.	1972	Sulfur-containing polypeptides. XV. Synthetic routes to the A6-13 segment of ovine insulin
GB1601754A (en)	1981-11-04	Pharmacologically active aligopeptide derivatives
Frączak et al.	2016	Synthesis, binding affinities and metabolic stability of dimeric dermorphin analogs modified with β3‐homo‐amino acids
Li et al.	2001	Synthesis, conformational analysis and biological activities of lanthionine analogs of a cell adhesion modulator