LT3072B - Renin inhibiting n-(2-amino-2-oxoethyl)butanediamide derivatives - Google Patents
Renin inhibiting n-(2-amino-2-oxoethyl)butanediamide derivatives Download PDFInfo
- Publication number
- LT3072B LT3072B LTIP1092A LTIP1092A LT3072B LT 3072 B LT3072 B LT 3072B LT IP1092 A LTIP1092 A LT IP1092A LT IP1092 A LTIP1092 A LT IP1092A LT 3072 B LT3072 B LT 3072B
- Authority
- LT
- Lithuania
- Prior art keywords
- methyl
- cyclohexylmethyl
- dihydroxy
- oxoethyl
- amino
- Prior art date
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- 108090000783 Renin Proteins 0.000 title claims abstract description 23
- 102100028255 Renin Human genes 0.000 title claims abstract description 23
- 230000002401 inhibitory effect Effects 0.000 title description 3
- -1 2-(2-pyridinyl)ethyl Chemical group 0.000 claims abstract description 537
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 246
- 150000001875 compounds Chemical class 0.000 claims abstract description 106
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 92
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 32
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000003287 1H-imidazol-4-ylmethyl group Chemical group [H]N1C([H])=NC(C([H])([H])[*])=C1[H] 0.000 claims abstract description 8
- 206010020772 Hypertension Diseases 0.000 claims abstract description 8
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 142
- SNCZNSNPXMPCGN-UHFFFAOYSA-N butanediamide Chemical compound NC(=O)CCC(N)=O SNCZNSNPXMPCGN-UHFFFAOYSA-N 0.000 claims description 92
- 239000002253 acid Substances 0.000 claims description 53
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 53
- 150000001412 amines Chemical class 0.000 claims description 51
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 38
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 30
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 25
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 21
- 150000001408 amides Chemical class 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- MKLUDRDMPZHPBN-UHFFFAOYSA-N n'-(cyclopropylmethyl)butanediamide Chemical compound NC(=O)CCC(=O)NCC1CC1 MKLUDRDMPZHPBN-UHFFFAOYSA-N 0.000 claims description 15
- 150000003254 radicals Chemical class 0.000 claims description 14
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical group C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 6
- FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 claims description 6
- XRRDFIPYLFCYLU-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical group [CH2]C1=CC(C)=CC(C)=C1 XRRDFIPYLFCYLU-UHFFFAOYSA-N 0.000 claims description 5
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 5
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 5
- 125000006622 cycloheptylmethyl group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 5
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 5
- KGXQHPSVLZVNKT-ZCFIWIBFSA-N (2r)-2-(cyclopropylmethyl)butanediamide Chemical compound NC(=O)C[C@H](C(N)=O)CC1CC1 KGXQHPSVLZVNKT-ZCFIWIBFSA-N 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 239000001273 butane Substances 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000006513 pyridinyl methyl group Chemical group 0.000 claims description 3
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 3
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 claims description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 235000006679 Mentha X verticillata Nutrition 0.000 claims description 2
- 235000002899 Mentha suaveolens Nutrition 0.000 claims description 2
- 235000001636 Mentha x rotundifolia Nutrition 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- 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 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 2
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 2
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims 2
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 239000012351 deprotecting agent Substances 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- VHHROMDSBXTZLS-UHFFFAOYSA-N n'-(2-amino-2-oxoethyl)butanediamide Chemical class NC(=O)CCC(=O)NCC(N)=O VHHROMDSBXTZLS-UHFFFAOYSA-N 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 102000004881 Angiotensinogen Human genes 0.000 abstract description 6
- 108090001067 Angiotensinogen Proteins 0.000 abstract description 6
- 206010019280 Heart failures Diseases 0.000 abstract description 4
- 150000002431 hydrogen Chemical class 0.000 abstract description 2
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 2
- 206010007559 Cardiac failure congestive Diseases 0.000 abstract 1
- 125000004981 cycloalkylmethyl group Chemical group 0.000 abstract 1
- 125000005505 thiomorpholino group Chemical group 0.000 abstract 1
- 230000007704 transition Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 97
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 65
- 239000000203 mixture Substances 0.000 description 61
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
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- 235000019439 ethyl acetate Nutrition 0.000 description 32
- 238000005481 NMR spectroscopy Methods 0.000 description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
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- 239000003480 eluent Substances 0.000 description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
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- 239000000460 chlorine Substances 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 239000000047 product Substances 0.000 description 19
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- 239000011734 sodium Substances 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
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- 238000006243 chemical reaction Methods 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 101800000734 Angiotensin-1 Proteins 0.000 description 8
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- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000002461 renin inhibitor Substances 0.000 description 8
- 229940086526 renin-inhibitors Drugs 0.000 description 8
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- 239000012230 colorless oil Substances 0.000 description 7
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 7
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
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- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- RJIFZANHVPLCQD-UHFFFAOYSA-N N'-(1,3-thiazol-2-ylmethyl)butanediamide Chemical compound C(CCC(=O)N)(=O)NCC=1SC=CN=1 RJIFZANHVPLCQD-UHFFFAOYSA-N 0.000 description 3
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- 238000010438 heat treatment Methods 0.000 description 1
- QRYZBBMAFLIWPX-UHFFFAOYSA-N heptane-4,4-diamine Chemical compound NC(CCC)(CCC)N QRYZBBMAFLIWPX-UHFFFAOYSA-N 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-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
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- PZLXYMQOCNYUIO-UHFFFAOYSA-N lithium;hydrochloride Chemical compound [Li].Cl PZLXYMQOCNYUIO-UHFFFAOYSA-N 0.000 description 1
- XZAAKIMHGHTXDH-UHFFFAOYSA-M lithium;hydrogen peroxide;hydroxide Chemical compound [Li+].[OH-].OO XZAAKIMHGHTXDH-UHFFFAOYSA-M 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 239000010871 livestock manure Substances 0.000 description 1
- 241001515942 marmosets Species 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- CYEBJEDOHLIWNP-UHFFFAOYSA-N methanethioamide Chemical compound NC=S CYEBJEDOHLIWNP-UHFFFAOYSA-N 0.000 description 1
- YFEPBWKUBQUBKL-UHFFFAOYSA-N methyl 3-(1h-imidazol-5-yl)propanoate Chemical compound COC(=O)CCC1=CN=CN1 YFEPBWKUBQUBKL-UHFFFAOYSA-N 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- KGIFSOFINUZVPJ-UHFFFAOYSA-N n'-(1,3-thiazol-4-ylmethyl)butanediamide Chemical compound NC(=O)CCC(=O)NCC1=CSC=N1 KGIFSOFINUZVPJ-UHFFFAOYSA-N 0.000 description 1
- HEGBYQPDOKNVCY-UHFFFAOYSA-N n'-(pyridin-2-ylmethyl)butanediamide Chemical compound NC(=O)CCC(=O)NCC1=CC=CC=N1 HEGBYQPDOKNVCY-UHFFFAOYSA-N 0.000 description 1
- ZPKBJHZCBZEJTI-UHFFFAOYSA-N n'-(pyridin-3-ylmethyl)butanediamide Chemical compound NC(=O)CCC(=O)NCC1=CC=CN=C1 ZPKBJHZCBZEJTI-UHFFFAOYSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- DWVCPSQPTSNMRX-UHFFFAOYSA-N n-methyl-1,3-thiazol-2-amine Chemical compound CNC1=NC=CS1 DWVCPSQPTSNMRX-UHFFFAOYSA-N 0.000 description 1
- JISNPNCZGCBCHR-HNNXBMFYSA-N n-methyl-2-[[(1s)-1-phenylethyl]amino]-n-(2-pyridin-2-ylethyl)acetamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)CC(=O)N(C)CCC1=CC=CC=N1 JISNPNCZGCBCHR-HNNXBMFYSA-N 0.000 description 1
- DRZMWPNQKYFQAI-UHFFFAOYSA-N n-methyl-n-[2-(methylamino)ethyl]morpholine-4-carboxamide Chemical compound CNCCN(C)C(=O)N1CCOCC1 DRZMWPNQKYFQAI-UHFFFAOYSA-N 0.000 description 1
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- HVAMZGADVCBITI-UHFFFAOYSA-N pent-4-enoic acid Chemical compound OC(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000000580 secretagogue effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- JQOPNJHYOFVEMP-ZIAGYGMSSA-N tert-butyl (3r)-3-(cyclopropylmethyl)-4-oxo-4-[(4s)-2-oxo-4-propan-2-yl-1,3-oxazolidin-3-yl]butanoate Chemical compound CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)CC1CC1 JQOPNJHYOFVEMP-ZIAGYGMSSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- DFVRUHANEXOZGT-UHFFFAOYSA-N tert-butyl n-methyl-n-[2-(methylamino)ethyl]carbamate Chemical compound CNCCN(C)C(=O)OC(C)(C)C DFVRUHANEXOZGT-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000004035 thiopropyl group Chemical group [H]SC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US95147892A | 1992-09-25 | 1992-09-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| LTIP1092A LTIP1092A (en) | 1994-05-15 |
| LT3072B true LT3072B (en) | 1994-11-25 |
Family
ID=25491725
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LTIP1092A LT3072B (en) | 1992-09-25 | 1993-09-23 | Renin inhibiting n-(2-amino-2-oxoethyl)butanediamide derivatives |
Country Status (29)
| Country | Link |
|---|---|
| US (2) | US5541163A (fr) |
| EP (1) | EP0589445B1 (fr) |
| JP (1) | JP3490442B2 (fr) |
| KR (1) | KR950703520A (fr) |
| CN (1) | CN1090278A (fr) |
| AT (1) | ATE147720T1 (fr) |
| AU (1) | AU680829B2 (fr) |
| BG (1) | BG99542A (fr) |
| BR (1) | BR9307110A (fr) |
| CA (1) | CA2143300C (fr) |
| CO (1) | CO4560549A1 (fr) |
| CZ (1) | CZ74895A3 (fr) |
| DE (1) | DE69307446T2 (fr) |
| EE (1) | EE03083B1 (fr) |
| FI (1) | FI951398A (fr) |
| HU (2) | HUT70432A (fr) |
| IL (1) | IL107092A (fr) |
| LT (1) | LT3072B (fr) |
| LV (1) | LV10945B (fr) |
| MX (1) | MX9305918A (fr) |
| NO (1) | NO951133L (fr) |
| NZ (1) | NZ255301A (fr) |
| PH (1) | PH30881A (fr) |
| PL (1) | PL174454B1 (fr) |
| RU (1) | RU95113586A (fr) |
| SK (1) | SK37695A3 (fr) |
| TW (1) | TW239117B (fr) |
| WO (1) | WO1994007846A1 (fr) |
| ZA (1) | ZA937079B (fr) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR9307111A (pt) * | 1992-09-25 | 1999-06-15 | Boehringer Ingelheim Ca Ltd | Derivados de n-(hidroxietil) butanodiamida como inibidores de renina |
| CA2165996C (fr) * | 1995-12-22 | 2002-01-29 | Murray Douglas Bailey | Preparation stereoselective de composes de type succinique avec substitution en 2 |
| US6096759A (en) * | 1997-09-19 | 2000-08-01 | Georgetown University | Method for treating essential hypertension |
| WO2005037317A2 (fr) * | 2003-10-17 | 2005-04-28 | Cornell Research Foundation, Inc. | Renine d'origine mastocytaire |
| US10517839B2 (en) * | 2008-06-09 | 2019-12-31 | Cornell University | Mast cell inhibition in diseases of the retina and vitreous |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0278158A2 (fr) | 1986-11-12 | 1988-08-17 | Merck & Co. Inc. | Inhibiteurs de rénine contenant des remplaçants de phénylalanyl-histidine |
| US4839357A (en) | 1987-10-02 | 1989-06-13 | Merck & Co., Inc. | Renin inhibitors containing phenylalanyl-histidine replacements |
| EP0402646A1 (fr) | 1989-05-23 | 1990-12-19 | Abbott Laboratories | Composés inhibiteurs de la protease retrovirale |
| CA2025093A1 (fr) | 1989-09-12 | 1991-03-13 | Holger Heitsch | Derives d'acides amines inhibiteurs de la renine, procede de preparation, agents les contenant et leur utilisation |
| US5001113A (en) | 1987-10-14 | 1991-03-19 | Merck & Co., Inc. | Di- or tripeptide renin inhibitors containing lactam conformational restriction in ACHPA |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5006511A (en) * | 1981-10-14 | 1991-04-09 | Merck & Co., Inc. | Di- or tripeptide renin inhibitors containing lactam conformational restriction in achpa |
| EP0312283A3 (fr) * | 1987-10-14 | 1990-05-09 | Merck & Co. Inc. | Inhibiteurs de la rénine di-ou tripeptidiques, contenant une restriction conformationnelle du type lactame dans ACHPA |
| US5055466A (en) * | 1987-11-23 | 1991-10-08 | E. R. Squibb & Sons, Inc. | N-morpholino derivatives and their use as anti-hypertensive agents |
| CA1329680C (fr) * | 1987-11-23 | 1994-05-17 | Harold Norris Weller, Iii | Derives d'un alcool n-heterocyclique |
| AU615313B2 (en) * | 1988-07-01 | 1991-09-26 | G.D. Searle & Co. | Aminoalkylaminocarbonyl aminodiol amino acid derivatives as anti-hypertensive agents |
| IE902446A1 (en) * | 1989-07-26 | 1991-02-13 | Abbott Lab | Peptidyl aminodiol renin inhibitors |
| US5063208A (en) * | 1989-07-26 | 1991-11-05 | Abbott Laboratories | Peptidyl aminodiol renin inhibitors |
| JPH0532602A (ja) * | 1991-07-26 | 1993-02-09 | Terumo Corp | ナフチルメチルアミン誘導体及びこれを含有するレニン阻害剤 |
-
1993
- 1993-09-15 BR BR9307110A patent/BR9307110A/pt not_active Application Discontinuation
- 1993-09-15 SK SK376-95A patent/SK37695A3/sk unknown
- 1993-09-15 JP JP50854294A patent/JP3490442B2/ja not_active Expired - Fee Related
- 1993-09-15 HU HU9500871A patent/HUT70432A/hu unknown
- 1993-09-15 WO PCT/CA1993/000380 patent/WO1994007846A1/fr not_active Application Discontinuation
- 1993-09-15 PL PL93308180A patent/PL174454B1/pl unknown
- 1993-09-15 CA CA002143300A patent/CA2143300C/fr not_active Expired - Fee Related
- 1993-09-15 CZ CZ95748A patent/CZ74895A3/cs unknown
- 1993-09-15 KR KR1019950701149A patent/KR950703520A/ko not_active Application Discontinuation
- 1993-09-15 AU AU49403/93A patent/AU680829B2/en not_active Ceased
- 1993-09-15 NZ NZ255301A patent/NZ255301A/en unknown
- 1993-09-15 RU RU95113586/04A patent/RU95113586A/ru unknown
- 1993-09-17 US US08/122,280 patent/US5541163A/en not_active Expired - Lifetime
- 1993-09-23 AT AT93115326T patent/ATE147720T1/de not_active IP Right Cessation
- 1993-09-23 PH PH46946A patent/PH30881A/en unknown
- 1993-09-23 IL IL107092A patent/IL107092A/xx not_active IP Right Cessation
- 1993-09-23 EP EP93115326A patent/EP0589445B1/fr not_active Expired - Lifetime
- 1993-09-23 DE DE69307446T patent/DE69307446T2/de not_active Expired - Lifetime
- 1993-09-23 LT LTIP1092A patent/LT3072B/lt not_active IP Right Cessation
- 1993-09-24 CO CO93410100A patent/CO4560549A1/es unknown
- 1993-09-24 MX MX9305918A patent/MX9305918A/es not_active IP Right Cessation
- 1993-09-24 ZA ZA937079A patent/ZA937079B/xx unknown
- 1993-09-24 TW TW082107871A patent/TW239117B/zh active
- 1993-09-25 CN CN93117983A patent/CN1090278A/zh active Pending
-
1994
- 1994-11-23 EE EE9400334A patent/EE03083B1/xx unknown
-
1995
- 1995-03-24 NO NO951133A patent/NO951133L/no unknown
- 1995-03-24 FI FI951398A patent/FI951398A/fi not_active Application Discontinuation
- 1995-04-03 BG BG99542A patent/BG99542A/bg unknown
- 1995-04-25 LV LVP-95-107A patent/LV10945B/en unknown
- 1995-06-23 HU HU95P/P00428P patent/HU211315A9/hu unknown
-
1996
- 1996-02-01 US US08/595,327 patent/US5693619A/en not_active Expired - Lifetime
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0278158A2 (fr) | 1986-11-12 | 1988-08-17 | Merck & Co. Inc. | Inhibiteurs de rénine contenant des remplaçants de phénylalanyl-histidine |
| US4839357A (en) | 1987-10-02 | 1989-06-13 | Merck & Co., Inc. | Renin inhibitors containing phenylalanyl-histidine replacements |
| US5001113A (en) | 1987-10-14 | 1991-03-19 | Merck & Co., Inc. | Di- or tripeptide renin inhibitors containing lactam conformational restriction in ACHPA |
| EP0402646A1 (fr) | 1989-05-23 | 1990-12-19 | Abbott Laboratories | Composés inhibiteurs de la protease retrovirale |
| CA2025093A1 (fr) | 1989-09-12 | 1991-03-13 | Holger Heitsch | Derives d'acides amines inhibiteurs de la renine, procede de preparation, agents les contenant et leur utilisation |
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