PH26584A - Beta-amino-boronic acid derivatives - Google Patents
Beta-amino-boronic acid derivatives Download PDFInfo
- Publication number
- PH26584A PH26584A PH39613A PH39613A PH26584A PH 26584 A PH26584 A PH 26584A PH 39613 A PH39613 A PH 39613A PH 39613 A PH39613 A PH 39613A PH 26584 A PH26584 A PH 26584A
- Authority
- PH
- Philippines
- Prior art keywords
- alkyl
- amino
- methyl
- denotes
- formula
- Prior art date
Links
- 229910052799 carbon Inorganic materials 0.000 claims description 103
- 150000001875 compounds Chemical class 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 125000002950 monocyclic group Chemical group 0.000 claims description 13
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 5
- 229910052796 boron Inorganic materials 0.000 claims description 5
- 239000008177 pharmaceutical agent Substances 0.000 claims 1
- -1 amino, amidino Chemical group 0.000 description 110
- 150000003254 radicals Chemical class 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 239000002904 solvent Substances 0.000 description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 15
- 108090000783 Renin Proteins 0.000 description 14
- 102100028255 Renin Human genes 0.000 description 13
- 238000000034 method Methods 0.000 description 12
- 101800000734 Angiotensin-1 Proteins 0.000 description 11
- 102400000344 Angiotensin-1 Human genes 0.000 description 11
- 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 11
- 125000002619 bicyclic group Chemical group 0.000 description 11
- 210000002381 plasma Anatomy 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 150000002431 hydrogen Chemical class 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 125000004434 sulfur atom Chemical group 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 150000001721 carbon Chemical group 0.000 description 8
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229910052792 caesium Inorganic materials 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 230000000875 corresponding effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 125000001589 carboacyl group Chemical group 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
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- 229940086526 renin-inhibitors Drugs 0.000 description 5
- 150000003457 sulfones Chemical class 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 150000008064 anhydrides Chemical class 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- BQOVGKGIQZSJPJ-UHFFFAOYSA-N dimethyl 2,2-bis(thiophen-2-ylmethyl)propanedioate Chemical compound C=1C=CSC=1CC(C(=O)OC)(C(=O)OC)CC1=CC=CS1 BQOVGKGIQZSJPJ-UHFFFAOYSA-N 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
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- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
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- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox 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](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 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000005862 Angiotensin II Human genes 0.000 description 3
- 101800000733 Angiotensin-2 Proteins 0.000 description 3
- 102000004881 Angiotensinogen Human genes 0.000 description 3
- 108090001067 Angiotensinogen Proteins 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000579218 Homo sapiens Renin Proteins 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 229950006323 angiotensin ii Drugs 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 238000004587 chromatography analysis Methods 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000005883 dithianyl group Chemical group 0.000 description 3
- 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000003127 radioimmunoassay Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- HDNXGFGVFDEIJW-HOTGVXAUSA-N (2s)-3-(1h-imidazol-5-yl)-2-[[(2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]propanoic acid Chemical compound C([C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(O)=O)C1=CC=CC=C1 HDNXGFGVFDEIJW-HOTGVXAUSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- QUIJMHDIAFOPRK-UHFFFAOYSA-N 1-cyclooctylazocane Chemical group C1CCCCCCC1N1CCCCCCC1 QUIJMHDIAFOPRK-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
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- SNDPXSYFESPGGJ-UHFFFAOYSA-N 2-aminopentanoic acid Chemical compound CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
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- 241001465754 Metazoa Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
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- 241000288906 Primates Species 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
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- 230000009471 action Effects 0.000 description 2
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- 238000006193 diazotization reaction Methods 0.000 description 2
- PIIHAJHYNTWOAF-UHFFFAOYSA-N dimethyl 2-(thiophen-2-ylmethyl)propanedioate Chemical compound COC(=O)C(C(=O)OC)CC1=CC=CS1 PIIHAJHYNTWOAF-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 125000000267 glycino group Chemical group [H]N([*])C([H])([H])C(=O)O[H] 0.000 description 2
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- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- ALBYIUDWACNRRB-UHFFFAOYSA-N hexanamide Chemical compound CCCCCC(N)=O ALBYIUDWACNRRB-UHFFFAOYSA-N 0.000 description 2
- BMVXCPBXGZKUPN-UHFFFAOYSA-O hexylazanium Chemical compound CCCCCC[NH3+] BMVXCPBXGZKUPN-UHFFFAOYSA-O 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 2
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- 230000002401 inhibitory effect Effects 0.000 description 2
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- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
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- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
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- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- KEDYTOTWMPBSLG-HILJTLORSA-N ramiprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)C(O)=O)CC1=CC=CC=C1 KEDYTOTWMPBSLG-HILJTLORSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000029865 regulation of blood pressure Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- 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
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- 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
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
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- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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Description
HOECHST AKTIENGESELLSCHAFT HOE 88/F 336 Dr.WI/PP
Description 9 6 5 S A p-Amino-boronic acid derivatives °° oo
The invention relates to compounds of the formula I ~ . oT RZ R3 r4 ; i
A-N-CH-CO-NH-CH- CH- RS
B or® or? in which
A denotes a radical of the formula 1I, III or IV ; py EE
R® RE ! 0 : \ & a “2 .
Po L a
R'-N-cw.-c- © Lo An \ cl :
Em r10 r® 0 { 9 Lo \ :
Rl . CH- CH - C - \ (LEI) wo © 10 . ril . (CHp) - CH - C - (IV) ' : (CHa Im
R12 ) in which
R! a) denotes hydrogen, (C,-C,,)-alkyl, which is option- ally mono- or diunsaturated and is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (C,-C,;)-alkoxy, carbamoyl, (C,-Cy)-alkanoyloxy, carboxyl, (C,~C,)-alkoxycarbonyl, F, Cl, Br, I, amino, amidino, which can optionally be substi- tuted by one, two or three (C,~C,)-alkyl radicals,
-2- 26584 guanidino, which can optionally be substituted by one, two, three or four (C,~-C,)-alkyl radicals, (C,-C,)-alkylamino, di-(C,-C;)~alkylamino, (C,-C;)- alkoxycarbonylamino, (C,~-C,s)-aralkoxycarbonyl- amino and 9-fluorenylmethoxycarbonylamino; mono-, bi- or tricyclic (C;-C,4)-cycloalkyl, (C3-Cj3)-cycloalkyl-(C,-C¢)-alkyl or (Ce-C,,)-aryl, the cycloalkyl part optionally being substituted by (C,-Cs)-alkyl and aryl optionally being substi- tuted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C,-C,)-alkoxy, (C,-C,)-alkyl, (C,-C,)- alkoxycarbonyl, amino and trifluoromethyl; (Ce¢-Cy4)-aryl-(C,-C¢)-alkyl, in which the aryl part is optionally substituted by one or two identical or different radicals from the series comprising
F, Cl, Br, I, hydroxyl, (C,-C,)-alkoxy, (C,-C,)~- alkyl, (C,-C,;)-alkoxycarbonyl, amino, (C,-C,)- alkylamino, di-(C,-C,)-alkylamino, carboxyl, carboxymethoxy, amino-(C,-C,)-alkyl, (Cy-C;)~- alkylamino-(C,~C;)-alkyl, -di-(C,-C,)-alkylamino- (C,-C,)-alkyl, (C,-C,)-alkoxycarbonylmethoxy, car- bamoyl, sulfamoyl, (C,-C;)-alkoxysulfonyl and sulfo- and guanidino-(C,-Cy)-alkyl; or represents the radical of a 5- or 6-membered monocyclic or 9- or l1l0-membered bicyclic partly or completely hydrogenated heteroaromatic having at least 1 carbon atom, 1 - 4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members and which is optionally mono-, di- or trisubstituted like the (C¢-C,,)-aryl defined under a,), or a,) denotes a radical of the formula V
RV - Ww (V) in which RY is defined as R' under a,) and W represents -CO-, -0-CO-, -S0,-, -SO-, =-NH-SO,-, -NH-CO-, -CH(OH)- or -N(OH)-;
so 26584
R? denotes hydrogen or (C,-Cs) alkyl, or, together with
R’ and the atoms carrying these, forms a mono- Or bicyclic, saturated or partly unsaturated ring system having 5-12 ring members;
R® and R® independently of one another are defined as R! under a,) or, together with R® or with R® and the atoms carrying these, form ring systems having 5-12 ring members, as defined above;
R* denotes (C;-C,;)-alkyl, mono-, bi- or tricyclic (C3-Cye) -CYC loalkyl, (C5-C,s) -CYC loalkylmethyl or (Cs-C,s) -cycloalkylethyl, the cycloalkyl part option- ally being substituted by (C,-C¢)-alkyl; dithiolanyl; (Ce~Cyi)-arylmethyl; dithiolanylmethyl; dithiolanyl- ethyl; dithianyl; dithianylmethyl or dithianylethyl;
R® denotes hydrogen; azido; azido-(C,-C,)-alkyl; (C,-C,;) -alkyl, which can optionally be substituted by hydroxyl, azido or hydroxyl and azido; (C3-Cy2)- cycloalkyl; (C,-C,,) -cycloalkyl-(C,-Cg)-alkyl: (C,-Cyp) ~cycloalkylsulfonyl-(Cy-Cs) -alkyls (C,~Ce) - alkylsulfonyl-(C,-Ce¢)-alkyl; (Ce~C,.) —aryl or (Ce=Cis)- aryl-(C,-C¢)-alkyl, it also being possible for aryl to represent the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic hetero- aromatic having at least carbon atom, 1 - 4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members and which can also be partly or completely hydrogenated, and it is like- wise possible that aryl and heteroaryl can be substituted as defined under a),
R® and R’ independently of one another denote hydrogen or (C,-Cs)-alkyl; or, together with the boron atom and the oxygen atoms, form a mono-, bi- or tricyclic, saturated or partly unsaturated, mono-, di-, tri- or tetra-(C,-C¢)-
“te 26584 alkylated or -phenylated ring system having 5-18 ring members, which, in addition to the boron atom, the oxygen atoms and the carbon atom(s), can also contain an -0O- member, an -NR!*- member or a -CR¥R!’- member;
R® represents hydrogen or (C,~Cy;)-alkyl, or, together with R® and the atoms carrying these, forms a mono- or bicyclic, saturated or partly unsaturated ring system having 5-12 ring members;
RY is hydrogen or (C,-Cg)-alkyl, or, together with R! or
R® and the atoms carrying these, forms a mono- or bicyclic, saturated or partly unsaturated ring system having 5-12 ring members, which, in addition to the carbon atom, can also contain 1 sulfur atom, which can optionally be oxidized to the sulfoxide or sulfone;
R' and R' independently of one another denote hydrogen, hydroxyl or (C4,-C,,)-aryl, aryl optionally being sub- stituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C,;-C;)-alkoxy, (C,-C,)-alkyl, (C,-C,)- alkoxycarbonyl, amino, (C;-C,)-alkylamino, di-(C,-C,)- alkylamino, carboxyl, carboxymethoxy, amino-(C,-C,)- alkyl, (C,-C,)-alkylamino-(C,-C,)-alkyl, di-(C,-C,;)- alkylamino-(C,-C,)-alkyl, (C,~C,)-alkoxycarbonyl- methoxy, carbamoyl, sulfamoyl, (C,~C,)-alkoxysulfonyl and sulfo- and guanidino-(C,~Cgz)-alkyl; or represent the radical of a 5- or 6-membered monocyclic or 9- or l0-membered bicyclic, optionally partly or com- pletely hydrogenated heteroaromatic having at least 1 carbon atom, 1 - 4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members and which is optionally mono- or disubsti- tuted like (Cq-C,,)-aryl above, n and m independently of one another can be 0, 1, 2,
- 5 = 3 or 4,
R!* denotes hydrogen or (C,-C,;)-alkyl, which is option- ally mono- Or diunsaturated and is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (C,-C,) -alkoxy, amino and mono- Or di-(C,-C;)-alkyl- amino, and
R™ and RY independently of one another denote hydrogen, (C,-Cg)-alkyl, hydroxymethyl, 2-hydroxyethyl, (3- hydroxysulfonyl, 2-hydroxypropyl)amino, (2-hydroxy- sul fonylethyl)amino, (2-hydroxysulfonylpropyl)amino, (carboxymethyl)amino or bis (2-hydroxyethyl)amino, and physiologically tolerated salts thereof.
A radical of a 5- or 6-membered monocyclic or 9- or 10- membered bicyclic heteroaromatic having at least 1 carbon atom, 1 - 4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members is understood as meaning radicals of heteroaromatics such as are defined, for example, in Katritzky and Lagowski, Chemie der Heterocyclen [Chemistry of the Heterocyclics],
Berlin, Heidelberg 1968. The heteroaromatic radical can be substituted by one, two Or three, preferably one or two, identical or different radicals from the series comprising F, Cl, Br, 1, hydroxyl, (C,~-C,)-alkoxy, (Ci- c,)-alkyl, (C,-C,)-alkoxycarbonyl, amino and trifluoro- methyl. Examples of monocyclic heteroaromatics are thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-triazole, thia- zole, tetrazole, isothiazole, oxazole and isoxazole.
Examples of bicyclic heteroaromatics are benzothiophene, benzofuran, indole, isoindole, indazole, benzimidazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline and cinnoline. Corresponding statements apply to radicals derived from heteroaryl, such as, for example, completely or partly hydrogenated heteroaryl, inter alia also, for example, benzodioxolane, hetero-
-6 ~ aryloxy, heteroarylthio and heteroaryl-alkyl.
Alkyl can be straight-chain or branched. The correspond- ing statement applies to radicals derived therefrom, such as, for example, alkoxy, alkylthio, alkylamino, dialkyl- amino, alkylsulfinyl, alkylsulfonyl, alkanoyl or aralkyl. (Ce-C,.)-Aryl is, for example, phenyl, naphthyl, bi- phenylyl or fluorenyl; phenyl and naphthyl are preferred.
Corresponding statements apply to radicals derived therefrom, such as, for example, aryloxy, aroyl, aralkyl and aralkyloxy. Aralkyl is understood as meaning an unsubstituted or substituted (Ce-C,,)-aryl radical linked to (C,-C¢)-alkyl, such as, for example, benzyl, 1- and 2- naphthylmethyl, halobenzyl and alkoxybenzyl, but aralkyl would not be limited to the radicals mentioned.
Salts of compounds of the formula I are to be understood as meaning, in particular, pharmaceutically usable or non-toxic salts.
Such salts are formed, for example, from compounds of the formula I which contain acid groups, for example car- boxyl, with alkali metals or alkaline earth metals, such as Na, K, Mg and Ca, and with physiologically tolerated organic amines, such as, for example, triethylamine and tri-(2-hydroxy-ethyl)-amine.
Compounds of the formula I which contain basic groups, for example an amino group or a guanidino group, form salts with inorganic acids, such as, for example, hydro- chloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.
Compounds of the formula I in which the radicals are defined as follows are preferred:
A is as defined on page 1,
R preferably denotes hydrogen or represents (C,-C,,)- alkyl; cyclopentyl; cyclohexyl; cyclopentyl-(C,-C,,)- alkyl; cyclohexyl-(C,-C,,)-alkyl; optionally substi- tuted phenyl-(C,-Cg)-alkyl; 2-pyridyl-(C;-Cg)-alkyl; 3-pyridyl-(C,-Cg)-alkyl; 4-pyridyl-(C,-Cs) -alkyl; H,N- (C,-C,o)-alkyl; HO-(C,~-C,,)-alkyl; (C,~C,)-alkoxy- (C,-Cyo)-alkyl; (C,-C,)-alkoxycarbonyl-(C,-C,,)-alkyl; (C,-Cy)-alkylsulfonyl; (C,-Cg)-alkylsulfinyl; (C,-Cq)- hydroxyalkylsulfonyl; (C,-Cs) ~-hydroxy-alkylsulfinyl; hydroxy-(C,-C,,)-alkanoyl, such as 2-hydroxypropio- : nyl, 3-hydroxypropionyl, 3-hydroxybutyryl or 2- hydroxy-3-methyl-butyryl; (C,-Cs)-alkanoyloxy-(C,-
Co) -alkyl; (C,-C,;)-alkanoyl, such as n-decanoyl, formyl, acetyl, propionyl, pivaloyl, isovaleryl or isobutyryl; optionally protected amino-(C,~-Cy,)- alkanoyl, such as (3-amino-3,3-dimethyl)propionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 4-N-tert.-butoxycarbonylaminobutyryl, 5-N-tert.- butoxycarbonylaminopentanoyl or 6-N-tert.-butoxy- carbonylaminohexanoyl; di-(C,-C,)-alkylamino-(C,-
C,,)-alkanoyl, such as dimethylaminoacetyl; piperi- dino-4-carbonyl; morpholino-4-carbonyl; (Cy3=Cy) - cycloalkylcarbonyl, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclo- hexylcarbonyl; (Cg=Cyo) -aryl-(C,-C,,) -alkanoyl, such as phenylacetyl, phenylpropanoyl or phenylbutanoyl; 2- pyridyl-(C,-C¢)-alkanoyl; 3-pyridyl-(C,~Cg)~alkanoyl; 4-pyridyl-(C,~C,y)-alkanoyl; benzoyl which is option- ally substituted by halogen, (C,-C,)-alkyl, (C,-C;)- alkoxy or (C,-C,)-alkoxycarbonyl, such as 4-chloro- benzoyl, 4-methylbenzoyl, 2-methoxycarbonylbenzoyl or 4-methoxybenzoyl; pyrrolyl-2-carbonyl, pyridyl- 3-carbonyl; benzenesulfonyl; (C;~Cy) -alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, isobutoxy- carbonyl or tert.-butoxycarbonyl; substituted (C,-
C,o)-alkoxycarbonyl, such as 2-(trimethylsilyl)-
ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 1,1-dimethyl-2,2,2~trichloroethoxycarbonyl;(C¢-C,,)- aryl-(C,~Cg)-alkoxycarbonyl, such as benzyloxycar- bonyl, 1- or /2-naphthylmethoxycarbonyl or 9- fluorenylmethoxycarbonyl; or R!, together with R, preferably forms a mono- or bicyclic saturated or partly unsaturated ring system having 5-12 ring members, which, in addition to carbon, can also contain 1 sulfur atom, which can optionally be oxidized to the sulfoxide or sulfone,
R? is preferably hydrogen, methyl or ethyl, or, together with R’ and the atoms carrying these, preferably forms pyrrolidine or piperidine, each of which can also be fused with cyclopentyl, cyclohexyl or phenyl,
R’ and R® independently of one another are preferably hydrogen; (C;-C,,)-alkyl, which is optionally mono- = or diunsaturated and which is optionally substituted ' by up to 3 identical or different radicals from the series comprising hydroxyl, (C,-C,)-alkoxy, (C,-C,)- alkanoyloxy, carboxyl, (C,-C,)-alkoxycarbonyl, Cl,
Br, amino, amidino, guanidino, carbamoyl, (C,-C;)- alkoxycafbonylamino, (Ce¢-C,s) ~aralkoxycarbonylamino and 9-fluorenylmethoxycarbonylamino; (C,-C,,)-cyclo- alkyl, (C,;-C,;)-cycloalkyl-(C,-C;)-alkyl or mono- or bicyclic (Ce-C,,)-aryl-(C,-C;)-alkyl, which is option- ally substituted by one or two identical or dif- ferent radicals from the series comprising F, Cl,
Br, I, hydroxyl, (C;-C,)-alkoxy, (C,-C,)-alkyl, (C,-
C,)-alkylcarbonyl, amino and trifluoromethyl; or preferably represents (C,-C;)-alkyl, substituted by the radical of a 5- or 6-membered monocyclic or 9- or l0-membered bicyclic, optionally partly or com- pletely hydrogenated heteroaromatic having at least 1 carbon atom, 1 - 4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members and which is optionally mono- or disubsti-
tuted as described for the aryl part on page 2, or, together with R® or R°, form ring systems as described above under R%;
R* is preferably (C;-C,;)-alkyl; mono-, bi- or tricyclic (C,-Cy5) -cycloalkyl or (C,-Cyp) -cycloalkylmethyl, the cycloalkyl part optionally being substituted by (C,-C,)-alkyl; (Ce=Ci14) -arylmethyl; dithiolanyl; dithiolanylmethyl; dithianyl or dithianylmethyl; rR’ preferably represents hydrogen, azido, azido-(C,-C,)- alkyl, (C,-C,;)-alkyl, (C;-C,,) -cycloalkyl, (C3-Cy2)- cycloalkyl-(C;-Cs) -alkyl, (2-pyridyl)-(C,-C,)-alkyl, (3-pyridyl)-(C,-C,)-alkyl, (4-pyridyl)-(Ci-Cy)-alkyl, imidazol-2-yl, imidazol-1-yl, imidazol-4-yl, (imidazol-2-yl)-(C,-C,)-alkyl, (imidazol-1-yl)- (c,~C,)-alkyl, (imidazol-4-yl) -(Cc,-C,)-alkyl, [1- (C,-Cq) -alkylimidazol-2-y1]-(C,-Ci)-alkyl, (imid- azolin-2-yl)-(C,-C,)-alkyl or [1-(C,-Cs)-alkylimida- zolin-2-yl}-(C,-C,)-alkyl;
R® and R’ independently of one another are preferably hydrogen or, together with the boron atom and the oxygen atoms, form a mono-, bi- or tricyclic, saturated or partly unsaturated mono-, di-, tri- or tetraalkylated or -phenylated ring system having 5 - 18 ring members, which, in addition to the boron atom, the oxygen atoms and the carbon atom(s), can also contain an -O- member, an -NR!*- member or a -
CR*R!*- member;
R® is preferably hydrogen, methyl or ethyl, or, to- gether with R® and the atoms carrying these, forms pyrrolidine or piperidine, each of which can addi- tionally be fused with cyclopentyl, cyclohexyl or phenyl;
RY is preferably hydrogen or methyl, or, together with
R! or R® and the atoms carrying these, forms a mono-
or bicyclic saturated or partly unsaturated ring system having 5 - 12 ring members, which, in addi- tion to carbon, can also contain 1 sulfur atom, which can optionally be oxidized to the sulfoxide or sulfone;
R!! and R!? independently of one another are preferably hydrogen, hydroxyl, phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 1-, 2- or 4-imidazolyl, 1- or 2- naphthyl or 2- or 3-benzo[b]thienyl, n and m independently of one another can denote 0, 1, 2, 3 or 4,
Rr? is preferably hydrogen or (C,-C,;)-alkyl; and
R™ and R!’ independently of one another preferably denote hydrogen, hydroxymethyl, 2-hydroxyethyl, (3- hydroxysulfonyl, 2-hydroxypropyl)amino, (2-hydroxy- sulfonylethyl)amino, (2-hydroxysulfonylpropyl)amino, (carboxymethyl)amino or bis(2-hydroxyethyl)amino.
R! particularly preferably denotes (C,-C4)-alkylsul- fonyl; (C,~Cg)-alkylsulfinyl; (C,-Cg)-hydroxyalkylsul- fonyl, in particular 2-hydroxyethylsulfonyl or 2- hydroxypropylsulfonyl; hydroxy-(C,-C,,) ~alkanoyl, such as 2-hydroxypropionyl, 3-hydroxypropionyl, 3- hydroxybutyryl or 2-hydroxy-3-methylbutyryl; (C,-C¢)- alkanoyloxy-(C,-C,,)-alkyl; (C,-C,;)alkanoyl, such as n-decanoyl, formyl, acetyl, propionyl, pivaloyl, isovaleryl or isobutyryl; amino-(C,~C,,)-alkanoyl, such as (3-amino, 3,3-dimethyl)propionyl, 4-amino- butyryl, S5-aminopentanoyl, 6-aminchexanoyl; di-(C,-
C,)-alkylamino-(C,-C,;) ~alkanoyl, such as dimethyl- aminoacetyl; piperidino-4-carbonyl; morpholino-4- carbonyl; (C,-Cg)-cycloalkylcarbonyl, such as cyclo- propylcarbonyl, cyclobutylcarbonyl, cyclpentylcar- bonyl or cyclohexylcarbonyl; (Cg¢-C,,)-aryl-(C,-Cy)- alkanoyl, such as phenylacetyl, phenylpropanoyl or phenylbutanoyl; 2-pyridyl-(C,-Cq)-alkanoyl; 3-pyr- idyl-(C,-C,)-alkanoyl; 4-pyridyl-(C,-Cy)-alkanoyl; benzoyl which is optionally substituted by halogen, (c,-C,)-alkyl, (C,-C;)-alkoxy or (C,-C,)-alkoxycar- bonyl, such as 4-chlorobenzoyl, 4-methylbenzoyl, 2- methoxycarbonylbenzoyl or 4-methoxybenzoyl; pyr- rolyl-2-carbonyl; pyridyl-3-carbonyl; benzenesul- fonyl; (C,-C,)-alkoxycarbonyl, such as methoxycar- bonyl, ethoxycarbonyl, isobutoxycarbonyl or tert.- butoxycarbonyl; substituted (C,-C,0) alkoxycarbonyl, such as 2-(trimethylsilyl)-ethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl or 1,1-dimethyl-2,2,2- trichloroethoxycarbonyl; or (Cg-C;,)-aryl-(C,~Cq)- alkoxycarbonyl, such as benzyloxycarbonyl, 1- or 2- naphthylmethoxycarbonyl or 9-fluorenylmethoxycar- bonyl, rR? particularly preferably denotes hydrogen or methyl, or, together with R’ and the -N-CH- group carrying these radicals, forms a tetrahydroisoquinoline or azabicyclooctane skeleton,
R® and R' independently of one another are particularly preferably hydrogen, methyl, ethyl, isopropyl, n- propyl, n-butyl, isobutyl, sec.-butyl, 3-guanidino- propyl, carbamoylmethyl, 2-carbamoylethyl, carboxy- methyl, 2-carboxyethyl, mercaptomethyl, 2-(methyl- thio)ethyl, (l-mercapto,l-methyl)ethyl, hydroxy- methyl, l-hydroxyethyl, amino, aminomethyl, 2- aminoethyl, 3-aminopropyl, 4-aminobutyl, N,N- dimethylamino, cyclohexylmethyl, imidazol-4-yl- methyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, indol-3-yl-methyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, (benzodi- oxolan-5-yl)methyl, 2-thienyl, 2-thienylmethyl, 2- (2-thienyl)-ethyl, 3-thienyl, 3-thienylmethyl, 2-(3- thienyl)ethyl, 4-chlorobenzyl, 2-(methylsulfinyl)- ethyl, 2-(methylsulfonyl)ethyl, 2-pyridylmethyl, 3- pyridylmethyl, 4-pyridylmethyl, cyclohexyl, (1-
methyl-imidazol-4-yl)methyl, (3-methyl-imidazol-4- yl)methyl, phenyl, 1l-naphthylmethyl, 2-naphthyl- methyl, 2-phenylethyl, 2-thiazolylmethyl, 4-thi- azolylmethyl, 3-pyrazolylmethyl, 4-pyrimidinyl- methyl, indol-2-yl-methyl, 2-benzo[b]thienylmethyl, 3-benzo[b]thienylmethyl or 2-furylmethyl, or with R? or R®° form ring systems as defined above under R?, rR is particularly preferably (C;-C,,)-alkyl; mono- or bicyclic (C,;-C,,)-cycloalkyl or (C,-C,;)-cycloalkyl- methyl, the cycloalkyl part optionally being substi- tuted by (C,-C,)-aryl; (Cg-C,o)-arylmethyl; dithio- lanyl; dithiolanylmethyl; dithianyl or dithianyl- methyl,
R® is particularly preferably hydrogen, azido, azido- methyl, 2-azidoethyl, (C,-C;)-alkyl, (C,-C,;)-cyclo- alkyl, (C,-C,;)-cycloalkyl-(C,~C,)-alkyl, 3-(2-pyri- dyl)-propyl, 3-(3-pyridyl)-propyl, 3-(4-pyridyl)- propyl, imidazol-2-yl, imidazol-1-yl, imidazol-4-yl, (imidazol-2-yl)-propyl, (imidazol-1-yl)-propyl, (imidazol-4-yl)-propyl, [1-(C,-C,)-alkylimidazol-2- yl]-propyl or (imidazolin-2-yl)-propyl,
R® and R’ are as defined on page 9,
R® particularly preferably denotes hydrogen or methyl, or, together with R® and the -N-CH- group carrying these radicals, forms a tetrahydroisoquinoline or azabicyclooctane skeleton,
RY particularly preferably denotes hydrogen, or, together with R! and the atoms carrying these, forms a mono- or bicyclic saturated or partly unsaturated ring system having 5-12 ring members, which, in addition to carbon, also contains 1 sulfur atom, which is particularly preferably oxidized to the sulfone, or, together with R® and the atoms carrying these, forms a thiochroman system, the sulfur atom of which is particularly preferably oxidized to the sulfone,
RY and RY? independently of one another are particularly preferably hydrogen, hydroxyl, phenyl, 2-thienyl, 2-, 3- or 4-pyridyl, 1- or 2-imidazolyl, l-naphthyl or 2- or 3-benzo[b]thienyl, n and m independently of one another are particularly preferably 0, 1 or 2,
R® is particularly preferably hydrogen or (C,-C,)-alkyl, and
R!* and R!® are as defined on page 10.
The invention furthermore relates to a process for the preparation of compounds of the formula I, which com- prises coupling a fragment having a terminal hydroxyl group or a reactive derivative thereof with a correspond- ing fragment having a free amino group, if appropriate splitting off (a) protective group(s) temporarily intro- duced to protect other functional groups, and if appro- priate converting the compound thus obtained into its physiologically tolerated salt.
Fragments of a compound of the formula I having a ter- minal carboxyl group have the following formulae VI and
VII
A - OH (VI)
A-N-CH-C- OH (VII) 0
Fragments of a compound of the formula I having a ter- minal amino group have the following formulae VIII to X rR? rR o RZ RI oo r4 ) ) # | ; " i 5 (VIII)
HN - CH- C- N- CH - C- HN - CH - CH - R \ or® or’
RZ rR3 0 r4 ' i" 5 (1X)
HN - CH - C - HN - CH - CH - R ! \ or® or’ kd
H,N - CH- CH - R (X)
B or® or’
Methods which are suitable for the production of an amide 5 bond are described, for example, in Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry],
Volume 15/2; and Bodanszky et al., Peptide Synthesis, 2nd ed. (Wiley & Sons, New York 1976) or Gross and
Meienhofer, The Peptides: Analysis, Synthesis, Biology (Academic Press, New York 1979). The following methods are preferably used: active ester methods with N-hydroxy- succinamide, l-hydroxybenzotriazole or 3-hydroxy-4-oxo- 3,4-dihydro-1,2,3-benzotriazine as the alcohol component, coupling with a carbodiimide, such as dicyclohexylcarbo- diimide, or with propanephosphonic anhydride and the mixed anhydride method with pivaloyl chloride or ethyl or isobutyl chloroformate.
Fragments of the formula VI where they a) fall under formula II are synthesized by the gener- ally known methods for the preparation of amino acids; b) fall under formula III are synthesized starting from the corresponding amino acids, the chirality center thereof being retained. Diazotization at -20°C to 50°C in dilute mineral acids leads to a-bromo- carboxylic acids or, via the lactic acids, to a- trifluoromethanesulfonyloxy-carboxylic acids, which can be reacted with a nucleophile carrying R!' and
RY; c) fall under formula IV are prepared starting from malonic esters, alkylation of which with arylalkyl halides gives mono- or disubstituted malonic esters, which, after hydrolysis, can be converted into the desired derivatives by decarboxylation. In the case where one of the radicals R!' or R'? denotes hydroxyl, the corresponding amino acid is used as the starting substance and diazotization (as described above) gives the lactic acid (number of CH; groups carrying
R! or R? = 0), or the substituted malonic acid is used as the starting substance, monohydrolysis and selective reduction (with, for example, diborane or
LiAlH,) giving the 2-substituted 3~-hydroxy-propionic acid.
Fragments of the formula VII are synthesized by the generally known methods for the preparation of amino acids and peptides.
For the synthesis of the fragments of the formula X, N- protected a-amino acids are converted into the a-amino- aldehydes in accordance with the method of B. Castro et al. (Synthesis 1983, 676). A Wittig reaction with a phosphonium salt carrying the radical R® then takes place, followed by hydroboronation.
The preliminary and subsequent operations required for the preparation of compounds of the formula I, such as
/ - 16 - introduction and splitting off of protective groups, are known from the literature and are described, for example, in T.W. Greene "Protective Groups in Organic Synthesis” (John Wiley & Sons, New York, 1981). Salts of compounds of the formula I with salt-forming groups are prepared in a manner which is known per se, for example by reacting a compound of the formula I having a basic group with a stoichiometric amount of a suitable acid, or reacting compounds of the formula I having an acid group with a stoichiometric amount of a suitable base. Stereoisomer mixtures, in particular diastereomer mixtures, which are obtained, if appropriate, in the synthesis of /¢ompounds of the formula I, can be resolved in a manner which is known per se by fractional crystallization or by chroma- tography.
The compounds of the formula I according to the invention exhibit enzyme-inhibiting properties, and in particular they inhibit aspartyl proteases, such as renin.
Renin is secreted into the blood circulation by the juxtaglomerular cells of the kidneys as a result of various stimuli (volume depletion, sodium deficiency, 8- receptor stimulation). In the blood circulation it splits off the decapeptide angiotensin I from the angioten- sinogen secreted from the liver. This angiotensin I is converted into angiotensin II by "angiotensin converting enzyme" (ACE). Angiotensin II plays an essential role in blood pressure regulation, since it increases the blood pressure directly by vasoconstriction. In addition, it stimulates the secretion of aldosterone from the adrenal gland and in this way, via inhibition of the excretion of sodium, increases the extracellular fluid volume, which in turn contributes towards increasing the blood pres- sure. Inhibitors of the enzymatic activity of renin cause reduced formation of angiotensin I, which results in reduced formation of angiotensin II. The reduction in the concentration of this active peptide hormone is the direct cause of the antihypertensive action of renin inhibitors.
The activity of renin inhibitors can be investigated by in vitro tests. In these, the reduction of the formation of angiotensin I is measured in various systems (human plasma and purified human renin). 1. Test principle
For example, human plasma which contains both renin and angiotensinogen is incubated at 37°C with the compound to be tested. During this incubation, angiotensin I is liberated from the angiotensinogen under the action of renin, and can subsequently be measured with a commer- cially available radioimmunoassay method. This angio- tensin liberation is inhibited by renin inhibitors. 2. Isolation of the plasma
The blood is obtained from volunteer subjects (about 0.5 1 per person; Bluko withdrawal apparatus from ASID
Bonz und Sohn, Unterschleissheim) and is collected in partially evacuated bottles, while cooling with ice. The coagulation is prevented by addition of EDTA (final concentration 10 mM). After centrifugation (Rotor HS 4 (Sorvall), 3500 r.p.m., 0-4°C, 15 minutes; repeat if necessary), the plasma is carefully pipetted off and frozen in suitable portions at -30°C. Only plasmas with a sufficiently high renin activity are used for the test.
Plasmas with a lower renin activity are activated (prorenin -> renin) by a low temperature treatment (-4°C, 3 days). 3. Test procedure
Angiotensin I is determined with the Renin-Maia® kit (Seronon Diagnostics S.A., Coinsins, Switzerland). The plasma is incubated in accordance with the instructions given with the kit:
Incubation batch: 1000 ul of plasma (thawed at 0-4°C) 100 ul of phosphate buffer (pH 7.4) addition of 10" M ramipri late) 100 ul of PMSF solution sl of 0.1 % strength Genapol PFIC 12 ul of DMSO or test preparation
The test preparations are in general dissolved in a 10 concentration of 102 M in 100 % pure dimethyl sulfoxide (DMSO) and the solutions are diluted appropriately with
DMSO; the incubation batch contains not more than 1 % of
DMSO.
The batches are mixed with ice and placed in a water bath (37°C) for 1 hour for incubation. A total of 6 samples (in each case 100 ul) are taken from an additional batch without inhibitor and without further incubation in order to determine the initial angiotensin I content of the plasma used.
The concentrations of the test preparations are chosen so that approximately the range from 10 - 90 % enzyme inhibition is covered (at least five concentrations). At the end of the incubation time, three 100 ul samples from each batch are frozen on dry ice in pre-cooled Eppendorf vessels and kept at about -25°C for the angiotensin I determination (mean value of three individual samples).
Angiotensin I radioimmunoassay (RIA)
The use instructions of the RIA kit (Renin Maiee kit,
Serono Diagnostics S.A., Coinsins, Switzerland) are followed exactly.
The calibration curve covers the range from 0.2 to 25.0 ng of angiotensin I per ml. The base angiotensin I content of the plasma is subtracted from all the measure- ment values. The plasma renin activity (PRA) is given in ng of Ang I/ml x hour. The PRA values in the presence of the test substances are based on a batch without in- hibitor (= 100 %) and given as % residual activity. The 1C,, value is read off from the plot of the % residual activity against the concentration (M) of the test preparation (logarithmic scale).
The compounds of the general formula I described in the present invention exhibit inhibiting actions in the in vitro test at concentrations of about 107° to 107° mol/l.
Renin inhibitors cause a reduction in blood pressure in animals with salt depletion. Since human renin differs from the renin of other species, primates, such as, for example, rhesus monkeys, are used for the in vivo test of renin inhibitors. Primate renin and human renin are largely homologous in their sequence. An endogenous renin secretion is stimulated by intravenous injection of furosemide. The test compounds are then administered and their action on the blood pressure and heart rate is measured. The compounds of the present invention are active here in a dose range of about 0.1 - 5 mg/kg intravenously, on intraduodenal administration by a gastroscope in the dose range of about 1 - 50 mg/kg. The compounds of the general formula I described in the present invention can be used as antihypertensives and for the treatment of cardiac insufficiency.
T - 20 -
The invention furthermore relates to the use of compounds of the formula I for the preparation of pharmaceuticals for the therapy of high blood pressure and treatment of congestive cardiac insufficiency and to the pharmaceuticals mentioned.
Pharmaceutical preparations contain an effective amount of the active compounds of the formula I together with an inorganic or organic pharmaceutically usable excipient.
They can be administered intranasally, intravenously, subcutaneously, perorally or intraduodenally. The dosage of the active compound depends on the warm-blooded species, the body weight, the age and the mode of admini- stration.
The pharmaceutical preparations of the present invention are prepared by dissolving, mixing, granulating or tablet-coating processes which are known per se.
For the oral use form, the active compounds are mixed with the additives customary for these, such as excipi- ents, stabilizers or inert diluents, and the mixture is brought by customary methods into suitable presentation forms, such as tablets, coated tablets, hard gelatine push-fit capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. Examples of inert excipients which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate,
lactose, glucose, magnesium stearylfumarate or starch, in particular maize starch. Formulation can be effected here either in the form of dry granules or in the form of moist granules. Examples of possible oily excipients or solvents are vegetable or animals oils, such as sunflower oil and cod-liver oil.
For subcutaneous or intravenous administration, the active compounds or physiologically tolerated salts thereof are brought into solutions, suspensions or emulsions, if desired with the substances customary for these, such as solubilizing agents, emulsifiers or other additives. Examples of possible solvents are: water, physiological saline solutions or alcohols, for example ethanol, propanediol or glycerol, and in addition also sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents men- tioned.
List of abbreviations used
Ac acetyl
Boc tert. -butoxycarbonyl bp, boiling point under xx mm Hg
BuLi n-butyllithium
DCC dicyclohexylcarbodiimide
DCI desorption chemical ionization __
DIP diisopropyl ether
DMF dimethyl formamide
DMSO dimethyl sulfoxide
DNP 2,4-dinitrophenyl
EA ethyl acetate
EX electron impact
Etoc ethoxycarbonyl
FAB fast atom bombardment \ 'H hexane
HOBt 1-hydroxybenzotriazole
Iva isovaleryl
M molecular peak
M.p. melting point
MeOH methanol ; MS mass spectrum
MTB methyl tert.-butyl ether
Nle norleucine
Nva norvaline
R.T. room temperature
THF tetrahydrofuran
Thi p-2-thienylalanine
TLC thin layer chromatography
Zz benzyloxycarbonyl.
The other abbreviations used for amino acids correspond to the three-letter code customary in peptide chemistry, such as is described in Eur J. Biochem. 138, 9 - 37 (1984). Unless expressly indicated otherwise, the amino acids are always in the L-configuration.
The following examples serve to illustrate the present invention, without this being limited thereto.
Example 1 9 {3-tert.-Butylsulfonyl, 2-(2)-tHienylmethyl Jpropionyl-
Nva-[l-cyclohexylmethyl, 2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl), 5-methyl)hexylamide 346 mg of [3-tert.-butylsulfonyl,2-(2)-thienylmethyl]- propionyl-Nva-OH are dissolved in 40 ml of THF and first 98 ul of N-methylmorpholine and then 115 ul of isobutyl chloroformate are injected in at -20°C. After 10 minutes at -20°C, 123 ul of triethylamine are added. The mixed anhydride thus obtained is injected into a solution of 400 mg of [l-cyclohexylmethyl, 2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl), 5-methyl]hexylammonium tri- fluoroacetate in 40 ml of THF. The mixture is stirred at -20°C for 1 hour and left to stand at R.T. for 22 hours.
It is diluted with 100 ml of MTB and washed twice with 30 ml of 5 % strength aqueous NaHSO, solution each time and twice with 30 ml of 5 % strength aqueous Na,CO, solution each time. The organic phase is dried over Na,SO, and the solvent is removed in vacuo. Chromatography on silica gel with MTB/DIP = 1:1 gives 160 mg of the title compound as colorless crystals.
R, (MTB/DIP 1:1) = 0.50 MS (FAB): 709 (M+l) a) [3-t-Butylsulfonyl, 2-(2-thienylmethyl) ]propionyl-Nva-
OH
490 mg of [3-t-butylsulfonyl, 2-(2-thienylmethyl) ]Jpropio- nyl-Nva-OMe are dissolved in 4 ml of methanol, 0.4 ml of
H,0 and 0.7 ml of 2N NaOH are added and the mixture is stirred at R.T. for 5 hours. It is acidified to pH = 2 with NaHSO, solution and extracted 3x with 50 ml of EA.
The extract is then dried over Na,SO, and the solvent is removed in vacuo. 470 mg of pale yellow resin are ob- tained.
R, (EA) = 0.24 MS (FAB): 390 (M+1) b) [3-t-Butylsulfonyl, 2-(2-thienylmethyl)]propionyl-Nva-
OMe 1.5 g of [3-t-butylsulfonyl, 2-(2-thienylmethyl) ]Jpro- pionic acid and 0.95 g of Nva-OMe x HCl are dissolved in 40 ml of CH,Cl,, and first 3.8 ml of triethylamine and then 3.5 ml of a 50 % strength solution of propanephos- phonic anhydride in CHCl, are added at 10°C. The mixture is stirred at R.T. for 20 hours, the solvent is removed in vacuo, the residue is taken up in 100 ml of MTB and the mixture is washed with 100 ml each of NaHSO, solution and NaHCO, solution. It is dried over Na,SO,, the solvent is removed in vacuo and the residue is chromatographed with EA/H 1:1. 2 diastereomeric oils are obtained and are further processed separately.
Diastereomer 1 R, (EA/H 1:1) = 0.30 0.95 g
Diastereomer 2 R, (EA/H 1:1) = 0.20 0.95 g
MS (DCI, the same for both diastereomers): 404 (M+l) c) [3-t-Butylsulfonyl,2-(2-thienylmethyl) ]propionic acid 4.4 g of methyl [3-t-butylsulfonyl,2-(2-thienylmethyl)]- propionate are suspended in 50 ml of 5N HCl and the suspension is heated under reflux for 2 hours. After cooling, it is extracted 3x with 50 ml of EA, the extract is dried over Na,SO, and the solvent is removed in vacuo. 4.0 g of the title compound are obtained as a pale yellow oil.
R, (MTB) = 0.15 - 0.25 MS (DCI): 291 (M+1) d) Methyl [3-t-butylsulfonyl, 2-(2-thienylmethyl) ]pro- pionate 8.4 g of methyl [3-t-butylsulfonyl,2-(2-thienylmethyl)]- propionate are dissolved in 100 ml of CH,Cl,, and 10.6 g of m-chloroperbenzoic acid are added in portions, while cooling with ice. The mixture is stirred at R.T. for 1 hour and then washed first with 100 ml of 10 % strength
Na,SO, and then with 100 ml of NaHCO,. It is dried over
Na,SO, and the solvent is removed in vacuo. 7.2 g of the title compound are obtained as a colorless oil.
R, (MTB) = 0.56 MS (DCI): 305 (M+1) e) Methyl [3-t-butylthio, 2-(2-thienylmethyl)]propionate 6.1 ml of t-butyl mercaptan are dissolved in 100 ml of
MeOH (anhydrous) and 130 mg of NaH are added under argon. 7.6 g of methyl 2-(2-thienylmethyl)acrylate are then added dropwise and the mixture is stirred at R.T. for 4 hours. The solvent is removed in vacuo, the residue is taken up in 100 ml of MTB and the mixture is washed with 100 ml of 5 % strength NaHSO, solution. It is dried over
Na,SO, and the solvent is removed in vacuo. 10.4 g of the title compound are obtained as a pale yellow liquid, which is used further without purification and charac- terization.
R, (DIP/H 1:5) = 0.31 f) Methyl 2-(2-thienylmethyl)acrylate 11.8 g of monomethyl 2-thienylmethylmalonate, 5.8 ml of diethylamine and 5.0 ml of 36 % strength aqueous form- aldehyde solution are stirred at R.T. under argon for 1 hour. The water is then removed in vacuo and the residue is chromatographed. 7.6 g of the title compound are obtained as a colorless liquid.
R, (MTB/H 1:5) = 0.49 g) Monomethyl 2-thienylmethylmalonate 20.1 g of dimethyl 2-thienylmethylmalonate are dissolved in 300 ml of MeOH and 5.0 g of KOH are added. The mixture is stirred at R.T. for 7 hours, the solvent is removed in vacuo and the residue is taken up with 100 ml each of 5 % strength Na,CO, solution and EA. The aqueous phase is then acidified to pH = 2 and extracted 3x with 100 ml of EA each time. The extract is dried over Na,SO, and the solvent is removed in vacuo. 16.0 g of the title compound are obtained as a pale yellow oil. h) Dimethyl 2-thienylmethylmalonate : 87.8 g of dimethylmalonate and 41.0 g of potassium t- butylate are dissolved in 1.11 of THF (anhydrous), while cooling with ice, and 44.1 g of 2-thienylmethyl chloride
- 26 ~- in 500 ml of THF are added dropwise, under argon. The mixture is stirred at R.T. for 3 hours, the KCl is filtered off, the solvent is removed in vacuo and the residue is chromatographed. 33.8 g of the title compound (I) are obtained as a colorless oil alongside 8.8 g of dimethyl bis-(2-thienylmethyl)malonate (II)
R, (I) (toluene/DIP 20:1) = 0.35
R, (II) (toluene/DIP 20:1) = 0.44 g) 2-Thienylmethyl chloride 252 g of thiophene are suspended in 128 ml of concen- trated aqueous HCl and HCl gas is passed in at 0°C for 1 hour. 255 ml of 35 % strength aqueous formaldehyde solution are then added dropwise without interrupting the stream of HCl, and the mixture is stirred at 0°C for a further 15 minutes. After removal of the organic phase, the aqueous phase is extracted twice more with 600 ml of
CH,Cl,. The extract is then washed twice with 600 ml of saturated aqueous Na,CO, solution and dried over Na,SO,, the solvent is removed in vacuo and the residue is distilled. 174 g of the title compound are obtained as a colorless liquid. bp,, = 81 - 84°C h) [1-Cyclohexylmethyl, 2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl), 5-methyl]hexylammonium trifluoro- acetate 520 mg of Z-[l-cyclohexylmethyl, 2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl), 5-methyl}hexylamine and 95 xl of trifluoroacetic acid are dissolved in 10 ml of EtOH, 105 mg of Pd/C are added and hydrogenation is carried out ’ at R.T. under a pressure of 1 bar for 2.5 hours. The catalyst is then filtered off and the solvent is removed in vacuo. 400 mg of the title compound are obtained as a colorless oil which is used further without purification.
MS (DCI) : 338 (M+1) i) 2Z-[1-Cyclohexylmethyl, 2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl), 5-methyl]hexylamine 6.5 g of 2-(1l-cyclohexylmethyl, 5-methyl)-hex-2-en-amine are dissolved in 190 ml of THF under argon. 5.7 ml of
BH,-S(CH,), are added dropwise at 0°C and the mixture is stirred at R.T. for 1 hour. Water is then slowly added dropwise until the evolution of hydrogen has ended, The solvent is removed in vacuo and subsequently evaporated twice on a rotary evaporator with 100 ml of toluene each time. The residue is dissolved in 120 ml of CHCl, and 11.2 g of pinacol are added. The mixture is boiled for 4 hours over a water separator, the CH, Cl, is removed in vacuo and the residue is chromatographed on silica gel with EA/n-hexane = 1:8. 4.7 g of the title compound are obtained as a diastereomer mixture, which can be separ- ated by renewed chromatography.
R, (EA/n-hexane = 1:8) = 0.25 MS (DCI) : 472 (M+1) 0.22 k) 2-(1-Cyclohexylmethyl, S-methyl)-hex-2-en-amine 13.1 g of (isopentyl, triphenyl)phosphonium bromide are suspended in 280 ml of THF, and 3.2 g of potassium tert.- butylate are added. The mixture is stirred at R.T. for 2.5 hours and then cooled to 0°C, and 8.3 g of 2-(2(S)- cyclohexylmethyl)-aminoacetaldehyde in 100 ml of THF are added dropwise. The mixture is stirred at R.T. for 1 hour, 200 ml of MTB are added and the mixture is washed twice with 50 ml of 5 % strength agueous NaHSO, solution each time and twice with 50 ml of 5 % strength aqueous
NaHCO, solution each time. The organic phase is dried over
Na,SO, and the solvent is removed in vacuo. Chromatography on silica gel gives 6.5 g of the title compound as a colorless oil.
R, (EA/n-hexane = 1:8) = 0.28 MS (DCI) : 344 (M+l)
Examples 2 and 3 were synthesized analogously to Example 1:
Example 2 [2-(S)-Benzyl,3-tert.-butylsulfonyl]propionyl-Nva-[1- cyclohexylmethyl,2-(4,4,5,5-tetramethyl-1,3,2-dioxa- borolan-2-yl),5-methyl Jhexylamide
R, (MTB/DIP 1:1) = 0.52 MS (FAB) : 703 (M+1)
Example 3 [3-tert.-Butylsulfonyl,2-(l-naphthylmethyl)}propionyl-
Val-[l-cyclohexylmethyl,2-(4,4,5,5-tetramethyl-1,3,2~ P-9 dioxaborolan-2-yl),2-cyclopentyl Jmethylamide
R, (MTB/DIP 1:1) = 0.42 MS (FAB) : 751 (M+1)
Example 4
Boc-Phe-His-[1-Cyclohexylmethyl, 2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl),5-methyl Jhexylamide 300 mg of Boc-Phe-His(DNP)-[Cyclohexylmethyl, 2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl),5-methyl]-hexylamide are dissolved in 5 ml of acetonitrile and 281 xl of thiophenol are added. The mixture is stirred for 3 hours at R.T., the solvent is removed in vacuo and the residue is chromatographed on silica gel with MeOH/EA 1:20. 130 mg of the title compound are obtained as a colorless ~ amorphous powder.
R, (EA/MeOH 20:1) = 0.35 MS (FAB) : 722 (M+1)
26584 = a) 'Boc-Phe-His (DNP)-[1-Cyclohexylmethyl,2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl),5-methyl]hexylamide
The title compound was synthesized analogously to Example 1.
R, (MTB) = 0.27 MS (FAB) : 872 (M+l)
Example 5 was synthesized analogously to Example 4:
Example 5 [2-(S)-Benzyl,3-tert.-butylsulfonyl]propionyl-His-[1- cyclohexylmethyl,2-(4,4,5,5-tetramethyl-1,3,2-dioxa- borolan-2-yl),5-methyl Jhexylamide
R, (EA/MeOH 10:1) = 0.20 MS (FAB) : 741 (M+1)
Example 6 [2-(S)-Benzyl,3-tert.-butylsulfonyl]propionyl-His-[1- cyclohexylmethyl, 2-dihydroxyboryl,5-methyl Jhexylamide 217 mg of the title compound of Example 5 and 220 ul of titanium isopropoxide are dissolved in 100 ml of n- propanol and boiled for 8 hours under a Soxhlet extractor which is filled with 0.3 nm molecular sieve. The reaction solution is poured onto 100 ml of saturated NaHCO, solu- tion, the TiO, is filtered off, the solution is extracted 3 times with 50 ml of EA and dried over Na,SO,. The solvent is removed in vacuo and chromatographed on silica gel with CH,C1,/MeOH 10:1. 43 mg of the title compound are obtained as a white amorphous powder.
R, (CH,C1l,/MeOH 10:1) = 0.28 MS (FAB) : 659 (M+1)
Claims (2)
- - 3¢ - — ENCLOSURE I HOE B8B/F 336 NEW PATENT CLAIMI. A compound of the formula I rR? R3 rR? I { ! 5 A-N-CH-CO-NH-CH-CHG-R B /\ (1) or® or’ in which ” A denotes a radical of the formula II or III A: (x1) R' - N-cH-cC- 1 | i " v R* - CH - CH - C - : = E * G . = ~~ 3 in which - . rl denotes (C1-%)-alkyl, or Rl denotes a radical of the formula R1' - w (v) | | h - in which rl is defined as rR? above and W represents -0-CO- or - - ) ~~ R” denotes hydrogen; R3 denotes (C,-C4)-alkyl or imidazolyl-(C,-C,)-alkyl; RY denotes (Cg-Cgl-cycloalkyl -(C,-C,)-alkyl, R® denotes (C,-Cg)-alkyl; RS and rR’ independently of one another denote hydrogen or, together with the boron atom and the oxygen atoms, form a monocyclic, sesturated mono-, di-, tri- or J tetra-(C,-C,)-alkylated ring system having 5-7 ring members;v8 . . R™ denotes (Cg-Cy 4) -aryl-(C, -C,)-alkylor thienyl-(C,-C,)-8alkyl; 9 R™ represents hydrogen; p10 is hydrogen or a physiologically tolerated salt thereof.
- 2. A pharmaceutical agent containing a compound of the formula I as claimed in
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3840452A DE3840452A1 (en) | 1988-12-01 | 1988-12-01 | (BETA) -amino-boronic acid DERIVATIVES |
Publications (1)
Publication Number | Publication Date |
---|---|
PH26584A true PH26584A (en) | 1992-08-19 |
Family
ID=6368210
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PH39613A PH26584A (en) | 1988-12-01 | 1989-11-29 | Beta-amino-boronic acid derivatives |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0371467A3 (en) |
JP (1) | JPH02193997A (en) |
KR (1) | KR900009663A (en) |
AU (1) | AU616819B2 (en) |
CA (1) | CA2004303A1 (en) |
DE (1) | DE3840452A1 (en) |
DK (1) | DK605489A (en) |
FI (1) | FI895718A0 (en) |
IL (1) | IL92497A0 (en) |
NO (1) | NO894790L (en) |
NZ (1) | NZ231578A (en) |
PH (1) | PH26584A (en) |
PT (1) | PT92442A (en) |
ZA (1) | ZA899152B (en) |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ229053A (en) * | 1988-05-11 | 1990-12-21 | Du Pont | Pharmaceutical compositions comprising a protein or peptide and an alpha-aminoboronic acid derivative to stabilise and improve the delivery of the protein or peptide |
US4983589A (en) * | 1989-12-14 | 1991-01-08 | Chevron Research And Technology Company | Fungicidal imidazole diphenylaliphaticboranes and derivatives thereof |
GB9017694D0 (en) * | 1990-08-13 | 1990-09-26 | Sandoz Ltd | Improvements in or relating to organic chemistry |
GB9024775D0 (en) * | 1990-11-14 | 1991-01-02 | Axis Research | Chemical compounds |
US5554728A (en) * | 1991-07-23 | 1996-09-10 | Nexstar Pharmaceuticals, Inc. | Lipid conjugates of therapeutic peptides and protease inhibitors |
US6825169B1 (en) | 1991-10-22 | 2004-11-30 | Trustees Of Tufts College | Inhibitors of dipeptidyl-aminopeptidase type IV |
US5888992A (en) * | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
US6071895A (en) * | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
ATE253050T1 (en) | 1992-03-11 | 2003-11-15 | Narhex Ltd | AMINE DERIVATIVES OF OXO- AND HYDROXY-SUBSTITUTED HYDROCARBONS |
RU2126794C1 (en) * | 1992-03-11 | 1999-02-27 | Нархекс Лимитед | Amino-derivatives of oxo- or hydroxy-substituted hydrazines, method of their synthesis and pharmaceutical compositions for inhibition of retrovirus protease |
US5559256A (en) * | 1992-07-20 | 1996-09-24 | E. R. Squibb & Sons, Inc. | Aminediol protease inhibitors |
EP0655068B1 (en) * | 1992-08-14 | 1997-12-17 | The Procter & Gamble Company | Process for synthesizing a beta-aminoalkylboronic acid and ester thereof |
US5354491A (en) * | 1992-08-14 | 1994-10-11 | The Procter & Gamble Company | Liquid detergent compositions containing protease and certain β-aminoalkylboronic acids and esters |
US5442100A (en) * | 1992-08-14 | 1995-08-15 | The Procter & Gamble Company | β-aminoalkyl and β-N-peptidylaminoalkyl boronic acids |
TR28578A (en) * | 1993-08-13 | 1996-11-04 | Procter & Gamble | Liquid detergent compositions containing protease and some of -aminoalkylboronic acid and esters. |
IL110898A0 (en) * | 1993-09-10 | 1994-11-28 | Narhex Australia Pty Ltd | Polar-substituted hydrocarbons |
US5431842A (en) * | 1993-11-05 | 1995-07-11 | The Procter & Gamble Company | Liquid detergents with ortho-substituted phenylboronic acids for inhibition of proteolytic enzyme |
US5965532A (en) | 1996-06-28 | 1999-10-12 | Trustees Of Tufts College | Multivalent compounds for crosslinking receptors and uses thereof |
US6040145A (en) | 1997-05-07 | 2000-03-21 | Tufts University | Potentiation of the immune response |
US6100234A (en) * | 1997-05-07 | 2000-08-08 | Tufts University | Treatment of HIV |
KR100458403B1 (en) | 1997-09-29 | 2004-11-26 | 포인트 써러퓨틱스, 인크. | Stimulation of Hematopoietic Cells in vitro |
BR9910251A (en) | 1998-05-04 | 2001-01-02 | Point Therapeutics Inc | Hematopoietic stimulation |
US6890904B1 (en) | 1999-05-25 | 2005-05-10 | Point Therapeutics, Inc. | Anti-tumor agents |
EP2802593A1 (en) * | 2012-01-09 | 2014-11-19 | The University of Tromsoe | Therapeutic boron-containing compounds |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4537773A (en) * | 1983-12-05 | 1985-08-27 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid derivatives |
US4499082A (en) * | 1983-12-05 | 1985-02-12 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid peptides |
-
1988
- 1988-12-01 DE DE3840452A patent/DE3840452A1/en not_active Withdrawn
-
1989
- 1989-11-28 EP EP19890121966 patent/EP0371467A3/en not_active Withdrawn
- 1989-11-29 PT PT92442A patent/PT92442A/en not_active Application Discontinuation
- 1989-11-29 PH PH39613A patent/PH26584A/en unknown
- 1989-11-29 NZ NZ231578A patent/NZ231578A/en unknown
- 1989-11-29 FI FI895718A patent/FI895718A0/en not_active IP Right Cessation
- 1989-11-29 KR KR1019890017374A patent/KR900009663A/en not_active Application Discontinuation
- 1989-11-29 IL IL92497A patent/IL92497A0/en unknown
- 1989-11-30 NO NO89894790A patent/NO894790L/en unknown
- 1989-11-30 ZA ZA899152A patent/ZA899152B/en unknown
- 1989-11-30 CA CA002004303A patent/CA2004303A1/en not_active Abandoned
- 1989-11-30 DK DK605489A patent/DK605489A/en not_active Application Discontinuation
- 1989-11-30 JP JP1309435A patent/JPH02193997A/en active Pending
- 1989-11-30 AU AU45665/89A patent/AU616819B2/en not_active Ceased
Also Published As
Publication number | Publication date |
---|---|
DK605489D0 (en) | 1989-11-30 |
CA2004303A1 (en) | 1990-06-01 |
AU4566589A (en) | 1990-06-07 |
JPH02193997A (en) | 1990-07-31 |
NO894790D0 (en) | 1989-11-30 |
ZA899152B (en) | 1990-09-26 |
EP0371467A3 (en) | 1991-04-03 |
NO894790L (en) | 1990-06-05 |
NZ231578A (en) | 1992-02-25 |
IL92497A0 (en) | 1990-08-31 |
KR900009663A (en) | 1990-07-05 |
DK605489A (en) | 1990-06-02 |
DE3840452A1 (en) | 1990-06-07 |
AU616819B2 (en) | 1991-11-07 |
FI895718A0 (en) | 1989-11-29 |
PT92442A (en) | 1990-06-29 |
EP0371467A2 (en) | 1990-06-06 |
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