MXPA98000411A - Quimi compounds - Google Patents
Quimi compoundsInfo
- Publication number
- MXPA98000411A MXPA98000411A MXPA/A/1998/000411A MX9800411A MXPA98000411A MX PA98000411 A MXPA98000411 A MX PA98000411A MX 9800411 A MX9800411 A MX 9800411A MX PA98000411 A MXPA98000411 A MX PA98000411A
- Authority
- MX
- Mexico
- Prior art keywords
- compound
- compound according
- benzofuranyl
- alkyl
- pyrazino
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 87
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N Cyclic guanosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 claims abstract description 12
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 11
- 239000012453 solvate Substances 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 5
- 150000004677 hydrates Chemical class 0.000 claims abstract description 5
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 5
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 5
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 4
- 230000001225 therapeutic Effects 0.000 claims abstract description 4
- -1 5-benzofuranyl Chemical group 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000000969 carrier Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- FFCZQVKVWGGQFB-UHFFFAOYSA-N 9H-pyrido[3,4-b]indole-1,4-dione Chemical compound N1C2=CC=CC=C2C2=C1C(=O)N=CC2=O FFCZQVKVWGGQFB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000005755 formation reaction Methods 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 150000003141 primary amines Chemical class 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 4
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical group CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 3
- 230000003389 potentiating Effects 0.000 abstract description 3
- 125000001188 haloalkyl group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 239000000543 intermediate Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 208000006673 Asthma Diseases 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 230000002829 reduced Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 206010002388 Angina unstable Diseases 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- 102000002723 Atrial Natriuretic Factor Human genes 0.000 description 3
- 101800001288 Atrial natriuretic factor Proteins 0.000 description 3
- 101800001866 Atrial natriuretic peptide Proteins 0.000 description 3
- 206010006451 Bronchitis Diseases 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 description 3
- 208000010412 Glaucoma Diseases 0.000 description 3
- 206010061216 Infarction Diseases 0.000 description 3
- 208000002551 Irritable Bowel Syndrome Diseases 0.000 description 3
- 206010034636 Peripheral vascular disease Diseases 0.000 description 3
- 229940068968 Polysorbate 80 Drugs 0.000 description 3
- 201000001068 Prinzmetal angina Diseases 0.000 description 3
- 208000008425 Protein Deficiency Diseases 0.000 description 3
- 208000002815 Pulmonary Hypertension Diseases 0.000 description 3
- 208000003782 Raynaud Disease Diseases 0.000 description 3
- 206010037912 Raynaud's phenomenon Diseases 0.000 description 3
- 206010039085 Rhinitis allergic Diseases 0.000 description 3
- 208000007718 Stable Angina Diseases 0.000 description 3
- 208000007814 Unstable Angina Diseases 0.000 description 3
- 201000009961 allergic asthma Diseases 0.000 description 3
- 201000001320 atherosclerosis Diseases 0.000 description 3
- 230000001684 chronic Effects 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 201000001881 impotence Diseases 0.000 description 3
- KMAKOBLIOCQGJP-UHFFFAOYSA-M indole-3-carboxylate Chemical compound C1=CC=C2C(C(=O)[O-])=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-M 0.000 description 3
- 200000000018 inflammatory disease Diseases 0.000 description 3
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 201000011528 vascular disease Diseases 0.000 description 3
- LLLBDLDNTMMZHL-UHFFFAOYSA-N 1-benzofuran-5-carbaldehyde Chemical compound O=CC1=CC=C2OC=CC2=C1 LLLBDLDNTMMZHL-UHFFFAOYSA-N 0.000 description 2
- 210000004204 Blood Vessels Anatomy 0.000 description 2
- 108010082834 Brain Natriuretic Peptide Proteins 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- YYLLIJHXUHJATK-UHFFFAOYSA-N Cyclohexyl acetate Chemical compound CC(=O)OC1CCCCC1 YYLLIJHXUHJATK-UHFFFAOYSA-N 0.000 description 2
- 210000003038 Endothelium Anatomy 0.000 description 2
- 206010061173 Gastrointestinal motility disease Diseases 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 230000001058 adult Effects 0.000 description 2
- 201000010105 allergic rhinitis Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 201000006233 congestive heart failure Diseases 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000000268 renotropic Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical compound OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 description 1
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 1
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 102000004008 5'-Nucleotidase Human genes 0.000 description 1
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- 229960004373 Acetylcholine Drugs 0.000 description 1
- 108060001001 BRK1 Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N Bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
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- 229960001681 Croscarmellose Sodium Drugs 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- 229940030606 DIURETICS Drugs 0.000 description 1
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- 102100011311 KNG1 Human genes 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L Magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 229940057948 Magnesium stearate Drugs 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- TYRGLVWXHJRKMT-QMMMGPOBSA-N N-BENZYLOXYCARBONYL-L-SERINE-BETALACTONE Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 description 1
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- 206010062237 Renal impairment Diseases 0.000 description 1
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- 229960002622 Triacetin Drugs 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
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- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
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- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
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- 239000008103 glucose Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
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- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
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- IIRDTKBZINWQAW-UHFFFAOYSA-N hexaethylene glycol Chemical class OCCOCCOCCOCCOCCOCCO IIRDTKBZINWQAW-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
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- 230000001631 hypertensive Effects 0.000 description 1
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- 238000003018 immunoassay Methods 0.000 description 1
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- 238000007918 intramuscular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 media Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- KCUNTYMNJVXYKZ-SNVBAGLBSA-N methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C[C@@H](N)C(=O)OC)=CNC2=C1 KCUNTYMNJVXYKZ-SNVBAGLBSA-N 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- KMPIYXNEROUNOG-GWTDSMLYSA-M sodium;9-[(4aR,6R,7R,7aS)-7-hydroxy-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-6-yl]-2-amino-3H-purin-6-one Chemical compound [Na+].C([C@H]1O2)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H]2N1C=NC2=C1NC(N)=NC2=O KMPIYXNEROUNOG-GWTDSMLYSA-M 0.000 description 1
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Abstract
The present invention relates to a compound of the formula (I), and the solvates (eg, hydrates) thereof, in which: R 0 represents hydrogen, halogen or C 1 -C 6 alkyl; R 1 represents hydrogen or C 1 -C 6 alkyl; -C6: R2 represents the bicyclic ring, which may be optionally substituted by one or more groups selected from halogen and C1-C3 alkyl, and R3 represents hydrogen or C1-C3 alkyl. A compound of the present invention is a potent and selective inhibitor of cGMP-specific PDE which has utility in a variety of therapeutic areas wherein said inhibition is beneficial.
Description
CHEMICAL COMPOUNDS
This invention relates to a series of tetracyclic derivatives / to the processes for their preparation, the pharmaceutical compositions containing them and their use as therapeutic agents. In particular, the invention relates to tetracyclic derivatives which are potent and selective inhibitors of the phosphodiesterase specific for 3 ', 5' cyclic guanosine monophosphate (cGMP-specific PDE) which have utility in a variety of therapeutic areas where Inhibition is considered beneficial, including the treatment of cardiovascular disorders. Thus, according to a first aspect, the present invention provides the compounds of the formula (i).
and solvates (eg, hydrates) thereof, in which:
R, 0 represents hydrogen, halogen or C? -C6 alkyl; R1 represents hydrogen or C? -C6 alkyl; R2 represents the bicyclic ring
which may be optionally substituted by one or more groups selected from halogen and C? -C3 alkyl; and R3 represents hydrogen or C1-C3 alkyl. The term "halogen" when used herein defines bromine, chlorine, fluorine and iodine. The terms "C1-C3 alkyl" and Ci-C * alkyl "when used herein define a straight or branched alkyl chain such as methyl, ethyl, i-propyl, n-butyl, pentyl, hexyl or the like. Particularly preferred subgroup of the compounds according to the present invention are the compounds wherein R ° represents hydrogen Another preferred subgroup includes the compounds wherein R 1 is selected from hydrogen, methyl and isopropyl Preferably, R 2 represents an unsubstituted bicyclic ring
Still another subgroup of compounds of the formula (i) are the compounds wherein RJ represents hydrogen or methyl.
It should be understood that the present invention covers all suitable combinations of the particular and preferred groupings heretofore described. The compounds of the formula (I) can contain one or more asymmetric centers and can thus exist as enantiomers or diastereoisomers. It should be understood that the invention includes mixtures and separate individual isomers of the compounds of formula (I). Particularly preferred are the 6R and 12aR isomers. Particular individual compounds of the invention include: (6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -2-ethyl-pyrazino [2 ', 1': 6 , lyrido [3, -b] indol-1, -dione; (6R, 12aR) -2.3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -pyrazino [2 ', 1': 6, lyrido [3, -b] indole-1, 4 -diona; (3S, 6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -3-methyl-pyrazino [2 ', 1': 6, lyrido [3, -b ] indol-l, 4-dione; (3S, 6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -2,3-dimethyl-pyrazino [2 ', 1': 6, l] pyrido [ 3, 4-b] indole-1,4-dione; (6R, 12aR) -2,3,6,7,12,16-hexahydro-6- (5-benzofuranyl) -2-isopropyl-pyrazino [2 ', 1': 6, lyrido [3, 4-b] indole-1, -dione; and physiologically acceptable solvates (eg hydrates) thereof.
A more particular compound of the invention is: (6R, l2aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -2-methyl-pyrazino [2 ', 1': 6 , lyrido [3, -b] indol-1, -dione; and physiologically acceptable solvates (eg hydrates) thereof. The compounds of the present invention have been shown to be potent and selective inhibitors of cGMP specific PDE. In this way, the compounds of formula (I) are of interest for use in therapy, specifically for the treatment of a number of states wherein the inhibition of cGMP specific PDE is considered beneficial. As a consequence of the selective inhibition of PDE V exhibited by the compounds of the present invention, cGMP levels rise, which in turn can give rise to anti-platelet, anti-neutrophil, anti-vasospastic, beneficial activities, vasodilators, natriuretics and diuretics, as well as the potentiation of endothelium-derived relaxation factor effects (EDRF), nitrovasodilators, atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), peptide-type C (CNP) and dependent narcotic agents of the endothelium such as bradykinin, acetylcholine and 5-HT ?. The compounds of the formula (I), therefore, have utility in the treatment of various disorders, including. It will be appreciated that references herein made to the treatment extend to prophylaxis as well as treatment of established states. It will also be appreciated that "a compound of the formula (I) ', or a physiologically acceptable salt or solvate thereof can be administered as a raw material compound, or as a pharmaceutical composition containing any entity. Thus, another aspect of the invention provides a compound of the formula (I) for use in the treatment of stable, unstable and variant angina (Prinzmetal), hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure. , renal impairment, atherosclerosis, reduced blood vessel opening states (eg, post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, infarction, bronchitis, chronic asthma, allergic asthma, rhinitis allergic, glaucoma, erectile dysfunction or diseases characterized by bowel motility disorders (eg IBS). According to another aspect of the invention, there is provided the use of a compound of the formula (I) for the manufacture of a medicament for the treatment of stable, unstable and variant angina (Prinzmetal), hypertension, pulmonary hypertension, chronic obstructive pulmonary disease. , congestive heart deficiency, renal deficiency, atherosclerosis, reduced blood vessel opening states (eg, post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, infarction, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction or diseases characterized by bowel motility disorders (eg, IBS). In another aspect, the invention provides a method for the treatment of stable, unstable and variant angina (Prinzmetal), hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal deficiency, atherosclerosis, reduced vessel opening states. blood disorders (eg, po = t-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, infarction, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction or diseases characterized by disorders of bowel motility (eg IBS), in an animal body, human or non-human, consisting of administering to said body, a therapeutically effective amount of a compound of formula (I).
The compounds of the invention can be administered by any suitable route, for example, oral, buccal, sublingual, rectal, vaginal, nasal. Topical or parenteral (including intravenous, intramuscular, subcutaneous and intracoronary). Oral administration is usually preferred. For administration to men, during the curative or prophylactic treatment of the disorders identified in the above, oral doses of a compound of the formula (I) will generally be in the range of 0.5-800 mg daily for an average adult patient (70 kg). For a common adult patient, individual tablets or capsules contain from 0.2-400 mg of the active compound, in a pharmaceutically acceptable vehicle or carrier, for administration in single or multiple doses, once or several times per day. Doses for intravenous, buccal or sublingual administration will usually be within the range of 0.1-400 mg per single dose as required. In practice the doctor will determine the actual dosage regimen, which will be more suitable for an individual patient and will vary with the age, weight and response of the particular patient. The above dosages are examples of the average case but there may be individual cases where higher or lower dosing ranges are necessary, and these will be within the scope of the invention. For human use, a compound of the formula (I) can be administered alone, but will generally be administered mixed with a pharmaceutically selected carrier in relation to the proposed route of administration and normal pharmaceutical practice. For example, the compound can be administered orally, buccally or sublingually, in the form of tablets, containing the excipients such as starch or lactose, or in capsules or ovules alone or in mixtures with excipients or in the form of elixirs or suspensions containing the agents flavors or colorants. These liquid preparations can be made with the pharmaceutically acceptable additives as suspending agents (eg, methylcellulose, a semi-synthetic glyceride such as Witepsol or mixtures of glycerides, such as a mixture of apricot kernel oil and PEG-6 esters or mixtures of PEG-8 and caprylic / capric glycerides A compound can also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously or intracoronary.For parenteral administration, the compound is best used in the form of a sterile aqueous solution which it may contain other substances, for example salts or monosaccharides such as mannitol or glucose, to make the solution isotonic with the blood.In this way, the invention provides, in another aspect, a pharmaceutical composition containing a compound of the formula (I) together with a pharmaceutically acceptable diluent or carrier therefor.In addition, in the present invention, a p A process for preparing a pharmaceutical composition containing a compound of the formula (I), the process of which comprises mixing a compound of the formula (I) together with a pharmaceutically acceptable diluent or carrier therefor. A compound of the formula (I) can also be used in combination with other therapeutic agents which may be useful in the treatment of the aforementioned disease states. In this manner, the invention provides in another aspect, a combination of a compound of the formula (I) together with another therapeutically active agent. The combination mentioned in the above may conveniently be presented for use in the form of a pharmaceutical formulation and in this manner, the pharmaceutical compositions containing a combination, as defined above, together with a pharmaceutically acceptable diluent or carrier, comprises another aspect of the invention. The individual components of this combination can also be administered sequentially or simultaneously in separate pharmaceutical formulations. Suitable doses of the known therapeutic agents for use in combination with a compound of the formula (I) will be readily apparent to those skilled in the art. The compounds of formula (I) can be prepared by any method known in the art or by the following processes forming part of the present invention. In the following methods R °, R1, R2 and R3 are as defined in the above formula (I) unless otherwise specified. In this way, a first process (A) for preparing a compound of the formula (I) comprises the treatment of a compound of the formula (II):
(wherein Alk represents C? -Cfe alkyl, for example methyl or ethyl, and Hai is a halogen atom, for example, chloro) with a primary amine RXNH2 in a suitable solvent such as an alcohol (e.g. ., methanol or ethanol) or a mixture of solvents, conveniently, at a temperature of 20 ° C to the reflux temperature (e.g., around 50 ° C). According to a second process (B) for preparing a co in a suitable solvent such as an alcohol (eg, methanol or ethanol) or a mixture of solvents, conveniently at a temperature of 20 ° C until the reflux temperature (e.g., around 50 ° C). According to a second process (B) for preparing a compound of the formula (I), it comprises the hydrogenation of a compound of the formula (III)
wherein Alk is defined as above and Cbz represents a carbobenzyloxy group, in the presence of a catalyst such as palladium on active carbon, in a suitable solvent, such as alcohol, e.g. , methanol or ethanol, at elevated temperature. A compound of the formula (II) can be conveniently prepared by the treatment of a compound of the formula (IV)
with a haloacetyl halide (e.g., chloroacetyl chloride) in a suitable solvent such as halogenated hydrocarbon (e.g., trichloromethane or dichloromethane), or an ether (e.g., tetrahydrofuran), preferably in the presence of a base such as a organic amine (e.g., trialkylane as triethylamine) or an alkali metal carbonate or bicarbonate (e.g., NaHCOs). The reaction can be conveniently carried out at a temperature from -20 ° C to + 20 ° C (e.g., around 0 ° C.) A compound of the formula (IV) can be conveniently prepared from tryptophan alkyl ester of the formula (V)
This step consists of the Pictet-Spengler cyclization between a compound of the formula (V) and an aldehyde R2CHO. The reaction can be conveniently carried out in a suitable solvent such as halogenated hydrocarbon (eg, dichloromethane) or an aromatic hydrocarbon (eg toluene) in the presence of an acid such as trifluoroacetic acid. The reaction can be conveniently carried out at a temperature from -20 ° C to reflux to provide a compound of formula (III) in one step. The reaction can also be carried out in a solvent such as an aromatic hydrocarbon (eg, benzene or toluene) at reflux, optionally using a Dean-Stark apparatus to trap the water that is produced. The reaction provides a mixture of cis and trans isomers which can be of individual enantiomers or racemates of pairs of cis or trans isomers depending on whether racemic or enantiomerically pure tryptophan alkyl ester is used as starting material. The individual cis or trans enantiomers may conveniently be separated from mixtures thereof by fractional crystallization or by chromatography (eg, flash column chromatography) using suitable solvents and eluents. In the same way, the cis and trans isomeric pairs can be separated by chromatography (e.g., flash column chromatography) using suitable eluents. An optically pure trans isomer can also be converted to an optically pure cis isomer using suitable epimerization methods. One of these processes consists in the treatment of the trans-isomer a mixture (eg, 1: 1 mixture) of cis and trans isomers with aqueous or methanolic acid chloride at a temperature from 0 ° C to the reflux temperature of the solution. The mixture is then subjected to chromatography (e.g., flash column chromatography) to separate the resulting diastereoisomers. A compound of the formula (III) can be prepared by reacting a compound of the formula (IV)) as described above, with a compound of the formula (VI)
where Cbz is as defined in the above. Properly, the reaction is carried out in the presence of 1,3-dicyclohexylcarbodiimide (DCC), in a solvent, such as halogenated hydrocarbon (eg, dichloromethane) of 0 ° C at room temperature. The compounds of the formula (V) and (VI) are known compounds and can be prepared by the normal methods described below. The compounds of the invention can be isolated together with the solvent molecules by crystallization from or evaporation of an appropriate solvent. Thus, according to another aspect of the invention, we provide a process (C) for preparing one or the formula (I) or a solvate (eg, hydrate) of these comprising process (A) or ( B) as described in the foregoing, followed by: i) an interconversion step; and / or ii) the formation of the solvate (eg, hydrate). The synthesis of the compounds of the invention and of the intermediates for use herein are illustrated by the following non-limiting examples. Intermediates 1 and 2 cis isomer of 1, 2, 3, 4-tetrahydro-l- (5-benzofuranyl) -9H-pyrido [3, -b] indole-3-carboxylate of (IR, 3R) -methyl and trans isomer 1,2,3-tetrahydro-l- (5-benzofuranyl) -9H-pyrido [3,4-b] indol-3-carboxylic acid (1S, 3R) -methyl ester To a stirred solution of D-tryptophan methyl ester (3.73 g) and 5-formyl-benzofuran-1 (2.5 g) in anhydrous dichloromethane (100 ml), cooled to 0 ° C, trifluoroacetic acid (2.63 ml) is added dropwise and the solution is allowed to react at room temperature . After 72 hours the solution is washed with a saturated aqueous solution of NaHCOj, then with water and dried over sodium sulfate. The organic layer is evaporated under reduced pressure and the residue is purified by flash chromatography eluting with dichloromethane / ethyl acetate (90/10) to give the first isomer ci = (intermediate 1) (3 g) as an amorphous compound, followed by the trans isomer (intermediate 2) (2.5 g) as white crystals. P. f. : 194-195 ° C. 1 The synthesis of 5-formyl-benzofuran is described in Chi ie Thérapeutique 4, pp 221-227 (1966).
Intermediate 3 1,2, 3, -tetrahydro-l- (5-benzofuranyl) -2-chloroacetyl-9H-pyrido [3, -b] indol-3-carboxylate of (IR, 3R) -methyl to a stirring solution of intermediate 1 (2 g) and thythylamine (0.88 ml) in anhydrous dichloromethane (40 ml) cooled to 0 ° C, chloroacetyl chloride (0.5 ml) is added dropwise and the solution is stirred at the same temperature for one hour . The solution is washed with water, dried over sodium sulfate and evaporated to dryness and the residue recrystallized from methanol to give the title compound (1.8 g) as pale yellow crystals, e.g. .F. 227-228 ° C.
Intermediate 4 1,2,3,4-tetrahydro-l- (5-benzofuranyl) -2- (2- (S) -benzyloxycarbonylaminopropionyl) -9H-pyrido [3, -b] indole-3-carboxylate of (IR, 3R) -methyl To an agitated solution of (S) -2-benzyloxycarbonylaminopropionic acid (1.3 g) and 1,3-dicyclohexylcarbodiimide (DCC) (1.2 g) in anhydrous dichloromethane (50 ml) at 0 ° C is added the intermediate 1 (1.0 G). The resulting mixture is stirred for 72 hours, then the resulting precipitate is removed by filtration. The filtrate is evaporated to dryness and the residue is purified by flash chromatography eluting with cyclohexane / ethyl acetate (60/40) to give the title compound as white crystals (1.4 g). p. F. 91-92 ° C
Intermediate 5 1,2,3,4-tetrahydro-1- (5-benzofuranyl) -2- [2- (S) -benzyloxycarbinylmethylamino) propionyl] -9H-pyrido [3,4-b] indole-3-carboxylate (IR, 3R) -methyl The same procedure was used as in the preparation of intermediate 4, but starting from 2- (S) -benzyloxycarbonylmethylamino) propionic acid (0.82 g) and using intermediate 1 (0.6 g), DCC (0.72 g) and dichloromethane (25 ml) produced, after chromatography, eluting with cyclohexane / ethyl acetate (70/30), the title compound as a white foam. 'H NMR (240MHz, CDC13) d 7.7 (s, lH), 7.6 (d, 2H), 7.4-7.05 (m, llH), 6.6 (d, lH), 5.4-5.0 (m, 4H), 3.5 ( d, lH), 3.5 (d, lH), 3.0 (m, lH), 2.9-2.7 (m, 6H), 2.6 (dd, 1H), 1.3 (s, 3H).
Example 1 (6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -2-methyl-pyrazino [2 ', 1': 6, lyrido [3, 4- b] indole-1,4-dione To a stirred suspension of intermediate 3 (0.42 g) in methanol (30 ml) is added at room temperature a solution of methylamine (33% in EtOH) (0.47 ml) and the resulting mixture it is heated at 50 ° C with N¿ for 72 hours. The solvent is removed under reduced pressure and dissolved in dichloromethane. After washing with water, drying over sodium sulfate and evaporating to dryness, the impure product is purified by crystallization from methanol to yield the title compound as white crystals (0.21 g). p. F. 291-293 ° C. Analysis for C22H19Nj? 3. Calculated: C, 71.68; H, 4.97; N, 10.90; Found: C, 71.5; H, 4.91; N, 10.74%. [a] '' = + 55.7 ° (C = 1; CHC13). The following compounds were obtained in a similar way:
Example 2 (6R, 12aR) -2, 3, 6,7, 12, 12a-hexahydro-6- (5-benzofuranyl) -pyrazino [2f, 1": 6, lyridido [3,4-b] indole-1 , 4-dione The same procedure was used for the preparation of Example 1, but starting from ammonia and intermediate 3 to produce, after recrystallization from methanol, the title compound as white crystals, mp 310-311. ° C.
Analysis for C22H? / N? 3. Calculated: C, 70.03; H,. 88; N, 10. 94; Found: C, 70.01; H, .8; N, 10.61%. [a] = + 60.4 ° (C = 0.5, pyridine).
Example 3 (6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -2-isopropyl-pyrazino [2 ', 1: 6, lyrido [3, 4-b] ] indol-1, -dione The same procedure is used for the preparation of Example 1, but starting from isopropyl ina and intermediate 3 to produce, after recrystallization from methanol, the title compound as white crystals. p. F. 291-292 ° C. Analysis for C 25 H 23 N 3 3 3 (0.6 MeOH): Calculated: C, 71.06; H, 5.92; N, 9.71; Found: C, 71.06; H, 5.92; N, 9.77%. [a] 20D = + 37.9 ° (C = 1; CHC13).
Example 4 (3S, 6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -3-methyl-pyrazino [2 ', 1: 6, 1-pyrido [3, 4 -b] indole-1,4-dione A solution of intermediate 4 (0.3 g) in the presence of 10% Pd / C (30 mg) in methanol (10 ml) is stirred under a hydrogen atmosphere at 50 ° C. for 2 hours. The reaction mixture is cooled, filtered through Celite, the filter cake is washed with methanol and the filtrate is evaporated in vacuo. The residue is purified by flash chromatography eluting with dichloromethane / methane (98/2) to yield the title compound as white crystals after recrystallization from methanol (0.15 g). p. F. 150-151 ° C. Analysis for C¿3H? And N_, 03 (0.1 MeOH): Calculated: C, 71.39; H, 5.03; N, 10.81; Found: C, 71.08; H, 5.16; N, 10.50%. [a] 0D = + 50 ° (C = 0.25; CHC13).
Example 5 (3S, 6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -2,3-dimethyl-pyrazino [2 ', 1': 6, lyrido [ 3, -b] indole-1,4-dione The same procedure is used for the preparation of Example 4, but starting from intermediate 5 (0.52 g) and using 10% Pd / C (50 mg) in methanol (20 ml) to produce, after recrystallization from methanol, the title compound as white crystals
(40 mg). p. f. 323-324 ° C. Analysis for C2 «? H2? 303 (0.1 MeOH):
Calculated: C, 71.52; H, 5.35; N, 10.43; Found: C, 71.71; H, 5.44; N, 10.39%, [aj ^ D = + 53 ° (C = 0.35, CHC13).
TABLETS FOR ORAL ADMINISTRATION A. Direct compression
The active ingredient was sieved and combined with the excipients. The resulting mixture was compressed into tablets.
The active ingredient is sifted and mixed with the exipients. The resulting mixture is compressed into tablets.
B. HUMID GRANULATION
Polyvinyl pyrrolidione, polyethylene glycol and polysorbate 80 are dissolved in water. The resulting solution is used to granulate the active ingredient. After drying, the granules are screened, then extruded at elevated temperatures and pressures. The extruded product is crushed and / or sieved then combined with microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. The resulting mixture is compressed into tablets.
The active ingredient is sifted and combined with lactose, starch and pregelatinized corn starch. The polysorbate 80 is dissolved in purified water. Suitable volumes of the polysorbate 80 solution are added and the powders are granulated. After drying, the granules are sieved and combined with magnesium stearate. The granules are then compressed into tablets. It is possible to prepare tablets with other hardness by modifying the proportion of the active ingredient with the other excipients.
COATED TABLETS The formulations of the aforementioned tablets are coated with film.
* Water does not appear in the final product. The maximum theoretical weight of the solids applied during the coating was 20 mg / tablet. Opadry white is a trademarked material obtainable from Colorcon Limited, UK that contains hydroxypropyl methylcellulose, titanium dioxide and triacetin. The tablets were coated using the coating suspension in conventional coating equipment.
CAPSULES
The active ingredient is sifted and combined with the excipients. The mixture is filled into size 1 hard gelatin capsules using suitable equipment.
The active ingredient is sifted and combined with the excipients. The mixture is filled into size 1 hard gelatin capsules using the appropriate equipment. Other doses can be prepared by modifying the proportion of the active ingredient to the excipients, the filling weight and if necessary changing the size of the capsule.
The active ingredient is sifted and combined with Labrafil. The suspension is filled into soft gelatin capsules using appropriate equipment.
Inhibitory effect of PDE-cGMP The cGMP-specific PDE activity of the compounds of the present invention was measured using a one step assay adapted from Wells et al. (Wells, J. N.,
Baird, C.E., Wu, Y. J. and Hardman, J. G., Biochem. Biophys,. Acta 384, 430 (1975)). The reaction medium contained 50mM Tris-HCl, pH 7.5, 5mM Mg-acetate, 5'-nucleotidase 250μg / ml; EGTA l M and 8- [H!] - cGMP 0.15 μM. The enzyme used was recombinant human PDE V (ICOS, Seattle USA). The compounds of the invention were dissolved in DMSO for a final concentration of 2% in the assay. The incubation time was 30 minutes during which the total conversion of the substrate did not exceed 302,.
The IC_, U values for the compounds examined were determined from the concentration-response curves using normal concentrations in the range from 10 nm to 10 μM. Testing against other PDE enzymes using the standard methodology also demonstrated that the compounds of the invention are highly selective for the cGMP-specific PDE enzyme.
Measurements of cGMP concentration Rat aortic smooth muscle cells (CMLR) prepared according to Chamley et al. in Cell Tissue Res. 177, 503-522 (1977) were used between the tenth and twenty-fifth step in confluence, in 24 well culture plates. The aspirated culture medium was replaced with PBS (0.5 ml) with a content of the test compound at the appropriate concentration. After 30 minutes at 37 ° C, the particulate guanylate cyclase was stimulated by the addition of ANF (100 nM) for 10 minutes. At the end of the incubation, the medium was removed and two extractions were carried out by the addition of 65% ethanol. (0.25 mi). The two ethanolic extracts were combined and evaporated to dryness using a Speed-vac system. After acetylation, cGMP was measured by scintillation proximity immunoassay (AMERSHAM). The EC50 values were expressed as the dose that produces half of the stimulation at saturation concentrations.
Biological Data It was commonly found that the compounds according to the present invention have a value of 1C, or less than 500nM and an EC50 value of less than 5μM. The data of the in vitro tests for the representative compounds of the invention are given in the following table: Table 1. Results In vi tro
The hypotensive effects of the compounds according to the invention as identified in Table 2 were studied in spontaneously hypertensive conscious rats (REH). The compounds were administered orally at a dose of 5 mg / kg in a mixture of 5% DMF and 95% olive oil. Blood pressure was measured from a catheter inserted into the carotid artery and recorded for 5 hours after administration. The results are expressed as the area under the curve (AUC) from 0 to 5 hours, mmHg.hor (from the drop in blood pressure over time) Table 2. In vivo results
Claims (1)
- CLAIMS A compound of the formula (I) and solvates (eg, hydrates) thereof, in which: R ° represents hydrogen, halogen or C? -C6 alkyl; R1 represents hydrogen or C? -C6 alkyl; R2 represents the bicyclic ring which may be optionally substituted by one or more groups selected from halogen and d-C alkyl; and R3 represents hydrogen or C1-C3 alkyl. The compound according to claim 1, wherein R ° represents hydrogen. The compound according to claim 1 or claim 2, wherein R1 is selected from hydrogen, methyl and isopropyl. The compound according to any of claims 1-3, wherein R 3 represents hydrogen or methyl. The compounds (6R, 12aR) -2.3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -2-methyl-pyrazino [2 ', 1': 6, l] pyrido [3, 4-b] indole-1,4-dione; (6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -pyrazino [2 ', 1': 6, lyridido [3,4-b] indol-1, 4-dione; (3S6R, 12aR) -2.3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -3-methyl-pyrazino [2 ', 1': 6, lyrido [3, -b] indole -1, 4-dione; (3S, 6R, 12aR) -2,3,6,7,12, 12a-hexahydro-6- (5-benzofuranyl) -2, 3-dimethyl-pyrazino [2 ', 1': 6, l] pyrido [ 3,4-b] indole-l, 4-dione; (6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl) -2-isopropyl-pyrazino [2 ', 1': 6, lyrido [3, 4-b] indole-1, -dione; and the physiologically acceptable solvates thereof. (6R, 12aR) -2,3,6,7,12,12a-hexahydro-6- (5-benzofuranyl) -2-methyl-pyrazino [2 ', 1': 6, lyrido [3, -b] indole -1, 4-dione. and the physiologically acceptable solvates thereof. The compound according to any of claims 1-6 for use in therapy. 8. The compound according to any of claims 1-6 for use in the treatment states wherein inhibition of PDE specific for cGMP is of therapeutic benefit. 9. The use of a compound according to any of claims 1-6 for the manufacture of a medicament for the treatment of the states where inhibition of cGMP-specific PDE is of therapeutic benefit. 10. A method for the treatment of conditions wherein the inhibition of cGMP-specific PDE is beneficial in a human or non-human animal body, which comprises the administration to said body of a therapeutically effective amount of a compound according to any of claims 1-6. 11. A pharmaceutical composition containing a compound according to any of claims 1-6, together with a pharmaceutically acceptable diluent or carrier therefor. 2- A process for preparing a pharmaceutical composition containing a compound according to any of claims 1-6, which process comprises mixing the compound together with a pharmaceutically acceptable diluent or carrier therefor. A process (A) for preparing a compound according to claim 1, comprising the treatment of a compound of the formula (II) (in which Alk represents C? -C "alkyl, for example methyl or ethyl, and Hai is a halogen atom, for example, chloro) with a primary amine R'aNH ?; or, a process (B) comprising the hydrogenation of a compound of the formula (III) wherein Alk is defined as above and Cbz represents a carbobenzyloxy group, in the presence of a catalyst in a suitable solvent such as alcohol, at elevated temperature; or a process (C) which comprises process (A) or (B) followed by i) an interconversion step; and / or ii) the formation of the solvate.
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PCT/EP1996/003025 WO1997003985A1 (en) | 1995-07-14 | 1996-07-11 | Cyclic gmp-specific phosphodiesterase inhibitors |
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EP (1) | EP0846118B1 (en) |
JP (1) | JP4150818B2 (en) |
CN (1) | CN1069318C (en) |
AR (1) | AR003455A1 (en) |
AT (1) | ATE216997T1 (en) |
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BR (1) | BR9609780A (en) |
CA (1) | CA2226761A1 (en) |
CO (1) | CO4700455A1 (en) |
CZ (1) | CZ3298A3 (en) |
DE (1) | DE69621026T2 (en) |
ES (1) | ES2176471T3 (en) |
GB (1) | GB9514465D0 (en) |
HR (1) | HRP960321B1 (en) |
HU (1) | HUP9900006A3 (en) |
IL (1) | IL122923A0 (en) |
MX (1) | MX9800411A (en) |
NO (1) | NO980154L (en) |
PL (1) | PL324527A1 (en) |
SK (1) | SK3898A3 (en) |
WO (1) | WO1997003985A1 (en) |
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1995
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1996
- 1996-07-05 HR HR960321A patent/HRP960321B1/en not_active IP Right Cessation
- 1996-07-11 CZ CZ9832A patent/CZ3298A3/en unknown
- 1996-07-11 EP EP96923986A patent/EP0846118B1/en not_active Expired - Lifetime
- 1996-07-11 DE DE69621026T patent/DE69621026T2/en not_active Expired - Fee Related
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- 1996-07-11 AT AT96923986T patent/ATE216997T1/en active
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- 1996-07-11 BR BR9609780A patent/BR9609780A/en not_active Application Discontinuation
- 1996-07-11 WO PCT/EP1996/003025 patent/WO1997003985A1/en active IP Right Grant
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