UA80821C2

UA80821C2 - 7-aryl-3,9-diazabicyclo (3.3.1)non-6-ene derivatives and their use as renin inhibitors in the treatment of hypertension, cardiovascular or renal diseases

7-aryl-3,9-diazabicyclo (3.3.1)non-6-ene derivatives and their use as renin inhibitors in the treatment of hypertension, cardiovascular or renal diseases Download PDF

Info

Publication number: UA80821C2
Authority: UA; Ukraine
Prior art keywords: phenyl; diazabicyclo; propyl; trifluorophenoxy; acid
Prior art date: 2002-04-29

Application number

UA20041109469A

Other languages

English (en)

Ukrainian (uk)

Priority date

2002-04-29

Filing date

2003-08-04

Publication date

2007-11-12

2003-08-04 Application filed filed Critical

2007-11-12 Publication of UA80821C2 publication Critical patent/UA80821C2/uk

Links

206010020772 Hypertension Diseases 0.000 title claims description 9
208000024172 Cardiovascular disease Diseases 0.000 title claims description 4
230000002526 effect on cardiovascular system Effects 0.000 title claims description 3
208000017169 kidney disease Diseases 0.000 title claims description 3
239000002461 renin inhibitor Substances 0.000 title description 11
229940086526 renin-inhibitors Drugs 0.000 title description 11
150000001875 compounds Chemical class 0.000 claims abstract description 417
238000000034 method Methods 0.000 claims abstract description 408
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
241000700159 Rattus Species 0.000 claims description 672
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 605
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 592
239000000203 mixture Substances 0.000 claims description 377
238000011160 research Methods 0.000 claims description 231
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 155
-1 racemates Chemical class 0.000 claims description 149
239000002253 acid Substances 0.000 claims description 146
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 145
239000002904 solvent Substances 0.000 claims description 126
GCJYLAWVUWEHLW-UHFFFAOYSA-N n-[(2-chlorophenyl)methyl]cyclopropanamine Chemical compound ClC1=CC=CC=C1CNC1CC1 GCJYLAWVUWEHLW-UHFFFAOYSA-N 0.000 claims description 112
SASNBVQSOZSTPD-UHFFFAOYSA-N n-methylphenethylamine Chemical compound CNCCC1=CC=CC=C1 SASNBVQSOZSTPD-UHFFFAOYSA-N 0.000 claims description 110
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 105
LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 82
229910052799 carbon Inorganic materials 0.000 claims description 78
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 71
125000000217 alkyl group Chemical group 0.000 claims description 55
MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 claims description 33
BTBDLUOYLCXSMK-UHFFFAOYSA-N n-[(3,5-dimethoxyphenyl)methyl]cyclopropanamine Chemical compound COC1=CC(OC)=CC(CNC2CC2)=C1 BTBDLUOYLCXSMK-UHFFFAOYSA-N 0.000 claims description 32
125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 32
HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical compound [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 0.000 claims description 31
125000003070 2-(2-chlorophenyl)ethyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 30
150000007513 acids Chemical class 0.000 claims description 29
125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 25
125000003118 aryl group Chemical group 0.000 claims description 24
150000003839 salts Chemical class 0.000 claims description 21
IBVNNEPIXJSRAS-UHFFFAOYSA-N 3-(2-chlorophenyl)propan-1-amine Chemical compound NCCCC1=CC=CC=C1Cl IBVNNEPIXJSRAS-UHFFFAOYSA-N 0.000 claims description 20
UZYPFBRRGVZJNV-UHFFFAOYSA-N n-[(2-fluorophenyl)methyl]cyclopropanamine Chemical compound FC1=CC=CC=C1CNC1CC1 UZYPFBRRGVZJNV-UHFFFAOYSA-N 0.000 claims description 20
WYQUCNZBUBLJHN-UHFFFAOYSA-N n-[(2-methylphenyl)methyl]cyclopropanamine Chemical compound CC1=CC=CC=C1CNC1CC1 WYQUCNZBUBLJHN-UHFFFAOYSA-N 0.000 claims description 20
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 19
KJYVKUQRRKDPAX-UHFFFAOYSA-N n-[(2,3-dichlorophenyl)methyl]cyclopropanamine Chemical compound ClC1=CC=CC(CNC2CC2)=C1Cl KJYVKUQRRKDPAX-UHFFFAOYSA-N 0.000 claims description 16
USBAUXJPPHVCTF-UHFFFAOYSA-N n-benzylcyclopropanamine Chemical compound C=1C=CC=CC=1CNC1CC1 USBAUXJPPHVCTF-UHFFFAOYSA-N 0.000 claims description 16
229910052736 halogen Inorganic materials 0.000 claims description 15
239000001257 hydrogen Substances 0.000 claims description 15
229910052739 hydrogen Inorganic materials 0.000 claims description 15
CRIMYHBFDHWKQY-UHFFFAOYSA-N n-[(2,3-dimethylphenyl)methyl]cyclopropanamine Chemical compound CC1=CC=CC(CNC2CC2)=C1C CRIMYHBFDHWKQY-UHFFFAOYSA-N 0.000 claims description 15
150000002367 halogens Chemical class 0.000 claims description 14
125000003342 alkenyl group Chemical group 0.000 claims description 12
125000000753 cycloalkyl group Chemical group 0.000 claims description 12
ILHIZUJWNGLALK-UHFFFAOYSA-N n-(2-phenylethyl)cyclopropanamine Chemical compound C1CC1NCCC1=CC=CC=C1 ILHIZUJWNGLALK-UHFFFAOYSA-N 0.000 claims description 12
SBKDFWWYKALTKE-UHFFFAOYSA-N n-[(2-bromophenyl)methyl]cyclopropanamine Chemical compound BrC1=CC=CC=C1CNC1CC1 SBKDFWWYKALTKE-UHFFFAOYSA-N 0.000 claims description 12
CEQDKNLDFWAMEL-UHFFFAOYSA-N n-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]cyclopropanamine Chemical compound FC(F)(F)C1=CC=CC(CNC2CC2)=C1Cl CEQDKNLDFWAMEL-UHFFFAOYSA-N 0.000 claims description 12
125000003545 alkoxy group Chemical group 0.000 claims description 11
150000001721 carbon Chemical group 0.000 claims description 11
125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
206010019280 Heart failures Diseases 0.000 claims description 10
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
125000001072 heteroaryl group Chemical group 0.000 claims description 10
LJBFNXZKZYKGFY-UHFFFAOYSA-N n-[(3-methylphenyl)methyl]cyclopropanamine Chemical compound CC1=CC=CC(CNC2CC2)=C1 LJBFNXZKZYKGFY-UHFFFAOYSA-N 0.000 claims description 10
229910052757 nitrogen Inorganic materials 0.000 claims description 10
208000001647 Renal Insufficiency Diseases 0.000 claims description 9
239000000969 carrier Substances 0.000 claims description 9
201000006370 kidney failure Diseases 0.000 claims description 9
CUPDQCKBQJVOMC-UHFFFAOYSA-N n-[(2-fluoro-5-methoxyphenyl)methyl]cyclopropanamine Chemical compound COC1=CC=C(F)C(CNC2CC2)=C1 CUPDQCKBQJVOMC-UHFFFAOYSA-N 0.000 claims description 9
NUPAMNLYORQZRV-UHFFFAOYSA-N n-[(3-methoxyphenyl)methyl]cyclopropanamine Chemical compound COC1=CC=CC(CNC2CC2)=C1 NUPAMNLYORQZRV-UHFFFAOYSA-N 0.000 claims description 9
241000238557 Decapoda Species 0.000 claims description 8
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
125000002947 alkylene group Chemical group 0.000 claims description 8
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
201000010099 disease Diseases 0.000 claims description 8
230000000877 morphologic effect Effects 0.000 claims description 8
ORZRHMRDNOCKDU-UHFFFAOYSA-N n-[(3,4-dimethoxyphenyl)methyl]cyclopropanamine Chemical compound C1=C(OC)C(OC)=CC=C1CNC1CC1 ORZRHMRDNOCKDU-UHFFFAOYSA-N 0.000 claims description 8
VALINFAZSMPKJJ-UHFFFAOYSA-N n-[(3-chlorophenyl)methyl]cyclopropanamine Chemical compound ClC1=CC=CC(CNC2CC2)=C1 VALINFAZSMPKJJ-UHFFFAOYSA-N 0.000 claims description 8
XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 claims description 8
239000005541 ACE inhibitor Substances 0.000 claims description 7
125000004450 alkenylene group Chemical group 0.000 claims description 7
125000000304 alkynyl group Chemical group 0.000 claims description 7
229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 7
229910052740 iodine Inorganic materials 0.000 claims description 7
206010063897 Renal ischaemia Diseases 0.000 claims description 6
ANCFTHKEGKDXKD-UHFFFAOYSA-N n-[[3-(trifluoromethoxy)phenyl]methyl]cyclopropanamine Chemical compound FC(F)(F)OC1=CC=CC(CNC2CC2)=C1 ANCFTHKEGKDXKD-UHFFFAOYSA-N 0.000 claims description 6
125000001424 substituent group Chemical group 0.000 claims description 6
BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 5
229910052731 fluorine Inorganic materials 0.000 claims description 5
125000000623 heterocyclic group Chemical group 0.000 claims description 5
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
WRRVCXHKEDNRNB-UHFFFAOYSA-N n-[(3,5-difluorophenyl)methyl]cyclopropanamine Chemical compound FC1=CC(F)=CC(CNC2CC2)=C1 WRRVCXHKEDNRNB-UHFFFAOYSA-N 0.000 claims description 5
230000002265 prevention Effects 0.000 claims description 5
208000037803 restenosis Diseases 0.000 claims description 5
230000002792 vascular Effects 0.000 claims description 5
229910052727 yttrium Inorganic materials 0.000 claims description 5
201000001320 Atherosclerosis Diseases 0.000 claims description 4
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
206010007559 Cardiac failure congestive Diseases 0.000 claims description 4
QXKAIJAYHKCRRA-JJYYJPOSSA-N D-arabinonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C(O)=O QXKAIJAYHKCRRA-JJYYJPOSSA-N 0.000 claims description 4
208000010228 Erectile Dysfunction Diseases 0.000 claims description 4
208000010412 Glaucoma Diseases 0.000 claims description 4
206010018364 Glomerulonephritis Diseases 0.000 claims description 4
125000004093 cyano group Chemical group *C#N 0.000 claims description 4
230000006806 disease prevention Effects 0.000 claims description 4
OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical group CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 4
125000005842 heteroatom Chemical group 0.000 claims description 4
201000001881 impotence Diseases 0.000 claims description 4
208000031225 myocardial ischemia Diseases 0.000 claims description 4
210000000056 organ Anatomy 0.000 claims description 4
235000019260 propionic acid Nutrition 0.000 claims description 4
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 claims description 4
238000002054 transplantation Methods 0.000 claims description 4
125000000301 2-(3-chlorophenyl)ethyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
101800000734 Angiotensin-1 Proteins 0.000 claims description 3
102400000344 Angiotensin-1 Human genes 0.000 claims description 3
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 claims description 3
210000004165 myocardium Anatomy 0.000 claims description 3
WOHOHPONCSKXSQ-UHFFFAOYSA-N n-ethyl-2-phenylethanamine Chemical compound CCNCCC1=CC=CC=C1 WOHOHPONCSKXSQ-UHFFFAOYSA-N 0.000 claims description 3
238000001356 surgical procedure Methods 0.000 claims description 3
229940127291 Calcium channel antagonist Drugs 0.000 claims description 2
241001465754 Metazoa Species 0.000 claims description 2
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
239000000480 calcium channel blocker Substances 0.000 claims description 2
239000002934 diuretic Substances 0.000 claims description 2
229940030606 diuretics Drugs 0.000 claims description 2
MLHBZVFOTDJTPK-UHFFFAOYSA-N n-methyl-3-phenylpropan-1-amine Chemical compound CNCCCC1=CC=CC=C1 MLHBZVFOTDJTPK-UHFFFAOYSA-N 0.000 claims description 2
239000011591 potassium Substances 0.000 claims description 2
229910052700 potassium Inorganic materials 0.000 claims description 2
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 7
206010038419 Renal colic Diseases 0.000 claims 3
206010012601 diabetes mellitus Diseases 0.000 claims 3
229960003444 immunosuppressant agent Drugs 0.000 claims 3
230000001861 immunosuppressant effect Effects 0.000 claims 3
239000003018 immunosuppressive agent Substances 0.000 claims 3
208000002815 pulmonary hypertension Diseases 0.000 claims 3
208000035475 disorder Diseases 0.000 claims 2
FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical group CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims 2
HVFSJXUIRWUHRG-UHFFFAOYSA-N oic acid Natural products C1CC2C3CC=C4CC(OC5C(C(O)C(O)C(CO)O5)O)CC(O)C4(C)C3CCC2(C)C1C(C)C(O)CC(C)=C(C)C(=O)OC1OC(COC(C)=O)C(O)C(O)C1OC(C(C1O)O)OC(COC(C)=O)C1OC1OC(CO)C(O)C(O)C1O HVFSJXUIRWUHRG-UHFFFAOYSA-N 0.000 claims 2
DTJKAALGEAHUIV-UHFFFAOYSA-N 2-(2-chlorophenyl)-n-methylethanamine Chemical compound CNCCC1=CC=CC=C1Cl DTJKAALGEAHUIV-UHFFFAOYSA-N 0.000 claims 1
125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 claims 1
125000006495 3-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 claims 1
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239000000219 Sympatholytic Substances 0.000 claims 1
239000012190 activator Substances 0.000 claims 1
239000000654 additive Substances 0.000 claims 1
239000002160 alpha blocker Substances 0.000 claims 1
239000002876 beta blocker Substances 0.000 claims 1
238000007675 cardiac surgery Methods 0.000 claims 1
239000002308 endothelin receptor antagonist Substances 0.000 claims 1
125000005843 halogen group Chemical group 0.000 claims 1
125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
229960003975 potassium Drugs 0.000 claims 1
239000002464 receptor antagonist Substances 0.000 claims 1
229940044551 receptor antagonist Drugs 0.000 claims 1
230000000948 sympatholitic effect Effects 0.000 claims 1
238000012876 topography Methods 0.000 claims 1
238000007631 vascular surgery Methods 0.000 claims 1
229940124549 vasodilator Drugs 0.000 claims 1
239000003071 vasodilator agent Substances 0.000 claims 1
238000002360 preparation method Methods 0.000 abstract description 216
108090000783 Renin Proteins 0.000 abstract description 5
102100028255 Renin Human genes 0.000 abstract description 4
239000003112 inhibitor Substances 0.000 abstract description 4
239000004480 active ingredient Substances 0.000 abstract description 2
YJTZZSKGEPHUTF-UHFFFAOYSA-N 3,9-diazabicyclo[3.3.1]non-4-ene Chemical class C1NC=C2CCCC1N2 YJTZZSKGEPHUTF-UHFFFAOYSA-N 0.000 abstract 1
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 238
238000000746 purification Methods 0.000 description 225
BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 161
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 150
230000002829 reductive effect Effects 0.000 description 126
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 106
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YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 87
MCNQUWLLXZZZAC-UHFFFAOYSA-N 4-cyano-1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-n-piperidin-1-ylpyrazole-3-carboxamide Chemical compound C1=CC(OC)=CC=C1C1=C(C#N)C(C(=O)NN2CCCCC2)=NN1C1=CC=C(Cl)C=C1Cl MCNQUWLLXZZZAC-UHFFFAOYSA-N 0.000 description 83
239000000284 extract Substances 0.000 description 76
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VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 51
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229940126062 Compound A Drugs 0.000 description 45
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 45
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229910052760 oxygen Inorganic materials 0.000 description 17
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230000003197 catalytic effect Effects 0.000 description 13
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