TWI243164B - Acylated indanyl amines and their use as pharmaceuticals - Google Patents
Acylated indanyl amines and their use as pharmaceuticals Download PDFInfo
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- TWI243164B TWI243164B TW091102295A TW91102295A TWI243164B TW I243164 B TWI243164 B TW I243164B TW 091102295 A TW091102295 A TW 091102295A TW 91102295 A TW91102295 A TW 91102295A TW I243164 B TWI243164 B TW I243164B
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- phenyl
- alkyl
- methyl
- heteroaryl
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- -1 Acylated indanyl amines Chemical class 0.000 title claims abstract description 385
- 239000003814 drug Substances 0.000 title abstract description 14
- 125000001424 substituent group Chemical group 0.000 claims abstract description 165
- 150000001875 compounds Chemical class 0.000 claims abstract description 119
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 99
- 125000003118 aryl group Chemical group 0.000 claims abstract description 41
- 238000011282 treatment Methods 0.000 claims abstract description 13
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 8
- 206010020772 Hypertension Diseases 0.000 claims abstract description 7
- 208000029078 coronary artery disease Diseases 0.000 claims abstract description 7
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 6
- 206010019280 Heart failures Diseases 0.000 claims abstract description 6
- 230000006378 damage Effects 0.000 claims abstract description 6
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims abstract description 5
- 208000002249 Diabetes Complications Diseases 0.000 claims abstract description 5
- 206010048554 Endothelial dysfunction Diseases 0.000 claims abstract description 5
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 5
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 5
- 230000008694 endothelial dysfunction Effects 0.000 claims abstract description 5
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 4
- 208000010228 Erectile Dysfunction Diseases 0.000 claims abstract description 4
- 208000007530 Essential hypertension Diseases 0.000 claims abstract description 4
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 4
- 208000017442 Retinal disease Diseases 0.000 claims abstract description 4
- 206010038923 Retinopathy Diseases 0.000 claims abstract description 4
- 201000004239 Secondary hypertension Diseases 0.000 claims abstract description 4
- 208000006011 Stroke Diseases 0.000 claims abstract description 4
- 230000033115 angiogenesis Effects 0.000 claims abstract description 4
- 208000006673 asthma Diseases 0.000 claims abstract description 4
- 208000020832 chronic kidney disease Diseases 0.000 claims abstract description 4
- 208000022831 chronic renal failure syndrome Diseases 0.000 claims abstract description 4
- 208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 4
- 201000001881 impotence Diseases 0.000 claims abstract description 4
- 230000002093 peripheral effect Effects 0.000 claims abstract description 4
- 208000002815 pulmonary hypertension Diseases 0.000 claims abstract description 4
- 208000007718 Stable Angina Diseases 0.000 claims abstract description 3
- 239000003433 contraceptive agent Substances 0.000 claims abstract description 3
- KKJUPNGICOCCDW-UHFFFAOYSA-N 7-N,N-Dimethylamino-1,2,3,4,5-pentathiocyclooctane Chemical compound CN(C)C1CSSSSSC1 KKJUPNGICOCCDW-UHFFFAOYSA-N 0.000 claims abstract 4
- 206010016654 Fibrosis Diseases 0.000 claims abstract 3
- 230000007882 cirrhosis Effects 0.000 claims abstract 3
- 208000017169 kidney disease Diseases 0.000 claims abstract 3
- 208000007814 Unstable Angina Diseases 0.000 claims abstract 2
- 229940124558 contraceptive agent Drugs 0.000 claims abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims description 184
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 128
- 239000000203 mixture Substances 0.000 claims description 75
- 230000002079 cooperative effect Effects 0.000 claims description 70
- 125000005843 halogen group Chemical group 0.000 claims description 62
- 150000001412 amines Chemical class 0.000 claims description 60
- 125000003545 alkoxy group Chemical group 0.000 claims description 44
- 101100258315 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) crc-1 gene Proteins 0.000 claims description 43
- 125000005842 heteroatom Chemical group 0.000 claims description 39
- 125000000623 heterocyclic group Chemical group 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 38
- 239000002253 acid Substances 0.000 claims description 37
- 125000002577 pseudohalo group Chemical group 0.000 claims description 36
- 125000003277 amino group Chemical group 0.000 claims description 33
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 31
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 229910052731 fluorine Inorganic materials 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 23
- 150000003254 radicals Chemical class 0.000 claims description 20
- 230000002829 reductive effect Effects 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 239000007789 gas Substances 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 229920006395 saturated elastomer Polymers 0.000 claims description 14
- 125000001931 aliphatic group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical group NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000000468 ketone group Chemical group 0.000 claims description 10
- 125000001624 naphthyl group Chemical group 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 9
- 210000004204 blood vessel Anatomy 0.000 claims description 9
- 229910052796 boron Inorganic materials 0.000 claims description 9
- 230000003511 endothelial effect Effects 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 8
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000002619 bicyclic group Chemical group 0.000 claims description 8
- 229930194542 Keto Natural products 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 230000002792 vascular Effects 0.000 claims description 6
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 5
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 5
- 206010003119 arrhythmia Diseases 0.000 claims description 5
- 230000006793 arrhythmia Effects 0.000 claims description 5
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 5
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 5
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- COWZPSUDTMGBAT-UHFFFAOYSA-N 5-bromothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)S1 COWZPSUDTMGBAT-UHFFFAOYSA-N 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 230000001965 increasing effect Effects 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 3
- 208000004998 Abdominal Pain Diseases 0.000 claims description 3
- 208000002881 Colic Diseases 0.000 claims description 3
- 206010012655 Diabetic complications Diseases 0.000 claims description 3
- 206010038743 Restlessness Diseases 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000007903 gelatin capsule Substances 0.000 claims description 3
- 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 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 239000007943 implant Substances 0.000 claims description 3
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 3
- 239000003094 microcapsule Substances 0.000 claims description 3
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- 239000003826 tablet Substances 0.000 claims description 3
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
- MHQIZLXEJZNBQI-UHFFFAOYSA-N 1h-inden-1-amine Chemical class C1=CC=C2C(N)C=CC2=C1 MHQIZLXEJZNBQI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004463 2,4-dimethyl-thiazol-5-yl group Chemical group CC=1SC(=C(N1)C)* 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 239000007822 coupling agent Substances 0.000 claims description 2
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- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 2
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- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
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- 239000008194 pharmaceutical composition Substances 0.000 claims 13
- 125000003226 pyrazolyl group Chemical group 0.000 claims 4
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- 125000001544 thienyl group Chemical group 0.000 claims 4
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims 3
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- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims 3
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- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims 2
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- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- BPADEIVDGUQIMG-UHFFFAOYSA-N 1-ethenoxy-3-methoxybenzene Chemical compound COC1=CC=CC(OC=C)=C1 BPADEIVDGUQIMG-UHFFFAOYSA-N 0.000 claims 1
- NIBFJPXGNVPNHK-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-4-carbaldehyde Chemical group C1=CC(C=O)=C2OC(F)(F)OC2=C1 NIBFJPXGNVPNHK-UHFFFAOYSA-N 0.000 claims 1
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims 1
- DVXNCMVEXZVYMF-UHFFFAOYSA-N 2,6-dimethoxy-3-pyridin-3-ylpyridine Chemical group COc1ccc(-c2cccnc2)c(OC)n1 DVXNCMVEXZVYMF-UHFFFAOYSA-N 0.000 claims 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- FFXFDLYVAUDTCC-UHFFFAOYSA-N 2-ethylpyrimidin-4-amine Chemical compound CCC1=NC=CC(N)=N1 FFXFDLYVAUDTCC-UHFFFAOYSA-N 0.000 claims 1
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- LCMXOGJHXOFWNQ-UHFFFAOYSA-N 3-chloro-4-methylthiophene-2-carboxylic acid Chemical compound CC1=CSC(C(O)=O)=C1Cl LCMXOGJHXOFWNQ-UHFFFAOYSA-N 0.000 claims 1
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- TUNHTOJGOPCLTD-UHFFFAOYSA-N 5-ethenylthiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(C=C)S1 TUNHTOJGOPCLTD-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- C07C2601/00—Systems containing only non-condensed rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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| Application Number | Priority Date | Filing Date | Title |
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| EP01102850 | 2001-02-13 |
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| TWI243164B true TWI243164B (en) | 2005-11-11 |
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| TW091102295A TWI243164B (en) | 2001-02-13 | 2002-02-08 | Acylated indanyl amines and their use as pharmaceuticals |
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