SK61098A3 - Amidine and isothiourea derivatives as inhibitors of nitric oxide synthase - Google Patents

Amidine and isothiourea derivatives as inhibitors of nitric oxide synthase Download PDF

Info

Publication number: SK61098A3
Authority: SK; Slovakia
Prior art keywords: formula; compound; thiophenecarboximidamide; tetrahydroisoquinolin; alkyl
Prior art date: 1995-11-07

Application number

SK610-98A

Other languages

English (en)

Slovak (sk)

Inventor

James Macdonald

James Matz

William Shakespeare

Original Assignee

Astra Ab

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1995-11-07

Filing date

1996-11-06

Publication date

1999-01-11

1996-01-25 Priority claimed from SE9600275A external-priority patent/SE9600275D0/xx

1996-09-11 Priority claimed from SE9603300A external-priority patent/SE9603300D0/xx

1996-09-11 Priority claimed from SE9603301A external-priority patent/SE9603301D0/xx

1996-11-06 Application filed by Astra Ab filed Critical Astra Ab

1999-01-11 Publication of SK61098A3 publication Critical patent/SK61098A3/sk

Links

102000008299 Nitric Oxide Synthase Human genes 0.000 title description 3
108010021487 Nitric Oxide Synthase Proteins 0.000 title description 3
150000001409 amidines Chemical class 0.000 title description 3
150000002541 isothioureas Chemical class 0.000 title description 3
239000003112 inhibitor Substances 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 291
150000003839 salts Chemical class 0.000 claims abstract description 57
238000000034 method Methods 0.000 claims abstract description 51
230000003287 optical effect Effects 0.000 claims abstract description 17
230000008569 process Effects 0.000 claims abstract description 16
238000002360 preparation method Methods 0.000 claims abstract description 8
-1 N- (1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizin-10-yl) -2-thiophenecarboximidamide N- (1,2,3,5,6,10b-hexahydropyrrolo [2,1-a] isoquinolin-9-yl) -2-thiophenecarboximidamide Chemical compound 0.000 claims description 75
125000000217 alkyl group Chemical group 0.000 claims description 46
239000002253 acid Substances 0.000 claims description 28
MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 25
230000015572 biosynthetic process Effects 0.000 claims description 25
229910052739 hydrogen Inorganic materials 0.000 claims description 25
238000011282 treatment Methods 0.000 claims description 25
229910052760 oxygen Inorganic materials 0.000 claims description 23
238000003786 synthesis reaction Methods 0.000 claims description 23
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 22
229910052717 sulfur Inorganic materials 0.000 claims description 20
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 18
239000001257 hydrogen Substances 0.000 claims description 16
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
208000024891 symptom Diseases 0.000 claims description 15
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
229910052757 nitrogen Inorganic materials 0.000 claims description 14
229910052799 carbon Inorganic materials 0.000 claims description 13
125000004494 ethyl ester group Chemical group 0.000 claims description 12
208000002193 Pain Diseases 0.000 claims description 11
230000036407 pain Effects 0.000 claims description 11
230000000694 effects Effects 0.000 claims description 10
238000011321 prophylaxis Methods 0.000 claims description 10
206010010904 Convulsion Diseases 0.000 claims description 9
206010021143 Hypoxia Diseases 0.000 claims description 9
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
230000007954 hypoxia Effects 0.000 claims description 9
125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 8
201000010099 disease Diseases 0.000 claims description 8
125000005842 heteroatom Chemical group 0.000 claims description 8
208000028867 ischemia Diseases 0.000 claims description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
125000004093 cyano group Chemical group *C#N 0.000 claims description 7
235000019253 formic acid Nutrition 0.000 claims description 7
229910052736 halogen Inorganic materials 0.000 claims description 7
150000002367 halogens Chemical class 0.000 claims description 7
230000002401 inhibitory effect Effects 0.000 claims description 7
201000010901 lateral sclerosis Diseases 0.000 claims description 6
208000005264 motor neuron disease Diseases 0.000 claims description 6
ATGLKCZSFUKNNY-UHFFFAOYSA-N n'-(1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinolin-9-yl)thiophene-2-carboximidamide Chemical compound C=1C=C2CCN3CCCC3C2=CC=1NC(=N)C1=CC=CS1 ATGLKCZSFUKNNY-UHFFFAOYSA-N 0.000 claims description 6
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
208000019695 Migraine disease Diseases 0.000 claims description 5
102000001708 Protein Isoforms Human genes 0.000 claims description 5
108010029485 Protein Isoforms Proteins 0.000 claims description 5
239000003814 drug Substances 0.000 claims description 5
UGWUAMXUMUFZJU-UHFFFAOYSA-N methyl 2-[7-[[amino(thiophen-2-yl)methylidene]amino]-1,2,3,4-tetrahydroisoquinolin-1-yl]acetate Chemical compound C1=C2C(CC(=O)OC)NCCC2=CC=C1NC(=N)C1=CC=CS1 UGWUAMXUMUFZJU-UHFFFAOYSA-N 0.000 claims description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
239000008194 pharmaceutical composition Substances 0.000 claims description 5
IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 4
125000003545 alkoxy group Chemical group 0.000 claims description 4
206010013663 drug dependence Diseases 0.000 claims description 4
238000004519 manufacturing process Methods 0.000 claims description 4
206010027599 migraine Diseases 0.000 claims description 4
CCVDATBMBXGSFN-UHFFFAOYSA-N n'-(2,3,4,6,11,11a-hexahydro-1h-pyrazino[1,2-b]isoquinolin-8-yl)thiophene-2-carboximidamide Chemical compound C=1C=C2CC3CNCCN3CC2=CC=1NC(=N)C1=CC=CS1 CCVDATBMBXGSFN-UHFFFAOYSA-N 0.000 claims description 4
230000001537 neural effect Effects 0.000 claims description 4
125000004193 piperazinyl group Chemical group 0.000 claims description 4
208000011117 substance-related disease Diseases 0.000 claims description 4
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
125000004432 carbon atom Chemical group C* 0.000 claims description 3
239000003085 diluting agent Substances 0.000 claims description 3
230000003301 hydrolyzing effect Effects 0.000 claims description 3
230000005764 inhibitory process Effects 0.000 claims description 3
DMBHBIPONNZJOA-UHFFFAOYSA-N n'-(1-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)thiophene-2-carboximidamide Chemical compound C1=C2C(CC)NCCC2=CC=C1NC(=N)C1=CC=CS1 DMBHBIPONNZJOA-UHFFFAOYSA-N 0.000 claims description 3
LMYCEZQXCODIDE-UHFFFAOYSA-N n'-(1-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)thiophene-2-carboximidamide Chemical compound C1=C2C(CCC)NCCC2=CC=C1NC(=N)C1=CC=CS1 LMYCEZQXCODIDE-UHFFFAOYSA-N 0.000 claims description 3
CPDULLYYCFTFPE-UHFFFAOYSA-N n'-(3-ethyl-2-methyl-3,4-dihydro-1h-isoquinolin-7-yl)thiophene-2-carboximidamide Chemical compound C1=C2CN(C)C(CC)CC2=CC=C1N=C(N)C1=CC=CS1 CPDULLYYCFTFPE-UHFFFAOYSA-N 0.000 claims description 3
230000000626 neurodegenerative effect Effects 0.000 claims description 3
125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
230000002152 alkylating effect Effects 0.000 claims description 2
125000003118 aryl group Chemical group 0.000 claims description 2
UURIRDNWIJURMF-UHFFFAOYSA-N n'-(1,2-dimethyl-3,4-dihydro-1h-isoquinolin-7-yl)thiophene-2-carboximidamide Chemical compound C1=C2C(C)N(C)CCC2=CC=C1N=C(N)C1=CC=CS1 UURIRDNWIJURMF-UHFFFAOYSA-N 0.000 claims description 2
IDLFHBYWNAIQFX-UHFFFAOYSA-N n'-(1,3,4,6,11,11a-hexahydro-[1,4]oxazino[4,3-b]isoquinolin-8-yl)thiophene-2-carboximidamide Chemical compound C=1C=C2CC3COCCN3CC2=CC=1NC(=N)C1=CC=CS1 IDLFHBYWNAIQFX-UHFFFAOYSA-N 0.000 claims description 2
ZEDBASNMHHGHJK-UHFFFAOYSA-N n'-(2-methyl-1-propyl-3,4-dihydro-1h-isoquinolin-7-yl)thiophene-2-carboximidamide Chemical compound C1=C2C(CCC)N(C)CCC2=CC=C1NC(=N)C1=CC=CS1 ZEDBASNMHHGHJK-UHFFFAOYSA-N 0.000 claims description 2
GWHQHGCYQGLWPW-UHFFFAOYSA-N n'-[1-(2-oxo-2-pyrrolidin-1-ylethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]thiophene-2-carboximidamide Chemical compound C=1C=CSC=1C(N)=NC(C=C12)=CC=C1CCNC2CC(=O)N1CCCC1 GWHQHGCYQGLWPW-UHFFFAOYSA-N 0.000 claims description 2
125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
125000003386 piperidinyl group Chemical group 0.000 claims description 2
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 2
125000001544 thienyl group Chemical group 0.000 claims description 2
QKYHFLPSEJPFAV-UHFFFAOYSA-N n'-(3-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)thiophene-2-carboximidamide Chemical compound C1=C2CNC(CC)CC2=CC=C1NC(=N)C1=CC=CS1 QKYHFLPSEJPFAV-UHFFFAOYSA-N 0.000 claims 3
LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 claims 2
FGDLUEVYAJIMPR-UHFFFAOYSA-N 2-[7-[[amino(thiophen-2-yl)methylidene]amino]-1,2,3,4-tetrahydroisoquinolin-1-yl]-n,n-diethylacetamide Chemical compound C1=C2C(CC(=O)N(CC)CC)NCCC2=CC=C1NC(=N)C1=CC=CS1 FGDLUEVYAJIMPR-UHFFFAOYSA-N 0.000 claims 1
YNDYDLKLFZDFRR-UHFFFAOYSA-N 2-[7-[[amino(thiophen-2-yl)methylidene]amino]-1,2,3,4-tetrahydroisoquinolin-1-yl]-n-ethylacetamide Chemical compound C1=C2C(CC(=O)NCC)NCCC2=CC=C1N=C(N)C1=CC=CS1 YNDYDLKLFZDFRR-UHFFFAOYSA-N 0.000 claims 1
IQLICCFLLRSYPW-UHFFFAOYSA-N 2-[7-[[amino(thiophen-2-yl)methylidene]amino]-1,2,3,4-tetrahydroisoquinolin-1-yl]acetamide Chemical compound C1=C2C(CC(=O)N)NCCC2=CC=C1N=C(N)C1=CC=CS1 IQLICCFLLRSYPW-UHFFFAOYSA-N 0.000 claims 1
PFNSIYTVEXXBIG-UHFFFAOYSA-N N'-(2-ethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)thiophene-2-carboximidamide Chemical compound C=1C=C2OC(CC)CNCC2=CC=1N=C(N)C1=CC=CS1 PFNSIYTVEXXBIG-UHFFFAOYSA-N 0.000 claims 1
102000006538 Nitric Oxide Synthase Type I Human genes 0.000 claims 1
108010008858 Nitric Oxide Synthase Type I Proteins 0.000 claims 1
ROIYJTOJEOGKIX-UHFFFAOYSA-N n'-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)thiophene-2-carboximidamide Chemical compound C1=C2C(C)NCCC2=CC=C1NC(=N)C1=CC=CS1 ROIYJTOJEOGKIX-UHFFFAOYSA-N 0.000 claims 1
BXCIQCPGQVWEMZ-UHFFFAOYSA-N n'-(2,3-dimethyl-3,4-dihydro-1h-isoquinolin-7-yl)thiophene-2-carboximidamide Chemical compound C1=C2CN(C)C(C)CC2=CC=C1N=C(N)C1=CC=CS1 BXCIQCPGQVWEMZ-UHFFFAOYSA-N 0.000 claims 1
ZNMDQGOGSWJFLG-UHFFFAOYSA-N n'-(3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)thiophene-2-carboximidamide Chemical compound C1=C2CNC(C)CC2=CC=C1NC(=N)C1=CC=CS1 ZNMDQGOGSWJFLG-UHFFFAOYSA-N 0.000 claims 1
ZPDHQNXHEPABOG-UHFFFAOYSA-N n'-(3-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)thiophene-2-carboximidamide Chemical compound C1=C2CNC(CCC)CC2=CC=C1NC(=N)C1=CC=CS1 ZPDHQNXHEPABOG-UHFFFAOYSA-N 0.000 claims 1
CNJKWKSYKMEFPA-UHFFFAOYSA-N n'-(4-hydroxy-2,3,4,5-tetrahydro-1h-2-benzazepin-8-yl)thiophene-2-carboximidamide Chemical compound C=1C=C2CC(O)CNCC2=CC=1N=C(N)C1=CC=CS1 CNJKWKSYKMEFPA-UHFFFAOYSA-N 0.000 claims 1
JYHQKKQHOKMNDH-UHFFFAOYSA-N n'-[1-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]thiophene-2-carboximidamide Chemical compound C1=C2C(CCO)NCCC2=CC=C1NC(=N)C1=CC=CS1 JYHQKKQHOKMNDH-UHFFFAOYSA-N 0.000 claims 1
JCWOSCGPVGVFQL-UHFFFAOYSA-N n'-[1-(2-morpholin-4-yl-2-oxoethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]thiophene-2-carboximidamide Chemical compound C=1C=CSC=1C(N)=NC(C=C12)=CC=C1CCNC2CC(=O)N1CCOCC1 JCWOSCGPVGVFQL-UHFFFAOYSA-N 0.000 claims 1
XGXYKBKHRGSXLZ-UHFFFAOYSA-N n'-[1-(2-oxo-2-piperidin-1-ylethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]thiophene-2-carboximidamide Chemical compound C=1C=CSC=1C(N)=NC(C=C12)=CC=C1CCNC2CC(=O)N1CCCCC1 XGXYKBKHRGSXLZ-UHFFFAOYSA-N 0.000 claims 1
ASKGVOQFZKGECL-UHFFFAOYSA-N n'-[1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl]thiophene-2-carboximidamide Chemical compound CC1=NOC(CC2C3=CC(NC(=N)C=4SC=CC=4)=CC=C3CCN2)=N1 ASKGVOQFZKGECL-UHFFFAOYSA-N 0.000 claims 1
230000002265 prevention Effects 0.000 claims 1
239000000203 mixture Substances 0.000 abstract description 87
238000002560 therapeutic procedure Methods 0.000 abstract description 3
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 226
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 153
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 146
239000007787 solid Substances 0.000 description 134
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 126
239000000243 solution Substances 0.000 description 113
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 111
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 111
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 86
239000011541 reaction mixture Substances 0.000 description 85
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 74
239000003921 oil Substances 0.000 description 60
235000019198 oils Nutrition 0.000 description 60
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 57
238000006243 chemical reaction Methods 0.000 description 55
239000002904 solvent Substances 0.000 description 55
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
229910052943 magnesium sulfate Inorganic materials 0.000 description 42
235000019341 magnesium sulphate Nutrition 0.000 description 42
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
239000000047 product Substances 0.000 description 40
238000010992 reflux Methods 0.000 description 33
239000000284 extract Substances 0.000 description 27
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 26
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 25
238000001914 filtration Methods 0.000 description 25
FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 24
238000003756 stirring Methods 0.000 description 24
UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 22
239000012074 organic phase Substances 0.000 description 22
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 21
229910000043 hydrogen iodide Inorganic materials 0.000 description 21
AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 21
IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 17
239000000908 ammonium hydroxide Substances 0.000 description 17
239000000706 filtrate Substances 0.000 description 17
239000000725 suspension Substances 0.000 description 17
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 15
239000003054 catalyst Substances 0.000 description 15
239000002585 base Substances 0.000 description 14
238000001816 cooling Methods 0.000 description 14
239000000741 silica gel Substances 0.000 description 13
229910002027 silica gel Inorganic materials 0.000 description 13
238000001704 evaporation Methods 0.000 description 12
230000008020 evaporation Effects 0.000 description 12
239000000463 material Substances 0.000 description 12
239000004323 potassium nitrate Substances 0.000 description 12
235000010333 potassium nitrate Nutrition 0.000 description 12
239000002244 precipitate Substances 0.000 description 12
AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 11
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 11
AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 11
229910000085 borane Inorganic materials 0.000 description 11
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
229910000041 hydrogen chloride Inorganic materials 0.000 description 11
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
239000012458 free base Substances 0.000 description 10
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
239000008346 aqueous phase Substances 0.000 description 9
238000005515 capillary zone electrophoresis Methods 0.000 description 9
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 9
239000010410 layer Substances 0.000 description 9
238000001953 recrystallisation Methods 0.000 description 9
OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
239000000543 intermediate Substances 0.000 description 8
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
229920006395 saturated elastomer Polymers 0.000 description 8
229910000033 sodium borohydride Inorganic materials 0.000 description 8
239000012279 sodium borohydride Substances 0.000 description 8
230000002378 acidificating effect Effects 0.000 description 7
229910021529 ammonia Inorganic materials 0.000 description 7
238000004440 column chromatography Methods 0.000 description 7
239000010779 crude oil Substances 0.000 description 7
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
238000006722 reduction reaction Methods 0.000 description 7
239000000126 substance Substances 0.000 description 7
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
UXMXHFZLCVIFOJ-UHFFFAOYSA-N 3-ethyl-1,2,3,4-tetrahydroisoquinolin-7-amine;dihydrochloride Chemical compound Cl.Cl.C1=C(N)C=C2CNC(CC)CC2=C1 UXMXHFZLCVIFOJ-UHFFFAOYSA-N 0.000 description 6
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
230000003197 catalytic effect Effects 0.000 description 6
239000012043 crude product Substances 0.000 description 6
239000003480 eluent Substances 0.000 description 6
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
230000009467 reduction Effects 0.000 description 6
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
- 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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Life Sciences & Earth Sciences (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Bioinformatics & Cheminformatics (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Engineering & Computer Science (AREA)
Biomedical Technology (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Neurology (AREA)
Pain & Pain Management (AREA)
Neurosurgery (AREA)
Epidemiology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Treating Waste Gases (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Exhaust Gas Treatment By Means Of Catalyst (AREA)
Gas Separation By Absorption (AREA)
Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Other In-Based Heterocyclic Compounds (AREA)

SK610-98A 1995-11-07 1996-11-06 Amidine and isothiourea derivatives as inhibitors of nitric oxide synthase SK61098A3 (en)

Applications Claiming Priority (6)

Application Number	Priority Date	Filing Date	Title
US627695P	1995-11-07	1995-11-07
US625395P	1995-11-07	1995-11-07
SE9600275A SE9600275D0 (sv)	1996-01-25	1996-01-25	Compounds
SE9603300A SE9603300D0 (sv)	1996-09-11	1996-09-11	Compounds
SE9603301A SE9603301D0 (sv)	1996-09-11	1996-09-11	Compounds and compositions
PCT/SE1996/001425 WO1997017344A1 (en)	1995-11-07	1996-11-06	Amidine and isothiourea derivatives as inhibitors of nitric oxide synthase

Publications (1)

Publication Number	Publication Date
SK61098A3 true SK61098A3 (en)	1999-01-11

Family

ID=27532790

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
SK610-98A SK61098A3 (en)	1995-11-07	1996-11-06	Amidine and isothiourea derivatives as inhibitors of nitric oxide synthase

Country Status (24)

Country	Link
EP (1)	EP0861250B1 (de)
JP (1)	JP2000500132A (de)
KR (1)	KR19990067349A (de)
AT (1)	ATE213241T1 (de)
AU (1)	AU701329B2 (de)
BR (1)	BR9611276A (de)
CA (1)	CA2235301A1 (de)
CZ (1)	CZ139298A3 (de)
DE (1)	DE69619259T2 (de)
DK (1)	DK0861250T3 (de)
EE (1)	EE9800141A (de)
ES (1)	ES2171743T3 (de)
HU (1)	HUP9900142A3 (de)
IL (1)	IL124296A0 (de)
IS (1)	IS4725A (de)
NO (1)	NO982072L (de)
NZ (1)	NZ322227A (de)
PL (1)	PL326554A1 (de)
PT (1)	PT861250E (de)
SI (1)	SI0861250T1 (de)
SK (1)	SK61098A3 (de)
TR (1)	TR199800813T2 (de)
TW (1)	TW458978B (de)
WO (1)	WO1997017344A1 (de)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
AU4947197A (en) *	1996-10-16	1998-05-11	Glaxo Group Limited	Tetrahydro-6h-pyrazino{1,2-b}isoquinoline 1,4-diones as apoprotein b-100 inhibitors
SE9701681D0 (sv) *	1997-05-05	1997-05-05	Astra Ab	New compounds
SE9901901D0 (sv) *	1999-05-26	1999-05-26	Astra Ab	Compounds
US7393652B2 (en)	2000-05-10	2008-07-01	The Trustees Of Columbia University In The City Of New York	Methods for identifying a chemical compound that directly enhances binding of FKBP12.6 to PKA-phosphorylated type 2 ryanodine receptor (RyR2)
EA006082B1 (ru)	2001-12-19	2005-08-25	Х. Лундбекк А/С	Производные 3,4-дигидро-1h-изохинолин-2-ила
US6608193B2 (en) *	2001-12-21	2003-08-19	The Procter & Gamble Company	Methods for synthesis of amino-tetrahydroisoquinoline ring compounds
WO2004014885A1 (en) *	2002-08-07	2004-02-19	Neuraxon Inc.	Amino benzothiazole compounds with nos inhibitory activity
US7544678B2 (en)	2002-11-05	2009-06-09	The Trustees Of Columbia University In The City Of New York	Anti-arrythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2)
AU2004220548A1 (en)	2003-03-07	2004-09-23	The Trustees Of Columbia University, In The City Of New York	Type 1 ryanodine receptor-based methods
US8710045B2 (en)	2004-01-22	2014-04-29	The Trustees Of Columbia University In The City Of New York	Agents for preventing and treating disorders involving modulation of the ryanodine receptors
US20100105657A1 (en) *	2005-07-05	2010-04-29	Astrazeneca Ab	Compounds, Process for their Preparation, Intermediates, Pharmaceutical Compositions and their use in the Treatment of 5-HT6 Mediated Disorders such as Alzheimer's Disease, Cognitive Disorders, Cognitive Impairment Associated with Schizophrenia, Obesity and Parkinson's Disease
WO2008108445A1 (ja)	2007-03-07	2008-09-12	Takeda Pharmaceutical Company Limited	ベンゾオキサゼピン誘導体およびその用途
KR102480808B1 (ko)	2016-12-23	2022-12-22	다이이찌 산쿄 가부시키가이샤	Ｔｎａｐ 저해 활성을 갖는 술폰아미드 화합물

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5885985A (en) *	1993-03-23	1999-03-23	Astra Aktiebolag	Guanidine derivatives useful in therapy
IL110643A (en) *	1993-08-12	1998-07-15	Astra Ab	Amidine derivatives their preparation and pharmaceutical compositions containing them
EP0723438A1 (de) *	1993-10-04	1996-07-31	The Wellcome Foundation Limited	Substitutierte harnstoff und isothioharnstoff derivate als no synthase inhibitoren
TW397812B (en) *	1995-02-11	2000-07-11	Astra Ab	Bicyclic isothiourea derivatives useful in therapy

1996
- 1996-10-30 TW TW085113282A patent/TW458978B/zh active
- 1996-11-06 NZ NZ322227A patent/NZ322227A/xx unknown
- 1996-11-06 IL IL12429696A patent/IL124296A0/xx unknown
- 1996-11-06 SI SI9630451T patent/SI0861250T1/xx unknown
- 1996-11-06 CA CA002235301A patent/CA2235301A1/en not_active Abandoned
- 1996-11-06 AU AU75927/96A patent/AU701329B2/en not_active Ceased
- 1996-11-06 PT PT96938584T patent/PT861250E/pt unknown
- 1996-11-06 PL PL96326554A patent/PL326554A1/xx unknown
- 1996-11-06 EP EP96938584A patent/EP0861250B1/de not_active Expired - Lifetime
- 1996-11-06 TR TR1998/00813T patent/TR199800813T2/xx unknown
- 1996-11-06 DK DK96938584T patent/DK0861250T3/da active
- 1996-11-06 KR KR1019980703356A patent/KR19990067349A/ko not_active Withdrawn
- 1996-11-06 JP JP9518124A patent/JP2000500132A/ja active Pending
- 1996-11-06 BR BR9611276A patent/BR9611276A/pt not_active Application Discontinuation
- 1996-11-06 WO PCT/SE1996/001425 patent/WO1997017344A1/en not_active Ceased
- 1996-11-06 ES ES96938584T patent/ES2171743T3/es not_active Expired - Lifetime
- 1996-11-06 HU HU9900142A patent/HUP9900142A3/hu unknown
- 1996-11-06 AT AT96938584T patent/ATE213241T1/de not_active IP Right Cessation
- 1996-11-06 CZ CZ981392A patent/CZ139298A3/cs unknown
- 1996-11-06 DE DE69619259T patent/DE69619259T2/de not_active Expired - Fee Related
- 1996-11-06 SK SK610-98A patent/SK61098A3/sk unknown
- 1996-11-06 EE EE9800141A patent/EE9800141A/xx unknown
1998
- 1998-04-24 IS IS4725A patent/IS4725A/is unknown
- 1998-05-06 NO NO982072A patent/NO982072L/no not_active Application Discontinuation

Also Published As

Publication number	Publication date
BR9611276A (pt)	1999-01-26
HUP9900142A3 (en)	2001-08-28
PT861250E (pt)	2002-07-31
WO1997017344A1 (en)	1997-05-15
DE69619259T2 (de)	2002-09-19
DK0861250T3 (da)	2002-04-29
NO982072D0 (no)	1998-05-06
DE69619259D1 (de)	2002-03-21
ES2171743T3 (es)	2002-09-16
PL326554A1 (en)	1998-09-28
EP0861250B1 (de)	2002-02-13
MX9803453A (es)	1998-09-30
TR199800813T2 (xx)	1998-07-21
KR19990067349A (ko)	1999-08-16
IL124296A0 (en)	1998-12-06
NO982072L (no)	1998-07-03
EE9800141A (et)	1998-10-15
SI0861250T1 (en)	2002-06-30
EP0861250A1 (de)	1998-09-02
TW458978B (en)	2001-10-11
NZ322227A (en)	1999-11-29
HUP9900142A2 (hu)	1999-05-28
JP2000500132A (ja)	2000-01-11
AU7592796A (en)	1997-05-29
CZ139298A3 (cs)	1998-09-16
IS4725A (is)	1998-04-24
AU701329B2 (en)	1999-01-28
ATE213241T1 (de)	2002-02-15
CA2235301A1 (en)	1997-05-15

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