JP2002531548A - Ｎ−（２−フェニルー４−ピペリジニルブチル）−５，６，７，８−テトラヒドロー１−ナフタレンカルボキサミド、およびニューロキニン１（ｎｋ１）および／またはニューロキニン２（ｎｋ２）リセプター拮抗薬としてのそれらの使用 - Google Patents
Ｎ−（２−フェニルー４−ピペリジニルブチル）−５，６，７，８−テトラヒドロー１−ナフタレンカルボキサミド、およびニューロキニン１（ｎｋ１）および／またはニューロキニン２（ｎｋ２）リセプター拮抗薬としてのそれらの使用Info
- Publication number
- JP2002531548A JP2002531548A JP2000586691A JP2000586691A JP2002531548A JP 2002531548 A JP2002531548 A JP 2002531548A JP 2000586691 A JP2000586691 A JP 2000586691A JP 2000586691 A JP2000586691 A JP 2000586691A JP 2002531548 A JP2002531548 A JP 2002531548A
- Authority
- JP
- Japan
- Prior art keywords
- tetrahydro
- methyl
- methoxy
- alkyl
- mmol
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
- -1 N- (2-phenyl-4-piperidinylbutyl) -5,6,7,8-tetrahydro-1-naphthalenecarboxamide Chemical compound 0.000 title claims abstract description 149
- 102100024304 Protachykinin-1 Human genes 0.000 title description 48
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 title description 36
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 title description 23
- 239000002464 receptor antagonist Substances 0.000 title description 4
- 229940044551 receptor antagonist Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 124
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- 125000001424 substituent group Chemical group 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 24
- 150000002431 hydrogen Chemical group 0.000 claims description 17
- 208000006673 asthma Diseases 0.000 claims description 15
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000001589 carboacyl group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 8
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 7
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 7
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- SNCZNSNPXMPCGN-UHFFFAOYSA-N butanediamide Chemical compound NC(=O)CCC(N)=O SNCZNSNPXMPCGN-UHFFFAOYSA-N 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Chemical group C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 4
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 206010047700 Vomiting Diseases 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 3
- 230000008673 vomiting Effects 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- OBHBPXMWSDXYBR-UDKJZQBVSA-N 3-cyano-n-[(2s)-2-(3,4-dichlorophenyl)-4-[4-[2-[(s)-methylsulfinyl]phenyl]piperidin-1-yl]butyl]-2-ethyl-n-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide Chemical compound C([C@H](CN(C)C(=O)C1=C2CCCCC2=CC(=C1CC)C#N)C=1C=C(Cl)C(Cl)=CC=1)CN(CC1)CCC1C1=CC=CC=C1[S@](C)=O OBHBPXMWSDXYBR-UDKJZQBVSA-N 0.000 claims description 2
- VMGLUFOETPZIEO-HCRJBYBTSA-N 3-cyano-n-[(2s)-2-(3,4-dichlorophenyl)-4-[4-[2-[(s)-methylsulfinyl]phenyl]piperidin-1-yl]butyl]-2-methoxy-n-methylsulfonyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide Chemical compound C([C@H](CN(C(=O)C1=C2CCCCC2=CC(=C1OC)C#N)S(C)(=O)=O)C=1C=C(Cl)C(Cl)=CC=1)CN(CC1)CCC1C1=CC=CC=C1[S@](C)=O VMGLUFOETPZIEO-HCRJBYBTSA-N 0.000 claims description 2
- FHTGIBZAEUFTMT-CGQQATSGSA-N 3-cyano-n-[(2s)-2-(3,4-dichlorophenyl)-4-[4-[2-[(s)-methylsulfinyl]phenyl]piperidin-1-yl]butyl]-n,2-dimethyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide Chemical compound C([C@H](CN(C)C(=O)C=1C=2CCCCC=2C=C(C=1C)C#N)C=1C=C(Cl)C(Cl)=CC=1)CN(CC1)CCC1C1=CC=CC=C1[S@](C)=O FHTGIBZAEUFTMT-CGQQATSGSA-N 0.000 claims description 2
- 206010046543 Urinary incontinence Diseases 0.000 claims description 2
- UCHNYFBTBPTIAE-CGQQATSGSA-N n-[(2s)-2-(3,4-dichlorophenyl)-4-[4-[2-[(s)-methylsulfinyl]phenyl]piperidin-1-yl]butyl]-2-methoxy-n,3-dimethyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide Chemical compound C([C@H](CN(C)C(=O)C1=C2CCCCC2=CC(C)=C1OC)C=1C=C(Cl)C(Cl)=CC=1)CN(CC1)CCC1C1=CC=CC=C1[S@](C)=O UCHNYFBTBPTIAE-CGQQATSGSA-N 0.000 claims description 2
- KJGYWDDQBYCWPI-CGQQATSGSA-N n-[(2s)-2-(3,4-dichlorophenyl)-4-[4-[2-[(s)-methylsulfinyl]phenyl]piperidin-1-yl]butyl]-3-methoxy-n,2-dimethyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide Chemical compound C([C@H](CN(C)C(=O)C=1C=2CCCCC=2C=C(C=1C)OC)C=1C=C(Cl)C(Cl)=CC=1)CN(CC1)CCC1C1=CC=CC=C1[S@](C)=O KJGYWDDQBYCWPI-CGQQATSGSA-N 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 150000007945 N-acyl ureas Chemical class 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 10
- 230000008485 antagonism Effects 0.000 abstract description 8
- 108010040722 Neurokinin-2 Receptors Proteins 0.000 abstract description 5
- 102100037342 Substance-K receptor Human genes 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 100
- 238000001819 mass spectrum Methods 0.000 description 59
- 239000000203 mixture Substances 0.000 description 59
- 239000000243 solution Substances 0.000 description 59
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 46
- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000007787 solid Substances 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- 239000002904 solvent Substances 0.000 description 25
- 235000019439 ethyl acetate Nutrition 0.000 description 21
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 20
- 238000012360 testing method Methods 0.000 description 18
- 238000000921 elemental analysis Methods 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 17
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 16
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 16
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 16
- 239000005557 antagonist Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 102400000097 Neurokinin A Human genes 0.000 description 15
- 101800000399 Neurokinin A Proteins 0.000 description 15
- HEAUFJZALFKPBA-YRVBCFNBSA-N Neurokinin A Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)O)C1=CC=CC=C1 HEAUFJZALFKPBA-YRVBCFNBSA-N 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 239000000556 agonist Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 13
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 12
- 239000005909 Kieselgur Substances 0.000 description 12
- 101800003906 Substance P Proteins 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
- 102000005962 receptors Human genes 0.000 description 12
- 108020003175 receptors Proteins 0.000 description 12
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 11
- 102000015605 Neurokinin NK2 receptors Human genes 0.000 description 11
- 108050004872 Neurokinin NK2 receptors Proteins 0.000 description 11
- 229910002091 carbon monoxide Inorganic materials 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 238000005917 acylation reaction Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 230000010933 acylation Effects 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 9
- 238000006268 reductive amination reaction Methods 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 102000003141 Tachykinin Human genes 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 108060008037 tachykinin Proteins 0.000 description 8
- WXIAUXKXOZCTGZ-UHFFFAOYSA-N 5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride Chemical compound C1CCCC2=C1C=CC=C2C(=O)Cl WXIAUXKXOZCTGZ-UHFFFAOYSA-N 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- ZQLTWFUHOAKXRJ-HTRDMIOFSA-N (2s)-2-(3,4-dichlorophenyl)-n-methyl-4-[2-[2-[(s)-methylsulfinyl]phenyl]piperidin-1-yl]butan-1-amine Chemical compound C([C@H](CNC)C=1C=C(Cl)C(Cl)=CC=1)CN1CCCCC1C1=CC=CC=C1[S@](C)=O ZQLTWFUHOAKXRJ-HTRDMIOFSA-N 0.000 description 6
- OWQHJBDJVOOBBU-XBBWARJSSA-N (2s)-2-(3,4-dichlorophenyl)-n-methyl-4-[4-[2-[(s)-methylsulfinyl]phenyl]piperidin-1-yl]butan-1-amine Chemical compound C([C@H](CNC)C=1C=C(Cl)C(Cl)=CC=1)CN(CC1)CCC1C1=CC=CC=C1[S@](C)=O OWQHJBDJVOOBBU-XBBWARJSSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 229910004373 HOAc Inorganic materials 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 238000010253 intravenous injection Methods 0.000 description 5
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 5
- 210000001147 pulmonary artery Anatomy 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- SVAVTRDPSCZNRE-UHFFFAOYSA-N 2,3-dimethoxy-5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride Chemical compound C1CCCC2=C1C=C(OC)C(OC)=C2C(Cl)=O SVAVTRDPSCZNRE-UHFFFAOYSA-N 0.000 description 4
- RKBFNBCMAGYJLJ-UHFFFAOYSA-N 2-methoxy-5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride Chemical compound C1CCCC2=C(C(Cl)=O)C(OC)=CC=C21 RKBFNBCMAGYJLJ-UHFFFAOYSA-N 0.000 description 4
- NUVWNNAOCKXGGB-UHFFFAOYSA-N 3,4-dimethoxy-5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride Chemical compound C1CCCC2=C(OC)C(OC)=CC(C(Cl)=O)=C21 NUVWNNAOCKXGGB-UHFFFAOYSA-N 0.000 description 4
- JKQZNXMOSDSMAV-UHFFFAOYSA-N 3-cyano-5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride Chemical compound C1CCCC2=C1C=C(C#N)C=C2C(=O)Cl JKQZNXMOSDSMAV-UHFFFAOYSA-N 0.000 description 4
- YDROFLKVNJGOFR-UHFFFAOYSA-N 3-methoxy-5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride Chemical compound C1CCCC2=C1C=C(OC)C=C2C(Cl)=O YDROFLKVNJGOFR-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- NHXYSAFTNPANFK-HDMCBQFHSA-N Neurokinin B Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC(O)=O)C1=CC=CC=C1 NHXYSAFTNPANFK-HDMCBQFHSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 230000008602 contraction Effects 0.000 description 4
- 238000011067 equilibration Methods 0.000 description 4
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000011777 magnesium 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
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- DSDNAKHZNJAGHN-MXTYGGKSSA-N resiniferatoxin Chemical compound C1=C(O)C(OC)=CC(CC(=O)OCC=2C[C@]3(O)C(=O)C(C)=C[C@H]3[C@@]34[C@H](C)C[C@@]5(O[C@@](O4)(CC=4C=CC=CC=4)O[C@@H]5[C@@H]3C=2)C(C)=C)=C1 DSDNAKHZNJAGHN-MXTYGGKSSA-N 0.000 description 1
- 229940073454 resiniferatoxin Drugs 0.000 description 1
- 210000001533 respiratory mucosa Anatomy 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 108010078913 substance P (6-11) Proteins 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000002466 tachykinin receptor agonist Substances 0.000 description 1
- KFBBIBBBJUCPIT-LRKHVIJYSA-N tert-butyl carbamate;(2s)-2-(3,4-dichlorophenyl)-n-methyl-4-[4-[2-[(s)-methylsulfinyl]phenyl]piperidin-1-yl]butan-1-amine Chemical compound CC(C)(C)OC(N)=O.C([C@H](CNC)C=1C=C(Cl)C(Cl)=CC=1)CN(CC1)CCC1C1=CC=CC=C1[S@](C)=O KFBBIBBBJUCPIT-LRKHVIJYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- LJJKNPQAGWVLDQ-SNVBAGLBSA-N thiorphan Chemical compound OC(=O)CNC(=O)[C@@H](CS)CC1=CC=CC=C1 LJJKNPQAGWVLDQ-SNVBAGLBSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000001170 unmyelinated nerve fiber Anatomy 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9826941.8A GB9826941D0 (en) | 1998-12-09 | 1998-12-09 | Compounds |
| GB9826941.8 | 1998-12-09 | ||
| PCT/GB1999/004118 WO2000034243A1 (en) | 1998-12-09 | 1999-12-06 | N-(2-phenyl-4-piperidinybutyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxamides and their use as neurokinin 1 (nk1) and/or neurokinin 2 (nk2) receptor antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2002531548A true JP2002531548A (ja) | 2002-09-24 |
| JP2002531548A5 JP2002531548A5 (enExample) | 2007-01-25 |
Family
ID=10843818
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000586691A Pending JP2002531548A (ja) | 1998-12-09 | 1999-12-06 | Ｎ−（２−フェニルー４−ピペリジニルブチル）−５，６，７，８−テトラヒドロー１−ナフタレンカルボキサミド、およびニューロキニン１（ｎｋ１）および／またはニューロキニン２（ｎｋ２）リセプター拮抗薬としてのそれらの使用 |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US6403601B1 (enExample) |
| EP (1) | EP1137637A1 (enExample) |
| JP (1) | JP2002531548A (enExample) |
| AU (1) | AU1667500A (enExample) |
| GB (1) | GB9826941D0 (enExample) |
| WO (1) | WO2000034243A1 (enExample) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6898636B1 (en) * | 1999-02-04 | 2005-05-24 | Intralinks, Inc. | Methods and systems for interchanging documents between a sender computer, a server and a receiver computer |
| GB9911017D0 (en) * | 1999-05-13 | 1999-07-14 | Zeneca Ltd | Pharmaceutical compositions |
| JP2003530388A (ja) * | 2000-04-06 | 2003-10-14 | アストラゼネカ・アクチエボラーグ | 医薬として使用するための新規なニューロキニン拮抗薬 |
| US6903092B2 (en) | 2000-04-06 | 2005-06-07 | Peter Bernstein | Naphthamide neurokinin antagonists for use as medicaments |
| ATE308513T1 (de) * | 2000-04-06 | 2005-11-15 | Naphthamid-neurokinin antagonisten zur verwendung als medikamente | |
| US6846814B2 (en) | 2000-04-06 | 2005-01-25 | Astra Zeneca Ab | Neurokinin antagonists for use as medicaments |
| GB0015246D0 (en) * | 2000-06-22 | 2000-08-16 | Astrazeneca Ab | Method for the treatment of urinary incontinence |
| SE0103668D0 (sv) * | 2001-11-02 | 2001-11-02 | Astrazeneca Ab | Method for the treatment of overactive blader |
| SE0103795D0 (sv) | 2001-11-02 | 2001-11-02 | Astrazeneca Ab | Compounds and method for the treatment of överactive bladder |
| TW200508221A (en) | 2003-06-13 | 2005-03-01 | Astrazeneca Ab | New azetidine compounds |
| US20040265238A1 (en) | 2003-06-27 | 2004-12-30 | Imtiaz Chaudry | Inhalable formulations for treating pulmonary hypertension and methods of using same |
| GB0418045D0 (en) | 2004-08-12 | 2004-09-15 | Glaxo Group Ltd | Compounds |
| SE0403005D0 (sv) * | 2004-12-09 | 2004-12-09 | Astrazeneca Ab | New use |
| AR057828A1 (es) | 2005-09-29 | 2007-12-19 | Astrazeneca Ab | Compuestos derivados de azetidina, su preparacion y composicion farmaceuutica |
| AR056087A1 (es) * | 2005-09-29 | 2007-09-19 | Astrazeneca Ab | Derivados de azetidina como antagonistas de receptores de neuroquina nk |
| US8106208B2 (en) | 2006-05-18 | 2012-01-31 | Albireo Ab | Benzamide compounds that act as NK receptor antagonists |
| EP2117538A1 (en) | 2007-01-24 | 2009-11-18 | Glaxo Group Limited | Pharmaceutical compositions comprising 2-methoxy-5- (5-trifluoromethyl-tetrazol-i-yl-benzyl) - (2s-phenyl-piperidin-3s-yl-) |
| CN120476107A (zh) | 2022-12-15 | 2025-08-12 | 先正达农作物保护股份公司 | 可用作杀有害生物剂的新型的二环-甲酰胺化合物 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0625509A1 (en) * | 1993-05-17 | 1994-11-23 | Zeneca Limited | N-alkyl substituted piperidine-derivatives with neurokinin receptor antagonist activity |
| EP0630887A1 (en) * | 1993-05-24 | 1994-12-28 | Zeneca Limited | 4-(aryl-substituted)-piperidines as neurokinin receptor antagonists |
| WO1998007722A1 (en) * | 1996-08-23 | 1998-02-26 | Pfizer Limited | Quaternary ammonium compounds as tachykinin antagonist |
| US5789422A (en) * | 1996-10-28 | 1998-08-04 | Schering Corporation | Substituted arylalkylamines as neurokinin antagonists |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL99320A (en) * | 1990-09-05 | 1995-07-31 | Sanofi Sa | Arylalkylamines, their preparation and pharmaceutical compositions containing them |
-
1998
- 1998-12-09 GB GBGB9826941.8A patent/GB9826941D0/en not_active Ceased
-
1999
- 1999-12-06 US US09/857,833 patent/US6403601B1/en not_active Expired - Fee Related
- 1999-12-06 AU AU16675/00A patent/AU1667500A/en not_active Abandoned
- 1999-12-06 JP JP2000586691A patent/JP2002531548A/ja active Pending
- 1999-12-06 EP EP99959534A patent/EP1137637A1/en not_active Withdrawn
- 1999-12-06 WO PCT/GB1999/004118 patent/WO2000034243A1/en not_active Ceased
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0625509A1 (en) * | 1993-05-17 | 1994-11-23 | Zeneca Limited | N-alkyl substituted piperidine-derivatives with neurokinin receptor antagonist activity |
| EP0630887A1 (en) * | 1993-05-24 | 1994-12-28 | Zeneca Limited | 4-(aryl-substituted)-piperidines as neurokinin receptor antagonists |
| WO1998007722A1 (en) * | 1996-08-23 | 1998-02-26 | Pfizer Limited | Quaternary ammonium compounds as tachykinin antagonist |
| US5789422A (en) * | 1996-10-28 | 1998-08-04 | Schering Corporation | Substituted arylalkylamines as neurokinin antagonists |
Also Published As
| Publication number | Publication date |
|---|---|
| US6403601B1 (en) | 2002-06-11 |
| EP1137637A1 (en) | 2001-10-04 |
| GB9826941D0 (en) | 1999-02-03 |
| AU1667500A (en) | 2000-06-26 |
| WO2000034243A1 (en) | 2000-06-15 |
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