JP5165581B2 - アルキルスルホンアミドキノリン - Google Patents
アルキルスルホンアミドキノリン Download PDFInfo
- Publication number
- JP5165581B2 JP5165581B2 JP2008545536A JP2008545536A JP5165581B2 JP 5165581 B2 JP5165581 B2 JP 5165581B2 JP 2008545536 A JP2008545536 A JP 2008545536A JP 2008545536 A JP2008545536 A JP 2008545536A JP 5165581 B2 JP5165581 B2 JP 5165581B2
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- compounds
- quinoline
- carboxylic acid
- alkyl
- 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.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 claims description 103
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- 125000000217 alkyl group Chemical group 0.000 description 33
- 238000000034 method Methods 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 108010040716 Neurokinin-3 Receptors Proteins 0.000 description 26
- 102000002003 Neurokinin-3 Receptors Human genes 0.000 description 26
- 229910052736 halogen Inorganic materials 0.000 description 24
- 150000002367 halogens Chemical class 0.000 description 24
- 125000003118 aryl group Chemical group 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 16
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- 125000004093 cyano group Chemical group *C#N 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 13
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- 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 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
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- 239000002904 solvent Substances 0.000 description 12
- 238000001727 in vivo Methods 0.000 description 11
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- 239000002243 precursor Substances 0.000 description 10
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- 208000035475 disorder Diseases 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
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- 235000011152 sodium sulphate Nutrition 0.000 description 7
- NHDWSGJQZXPZHF-UHFFFAOYSA-N 3-(methanesulfonamido)-2-phenylquinoline-4-carboxylic acid Chemical compound N1=C2C=CC=CC2=C(C(O)=O)C(NS(=O)(=O)C)=C1C1=CC=CC=C1 NHDWSGJQZXPZHF-UHFFFAOYSA-N 0.000 description 6
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- 239000003814 drug Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- XBJQOJZJCMQHMT-XMMPIXPASA-N n-[(s)-cyclopropyl(phenyl)methyl]-3-(methanesulfonamido)-2-phenylquinoline-4-carboxamide Chemical compound C1([C@H](NC(=O)C2=C3C=CC=CC3=NC(=C2NS(=O)(=O)C)C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 XBJQOJZJCMQHMT-XMMPIXPASA-N 0.000 description 6
- PJSPCXBSTRGZBT-DEOSSOPVSA-N n-[(s)-cyclopropyl-(3-fluorophenyl)methyl]-3-(methanesulfonamido)-2-phenylquinoline-4-carboxamide Chemical compound C1([C@H](NC(=O)C2=C3C=CC=CC3=NC(=C2NS(=O)(=O)C)C=2C=CC=CC=2)C=2C=C(F)C=CC=2)CC1 PJSPCXBSTRGZBT-DEOSSOPVSA-N 0.000 description 6
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- VWLDDKZXFWYZEW-QFIPXVFZSA-N 3-(aminomethyl)-2-phenyl-n-[(1s)-1-phenylpropyl]quinoline-4-carboxamide Chemical compound N([C@@H](CC)C=1C=CC=CC=1)C(=O)C(C1=CC=CC=C1N=1)=C(CN)C=1C1=CC=CC=C1 VWLDDKZXFWYZEW-QFIPXVFZSA-N 0.000 description 5
- 102100024304 Protachykinin-1 Human genes 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
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- 239000012267 brine Substances 0.000 description 5
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- ZUXMOOQOTSPQOJ-KRWDZBQOSA-N n-[(1s)-1-cyclohexylethyl]-3-(methanesulfonamido)-2-phenylquinoline-4-carboxamide Chemical compound N([C@@H](C)C1CCCCC1)C(=O)C(C1=CC=CC=C1N=1)=C(NS(C)(=O)=O)C=1C1=CC=CC=C1 ZUXMOOQOTSPQOJ-KRWDZBQOSA-N 0.000 description 5
- FAFNPIOCLONCCT-AREMUKBSSA-N n-[(s)-cyclopropyl(phenyl)methyl]-3-(cyclopropylsulfonylamino)-2-phenylquinoline-4-carboxamide Chemical compound C1([C@H](NC(=O)C=2C3=CC=CC=C3N=C(C=2NS(=O)(=O)C2CC2)C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 FAFNPIOCLONCCT-AREMUKBSSA-N 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
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- AZWSBQMGBORCLD-QFIPXVFZSA-N 3-(azidomethyl)-2-phenyl-n-[(1s)-1-phenylpropyl]quinoline-4-carboxamide Chemical compound N([C@@H](CC)C=1C=CC=CC=1)C(=O)C(C1=CC=CC=C1N=1)=C(CN=[N+]=[N-])C=1C1=CC=CC=C1 AZWSBQMGBORCLD-QFIPXVFZSA-N 0.000 description 4
- CRVQCFMGYFAJBU-UHFFFAOYSA-N 3-(azidomethyl)-2-phenylquinoline-4-carboxylic acid Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(CN=[N+]=[N-])C=1C1=CC=CC=C1 CRVQCFMGYFAJBU-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
- C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2
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Description
R1はH、C1-4アルキル-、C3-6シクロアルキル-及びC1-4アルキルOC(O)-から選ばれ;
Aはフェニル又はC3-7シクロアルキル-であり;
R2は各々独立して、H、-OH、-NH2、-CN、ハロゲン、C1-6アルキル-、C3-7シクロアルキル-、C1-6アルコキシ-及びC1-6アルコキシC1-6アルキル-から選ばれ;
nは1、2又は3であり;
R3は各々独立して、H、-OH、-NH2、-NO2、-CN、ハロゲン、C1-6アルキル-、C1-6アルコキシ- 及びC1-6アルコキシC1-6アルキル-から選ばれ;
mは1、2又は3であり;
rは0、1、2又は3であり;
R4はC1-4アルキル-、C1-6アルコキシC1-6アルキル-、C3-7シクロアルキル-及びE-(CH2)p-から選ばれ、ここでEは-NR6R7、-SR6、-SOC1-6アルキル、-SO2C1-6アルキル、N+(O-)R6R7、-NR6SO2R7、アリール、及び1、2、3若しくは4個の窒素原子を有するN-若しくはC-結合5-若しくは6-員芳香族若しくは非芳香族の複素環式環又はそのN-オキシドから選ばれ、そしてpは0、1、2、3、4又は5であり;
R5は各々独立して、H、-OH、-CN、ハロゲン、-R6、-OR6、-NR6R7、-SR6、-SOR6及び-SO2R6から選ばれ;
qは1、2又は3であり;
ここで、
R6及びR7は各々独立して、H、C1-6直鎖又は分岐鎖アルキル基、C2-6 直鎖又は分岐鎖アルケニル又はアルキニル基、及び0、1又は2個の二重又は三重結合を有するC3-7炭素環式基から選ばれ、ここで該基は非置換であるか、又は-OH、=O、-NH2、-CN、ハロゲン、アリール及びC1-3アルコキシ-から選ばれる1個又はそれ以上の基で置換されており;
R8はH、C1-5直鎖若しくは分岐鎖アルキル基、又はC3-5 シクロアルキル基から選ばれ、該基は非置換であるか、又は-OH、=O、-NH2、-CN、ハロゲン、アリール及びC1-3アルコキシ-から選ばれる1個若しくはそれ以上の基で置換されており;
そして
R4がE-(CH2)p-でありそして該EがN若しくはC結合5-若しくは6-員の芳香族若しくは非芳香族複素環式環又はそのN-オキシドである場合、該Eは非置換であるか、又は独立して-OH、=O、-NH2、-CN、ハロゲン、C1-4アルキル-、C1-4アルコキシ-、C1-4アルキル-CO-、NR6R7、アリール及び1、2、3若しくは4個の窒素原子を有する5-若しくは6-員の芳香族若しくは非芳香族の複素環式環から選ばれる1、2若しくは 3個の置換基を有し;
そして
R1、R2、R3又はR4がアルキル、シクロアルキル、アルコキシ又はアルコキシアルキル基である場合、該基は非置換であるか、又は各々独立して-OH、-NH2、-CN、フェニル及びハロゲンから選ばれる1、2、3、4若しくは 5個の置換基を有する)
の化合物である。
R1はH、C1-4アルキル-、C3-6シクロアルキル-及びC1-4アルキルOC(O)-から選ばれ;
Aはフェニル又はC3-7シクロアルキル-であり;
R2は各々独立して、H、-OH、-NH2、-CN、ハロゲン、C1-6アルキル-、C3-7シクロアルキル-、C1-6アルコキシ-及びC1-6アルコキシC1-6アルキル-から選ばれ;
Nは1、2又は3であり;
R3は各々独立して、H、-OH、-NH2、-NO2、-CN、ハロゲン、C1-6アルキル-、C1-6アルコキシ-及びC1-6アルコキシC1-6アルキル-から選ばれ;
mは1、2又は3であり;
rは0、1、2又は3であり;
R4はC1-4アルキル-、C1-6アルコキシC1-6アルキル-、C3-7シクロアルキル-及びE-(CH2)p-から選ばれ、ここでEは-NR6R7、-SR6、-SOC1-6アルキル、-SO2C1-6アルキル、N+(O-)R6R7、-NR6SO2R7、アリール、及び1、2、3若しくは4個の窒素原子を有するN-若しくはC-結合5-若しくは6-員芳香族若しくは非芳香族の複素環式環又はそのN-オキシドから選ばれ、そしてpは0、1、2、3、4又は5であり;
R5は各々独立して、H、-OH、-CN、ハロゲン、-R6、-OR6、-NR6R7、-SR6、-SOR6及び-SO2R6から選ばれ;
qは1、2又は3であり;
R8はH、C1-5直鎖若しくは分岐鎖アルキル基、又はC3-5シクロアルキル基から選ばれ、該基は非置換であるか、又は-OH、=O、-NH2、-CN、ハロゲン、アリール及びC1-3アルコキシ-から選ばれる1個又はそれ以上の基で置換されており;
ここで、
R6及びR7は各々独立して、H、C1-6直鎖又は分岐鎖アルキル基、C26直鎖又は分岐鎖アルケニル又はアルキニル基、及び0、1又は2個の二重又は三重結合を有するC3-7炭素環式基から選ばれ、ここで該基は非置換であるか、又は-OH、=O、-NH2、-CN、ハロゲン、アリール及びC1-3アルコキシ-から選ばれる1個若しくはそれ以上の基で置換されており;
そして
R4がE-(CH2)p-でありそして該EがN若しくはC結合5-若しくは6-員の芳香族若しくは非芳香族の複素環式環又はそのN-オキシドである場合、該Eは非置換であるか、又は独立して-OH、=O、-NH2、-CN、ハロゲン、C1-4アルキル-、C1-4アルコキシ-、C1-4アルキル-CO-、-NR6R7、アリール及び1、2、3若しくは4個の窒素原子を有するN-若しくはC-結合5-若しくは6-員芳香族若しくは非芳香族の複素環式環若しくはそのN-オキシドから選ばれ、そして
R1、R2、R3又はR4がアルキル、シクロアルキル、アルコキシ又はアルコキシアルキル基である場合、該基は非置換であるか、又は各々独立して-OH、-NH2、-CN、フェニル及びハロゲンから選ばれる1、2、3、4若しくは 5個の置換基を有する)
の化合物、それらの立体異性体、エナンチオマー、生体内で加水分解可能な前駆体及び薬学的許容塩である。
の化合物であり、かかる化合物は式Iでrが0の化合物、それらの生体内で加水分解可能な前駆体及び薬学的許容塩である。
Aがフェニル;
R1がC1-4アルキル-、C3-6シクロアルキル-及びC1-4アルキルOC(O)-から選ばれ;
R2がH、ハロゲン及び非置換C1-6アルコキシ-から選ばれ;
R3がH又はハロゲン;
R8がH又はメチル;
N及びmが両方とも1;そして
R1又はR4がアルキル、シクロアルキル、又はアルコキシアルキル基である場合、該基は非置換であるか、又は各々独立して-OH、-NH2、-CN及びハロゲンから選ばれる1、2、3、4若しくは 5個の置換基を有する、
化合物、それらの立体異性体、エナンチオマー、生体内で加水分解可能な前駆体及び薬学的許容塩である。
Aがフェニル;
R1がC1-4アルキル-及びC3-6シクロアルキル-から選ばれ;
R2がH、ハロゲン及び非置換C1-6アルコキシ-から選ばれ;
R3がH又はハロゲン;
R8がH又はメチル;
n及びmが両方とも1;
R4がC1-4アルキル-及びE-(CH2)p-から選ばれ、ここでEは1、2、3又は 4個の窒素原子を有する置換又は非置換のN-結合5-又は6-員芳香族又は非芳香族の複素環式環であり、そして
R5がH、
である化合物、それらの立体異性体、エナンチオマー、生体内で加水分解可能な前駆体及び薬学的許容塩である。
Aがフェニル;
R1がエチル又はシクロプロピル;
R2がH、F及び-OCH3から選ばれ;
R3がH又はF;
R8がH;
n、m及びqがそれぞれ1、そして
R5が各々独立してH、-OH及びハロゲンから選ばれる、
化合物、それらの立体異性体、エナンチオマー、生体内で加水分解可能な前駆体及び薬学的許容塩である。
の化合物、それらの生体内で加水分解可能な前駆体及び薬学的許容塩である。
3-メタンスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸(1-フェニル-プロピル)-アミド;
3-エタンスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸(1-フェニル-プロピル)-アミド;
2-フェニル-3-トリフルオロメタンスルホニルアミノ-キノリン-4-カルボン酸(1-フェニル-プロピル)-アミド;
2-フェニル-3-(2,2,2-トリフルオロ-エタンスルホニルアミノ)-キノリン-4-カルボン酸(1-フェニル-プロピル)-アミド;
2-フェニル-3-(プロパン-1-スルホニルアミノ)-キノリン-4-カルボン酸(1-フェニル-プロピル)-アミド;
2-フェニル-3-(3,3,3-トリフルオロ-プロパン-1-スルホニルアミノ)-キノリン-4-カルボン酸(1-フェニル-プロピル)-アミド;
3-シクロプロパンスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸(1-フェニル-プロピル)-アミド;
3-メタンスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸(シクロプロピル-フェニル-メチル)-アミド;
3-メタンスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸[1-(3-フルオロ-フェニル)-プロピル]-アミド;
3-メタンスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸[シクロプロピル-(3-フルオロ-フェニル)-メチル]-アミド;
2-(3-フルオロ-フェニル)-3-メタンスルホニルアミノ-キノリン-4-カルボン酸(1-フェニル-プロピル)-アミド;
2-(3-フルオロ-フェニル)-3-メタンスルホニルアミノ-キノリン-4-カルボン酸(シクロプロピル-フェニル-メチル)-アミド;
2-(3-フルオロ-フェニル)-3-メタンスルホニルアミノ-キノリン-4-カルボン酸[1-(3-フルオロ-フェニル)-プロピル]-アミド;
2-(3-フルオロ-フェニル)-3-メタンスルホニルアミノ-キノリン-4-カルボン酸[シクロプロピル-(3-フルオロ-フェニル)-メチル]-アミド;
3-メタンスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸((S)-1-フェニル-プロピル)-アミド;
3-エタンスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸((S)-1-フェニル-プロピル)-アミド;
2-フェニル-3-トリフルオロメタンスルホニルアミノ-キノリン-4-カルボン酸((S)-1-フェニル-プロピル)-アミド;
2-フェニル-3-(2,2,2-トリフルオロ-エタンスルホニルアミノ)-キノリン-4-カルボン酸((S)-1-フェニル-プロピル)-アミド;
2-フェニル-3-(プロパン-1-スルホニルアミノ)-キノリン-4-カルボン酸((S)-1-フェニル-プロピル)-アミド;
3-シクロプロパンスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸((S)-1-フェニル-プロピル)-アミド;
3-メタンスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸((S)-シクロプロピル-フェニル-メチル)-アミド;
3-メタンスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸[(S)-1-(3-フルオロ-フェニル)-プロピル]-アミド;
3-メタンスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸[(S)-シクロプロピル-(3-フルオロ-フェニル)-メチル]-アミド;
2-(3-フルオロ-フェニル)-3-メタンスルホニルアミノ-キノリン-4-カルボン酸((S)-1-フェニル-プロピル)-アミド;
2-(3-フルオロ-フェニル)-3-メタンスルホニルアミノ-キノリン-4-カルボン酸((S)-シクロプロピル-フェニル-メチル)-アミド;
2-(3-フルオロ-フェニル)-3-メタンスルホニルアミノ-キノリン-4-カルボン酸[(S)-1-(3-フルオロ-フェニル)-プロピル]-アミド;
2-(3-フルオロ-フェニル)-3-メタンスルホニルアミノ-キノリン-4-カルボン酸[(S)-シクロプロピル-(3-フルオロ-フェニル)-メチル]-アミド;
3-(メタンスルホニルアミノ-メチル)-2-フェニル-キノリン-4-カルボン酸(1-フェニル-プロピル)-アミド;
3-(エタンスルホニルアミノ-メチル)-2-フェニル-キノリン-4-カルボン酸(1-フェニル-プロピル)-アミド;
3-(メタンスルホニルアミノ-メチル)-2-フェニル-キノリン-4-カルボン酸((S)-1-フェニル-プロピル)-アミド;
3-(エタンスルホニルアミノ-メチル)-2-フェニル-キノリン-4-カルボン酸((S)-1-フェニル-プロピル)-アミド;
N-[(1S)-シクロプロピル(フェニル)メチル]-3-[(メチルスルホニル)アミノ]-2-フェニルキノリン-4-カルボキサミド;
N-[(1S)-シクロプロピル(3-フルオロフェニル)メチル]-3-[(メチルスルホニル)アミノ]-2-フェニルキノリン-4-カルボキサミド;
N-[(1S)-1-シクロヘキシルエチル]-3-[(メチルスルホニル)アミノ]-2-フェニルキノリン-4-カルボキサミド;
N-[(1R, 2S)-2-ヒドロキシ-1-フェニルプロピル]-3-[(メチルスルホニル)アミノ]-2-フェニルキノリン-4-カルボキサミド;
N-[(S)-シクロプロピル(フェニル)メチル]-3-[(シクロプロピルスルホニル)アミノ]-2-フェニルキノリン-4-カルボキサミド;及び
3-(メタンスルホニル-メチル-アミノ)-2-フェニル-キノリン-4-カルボン酸((S)-1-フェニル-プロピル)-アミド;
それらの立体異性体、エナンチオマー、生体内で加水分解可能な前駆体及び薬学的許容塩。
他に指示がない限り、本明細書で使用するC1-6アルキルは、単独で又は他の基の一部として、メチル、エチル、n-プロピル、n-ブチル、i-プロピル、i-ブチル、t-ブチル、s-ブチル基を含むが、これらに限定されず、アルキル基は直鎖又は分岐鎖であり得る。
本明細書で使用する芳香族又は非芳香族の複素環式環は、N-若しくはC-結合のフリル、イミダゾリル、オキサゾリル、ピロリジニル、チアゾリル、チオフェニル、ピロリル、モルホリニル、ピペリジニル、ピペラジニル、ピラジニル、ピリジル、ピリミジニル、インダニル、インドリル、キノリニル、イソキノリニル、キナゾリニル、キノキサリニル、ベンゾ[b]チオフェニル、ベンゾオキサゾリル、又はベンゾチアゾリルを含むが、これらに限定されない。
EtOAcとは、酢酸エチルを云う。
EDCとは、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミドを云う。
EDTAとは、エチレンジアミン四酢酸を云う。
HEPESとは、4-(2-ヒドロキシエチル)-1-ピペラジンエタンスルホン酸一ナトリウム塩を云う。そして
TEAとは、トリエチルアミンを云う。
述べることができる式Iの化合物の酸付加塩には、鉱酸の塩、例えば塩酸塩及び臭化水素酸塩;及び有機酸で形成された塩、例えばギ酸塩、酢酸塩、マレイン酸塩、安息香酸塩、酒石酸塩及びフマル酸塩が含まれる。
式Iの化合物は、下記のスキームに示された方法により製造し得る。
一般に、本発明の化合物は、2-アミノ-1-フェニル-エタノン及びアルキルスルホニルクロリドをTEA及びDCMの存在下で反応させて、N-(2-オキソ-2-フェニル-エチル)-アルキルスルホンアミドを生成させ;該アルキルスルホンアミドをNaOH、及びエタノール中THFで処理して3-アルキルスルホニルアミノ-2-フェニル-キノリン-4-カルボン酸を生成させ、そして該カルボン酸をアリールアミンとEDCl及びHOBTの存在下で反応させて、式Iの化合物を生成させることにより製造し得る。
別の側面では、本発明は、本明細書に記載した式Iの化合物、並びにかかる化合物の治療及び治療に有用な組成物での使用に関する。
別の側面では、本発明は、NK-3受容体の作用を通して媒介される疾患を治療するための本明細書に記載した化合物の使用を包含する。かかる側面は、NK-3受容体の調節が有益である疾患又は状態の治療又は予防方法を包含し、該方法は本発明の拮抗化合物の治療有効量を上記疾患又は状態に罹患している対象(subject)に投与することを含む。
本発明の化合物、そのエナンチオマー、及びその薬学的許容塩は、単独で、又は経腸若しくは非経口投与用の適切な医薬製剤の形態で使用し得る。本発明の更なる側面によると、本発明の化合物を好ましくは80質量%未満、更に好ましくは50質量%未満で、不活性の薬学的に許容される賦形剤、滑沢剤又は担体と混合して含む薬学的組成物が提供される。
− 錠剤及び糖衣錠には:ラクトース、澱粉、タルク、ステアリン酸;
− カプセルには:酒石酸又はラクトース;
− 注射可能な液剤には:水、アルコール、グリセリン、植物油;
− 坐薬には:天然又は硬化油又はワックス
である。
理解の明確化のための、式示及び実施施とした典型的化合物及び方法により、本発明を説明する。しかしながら、当業者には、本発明の化合物、製法及び方法の教示を熟考することにより、本発明の趣旨又は範囲から逸脱することなく、それらの修飾及び変更をなし得ることは明らかである。
2-アミノ-1-フェニルエタノンヒドロクロリド(1a)(1715 mg, 10 mmol)のDMF(20 mL)溶液にTEA(2.8 mL, 20 mmol)を加えた。氷-水浴下冷却して、メチルスルホニルクロリド(0.77 mL, 10 mmol)をゆっくり加え、そして反応混合物をRTで12時間攪拌した。混合物をジクロロメタンとブラインの間で分配し、硫酸ナトリウムで乾燥し、そして次に減圧下で濃縮して標題の化合物(2100 mg, 98%)をオフホワイト色の固体として得た。MS APCI, m/z = 214 (M+1)。LCMS: 1.19 min。
イサチン(441 mg, 3 mmol)に水酸化ナトリウム(1.15 g, 29.0 mmol)の水(2.5 mL)溶液を加えた。生じた褐色沈殿物を85℃に加熱する前にRTで20分間激しく攪拌した。次にN-(2-オキソ-2-フェニルエチル)メタンスルホンアミド(1b)(639 mg, 3.0 mmol)のエタノール/THF/水(6.3 mL/1.25 mL/6.3 mL)溶液を30分にわたって滴下して加えた。反応混合物を85℃で更に4時間攪拌した後RTに冷却した。全有機溶媒を減圧下で除去し、そして水性残留物を約6mlの容量に減少させた。水性残留物をエーテル(3 x 10 mL)で洗い、そして次に水性残留物を冷却しながら酢酸でpH4に酸性化した。生成した沈殿物を集め、水で洗い、そして乾燥して、標題の化合物を固体として得た(721 mg, 70.3%)。1H NMR (300MHz, CDCl3) δ3.11 (s, 3H), 7.05 (d, 1H), 7.39 (d, 2H), 7.64 (m, 2H), 7.78 (m, 1H), 8.06 (m, 1H), 8.19 (m, 1H), 8.47 (m, 1H), 10.03 (b, 2H). MS APCI, m/z = 343 (M+1)。LCMS: 1.07 min。
3-(ブロモメチル)-2-フェニルキノリン-4-カルボキシレート(2a)(2000 mg, 5.618 mmol)のTHF/DMF(50 mL/10 mL)溶液にナトリウムアジド(402 mg, 6.18 mmol)を加え、そして反応混合物をRTでN2下にて12時間攪拌した。全溶媒を減圧下で除去し、そして残留物を酢酸エチルとブラインの間で分配し、硫酸ナトリウムで乾燥し、そして次に減圧下で濃縮した。残留物をクロマトグラフィーにより10%酢酸エチル/ヘキサンで溶離して標題の化合物(1781 mg, 99.7%)をオフホワイト色の固体として得た。MS APCI, m/z = 319 (M+1)。LCMS: 2.34 min。
3-(アジドメチル)-2-フェニルキノリン-4-カルボン酸メチル(2b)(1781 mg, 5.0 mmol)のメタノール(50 mL)溶液に水酸化リチウム一水和物(674 mg, 28.1 mmol)の水(25 mL)溶液を加えた。反応混合物を還流しながら4時間攪拌し、そして残留物を1N HClでpH 2に酸性化した。反応混合物の容量を減圧下で減少させた。得られた水性相を酢酸エチル(150 mL)で抽出した。有機相を分離し、そしてブライン(20 ml)で洗い、硫酸ナトリウムで乾燥し、次に減圧下で濃縮した。酢酸エチル/ヘキサンから結晶化させて、標題の化合物(1200 mg, 66 %)をオフホワイト色の固体として得た。MS APCI, m/z = 305 (M+1)。LCMS: 1.09 min。
3-(アジドメチル)-2-フェニルキノリン-4-カルボン酸(2c)(997 mg, 3.28 mmol)、HOBT水和物(760 mg, 4.92 mmol)、4-メチルモルホリン(551μL, 4.92 mmol)のテトラヒドロフラン(50 mL)溶液にEDC(960 mg, 4.92 mmol)をRTでN2下で加えた。次に(S)-1-フェニルプロピルアミン(488.5 mg, 3.62 mmol)を加え、反応混合物をRTで12時間攪拌した。全溶媒を減圧下で除去し、そして残留物を酢酸エチルと10%重炭酸ナトリウム水溶液の間で分配し、硫酸ナトリウムで乾燥し、次に減圧下で濃縮した。残留物をクロマトグラフィーにより、15-25%酢酸エチル/ヘキサンで溶離して精製して、標題の化合物(1000 mg, 73%)を淡黄色固体として得た。1H NMR (300MHz, CDCl3) δ0.94 (t, 3H), 2.01 (m, 2H), 5.17 (q, 1H), 5.19 (s, 2H), 5.72 (b, 1H), 7.21 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.49 (m, 2H). MS APCI, m/z = 422 (M+1)。LCMS: 2.47 min。
3-(アジドメチル)-2-フェニル-N-[(1s)-1-フェニルプロピル]キノリン-4-カルボキサミド(2d)(1000 mg, 2.37 mmol)のエタノール(200 mL)溶液にPd/C(10 %, 1190 mg)及びHCl(2N, 2.5 mL)を加えた。反応混合物を50 psi H2 下でRTにて1.5時間水素化した。触媒を珪藻土の厚い層を通してろ過して除去し、フィルターをエタノールで洗い、そして洗浄液とエタノール溶媒を合わせ、そして減圧下で濃縮した。ジクロロメタン及びエーテルから結晶化させて、標題の化合物(940 mg, 92 %)を塩化水素塩として得た。1H NMR (300MHz, CDCl3) δ0.92 (t, 3H), 2.01 (m, 2H), 3.18 (b, 3H), 4.39 (t, 2H), 5.16 (q, 1H), 7.30 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.44 (m, 2H). MS APCI, m/z = 396 (M+1)。LCMS: 1.70 min。
NK-3受容体結合活性:
一般に、NK-3r結合活性は、Krauseら (Proc. Natl. Acad. Sci. USA 94: 310-315, 1997)に記載されたようにして行うアッセイを用いて評価し得る。NK-3rの相補的DNAを、ヒト視床下部RNAから標準的手順を用いてクローニングする。受容体cDNAを、チャイニーズハムスター卵巣細胞系にトランスフェクションした適切な発現ベクターに挿入し、そして安定に発現するクローン細胞系を単離し、特性決定して実験に使用できる。
ヒトNK-3 受容体遺伝子を、他のヒトNK受容体について記載した方法(Aharonyら, Mol. Pharmacol. 45:9-19, 1994; Cacceseら, Neuropeptides 33, 239-243, 1999)と同様の方法を用いてクローン化した。クローン化NK-3受容体のDNA配列は、コーディング配列のヌクレオチド1320にサイレントT>C一塩基変化を有する公表された配列(Buellら、FEBS Letts. 299,90-95, 1992; Huangら、Biochem. Biophys. Res. Commun. 184,966-972, 1992)と異なった。変化はサイレントなので、クローン化された遺伝子は、公表された配列と同一の、コードされたNK-3 受容体タンパク質の一次アミノ酸配列を与える。受容体cDNAを用いて、標準的方法によりCHO-K1細胞をトランスフェクションし、そして受容体を安定に発現するクローンを単離しそして特性決定した。これらの細胞からの原形質膜を公表されたようにして(Aharonyら、1994)調製した。
[125I]-MePhe7-NKBを用いる受容体結合アッセイ法は、Aharonyら、J. Pharmacol. Expe
r. Ther., 274:1216-1221, 1995に記載された方法を変更した。
競合実験を、膜(2μgタンパク質/反応)、試験競合物、及び[125I]-MePhe7NKB (0.2 nM)を含むアッセイバッファ(50mM tris-HCl, 4mM MnCl2, 10μM チオルファン, pH7.4) 0.2 mL中で行った。非標識の相同体リガンド(0.5μM)を使用して非特異性結合を規定した。インキュベーションを25℃にて90分間行った。受容体−結合リガンドを、パッカードハーベスター(Packard Harvester)で真空濾過して、0.5% BSAに前浸漬したGF/Cプレート上に単離した。プレートを0.02M Tris、pH 7.4で洗った。平衡結合定数(KD及びKi)、受容体密度(Bmax)の計算、及び統計分析を先の文献(Aharonyら、1995)のようにして、GraphPadプリズム又はIDBS XLfitソフトウェアを使用して実施した。
一般に、NK-3機能活性は、安定にNK-3r-を発現する細胞系中でカルシウム動員アッセイを用いて評価し得る。メチルPhe7-ニューロキニンBアゴニストにより誘導されるカルシウム動員は、FLIPR(Molecular Dvices社)機器を用いて、製造者によって記載された方法で監視し得る。アゴニストを細胞に添加し、蛍光反応を最大5分連続的に記録し得る。アンタゴニストの作用を、メチルPhe7-ニューロキニンBアゴニストの投与前に細胞を予備インキュベートすることにより評価し得る。アゴニストの作用を、かかる系内のそれらの固有活性を観察することにより評価し得る。
NK-3受容体発現CHO細胞を増殖培地(HamのF12倍地、10% FBS、2mMのL-グルタミン、及び50mg/mLのハイグロマイシンB)中に維持した。アッセイの1日前に、細胞を2 mMのL-グルタミンを有するウルトラカルチャー(Ultraculture)培地(Cambrex Bio Science)中の384-穴プレートに分配して、70-90%密集度を達成した。NK-3受容体-誘発カルシウム動員を定量するために、細胞をまず、ハンクの平衡塩類溶液、15 mMのHEPES、及び2.5 mMのプロベネシド、pH7.4から成るアッセイバッファで洗った。次に細胞にアッセイバッファ中でFluo4/AM色素 (4.4μM)をローディングした。細胞を1時間インキュベートし、そして次にアッセイバッファで洗い、0.02-300 nMのセンクチド(senktide)に曝露し、そして蛍光反応をFLIPR機器(Molecular Devices Corporation)を用いて記録した。アゴニスト反応の拮抗作用を定量するために、細胞を、濃度を変えた試験化合物を用いて2-20分間予備インキュベートし、次に単独で約70%の最大カルシウム反応を引き出す濃度である2 nMのセンクチドに曝露した。得られたデータを、XLfitソフトウェア(IDBS製造社)を用いて分析して、EC50値及びIC50値を決定した。
Claims (2)
- 3-[(メチルスルホニル)アミノ]-2-フェニル-N-[(1S)-1-フェニルプロピル]キノリン-4-カルボキサミド又はその薬学的許容塩である化合物。
- 3-[(メチルスルホニル)アミノ]-2-フェニル-N-[(1S)-1-フェニルプロピル]キノリン-4-カルボキサミドである、請求項1に記載の化合物。
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- 2006-12-11 AU AU2006325572A patent/AU2006325572B2/en not_active Ceased
- 2006-12-11 PL PL06835833.2T patent/PL1968944T3/pl unknown
- 2006-12-11 KR KR1020087014020A patent/KR20080075867A/ko not_active Application Discontinuation
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- 2006-12-11 US US12/096,997 patent/US20080293765A1/en not_active Abandoned
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Also Published As
Publication number | Publication date |
---|---|
BRPI0619746A2 (pt) | 2011-10-11 |
TW200804288A (en) | 2008-01-16 |
EP1968944A4 (en) | 2011-01-12 |
RU2008121761A (ru) | 2010-01-20 |
US20080293765A1 (en) | 2008-11-27 |
HK1121759A1 (zh) | 2009-04-30 |
AU2006325572B2 (en) | 2011-02-24 |
JP2009519331A (ja) | 2009-05-14 |
EP1968944A1 (en) | 2008-09-17 |
HUE029805T2 (en) | 2017-03-28 |
UY30001A1 (es) | 2007-07-31 |
RU2421447C2 (ru) | 2011-06-20 |
EP1968944B1 (en) | 2016-04-20 |
IL191628A0 (en) | 2008-12-29 |
WO2007069977A1 (en) | 2007-06-21 |
KR20080075867A (ko) | 2008-08-19 |
DK1968944T3 (en) | 2016-08-01 |
PT1968944T (pt) | 2016-07-29 |
AR056890A1 (es) | 2007-10-31 |
ES2571834T3 (es) | 2016-05-27 |
US7608628B2 (en) | 2009-10-27 |
NO20083029L (no) | 2008-07-09 |
ECSP088546A (es) | 2008-07-30 |
PL1968944T3 (pl) | 2016-11-30 |
TW201018662A (en) | 2010-05-16 |
US8071621B2 (en) | 2011-12-06 |
US20100029717A1 (en) | 2010-02-04 |
CA2633129A1 (en) | 2007-06-21 |
AU2006325572A1 (en) | 2007-06-21 |
US20080021062A1 (en) | 2008-01-24 |
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