CN1516589A - 用作加压素激动剂的n-联苯羰基-和n-苯基吡啶基羰基取代的二环和三环氮杂�类和二氮杂�类化合物 - Google Patents
用作加压素激动剂的n-联苯羰基-和n-苯基吡啶基羰基取代的二环和三环氮杂�类和二氮杂�类化合物 Download PDFInfo
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- CN1516589A CN1516589A CNA028119045A CN02811904A CN1516589A CN 1516589 A CN1516589 A CN 1516589A CN A028119045 A CNA028119045 A CN A028119045A CN 02811904 A CN02811904 A CN 02811904A CN 1516589 A CN1516589 A CN 1516589A
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- Prior art keywords
- chemical compound
- alkyl
- biphenyl
- acceptable salt
- ketone
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- -1 N-phenylpyridylcarbonyl Chemical group 0.000 title claims abstract description 12
- 239000000556 agonist Substances 0.000 title claims description 12
- 150000001538 azepines Chemical class 0.000 title 1
- 150000004908 diazepines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 150
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 51
- 150000002367 halogens Chemical class 0.000 claims abstract description 49
- 150000003839 salts Chemical group 0.000 claims abstract description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 26
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 20
- 239000000651 prodrug Chemical group 0.000 claims abstract description 14
- 229940002612 prodrug Drugs 0.000 claims abstract description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 81
- 235000010290 biphenyl Nutrition 0.000 claims description 57
- 150000002576 ketones Chemical class 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- VLRGXXKFHVJQOL-UHFFFAOYSA-N 3-chloropentane-2,4-dione Chemical compound CC(=O)C(Cl)C(C)=O VLRGXXKFHVJQOL-UHFFFAOYSA-N 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
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- 241000124008 Mammalia Species 0.000 claims description 3
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- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
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- BJUDSIVFKLKWJJ-UHFFFAOYSA-N [2-chloro-4-(2-methylphenyl)phenyl]-(6,11-dihydropyrrolo[2,1-c][1,4]benzodiazepin-5-yl)methanone Chemical compound CC1=CC=CC=C1C(C=C1Cl)=CC=C1C(=O)N1C2=CC=CC=C2CN2C=CC=C2C1 BJUDSIVFKLKWJJ-UHFFFAOYSA-N 0.000 claims description 2
- 208000015294 blood coagulation disease Diseases 0.000 claims description 2
- RSRBZRBXNCOVQZ-UHFFFAOYSA-N bis(6-phenylpyridin-3-yl)methanone Chemical compound C=1C=C(C=2C=CC=CC=2)N=CC=1C(=O)C(C=N1)=CC=C1C1=CC=CC=C1 RSRBZRBXNCOVQZ-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 20
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- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- 125000004434 sulfur atom Chemical group 0.000 abstract 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 abstract 1
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- 239000007787 solid Substances 0.000 description 11
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
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- 125000003435 aroyl group Chemical group 0.000 description 4
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- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
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- 150000003233 pyrroles Chemical class 0.000 description 1
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical compound C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 description 1
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- 238000012453 sprague-dawley rat model Methods 0.000 description 1
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- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
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- 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
式(I)或(II)化合物或其可药用盐或前药形式:其中Y是选自NR或-(CH<sub>2</sub>)<sub>n</sub>的部分;其中R是氢或(C<sub>1</sub>-C<sub>6</sub>)低级烷基,且n是1;(Z)代表(1)苯环,所述苯环可任选被一个或两个独立地选自下列的取代基取代:氢、(C<sub>1</sub>-C<sub>6</sub>)低级烷基、卤素、氰基、CF<sub>3</sub>、羟基、(C<sub>1</sub>-C<sub>6</sub>)低级烷氧基、(C<sub>1</sub>-C<sub>6</sub>)低级烷氧基羰基、羧基、-CONH<sub>2</sub>、-CONH[(C<sub>1</sub>-C<sub>6</sub>)低级烷基]、-CON[(C<sub>1</sub>-C<sub>6</sub>)低级烷基]<sub>2</sub>;或(2)具有一个氮原子的6-元芳族(不饱和)杂环,所述杂环可任选被(C<sub>1</sub>-C<sub>6</sub>)低级烷基、卤素或(C<sub>1</sub>-C<sub>6</sub>)低级烷氧基取代;(W)代表(1)苯环,所述苯环可任选被一个或两个独立地选自下列的取代基取代:氢、(C<sub>1</sub>-C<sub>6</sub>)低级烷基、卤素、氰基、CF<sub>3</sub>、羟基、(C<sub>1</sub>-C<sub>6</sub>)低级烷氧基、或(C<sub>1</sub>-C<sub>6</sub>)低级烷氧基羰基、羧基、-CONH<sub>2</sub>、-CONH[(C<sub>1</sub>-C<sub>6</sub>)低级烷基]、-CON[(C<sub>1</sub>-C<sub>6</sub>)低级烷基]<sub>2</sub>;或(2)具有一个氮原子的5-元芳族(不饱和)杂环,所述杂环可任选被(C<sub>1</sub>-C<sub>6</sub>)低级烷基、(C<sub>1</sub>-C<sub>6</sub>)低级烷氧基或卤素取代;或(3)具有一个氮原子的6-元芳族(不饱和)杂环,所述杂环可任选被(C<sub>1</sub>-C<sub>6</sub>)低级烷基、卤素或(C<sub>1</sub>-C<sub>6</sub>)低级烷氧基取代;(X)代表具有一个硫原子的5-元芳族(不饱和)杂环,所述杂环可任选被(C<sub>1</sub>-C<sub>6</sub>)低级烷基、卤素或(C<sub>1</sub>-C<sub>6</sub>)低级烷氧基取代;R<sub>1</sub>是式(O或N)所示部分,且R<sub>2</sub>、R<sub>3</sub>、R<sub>7</sub>、R<sub>8</sub>和R<sub>9</sub>独立地选自氢、(C<sub>1</sub>-C<sub>3</sub>)低级烷基、OCH<sub>3</sub>、卤素、CF<sub>3</sub>、-SCH<sub>3</sub>、OCF<sub>3</sub>、SCF<sub>3</sub>或CN。
Description
本发明涉及起加压素V2激动剂作用的联苯类化合物,以及使用这些化合物的治疗方法和药物组合物。
发明背景
加压素通过将尿浓缩在肾的收集管中而在水分保持中起着关键作用。在受体上没有加压素存在的情况下,肾的收集管比较不能被水渗透,因此在经由肾小球过滤,流过近侧肾曲小管、Henle袢和远侧肾曲小管后形成的低渗液体将作为稀的尿液排泄出去。然而,在脱水、容量排空或失血期间,加压素从脑中释放出来,激活肾收集管中的加压素V2受体,使得收集管非常易于被水渗透;这样水被重吸收,并且排泄出浓缩的尿液。Aquaporins(水通道膜蛋白)在该复杂过程中起重要作用(关于哺乳动物aquaporins的综述参见Beitz和Schutz,Current Medicinal Chemistry,6,457-467(1999))。在中枢性或神经原性尿崩症患者和动物中,脑中加压素的合成缺损,因此他们产生非常少的加压素或不产生加压素,但是他们肾中的加压素受体是正常的。因为不能浓缩尿,它们可能产生多达体积是其健康情况下的10倍的尿液,并且对加压素和加压素V2激动剂的作用非常敏感。加压素和去氨加压素(1-去氨基-8D-精氨酸加压素)是天然加压素的肽类似物,目前其正用于中枢性尿崩症患者。加压素V2激动剂也可用于治疗夜间遗尿、夜尿症、尿失禁以及在需要时暂时延迟排尿。
加压素通过激活其V1a受体而施加血管收缩作用以提高血压。加压素V1a受体拮抗剂将抵消该作用。加压素和加压素样激动剂引起VIII因子和von Willebrand因子从细胞内贮库中释放,因此它们可用于治疗出血病症例如血友病。加压素和加压素样激动剂还将组织型纤溶酶原激活物(t-PA)释放到血液循环内,因此它们可用于溶解血凝块,例如在心肌梗塞和其它血栓栓塞病症患者中溶解血凝块(Jackson,“加压素和影响肾保持水分的其它物质”,Goodman和Gilman,ThePharmacological Basis of Therapeutics,9th ed.,Hadman,Limbird,Molinoff,Ruddon和Gilman Eds.,McGraw-Hill,NewYork,pp.715-731(1996);Lethagen,Ann.Hematol.69,173-180(1994);Cash等人,Brit.J.Haematol.,27,363-364(1974);David,Regulatory Peptides,45,311-317(1993);Burggraaf等人,Cli.Sci.,86,497-503(1994))。
最近已经公开了非肽类加压素拮抗剂。Albright等人在下列专利中描述了用作加压素拮抗剂或加压素和催产素拮抗剂的三环氮杂化合物:U.S.专利5,516,774(1996),U.S.专利5,532,235(1996),U.S.专利5,536,718,U.S.专利5,610,156(1997),U.S.专利5,612,334(1997),U.S.专利5,624,923(1997),U.S.专利5,654,297(1997),U.S.专利5,686,445(1997),U.S.专利5,693,635(1997),U.S.专利5,696,112(1997),U.S.专利5,700,796(1997),U.S.专利5,719,278(1998),U.S.专利5,733,905(1998),U.S.专利5,736,538(1998),U.S.专利5,736,540(1998),U.S.专利5,739,128(1998),U.S.专利5,747,487(1998),U.S.专利5,753,648(1998),U.S.专利5,760,031(1998),U.S.专利5,780,471(1998);J.P.0801460-A(1996)中公开了用作加压素拮抗剂的四氢苯并二氮杂衍生物;Ogawa等人在WO 9534540-A中公开了用作加压素和催产素拮抗剂以及用作加压素激动剂的苯并杂环衍生物;Ogawa等人在WO97/22951(1997)和U.S.专利6,096,736(2000)中公开了可用作加压素拮抗剂、加压素激动剂和催产素拮抗剂的具有抗加压素活性、催产素拮抗活性和加压素激动剂活性的苯并氮杂衍生物;并且Venkatesan等人在U.S.专利5,521,173(1996)中公开了用作加压素和催产素拮抗剂的三环苯并氮杂衍生物;Ohtahe等人在WO99/65525(1999)中公开了降低眼睛张力的活性剂和表现出加压素V1受体拮抗作用的磷酸酯衍生物;Hoekstra等人在WO 00/43398(2000)中公开了用作治疗涉及血管阻力增加和心脏机能不全的病症的加压素受体拮抗剂的三环苯并二氮杂化合物。
Albright等人尤其在U.S.专利5,849,735(1998)和WO 96/22282A1(1996)中公开了一组用作V1和/或V2加压素受体拮抗剂和催产素受体拮抗剂的涉及本申请的三环二苯并二氮杂、吡咯并苯并二氮杂和吡咯并吡啶并二氮杂化合物。
Albright等人在U.S.专利5,532,235(1996)中公开了一亚组用作V1和/或V2加压素受体拮抗剂的三环苯并氮杂化合物。
Venkatesan等人也在U.S.专利5,521,173(1996)、WO 96/22292(1996)和U.S.专利5,780,471(1998)中公开了一亚组具有加压素和催产素拮抗剂活性的三环苯并氮杂化合物。
Albright等人也在U.S.专利5,696,112(1997)和WO 96/22 294中泛泛地描述了一亚组用作V1和/或V2加压素受体拮抗剂的二环氮杂化合物。
发明概述
本发明涉及新的和已知的化合物,所述化合物选自式(I)或(II)化合物或其可药用盐或前药形式:
其中:
Y是选自NR或-(CH2)n的部分;
其中R是氢或(C1-C6)烷基,
且n是1;
代表(1)苯环,所述苯环可任选被一个或两个独立地选自下列的取代基取代:氢、(C1-C6)烷基、卤素、氰基、CF3、羟基、(C1-C6)烷氧基、(C1-C6烷氧基)羰基、羧基、-CONH2、-CONH[(C1-C6)烷基]、-CON[(C1-C6)烷基]2;
或(2)具有一个氮原子的6-元芳族(不饱和)杂环,所述杂环可任选被(C1-C6)烷基、卤素或(C1-C6)烷氧基取代;
代表(1)苯环,所述苯环可任选被一个或两个独立地选自下列的取代基取代:氢、(C1-C6)烷基、卤素、氰基、CF3、羟基、(C1-C6)烷氧基、或(C1-C6烷氧基)羰基、羧基、-CONH2、-CONH[(C1-C6)烷基]、-CON[(C1-C6)烷基]2;
或(2)具有一个氮原子的5-元芳族(不饱和)杂环,所述杂环可任选被(C1-C6)烷基、(C1-C6)烷氧基或卤素取代;
或(3)具有一个氮原子的6-元芳族(不饱和)杂环,所述杂环可任选被(C1-C6)烷基、卤素或(C1-C6)烷氧基取代;
代表具有一个硫原子的5-元芳族(不饱和)杂环,所述杂环可任选被(C1-C6)烷基、卤素或(C1-C6)烷氧基取代;
R1是下式所示部分
其中Ar是下列部分:
R4是如下所示的部分
且R2、R7、R8和R9独立地选自氢、(C1-C3)烷基、OCH3、卤素、CF3、SCH3、OCF3、SCF3或CN。
一亚组本发明化合物包括下式所示的化合物或其可药用盐或前药形式:
其中:
R3和R5独立地选自:H、C1-C6烷基、卤素、氰基、CF3、羟基、C1-C6烷氧基、C1-C6烷氧基羰基、羧基、-CONH2、-CONH[C1-C6烷基]、-CON[C1-C6烷基]2;
R2、R7、R8和R9分别独立地选自氢、C1-C3烷基、OCH3、卤素、CF3、SCH3、OCF3、SCF3或CN;且
R10是选自C1-C6烷基、卤素或C1-C6烷氧基的基团。
另一组本发明化合物包括下式所示的化合物或其可药用盐或前药形式:
其中:
R是氢或C1-C6烷基;
R3和R5独立地选自:H、C1-C6烷基、卤素、氰基、CF3、羟基、C1-C6烷氧基、C1-C6烷氧基羰基、羧基、-CONH2、-CONH[C1-C6烷基]、-CON[C1-C6烷基]2;
R2、R7、R8和R9分别独立地选自氢、C1-C3烷基、OCH3、卤素、CF3、SCH3、OCF3、SCF3或CN;且
R10是选自C1-C6烷基、卤素或C1-C6烷氧基的基团。
另一组本发明化合物包括下式所示的化合物或其可药用盐或前药形式:
其中:
R2、R7、R8和R9分别独立地选自氢、C1-C3烷基、OCH3、卤素、CF3、SCH3、OCF3、SCF3或CN;且
R11和R12独立地选自C1-C6烷基、卤素或C1-C6烷氧基。
另一组本发明化合物包括下式所示的化合物或其可药用盐或前药形式:
其中:
R2、R7、R8和R9分别独立地选自氢、C1-C3烷基、OCH3、卤素、CF3、SCH3、OCF3、SCF3或CN;
R10是选自C1-C6烷基、卤素或C1-C6烷氧基的基团;且
R13是C1-C6烷基、卤素或C1-C6烷氧基。
单独的一小组本发明化合物包括下式所示的化合物或其可药用盐或前药形式:
其中:
R是氢或C1-C6烷基;
R3、R5、R3'和R5'独立地选自H、C1-C6烷基、卤素、氰基、CF3、羟基、C1-C6烷氧基、(C1-C6烷氧基)羰基、羧基、-CONH2、-CONH[C1-C6烷基]、-CON[C1-C6烷基]2;
R2、R7、R8和R9分别独立地选自氢、C1-C3烷基、OCH3、卤素、CF3、SCH3、OCF3、SCF3或CN。
本文所用的描述烷氧基或烷基的术语“低级”应当理解为是指这些基团具有1-6个碳原子。作为基团或基团的一部分的烷基的实例是直链或支链,具有例如1-6个(例如1-4个)碳原子,例如甲基、乙基、丙基、异丙基、丁基。卤素是指氟、氯、溴或碘。
Y的实例是-CH2-、-NH-、-NCH3-和-NCH2CH3-。
Z的实例是稠合的苯。W可以是例如选自苯、吡啶(2,3位)和吡咯(1,2位)的稠合环。所述稠合环可以如本文所述被取代。
优选的本发明化合物是:
实施例1
(2′-甲氧基-[1,1’-联苯]-4-基)-(5H,11H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-甲酮;
实施例2
(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-(3’-甲基-[1,1’-联苯]-4-基)-甲酮;
实施例3
(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-(4’-甲氧基-[1,1’-联苯]-4-基)-甲酮;
实施例4
[1,1’-联苯]-4-基-(5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)-甲酮;
实施例5
[1,1’-联苯]-4-基-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)甲酮;
实施例6
[1,1’-联苯]-4-基-(5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)甲酮;
实施例7
[1,1’-联苯]-4-基-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)甲酮;
实施例8
[1,1’-联苯]-4-基-(5,6,7,8-四氢-噻吩并[3,2-b]氮杂-4-基)-甲酮;
实施例9
(5H,11H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10-基)-(6-苯基-吡啶-3-基)-甲酮;
实施例10
(5H,11H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10-基)-(4’-甲氧基-3-甲基-[1,1’-联苯]-4-基)-甲酮;
实施例11
[1,1’-联苯]-4-基-(4H,10H-3a,5,9-三氮杂-苯并[f]甘菊环-9-基)-甲酮;
本领域技术人员应当理解,某些本发明化合物可含有一个或多个不对称中心,并因此可以存在立体异构体和非对映体。本发明包括具有所述活性的这样的立体异构体和非对映体;以及外消旋和拆分的对映异构纯的立体异构体及其可药用盐。立体异构体可通过本领域技术人员已知的标准方法以纯的形式获得。还应当理解,本发明包括具有所述活性的所有可能的区域异构体及其混合物。这样的区域异构体可以通过本领域技术人员已知的标准分离方法以纯的形式获得。
本发明还提供了治疗可通过加压素受体激动剂活性来治疗或减轻的病症的方法,这样的病症包括但不限于尿崩症、夜间遗尿、夜尿症、尿失禁或出血和凝血病症。本发明还提供了在人或其它哺乳动物中于需要时诱导暂时延迟排尿的方法。每一这些方法包括给有此需要的人或其它哺乳动物施用有效量的本发明化合物或药物组合物。
本发明相应地提供了药物组合物,其中包含药物有效量的本发明化合物以及可药用载体或赋形剂。本发明特别提供了包含有效量的本发明化合物和可药用载体的药物组合物。在本文中,药物有效量化合物应理解为,至少是在诱导暂时延迟排尿或者治疗、抑制或减轻欲治疗疾病或缓解其症状方面提供理想结果的最小量。
优选使组合物适于口服给药。然而,也可以使它们适于其它给药方式,例如给心力衰竭患者非胃肠道给药。
为了获得给药一致性,本发明组合物优选呈单位剂量的形式。合适的单位剂型包括片剂、胶囊和在小药囊或小瓶中的粉剂。这种单位剂型可含有0.1-1000mg、优选2-50mg本发明化合物。单位剂型进一步优选含有5-25mg本发明化合物。本发明化合物可以以约0.01-100mg/kg或优选0.1-10mg/kg的剂量范围口服给药。这样的组合物可每天给药1-6次、更通常每天1-4次。可用常规赋形剂例如填充剂、崩解剂、粘合剂、润滑剂、矫味剂等配制本发明组合物。可按照常规方法,例如类似于用于已知抗高血压剂、利尿剂和β-阻断剂的方式配制本发明组合物。
本发明还提供了制备本发明化合物的方法。
本发明方法
本发明通式(I)化合物可按照反应方案I所示的方法方便地制得。
反应方案I
因此,在非质子溶剂例如二氯甲烷、N,N-二甲基甲酰胺或四氢呋喃中,在无机碱例如碳酸钾存在下,或者在有机碱例如吡啶、4-(二甲基氨基)吡啶或叔胺例如三乙胺或N,N-二异丙基乙胺存在下,用适当取代的酰化剂例如芳酰基卤,优选式(2,J=COCl或COBr)所示适当取代的酰氯(溴)于-5℃-50℃温度下处理式(1)所示三环氮杂(二氮杂)化合物,以获得其中R1如上所定义的所需通式(I)化合物。
或者,式(2)酰化剂可以是相应羧酸的混合酐,例如可按照Inanaga等人,Bull.Chem.Soc.Jpn.,52,1989(1979)的方法,在非质子有机溶剂例如二氯甲烷中通过用2,4,6-三氯苯甲酰氯处理所述酸而制得的混和酸酐。在溶剂例如二氯甲烷中,在有机碱例如4-(二甲基氨基)吡啶存在下,用式(1)所示三环氮杂(二氮杂)化合物于0℃-溶剂回流温度下处理通式(2)所述混合酸酐,获得反应方案I中的酰化衍生物(I)。
式(2)酰化中间体最终是根据其与R1基团的相容性,以及其与式(1)所示三环氮杂(二氮杂)化合物的反应性来选择的。
同样,如反应方案II所示,在类似于上述的条件下处理式(3)二环氮杂化合物,获得其中R1如上所定义的所需通式(II)化合物。
反应方案II
反应方案I和II中的所需式(2)中间体可通过反应方案III所示的方法方便地制得。因此,在Pd(O)催化剂存在下,以及在或不在无机盐(例如LiCl)存在下,将其中A是CH或氮,且R2如上所定义的式(4,其中P是羧酸保护基,优选P=烷基或苄基,M=I、Br、Cl或OTf)所示适当取代的芳基(杂芳基)碘化物(溴化物、氯化物或三氟甲磺酸酯)与其中R7、R8和R9如上所定义的式(5,W=Sn(三烷基)3,优选Sn(n-Bu)3)所示芳基(杂芳基)三(烷基)锡(IV)衍生物反应,以获得酯中间体(6)。然后通过水解、氢解或本领域已知的类似方法将羧酸脱保护,之后将酸中间体(7)活化,以获得适于分别与式(1)所示三环氮杂(二氮杂)化合物或式(3)二环氮杂化合物偶联的所需式(8)化合物,其中A、R2、R7、R8和R9如上所定义。
反应方案III
或者,反应方案III中的所需式(6)中间体可这样制得:在溶剂混合物例如甲苯-乙醇-水、丙酮-水、水或水-乙腈中,在钯催化剂例如乙酸钯(II)或四(三苯基膦)钯(O)和有机碱例如三乙胺或无机碱例如碳酸钠(碳酸钾或碳酸铯)存在下,加入或不加入溴化(碘化)四丁基铵,于室温-溶剂的回流温度下,将碘化物(溴化物、氯化物、三氟甲磺酸酯)(4,M=I、Br、Cl或OTf)与式(5,W优选=B(OH)2)所示适当取代的芳基(杂芳基)硼衍生物偶联(Suzuki,Pure & Appl.Chem.66,213-222(1994);Badone等人,J.Org.Chem.62,7170-7173(1997);Wolfe等人,J.Am.Chem.Soc.121,9559(1999);Shen,Tetr.Letters 38,5575(1997))。根据反应底物和取代基的性质来选择(4)与硼酸中间体的Suzuki偶联的确切条件。
反应方案III中的所需式(6)中间体可按照类似方法,在溶剂例如二氧杂环己烷中,在碳酸钾和Pd(O)催化剂存在下,由溴化物(4,M=Br)和硼酸(5)制得。
或者,将式(5,W=Br、Cl、I、OTf)所示碘化物(溴化物、氯化物、或三氟甲磺酸酯)与式(4,M=
B(OH)2或SnBu3)所示二(频那醇(pinacolato))二硼[硼酸或三烷基锡(IV)]衍生物进行交叉偶联,以获得按反应方案III中的方式被转化成(I)或(II)的所需式(6)中间体。
反应方案III中所需的式(4,M=Br或I)所示适当取代的芳基(杂芳基)卤化物可商购获得,或者是本领域中已知的,或者可如下所述以定量产率和高纯度容易地获得:将相应的取代的苯胺类化合物(4,P=H、烷基或苄基,M=NH2)重氮化,然后将中间体重氮盐与碘和碘化钾在酸性水介质中反应(基本上按照Street等人,.J.Med.Chem.36,1529(1993)和Coffen等人,J.Org.Chem.49,296(1984)的方法)或者与溴化亚铜(I)反应(March,Advanced Organic Chemistry,3rd Edn.,p.647-648,John Wiley & Sons,New York(1985))。
或者,反应方案III中的所需式(7,A=CH)中间体可如反应方案IV所示,通过下述方式方便地制得:依据Ishiyama等人,Tetr.Lett.38,3447-3450(1997)和Giroux等人,Tetr.Lett.38,3841-3844(1997)的一般方法,将其中R7、R8和R9如上所定义的式(11)所示适当取代的频那醇硼烷与其中R2如上所定义的式(12,Y=OTf)三氟甲磺酸芳基酯或式(12,Y=Br、I)芳基卤化物进行交叉偶联反应,然后将式(13)腈中间体进行碱性或酸性水解(参见March,Advanced OrganicChemistry,3rd Edn.,John Wiley & Sons,New York,p.788(1985))。
反应方案IV
或者,将式(9,X=Br、I或OTf)所示碘化物(溴化物或三氟甲磺酸酯)与式(12,Y=
B(OH)2或SnBu3)所示二(频那醇)二硼[硼酸或三烷基锡(IV)]衍生物反应,以获得所需的式(13)中间体,按照反应方案V的方法将该中间体转化成(7)。
反应方案IV中的所需式(11)苯基硼酸酯可这样方便地制得:按照Ishiyama等人,J.Org.Chem.60,7508-7510(1995)和Giroux等人,Tetr.Lett.38,3841-3844(1997)描述的方法,将二硼酸的频那醇酯(10)与适当取代的芳基卤化物,优选溴化物或碘化物(9,X=Br、I)或三氟甲磺酸芳基酯(9,X=OTf)进行钯催化的交叉偶联反应。
或者,反应方案III中的所需式(I)化合物可通过反应方案V所示的方法制得。
反应方案V
因此,使用任一种前述方法,用适当取代的酰化剂例如其中A和R2如上所定义的式(14,J=COCl或COBr;X=I、Br)所示卤代芳酰基(杂芳酰基)卤,优选碘代(溴代)芳酰基(杂芳酰基)氯(溴)处理式(1)所示三环氮杂(二氮杂)化合物,以获得反应方案V中的通式(15)酰化中间体。使用任一种前述方法,以类似方式将式(3)二环氮杂化合物转化成反应方案V中的所需式(16)化合物。
或者,式(14)酰化剂可以是相应羧酸的混和酸酐。按照上述方法,用式(1)所示三环氮杂(二氮杂)化合物或式(3)二环氮杂化合物处理通式(14)混和酸酐,以分别获得中间体酰化衍生物(15)和(16)。
式(14)酰化中间体最终是根据其与A和R2基团的相容性,以及其分别与式(1)所示三环氮杂(二氮杂)化合物或式(3)二环氮杂化合物的反应性来选择的。
在非质子有机溶剂例如甲苯或N,N-二甲基甲酰胺中,在催化剂例如四(三苯基膦)钯(O)存在下,将(15,X=I)或(16,X=I)与适当取代的有机锡试剂,例如三烷基锡(IV)衍生物,优选其中R7、R8和R9如上所定义的式(5,W=SnBu3)所示三正丁基锡(IV)衍生物于室温-150℃温度下进行Stille偶联反应(参见Farina等人,J.Org.Chem,59,5905(1994)以及其中所引用的文献),以分别获得所需的式(I)或(II)化合物,其中
Y、A、R2、R7、R8和R9如上所定义。
或者,在溶剂混合物例如甲苯-乙醇-水中,在Pd(O)催化剂和碱例如碳酸钠存在下,将式(15,X=Cl、Br或I)或式(16,X=Cl、Br或I)化合物与其中A、R2、R7、R8和R9如上所定义的式(5,W=B(OH)2)所示适当取代的芳基(杂芳基)硼酸于室温-溶剂回流温度下反应,以以分别获得所需的式(I)或(II)化合物,其中
Y、A、R2、R7、R8和R9如上所定义。
反应方案V中优选的式(14)所示取代的芳酰基(杂芳酰基)氯(溴)(X=I、Br;J=COCl或COBr,其中A和R2如上所定义)可商购获得,或者是本领域中已知的,或者可通过类似于文献中制备已知化合物的方法方便地制得。
反应方案V中的式(5,W=Sn(烷基)3,烷基优选为正丁基)中间体可商购获得,或者可如反应方案VI所示,通过首先将其中R7、R8和R9如上所定义的式(17)所示相应的溴代原料与正丁基锂反应,然后将锂化中间体与三烷基(优选三甲基或三正丁基)氯化锡(IV)反应来制得。
反应方案VI
优选的式(5,W=B(OH)2)所示取代的芳基(杂芳基)硼酸可商购获得,或者是本领域中已知的,或者可通过类似于文献中制备已知化合物的方法方便地制得。
或者,如反应方案VII所示,将适当取代的芳酰基(杂芳酰基)卤,优选其中A和R2如上所定义的式(18,J=COCl)所示芳酰基(杂芳酰基)氯与式(1)所示三环氮杂(二氮杂)化合物反应,以获得式(19)溴化物中间体。然后在Pd(O)催化剂例如四(三苯基膦)钯(O)和氯化锂存在下,将(19)与六烷基二锡(优选六正丁基二锡(IV))反应,以获得式(20)锡烷中间体。之后在Pd(O)催化剂例如四(三苯基膦)钯(O)存在下,将三正丁基锡(IV)衍生物(20)与其中R7、R8和R9如上所定义的式(21,M=溴或碘)所示适当取代的芳基(杂芳基)卤化物反应,以获得所需的式(I)化合物,其中
A、Y、R2、R7、R8和R9如上所定义。
反应方案VII
其中
A、R2、R7、R8和R9如上所定义的反应方案II中的式(II)所需化合物可依据上述反应方案VII,通过将式(3)二环氮杂化合物与式(18)和(21)中间体反应而以类似方式制得。
依据下述方法测定本发明化合物的生物活性。
测试化合物在正常的清醒且给予水的大鼠中的加压素V
2
激动剂作
用
给体重为350-500g的雄性或雌性血压正常的Sprague-Dawley大鼠(Charles River Laboratories,Inc.,Kingston,NY)提供可自由摄取的标准啮齿动物食物(Purina Rodent Lab.Chow 5001)和水。在测试的当天,将大鼠独立地放置在代谢笼子中,所述代谢笼子装配有用于将粪便与尿液分离开的装置和用来收集尿液的容器。在10mL/kg的体积中以10mg/Kg的口服剂量给予测试化合物或参照剂。所用载体是在20%二甲亚砜(DMSO)中的2.5%预煮沸过的玉米淀粉。给药测试化合物30分钟后,使用给料针头通过管饲法将30mL/Kg的水提供到大鼠的胃中。在测试期间,不给大鼠提供水或食物。给药测试化合物之后,收集4小时的尿液。在4小时结束时,测定尿液体积。使用Fiske One-Ten Osmometer(Fiske Associates,Norwood,MA,02062)或Advanced CRYOMATIC Osmometer,Model 3C2(AdvancedInstruments,Norwood,MA)测定尿液重量克分子渗透浓度。在Beckman SYNCHRON EL-ISE Electrolyte System分析仪中,用离子选择性电极测定Na+、K+和Cl-离子。尿液重量克分子渗透浓度应当成比例地增加。在筛选测试中,每种化合物使用两只大鼠。如果两只大鼠的尿液体积差异大于50%,则使用第三只大鼠。
该实验的结果如表1所示。
表1
实施例 | 尿液体积(%减少)a | 尿液重量克分子渗透浓度(%增加)b | 大鼠类型c |
1 | 67 | 163 | CD |
2 | 27 | 33 | CD |
3 | 18 | 78 | CD |
4 | 56 | 151 | CD |
5 | 22 | 26 | CD |
6 | 87 | 247 | CD |
7 | 70 | 189 | CD |
8 | 35 | 73 | CD |
9 | 62 | 156 | CD |
10 | 60 | 234 | CD |
a在10mg/Kg的剂量下,与对照相比尿液体积的减少百分比
b在10mg/Kg的剂量下,与对照相比重量克分子渗透浓度的增加百分比
c所用的大鼠模型:Sprague-Dawley(CD)
提供下述实施例是为了举例说明,而不是限制本发明的范围。
实施例1
(2’-甲氧基-[1,1’-联苯]-4-基)-(5H,11H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-甲酮
步骤A.2’-甲氧基-[1,1’-联苯]-4-甲酸乙酯
用氮气将4-溴苯甲酸乙酯(2.7mL,16.5mmol)、2-甲氧基硼酸(2.5g,16.5mmol)和碳酸钠(7.7g,72.6mmol)在甲苯∶乙醇∶水(75mL∶37mL∶37mL)中的混合物吹洗1小时。加入四(三苯基膦)钯(O)催化剂(0.96g,0.83mmol)后,将该反应混合物在100℃加热过夜。冷却后,经由硅藻土过滤该混合物,然后用乙酸乙酯洗涤。用水洗涤有机层,用无水硫酸钠干燥,过滤并真空浓缩,获得了棕色油状物。通过快速色谱法纯化残余物,使用25%-50%二氯甲烷在己烷中的混合物进行梯度洗脱,获得了本标题化合物(3.8g,89.9%),为浅黄色油状物。
1H-NMR(DMSO-d6,400MHz):δ1.32(t,3H),3.76(s,3H),4.32(q,2H),7.02-7.06(m,1H),7.12-7.14(m,1H),7.31-7.33(m,1H),7.36-7.40(m,1H),7.59-7.63(m,2H),7.96-7.99(m,2H).
MS[EI,m/z]:256[M]+.
元素分析
C16H16O3的计算值:C 74.98,H 6.29.实测值:C 75.11,H 6.71.
步骤B.2’-甲氧基-[1,1’-联苯]-4-甲酸
将步骤A的2’-甲氧基-[1,1’-联苯]-4-甲酸乙酯(3.7g,14.4mmol)在四氢呋喃(40mL)和1 N氢氧化钠(30mL,30mmol)中的混合物加热回流过夜。冷却后,将该反应混合物真空浓缩,用2N盐酸将残余物酸化,获得了白色固体,通过过滤收集,真空干燥,获得了本标题化合物(3.2g,97.4%),为白色固体,m.p.250-253℃。
1H-NMR(DMSO-d6,400MHz):δ3.78(s,3H),7.04-7.08(m,1H),7.13-7.16(m,1H),7.32-7.35(m,1H),7.37-7.41(m,1H),7.59-7.62(m,2H).7.96-7.99(m,2H),12.92(宽s,1H).
MS[EI,m/z]:228[M]+.
元素分析
C14H12O3+0.01CH2Cl2+0.04C4H8O的计算值:C 73.34,H 5.39.实测值:C 72.74,H 5.46.
步骤C.(2’-甲氧基-[1,1’-联苯]-4-基)-(5H,11H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-甲酮
将步骤B的2’-甲氧基-[1,1’-联苯]-4-甲酸(1.0g,4.38mmol)在亚硫酰氯(6mL)中的悬浮液加热回流30分钟。冷却后,真空除去亚硫酰氯。将残余物溶解在甲苯中,并真空浓缩,获得了酰氯粗产物,为黄色固体。将该固体溶解在二氯甲烷(10mL)中,把该溶液缓慢地加到10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂(0.97g,5.27mmol)和N,N-二异丙基乙胺(1.6mL,9.19mmol)在二氯甲烷(30mL)内的溶液中。搅拌2小时后,用水中止该反应。用1N盐酸、1N氢氧化钠和盐水洗涤有机层,用无水硫酸钠干燥,过滤并真空浓缩,获得了黄色泡沫状物。通过快速色谱法纯化残余物,使用15%-25%乙酸乙酯在己烷中的混合物进行梯度洗脱,获得了本标题化合物,为白色泡沫状物,将其从乙酸乙酯/己烷中重结晶,获得了(1.4g,81.0%)白色固体,m.p.145-147℃。
1H-NMR(DMSO-d6,400MHz):δ3.71(s,3H),4.80-5.40(broad s,4H),5.92-5.93(m,1H),5.95(s,1H),6.82(t,1H),6.96-7.00(m,2H),7.08(d,1H),7.12-7.21(m,3H),7.29-7.35(m,5H),7.47-7.49(m,1H)
MS[(+)ESI,m/z]:395[M+H]+.
元素分析
C26H22N2O2+0.08C4H8O2的计算值:C 78.73,H 5.68,N 6.98.实测值:C 78.47,H 5.77,N 7.00。
实施例2
(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-(3’-甲基-[1,1’-联苯]-4-基)-甲酮
步骤A.3’-甲基-[1,1’-联苯]-4-甲酸乙酯
用氮气将4-溴苯甲酸乙酯(2.7mL,16.5mmol)、3-甲基苯基硼酸(2.2g,16.2mmol)和碳酸钠(7.5g,70.8mmol)在甲苯:乙醇:水(75mL:37mL:37mL)中的混合物吹洗1小时。加入四(三苯基膦)钯(O)催化剂(0.94g,0.81mmol)后,将该反应在100℃加热过夜。冷却后,经由硅藻土过滤该混合物,然后用乙酸乙酯洗涤。用水洗涤有机层,用无水硫酸钠干燥,过滤并真空浓缩,获得了棕色油状物。通过快速色谱法纯化残余物,使用25%-50%二氯甲烷在己烷中的混合物进行梯度洗脱,获得了本标题化合物(3.4g,87.3%),为无色油状物。
1H-NMR(DMSO-d6,400MHz):δ1.34(t,3H),2.39(s,3H),4.34(q,2H),7.23-7.25(m,1H),7.39(t,1H),7.51-7.55(m,2H),7.79-7.82(m,2H),8.01-8.04(m,2H).
MS[EI,m/z]:240[M]+.
元素分析
C16H16O2的计算值:C 79.97,H 6.71.实测值:C 79.54,H 6.71。
步骤B.3’-甲基-[1,1’-联苯]-4-甲酸
将步骤A的3’-甲基-[1,1’-联苯]-4-甲酸乙酯(3.3g,13.7mmol)在四氢呋喃(40mL)和1 N氢氧化钠(27.5mL,27.5mmol)中的溶液加热回流过夜。冷却后,将该反应真空浓缩。用2N盐酸洗涤残余物,获得了白色固体,通过过滤收集,并真空干燥,获得了本标题化合物(2.9g,99.7%),为白色固体,m.p.198-200℃。
1H-NMR(DMSO-d6,400MHz):δ2.39(s,3H),7.24(d,1H),7.39(t,1H),7.51-7.56(m,2H),7.77-7.80(m,2H),8.00-8.03(m,2H),12.96(宽s,1H).
MS[EI,m/z]:212[M]+.
元素分析
C14H2O2的计算值:C 79.22,H 5.70.实测值:C 78.82,H 5.87.
步骤C.(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-(3’-甲基-[1,1’联苯]-4-基)-甲酮
将步骤B的3’-甲基-[1,1’-联苯]-4-甲酸(0.50g,2.36mmol)在亚硫酰氯(3mL)中的悬浮液加热回流30分钟。冷却后,真空除去亚硫酰氯。将残余物溶解在甲苯中,并真空浓缩,获得了酰氯粗产物,为黄色油状物。然后将该酰氯溶解在二氯甲烷(5mL)中,并缓慢地加到10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂(0.65g,3.53mmol)和N,N-二异丙基乙胺(0.90mL,5.17mmol)在二氯甲烷(15mL)内的溶液中。搅拌2小时后,用水中止该反应。用1N盐酸、1N氢氧化钠和盐水洗涤有机层,用无水硫酸钠干燥,并真空浓缩,获得了白色泡沫状物。通过快速色谱法纯化残余物,使用15%-25%乙酸乙酯在己烷中的混合物进行梯度洗脱,获得了白色泡沫状物,通过从乙酸乙酯/己烷中超声处理来结晶,获得了本标题化合物(0.74g,82.8%),为白色固体,m.p.128-130℃。
1H-NMR(DMSO-d6,400MHz):δ2.35(s,3H),4.80-5.40(broad s,4H),5.93-5.95(m,1H),5.97(s,1H),6.85(t,1H),6.96-6.98(m,1H),7.12(t-1H),7.17-7.21(m,2H),7.30-7.44(m,5H),7.48-7.54(m,3H).
MS[EI,m/z]:378[M]+.
元素分析
C26H22N20+0.10C4H8O2的计算值:C 81.88,H 5.93,N 7.23.实测值:C 81.54,H 5.99,N 7.29.
实施例3
(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-(4’-甲氧基[1,1’-联苯]-4-基)-甲酮
步骤A.4’-甲氧基-[1,1’-联苯]-4-甲酸乙酯
用氮气将4-溴苯甲酸乙酯(2.7mL,16.5mmol)、4-甲氧基苯基硼酸(2.5g,16.05mmol)和碳酸钠(7.7g,72.6mmol)在甲苯∶乙醇∶水(75mL∶37mL∶37mL)中的混合物吹洗1小时。加入四(三苯基膦)钯(O)催化剂(0.95g,0.82mmol)后,将该反应在100℃加热过夜。冷却后,经由硅藻土过滤该混合物,然后用乙酸乙酯洗涤。用水洗涤有机层,用无水硫酸钠干燥,过滤并真空浓缩,获得了棕色固体。通过快速色谱法纯化残余物,使用25%-50%二氯甲烷在己烷中的混合物进行梯度洗脱,获得了本标题化合物(4.05g,95.8%),为浅黄色固体,m.p.101-103℃。
1H-NMR(DMSO-d6,400MHz):61.34(t,3H),3.81(s,3H),4.33(9,2H),7.05-7.07(m,2H),7.69-7.71(m,2H),7.77-7.79(m,2H),7.98-8.01(m,2H).
MS[EI,m/z]:256[M]+.
元素分析
C16H16O3的计算值:C 74.98,H 6.29.实测值:C 74.92,H 6.16.
步骤B.4’-甲氧基-[1,1’-联苯]-4-甲酸
将步骤A的酯(3.9g,15.2mmol)在四氢呋喃(50mL)中的溶液用IN氢氧化钠(31mL,31mmol)处理,然后加热回流过夜。冷却后,将该反应混合物真空浓缩。用2N盐酸洗涤残余物,获得了白色固体,通过过滤收集,并真空干燥,获得了本标题化合物(3.4g,98.0%),为白色固体,m.p.250-254℃。
1H-NMR(DMSO-d6,400MHz):δ3.81(s,3H),7.04-7.08(m,2H),7.68-7.71(m,2H),7.73-7.77(m,2H),7.98-8.01(m,2H),12.91(broad s,1H).
MS [(-)ESI,m/z]:227[M-H]-.
元素分析
C14H12O3的计算值:C 73.67,H 5.30.实测值:C 73.11,H 5.41。
步骤C.(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-(4’-甲氧基-[1,1’-联苯]-4-基)-甲酮
将步骤B的羧酸(1.0g,4.38mmol)在亚硫酰氯(6mL)中的悬浮液加热回流小时。冷却后,真空除去亚硫酰氯。将残余物溶解在甲苯中,并真空浓缩,获得了酰氯粗产物,为浅棕色固体。然后将该酰氯溶解在二氯甲烷(10mL)中,并缓慢地加到10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂(1.2g,6.52mmol)和N,N-二异丙基乙胺(1.7mL,9.76mmol)在二氯甲烷(25mL)内的溶液中。搅拌2小时后,用水中止该反应。用1N盐酸、1N氢氧化钠和盐水洗涤有机层,用无水硫酸钠干燥,过滤并真空浓缩,获得了黄色泡沫状物。通过快速色谱法纯化残余物,使用15%-50%乙酸乙酯在己烷中的混合物进行梯度洗脱,获得了本标题化合物(1.5g,86.8%),为白色固体,m.p.187-189℃。
1H-NMR(DMSO-d6,400MHz):δ3.76(s,3H),4.80-5.40(宽s,4H),5.92-5.94(m,1H),5.96(s,1H),6.83(t,1H),6.94-6.99(m,3H),7.10(t,1H),7.15-7.19(m,1H),7.32(d,2H),7.47-7.49(m,3H),7.55-7.58(m,2H).
MS[(+)ESI,m/z]:395[M+H]+.
元素分析
C26H22N2O2+0.20CH2Cl2的计算值:C 76.48,H 5.49,N 6.81.
实测值:C 76.10,H 5.68,N 6.87.
实施例4
[1,1’-联苯]-4-基-(5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)-甲酮
在氮气氛下,向6,11-二氢-5H-吡啶并[2,3-b][1,5]苯并二氮杂(1.0g,5.07mmol)在N,N-二甲基甲酰胺(10mL)内的溶液中加入碳酸钾固体(0.74g,5.35mmol)。向该混合物中滴加4-联苯羰基氯(1.4g,6.46mmol)在N,N-二甲基甲酰胺(5mL)内的溶液,并在室温搅拌1小时。然后用水稀释该混合物,并用乙酸乙酯萃取。将有机萃取液合并,用1N氢氧化钠洗涤,用无水硫酸钠干燥,蒸发至干,获得了粉红色泡沫状物,通过快速色谱法纯化。用25%乙酸乙酯在己烷中的混合物洗脱,获得了白色泡沫状物,将其再溶解在二氯甲烷中,真空浓缩至泡沫状物,然后通过从乙酸乙酯/己烷中超声处理来结晶,获得了本标题化合物(1.28g,66.9%),为白色固体,m.p.175-177℃。
1H-NMR(DMSO-d6,400MHz):δ4.11(d,1H),5.60(d,1H),6.53-6.59(m,1H),6.68-6.70(m,1H),6.72-6.78(m,1H),7.04-7.09(m,1H),7.20(d,2H),7.32-7.36(m,2H),7.37-7.43(m,2H),7.48-7.61(m,5H),8.10-8.12(m,1H),9.62(s,1H).
MS[(+)ESI,m/z]:378[M+H]+.
元素分析
C25H19N3O+.05C4H8O2+.05CH2Cl2的计算值:C 78.55,H 5.09,N 10.88.
实测值:C 78.55.H 4.90,N 10.87.
实施例5
[1,1’-联苯]-4-基-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)甲酮
将用己烷洗涤、并在氮气氛下干燥的氢化钠(60%悬浮液,0.10g,2.5mmol)悬浮在无水N,N-二甲基甲酰胺(15mL)中。加入实施例4的1,1’-联苯-4-基-(5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)-甲酮(0.76g,2.0mmol)后,加入甲基碘(0.15mL,2.4mmol)。搅拌1小时后,用水中止该反应,用二氯甲烷萃取。用无水硫酸钠将有机层干燥,并真空浓缩,获得了黄色固体。通过快速色谱法纯化残余物,使用25%-35%乙酸乙酯在己烷中的混合物进行梯度洗脱,获得了白色泡沫状物,将其再溶解在二氯甲烷中,真空浓缩至泡沫状物,然后通过从乙酸乙酯/己烷中超声处理来结晶,获得了本标题化合物(0.48g,61.3%),为白色固体,m.p.220-223℃。
1H-NMR(DMSO-d6,400MHz):δ3.55(s,3H),4.28-4.40(broad m,1H),5.70-5.85(宽m,1H),6.88-6.97(m,2H),7.02-7.05(m,1H),7.26(t,1H),7.32-7.38(m,4H),7.43(t,2H),7.55-7.63(m,5H),8.22-8.24(m,1H).
MS[(+)APCl,m/z]:392[M+H]+.
元素分析
C26H21N3O+0.04C4H8O2+0.20CH2Cl2的计算值:C 76.85,H 5.31,N 10.20.
实测值:C 76.99,H 5.20,N 9.98.
实施例6
[1,1’-联苯]-4-基-(5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)甲酮
将溶解在N,N-二甲基甲酰胺(10mL)中的4-联苯-羰基氯(1.19g)滴加到5,11-二氢-10H-二苯并[b,e][1,4]二氮杂(0.98g)在N,N-二甲基甲酰胺(10mL)内的冰冷溶液中。在室温搅拌过夜后,将该反应混合物倒入水和二氯甲烷中。然后将有机层依次用水和饱和碳酸氢钠洗涤,用无水硫酸钠干燥。将该溶液经由Magnesol短柱过滤,用另外的二氯甲烷洗脱。将合并的洗脱液回流,期间逐渐加入己烷直至开始发生结晶。冷却并过滤,获得了本标题化合物(0.72g),m.p.180-182℃。
元素分析
C26H20N2O的计算值:C 82.95,H 5.35,N 7.44.实测值:C 82.84,H 5.24,N 7.40.
实施例7
[1,1’-联苯]-4-基-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)甲酮
将实施例6的[1,1’-联苯]-4-基-(5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)-甲酮(0.97g)加到氢化钠(2当量,60%油悬浮液,用己烷洗涤过)和N,N-二甲基甲酰胺(25mL)中。加入碘甲烷(0.45g),搅拌过夜后,将该混合物倒入盐水内。收集沉淀,再溶解在二氯甲烷中,经由Magnesol短柱过滤该溶液。用几份-定体积的二氯甲烷洗涤该柱,将合并洗脱液回流,期间逐渐加入己烷直至开始结晶。冷却并过滤,获得了本标题化合物(0.89g),m.p.198-201℃。
MS[(+)ESI,m/z]:391[M+H]+。
实施例8
[1,1’-联苯]-4-基-(5,6,7,8-四氢-噻吩并[3,2-b]氮杂-4-基)-甲酮
步骤A.5,6,7,8-四氢-4H-噻吩并[3,2-b]氮杂
将6,7-二氢-5H-苯并[b]噻吩-4-酮肟(1.67g)在无水二氯甲烷(100mL)中的溶液冷却至0℃。滴加氢化二异丁基铝(50ml,1M己烷溶液)后,将该混合物在0℃搅拌3小时,然后用二氯甲烷(50mL)稀释。加入氟化钠(8.4g),然后加入水(2.7mL)。将该反应混合物剧烈搅拌30分钟,然后过滤并浓缩,获得了本标题化合物(0.81g),为白色固体。
1H-NMR(200mHz,CDCl3):δ1.70(m,2H),1.87(m,2H),2.75(m,2H),3.05(m,2H),3.50(brs,1H),6.51(d,1H),6.82(d,1H).
步骤B.1,1’-联苯-4-基-(5,6,7,8-四氢-噻吩并[3,2-b]氮杂-4-基)-甲酮
将步骤A的5,6,7,8-四氢-4H-噻吩并[3,2-b]氮杂(0.300g)与N,N-二异丙基乙胺(0.5mL)在二氯甲烷(25mL)中的溶液冷却至0℃。向其中加入4-联苯羰基氯(0.518g)在二氯甲烷(5ml)中的溶液。将该溶液搅拌过夜,同时温热至室温,然后用0.1N盐酸、碳酸氢钠水溶液和盐水洗涤。用无水硫酸钠将有机层干燥,过滤并蒸发至油状物。通过快速硅胶色谱纯化该残余物,获得了本标题化合物,为白色固体(0.490g),m.p.164-166℃。
1R(KBr,cm-1)1630
NMR(400mHz,DMSO-d6):δ1.82(br,2H),2.04(br,2H),2.95(dd, 2H),3.90(br,2H),6.23(br s,1H),6.65(br s,1H),7.34,(m,3H),7.43,(m,4H),7.55(dd,2H).
MS[EI,m/z]:333[M]+.
元素分析
C21H19NOS的计算值:C 75.64,H 5.74,N 4.20.实测值:C 75.37,H 5.79,N 4.12.
实施例9
(5H,11H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10-基)-(6-苯基-吡啶-3-基)-甲酮
用氮气将5H,11H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10-基)-(6-氯吡啶-3-基)-甲酮(0.323g)和苯基硼酸(0.185g)在甲苯/1M碳酸钠水溶液/乙醇(6mL/2mL/1mL)混合物中的悬浮液喷射5分钟。向该搅拌着的混合物中加入乙酸钯(II)(0.0135g)。然后将该反应在氮气静压下加热回流14小时。用乙酸乙酯稀释该悬浮液,用饱和碳酸氢钠水溶液和盐水洗涤。将有机层用无水硫酸钠干燥,过滤并真空蒸发,获得了绿色泡沫状物(0.360g)。在Merck硅胶上通过快速色谱法纯化残余物,用25%乙酸乙酯在己烷中的混合物洗脱,获得了本标题化合物(0.250g),为白色泡沫状物,将其从丙酮/己烷中重结晶,获得了黄色针状物,m.p.171-174℃。
1H-NMR(DMSO-d6,400mHz):δ5.37(brs,2H),5.92(t,1H),5.97(s,1H),6.83(t,1H),7.03(d,1H),7.10(t,1H),7.19(t,1H),7.45(m,4H),7.75(d,1H),7.85(d,1H),8.02(dd,2H),8.48(br,1H)
元素分析
C24H19N3O.0.25H2O的计算值:C 77.70,H 5.31,N 11.36.实测值:C 77.70,H 5.23,N 11.39.
实施例10
(5H,11H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10-基)-(4’-甲氧基-3-甲基-[1,1’-联苯]-4-基)-甲酮
步骤A.4’-甲氧基-3-甲基-[1,1’-联苯]-4-甲酸
用氮气将在甲苯、水和乙醇(15mL∶6mL∶3mL)混合物中的4-溴-2-甲基-苯甲酸(2.15g,10mmol)、4-甲氧基-苯基硼酸(1.52g,10mmol)和碳酸钠(3.24g,30mmol)喷射5分钟。向该混合物中加入乙酸钯(0.014g)。在氮气静压下将该混合物加热回流24小时。用水和乙酸乙酯(各50mL)将样本稀释,将pH调节至1。分离各层,用乙酸乙酯萃取水相。将有机萃取液合并,用水和盐水洗涤。用无水硫酸钠将样本干燥,过滤并真空浓缩。将所得固体从乙酸乙酯/己烷中重结晶,获得了本标题化合物(2.16g),为白色固体,m.p199-201℃。
1H NMR(DMSO-d6,400MHz);δ2.57(s,3H),3.79(s,3H),7.02(m,2H),7.21(dd,1H);7.55(s,1H);7.67(m,2H);7.87(d,1H);12.73(s,1H)
MS[EI,m/z]:242[M]+.
元素分析
C15H14O3的计算值:C 74.36,H 5.82.实测值:C 73.92,H 5.93.
步骤B.(5H,11H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10-基)-(4’-甲氧基-3-甲基-[1,1’-联苯]-4-基)-甲酮
将步骤A的4’-甲氧基-3-甲基-联苯-4-甲酸(0.486g,2mmol)和亚硫酰氯(3mL)的混合物搅拌30分钟,然后温热至回流,并回流15分钟。将该反应产物溶解在甲苯(10mL)中,真空浓缩。该操作重复2次,获得了酰氯粗产物。将该酰氯粗产物溶解在二氯甲烷(10mL)中,并将该溶液滴加到10,11-二氢-5H-苯并[e]吡咯并[1,2-a][1,4]-二氮杂(0.368g,2mmol)、三乙胺(0.4mL,2.8mmol)和催化量的4-(二甲基氨基)吡啶的冰冷溶液(0℃)中。将该溶液在室温搅拌过夜,然后用1N盐酸中止反应。用水和二氯甲烷将该混合物稀释,用0.1N盐酸、0.1N氢氧化钠和水洗涤有机层。用无水硫酸钠将该溶液干燥,浓缩,获得了泡沫状物。通过快速色谱法纯化残余物,用30%乙酸乙酯在己烷中的混合物洗脱,获得了泡沫状物(0.700g),用乙醚和少量乙酸乙酯将其研制和超声处理,获得了本标题化合物(0.600g),为白色固体。
1H-NMR(DMSO-d6,400MHz):δ2.37(s,3H),3.76(s,3H),5.10(br s,2H),5.25(br s,2H),5.90(t,1H),5.96(br s,1H),6.8-7.6(m,12H)
MS[(+)ESI,m/z]:409[M+H]+.
元素分析
C27H24N2O2的计算值:C 79.39,H 5.92,N 6.86.实测值:C 78.51,H 5.98,N 6.66.
实施例11
[1,1’-联苯]-4-基-(4H,10H-3a,5,9-三氮杂-苯并[f]甘菊环-9-基)-甲酮
步骤A.2-氯甲基-吡啶-3-甲酸甲酯
将2-甲基烟酸甲酯(20.0g,0.132mol)和三氯异氰脲酸(46.0g,0.198mol)在二氯甲烷(100mL)中的溶液于室温搅拌过夜。然后将该反应混合物用饱和碳酸钠水溶液和饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,将溶剂真空蒸发,获得了本标题化合物,为黄色液体(11.2g),其直接用于下一步骤。
步骤B.2-(2-甲酰基-吡咯-1-基甲基)-吡啶-3-甲酸甲酯
在氮气氛下,向氢化钠(5.8g,0.12mol)在无水N,N-二甲基甲酰胺(25mL)内的悬浮液中缓慢地加入吡咯-2-甲醛(10.5g,0.11mol)在N,N-二甲基甲酰胺(10mL)中的溶液,将该反应混合物在室温搅拌30分钟。然后将该反应冷却至5℃,缓慢地加入步骤A的2-氯甲基-吡啶-3-甲酸甲酯,同时将温度保持在20℃或20℃以下。加入完成后,将该反应在室温搅拌30分钟。将该混合物蒸发至干,把残余物溶解在乙酸乙酯(250mL)中。用水洗涤该溶液,用无水硫酸镁干燥。然后真空除去溶剂,获得了深色固体结晶(23.4g),通过硅胶色谱纯化,用乙酸乙酯/石油醚进行梯度洗脱,获得了本标题化合物,为黄褐色固体结晶(13.75g),m.p.91-93℃。
步骤C.[3-(2-甲酰基-吡咯-1-基-甲基)-吡啶-2-基]-氨基甲酸苄酯
向步骤B的2-(2-甲酰基-吡咯-1-基甲基)-吡啶-3-甲酸甲酯(13.65g,55.9mmol)在甲醇(50mL)内的搅拌着的溶液中加入氢氧化钠(2.2g,55.9mmol.)。将该反应混合物在氮气氛下回流2小时,然后真空除去溶剂。将一部分黄色残余固体(5g)悬浮在苯甲醇(20mL)和苯(30mL)的混合物中。加入二苯基磷酰叠氮(6.54g,1.2当量),将该反应缓慢地加热至回流。回流1小时后,将该混合物冷却,并用水洗涤,用无水硫酸镁干燥,过滤并蒸发至干,获得了本标题化合物,为黄褐色固体结晶(4.4g),m.p.109-111℃。
步骤D.9,10-二氢-4H-3a,5,9-三氮杂-苯并[f]甘菊环
将含有10%披钯炭(10mg)、硫酸镁(0.010g)和5滴乙酸的步骤B的[3-(2-甲酰基-吡咯-1-基-甲基)-吡啶-2-基]-氨基甲酸苄酯(1.0g)在乙酸乙酯(10mL)中的搅拌着的混合物在大气压下氢化直至不再消耗氢气为止。然后将该反应混合物经由硅藻土过滤,并真空除去溶剂。通过硅胶色谱纯化粗产物(黄色固体结晶,0.530g),用乙酸乙酯在石油醚中的混合物进行梯度洗脱,获得了本标题化合物,为黄色固体结晶,m.p.171-172℃。
步骤E.1,1’-联苯-4-基-(4H,10H-3a,5,9-三氮杂-苯并[f]甘菊环-9-基)-甲酮
将步骤D的9,10-二氢-4H-3a,5,9-三氮杂-苯并[f]甘菊环(0.54mmol)、4-苯基苯甲酰氯(1.08mmol)和三乙胺(1.08mmol)在甲苯中的搅拌着的混合物于氮气氛下回流72小时。将该反应冷却,真空除去溶剂。通过Merck-60硅胶色谱纯化残余物,用5-20%乙酸乙酯在己烷中的混合物进行梯度洗脱,获得了本标题化合物,为黄褐色固体。
1H-NMR(DMSO-d6,400MHz):δ5.1(bs,2H),5.4(s,2H);5.9(m,1H),6.0(s,1H),6.9(m,1H),7.1(m,1H),7.3-8.7(m,10H),8.3(m,1H).
MS[APCl,m/z]:366[M+H]+.
元素分析
C24H19N3O+0.5H2O的计算值:C 76.99,H 5.38,N 11.22.实测值:C 77.28,H 5.22,N 10.71.
下列实施例是依据下述一般方法A制备的。
一般方法A
步骤A.通过在二氯甲烷中用草酰氯(1.5mmol)和催化量的N,N-二甲基甲酰胺处理来将任选取代的卤代芳基羧酸(1.1mol)转化成酰氯。当HPLC分析表明羧酸已转化完全时,真空除去所有挥发性组分。将残余物溶解在二氯甲烷中,滴加到适当取代的10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂、11-甲基-6,11-二氢-5H-吡啶并[2,3-b][1,5]苯并二氮杂或5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂(1mmol)与N,N-二异丙基乙胺(1.2mmol)在二氯甲烷内的搅拌着的冷(0℃)溶液中。1-16小时后,用二氯甲烷稀释该混合物,并用10%碳酸氢钠水溶液洗涤。用无水硫酸钠将合并的有机萃取液干燥,过滤并浓缩。
步骤B.向残余物中加入适当取代的芳基硼酸(1.2mmol)、碳酸钾(2.5mmol)、溴化四丁基铵(1mmol)、乙酸钯(II)(3%mol)和水/乙腈(1∶1.2mL)。将该混合物在70℃加热1.5小时,然后加入乙酸乙酯,用水洗涤有机相。将该溶液经由小的硅藻土塞过滤,并浓缩至干。
实施例12
[3-氯-2’-甲基-(1,1’-联苯)-4-基]-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)-甲酮
HRMS[(+)ESI,m/z]:439.15770[M+H]+.C28H24ClN2O的计算值:439.15716.
实施例13
[3-氯-2’-甲氧基-(1,1’-联苯)-4-基]-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)-甲酮
HRMS[(+)ESI,m/z]:455.15195[M+H]+.C28H24ClN2O2的计算值:455.15208.
实施例14
[3-氯-3’-甲氧基-(1,1’-联苯)-4-基]-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)-甲酮
HRMS[(+)ESI,m/z]:455.15195[M+H]+.C28H24ClN2O2的计算值:455.15208.
实施例15
[2’-甲基-(1,1’-联苯)-4-基]-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)-甲酮
HRMS[(+)ESI,m/z]:405.19555[M+H]+.C28H25N2O的计算值:405.19614.
实施例16
[2’-甲氧基-(1,1’-联苯)-4-基]-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)-甲酮
HRMS[(+)ESI,m/z]:421.19021[M+H]+.C28H25N2O2的计算值:421.19106.
实施例17
[3’-甲氧基-(1,1’-联苯)-4-基]-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)-甲酮
HRMS[(+)ESI,m/z]:421.19067[M+H]+.C28H25N2O2的计算值:421.19106.
实施例18
[3-氯-2’-甲基-(1,1’-联苯)-4-基]-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)-甲酮
HRMS[(+)ESI,m/z]:440.15163[M+H]+.C27H23ClN3O的计算值:440.15241.
实施例19
[3-氯-2’-甲氧基-(1,1’-联苯)-4-基]-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)-甲酮
HRMS[(+)ESI,m/z]:456.14731[M+H]+.C27H23ClN3O2的计算值:456.14732.
实施例20
[3-氯-3’-甲氧基-(1,1’-联苯)-4-基]-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)-甲酮
HRMS[(+)ESI,m/z]:456.14687[M+H]+.C27H23ClN3O2的计算值:456.14732.
实施例21
[2’-甲基-(1,1’-联苯)-4-基]-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)-甲酮
HRMS[(+)ESI,m/z]:406.19025[M+H]+.C27H24N3O的计算值:406.19139.
实施例22
[2’-甲氧基-(1,1’-联苯)-4-基]-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)-甲酮
HRMS[(+)ESI,m/z]:422.18706[M+H]+.C27H24N3O2的计算值:422.18631.
实施例23
[3’-甲氧基-(1,1’-联苯)-4-基]-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)-甲酮
HRMS[(+)ESI,m/z]:422.18617[M+H]+.C27H24N3O2的计算值:422.18631.
实施例24
[3-氯-2’-甲基-(1,1’-联苯)-4-基]-(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-甲酮
HRMS[(+)ESI,m/z]:413.14172[M+H]+.C26H22ClN2O的计算值:413.14151.
实施例25
[3-氯-2’-甲氧基-(1,1’-联苯)-4-基]-(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-甲酮
HRMS [(+)ESI,m/z]:429.13611[M+H]+.C28H22ClN2O2的计算值:429.13643.
实施例26
[3-氯-3’-甲氧基-(1,1’-联苯)-4-基]-(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-甲酮
HRMS[(+)ESI,m/z]:429.13622[M+H]+.C26H22ClN2O2的计算值:429.13643.
实施例27
[2’-甲基-(1,1’-联苯)-4-基]-(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-甲酮
HRMS[(+)ESI,m/z]:379.17963[M+H]+.C26H23N2O的计算值:379.18049.
实施例28
[2’-甲氧基-(1,1’-联苯)-4-基]-(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-甲酮
HRMS[(+)ESI,m/z]:395.17496[M+H]+.C28H23N2O2的计算值:395.17541.
实施例29
[3’-甲氧基-(1,1’-联苯)-4-基]-(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-甲酮
HRMS[(+)ESI,m/z]:395.17529[M+H]+.C26H23N2O2的计算值:395.17541.
Claims (38)
1.式(I)或(II)化合物或其可药用盐或前药形式
其中:
Y是选自NR或-(CH2)n的部分;
其中R是氢或(C1-C6)烷基,
且n是1;
代表:
(1)苯环,所述苯环可任选被一个或两个独立地选自下列的取代基取代:氢、(C1-C6)烷基、卤素、氰基、CF3、羟基、(C1-C6)烷氧基、(C1-C6)烷氧基羰基、羧基、-CONH2、-CONH[(C1-C6)烷基]、-CON[(C1-C6)烷基]2;或
(2)具有一个氮原子的6-元芳族(不饱和)杂环,所述杂环可任选被(C1-C6)烷基、卤素或(C1-C6)烷氧基取代;
代表:
(1)苯环,所述苯环可任选被一个或两个独立地选自下列的取代基取代:氢、(C1-C6)烷基、卤素、氰基、CF3、羟基、(C1-C6)烷氧基、或(C1-C6烷氧基)羰基、羧基、-CONH2、-CONH[(C1-C6)烷基]、-CON[(C1-C6)烷基]2;或
(2)具有一个氮原子的5-元芳族(不饱和)杂环,所述杂环可任选被(C1-C6)烷基、(C1-C6)烷氧基或卤素取代;或
(3)具有一个氮原子的6-元芳族(不饱和)杂环,所述杂环可任选被(C1-C6)烷基、卤素或(C1-C6)烷氧基取代;
代表具有一个硫原子的5-元芳族(不饱和)杂环,所述杂环可任选被(C1-C6)烷基、卤素或(C1-C6)烷氧基取代;
R1是下式所示部分
且R2、R3、R7、R8和R9独立地选自氢、(C1-C3)烷基、OCH3、卤素、CF3、-SCH3、OCF3、SCF3或CN。
5.权利要求1的化合物,其中所述化合物是下式所示化合物或其可药用盐或前药形式:
其中:
R2、R7、R8和R9分别独立地选自氢、C1-C3烷基、OCH3、卤素、CF3、SCH3、OCF3、SCF3或CN;
R10是选自C1-C6烷基、卤素或C1-C6烷氧基的基团;且
R13是C1-C6烷基、卤素或C1-C6烷氧基。
7.权利要求1的化合物,其中所述化合物是(2’-甲氧基-[1,1’-联苯]-4-基)-(5H,11H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)甲酮或其可药用盐形式。
8.权利要求1的化合物,其中所述化合物是(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-(3’-甲基-[1,1’-联苯]-4-基)甲酮或其可药用盐形式。
9.权利要求1的化合物,其中所述化合物是(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)-(4’-甲氧基-[1,1’-联苯]-4-基)甲酮或其可药用盐形式。
10.权利要求1的化合物,其中所述化合物是[1,1’-联苯]-4-基-(5,11-二氢苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)甲酮或其可药用盐形式。
11.权利要求1的化合物,其中所述化合物是[1,1’-联苯]-4-基-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)甲酮或其可药用盐形式。
12.权利要求1的化合物,其中所述化合物是[1,1’-联苯]-4-基-(5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)甲酮或其可药用盐形式。
13.权利要求1的化合物,其中所述化合物是[1,1’-联苯]-4-基-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)甲酮或其可药用盐形式。
14.权利要求2的化合物,其中所述化合物是[1,1’-联苯]-4-基-(5,6,7,8-四氢噻吩并[3,2-b]氮杂-4-基)甲酮。
15.权利要求1的化合物,其中所述化合物是(5H,11H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10-基)(6-苯基-吡啶-3-基)甲酮或其可药用盐形式。
16.权利要求1的化合物,其中所述化合物是(5H-11H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10-基)-(4’-甲氧基-3-甲基-[1,1’-联苯]-4-基)甲酮或其可药用盐形式。
17.权利要求1的化合物,其中所述化合物是[1,1’-联苯]-4-基]-(4H,10H-3a,5,9-三氮杂-苯并[f]甘菊环-9-基)-甲酮或其可药用盐形式。
18.权利要求1的化合物,其中所述化合物是[3-氯-2’-甲基-(1,1’-联苯)-4-基]-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)甲酮或其可药用盐形式。
19.权利要求1的化合物,其中所述化合物是[3-氯-2’-甲氧基-(1,1’-联苯)-4-基]-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)甲酮或其可药用盐形式。
20.权利要求1的化合物,其中所述化合物是[3-氯-3’-甲氧基-(1,1’-联苯)-4-基]-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)甲酮或其可药用盐形式。
21.权利要求1的化合物,其中所述化合物是[2’-甲基-(1,1’-联苯)-4-基]-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)甲酮或其可药用盐形式。
22.权利要求1的化合物,其中所述化合物是[2’-甲氧基-(1,1’-联苯)-4-基]-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)甲酮或其可药用盐形式。
23.权利要求1的化合物,其中所述化合物是[3’-甲氧基-(1,1’-联苯)-4-基]-(5-甲基-5,11-二氢-10H-二苯并[b,e][1,4]二氮杂-10-基)甲酮或其可药用盐形式。
24.权利要求1的化合物,其中所述化合物是[3-氯-2’-甲基-(1,1’-联苯)-4-基]-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)甲酮或其可药用盐形式。
25.权利要求1的化合物,其中所述化合物是[3-氯-2’-甲氧基-(1,1’-联苯)-4-基]-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)甲酮或其可药用盐形式。
26.权利要求1的化合物,其中所述化合物是[3-氯-3’-甲氧基-(1,1’-联苯)-4-基]-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)甲酮或其可药用盐形式。
27.权利要求1的化合物,其中所述化合物是[2’-甲基-(1,1’-联苯)-4-基]-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-c][1,4]二氮杂-6-基)甲酮或其可药用盐形式。
28.权利要求1的化合物,其中所述化合物是[2’-甲氧基-(1,1’-联苯)-4-基]-(11-甲基-5,11-二氢-苯并[2,3-e][1,4]二氮杂-6-基)甲酮或其可药用盐形式。
29.权利要求1的化合物,其中所述化合物是[3’-甲氧基-(1,1’-联苯)-4-基]-(11-甲基-5,11-二氢-苯并[b]吡啶并[2,3-e][1,4]二氮杂-6-基)甲酮或其可药用盐形式。
30.权利要求1的化合物,其中所述化合物是[3-氯-2’-甲基-(1,1’-联苯)-4-基]-(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)甲酮或其可药用盐形式。
31.权利要求1的化合物,其中所述化合物是[3-氯-2’-甲氧基-(1,1’-联苯)-4-基]-(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)甲酮或其可药用盐形式。
32.权利要求1的化合物,其中所述化合物是[3-氯-3’-甲氧基-(1,1’-联苯)-4-基]-(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)甲酮或其可药用盐形式。
33.权利要求1的化合物,其中所述化合物是[2’-甲基]-(1,1’-联苯)-4-基]-(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)甲酮或其可药用盐形式。
34.权利要求1的化合物,其中所述化合物是[2’-甲氧基-(1,1’-联苯)-4-基]-(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)甲酮或其可药用盐形式。
35.权利要求1的化合物,其中所述化合物是[3’-甲氧基-(1,1’-联苯)-4-基]-(10,11-二氢-5H-吡咯并[2,1-c][1,4]苯并二氮杂-10-基)甲酮或其可药用盐形式。
36.在有此需要的哺乳动物中治疗可通过加压素激动剂活性来治疗或减轻的病症的方法,所述方法包括给哺乳动物施用药物有效量的权利要求1-35任一项的化合物或其可药用盐或前药形式。
37.权利要求36的方法,其中所述可通过加压素激动剂活性来治疗或减轻的病症选自尿崩症、夜间遗尿、夜尿症、尿失禁、出血和凝血病症或暂时延迟排尿。
38.药物组合物,其中包含权利要求1-35任一项的化合物或其可药用盐或前药形式和可药用载体。
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EP (1) | EP1381370B1 (zh) |
JP (1) | JP2004530668A (zh) |
CN (1) | CN1516589A (zh) |
AT (1) | ATE355843T1 (zh) |
BR (1) | BR0208823A (zh) |
CA (1) | CA2444455A1 (zh) |
DE (1) | DE60218646T2 (zh) |
DK (1) | DK1381370T3 (zh) |
ES (1) | ES2282423T3 (zh) |
MX (1) | MXPA03009158A (zh) |
WO (1) | WO2002083145A1 (zh) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0210397D0 (en) | 2002-05-07 | 2002-06-12 | Ferring Bv | Pharmaceutical formulations |
FR2880885B1 (fr) * | 2005-01-14 | 2009-01-30 | Merck Sante Soc Par Actions Si | Derives d'acide phenylbenzoique, procedes pour leur preparation, compositions pharmaceutiques les contenant et applications en therapeutique |
WO2008103382A1 (en) * | 2007-02-20 | 2008-08-28 | Sergey Kozmin | Method for assembling high-purity chemical libraries, compounds suppressing acetyl coenzyme a carboxylase activities discovered by same |
KR100822592B1 (ko) * | 2007-03-23 | 2008-04-16 | 주식회사 하이닉스반도체 | 반도체 소자의 미세 패턴 형성방법 |
CA2988753A1 (en) | 2007-08-06 | 2009-02-12 | Serenity Pharmaceuticals, Llc | Methods and devices for desmopressin drug delivery |
US20100286045A1 (en) | 2008-05-21 | 2010-11-11 | Bjarke Mirner Klein | Methods comprising desmopressin |
LT2712622T (lt) * | 2008-05-21 | 2016-09-26 | Ferring B.V. | Burnoje disperguojamas desmopresinas, skirtas nikturijos netrikdomo miego pirminio periodo pailginimui |
US11963995B2 (en) | 2008-05-21 | 2024-04-23 | Ferring B.V. | Methods comprising desmopressin |
WO2016089797A1 (en) * | 2014-12-05 | 2016-06-09 | Merck Sharp & Dohme Corp. | Novel tricyclic compounds as inhibitors of mutant idh enzymes |
US10086000B2 (en) | 2014-12-05 | 2018-10-02 | Merck Sharp & Dohme Corp. | Tricyclic compounds as inhibitors of mutant IDH enzymes |
EP3226689B1 (en) * | 2014-12-05 | 2020-01-15 | Merck Sharp & Dohme Corp. | Novel tricyclic compounds as inhibitors of mutant idh enzymes |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
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US5736538A (en) | 1993-07-29 | 1998-04-07 | American Cyanamid Company | Tricyclic Benzazepine vasopressin antagonists |
US5516774A (en) | 1993-07-29 | 1996-05-14 | American Cyanamid Company | Tricyclic diazepine vasopressin antagonists and oxytocin antagonists |
US5686445A (en) | 1993-07-29 | 1997-11-11 | American Cyanamid Company | Pyridobenzoxazepine and pyridobenzothiazepine vasopressin antagonists |
US5693635A (en) | 1993-07-29 | 1997-12-02 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
US5747487A (en) | 1993-07-29 | 1998-05-05 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
US5739128A (en) | 1993-07-29 | 1998-04-14 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
US5760031A (en) | 1993-07-29 | 1998-06-02 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
US5736540A (en) | 1993-07-29 | 1998-04-07 | American Cyanamid Company | Tricyclic diazepine vasopressin antagonists and oxytocin antagonists |
US5733905A (en) | 1993-07-29 | 1998-03-31 | American Cyanamid Company | Tricyclic diazepine vasopressin antagonists and oxytocin antagonists |
DK1221440T3 (da) | 1994-06-15 | 2007-09-17 | Otsuka Pharma Co Ltd | Benzoheterocykliske derivater der er nyttige som vasopressin- eller oxytocinmodulatorer |
US5696112A (en) * | 1995-01-17 | 1997-12-09 | American Cyanamid Company | Fused heterocyclic azepines as vasopressin antagonists |
US5849735A (en) * | 1995-01-17 | 1998-12-15 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
AR002459A1 (es) | 1995-01-17 | 1998-03-25 | American Cyanamid Co | Antagonistas de vasopresina de benzacepina triciclicos, una composicion farmaceutica que los contiene, un metodo para tratar enfermedades y unprocedimiento para su preparacion. |
US5521173A (en) * | 1995-01-17 | 1996-05-28 | American Home Products Corporation | Tricyclic benzazepine vasopressin antagonists |
US5532235A (en) | 1995-01-17 | 1996-07-02 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
US5753648A (en) | 1995-01-17 | 1998-05-19 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
US5700796A (en) | 1995-01-17 | 1997-12-23 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
US5536718A (en) | 1995-01-17 | 1996-07-16 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
US5612234A (en) * | 1995-10-04 | 1997-03-18 | Lg Electronics Inc. | Method for manufacturing a thin film transistor |
TW359669B (en) | 1995-12-15 | 1999-06-01 | Otsuka Pharma Co Ltd | Benzazepine derivatives |
US6194407B1 (en) * | 1997-07-30 | 2001-02-27 | American Home Products Corporation | Tricyclic pyrido vasopressin agonists |
AU4168999A (en) | 1998-06-19 | 2000-01-05 | Wakamoto Pharmaceutical Co., Ltd. | Ocular tension lowering agents and phosphoric ester derivatives |
CZ302647B6 (cs) | 1999-01-19 | 2011-08-17 | Ortho-Mcneil Pharmaceutical, Inc. | Tricyklický benzodiazepin, farmaceutický prípravek s jeho obsahem a meziprodukty pro jeho prípravu |
CN1339036A (zh) * | 1999-02-04 | 2002-03-06 | 美国家用产品公司 | 作为血管加压素激动剂的噻吩基苯甲酰基苯并吖庚因 |
-
2002
- 2002-04-11 JP JP2002580949A patent/JP2004530668A/ja active Pending
- 2002-04-11 US US10/121,156 patent/US6903091B2/en not_active Expired - Fee Related
- 2002-04-11 DK DK02739139T patent/DK1381370T3/da active
- 2002-04-11 MX MXPA03009158A patent/MXPA03009158A/es active IP Right Grant
- 2002-04-11 WO PCT/US2002/011284 patent/WO2002083145A1/en active IP Right Grant
- 2002-04-11 BR BR0208823-1A patent/BR0208823A/pt not_active IP Right Cessation
- 2002-04-11 ES ES02739139T patent/ES2282423T3/es not_active Expired - Lifetime
- 2002-04-11 CA CA002444455A patent/CA2444455A1/en not_active Abandoned
- 2002-04-11 DE DE60218646T patent/DE60218646T2/de not_active Expired - Fee Related
- 2002-04-11 AT AT02739139T patent/ATE355843T1/de not_active IP Right Cessation
- 2002-04-11 CN CNA028119045A patent/CN1516589A/zh active Pending
- 2002-04-11 EP EP02739139A patent/EP1381370B1/en not_active Expired - Lifetime
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2004
- 2004-11-04 US US10/980,939 patent/US7223752B2/en not_active Expired - Fee Related
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2006
- 2006-08-11 US US11/502,982 patent/US7465722B2/en not_active Expired - Fee Related
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2008
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Also Published As
Publication number | Publication date |
---|---|
ES2282423T3 (es) | 2007-10-16 |
DE60218646T2 (de) | 2007-11-22 |
MXPA03009158A (es) | 2004-02-12 |
EP1381370A1 (en) | 2004-01-21 |
US20050075328A1 (en) | 2005-04-07 |
JP2004530668A (ja) | 2004-10-07 |
US7223752B2 (en) | 2007-05-29 |
DE60218646D1 (de) | 2007-04-19 |
US20060276456A1 (en) | 2006-12-07 |
DK1381370T3 (da) | 2007-05-21 |
CA2444455A1 (en) | 2002-10-24 |
US7465722B2 (en) | 2008-12-16 |
US6903091B2 (en) | 2005-06-07 |
WO2002083145A1 (en) | 2002-10-24 |
US20030018024A1 (en) | 2003-01-23 |
EP1381370B1 (en) | 2007-03-07 |
ATE355843T1 (de) | 2007-03-15 |
BR0208823A (pt) | 2004-03-09 |
US20090227565A1 (en) | 2009-09-10 |
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