CN114702503B - 甲酮化合物 - Google Patents
甲酮化合物 Download PDFInfo
- Publication number
- CN114702503B CN114702503B CN202210300836.8A CN202210300836A CN114702503B CN 114702503 B CN114702503 B CN 114702503B CN 202210300836 A CN202210300836 A CN 202210300836A CN 114702503 B CN114702503 B CN 114702503B
- Authority
- CN
- China
- Prior art keywords
- diazabicyclo
- triazol
- oct
- sulfonyl
- methanone
- 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.)
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- -1 Ketone compound Chemical class 0.000 title claims description 91
- 150000001875 compounds Chemical class 0.000 claims abstract description 211
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 72
- 201000010099 disease Diseases 0.000 claims abstract description 50
- 238000011282 treatment Methods 0.000 claims abstract description 50
- 238000011321 prophylaxis Methods 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims description 75
- 239000000203 mixture Substances 0.000 claims description 63
- 229910052739 hydrogen Inorganic materials 0.000 claims description 59
- 239000001257 hydrogen Substances 0.000 claims description 59
- 150000002431 hydrogen Chemical class 0.000 claims description 50
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 48
- 201000009273 Endometriosis Diseases 0.000 claims description 41
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 34
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 32
- 229910052731 fluorine Inorganic materials 0.000 claims description 30
- 239000000460 chlorine Substances 0.000 claims description 29
- 229910052801 chlorine Inorganic materials 0.000 claims description 28
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 27
- 239000011737 fluorine Substances 0.000 claims description 27
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 26
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 26
- 229910052794 bromium Inorganic materials 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 13
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 230000035755 proliferation Effects 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
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- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 7
- YQYLTIJEONNPMZ-UHFFFAOYSA-N [8-(benzenesulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone Chemical compound C1(=CC=CC=C1)S(=O)(=O)N1C2CN(CC1CC2)C(=O)C=1N=NNC=1 YQYLTIJEONNPMZ-UHFFFAOYSA-N 0.000 claims description 6
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- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 5
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- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 5
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- 206010013935 Dysmenorrhoea Diseases 0.000 claims description 4
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- 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 4
- 206010022489 Insulin Resistance Diseases 0.000 claims description 4
- MQFQQVWKRIYYPY-UHFFFAOYSA-N [8-(3-fluorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2H-triazol-4-yl)methanone Chemical compound FC=1C=C(C=CC=1)S(=O)(=O)N1C2CN(CC1CC2)C(=O)C1=CN=NN1 MQFQQVWKRIYYPY-UHFFFAOYSA-N 0.000 claims description 4
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- BVTHZYXIKYGYLN-UHFFFAOYSA-M FC=1C=C(C=C(C=1)F)S(=O)(=O)N1C2CN(CC1CC2)C(=O)C1=CN=N[N-]1.[Na+] Chemical compound FC=1C=C(C=C(C=1)F)S(=O)(=O)N1C2CN(CC1CC2)C(=O)C1=CN=N[N-]1.[Na+] BVTHZYXIKYGYLN-UHFFFAOYSA-M 0.000 claims description 3
- AQTRNKKNXJRNOL-UHFFFAOYSA-M FC=1C=C(C=CC=1)S(=O)(=O)N1C2CN(CC1CC2)C(=O)C1=CN=N[N-]1.[Na+] Chemical compound FC=1C=C(C=CC=1)S(=O)(=O)N1C2CN(CC1CC2)C(=O)C1=CN=N[N-]1.[Na+] AQTRNKKNXJRNOL-UHFFFAOYSA-M 0.000 claims description 3
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- 201000001421 hyperglycemia Diseases 0.000 claims description 3
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 3
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 3
- YARRHIGXCLWSRH-UHFFFAOYSA-N 2H-triazol-4-yl-[8-[2-(trifluoromethyl)phenyl]sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone Chemical compound N1N=NC(=C1)C(=O)N1CC2CCC(C1)N2S(=O)(=O)C1=C(C=CC=C1)C(F)(F)F YARRHIGXCLWSRH-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001506 1,2,3-triazol-5-yl group Chemical group [H]N1N=NC([H])=C1[*] 0.000 claims 6
- MOLKLIYWXFEEJM-UHFFFAOYSA-N 2h-triazole-4-carbaldehyde Chemical compound O=CC1=CNN=N1 MOLKLIYWXFEEJM-UHFFFAOYSA-N 0.000 claims 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical class O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims 1
- WOHBWFGDHOGFOI-UHFFFAOYSA-N 2-[[3-(2H-triazole-4-carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]sulfonyl]benzonitrile Chemical compound N1N=NC=C1C(=O)N1CC2CCC(C1)N2S(=O)(=O)C1=C(C#N)C=CC=C1 WOHBWFGDHOGFOI-UHFFFAOYSA-N 0.000 claims 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims 1
- FIBWCFZCCSZZQR-UHFFFAOYSA-N 2-chloro-6-[[3-(2H-triazole-4-carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]sulfonyl]benzonitrile Chemical compound ClC1=C(C#N)C(=CC=C1)S(=O)(=O)N1C2CN(CC1CC2)C(=O)C1=CN=NN1 FIBWCFZCCSZZQR-UHFFFAOYSA-N 0.000 claims 1
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- PCOGWTXZURKYQZ-UHFFFAOYSA-N 2-fluoro-5-[[3-(2H-triazole-4-carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]sulfonyl]benzonitrile Chemical compound FC1=C(C#N)C=C(C=C1)S(=O)(=O)N1C2CN(CC1CC2)C(=O)C1=CN=NN1 PCOGWTXZURKYQZ-UHFFFAOYSA-N 0.000 claims 1
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- YKZPBMRYQLDJPQ-UHFFFAOYSA-N 2H-triazol-4-yl-[8-(2,3,4-trifluorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone Chemical compound N1N=NC=C1C(=O)N1CC2CCC(C1)N2S(=O)(=O)C1=C(C(=C(C=C1)F)F)F YKZPBMRYQLDJPQ-UHFFFAOYSA-N 0.000 claims 1
- AKJAFQMNBPJOOG-UHFFFAOYSA-N 2H-triazol-4-yl-[8-(2,4,5-trifluorophenyl)sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone Chemical compound N1N=NC=C1C(=O)N1CC2CCC(C1)N2S(=O)(=O)C1=C(C=C(C(=C1)F)F)F AKJAFQMNBPJOOG-UHFFFAOYSA-N 0.000 claims 1
- NYBSTWRLGFLVNF-UHFFFAOYSA-N 2H-triazol-4-yl-[8-[2-(trifluoromethoxy)phenyl]sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone Chemical compound N1N=NC=C1C(=O)N1CC2CCC(C1)N2S(=O)(=O)C1=C(C=CC=C1)OC(F)(F)F NYBSTWRLGFLVNF-UHFFFAOYSA-N 0.000 claims 1
- RWFVCRBQOQHUSJ-UHFFFAOYSA-N 2H-triazol-4-yl-[8-[3-(trifluoromethoxy)phenyl]sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone Chemical compound N1N=NC=C1C(=O)N1CC2CCC(C1)N2S(=O)(=O)C1=CC(=CC=C1)OC(F)(F)F RWFVCRBQOQHUSJ-UHFFFAOYSA-N 0.000 claims 1
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- NLMZXRDJTPGYSL-UHFFFAOYSA-N 2H-triazol-4-yl-[8-[4-(trifluoromethyl)phenyl]sulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone Chemical compound N1N=NC=C1C(=O)N1CC2CCC(C1)N2S(=O)(=O)C1=CC=C(C=C1)C(F)(F)F NLMZXRDJTPGYSL-UHFFFAOYSA-N 0.000 claims 1
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Abstract
本发明涉及通式(I)的[8‑(苯基磺酰基)‑3,8‑二氮杂双环[3.2.1]辛‑3‑基](1H‑1,2,3‑三唑‑4‑基)甲酮化合物，其中R1、R2、R3、R4和R5如本文中所定义；制备所述化合物的方法，用于制备所述化合物的中间体化合物，包含所述化合物的药物组合物和结合物以及所述化合物作为单独药剂或与其他活性成分结合来制备药物组合物的用途，所述药物组合物用于治疗或预防疾病，特别是妇科疾病、增生性疾病、代谢性疾病或炎性疾病。
Description
本申请是题为“[8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-4-基)甲酮”的第201780032131.X号发明专利申请的分案申请。原申请对应国际申请PCT/EP2017/062359，申请日为2017年5月23日，优先权日为2016年5月26日。
本发明涉及如本文所述及定义的通式(I)的[8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-4-基)甲酮化合物，制备所述化合物的方法，用于制备所述化合物的中间体化合物，包含所述化合物的药物组合物和结合物以及涉及所述化合物用于制备药物组合物的用途，所述药物组合物用于治疗或预防疾病，特别是哺乳动物中的疾病，例如但不限于妇科疾病、过度增殖性疾病、代谢性疾病或炎性疾病。
背景技术
本发明涉及通式(I)的[8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-4-基)甲酮化合物，其抑制AKR1C3的酶活性。
醛酮还原酶家族1成员C3(AKR1C3，也称为类型5 17-β-羟基类固醇脱氢酶(17-β-HSD5))为酶的醛酮还原酶(AKR)超家族的成员，其将类固醇激素中的醛/酮基团还原成相应的醇，因此在雄激素、孕酮和雌激素代谢/活化/失活中起重要作用。
AKR1C3具有3α-HSD(羟基类固醇脱氢酶活性)、17β-HSD、20α-HSD和前列腺素(PG)F合酶活性。它催化雌酮(弱雌激素活性)转化为雌二醇(强效雌激素活性)、孕酮(强抗雌激素活性)转化为20-α-羟基孕酮(弱抗雌激素活性)和雄烯二酮转化为睾酮(Labrie等人FrontNeuroendocrinol.2001,22(3):185-212)。此外，AKR1C3催化PGH2转化为PGF2α以及PGD2转化为11β-PGF2，两者都以刺激炎症和增殖被熟知。此外，AKR1C3还被证明可代谢广谱的羰基化合物和异生素，包括临床使用的蒽环类抗生素(Bains等人J.Pharmacol Exp.Ther.2010,335:533-545；Novona等人Toxicol Lett.2008,181:1-6；Hofman等人Toxicology andApplied Pharmacology 2014,278:238-248)。
AKR1C3在若干种病理学病症/疾病中起作用：
子宫内膜异位：子宫内膜异位症是一种慢性的主要是雌激素依赖性的炎性疾病，其特征在于子宫腔外存在子宫内膜组织。子宫内膜异位症的主要症状是慢性骨盆疼痛和不孕症。
雌激素(E2)缺乏是临床证实的概念和子宫内膜异位症药物治疗的潜在主要作用机制。除了全身性雌激素水平外，越来越多的证据表明局部衍生的雌激素有助于子宫内膜异位病变的生长。最近已经描述了子宫内膜异位病变中的高组织内雌激素浓度，表明子宫内膜异位症中的高局部雌激素合成(Huhtinen等人J Clin Endocrinol Metab.2012,97(11):4228–4235)。因此，子宫内膜异位病变中局部E2产生的抑制被认为是治疗子宫内膜异位症的高度有吸引力的作用机制。
AKR1C3在子宫内膜异位病变中强烈表达，并且在卵巢中仅可轻微检测到(Smuc等人Mol Cell Endocrinol.2009,301(1-2):59-64)。在与CYP19A1(芳香酶)的协同作用中，预期AKR1C3是子宫内膜异位病变中局部E2产生的关键酶，产生前雌激素的环境，从而刺激雌激素敏感的子宫内膜异位细胞的增殖。因此，抑制AKR1C3应引起局部组织内E2水平降低，从而减少子宫内膜异位病变的增殖。由于AKR1C3仅在卵巢中略微表达而17βHSD1是主要的卵巢羟基类固醇脱氢酶，因此预计不会对卵巢雌激素的产生产生影响。
AKR1C3也是一种PGF2a合酶，除了子宫内膜异位病变中AKR1C3的上调外，已显示来自腹膜内子宫内膜异位症患者的正位和异位子宫内膜中PGF2a水平显著高于卵巢子宫内膜瘤患者的相似组织中的PGF2a水平(Sinreih等人Chemico-Biological Interactions2015,234:320-331)。期望子宫内膜异位组织中的PGF2a有助于子宫内膜异位症患者的炎症、疼痛和增殖，并且在子宫内膜异位病变中表达的AKR1C3期望有助于子宫内膜异位组织中的高局部PGF2a水平。
通过局部降低子宫内膜异位组织中的E2、睾酮和PGF2a水平，AKR1C3抑制具有减轻子宫内膜异位症患者的增殖、疼痛和炎症的潜力。
多囊性卵巢综合征(PCOS):
PCOS是常见的内分泌疾病，影响最高达10％的育龄妇女。临床上它与无排卵性不育、功能失调性出血、雄激素过高、高胰岛素血症和胰岛素耐受、肥胖和代谢综合征相关(Dunaif等人Endocrine Rev.1997,18:774-800)。雄性激素过高协会已经认识到PCOS的四个主要特征：排卵和月经功能障碍、生化高雄激素血症(hyperandrogenaemia)、临床高雄激素血症(hyperandrogonism)(例如痤疮、多毛症)和多囊卵巢(Azziz等人Clin EndocrinolMetab 2006,91:4237-45)。绝大多数患有PCOS的女性将出现雄激素过多症的临床症状，例如痤疮、多毛症或表现为原发性不孕症或月经过少的无排卵((Legro等人N Engl JMed2014,371:119-129)。患有PCOS的女性易感染葡萄糖耐受不良和代谢综合征(Taponen等人J of Clin Endocrinology and Metabolism 2004,89:2114-2118)，具有心血管疾病的相关危险因素和未来心血管事件可能增加的风险(Mani等人Clin Endocrinol 2013,78:926-934)。
雄激素过多症、多毛症和/或高雄激素血症是该综合征的关键组成，并且对于PCOS的诊断是强制性的(Azziz等人Clin Endocrinol Metab2006,91:4237-45)。虽然血清睾酮是高雄激素血症的生化评估的关键因素，但最近雄烯二酮被认为是PCOS相关的雄激素过高的更可靠的标志物，因为雄烯二酮在PCOS女性中以高浓度循环(Reilly等人J ClinEndocrinol Metab 2014,jc20133399)。
PCOS传统上被认为是卵巢疾病(Franks等人J Steroid Biochem MolecularBiology 1999,69:269-272)。然而，对PCOS中卵巢外和肾上腺外雄激素形成的关注日益突出，突出了脂肪雄激素形成等外周组织的作用(Quinkler等人J of Endocrinology 2004,183:331-342)。
AKR1C3是雄激素活化酶，已知主要将雄烯二酮转化为睾酮。已经记载了PCOS患者的脂肪组织中AKR1C3上调，表明脂肪中的ARK1C3表达显著地有利于PCOS患者中雄烯二酮的雄激素形成。此外还显示脂肪细胞中AKR1C3的表达通过胰岛素显著地增加，表明PCOS中高的胰岛素能通过增加女性皮下脂肪组织中的AKR1C3活性来驱动脂肪雄激素的形成(O′Reilly等人Lancet 2015,385Suppl 1:S16)。
AKR1C3也是一种PGF2a合酶，在过氧化物酶体增殖物激活受体γ(PPARγ)的内源性配体的形成中发挥抑制作用，所述PPARγ是胰岛素致敏药物的靶标(Spiegelman等人Diabetes 1998,47:507-514)。
选择性AKR1C3抑制可能提供一种新的治疗靶点，以减少雄激素负荷和改善PCOS的代谢表型。(O'Reilly M1,等人Lancet.2015 385Suppl 1:S16.；Du等人J Clin EndocrinolMetab.2009,94(7):2594-2601.)
癌症：AKR1C3在许多癌症中过度表达，所述癌症包括那些前列腺癌、乳腺癌、子宫癌、血液、肺癌、脑癌和肾癌，如子宫内膜癌(T.L.Rizner等人,Mol Cell Endocrinol 2006248(1-2),126-135)、肺癌(Q.Lan等人,Carcinogenesis 2004,25(11),2177-2181)、非何杰金氏淋巴瘤(Q.Lan等人,Hum Genet 2007,121(2),161-168)、膀胱癌(J.D.Figueroa,Carcinogenesis 2008,29(10),1955-1962)、慢性粒细胞白血病(J.Birthwistle,MutatRes 2009,662(1-2),67-74)、肾细胞癌(J.T.Azzarello,Int J Clin Exp Pathol 2009,3(2),147-155)、乳腺癌(M.C.Byrns,J Steroid Biochem Mol Biol 2010,118(3),177-187)，而其上调经常与肿瘤侵入性和侵袭性相关(Azzarello等人Int.J.Clin.Exp.Path.2009,3:147-155,Birtwistle等人Mutat.Res.2009,662:67-74；Miller等人Int.J.Clin.Exp.Path.2012,5:278-289)。AKR1C3能够分别将雌酮和孕酮直接还原为17β-雌二醇和20α-羟孕酮，从而增强这种促增殖信号(Smuc和Rizner,Chem BiolInteract.2009,178:228-33)。此外，AKR1C3的前列腺素F合酶活性催化PGH2转化为PGF2α以及PGD2转化为11β-PGF2，已知两者都刺激炎症和增殖。在没有AKR1C3活性的情况下，PGD2(而不是转化为PGF2)自发地脱水并重排以形成抗增殖和抗炎性PGJ2异构体，包括15d-PGJ2。总之，AKR1C3增加增殖性PGF2异构体并减少抗增殖PGJ2产物，因此AKR1C3具有影响激素依赖性和激素非依赖性癌症的潜力。在乳腺癌中，假定AKR1C3的作用可以产生前列腺素F2用(PTGFR)配体，其活化导致癌细胞存活(Yoda T等人,(2015)Mol Cell Endocrinol.15；413:236-247)。
前列腺癌:AKR1C3的表达升高与前列腺癌进展和侵袭性有关(Stanbrough M等人Cancer Res 2006,66:2815–25；Wako K等人J Clin Pathol.2008,61(4):448-54)。在激素依赖性前列腺癌中，AKR1C3将雄烯二酮转化为睾酮，而睾酮又过度活化雄激素受体并促进肿瘤生长(Penning等人Mol Cell Endocrinol.2006,248(1-2):182-91)。
在阉割抗性前列腺癌(CRPC)中，AKR1C3参与瘤内雄激素生物合成-它促进弱雄激素雄烯二酮(A'二酮)和5α-雄甾烷二酮(5α-二酮)分别转化为更活化的雄激素睾酮和DHT(Liu等人Cancer Res.2015,75(7):1413-22；Fung等人Endocr Relat Cancer 2006,13(1),169-180)。重要地是，与原发性前列腺癌相比，CRPC患者的AKR1C3表达增加(Stanbrough等人Cancer Res 2006,66:2815–2825；Hamid等人Mol Med 2012,18:1449–1455；Pfeiffer等人Mol Med 2011,17:657–664)。编码AKR1C3的AKR1C3基因的遗传多态性也被证明是前列腺癌的独立预测因子(Yu等人PLoS One 2013,8(1):e54627)。此外，AKR1C3依赖性重新雄激素合成被认为是抗CYP17A1抑制剂(如阿比特龙)的潜在机制(Mostaghel等人Clin CancerRes 2011,17:5913–5925；Cai等人Cancer Res 2011,71:6503–6513)。因此，在患有CRPC的患者中，AKR1C3可能是有希望的治疗试剂(Adeniji等人J Steroid Biochem Mol Biol2013,137:136-149)。在多中心I/II期研究中，在患有转移性阉割抗性前列腺癌的患者中测试了AKR1C3抑制剂。然而，新型雄激素生物合成抑制剂未显示临床活性的相关证据(Loriot等人Invest New Drugs 2014,32:995–1004)。最近的数据表明CRPC中AKR1C3活化是与抗雄激素(恩杂鲁胺)抗性相关的关键抗性机制。可以证明，与亲本细胞相比，雄激素前体如胆固醇、DHEA和孕酮以及雄激素在恩杂鲁胺抗性前列腺癌细胞中高度上调。数据表明在患有恩杂鲁胺抗性CRPC的患者中抑制AKR1C3途径可以用作恩杂鲁胺致敏治疗并且恢复功效(Liu等人Cancer Res.2015,75(7):1413-22)。据推测，与AKR1C3抑制剂共同治疗将克服恩杂鲁胺抗性并改善晚期前列腺癌患者的生存(Thoma等人Nature Reviews Urology 2015,12:124)。
蒽环类抗生素抗性癌症：蒽环类抗生素(或蒽环类抗菌素)是一类用于癌症化疗的药物，来自链霉菌属细菌波塞链霉菌表灰变种(Streptomyces peucetius var.caesius)(Fujiwara等人Critical Reviews in Biotechnology 1985,3(2):133)。这些化合物用于治疗许多癌症，包括白血病、淋巴瘤、乳腺癌、胃癌、子宫癌、卵巢癌、膀胱癌和肺癌。蒽环类抗生素是有史以来最有效的抗癌治疗方法之一。然而，蒽环类抗生素治疗癌症的临床成功因抗药性而黯然失色。人们普遍接受，将蒽环类抗生素酶还原为其效力较低的次级C13-羟基代谢物的提高构成了引起肿瘤中蒽环类抗生素抗性的机制之一(Gavelova等人,2008Chem.Biol.Interact 176,9-18；Heibein等人2012BMC Cancer 12,381)。酶促代谢，特别是阿霉素的酶促代谢是阿霉素化疗后观察到的心肌病的原因。显示AKR1C3涉及临床施用的蒽环霉素如阿霉素和柔红霉素的代谢(Novotna等，Toxicol.Letter 2008,181：1-6)。
在2012年，亚洲乳腺癌患者示出了AKR1C3基因变异与阿霉素药效学的相关性：一种遗传变异与基于阿霉素的治疗后较长的无进展生存期和总生存期相关，提示可能与阿霉素代谢相互作用(Voon等人British J of Clin Pharmacology 2012,75:1497-1505)。
最近可以证明AKR1C3有助于癌细胞对蒽环类抗生素治疗的抵抗力，因此同时给予特定的AKR1C3抑制剂和蒽环类抗生素可能是成功预防和治疗蒽环类抗生素抗性肿瘤的有效策略(Hofman等人Toxicology and Applied Pharmacology 2014,278:238–248)。
特应性皮炎:用抗原攻击特应性受试者导致PGD2和组胺的释放，表明PGD2对人皮肤的即时过敏反应几乎没有起作用，并且PGD2是特应性皮炎(AD)中促进皮肤炎症的脂质介质(Barr等人,Br JPharmacol.1988,94:773–80；Satoh等人J Immunol.2006,177:2621–9.；Shimura等人Am J Pathol.2010；176:227–37)。PGD2是相对不稳定的促炎性介质，其自发地转化为有效的抗炎介质15d-PGJ2。通过AKR1C3将PGD2代谢为促炎性9α,11β-PGF2来转移该转化(Mantel等人Exp Dermatol.2016,25(1):38-43)。
已经证明AKR1C3在人AD样品中上调，并且已经假定AKR1C3在介导皮肤病理学，特别是特应性皮炎中和瘢瘤中的炎症的作用(Mantel等人J Invest Dermatol.2012,132(4):1103-1110)Mantel等人Exp Dermatol.2016,25(1):38-43)。AKR1C3抑制可能是治疗AD和瘢瘤瘢的新选择。
炎症:AKR1C3参与前列腺素生物合成，催化PGH2转化为PGF2腺以及PGD2转化为11β-PGF2。据推测，AKR1C3的表达和上调通过直接引起9α,11β-PGF2合成率的增加和转移有效的抗炎介质15d-PGJ2的自发产生来忍耐炎症(Mantel等人J Invest Dermatol 2012,132(4):1103-1110)。AKR1C3的这种功能也涉及HL-60细胞(Desmond等人Cancer Res 2003,63:505-512)和MCF-7细胞(Byrns等人J Steroid Biochem Mol Biol 2010,118:177-187)。假定抑制AKR1C3增加15d-PGJ2，所述15d-PGJ2为一种抗炎脂质，其主要通过激活过氧化物酶体增殖物激活的受体γ(PPAR-γ)和/或抑制免疫细胞中的NF-κB信号传导来直接介导其作用(Maggi等人Diabetes 2000,49:346-355；Scher等人Clinical Immunology 2005,114:100-109)。先前的数据表明，PPAR-据活化减弱了小鼠皮肤和肺中过敏原诱导的炎症(Ward等人Carcinogenesis.2006,27(5):1074-80；Dahten等人J Invest Dermatol.2008,128(9):2211-8)。这表明AKR1C3抑制在抑制炎症中的作用。
其他疾病另外，AKR1C3抑制剂有潜力用于治疗前列腺增生(Roberts等人,Prostate 2006,66(4),392-404)、脱发(L.Colombe等人,Exp Dermatol 2007,16(9),762-769)、肥胖(P.A.Svensson等人,Cell Mol Biol Lett 2008,13(4),599-613)、过早性成熟(C.He,Hum Genet 2010,128(5),515-527)和慢性阻塞性肺病(S.Pierrou,Am J RespirCrit Care2007,175(6),577-586)。
AKR1C3的抑制剂记载于现有技术中：Flanagan等人Bioorganic&MedicinalChemistry 2014,22:967-977；Jamieson等人Journal of Medicinal Chemistry 2012,55:7746-7758；WO 2013/059245；WO 2013/142390；WO 2014/039820；WO 2013/045407；WO2014/128108和WO 2014/009274。
Heinrich等人European Journal of Medicinal Chemistry 2013,62:738-744涉及作为AKR1C3抑制剂的1-(4-(哌啶-1-基磺酰基)苯基)吡咯烷-2-酮。
WO 2007/111921(Amgen)涉及1-苯基磺酰基-二氮杂环酰胺化合物及其在治疗对羟基类固醇脱氢酶(HSD)调节有响应的病况或病症的方法中的用途，主要用于治疗糖尿病或肥胖症。在其他疾病中还具体提到了子宫内膜异位症。明确公开了11βHSD1、11βHSD2和17βHSD3。示出所公开的实施例抑制11βHSD1，其中IC50范围为<1nM-1000nM。然而，没有公开抑制或调节AKR1C3或其他HSD的酶活性。WO 2007/111921尤其涉及哌嗪化合物，例如表1的化合物编号4。然而，在WO 2007/111921中没有公开在2位和6位之间具有乙烯桥的哌嗪。
WO 2007/103456(Trimeris)涉及哌嗪衍生物和使用其治疗HIV感染和AIDS的方法。
WO 2008/024284(Merck)涉及磺酰化的哌嗪作为大麻素-1受体调节剂。
然而，现有技术没有记载本文中所描述和定义的本发明的通式(I)的[8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-4-基)甲酮化合物。
现已发现，本发明化合物具有令人惊讶和有利的性质，这构成了本发明的基础。
特别地，令人惊讶地发现本发明的化合物有效抑制AKR1C3，其中数据在生物实验部分中给出，因此可用于治疗或预防AKR1C3相关病症，例如妇科病症，特别是子宫内膜异位症相关的和多囊性卵巢综合征相关的妇科病症、病况和疾病，代谢病症，过度增殖性病症、病况和疾病以及炎症病症。
根据第一方面，本发明涉及通式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐或者它们的混合物:
其中：
R1表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或氰基；
R2表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基、氰基或SF5；
R3表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或羟基；
R4表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基、氰基或SF5；
R5表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或氰基；
其中R1和R2或R2和R3任选地以以下方式彼此连接：它们共同形成亚甲二氧基、亚乙二氧基、亚乙基氧基、三亚甲基氧基或选自以下的基团：
定义
当在本说明书中使用时，术语“包含”包括“由……组成(consisting of)”。
如果在本文中，任何术语被称为“如本文所述”，则意味着它可以在本文中的任何地方提及。
本文中提到的术语具有以下含义：
术语“卤素原子”意指氟、氯、溴或碘原子，特别是氟、氯或溴原子。
术语“C1-C3-烷基”意指具有1、2或3个碳原子的直链或支化的饱和的单价烃基，例如甲基、乙基、丙基、异丙基,例如甲基、乙基、正丙基或异丙基。
术语“C1-C3-卤代烷基”意指直链或支化的饱和的单价烃基，其中术语“C1-C3-烷基”如上所定义，并且其中一个或多个氢原子被相同或不同的卤素原子取代。特别地，所述卤素原子为氟原子。所述C1-C3-卤代烷基为例如,氟甲基、二氟甲基、三氟甲基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、五氟乙基、3,3,3-三氟丙基或1,3-二氟丙-2-基。
术语“C1-C3-烷氧基”意指式(C1-C3-烷基)-O-的直链或支化的饱和的单价基团，其中术语“C1-C3-烷基”如上所定义，例如甲氧基、乙氧基、正丙氧基或异丙氧基。
术语“C1-C3-卤代烷氧基”意指直链或支化的饱和的单价C1-C3-烷氧基，如上所定义，其中一个或多个氢原子被相同或不同的卤素原子取代。特别地，所述卤素原子为氟原子。所述C1-C3-卤代烷氧基为例如,氟甲氧基、二氟甲氧基或三氟甲氧基。
如本文中所使用，例如在“C1-C3-烷基”、“C1-C3-卤代烷基”、“C1-C3-烷氧基”或“C1-C3-卤代烷氧基”的定义的文中，术语“C1-C3”意指具有1至3个有限数量的碳原子，即1、2或3个碳原子的烷基。
当给出值的范围时，所述范围包括所述范围内的每个值和子范围。
例如:
"C1-C3"包括C1、C2、C3、C1-C3、C1-C2和C2-C3。
如本文中所用，术语“离去基团”意指在化学反应中作为其中带有键合电子的稳定形式被取代的原子或原子的基团。特别地，这种离去基团选自：卤化物，特别是氟化物、氯化物、溴化物或碘化物，(甲基磺酰基)氧基，[(三氟甲基)磺酰基]氧基，[(九氟丁基)磺酰基]氧基，(苯基磺酰基)氧基，[(4-甲基苯基)磺酰基]氧基，[(4-溴苯基)磺酰基]氧基，[(4-硝基苯基)磺酰基]氧基，[(2-硝基苯基)磺酰基]氧基，[(4-异丙基苯基)磺酰基]氧基，[(2,4,6-三异丙基苯基)磺酰基]氧基，[(2,4,6-三甲基苯基)磺酰基]氧基，[(4-叔丁基苯基)磺酰基]氧基和[(4-甲氧基苯基)磺酰基]氧基。
通式(I)的化合物可以作为同位素变体存在。因此，本发明包括通式(I)的化合物的一种或多种同位素变体，特别是通式(I)的含氘化合物。
术语化合物或试剂的“同位素变体”定义为表现出非天然比例的一种或多种构成这类化合物的同位素的化合物。
术语“通式(I)的化合物的同位素变体”定义为通式(I)的化合物，其表现出非天然比例的一种或多种构成这类化合物的同位素。
表述“非天然比例”意指这类同位素的比例高于其天然丰度。在本文中待应用的同位素的天然丰度记载于“Isotopic Compositions of the Elements 1997”,PureAppl.Chem.,70(1),217-235,1998。
这类同位素的实施例包括以下元素的稳定和放射性同位素：氢、碳、氮、氧、磷、硫、氟、氯、溴和碘，例如分别为2H(氘)、3H(氚)、11C、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I。
关于本文所述病症的治疗和/或预防，通式(I)化合物的同位素变体优选含有氘(“通式(I)的含氘化合物”)。其中结合一种或多种放射性同位素如3H或14C的通式(I)的化合物的同位素变体可用于药物和/或底物组织分布研究中。特别优选这些同位素，因为它们易于结合和检测。正电子发射同位素如18F或11C可掺入通式(I)的化合物中。通式(I)的化合物的这些同位素变体可用于体内成像应用。含氘和含13C的通式(I)的化合物可用于临床前或临床研究中的质谱分析。
通式(I)的化合物的同位素变体通常可以通过本领域技术人员已知的方法制备，例如本文的方案和/或实施例中描述的方法，通过将试剂取代为所述试剂的同位素变体，优选为含氘试剂。在某些情况下，根据所需的氘化位点，来自D2O的氘可直接掺入化合物中或掺入可用于合成这些化合物的试剂中。氘气也是将氘掺入分子中的有用试剂。烯键和炔键的催化氘化是掺入氘的快速途径。在氘气存在下的金属催化剂(即Pd、Pt和Rh)可用于在含有烃的官能团中直接将氘交换氢。各种氘代试剂和合成结构单元可从如下公司商购获得，例如C/D/N Isotopes,Quebec,Canada；Cambridge Isotope Laboratories Inc.,Andover,MA,USA以及CombiPhos Catalysts,Inc.,Princeton,NJ,USA。
术语“通式(I)的含氘化合物”定义为通式(I)的化合物，其中一个或多个氢原子被一个或多个氘原子取代，并且其中通式(I)的化合物的每个氘代位置的氘的丰度高于氘的天然丰度(约为0.015％)。特别地，在通式(I)的含氘化合物中，通式(I)的化合物的每个氘代位置处的氘的丰度高于10％、20％、30％、40％、50％、60％、70％或80％，优选高于90％、95％、96％或97％，甚至更优选在所述位置处高于98％或99％。可以理解，每个氘化位置的氘丰度与其他氘化位置的氘丰度无关。
一个或多个氘原子选择性掺入通式(I)的化合物可以改变分子的物理化学性质(例如酸性(C.L.Perrin,等人,J.Am.Chem.Soc.,2007,129,4490)、碱性(C.L.Perrin等人,J.Am.Chem.Soc.,2005,127,9641)、亲油性(B.Testa等人,Int.J.Pharm.,1984,19(3),271))和/或代谢谱(metabolic profile)，并可导致母体化合物与代谢物的比例或形成的代谢物的量的改变。这些改变可能引起某些治疗优势，因此在某些情况下可能是优选的。报道了在代谢物比例发生变化时，代谢速率和代谢转化降低(A.E.Mutlib等人,Toxicol.Appl.Pharmacol.,2000,169,102)。母体药物和代谢物暴露的这些变化对于通式(I)的含氘化合物的药效学、耐受性和功效可能具有重要的后果。在某些情况下，氘取代减少或消除了不希望的或有毒的代谢物的形成，并提高了所需代谢物的形成(例如Nevirapine:A.M.Sharma等人,Chem.Res.Toxicol.,2013,26,410；Efavirenz:A.E.Mutlib等人,Toxicol.Appl.Pharmacol.,2000,169,102)。在其他情况下，氘化的主要作用是降低全身清除速率。因此，化合物的生物半衰期增加。潜在的临床益处包括用降低的峰值水平和提高的谷值水平维持类似的全身暴露的能力。这可能导致较低的副作用和增强的功效，这取决于特定化合物的药代动力学/药效学关系。ML-337(C.J.Wenthur等人,J.Med.Chem.,2013,56,5208)和Odanacatib(K.Kassahun等人,WO2012/112363)为该氘效果的实施例。还报道了其他情况，其中降低的代谢速率导致药物暴露增加而不改变全身清除速率(例如Rofecoxib:F.Schneider等人,Arzneim.Forsch./Drug.Res.,2006,56,295；Telaprevir:F.Maltais等人,J.Med.Chem.,2009,52,7993)。示出该功效的氘化药物可降低剂量需求(例如更低的给药数量或更低的剂量以实现期望的效果)和/或可产生更低的代谢物负荷。
通式(I)的化合物可具有多个潜在的代谢攻击位点。为了优化上述对物理化学性质和代谢谱的影响，可以选择具有一种或多种氘-氢交换的特定模式的通式(I)的含氘化合物。特别地，通式(I)的含氘化合物的氘原子与碳原子连接和/或位于通式(I)的化合物的那些位置，所述位置为代谢酶的攻击位点，例如细胞色素P450。
当本文使用复数形式的化合物、盐、多晶型物、水合物、溶剂化物等时，这也意指单一化合物、盐、多晶型物、异构体、水合物、溶剂化物等。
“稳定化合物”或“稳定结构”是指足够稳定以从反应混合物中分离至有用纯度并配制成有效治疗剂的化合物。
此外，本发明的化合物可以互变异构体存在。例如，任何含有1,2,3-三唑部分的本发明的化合物均可作为1H互变异构体或3H互变异构体存在，或甚至作为任何量的两种互变异构体的混合物存在，即：
本发明包括本发明的化合物的所有可能的互变异构体，作为单一互变异构体或任何比例的所述互变异构体的任何混合物。
此外，本发明的化合物可以N-氧化物存在，其定义为本发明的化合物的至少一个氮被氧化。本发明包括所有这些可能的N-氧化物。
本发明还包括本发明的化合物的有用形式，例如代谢物、水合物、溶剂化物、前药、盐(特别是药学上可接受的盐)和/或共沉淀物。
本发明化合物可以水合物或溶剂化物形式存在，其中本发明的化合物含有作为化合物晶格的结构元素的极性溶剂，特别是水、甲醇或乙醇。极性溶剂，特别是水的量可以化学计量比或非化学计量比存在。在化学计量的溶剂化物如水合物的情况下，分别可能是半-、(半-)、单-、倍半-、二-、三-、四-、五-等溶剂化物或水合物。本发明包括所有这类水合物或溶剂化物。
此外，本发明的化合物可以游离形式存在，例如作为游离碱或作为游离酸或作为两性离子，或以盐的形式存在。所述盐可以是任何盐，有机或无机加成盐，特别是任何药学上可接受的有机或无机加成盐，其通常用于制药中或者用于例如分离或纯化本发明化合物。
术语“药学上可接受的盐”是指本发明的化合物的无机或有机酸加成盐，例如参见S.M.Berge等人J.Pharm.Sci.1977,66:1-19。
本发明的化合物的合适的药学上可接受的盐可为，例如，具有足够的碱性的在链或环中带有氮原子的本发明的化合物的酸加成盐，例如，与无机酸(inorganic acid)或“矿物酸(mineral acid)”或与有机酸的酸加成盐，所述无机酸例如为盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、二元硫酸、磷酸或硝酸；所述有机酸例如为甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡萄糖酸、3-羟基-2-萘甲酸、烟碱酸、双羟萘酸、果胶酯酸、3-苯基丙酸、特戊酸、2-羟基乙磺酸、衣康酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、海藻酸、马来酸、富马酸、D-葡萄糖酸、扁桃酸、抗坏血酸、葡庚糖、甘油磷酸、天冬氨酸、磺基水杨酸或硫氰酸。
另外，具有足够的酸性的本发明的化合物的另一种合适的药学上可接受的盐为碱金属盐，例如钠盐或钾盐；碱土金属盐，例如钙盐、镁盐或锶盐；或铝或锌盐；或衍生自氨或衍生自具有1至20个碳原子的有机伯胺、仲胺或叔胺的铵盐，例如乙胺、二乙胺、三乙胺、乙基二异丙基胺、单乙醇胺、二乙醇胺、三乙醇胺、二环己胺、二甲基氨基乙醇、二乙基氨基乙醇、三(羟基甲基)氨基甲烷、普鲁卡因、二苄胺、N-甲基吗啉、精氨酸、赖氨酸、1,2-乙二胺、N-甲基哌啶、N-甲基-葡萄糖胺、N,N-二甲基-葡萄糖胺、N-乙基葡糖胺、1,6-己二胺、葡萄糖胺、肌氨酸、丝氨醇、2-氨基-1,3-丙二醇、3-氨基-1,2-丙二醇、4-氨基-1,2,3-丁三醇，或含有1至20个碳原子的季铵离子的盐，例如四甲基铵、四乙基铵、四(正丙基)铵、四(正丁基)铵、N-苄基-N,N,N-三甲基铵、胆碱或苯扎氯铵。
本领域技术人员将进一步认识到，要求保护的化合物的酸加成盐可以通过利用许多已知方法中的任何一种使化合物与适当的无机或有机酸反应来制备。或者，本发明的酸性化合物的碱金属和碱土金属盐通过利用各种已知方法使本发明的化合物与适当的碱反应来制备。
本发明包括本发明的化合物的所有可能的盐，为单一盐或任何比例的所述盐的任何混合物。
在本文中，特别是在实验部分中，对于合成中间体和本发明的实施例，当作为通过各自的制备和/或纯化方法获得的与相应的碱或酸的盐形式提及化合物时，在大多数情况下，所述盐形式的精确化学计量组成是未知的。
除非另有说明，否则与盐有关的化学名称或结构式的后缀，例如“盐酸盐”、“三氟乙酸盐”、“钠盐”或“xHCl”、“xCF3COOH”、“x Na+”，意指盐形式，其盐形式的化学计量未指定。
这类似地适用于其中通过所述制备和/或纯化方法获得的作为溶剂化物(例如水合物)的合成中间体或实施例化合物或其盐的情况，其具有(如果定义的话)未知的化学计量组成。
另外，本发明包括本发明的化合物的所有可能的结晶形式或多晶型物，可以是单一多晶型物或任何比例的多于一种多晶型物的混合物。
此外，本发明还包括本发明的化合物的前药。本文中术语“前药”表示化合物，其本身可以是生物活性的或无活性的，但在它们在体内的停留时间内转化(例如代谢或水解)为本发明的化合物。
根据第一方面的第二个实施方案，本发明涉及上述通式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R1表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或氰基；
R2表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基、氰基或SF5；
R3表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或羟基；
R4表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基、氰基或SF5；
R5表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或氰基。
根据第一方面的第三个实施方案，本发明涉及上述通式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R1表示氢、氟、氯、溴、甲基、三氟甲基、甲氧基、三氟甲氧基或氰基；
R2表示氢、氟、氯、溴、甲基、三氟甲基、甲氧基、三氟甲氧基、氰基或SF5；
R3表示氢；
R4表示氢、氟、氯、溴、甲基、三氟甲基、甲氧基、三氟甲氧基、氰基或SF5；
R5表示氢、氟、氯、溴、甲基、三氟甲基、甲氧基、三氟甲氧基或氰基。
根据第一方面的第四个实施方案,本发明涉及上述通式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R1表示氢、氟、氯、溴、甲基或三氟甲基；
R2表示氢、氟、氯、溴、甲基、三氟甲基或SF5；
R3表示氢；
R4表示氢、氟、氯、溴、甲基、三氟甲基或SF5；
R5表示氢、氟、氯、溴、甲基或三氟甲基。
本发明的第一方面的其他实施方案：
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R1表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或氰基。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R1表示氢、氟、氯、溴、甲基、三氟甲基、甲氧基、三氟甲氧基或氰基。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R1表示氢、氟、氯、溴、甲基或三氟甲基。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R2表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基、氰基或SF5。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R2表示氢、氟、氯、溴、甲基、三氟甲基、甲氧基、三氟甲氧基,氰基或SF5。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R2表示氢、氟、氯、溴、甲基、三氟甲基或SF5。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R3表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或羟基。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R3表示氢。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R4表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基、氰基或SF5。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R4表示氢、氟、氯、溴、甲基、三氟甲基、甲氧基、三氟甲氧基、氰基或SF5。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R4表示氢、氟、氯、溴、甲基、三氟甲基或SF5。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R5表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或氰基。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R5表示氢、氟、氯、溴、甲基、三氟甲基、甲氧基、三氟甲氧基或氰基。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R5表示氢、氟、氯、溴、甲基或三氟甲基。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R1和R2或R2和R3以以下方式彼此连接：它们共同形成亚甲二氧基、亚乙二氧基、亚乙基氧基、三亚甲基氧基或
选自以下的基团：
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R1和R2或R2和R3以以下方式彼此连接：它们共同形成亚甲二氧基、亚乙二氧基、亚乙基氧基或三亚甲基氧基。
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R1和R2或R2和R3以以下方式彼此连接：它们共同形成选自以下的基团：
在第一方面的另一个实施方案中，本发明涉及上述式(I)的化合物及其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐以及它们的混合物，其中：
R1和R2或R2和R3以以下方式彼此连接：它们共同形成选自以下的基团：
在第一方面的另一个实施方案中，本发明涉及选自以下的化合物：
在第一方面的特定的另一个实施方案中，本发明在标题“本发明的第一方面的其他实施方案”下涉及两个或更多个上述实施方案的组合。
本发明包括在上述通式(I)的化合物的本发明任何实施方案或方面内的任何子组合。
本发明包括在通式(IV)或(VIII)的中间体化合物的本发明的任何实施方案或方面内的任何子组合。本发明包括下述本文的实施例部分中公开的通式(I)的化合物。
本发明的通式(I)的化合物可根据以下方案1制备。以下所述的方案和步骤阐明本发明的通式(I)的化合物的合成途径，而并不是限定性的。本领域技术人员清楚的是，可以各种方式修改方案1中示例的转化顺序。因此，该方案中举例说明的转化顺序不是限制性的。另外，任何取代基、R1、R2、R3、R4或R5的相互转化可在示例性转化之前和/或之后实现。这些修饰可以是本领域技术人员已知的例如保护基团的引入、保护基团的裂解、官能团的还原或氧化、卤化、金属化、取代或形成和醚的裂解。这些转化包括引入允许取代基进一步相互转化的官能团的那些转化。适当的保护基团及其引入和裂解是本领域技术人员公知的(参见例如T.W.Greene和P.G.M.Wuts的Protective Groups in Organic Synthesis,第3版,Wiley 1999)。具体的实施例记载于后续段落中。
制备通式(I)的化合物的两条途径记载于方案1中。
方案1：制备通式(I)的化合物的途径，其中R1、R2、R3、R4和R5具有对于上述通式(I)给出的含义。
方法1中列出的进行合成顺序所需的起始材料，即3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯(式(II))和3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(式(V))是本领域技术人员已知的，并是市售的，例如购自Arkpharminc,Achemblock或ASM chemicals。
通式(I)的化合物可根据方案1由式(II)的3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯组装，所述式(II)的3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯可在合适的溶剂(例如NMP或DCM)中，在室温至溶剂沸点范围内的反应温度下，在合适的碱(例如DIPEA)存在下，与适当的通式(VIII)的磺酰氯反应，以形成通式(III)的Boc保护的磺酰胺中间体。Boc-保护的中间体(III)可以在合适的酸(例如TFA)存在下在合适的溶剂(例如DCM或DCE)中脱保护，或在合适的溶剂(例如二噁烷)中并任选地在清除剂如水的存在下用HCl脱保护，以形成通式(IV)的中间体。通式(IV)的中间体可以通过在合适的偶联剂(例如HATU)存在下在合适的碱(例如DIPEA)存在下在合适的溶剂(例如NMP、DMF、DCM或THF)中，在室温至溶剂的沸点的范围内的反应温度下，与1H-1,2,3-三唑-5-羧酸反应转化为本发明的通式(I)的化合物。
或者，通式(I)的化合物可由3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(式(V))来合成，所述3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(式(V))通过在合适的偶联剂(例如HATU)存在下在合适的碱(例如DIPEA)存在下在合适的溶剂(例如NMP、DMF、DCM或THF)中，在室温至溶剂的沸点的范围内的反应温度下，与1H-1,2,3-三唑-5-羧酸反应以形成中间体(VI)。中间体(VI)的脱保护可以用合适的酸(例如TFA)在合适的溶剂(例如DCM或DCE)中进行，或在合适的溶剂(例如二噁烷)中用HCl进行。通式(VII)的中间体可通过在合适的碱(例如DIPEA)存在下在合适的溶剂(例如NMP或DCM)中，在室温至溶剂的沸点的范围内的反应温度下，与合适的通式(VIII)的磺酰氯反应转化为本发明的通式(I)的化合物。
根据第二方面，本发明涉及制备如上所定义的通式(I)的化合物的方法，所述方法包括使通式(IV)的中间体化合物与式(IX)的化合物反应从而得到通式(I)的化合物的步骤：
其中R1、R2、R3、R4和R5为对于如上所定义的通式(I)的化合物中的定义，
其中R1、R2、R3、R4和R5如上所定义。
根据第三方面，本发明涉及制备如上所定义的通式(I)的化合物的方法，所述方法包括使式(VII)的中间体化合物与通式(VIII)的化合物反应，从而得到通式(I)的化合物的步骤：
其中R1、R2、R3、R4和R5为对于如上所定义的通式(I)的化合物中的定义，
其中R1、R2、R3、R4和R5如上所定义。
本发明涉及制备本发明的通式(I)的化合物的方法，所述方法包括本文中实验部分描述的步骤。
根据第四方面，本发明涉及通式(III)、(IV)或(VII)的化合物
其中R1、R2、R3、R4和R5如对于权利要求1至5中任一项的通式(I)的化合物所定义，其中R1、R2、R3、R4和R5中至少一个不是氢。
根据第五方面，本发明涉及通式(III)、(IV)或(VII)的化合物用于制备权利要求1至5中任一项的通式(I)的化合物的用途
其中R1、R2、R3、R4和R5如对于权利要求1至5中任一项的通式(I)的化合物所定义，其中R1、R2、R3、R4和R5中至少一个不是氢。
本发明涉及下文的实施例部分中所公开的中间体。
如本文中所述，本发明的通式(I)的化合物可通过本领域技术人员已知的任何方法转化为任何盐，优选药学上可接受的盐。类似地，可以通过本领域技术人员已知的任何方法将本发明的通式(I)的化合物的任何盐转化为游离化合物。
适应症
本发明的通式(I)的化合物示出有价值的药理学作用谱，这是无法预测的。令人惊讶地发现本发明化合物可有效抑制AKR1C3。对于所要求保护的结构范围的主要部分，这些物质在体外示出对AKR1C3的强烈抑制(IC50值小于10nM)并且显著地甚至IC50约<1nM。
根据另一方面，本发明涉及上述通式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐(特别是其药学上可接受的盐)或它们的混合物，用于治疗或预防疾病。
本文中所述的术语“治疗(treating)”或“治疗(treatment)”是常规使用的，例如，为了对抗、减轻、减少、缓解、改善疾病或病症的状况等目的，管理或护理受试者；所述疾病或病症例如为妇科疾病、过度增殖性疾病、代谢疾病或炎性疾病。术语“疗法(therapy)”在此理解为与术语“治疗(treatment)”同义。
在本发明的上下文中，术语“防止(prevention)”、“预防(prophylaxis)”或“阻止(preclusion)”同义使用并指避免或减少感染、经受、遭受或患有疾病、病况、病症、损伤或健康问题或所述状态的发育或进展和/或所述状态的症状的风险。
可以部分或完全治疗或预防疾病、病况、病症、损伤或健康问题。
本发明涉及使用上述通式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐(特别是药学上可接受的盐)或它们的化合物来治疗哺乳动物和人的病症和疾病的方法，所述病症和疾病包括但不限于：
·妇科疾病，
·代谢疾病，
·过度增殖性疾病，以及
·炎性疾病。
妇科疾病本身包括任何妇科疾病、病症或病况。术语还包括但不限于，例如子宫内膜异位相关的妇科病症、病况和疾病，多囊卵巢综合征(PCOS)相关的妇科病症、病况和疾病，原发性和继发性痛经，性交困难，过早性成熟，子宫肌瘤，子宫平滑肌瘤和子宫出血性疾病。
子宫内膜异位相关的妇科病症、病况和疾病的实例包括但不限于：子宫内膜异位本身，子宫内膜异位症；子宫内膜异位相关的疼痛；子宫内膜异位相关的症状，其中所述症状特别是痛经、性交困难、排尿困难或大便困难；子宫内膜异位相关的增殖；以及骨盆过敏反应(pelvic hypersensitivity)。
多囊卵巢综合征(PCOS)相关的妇科病症、病况和疾病的实例包括但不限于：多囊卵巢综合征(PCOS)和多囊卵巢相关的症状，其中所述症状特别是PCOS中的高雄激素血症(hyperandrogenimia)、多毛症(hirsutims)、痤疮、脱发、代谢表型，如肥胖、高血糖、葡萄糖耐受不良、胰岛素耐受、高胰岛素血症、高胆固醇血症、高血压、高脂蛋白血症、高脂血症、高甘油三酯血症、血脂异常、代谢综合征II型糖尿病、肥胖。
代谢疾病包括但不限于，例如:高血糖、葡萄糖耐受不良、胰岛素耐受、高胰岛素血症、高胆固醇血症、高血压、高脂蛋白血症、高脂血症、高甘油三酯血症、血脂异常、代谢综合征II型糖尿病和肥胖，其与PCOS无关。
过度增殖性病症、病况和疾病包括但不限于，例如：良性前列腺增生(BPH)、实体瘤，例如乳腺、呼吸道、脑、生殖器官、消化道、泌尿道、眼睛、肝、皮肤、头及颈、甲状腺、甲状旁腺的癌症以及它们的远端转移。那些疾病还包括淋巴瘤、肉瘤和白血病。
乳腺癌的实例包括，但不限于侵入性导管癌、侵入性小叶癌以及原位导管癌和原位小叶癌。
呼吸道癌症的实例包括，但不限于小细胞和非小细胞肺癌，以及支气管腺癌和胸膜肺母细胞瘤。
脑癌的实例包括，但不限于脑干和下丘脑(hypophtalmic)胶质瘤、小脑和大脑的星形细胞瘤、成神经管细胞瘤、室管膜瘤以及神经外胚层和松果体肿瘤。
雄性生殖器官的肿瘤包括，但不限于睾丸癌以及激素依赖性和激素非依赖性前列腺癌，包括阉割抗性前列腺癌。
雌性生殖器官的肿瘤包括，但不限于子宫内膜癌、宫颈癌、卵巢癌、阴道癌和外阴癌以及子宫肉瘤。
消化道的肿瘤包括，但不限于肛门癌、结肠癌、结肠直肠癌、食道癌、胆囊癌、胃癌、胰腺癌、直肠癌、小肠癌和唾液腺癌。
泌尿道的肿瘤包括，但不限于膀胱癌、阴茎癌、肾脏癌、肾盂癌、输尿管癌、尿道癌和人乳头状肾癌。
眼癌包括，但不限于眼内黑素瘤和视网膜母细胞瘤。
肝癌的实例包括，但不限于肝细胞癌(有或没有纤维板层变体的肝细胞癌)、胆管癌(肝内胆管癌)和混合型肝细胞胆管癌。
皮肤癌包括，但不限于鳞状细胞癌、卡波西肉瘤、恶性黑素瘤、Merkel细胞皮肤癌和非黑素瘤性皮肤癌。
头颈癌包括，但不限于喉癌、下咽癌、鼻咽癌、口咽癌、唇癌和口腔癌和鳞状细胞癌。
淋巴瘤包括，但不限于AIDS相关的淋巴瘤、非霍奇金淋巴瘤、皮肤T细胞淋巴瘤、伯基特淋巴瘤、霍奇金病和中枢神经系统的淋巴瘤。
白血病包括，但不限于急性骨髓性白血病、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病、慢性骨髓性白血病和毛细胞白血病。肉瘤包括，但不限于软组织的肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。
炎性疾病包括但不限于，例如：任何炎性疾病、病症或病况本身，具有与其相关的炎性成分的任何病况，和/或以炎症为特征的任何病况，尤其包括急性、慢性、溃疡性、特异性、过敏性、被病原体感染、由于过敏反应引起的免疫反应、进入异物、物理损伤和坏死性炎症，以及本领域技术人员已知的其他形式的炎症。因此，为了本发明的目的，术语还包括炎性痛、一般性疼痛和/或发热。本发明的化合物还可用于治疗纤维肌痛、肌筋膜疾病、病毒感染(例如流感、感冒、带状疱疹、丙型肝炎和AIDS)、细菌感染、真菌感染、外科或牙科手术、恶性肿瘤(例如乳腺癌、结肠癌和前列腺癌)、关节炎、骨关节炎、幼年型关节炎、类风湿性关节炎、幼年型类风湿性关节炎、风湿热、强直性脊柱炎、何杰金病、系统性红斑狼疮、血管炎、胰腺炎、肾炎、滑囊炎、结膜炎、虹膜炎、巩膜炎、葡萄膜炎、伤口愈合、皮炎、湿疹、中风、糖尿病、自身免疫性疾病、过敏性疾病、鼻炎、溃疡、轻度至中度活性溃疡性结肠炎、家族性腺瘤性息肉病、冠心病、结节病、特应性皮炎和瘢痕以及任何其他有炎症成分的疾病。本发明化合物还可具有与炎症机制无关的作用，例如减少受试者的骨损失。在这方面可提及的病况包括骨质疏松症、骨关节炎、佩吉特病和/或牙周病。
优选地，本发明涉及使用上述通式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐(特别是药学上可接受的盐)或它们的混合物来治疗子宫内膜异位症和子宫内膜异位相关的疼痛和症状、多囊卵巢综合征、特应性皮炎、瘢瘤和前列腺癌(包括阉割抗性前列腺癌(CRPC))的方法。
根据另一方面，本发明涉及上述通式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐(特别是药学上可接受的盐)或它们的混合物，用于治疗或预防疾病，特别是妇科疾病、代谢疾病、过度增殖性疾病和炎性疾病。
根据另一方面，本发明涉及上述通式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐(特别是药学上可接受的盐)或它们的混合物用于治疗或预防疾病，特别是妇科疾病、代谢疾病、过度增殖性疾病和炎性疾病的用途。
根据另一方面，本发明涉及上述通式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐(特别是药学上可接受的盐)或它们的混合物在治疗或预防疾病，特别是妇科疾病、代谢疾病、过度增殖性疾病和炎性疾病的方法中的用途。
根据另一方面，本发明涉及上述通式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐(特别是其药学上可接受的盐)或它们的混合物用于制备用于预防或治疗疾病，特别是妇科疾病、代谢疾病、过度增殖性疾病和炎性疾病的药物组合物、优选药剂的用途。
根据另一方面，本发明涉及使用有效量的上述通式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物和盐(特别是药学上可接受的盐)或它们的混合物治疗或预防疾病，特别是妇科疾病、代谢疾病、过度增殖性疾病和炎性疾病的方法。
这些疾病(特别是妇科疾病、代谢疾病、过度增殖性疾病和炎性疾病)不仅已在人类中得到充分表征，而且在其他哺乳动物中也以类似的病因存在，并且可通过施用本发明的药物组合物来治疗。
药物组合物
根据另一方面，本发明涉及药物组合物，特别是药剂，其包含上述通式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物、盐(特别是药学上可接受的盐)或它们的混合物，以及一种或多种赋形剂，特别是一种或多种药学上可接受的赋形剂。可利用制备这类合适的剂量形式的药物组合物的常规方法
本发明还包括一种药物组合物，特别是药剂，其包含至少一种本发明的化合物，通常包含一种或多种惰性的、无毒的、药学上适合的赋形剂；以及提供其用于上述目的的用途。
本发明还提供一种药剂，其包含至少一种本发明的化合物，通常还包含一种或多种惰性的、无毒的、药学上适合的赋形剂，以及提供其用于上述目的的用途。
本发明的化合物可系统地和/或局部地作用。为此，其可以适合的方式给药，例如通过口服、肠胃外、肺、鼻、舌下、舌、口腔、直肠、阴道、真皮、经皮、结膜或耳途径给药，或作为植入物或支架给药。
对于这些给药途径，本发明的化合物可以合适的给药形式进行给药。
本发明的化合物可具有系统的或局部的活性。为此，它们可以适合的方式给药，例如通过口服、肠胃外、肺、鼻、舌下、舌、口腔、直肠、真皮、经皮、结膜、耳途径或作为植入物或支架给药。
对于这些给药途径，本发明的化合物可以合适的给药形式进行给药。
对于口服给药，可将本发明的化合物配制成本领域已知的可将本发明的化合物快速地或以缓和的方式释放的剂型，例如片剂(未包衣或包衣片剂，例如具有延迟溶解或不溶解的肠溶或控释包衣)、口腔中崩解的片剂、薄膜/糯米纸囊剂(wafers)、薄膜/冻干剂、胶囊剂(例如硬或软明胶胶囊剂)、糖衣片剂、颗粒剂、丸剂、粉末剂、乳剂、悬浮剂、气雾剂或溶液剂。可以将本发明的化合物以结晶和/或无定形和/或溶解形式掺入所述剂型中。
肠胃外给药可通过避免吸收步骤(例如通过静脉内、动脉内、心内、脊椎内或腰椎内)或包括吸收(例如通过肌内、皮下、皮内、经皮或腹膜内)而完成。适用于肠胃外给药的给药形式尤其为溶液剂、悬浮剂、乳剂、冻干剂或无菌粉末剂形式的注射和输液用制剂。
适用于其他给药途径的实例为可吸入药物形式(尤其是干粉吸入剂(powderinhalers)、喷雾剂)、滴鼻剂、鼻溶液剂或鼻喷雾剂；用于舌、舌下或口腔给药的片剂/薄膜/糯米纸囊剂/胶囊剂；栓剂；滴眼液、眼药膏、眼部浴液、眼用嵌入剂、滴耳液、耳喷雾剂、点耳粉剂、洗耳液、耳塞；阴道胶囊、水性悬浮液(乳液、搅拌混合物(mixturae agitandae))、亲脂性悬浮剂、乳液、软膏、乳膏、经皮治疗系统(例如贴剂)、乳剂(milk)、糊剂、泡沫剂、撒粉剂(dusting powders)、植入物或支架。
本发明的化合物可转化成所提及的给药形式。这可以本身已知的方式通过与惰性、无毒、药学上适合的赋形剂混合来完成。药学上合适的赋形剂尤其包括
·填充剂和载体(例如纤维素、微晶纤维素(例如，)、乳糖、甘露醇、淀粉、磷酸钙(例如，))，
·软膏基质(例如凡士林、石蜡、甘油三酯、蜡、羊毛蜡、羊毛蜡醇、羊毛脂、亲水性软膏、聚乙二醇)，
·栓剂基质(例如聚乙二醇、可可脂、硬脂)，
·溶剂(例如水、乙醇、异丙醇、甘油、丙二醇、中链长度甘油三酯脂肪油、液体聚乙二醇、石蜡)，
·表面活性剂、乳化剂、分散剂或润湿剂(例如，十二烷基硫酸钠、卵磷脂、磷脂、脂肪醇(例如，)、去水山梨糖醇脂肪酸酯(例如，)、聚氧乙烯去水山梨糖醇脂肪酸酯(例如，)、聚氧乙烯脂肪酸甘油酯(例如，)、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、甘油脂肪酸酯、泊洛沙姆(例如，))；
·缓冲剂以及酸和碱(例如，磷酸盐、碳酸盐、柠檬酸、乙酸、盐酸、氢氧化钠溶液、碳酸铵、氨丁三醇、三乙醇胺)；
·等渗剂(例如，葡萄糖、氯化钠)；
·吸附剂(例如，高分散二氧化硅)；
·增粘剂、凝胶形成剂、增稠剂和/或粘合剂(例如，聚乙烯吡咯烷酮、甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素钠、淀粉、卡波姆、聚丙烯酸(例如，)、海藻酸盐、明胶)；
·崩解剂(例如，改性淀粉、羧甲基纤维素钠、羟基乙酸淀粉钠(例如，)、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠(例如，))；
·流动调节剂、润滑剂、助流剂和脱模剂(例如，硬脂酸镁、硬脂酸、滑石、高分散二氧化硅(例如，))；
·包衣物质(例如，糖、虫胶)和用于以快速或以改性方式溶解的薄膜或扩散膜的成膜剂(例如，聚乙烯吡咯烷酮(例如，)、聚乙烯醇、羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、醋酸纤维素、醋酸纤维素邻苯二甲酸酯、聚丙烯酸酯、聚甲基丙烯酸酯(例如，))；
·胶囊物质(例如，明胶、羟丙基甲基纤维素)；
·合成聚合物(例如，聚交酯、聚乙交酯、聚丙烯酸酯、聚甲基丙烯酸酯(例如，)、聚乙烯吡咯烷酮(例如，)、聚乙烯醇、聚乙酸乙烯酯、聚环氧乙烷、聚乙二醇及其共聚物和嵌段共聚物)，
·增塑剂(例如，聚乙二醇、丙二醇、甘油、三醋酸甘油酯、柠檬酸三乙酯、邻苯二甲酸二丁酯)；
·渗透增强剂；
·稳定剂(例如，抗氧化剂例如抗坏血酸、抗坏血酸棕榈酸酯、抗坏血酸钠、丁基羟基苯甲醚、丁基羟基甲苯、没食子酸丙酯)；
·防腐剂(例如，对羟基苯甲酸酯、山梨酸、硫柳汞、苯扎氯铵、醋酸氯己定、苯甲酸钠)；
·着色剂(例如，无机颜料，例如氧化铁、二氧化钛)；
·调味剂、甜味剂、味道和/或气味遮蔽剂。
本发明还涉及药物组合物，其包含至少一种本发明的化合物，通常结合一种或多种药学上合适的赋形剂，并且涉及它们根据本发明的用途。
剂量
基于评价用于治疗特别是妇科疾病、代谢疾病、过度增殖性疾病和炎性疾病的化合物的已知的标准实验室技术，通过确定治疗哺乳动物上述病症的标准毒性检验和标准药理学试验，并且将这些结果与用于治疗这些病症的已知活性成分或药物的结果相比较，可以容易地确定本发明化合物的治疗各个目标适应症的有效剂量。根据诸如所使用的具体化合物和剂量单位、给药模式、疗程、所治疗患者的年龄和性别以及所治疗病症的性质和程度的考虑因素，可以在很大程度上改变在治疗这些病症的一种中待给予的活性成分的量。
所给予的活性成分的总量通常在每天约0.001mg/kg体重至约200mg/kg体重的范围内，优选每天约0.01mg/kg体重至约20mg/kg体重。临床上使用的给药计划在每天给药一至三次至每四周给药一次的范围内。另外，其中不给患者药物达某一时段的“休药期”，可以有益于药理学效果和耐受性之间的综合平衡。单位剂量可以含有约0.5mg至约1500mg活性成分，并且可以每天给药一次或多次，或每天少于一次。注射给药(包括静脉内、肌内、皮下和肠胃外注射以及使用输注技术)的平均日剂量，优选为0.01至200mg/kg总体重。优选，平均每天直肠给药方案为0.01至200mg/kg总体重。优选，平均每天阴道给药方案为0.01至200mg/kg总体重。优选，平均每天局部给药方案为0.1至200mg，每天给药一至四次。优选，透皮浓度要求保持0.01至200mg/kg的日剂量。优选，平均每天吸入剂量方案为0.01至100mg/kg总体重。
当然，对于每个患者来说，具体的初始和连续剂量方案根据诊断医生所确定的病症的性质和严重程度、使用的具体化合物的活性、患者的年龄和常规状况、给药时间、给药途径、药物的排泄率、药物组合等等而变化。治疗的目标模式和本发明化合物或其药学上可接受的盐或酯或组合物的剂量数，可以由本领域技术人员使用常规治疗试验来确定。
结合
本发明的化合物可单独使用或者，如果需要，可与其他活性化合物结合使用。
在本发明中，术语"结合"如本领域技术人员已知的使用，并且所述结合可为固定结合、非固定结合或成套试剂盒(kit-of-parts)。
在本发明中，"固定结合"如本领域技术人员已知的使用，并且定义为：其中例如第一活性成分(例如一种或多种本发明的通式(I)的化合物)和其他活性成分一起存在于一个单位剂量或单一实体中的结合。"固定结合"的一个实例是药物结合物，其中，第一活性成分和其他活性成分存在于同时给药的混合物中，例如，存在于一个制剂中。"固定结合"的另一个实例是药物结合物，其中，第一活性成分和其他活性成分存在于一个单元中，但不是成为混合物。
在本发明中，非固定结合或"成套试剂盒"如本领域技术人员已知的使用，并且定义为：其中第一活性成分和其他活性成分存在于多于一个的单元中的结合物。非固定结合或成套试剂盒的一个例子是其中第一活性成分和其他活性成分单独存在的结合物。可以单独、顺序、同时、并行或先后交错给予非固定结合或成套试剂盒的组分。
根据另一方面，本发明涉及药物结合物，特别是药剂，其包含至少一种本发明的通式(I)的化合物以及至少一种或多种其他活性成分，其特别是用于治疗和/或预防上述疾病。本发明的化合物可作为唯一的药物试剂或与一种或多种其他药物活性成分结合给药，其中所述结合不会引起不合格的副作用。本发明还包括这类药物结合物。
特别地，本发明涉及药物结合物，其中包含：
·一种或多种第一活性成分，特别是如上所定义的通式(I)的化合物，以及
·一种或多种上述其他活性成分。
通常，其他活性成分包括但不限于例如：抗细菌物质(例如青霉素、万古霉素、环丙沙星(ciprofloxacin))、抗病毒物质(例如阿昔洛维(aciclovir)、奥司他韦(oseltamivir))和抗真菌物质(例如萘替芬(naftifin)、制霉菌素)；以及γ球蛋白、免疫调节化合物和免疫抑制化合物，如环孢菌素(cyclosporin)、他克莫司(tacrolimus)、雷帕霉素(rapamycin)、吗替麦考酚酯(myco苯酚ate mofetil)、干扰素、皮质甾类(例如强的松(prednisone)、强的松龙(prednisolone)、甲基强的松龙(methylprednisolone)、氢化可的松(hydrocortisone)、倍他米松(betamethasone))、环磷酰胺(cyclophosphamide)、硫唑嘌呤(azathioprine)和柳氮磺胺吡啶(sulfasalazine)；对乙酰氨基酚、非甾族抗炎物质(NSAIDS)(阿司匹林、布洛芬、萘普生(naproxen)、依托度酸(etodolac)、塞来昔布(celecoxib)、秋水仙碱)。
此外，例如，本发明的化合物可以与已知的激素治疗剂结合。
特别地，本发明化合物可以与激素避孕药一起给药或与激素避孕药联合给药。激素避孕药可通过口服、皮下、经皮、子宫内或阴道内途径给药，例如作为联合口服避孕药(COC)或仅孕酮的药丸(POP)或含有激素的避孕器如植入物、膏药或阴道环给药。
COC包括但不限于包含雌激素(雌二醇)和孕激素(孕酮)的节育药丸或节育方法。雌激素部分在大多数COCs中为乙炔雌二醇。一些COCs含有雌二醇或戊酸雌二醇。
所述COC包含孕酮异炔诺酮(norethynodrel)、炔诺酮(norethindrone)、醋酸炔诺酮、乙炔二醇乙酸酯、炔诺孕酮(norgestrel)、左炔诺孕酮(levonorgestrel)、诺孕酯(norgestimate)、去氧孕烯(desogestrel)，孕二烯酮(gestodene)，屈螺酮(drospirenone)，地诺孕素(dienogest)或醋酸诺美孕酮(nomegestrol acetate)。
节育药丸包括例如但不限于雅司明(Yasmin)、Yaz，两者均含有乙炔雌二醇和屈螺酮；含有左炔诺孕酮和乙炔雌二醇的麦克洛吉诺(Microgynon)或Miranova；含有乙炔雌二醇和去氧孕烯的妈富隆(Marvelon)；含有乙炔雌二醇和地诺孕素的瓦莱塔(Valette)；含有乙炔雌二醇和醋酸氯地孕酮(chlormadinonacetate)的Belara和Enriqa；含有戊酸雌二醇和地诺孕素作为活性成分的Qlaira；和含有雌二醇和诺美孕酮的Zoely。
POP为避孕丸，其仅含有合成孕激素(孕酮)且不含雌激素。它们通俗地称为迷你药丸。
POP包括但不限于含有去氧孕烯的Cerazette；含有左炔诺孕酮的Microlut和含有炔诺酮的Micronor。
其他仅含Progeston的形式为子宫内避孕器(IUD)，例如Mirena Jaydess；含有左炔诺孕酮的Kyleeny；或注射剂，例如含有醋酸甲羟孕酮的得普乐(Depo-Provera)；或植入物，例如含有依托孕烯(etonogestrel)的依伴侬(Implanon)。
其他适合与本发明化合物结合的具有避孕作用的含激素装置为阴道环，如含有乙炔雌二醇和依托孕烯的Nuvaring；或经皮系统如避孕贴剂，例如含有乙炔雌二醇和诺孕曲明(norelgestromin)的Ortho-Evra或含有乙炔雌二醇和孕二烯酮(gestodene)的Apleek(Lisvy)。
本发明的一个优选实施方案是给予通式(I)的化合物结合COC或POP或其他仅含孕酮的形式以及如上所述的阴道环或避孕贴剂。
除了已经批准并上市的公知的药物外，本发明化合物还可结合P2X嘌呤受体家族(P2X3、P2X4)抑制剂、IRAK4抑制剂和前列腺素类EP4受体拮抗剂给药。
特别地，本发明化合物可结合药理学子宫内膜异位症试剂给药，用于治疗炎性疾病、炎性疼痛或一般疼痛病症和/或干扰子宫内膜异位增生和子宫内膜异位相关的症状，即结合微粒体前列腺素E合酶抑制剂(mPGES-1或PTGES)和催乳素受体的功能性阻断抗体和胃促胰酶的抑制剂进行。
对于肿瘤疗法，其他活性成分包括但不限于例如：131I-chTNT、阿倍瑞克(abarelix)、阿比特龙、阿柔比星、曲妥珠单抗-美坦新偶联物(ado-trastuzumabemtansine)、阿法替尼、阿柏西普、阿地白介素(aldesleukin)、alectinib、阿仑单抗(alemtuzumab)、阿仑棒酸、阿利维A酸(alitretinoin)、六甲蜜胺、氨磷汀、氨鲁米特、氨基乙酰丙酸己酯、氨柔比星、安吖啶、阿那曲唑、安西司亭、茴三硫(anetholeditholethione)、anetumab ravtansine、血管紧张素II、抗凝血酶III、阿瑞吡坦、阿西莫单抗、arglabin、三氧化二砷、门冬酰胺酶、阿西替尼、阿扎胞苷、巴利昔单抗(basiliximab)、贝洛替康(belotecan)、苯达莫司汀、贝索单抗(besilesomab)、贝利司他、贝伐单抗(bevacizumab)、贝沙罗汀(bexarotene)、比卡鲁胺、比生群、博来霉素、博纳吐单抗(blinatumomab)、硼替佐米、布舍瑞林、博舒替尼、乙酸阿比特龙酯(brentuximabvedotin)、白消安、卡巴他赛(cabazitaxel)、卡博替尼(cabozantinib)、降钙素(calcitonine)、亚叶酸钙(calcium folinate)、左亚叶酸钙、卡培他滨(capecitabine)、卡罗单抗(capromab)、卡铂、卡波醌(carboquone)、卡菲偌米布、卡莫氟、卡莫司汀、卡妥索单抗(catumaxomab)、西乐葆、西莫白介素、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯地孕酮、氮芥、西多福韦、西那卡塞、顺铂、克拉屈滨、氯膦酸、氯法拉滨(clofarabine)、考比替尼(cobimetinib)、copanlisib、克立他酶(crisantaspase)、克里唑蒂尼(crizotinib)、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、放线菌素D(dactinomycin)、daratumumab、达贝泊汀α贝泊汀αumumabn胞苷、达卡巴嗪、、达拉非尼(dabrafenib)、达沙替尼、柔红霉素、地西他滨、地加瑞克、地尼白介素-毒素连接物(denileukin diftitox)、地诺塞麦(denosumab)、地普奥肽、地洛瑞林(deslorelin)、去水卫矛醇(dianhydrogalactitol)、右雷佐生(dexrazoxane)、二溴螺氯铵(dibrospidium chloride)、去水卫矛醇、双氯芬酸(diclofenac)、dinutuximab、多西他赛(docetaxel)、多拉司琼、去氧氟尿苷、阿霉素、多柔比星+雌酮、屈大麻酚、依库丽珠单抗(eculizumab)、依决洛单抗、依利醋铵(elliptiniumacetate)、埃罗妥珠单抗(elotuzumab)、伊屈泼帕(eltrombopag)、血管内皮抑素、依诺他滨、恩扎鲁胺(enzalutamide)、表柔比星(epirubicin)、环硫雄醇(epitiostanol)、依泊汀α、依泊汀依、依泊汀ζ、依他铂、艾日布林(eribulin)、埃洛替尼、埃索美拉唑、雌二醇、雌莫司汀(estramustine)、乙炔雌二醇、依托泊苷(etoposide)、依维莫司(everolimus)、依西美坦、法屈唑、芬太尼、非格司亭、氟羚甲基睾丸素、氟尿苷、氟达拉滨、氟尿嘧啶、氟他胺、亚叶酸、福美坦、福沙吡坦、福莫司汀、氟维司群、钆布醇、加多利道、钆特酸葡胺、钆弗塞胺、钆塞酸、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥单抗(gemtuzumab)、羧肽酶、谷胱甘肽(glutoxim)、GM-CSF、戈舍瑞林、格兰西龙、粒细胞集落刺激因子、二盐酸组胺、组氨瑞林(histrelin)、羟基脲、I-125粒子、兰索拉唑、依班膦酸、替伊莫单抗(ibritumomabtiuxetan)、依鲁替尼、伊达比星、异环磷酰胺、伊马替尼、咪喹莫特、英丙舒凡(improsulfan)、吲地司琼、英卡膦酸、巨大戟醇甲基丁烯酸酯、干扰素α、干扰素β、干扰素γ、碘比醇、碘苄胍(123I)、碘美普尔、易普利姆玛(ipilimumab)、伊立替康、伊曲康唑、伊沙匹隆(ixabepilone)、ixazomib、兰瑞肽(lanreotide)、兰索拉唑(lansoprazole)、拉帕替尼(lapatinib)、Iasocholine、来那度胺(lenalidomide)、乐伐替尼(lenvatinib)、来格司亭(lenograstim)、蘑菇多糖(lentinan)、来曲唑、亮丙瑞林、左旋四咪唑、左炔诺孕酮、左甲状腺素钠、麦角乙脲、乐铂、洛莫斯汀、氯尼达明、马索罗酚、甲羟孕酮、甲地孕酮、美拉胂醇、美法仑、美雄烷、巯基嘌呤、美司钠、美沙酮、氨甲喋呤、甲氧呋豆素、甲基氨基酮戊酸盐、甲基泼尼松龙、甲基睾甾酮、甲酪氨酸、米伐木肽(mifamurtide)、米特福辛、米铂(miriplatin)、二溴甘露醇、丙脒腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、mogamulizumab、莫拉司亭、莫哌达醇、盐酸吗啡、硫酸吗啡、大麻隆、nabiximols、那法瑞林、纳洛酮+戊唑辛、纳曲酮、那托司亭(nartograstim)、耐昔妥珠单抗(necitumumab)、奈达铂(nedaplatin)、奈拉滨(nelarabine)、奈立膦酸、奈妥吡坦(netupitant)/帕洛诺司琼(palonosetron)、nivolumabpentetreotide、尼洛替尼(nilotinib)、尼鲁米特、尼莫唑、尼妥珠单抗(nimotuzumab)、嘧啶亚硝脲(nimustine)、尼达尼布(nintedanib)、二胺硝吖啶(nitracrine)、纳武单抗、阿托珠单抗、奥曲肽、奥法木单抗(ofatumumab)、奥拉帕尼(olaparib)、高三尖杉酯碱(omacetaxine mepesuccinate)、奥美拉唑(omeprazole)、奥坦西隆(ondansetron)、奥普瑞白介素(oprelvekin)、奥古蛋白、orilotimod、奥希替尼(osimertinib)、奥沙利铂(oxaliplatin)、羟考酮(oxycodone)、羟甲烯龙、ozogamicine、p53基因治疗、紫杉醇、帕泊昔布(palbociclib)、帕利夫明(palifermin)、钯-103粒子、帕洛诺司琼、帕米膦酸、帕尼单抗(panitumumab)、panobinostat、泮托拉唑(pantoprazole)、帕唑帕尼(pazopanib)、培加帕酶、PEG-倍他依泊汀(甲氧基PEG-倍他依泊汀)、帕母单抗、聚乙二醇非格司亭(pegfilgrastim)、聚乙二醇干扰素α聚乙二、培美曲唑、喷他佐辛、喷司他丁、培洛霉素、全氟丁烷、培磷酰胺、帕妥株单抗、溶链菌制剂(picibanil)、毛果芸香碱、吡柔比星、匹克生琼、普乐沙福(plerixafor)、普卡霉素、聚氨葡糖(poliglusam)、磷酸聚雌二醇、聚乙烯吡咯烷酮+透明质酸钠、多糖-K、泊马度胺、帕纳替尼、卟吩姆钠、普拉曲沙(pralatrexate)、泼尼莫司汀、泼尼松、甲基苄肼、丙考达唑、普萘洛尔、喹高利特(quinagolide)、雷贝拉唑、racotumomab、氯化镭223、拉多替尼、雷诺昔酚、雷替曲塞(raltitrexed)、雷莫司琼、雷莫芦单抗、雷莫司汀(ranimustine)、拉布立酶、雷佐生、refametinib、瑞戈非尼(regorafenib)、利塞膦酸、铼-186依替膦酸盐、利妥昔单抗(rituximab)、rolapitant、罗米地辛(romidepsin)、罗米司亭(romiplostim)、罗莫肽、roniciclib、来昔决南钐(153Sm)、沙莫司亭、沙妥莫单抗、胰泌素、司妥昔单抗(siltuximab)、sipuleucel-T、西佐喃、索布佐生、甘氨双唑钠(sodium glycididazole)、sonidegib、索拉非尼(sorafenib)、司坦唑醇(stanozolol)、链脲霉素(streptozocin)、舒尼替尼、他拉泊芬(talaporfin)、talimogene laherparepvec、他米巴罗汀(tamibarotene)、他莫昔芬、他喷他多、他索纳明(tasonermin)、替西白介素(teceleukin)、锝[99mTc]巯诺莫单抗、99mTc-HYNIC-[Tyr3]-奥曲肽、替加氟、替加氟+吉美嘧啶(gimeracil)+奥替拉西(oteracil)、替莫卟吩、替莫唑胺、西罗莫司(temsirolimus)、替尼泊苷、睾酮、替曲膦(tetrofosmin)、沙利度胺、硫替派、胸腺法新(thymalfasin)、促甲状腺素α、硫鸟嘌呤(tioguanine)、托珠单抗(tocilizumab)、托泊替康、托瑞米芬、托西莫单抗(tositumomab)、曲贝替定(trabectedin)、曲美替尼(trametinib)、曲马多(tramadol)、曲妥珠单抗、曲妥珠单抗美坦辛偶联物、曲奥舒凡(treosulfan)、维甲酸、曲氟尿苷+tipiracil、曲洛司坦、曲普瑞林、曲美替尼、曲磷胺、促血小板生成素、色氨酸、乌苯美司、瓦他拉尼、戊柔比星(valrubicin)、凡德他尼(vandetanib)、伐普肽、维罗非尼(vemurafenib)、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞宾、维莫德吉、伏立诺他(vorinostat)、伏氯唑、钇-90玻璃微球、净司他丁、净司他丁斯酯、唑来膦酸、佐柔比星。
对于前列腺癌的治疗，本发明特别包括药物结合物，其包含用于治疗前列腺癌的其他活性成分，所述其他活性成分包括但不限于：
·抗雄激素例如氟他胺(Flutamide(Eulexin))、比卡鲁胺(Bicalutamide(康士得(Casodex)))、尼鲁米特(Nilutamide(Nilandron))、Enzaluatmide(Xtandi)、ODM-201。
·CYP17A1抑制剂，例如阿比特龙和阿比特龙代谢物，
·5制还原酶抑制剂，例如非那雄胺或度他雄胺。
·雄激素剥夺疗法(ADT)，包括GNRHa和GNRH拮抗剂、LHRH激动剂，例如亮丙瑞林(Lupron，Eligard)、戈舍瑞林(Zoladex)、曲普瑞林(Trelstar)、组氨瑞林(Vantas)或LHRH激动剂，例如Degarelix。雄激素剥夺疗法(ADT)可以单独给药或与抗雄激素、5以还原酶抑制剂或CYP17A1抑制剂一起给药。
为了预防和治疗对化学治疗剂、特别是对蒽环类抗生素具有抗性的癌症，本发明特别包括药物结合物，其包含含有氧代基团的化学治疗剂，所述氧代基团作为其他活性成分可通过AKR1C3的酶活性而被还原。这种化学治疗剂的实例是蒽环类抗生素，例如但不限于柔红霉素、阿霉素、表柔比星和伊达比星。根据本发明，本发明的化合物伴随化学治疗剂、特别是蒽环类抗生素给药。
为了预防和治疗与蒽环类抗生素治疗如心肌病有关的副作用，本发明特别包括药物结合物，其包含蒽环类抗生素作为其他活性成分。
实验部分
NMR峰形式表示为它们出现在光谱中，未考虑可能的更高阶效应。
所选择的实施例的1H-NMR数据以1H-NMR峰列表的形式列出。对于每个单峰，给出以ppm计的δ值，随后是以圆括号记录的信号强度。来自不同峰的δ值-信号强度对被逗号隔开。因此，峰列表以以下通式描述：δ1(强度1),δ2(强度2),δi(强度i),δn(强度n)。
在印刷的NMR光谱中，尖峰的强度与信号的高度(以cm计)相关。当与其他信号比较时，该数据可以与信号强度的实际比例相关联。在宽信号的情况下，与光谱中显示的最强信号相比，显示了不止一个峰值或信号的中心及其相对强度。1H-NMR峰列表类似于传统的1H-NMR读数，因此通常包含传统NMR翻译中列出的所有峰。另外，类似于传统1H-NMR印出，峰列表可示出溶剂信号、衍生自目标化合物的立体异构体(也是本发明的主题)的信号和/或杂质峰。立体异构体的信号和/或杂质峰与目标化合物(例如纯度>90％)的峰相比通常示出更低强度。对于特定的制备方法，这类立体异构体和/或杂质可为典型的，因此基于“副产物指纹”，它们的峰可有助于识别我们制备方法的再现性。通过已知方法(MestReC，ACD模拟，或通过使用经验评估的期望值)计算目标化合物的峰值的专家可以根据需要，任选地使用额外的强度过滤器分离目标化合物的峰。这种操作类似于传统1H-NMR翻译中的峰值拾取。峰列表形式的NMR数据的记录的详细说明可见于出版物"Citation of NMR Peaklist Datawithin Patent Applications"(参见Research Disclosure Database Number 605005,2014,01Aug2014,或http://www.researchdisclosure.com/searching-disclosures)。在峰拾取过程中，如Research Disclosure Database Number 605005中所述，参数"MinimumHeight"可在1％至4％之间调整。根据化学结构和/或取决于测量化合物的浓度，将参数“MinimumHeight”设置为<1％可能是合理的。
使用ACD/Labs的ACD/Name软件生成化学名称。在某些情况下，使用通常接受的市售试剂名称代替ACD/Name产生的名称。
下表1列出了本段落和实施例部分中使用的缩写，只要它们未在文本正文中解释。其他缩写本身具有本领域技术人员通常已知的含义。
表1:缩写
其他缩写本身具有本领域技术人员通常已知的含义。
通过以下实施例说明本申请中描述的本发明的各个方面，这些实施例不意味着以任何方式限制本发明。
本文中描述的实施例测试实验用于说明本发明，并且本发明不限制于给出的实施例。
实验部分-综述部分
在实验部分中未描述合成的所有试剂可市售获得，或者是已知化合物或可由本领域技术人员通过已知方法由已知化合物形成。
根据本发明的方法制备的化合物和中间体可能需要纯化。有机化合物的纯化是本领域技术人员熟知的，并且存在纯化同一化合物的多种方法。在某些情况下，纯化不是必须的。在某些情况下化合物可通过结晶纯化。在某些情况下，可使用合适的溶剂搅拌杂质。在某些情况下，可以通过色谱法(特别是快速柱色谱法)使用例如预装的硅胶柱(例如BiotageSNAP柱或)结合Biotage自动纯化器系统(或Isolera)以及洗脱液例如己烷/乙酸乙酯或DCM/甲醇的梯度来纯化化合物。在某些情况下，可通过制备型HPLC使用例如装有二极管阵列检测器和/或在线电喷射电离质谱仪的Waters自动纯化器结合合适的预装反相柱和洗脱液例如水和乙腈的梯度来纯化化合物，所述梯度可包含添加剂例如三氟乙酸、甲酸或氨水。
在某些情况下，如上所述的纯化方法可以提供呈盐形式的具有足够碱性或酸性官能团的本发明的那些化合物，例如，在具有足够碱性的本发明的化合物的情况下，例如为三氟乙酸盐或甲酸盐；或在具有足够酸性的本发明的化合物的情况下，例如为铵盐。这种盐可以通过本领域技术人员已知的各种方法分别转化成其游离碱或游离酸形式，或者在随后的生物测定中用作盐。应理解，分离的和如本文所述的本发明化合物的具体形式(例如盐、游离碱等)不一定是唯一的形式，其中所述化合物可用于生物测定中以便量化具体的生物活性。
UPLC-MS标准方法
如下所述进行分析型UPLC-MS。除非显示负模式(ESI-)，否则从正模式电喷雾电离来记录质量(m/z)。在大多数情况下，使用方法1。如果没有，则显示负模式。
方法1:
仪器：Waters Acquity UPLCMS SingleQuad；柱：Acquity UPLC BEH C18 1.7μm,50x2.1mm；洗脱液A:水+0.1体积％甲酸(99％),洗脱液B:乙腈；梯度：0-1.6min 1-99％B,1.6-2.0min 99％B；流速0.8ml/min；温度：60℃；DAD扫描：210-400nm。
方法2:
仪器：Waters Acquity UPLCMS SingleQuad；柱：Acquity UPLC BEH C18 1.7μm,50x2.1mm；洗脱液A:水+0.2体积％氨水(32％),洗脱液B:乙腈；梯度：0-1.6min 1-99％B,1.6-2.0min 99％B；流速0.8ml/min；温度：60℃；DAD扫描：210-400nm。
方法3:
仪器：Waters Acquity UPLCMS SingleQuad；柱：Acquity UPLC BEH C18 1.7μm50x2.1mm；洗脱液A:水+0.1体积％甲酸(99％),洗脱液B:乙腈；梯度：0-1.6min 1-99％B,1.6-2.0min 99％B；流速0.8ml/min；温度：60℃；DAD扫描：210-400nm。
方法4:
系统：具有PDA检测器和Waters ZQ质谱仪的UPLC Acquity(Waters)；柱：AcquityBEH C18 1.7μm 2.1x50mm；温度：60℃；溶剂A:水+0.1％甲酸；溶剂B:乙腈；梯度：99％A至1％A(1.6min)至1％A(0.4min)；流速：0.8mL/min；注入体积：1.0μl(0.1mg-1mg/mL样品浓度)；检测：PDA扫描区域210-400nm-加固定波长254nm；MS ESI(+),扫描区域170-800m/z
方法5:
系统：Waters Aqcuity UPC2:溶剂管理器，样品管理器，柱管理器，PDA,QDa MS；柱：Viridis BEH 2-EP 5μm 100x4.6 mm；溶剂：A＝CO2 B＝甲醇+0,5体积％NH3(32％)；流速：4.0mL/min；梯度：0-7min 5-55％B；压力：100bar；温度：40℃；检测器：DAD 254nm
HLPC系统上的制备型色谱法：
为了纯化一些中间体和实施例，使用制备型反相或正相系统。可用的系统为：
Labomatic,Pump:HD-5000,馏分收集器：LABOCOL Vario-4000,UV-检测器:KnauerUVD 2.1S；柱：Chromatorex RP C18 10μm125x30 mm,洗脱液：A:水+0.1体积％甲酸(99％),洗脱液B:乙腈；检测：UV 254nm；软件：SCPA PrepCon5。
Waters自动纯化系统：Pump 2545,Sample Manager 2767,CFO,DAD 2996,ELSD2424,SQD；柱：XBrigde C18 5μm 100x30 mm；洗脱液A:水+0.1体积％甲酸,洗脱液B:乙腈；流速：50mL/min；温度：室温；检测：DAD扫描范围210–400nm；MS ESI+,ESI-,扫描范围160-1000m/z。
Waters自动纯化系统：Pump 2545,Sample Manager 2767,CFO,DAD 2996,ELSD2424,SQD；柱：XBrigde C18 5μm 100x30 mm；洗脱液A:水+0.2体积％氨水(32％),洗脱液B:乙腈；流速：50mL/min；温度：室温；检测：DAD扫描范围210–400nm；MS ESI+,ESI-,扫描范围160-1000m/z。
硅胶柱色谱：
为了纯化一些中间体和实施例，使用购自Biotage公司的装置进行硅胶柱色谱(“快速色谱法”)。使用预先填充有不同尺寸的硅胶的柱体，例如购自Biotage公司的“司的“age柱体，例如的硅胶，KP_SILe或购自Interchim公司的“司的“rchim，例如的硅胶的柱体，例如ESI-,767,CFO,DAD 2996,EL。
实验部分-中间体
中间体1
3,8-二氮杂双环[3.2.1]辛-3-基(1H-1,2,3-三唑-4-基)甲酮
步骤1.1:3-(1H-1,2,3-三唑-4-基羰基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
向经搅拌的500mg(2.36mmol)3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯于12mLNMP的溶液中加入532mg 1H-1,2,3-三唑-4-羧酸(4.71mmol,2eq)、1.23mL DIPEA(7.07mmol,3eq)和1.791g HATU(4.71mmol,2eq)。在RT下搅拌过夜后，使溶液进行制备型HPLC，得到378mg(52％)3-(1H-1,2,3-三唑-4-基羰基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯。
LC-MS(方法3):Rt＝0.91min；MS(ESIpos):m/z＝308[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:1.43(9H),1.53-1.72(2H),1.83(2H),2.92(1H),3.33(1H),4.14(1H),4.21(1H),4.30(1H),4.40(1H),8.29(1H),15.22(1H)。
步骤2:3,8-二氮杂双环[3.2.1]辛-3-基(1H-1,2,3-三唑-4-基)甲酮
向经搅拌和冷却(冰浴)的272mg(887μmol)3-(1H-1,2,3-三唑-4-基羰基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯于6mL DCM的溶液中加入0.3mL水和3mL TFA。3h之后，将混合物在真空下蒸发，用甲苯研磨并重新蒸发，得到376mg(200％)粗3,8-二氮杂双环[3.2.1]辛-3-基(1H-1,2,3-三唑-4-基)甲酮，其为TFA加合物，其无需进一步纯化即可用于后续步骤。
SFC-MS(方法5):Rt＝1.74min；MS(ESIpos):m/z＝208[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:1.67–2.00(4H),3.19(1H),3.61(1H),4.11(2H),4.40(1H),4.70(1H),8.40(1H)。
中间体2
8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛烷
步骤2.1:8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯
在RT下向经搅拌的100mg(0.47mmol)3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯于2ml DCE的溶液中加入246μL DIPEA(1.41mmol,3eq)和90μL苯磺酰氯(125mg,0.71mmol,1.5eq)并将混合物在RT下搅拌过夜。将有机相用NaHCO3水溶液(10％)洗涤三次并用水洗涤两次，干燥并蒸发，得到168mg(101％)标题化合物。
LC-MS(方法3):Rt＝1.26min；MS(ESIpos):m/z＝353[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:1.19(2H),1.36(11H),2.87(1H),3.01(1H),3.75(2H),4.19(2H),7.60(2H),7.70(1H),7.87(2H).
步骤2.2:8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛烷
在RT下向经搅拌的166mg(0.47mmol)8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯于1mL DCM的溶液中加入0.1mL水和3mL TFA。3h之后，将混合物在真空下蒸发，再溶解于叔丁醇中并冷冻干燥，得到171mg(143％)粗8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛烷，其为TFA加合物，其无需进一步纯化即可用于后续步骤。
LC-MS(方法1):Rt＝0.54min；MS(ESIpos):m/z＝253[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:1.40(2H),1.77(2H),3.19–3.51(4H),4.37(2H),7.55–7.66(2H),7.74(1H),7.90(1H),8.25–9.50(2H).
中间体3
8-{[2-(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛烷
步骤3.1:叔丁基-8-{[2-(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸酯
向经搅拌的4.246g(20mmol)3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯于100mlDCM的溶液中加入14ml DIPEA(80mmol,4eq)和9.78g 2-(三氟甲基)苯磺酰氯(40.0mmol,2eq)并将混合物在RT下搅拌过夜。将有机相在真空下除去并将残余物进行快速色谱(乙酸乙酯/己烷)，得到8.18g(97％)标题化合物。
LC-MS(方法1):Rt＝1.36min；MS(ESIpos):m/z＝365[M-tBu+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:1.38(9H),1.51–1.71(4H),2.83(1H),3.01(1H),3.76(2H),4.23(2H),7.91(2H),8.05(1H),8.27(1H)。
步骤3.2:8-{[2-(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛烷
向经搅拌的8g(19.45mmol)8-{[2-(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯于64mL DCM的溶液中加入3.3mL水和64mLTFA。3h之后，将混合物在真空下蒸发，用甲苯研磨和再蒸发。将残余物再溶解于DCM中，用NaHCO3水溶液(10％)和水洗涤并将有机相干燥并蒸发，得到6.20g(95％)标题化合物8-{[2-(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛烷。
LC-MS(方法1):Rt＝0.69min；MS(ESIpos):m/z＝321[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:1.54(2H),1.79(2H),2.60(2H),2.71(2H),4.02(2H),7.90(2H),8.03(1H),8.27(1H)。
中间体4
8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛烷盐酸盐(1:1)
步骤4.1:8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯
在RT下向经搅拌的100mg(0.47mmol)3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯于2ml DCE的溶液中加入246μL DIPEA(1.41mmol,3eq)和150mg 3,5-二氟苯磺酰氯(0.71mmol,1.5eq)并将混合物在RT下搅拌过夜。将有机相用NaHCO3水溶液(10％)洗涤三次并用水洗涤一次，干燥并蒸发，得到188mg(103％)标题化合物。
LC-MS(方法1):Rt＝1.34min；MS(ESIpos):m/z＝389[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:1.30(2H),1.38(9H),1.45(2H),2.89(1H),3.03(1H),3.76(2H),4.29(2H),7.68(3H)。
步骤4.2:8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛烷盐酸盐(1:1)
在冰冷却下向经搅拌的183mg(0.47mmol)8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯于3mL乙醇的溶液中加入1.8mL于二噁烷中的4M HCl(7mmol,15eq)并在RT下将混合物搅拌2h。再加入1mL于二噁烷中的4M HCl并在RT下搅拌3h后，将混合物在真空下蒸发并从叔丁醇中冷冻干燥，得到157mg(103％)标题化合物8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛烷盐酸盐(1:1)。
LC-MS(方法2):Rt＝0.64min；MS(ESIpos):m/z＝289[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.54(2H)1.94(2H)3.11(2H)3.18(2H),4.45(2H)7.72(3H),8.87–9.92(2H)
中间体5
8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛烷盐酸盐(1:1)
步骤5.1:8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯
向经搅拌的500mg(2.36mmol)3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯于DCM中的溶液中加入1.6ml DIPEA(9.4mmol,4eq)和380μL 3-氟苯磺酰氯(2.82mmol,1.2eq)并将混合物在RT下搅拌过夜。将有机相在真空下除去并将残余物进行快速色谱(乙酸乙酯/己烷)，得到844mg(97％)标题化合物。
LC-MS(方法2):Rt＝1.28min；MS(ESIpos):m/z＝315M-t-Bu+
1H-NMR(400MHz,氯FORM-d)δ[ppm]:7.68(1H),7.58(1H),7.51(1H),7.35-7.28(1H),4.19(2H),3.93(1H),3.77(1H),3.19-2.96(2H),1.69-1.54(4H),1.44(s,9H)
步骤5.2:8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛烷盐酸盐(1:1)
向经搅拌的840mg(2.27mmol)8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸酯于10mL乙醇的溶液中加入8.5mL于二噁烷中的4M HCl(34mmol,15eq)并在RT下将混合物搅拌72h。将混合物在真空下蒸发，用二乙醚研磨，过滤并在真空下干燥，得到735mg(105％)标题化合物8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛烷盐酸盐(1:1)。
LC-MS(方法2):Rt＝0.84min；MS(ESIpos):m/z＝271[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.36-1.54(2H)1.81-1.97(2H)2.98-3.13(2H)3.13-3.25(2H),4.40(2H)7.57-7.65(1H),7.66-7.73(1H)7.73-7.83(2H),9.10–9.90(1H)
以下中间体以类似于中间体2至5中给出的方法用合适的磺酰氯来合成。
实验部分–实施例
实施例1
[8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-4-基)甲酮
步骤1.1:
在0℃下向经搅拌并冷却的1.87g(57％的纯度,5.11mmol)-3,8-二氮杂双环[3.2.1]辛-3-基(1H-1,2,3-三唑-4-基)甲酮(中间体1)于25mL NMP的溶液中加入4.45mL(5eq,25.5mmol)DIPEA和0.63g(0.7eq,3.57mmol)苯磺酰氯，并在0℃下将混合物搅拌1h。在RT下搅拌过夜后，将混合物进行制备型HPLC，得到215mg(0.61mmol,12％)标题化合物3,8-二氮杂双环[3.2.1]辛-3-基(1H-1,2,3-三唑-4-基)甲酮。
LC-MS(方法1):Rt＝0.85min；MS(ESIpos):m/z＝348[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.193(3.38),1.211(5.65),1.228(4.02),1.262(0.76),1.382(1.39),1.406(3.26),1.427(1.85),1.510(1.94),2.323(0.45),2.327(0.62),2.331(0.43),2.518(2.26),2.523(1.43),2.665(0.45),2.669(0.63),2.673(0.45),2.963(3.11),2.992(3.35),3.397(2.90),4.282(3.57),4.337(7.53),4.368(3.35),7.593(6.59),7.597(2.73),7.611(16.00),7.631(11.11),7.690(3.31),7.693(6.32),7.696(3.91),7.707(2.79),7.711(8.65),7.716(2.33),7.727(1.88),7.730(2.99),7.885(11.98),7.889(15.82),7.894(4.11),7.907(12.63)。
步骤1.2:
在RT下向经搅拌的504mg(2mmol)8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛烷(中间体2)于6mL NMP的溶液中加入452mg(2eq,4mmol)1H-1,2,3-三唑-5-羧酸、1045μL(3eq,6mmol)DIPEA和1.52g(2eq,4mmol)HATU并将混合物搅拌6h。将混合物倒入乙酸乙酯中,用水洗涤，用硫酸钠干燥，蒸发并使用乙酸乙酯和己烷将残余物进行快速色谱，得到787mg(1.93mmol,96％)标题化合物3,8-二氮杂双环[3.2.1]辛-3-基(1H-1,2,3-三唑-4-基)甲酮。
步骤1.3:
向3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯(0.3mmol,750μL,0.4M)于DCE的溶液中加入于DCE中的苯磺酰氯(0.45mmol,900μL,0.5M,1.5eq)和0.9mmol DIPEA(156μL,3eq)并在RT下将混合物振荡过夜。加入2mL TFA/DCE 3:1，并在RT下将混合物振荡3h。蒸发溶剂之后，加入于NMP中的1H-1,2,3-三唑-5-羧酸(0.6mmol,1.2mL,2eq,0.5M)、928μLDIPEA(3.6mmol,12eq；调节pH至8)和于NMP中的HATU(0.6mmol,1.2mL,2eq,0.5M)，并将混合物振荡过夜，进行制备型HPLC之后，得到26mg(25％)标题化合物3,8-二氮杂双环[3.2.1]辛-3-基(1H-1,2,3-三唑-4-基)甲酮。
实施例2
1H-1,2,3-三唑-4-基[8-{[2-(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛-3-基]甲酮
类似于实施例1，步骤1.2，1.92g(50％的纯度，3.00mmol)8-{[2-(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛烷(中间体3)与0.678g(6mmol,2eq)1H-1,2,3-三唑-5-羧酸反应，后处理和纯化之后得到792mg(62％)标题化合物1H-1,2,3-三唑-4-基[(8-{[2-(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛-3-基]甲酮。
LC-MS(方法1):Rt＝0.96min；MS(ESIpos):m/z＝416[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.602(2.82),1.629(2.52),1.689(12.16),1.980(0.53),2.073(1.54),2.327(1.17),2.669(1.20),2.673(0.87),2.934(3.84),2.964(4.10),3.379(5.16),4.293(5.08),4.355(9.64),4.386(4.07),4.519(0.72),7.890(1.47),7.908(5.87),7.913(7.23),7.920(16.00),7.927(6.81),7.932(7.53),7.936(7.64),7.950(2.37),7.955(1.54),8.018(0.79),8.030(7.57),8.037(6.89),8.053(5.61),8.295(7.27),8.311(6.51),8.317(6.21),15.524(0.53)。
实施例3
{8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
类似于实施例1，步骤1.2，3.46g(12.00mmol)8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛烷(中间体4)与2.714g(12mmol,2eq)1H-1,2,3-三唑-5-羧酸反应，后处理和纯化之后得到1.93g(42％)标题化合物{8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮。
LC-MS(方法1):Rt＝0.93min；MS(ESIpos):m/z＝384[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.106(1.26),1.153(0.74),1.171(1.48),1.188(0.74),1.317(4.22),1.336(6.93),1.352(4.93),1.384(1.15),1.452(1.67),1.475(4.11),1.496(2.26),1.539(1.26),1.561(1.63),1.619(1.48),1.979(1.26),1.986(2.74),2.322(1.07),2.326(1.48),2.331(1.04),2.518(6.26),2.522(4.19),2.664(1.07),2.668(1.52),2.673(1.07),2.685(0.59),2.692(1.00),2.982(3.59),3.014(3.67),3.282(0.52),3.301(1.00),3.382(3.74),3.412(3.81),4.016(0.63),4.034(0.59),4.345(6.04),4.374(8.00),4.432(4.74),4.739(1.33),4.770(1.26),7.678(12.00),7.694(15.93),7.698(16.00),7.716(4.00),7.722(3.56),7.727(1.59),8.084(3.89),8.541(4.07),15.373(1.67),15.690(1.00)。
实施例4
{8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
类似于实施例1，步骤1.2，3.24g(12.00mmol)8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛烷(中间体5)与2.714g(12mmol,2eq)1H-1,2,3-三唑-5-羧酸反应，后处理和纯化之后得到1.15g(26％)标题化合物{8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮。
LC-MS(方法1):Rt＝0.89min；MS(ESIpos):m/z＝366[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.154(1.28),1.172(2.67),1.189(3.43),1.205(2.55),1.217(0.78),1.248(4.37),1.269(6.76),1.284(4.95),1.316(1.10),1.419(1.60),1.442(3.75),1.463(2.05),1.532(2.35),1.552(3.45),1.578(1.30),1.987(4.67),2.074(0.74),2.323(0.84),2.327(1.16),2.331(0.86),2.523(3.65),2.665(0.90),2.669(1.20),2.673(0.90),2.686(2.75),2.972(3.99),3.003(4.11),3.376(4.95),3.409(4.43),4.016(1.08),4.034(1.00),4.342(7.38),4.377(7.64),4.524(1.96),4.552(1.84),7.563(1.84),7.568(2.49),7.573(2.29),7.587(4.79),7.591(5.25),7.606(2.93),7.609(3.27),7.612(3.43),7.615(3.09),7.650(2.65),7.666(3.73),7.671(5.97),7.685(5.69),7.692(3.89),7.705(3.25),7.749(16.00),7.752(13.33),7.758(4.71),7.769(11.91),8.307(5.49)。
类似于实施例1,步骤1.1，使用3,8-二氮杂双环[3.2.1]辛-3-基(1H-1,2,3-三唑-4-基)甲酮(中间体1)，制备以下实施例:
类似于，实施例1,步骤1.2，使用给定的中间体制备以下实施例:
类似于实施例1,步骤1.3，使用3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯，制备以下实施例:
实施例75
5-({8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}羰基)-1,2,3-三唑-1-基钠
在RT下向经搅拌的6.16g(16mmol){8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮于170mL MeOH和70mL THF的溶液中加入甲醇钠的溶液(16mmol,1eq,30％于MeOH中)中。在RT下搅拌2h之后，加入250mL二乙醚以沉淀出产物。冷却和过滤之后，将固体在真空下干燥，得到4.88g(13mmol,87％)标题化合物5-({8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}羰基)-1,2,3-三唑-1-基钠。
LC-MS(方法1):Rt＝0.93min；MS(ESIpos):m/z＝384[M-Na++H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:1.088(0.43),1.255(3.70),1.426(0.96),1.623(0.98),2.361(0.88),2.634(0.81),2.838(0.93),3.172(0.95),3.373(0.48),4.349(7.53),5.654(0.91),7.582(16.00),7.655(1.88),7.660(1.72),7.673(3.97),7.677(4.37),7.690(7.92),7.699(8.03)。
实施例76
5-({8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}羰基)-1,2,3-三唑-1-基钠
类似实施例75于使经搅拌的4.99g(13.7mmol){8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮溶液与甲醇钠反应，得到4.89g(12.5mmol,92％)标题化合物5-({8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}羰基)-1,2,3-三唑-1-基钠。
LC-MS:Rt＝0.88min；MS(ESIpos):m/z＝365[M-Na++H]+
1H-NMR(600MHz,METHANOL-d4)δ[ppm]:-0.005(1.50),0.006(1.47),1.177(0.54),1.442(3.45),1.450(3.48),1.614(2.20),1.628(3.21),1.635(3.51),1.648(1.93),3.055(1.86),3.077(1.92),3.481(0.45),3.493(0.93),3.502(1.89),3.523(1.92),4.253(2.38),4.363(2.38),4.537(1.86),4.558(2.10),4.586(2.10),4.607(1.77),7.409(1.86),7.410(2.05),7.414(2.17),7.415(2.18),7.424(4.26),7.428(4.51),7.429(4.41),7.439(2.31),7.442(2.45),7.443(2.31),7.593(3.06),7.602(3.24),7.607(5.51),7.616(5.57),7.621(3.33),7.630(3.16),7.671(3.28),7.675(4.38),7.678(3.52),7.685(3.35),7.687(4.35),7.692(3.33),7.749(5.52),7.751(6.36),7.754(5.22),7.762(4.66),7.764(5.38),7.765(5.31),7.766(4.19),7.802(15.79),7.803(16.00),7.892(1.93)。
实验部分–生物测试
在选定的生物测定中测试实施例一次或多次。当测试多于一次时，数据被报告为平均值或中值，其中
·平均值，也称为算术平均值，表示获得的值之和除以测试次数，以及
·中值表示一组按升序或降序排列的值的中间数。如果数据集合中的值的数量是奇数，则中值是中间数值。如果数据集合中的值的数量是偶数，则中值是两个中间数值的算术平均值。
实施例进行合成一次或多次。当合成多于一次时，来自生物测定的数据表示利用从一个或多个合成批次的测试获得的数据集合计算的平均值或中值。
本发明的化合物的体外活性可在以下试验中证明：
AKR1C3-抑制活性测试
在下面段落中描述的AKR1C3测定中测量本发明的物质的AKR1C3-抑制活性。
基本上，通过量化由香豆酮产生的香豆醇来测定酶活性(Halim等人J.AM.CHEM.SOC.2008,130:14123–14128和Yee等人Proc.Natl.Acad.Sci.USA 2006,103:13304–13309)。在该测试中，利用AKR1C3通过NADPH-(烟酰胺腺嘌呤二核苷酸磷酸盐)依赖性还原非荧光香豆酮测定高荧光香豆醇的增加。
使用的酶是重组人AKR1C3(醛酮还原酶家族1成员C3；GenBank登录号NM_003739)。其在大肠杆菌(E.coli)中表达为GST(谷胱甘肽S转移酶)融合蛋白，并通过谷胱甘肽琼脂糖凝胶亲和层析纯化。通过用凝血酶消化和随后的尺寸排阻色谱法除去GST(Dufort,I.,Rheault,P.,Huang,XF.,Soucy,P.,以及Luu-The,V.,Endocrinology 140,568-574(1999))。
对于该测试，将50nl 100倍浓缩的测试物质的DMSO溶液移液到黑色小体积384孔微量滴定板(Greiner Bio-One，Frickenhausen，Germany)，加入2.5μl AKR1C3于测试缓冲液[50mM磷酸钾缓冲液pH 7，1mM DTT，0.0022％(w/v)Pluronic F-127，0.01％BSA(w/v)和蛋白酶抑制剂混合剂(完全，无EDTA的蛋白酶抑制剂混合剂，购自Roche)]的溶液中，并将混合物温育15分钟，以使酶在酶反应之前预结合至酶上。然后通过添加2.5μl NADPH于测试缓冲液中的溶液(20μM→于5μl测定体积中终浓度为10μM)和Coumberone(0.6μM→于5μl测定体积中终浓度为0.3μM)来开始酶反应。将所得混合物在22℃下温育，反应时间通常为90min。使AKR1C3的浓度和反应时间适应酶制剂各自的活性，并进行调节，使得测试在线性范围内进行。通常AKR1C3的浓度为1nM。通过添加2.5μl由在50mM HEPES pH7.5中的3μM作为抑制剂的EM-1404(US6,541,463)组成的终止溶液(3μMEM-1404→于7.5μl测定体积中终浓度为1μM)来终止反应。然后使用合适的测量仪器(购自BMG Labtechnologies的Pherastar)在520nm(在380nm激发)下测量香豆醇(Coumberole)的荧光。荧光强度用作形成的香豆醇的量的量度，因此用作AKR1C3酶活性的量度。将数据标准化(没有抑制剂的酶反应＝0％抑制；所有其他测定组分，但没有酶＝100％抑制)。通常，测试物质在相同的微量滴定板上以20μM至73pM(20μM、5.7μM、1.6μM、0.47μM、0.13μM、38nM、10.9nM、3.1nM、0.9nM、0.25nM和73pM，在测定之前在100倍浓缩的溶液的水平上通过用100％DMSO连续1：3稀释来制备稀释系列)范围内的11种不同浓度测定，每种浓度一式两份，并且IC50值为使用4参数拟合计算。
如上所述，检查了要求保护的药理学物质对AKR1C3酶的抑制活性(见表2)。对于所要求的结构范围的主要部分，这些物质在体外显示出对AKR1C3的强烈抑制，IC50值小于10nM，并且显著地甚至IC50值为约1nM。
表2:AKR1C3-抑制活性：实施例的IC50值
在相同的测试中分析了WO 2007/111921(比较实施例)的表1中的化合物编号4，以确定该化合物的AKR1C3-抑制活性。WO 2007/111921的表1中化合物编号4的IC50为1810nM。
在人原代脂肪细胞中抑制雄烯二酮形成睾酮
来自2名体重指数(BMI)分别为26和30的供体的人原代前成脂肪细胞分化为成熟脂肪细胞(由ZenBio,Cat#SA-1012-2 12well Platte；Cat#SA-1012-3 12well Platte订购)。将脂肪细胞在补充有1μM雄烯二酮和1μM、10μM化合物76或载体的脂肪细胞基础培养基(Fa.ZenBio,Cat#BM-1)+1％FCS+2.5io,Ca两性霉素B(Fa.Sigog，Cat#A2942)中温育48h。雄烯二酮用作形成睾酮的底物。温育后，收集脂肪细胞，并在“生物分析服务和研究供应者Pharm-Analyt”处通过LC/MS测定睾酮和雄烯二酮浓度。利用化合物76对雄烯二酮转化为睾酮的抑制作用确定为睾酮/雄烯二酮比例[％]。这表明化合物76在人原代脂肪细胞中抑制雄烯二酮形成睾酮(参见图1)。
狨猴(Callithrix jacchus)子宫内膜异位症模型
在狨猴中的非人灵长类动物子宫内膜异位症模型中测试化合物76的体内功效。
狨猴(Callithrix jacchus)是非月经物种，其中通过将子宫内膜组织注入腹膜腔诱导子宫内膜异位症(Einspanier,Lieder等人,2006)。使用具有确定的子宫内膜异位症的6-12岁女性普通狨猴(体重在358g至520g之间)并分成2组，每组n＝5只动物。在实际开始治疗之前，对动物进行剖腹手术并检查膀胱、子宫和卵巢上是否存在子宫内膜异位病变以测量每个病变的面积。对于第一次剖腹手术时的初始病变状态，将动物随机分成两个治疗组。基于每只动物的总病变面积的子宫内膜异位症严重程度在各组中类似地分布。
对于治疗组(5mg/kg化合物76)和载体治疗组，根据病变面积和病变数量，确定每只动物的总病变面积/尺寸[cm2]之和，并定义为治疗前状态。6周后开始治疗。试验化合物以胶囊(PC胶囊，Capsugel)形式每天口服给药一次。为了适应预期的剂量，制备活性化合物与乳糖的研磨，并将精确的剂量填充到各个胶囊中。每个胶囊分别涂有抗鼠尾草属的包衣(Eudragit EPO；Evonik)。在6周治疗期结束后，进行第二次剖腹手术，并根据总病变尺寸/面积确定子宫、卵巢和膀胱上病变的数量和尺寸，并定义为治疗后状态。
治疗前和治疗后的总病变尺寸/面积如图2A所示。在载体组中，在研究期间总病变尺寸[cm2]增加，而在用5mg/kg化合物76治疗6周后，所有动物的总病变尺寸显著降低。
治疗后总病变尺寸的减少可目测为两组(载体组，5mg/kg实施例76组)中治疗后与治疗前的总病变尺寸/面积的比例。比例1对应于稳定的病变尺寸。高于1的比例显示在实验过程中总病变尺寸增加，而低于1的比例显示总病变尺寸减小。图2A中显示的结果反映在图2B中：所有载体动物的比例均高于1，而用化合物76治疗的所有动物的比例均低于1。与基线相比，化合物76治疗的动物中总病变尺寸的平均减少为68.9％，而载体治疗动物的总病变尺寸与基线相比有所增加。
通过AKR1C3抑制干扰癌细胞中的蒽环类抗生素抗性
A549肺癌细胞表达AKR1C3。在实验开始前24小时接种A549细胞。24小时后，用新鲜培养基替换培养基，所述新鲜培养基含有1、10、50、100、200、500和1000nM柔红霉素、阿霉素和伊达比星，含有或不含1μM、10μM、30μM化合物76。在标准条件(37℃,5％CO2)下温育72小时后测定细胞活力。通过将MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓-溴化物；Sigma-Aldrich)的PBS溶液加入到细胞中至终浓度为1mg/ml来测量细胞活力，然后将细胞在标准条件下温育4h。吸出培养基，在自动振荡器上用二甲基亚砜裂解细胞15min。使用酶标仪(microplate reader)在570nm和690nm处测量吸光度。
附图说明
图1:用载体(白色柱)、1μM化合物76(灰色柱)或10μM化合物76(黑色柱)温育后，来自BMI为26(图1A)的供体和BMI为30(图1B)的供体的人原代脂肪细胞中1μM雄烯二酮转化为睾酮。示出了睾酮/雄烯二酮比例[％]。
图2:
(图2A)示出了在载体治疗组(左框)和化合物(5mg/kg，实施例76)治疗组(右框)的膀胱、卵巢和子宫处，具有确定的子宫内膜异位症的单个狨猴(n＝5)的治疗前和治疗后总病变尺寸。
(图2B)示出了用载体(左框)或5mg/kg实施例76(右框)治疗的具有确定的子宫内膜异位症的狨猴中膀胱、卵巢和子宫的治疗后/治疗前总病变尺寸的比例。虚线表示研究开始时的状态(第一次剖腹手术)。
Claims (13)
1.通式(I)的化合物或其立体异构体、互变异构体、盐或者它们的混合物在制备用于处理或预防疾病的药物中的用途，其中所述疾病为多囊卵巢相关的症状、子宫内膜异位相关的妇科病症、病况或疾病：
其中：
R1表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或氰基；
R2表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基、氰基或SF5；
R3表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或羟基；
R4表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基、氰基或SF5；
R5表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或氰基；
其中R1和R2或R2和R3任选地以以下方式彼此连接：它们共同形成亚甲二氧基、亚乙二氧基、亚乙基氧基、三亚甲基氧基或
选自以下的基团：
2.根据权利要求1的用途，其中：
R1表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或氰基；
R2表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基、氰基或SF5；
R3表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或羟基；
R4表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基、氰基或SF5；
R5表示氢、卤素、C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、硝基或氰基。
3.根据权利要求1的用途，其中：
R1表示氢、氟、氯、溴、甲基、三氟甲基、甲氧基、三氟甲氧基或氰基；
R2表示氢、氟、氯、溴、甲基、三氟甲基、甲氧基、三氟甲氧基、氰基或SF5；
R3表示氢；
R4表示氢、氟、氯、溴、甲基、三氟甲基、甲氧基、三氟甲氧基、氰基或SF5；
R5表示氢、氟、氯、溴、甲基、三氟甲基、甲氧基、三氟甲氧基或氰基。
4.根据权利要求1的用途，其中：
R1表示氢、氟、氯、溴、甲基或三氟甲基；
R2表示氢、氟、氯、溴、甲基、三氟甲基或SF5；
R3表示氢；
R4表示氢、氟、氯、溴、甲基、三氟甲基或SF5；
R5表示氢、氟、氯、溴、甲基或三氟甲基。
5.根据权利要求1的用途，其中通式(I)的化合物选自如下化合物或其立体异构体、互变异构体、盐或者它们的混合物，其选自：
1[8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-4-基)甲酮
2 1H-1,2,3-三唑-4-基[8-{[2-(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛-3-基]甲酮
3{8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
4{8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
5{8-[(3-氯苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
6{8-[(2-甲基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-4-基)甲酮
7{8-[(2-氯苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-4-基)甲酮
8[8-{[3-(五氟-λ-硫烷基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-4-基)甲酮
9{8-[(3,5-二氯苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-4-基)甲酮
10[8-{[3,5-二(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-5-基)甲酮
12{8-[(2,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-4-基)甲酮
13{8-[(3-甲基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
14{8-[(4-甲基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
15{8-[(2-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
16{8-[(4-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
17 3-{[3-(1H-1,2,3-三唑-5-基羰基)-3,8-二氮杂双环[3.2.1]辛-8-基]磺酰基}苄腈
18{8-[(3,5-二甲基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
19{8-[(2,5-二甲基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
20{8-[(3-甲氧基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
21{8-[(4-甲氧基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
22{8-[(4-氯苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
23{8-[(3,4-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
24{8-[(2,6-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
25{8-[(2,4-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
26{8-[(3-氯-2-甲基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
27{8-[(3-氯-2-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
28{8-[(3-氯-4-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
29 1H-1,2,3-三唑-5-基[8-{[3-(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛-3-基]甲酮
30{8-[(2,5-二氯苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
31{8-[(3-溴苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
32{8-[(2-溴苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
33 1H-1,2,3-三唑-5-基[8-{[3-(三氟甲氧基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛-3-基]甲酮
34[8-{[5-氯-2-(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-5-基)甲酮
35 2-{[3-(1H-1,2,3-三唑-5-基羰基)-3,8-二氮杂双环[3.2.1]辛-8-基]磺酰基}苄腈
36 1H-1,2,3-三唑-5-基[8-{[4-(三氟甲基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛-3-基]甲酮
37{8-[(4-羟基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
38{8-[(4-溴苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
39[8-(萘-1-基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-5-基)甲酮
40[8-(喹啉-8-基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-5-基)甲酮
41 1H-1,2,3-三唑-5-基[8-{[4-(三氟甲氧基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛-3-基]甲酮
42 1H-1,2,3-三唑-5-基[8-{[2-(三氟甲氧基)苯基]磺酰基}-3,8-二氮杂双环[3.2.1]辛-3-基]甲酮
43{8-[(4-硝基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
44{8-[(3-硝基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
45 1H-1,2,3-三唑-5-基{8-[(2,4,6-三甲基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}甲酮
46{8-[(2-硝基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
47{8-[(2,5-二甲氧基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-
基}(1H-1,2,3-三唑-5-基)甲酮
48{8-[(3,4-二氯苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
49{8-[(4-乙基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
50{8-[(2-氯-4-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
51{8-[(2-氯-6-甲基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
52{8-[(3,4-二甲氧基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
53{8-[(2,3-二氯苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
54[8-(2,1,3-苯并噻二唑-4-基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-
基](1H-1,2,3-三唑-5-基)甲酮
55[8-(2,1,3-苯并噁二唑-4-基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-5-基)甲酮
56 1H-1,2,3-三唑-5-基{8-[(2,4,6-三氯苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}甲酮
57{8-[(5-氯-2-甲氧基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-
基}(1H-1,2,3-三唑-5-基)甲酮
58[8-(2,1,3-苯并噻二唑-5-基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-5-基)甲酮
59 1H-1,2,3-三唑-5-基{8-[(2,3,4-三氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}甲酮
60 2-氟-5-{[3-(1H-1,2,3-三唑-5-基羰基)-3,8-二氮杂双环[3.2.1]辛-8-基]磺酰基}苄腈
61{8-[(5-氯-2-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
62 1H-1,2,3-三唑-5-基{8-[(2,4,5-三氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}甲酮
63{8-[(5-氯-2-甲基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
64{8-[(2-甲氧基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
65{8-[(5-溴-2-甲基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
66[8-(1,3-苯并二氧戊环-5-基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-5-基)甲酮
67{8-[(2-甲氧基-4-甲基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
68 2-氯-6-{[3-(1H-1,2,3-三唑-5-基羰基)-3,8-二氮杂双环[3.2.1]辛-8-基]磺酰基}苄腈
69[8-(2,3-二氢-1-苯并呋喃-7-基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1H-1,2,3-三唑-5-基)甲酮
70{8-[(2-氯-5-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
71{8-[(2-氯-3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
72{8-[(4-氟-2-甲氧基苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮
73 4-甲氧基-3-{[3-(1H-1,2,3-三唑-5-基羰基)-3,8-二氮杂双环[3.2.1]辛-8-基]磺酰基}苄腈
74 4-氯-3-{[3-(1H-1,2,3-三唑-5-基羰基)-3,8-二氮杂双环[3.2.1]辛-8-基]磺酰基}苄腈
75 5-({8-[(3,5-二氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}羰基)-1,2,3-三唑-1-基钠
76 5-({8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}羰基)-1,2,3-三唑-1-基钠。
6.根据权利要求1的用途，其中通式(I)的化合物为{8-[(3-氟苯基)磺酰基]-3,8-二氮杂双环[3.2.1]辛-3-基}(1H-1,2,3-三唑-5-基)甲酮或其立体异构体、互变异构体、水合物或盐。
7.根据权利要求1至6中任一项的用途，其中所述症状是高雄激素血症、多毛症、痤疮或脱发。
8.根据权利要求1至6中任一项的用途，其中所述多囊卵巢相关的症状为多囊卵巢综合征(PCOS)。
9.根据权利要求1至6中任一项的用途，其中所述多囊卵巢相关的症状为PCOS的代谢表型。
10.根据权利要求9的用途，其中所述PCOS的代谢表型为肥胖、高血糖、葡萄糖耐受不良、胰岛素耐受、高胰岛素血症、高胆固醇血症、高血压、高脂蛋白血症、高脂血症、高甘油三酯血症、血脂异常或代谢综合征II型糖尿病。
11.根据权利要求1至6中任一项的用途，其中所述子宫内膜异位相关的妇科病症、病况或疾病为子宫内膜异位相关的症状、子宫内膜异位相关的增殖或骨盆过敏反应。
12.据权利要求11的用途，其中所述子宫内膜异位相关的症状为子宫内膜异位本身、子宫内膜异位症或子宫内膜异位相关的疼痛。
13.据权利要求11的用途，其中所述子宫内膜异位相关的症状为痛经、性交困难、排尿困难或大便困难。
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| CN201780032131.XA CN109311898B (zh) | 2016-05-26 | 2017-05-23 | [8-(苯基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基](1h-1,2,3-三唑-4-基)甲酮 |
| CN202210300836.8A CN114702503B (zh) | 2016-05-26 | 2017-05-23 | 甲酮化合物 |
| PCT/EP2017/062359 WO2017202817A1 (en) | 2016-05-26 | 2017-05-23 | [8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl] (1h-1,2,3-triazol-4-yl)methanones |
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| CN (4) | CN114699413A (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| TW201825478A (zh) * | 2016-12-19 | 2018-07-16 | 德商拜耳製藥公司 | ［４－（苯基磺醯基）哌嗪－１－-基］（１ｈ－１，２，３－三唑－４-基）甲酮 |
| JP7178075B2 (ja) * | 2018-03-22 | 2022-11-25 | 株式会社ユニバーサルコーポレーション | Ａｋｒ１ｃ３選択的阻害剤及びその用途 |
| CN110183455B (zh) * | 2019-06-18 | 2021-04-20 | 中国医科大学 | 氮杂双环[3.2.1]辛-3-酮类化合物及其制备方法与其用途 |
| WO2021000862A1 (zh) | 2019-07-01 | 2021-01-07 | 深圳艾欣达伟医药科技有限公司 | Akr1c3抑制剂及医药用途 |
| UY38806A (es) * | 2019-08-01 | 2021-02-26 | Novartis Ag | Compuestos inhibidores tricíclicos de kars dependientes de akr1c3, composiciones y sus usos |
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