CN107207547A - 烟曲霉醇衍生物 - Google Patents
烟曲霉醇衍生物 Download PDFInfo
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- CN107207547A CN107207547A CN201580074539.4A CN201580074539A CN107207547A CN 107207547 A CN107207547 A CN 107207547A CN 201580074539 A CN201580074539 A CN 201580074539A CN 107207547 A CN107207547 A CN 107207547A
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- independently selected
- compound
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- alkyl
- halogen
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- 150000001875 compounds Chemical class 0.000 claims abstract description 264
- 150000003839 salts Chemical class 0.000 claims abstract description 79
- 238000000034 method Methods 0.000 claims abstract description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 28
- 201000010099 disease Diseases 0.000 claims abstract description 27
- 208000024891 symptom Diseases 0.000 claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- -1 Melbine Chemical compound 0.000 claims description 99
- 238000006467 substitution reaction Methods 0.000 claims description 71
- 229910052736 halogen Inorganic materials 0.000 claims description 65
- 150000002367 halogens Chemical class 0.000 claims description 64
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 25
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- 150000002924 oxiranes Chemical class 0.000 claims description 21
- 125000004429 atom Chemical group 0.000 claims description 19
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- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
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- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 claims description 6
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- ZHIPXAFNKGZMSC-UHFFFAOYSA-N bis(4-methylphenyl)-oxophosphanium Chemical compound C1=CC(C)=CC=C1[P+](=O)C1=CC=C(C)C=C1 ZHIPXAFNKGZMSC-UHFFFAOYSA-N 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 5
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- AVSDQXOSLOFOMB-UHFFFAOYSA-N FC(C1=CC=C(C=C1)[PH2]=O)(F)F Chemical class FC(C1=CC=C(C=C1)[PH2]=O)(F)F AVSDQXOSLOFOMB-UHFFFAOYSA-N 0.000 claims description 4
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- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 claims description 3
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 229950001286 terutroban Drugs 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- 125000001730 thiiranyl group Chemical group 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 230000009974 thixotropic effect Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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Abstract
本文公开了式(1)的化合物、其立体异构体以及所述化合物和立体异构体的药学上可接受的盐,其中R1和R2如说明书中所定义。本公开还涉及用于制备式(1)的化合物的材料和方法,含有其的药物组合物,以及其用于治疗与MetAP2有关的肥胖和相关疾病、病症和病状的用途。
Description
发明领域
本发明涉及烟曲霉醇衍生物,并且更具体来说是膦氧化物和膦酸烟曲霉醇酯衍生物(它们是甲硫氨酸氨基肽酶2(MetAP2)的抑制剂),含有其的药物组合物,以及其用于治疗与MetAP2有关的疾病、病症和病状(包括肥胖)的用途。
发明背景
甲硫氨酸氨基肽酶是与钴和锰离子结合的酶。金属酶广泛存在于原核生物和真核生物细胞中,并且以三种形式存在,即MetAP1A、MetAP1D和MetAP2。参见M.Leszczyniecka等人,Oncogene 25:3471-78(2006)。它们负责从新生蛋白中除去N-端甲硫氨酸残基,这是蛋白质成熟中的一个重要步骤并且很可能对于适当的功能性调节、细胞内靶向和蛋白质转换是必不可少的。参见S.M.Arfin等人,Proc.Natl.Acad.Sci.USA 92:7714-18(1995)。MetAP2的已知(不可逆)抑制剂包括天然产物烟曲霉素以及其更有效的半合成类似物TNP-470(AGM-1470)。参见D.Ingber等人,Nature 348:555-57(1990);还参见E.C.Griffith等人,Chemistry&Biology 4(6):461-471(1997)。两种化合物都抑制血管生成,并且TNP-470已在许多临床试验中作为用于癌症的治疗法进行了评估。参见例如R.S.Herbst等人,J.Clin.Oncology 20(22):4440-47(2002)(非小细胞肺癌);C.J.Logothetis等人,Clin.Cancer Res.7:1198-1203(2001)(进行性雄激素依赖性前列腺癌);W.M.Stadler等人,J.Clin.Oncology 17(8):2541-45(1999)(转移性肾癌);A.P.Kudelka等人,N.Engl.J.Med.338:991-92(1998)(转移性宫颈癌);A.P.Kudelka等人,Clin.CancerRes.3:1501-05(1997)(宫颈鳞状细胞癌);以及P.Bhargava等人,Clin.Cancer Res.5:1989-95(1999)(肉瘤、结肠直肠癌和黑色素瘤)。
许多研究也表明MetAP2抑制剂可以用于治疗肥胖。举例来说,在各种小鼠肥胖模型中测试TNP-470并且显示剂量依赖性、可逆性体重减轻和脂肪组织损失。参见M.A.Rupnick等人,Proc.Natl.Acad.Sci.USA 99(16):10730-35(2002)。也已显示TNP-470会预防小鼠的饮食诱导的肥胖。参见E.等人,Circulation Research 94(12):1579-88(2004)。已显示用烟曲霉素进行治疗会减少小鼠的饮食诱导的肥胖,如通过脂肪细胞发育不良所证明,而且不会显著影响脂肪组织血管生成。参见H.R.Lijnen等人,Obesity 18(12):2241-46(2010)。此外,发现MetAP2抑制剂CKD-732会减少食物摄入、降低体重、脂肪量并且减小基因和饮食诱导的肥胖小鼠的脂肪细胞的大小。参见Y.M.Kim等人,J.Mol.Endocrinology,38:455-65(2007)。最近,CKD-732(半草酸贝洛拉尼(beloranibhemioxalate))已在成年肥胖患者(例如,30≤BMI≤45kg/m2)中进行了早期临床试验。
MetAP2的一些抑制剂在WO 2012/130906A1、WO 2012/122264 A1、US 2012/004162A1、WO 2010/065877 A2、WO 2010/065883 A2、WO 2009/117902 A1、WO 2009/073445 A2、WO2003/027104 A1、WO 2002/042295 A2、US 2002/0151493 A1、US 6949584 B2、WO 99/59987A1、WO 99/59986 A1、WO 98/56372 A1、EP 0359036 A1和EP 0354787 A1中有所描述。
发明概要
本发明提供了烟曲霉醇衍生物和其药学上可接受的盐。本发明还提供了含有烟曲霉醇衍生物的药物组合物并且提供了其用于治疗与MetAP2抑制有关的疾病、病症和病状(包括肥胖)的用途。
本发明的一个方面提供了式1的化合物:
其立体异构体或所述化合物或立体异构体的药学上可接受的盐,其中:
R1和R2各自独立地选自苯基、C3-5杂芳基、-OR4和-N(R4)R5,其中每个苯基和C3-5杂芳基独立地经0至3个Ra取代,并且每个C3-5杂芳基具有5或6个环原子,其中1或2个是独立地选自N、O和S的杂原子;
每个Ra独立地选自卤基、-CN、R3和R4;
每个R3独立地选自-OR4、-N(R4)R5、-NR4C(O)R6、-NR4C(O)OR5、-C(O)OR4、-C(O)N(R4)R5、-C(O)N(R4)OR5、-C(O)N(R4)S(O)2R6、-N(R4)S(O)2R6、-SR4、-S(O)R6、-S(O)2R6和-S(O)2N(R4)R5;
每个R4和R5独立地选自
(a)C1-6烷基、C2-6烯基和C2-6炔基,各自经0至3个Rb取代,以及
(b)C3-8环烷基-(CH2)m-、C2-6杂环基-(CH2)m-、C6-14芳基-(CH2)m-和C1-9杂芳基-(CH2)m-,各自经0至3个Rc取代;
每个R6独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C3-8环烷基-(CH2)m-、C2-6杂环基-(CH2)m-、C6-14芳基-(CH2)m-和C1-9杂芳基-(CH2)m-,各自经0至3个Rd取代;
每个Rb独立地选自卤基、-CN和R7;
每个Rc独立地选自
(a)卤基、-CN和R7,以及
(b)C1-6烷基、C2-6烯基和C2-6炔基,各自经0至3个Rb取代;
每个Rd独立地选自
(a)卤基、-CN和R7,以及
(b)C1-6烷基,其经0至3个Rb取代;
每个R7独立地选自-OR8、-N(R8)R9、-NR8C(O)R9、-NR8C(O)OR9、-C(O)OR8、-C(O)N(R8)R9、-C(O)N(R8)OR9、-C(O)N(R8)S(O)2R9、-N(R8)S(O)2R9、-SR8、-S(O)R8、-S(O)2R8和-S(O)2N(R8)R9;
每个R8和R9独立地选自C1-6烷基、C3-8环烷基-(CH2)m-和C2-6杂环基-(CH2)m-,各自经0至3个独立地选自卤基和-CN的取代基取代;并且
每个m独立地选自0、1、2、3和4;
其中R4、R5和R6中所列的每个杂芳基部分独立地具有1至4个独立地选自N、O和S的杂原子,并且R4、R5、R6和R8中所列的每个杂环基部分独立地具有1至4个独立地选自N、O和S的杂原子。
本发明的另一个方面提供了一种化合物,其选自以下化合物:
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)二苯基膦氧化物;
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)二对甲苯基膦氧化物;
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)双(4-(三氟甲基)苯基)膦氧化物;
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)膦酸二甲酯;
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)膦酸二乙酯;前述化合物中任一种的立体异构体;以及
前述化合物或立体异构体中任一种的药学上可接受的盐
本发明的另一个方面提供了一种由以下结构表示的化合物:
本发明的另一个方面提供了一种由以下结构表示的化合物:
本发明的另一个方面提供了一种由以下结构表示的化合物:
本发明的另一个方面提供了一种由以下结构表示的化合物:
本发明的另一个方面提供了一种由以下结构表示的化合物:
本发明的另一个方面提供了一种药物组合物,其包括式1的化合物、其立体异构体或所述化合物或立体异构体的药学上可接受的盐,或先前段落中所定义的所述化合物、立体异构体或药学上可接受的盐中的任一种;以及药学上可接受的赋形剂。
本发明的另一个方面提供了一种式1的化合物、其立体异构体或所述化合物或立体异构体的药学上可接受的盐,或先前段落中所定义的所述化合物、立体异构体或药学上可接受的盐中的任一种,其用作药物。
本发明的另一个方面提供了一种式1的化合物、其立体异构体或所述化合物或立体异构体的药学上可接受的盐,或先前段落中所定义的所述化合物、立体异构体或药学上可接受的盐中的任一种,其用于治疗选自高血糖症、糖尿病、血脂异常、肥胖、胰岛素抗性、X代谢综合征、葡萄糖耐受不良、多囊卵巢综合征、心血管疾病、非酒精性肝脂肪变性、动脉粥样硬化和普拉德-威利综合征(Prader-Willi syndrome)的疾病、病症或病状。
本发明的另一个方面提供了一种式1的化合物、其立体异构体或所述化合物或立体异构体的药学上可接受的盐,或先前段落中所定义的所述化合物、立体异构体或药学上可接受的盐中的任一种的用途,其用于制造用于治疗与MetAP2有关的疾病、病症或病状的药物。
本发明的另一个方面提供了一种治疗与MetAP2有关的疾病、病症或病状的方法,所述方法包括向受试者施用有效量的式1的化合物、其立体异构体或所述化合物或立体异构体的药学上可接受的盐,或先前段落中所定义的所述化合物、立体异构体或药学上可接受的盐中的任一种。
本发明的另一个方面提供了一种治疗受试者的疾病、病症或病状的方法,所述方法包括向所述受试者施用有效量的式1的化合物、其立体异构体或所述化合物或立体异构体的药学上可接受的盐,或先前段落中所定义的所述化合物、立体异构体或药学上可接受的盐中的任一种,其中所述疾病、病症或病状选自高血糖症、糖尿病、血脂异常、肥胖、胰岛素抗性、X代谢综合征、葡萄糖耐受不良、多囊卵巢综合征、心血管疾病、非酒精性肝脂肪变性、动脉粥样硬化和普拉德-威利综合征。
本发明的另一个方面提供了有效量的式1的化合物、其立体异构体或所述化合物或立体异构体的药学上可接受的盐,或先前段落中所定义的所述化合物、立体异构体或药学上可接受的盐中的任一种;以及至少一种额外的药理学活性剂。
发明详述
除非另有指示,否则本公开使用下文所提供的定义。
当与化学取代基或部分(例如,C1-6烷基)结合使用时,“经取代”意味着所述取代基或部分的一个或多个氢原子已经一个或多个非氢原子或基团置换,但条件是符合价态需求并且由所述取代产生化学稳定的化合物。
当与可测量的数值变量结合使用时,“约(About)”或“约(approximately)”是指所述变量的指示值和所述变量的在指示值的实验误差内或在指示值的±10%内的所有值,无论哪个更大。
“烷基”是指直链和支链饱和烃基,其通常具有指定数目的碳原子(例如,C1-4烷基是指具有1至4(即,1、2、3或4)个碳原子的烷基,C1-6烷基是指具有1至6个碳原子的烷基,等等)。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、戊-1-基、戊-2-基、戊-3-基、3-甲基丁-1-基、3-甲基丁-2-基、2-甲基丁-2-基、2,2,2-三甲基乙-1-基、正己基等。
“烷二基”是指二价烷基,其中烷基如上文所定义,并且通常具有指定数目的碳原子(例如,C1-4烷二基是指具有1至4(即,1、2、3或4)个碳原子的烷二基,C1-6烷二基是指具有1至6个碳原子的烷二基,等等)。烷二基的实例包括亚甲基、乙-1,1-二基、乙-1,2-二基、丙-1,3-二基、丙-1,2-二基、丙-1,1-二基、丙-2,2-二基、丁-1,4-二基、丁-1,3-二基、丁-1,2-二基、丁-1,1-二基、异丁-1,3-二基、异丁-1,1-二基、异丁-1,2-二基等。
“烯基”是指具有一个或多个碳-碳双键并且通常具有指定数目的碳原子的直链和支链烃基。烯基的实例包括乙烯基、1-丙烯-1-基、1-丙烯-2-基、2-丙烯-1-基、1-丁烯-1-基、1-丁烯-2-基、3-丁烯-1-基、3-丁烯-2-基、2-丁烯-1-基、2-丁烯-2-基、2-甲基-1-丙烯-1-基、2-甲基-2-丙烯-1-基、1,3-丁二烯-1-基、1,3-丁二烯-2-基等。
“炔基”是指具有一个或多个碳-碳三键并且通常具有指定数目的碳原子的直链或支链烃基。炔基的实例包括乙炔基、1-丙炔-1-基、2-丙炔-1-基、1-丁炔-1-基、3-丁炔-1-基、3-丁炔-2-基、2-丁炔-1-基等。
“卤基”、“卤素”和“卤代”可互换使用并且是指氟、氯、溴和碘。
“卤烷基”、“卤烯基”和“卤炔基”分别是指经一个或多个卤素原子取代的烷基、烯基和炔基,其中烷基、烯基和炔基如上文所定义,并且其通常具有指定数目的碳原子。卤烷基的实例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、1-氟乙基、1,1-二氟乙基、1-氯乙基、1,1-二氯乙基、1-氟-1-甲基乙基、1-氯-1-甲基乙基等。
“环烷基”是指通常具有组成一个环或多个环的指定数目的碳原子的饱和单环和双环烃基(例如,C3-8环烷基是指具有3至8个碳原子作为环成员的环烷基)。双环烃基可以包括分离环(不共用碳原子的两个环)、螺环(共用一个碳原子的两个环)、稠环(共用两个碳原子和两个共有碳原子之间的键的两个环)以及桥环(共用两个碳原子、但无共用键的两个环)。环烷基可以通过任何环原子连接,除非所述连接将会违反价态需求,并且当有所指示时,可以任选地包括一个或多个非氢取代基,除非所述取代将会违反价态需求。
单环环烷基的实例包括环丙基、环丁基、环戊基、环己基等。稠合双环环烷基的实例包括双环[2.1.0]戊基(即,双环[2.1.0]戊-1-基、双环[2.1.0]戊-2-基和双环[2.1.0]戊-5-基)、双环[3.1.0]己基、双环[3.2.0]庚基、双环[4.1.0]庚基、双环[3.3.0]辛基、双环[4.2.0]辛基、双环[4.3.0]壬基、双环[4.4.0]癸基等。桥连环烷基的实例包括双环[2.1.1]己基、双环[2.2.1]庚基、双环[3.1.1]庚基、双环[2.2.2]辛基、双环[3.2.1]辛基、双环[4.1.1]辛基、双环[3.3.1]壬基、双环[4.2.1]壬基、双环[3.3.2]癸基、双环[4.2.2]癸基、双环[4.3.1]癸基、双环[3.3.3]十一烷基、双环[4.3.2]十一烷基、双环[4.3.3]十二烷基等。螺环烷基的实例包括螺[3.3]庚基、螺[2.4]庚基、螺[3.4]辛基、螺[2.5]辛基、螺[3.5]壬基等。分离的双环环烷基的实例包括从双(环丁烷)、环丁烷环戊烷、双(环戊烷)、环丁烷环己烷、环戊烷环己烷、双(环己烷)等衍生而来的那些环烷基。
“亚环烷基”是指二价单环环烷基,其中环烷基如上文所述,其通过所述基团的单个碳原子连接,并且通常具有组成环的指定数目的碳原子(例如,C3-6亚环烷基是指具有3至6个碳原子作为环成员的亚环烷基)。实例包括亚环丙基、亚环丁基、亚环戊基和亚环己基。
“环烯基”是指部分不饱和的单环和双环烃基,通常具有组成一个环或多个环的指定数目的碳原子。和环烷基一样,双环环烯基可以包括分离环、螺环、稠环或桥环。类似地,环烯基可以通过任何环原子连接,并且当有所指示时,可以任选地包括一个或多个非氢取代基,除非所述连接或取代将会违反价态需求。环烯基的实例包括如上文所描述的环烷基的部分不饱和类似物,诸如环丁烯基(即,环丁烯-1-基和环丁烯-3-基)、环戊烯基、环己烯基、双环[2.2.1]庚-2-烯基等。
“芳基”是指具有至少一个芳环的完全不饱和单环芳族烃和多环烃,单环与多环芳基都通常具有组成其环成员的指定数目的碳原子(例如,C6-14芳基是指具有6至14个碳原子作为环成员的芳基)。所述基团可以通过任何环原子连接,并且当有所指示时,可以任选地包括一个或多个非氢取代基,除非所述连接或取代将会违反价态需求。芳基的实例包括苯基、联苯基、环丁次苄基、茚基、萘基、苯并环庚基、联苯烯基、芴基、从环庚三烯阳离子衍生而来的基团等。
“亚芳基”是指二价芳基,其中芳基如上文所述。亚芳基的实例包括亚苯基(即,苯-1,2-二基)。
“杂环”和“杂环基”可互换使用并且是指具有由碳原子和1至4个独立地选自氮、氧和硫的杂原子组成的环原子的饱和或部分不饱和单环或双环。单环与双环基团通常在其一个环或多个环中具有指定数目的碳原子(例如,C2-6杂环基是指具有2至6个碳原子和1至4个杂原子作为环成员的杂环基)。和双环环烷基一样,双环杂环基可以包括分离的环、螺环、稠环和桥环。杂环基可以通过任何环原子连接,并且当有所指示时,可以任选地包括一个或多个非氢取代基,除非所述连接或取代将会违反价态需求或产生化学不稳定的化合物。杂环基的实例包括环氧乙烷基、硫杂丙环基、氮丙啶基(例如,氮丙啶-1-基和氮丙啶-2-基)、氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、1,4-二噁烷基、1,4-氧硫杂环己烷基、吗啉基、1,4-二噻烷基、哌嗪基、1,4-氮杂硫杂环己烷基、氧杂环庚烷基、硫杂环庚烷基、氮杂环庚烷基、1,4-二氧杂环庚烷基、1,4-氧杂硫杂环庚烷基、1,4-氧杂氮杂环庚烷基、1,4-二硫杂环庚烷基、1,4-硫氮杂环庚烷基、1,4-二氮杂环庚烷基、3,4-二氢-2H-吡喃基、3,6-二氢-2H-吡喃基、2H-吡喃基、1,2-二氢吡啶基、1,2,3,4-四氢吡啶基、1,2,5,6-四氢吡啶基、1,6-二氢嘧啶基、1,2,3,4-四氢嘧啶基以及1,2-二氢吡唑并[1,5-d][1,2,4]三嗪基。
“杂环-二基”是指通过基团的两个环原子连接的杂环基,其中杂环基如上文所述。它们通常在其一个环或多个环中具有指定数目的碳原子(例如,C2-6杂环-二基是指具有2至6个碳原子和1至4个杂原子作为环成员的杂环-二基)。杂环-二基的实例包括如上文所描述的杂环基团的多价类似物,诸如吗啉-3,4-二基、吡咯烷-1,2-二基、1-吡咯烷基-2-亚基、1-吡啶基-2-亚基、1-(4H)-吡唑基-5-亚基、1-(3H)-咪唑基-2-亚基、3-噁唑基-2-亚基、1-哌啶基-2-亚基、1-哌嗪基-6-亚基等。
“杂芳族”和“杂芳基”可互换使用并且是指不饱和单环芳族基团和具有至少一个芳环的多环基团,所述基团各自具有由碳原子和1至4个独立地选自氮、氧和硫的杂原子组成的环原子。单环与多环基团都通常具有指定数目的碳原子作为环成员(例如,C1-9杂芳基是指具有1至9个碳原子和1至4个杂原子作为环成员的杂芳基)并且可以包括任何上文所列的单环杂环与苯环稠合的任何双环基团。所述杂芳基可以通过任何环原子(或用于稠环的环原子)连接,并且当有所指示时,可以任选地包括一个或多个非氢取代基,除非所述连接或取代将会违反价态需求或产生化学不稳定的化合物。杂芳基的实例包括单环基团,诸如吡咯基(例如,吡咯-1-基、吡咯-2-基和吡咯-3-基)、呋喃基、噻吩基、吡唑基、咪唑基、异噁唑基、噁唑基、异噻唑基、噻唑基、1,2,3-三唑基、1,3,4-三唑基、1-氧杂-2,3-二唑基、1-氧杂-2,4-二唑基、1-氧杂-2,5-二唑基、1-氧杂-3,4-二唑基、1-硫杂-2,3-二唑基、1-硫杂-2,4-二唑基、1-硫杂-2,5-二唑基、1-硫杂-3,4-二唑基、四唑基、吡啶基、哒嗪基、嘧啶基以及吡嗪基。
杂芳基的实例还包括双环基团,诸如苯并呋喃基、异苯并呋喃基、苯并噻吩基、苯并[c]噻吩基、1H-吲哚基、3H-吲哚基、异吲哚基、1H-异吲哚基、吲哚啉基、异吲哚啉基、苯并咪唑基、1H-吲唑基、2H-吲唑基、苯并三唑基、1H-吡咯并[2,3-b]吡啶基、1H-吡咯并[2,3-c]吡啶基、1H-吡咯并[3,2-c]吡啶基、1H-吡咯并[3,2-b]吡啶基、3H-咪唑并[4,5-b]吡啶基、3H-咪唑并[4,5-c]吡啶基、1H-吡唑并[4,3-b]吡啶基、1H-吡唑并[4,3-c]吡啶基、1H-吡唑并[3,4-c]吡啶基、1H-吡唑并[3,4-b]吡啶基、7H-嘌呤基、吲哚嗪基、咪唑并[1,2-a]吡啶基、咪唑并[1,5-a]吡啶基、吡唑并[1,5-a]吡啶基、吡咯并[1,2-b]哒嗪基、咪唑并[1,2-c]嘧啶基、喹啉基、异喹啉基、噌啉基、喹唑啉基、喹喔啉基、酞嗪基、1,6-萘啶基、1,7-萘啶基、1,8-萘啶基、1,5-萘啶基、2,6-萘啶基、2,7-萘啶基、吡啶并[3,2-d]嘧啶基、吡啶并[4,3-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡啶并[2,3-d]嘧啶基、吡啶并[2,3-b]吡嗪基、吡啶并[3,4-b]吡嗪基、嘧啶并[5,4-d]嘧啶基、吡嗪并[2,3-b]吡嗪基、嘧啶并[4,5-d]嘧啶基、1,2,3,4-四氢吡啶并[2,3-b]吡嗪基、2,3-二氢苯并[b][1,4]二氧杂环己烯基、3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪基、2,3-二氢-1H-苯并[d]咪唑基、苯并[d]噻唑基、2,3-二氢-1H-吡咯并[2,3-b]吡啶基、[1,2,4]三唑并[1,5-a]吡啶基、2,3-二氢-1H-咪唑并[4,5-b]吡啶基、四唑并[1,5-a]吡啶基、7H-吡咯并[2,3-d]嘧啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-a]嘧啶基、4,5-二氢-1H-吡唑并[3,4-d]嘧啶基、2,3,6,7-四氢-1H-嘌呤基、5H-吡咯并[2,3-b]吡嗪基、咪唑并[1,2-a]吡嗪基、咪唑并[1,2-b]哒嗪基以及4,5,6,7-四氢吡唑并[1,5-a]吡嗪基。
“亚杂芳基”是指通过基团的两个环原子连接的杂芳基,其中杂芳基如上文所述。它们通常在其一个环或多个环中具有指定数目的碳原子(例如,C3-5亚杂芳基是指具有3至5个碳原子和1至4个杂原子作为环成员的亚杂芳基)。亚杂芳基的实例包括如上文所描述的杂芳基的多价类似物,诸如吡啶-2,3-二基、吡啶-3,4-二基、吡唑-4,5-二基、吡唑-3,4-二基等。
“氧代”是指双键结合的氧(=O)。
“离去基团”是指在包括取代反应、消除反应和加成-消除反应的碎裂过程期间离开分子的任何基团。离去基团可以是离核基团,其中所述基团与原先充当离去基团与分子之间的键的电子对一起离开,或可以是离电体基团,其中所述基团不与电子对一起离开。离核离去基团的离开能力取决于其碱强度,其中最强碱是最弱离去基团。常见离核离去基团包括氮(例如,来自重氮盐);磺酸盐,包括烷基磺酸盐(例如,甲磺酸盐)、氟烷基磺酸盐(例如,三氟甲磺酸盐、六氟乙磺酸盐、全氟丁磺酸盐和三氟乙磺酸盐)以及芳基磺酸盐(例如,甲苯磺酸盐、对溴苯磺酸盐、对氯苯磺酸盐和对硝基苯磺酸盐(nosylate))。其它基团包括碳酸盐、卤离子、羧酸盐阴离子、酚盐离子和醇盐。通过用酸处理可以使一些较强碱(诸如NH2 -和OH-)成为较好的离去基团。常见离电体离去基团包括质子、CO2和金属。
“相反对映异构体”是指为参考分子的不可重叠镜像的分子,其可以通过将所述参考分子的所有立体异构中心翻转来获得。举例来说,如果参考分子具有S绝对立体化学构型,那么相反对映异构体则具有R绝对立体化学构型。同样,如果参考分子具有S,S绝对立体化学构型,那么相反对映异构体则具有R,R立体化学构型,等等。
具有给定立体化学构型的化合物的“立体异构体(Stereoisomer)”和“立体异构体(stereoisomers)”是指化合物的相反对映异构体和任何非对映异构体,包括化合物的几何异构体(Z/E)。举例来说,如果化合物具有S,R,Z立体化学构型,那么其立体异构体将会包括其具有R,S,Z构型的相反对映异构体,并且其非对映异构体具有S,S,Z构型、R,R,Z构型、S,R,E构型、R,S,E构型、S,S,E构型和R,R,E构型。如果化合物的立体化学构型并未指定,那么“立体异构体”是指化合物的可能的立体化学构型中的任一种。
“基本上纯的立体异构体”及其变体是指含有具有特定立体化学构型并且占样品的至少约95%的化合物的样品。
“纯的立体异构体”及其变体是指含有具有特定立体化学构型并且占样品的至少约99.5%的化合物的样品。
“受试者”是指哺乳动物,包括人。
“药学上可接受的”物质是指适合于向受试者施用的那些物质。
“治疗(Treating)”是指逆转、缓解所述术语所应用的疾病、病症或病状,抑制所述疾病、病症或病状的进展,或预防所述疾病、病症或病状,或逆转、缓解所述疾病、病症或病状的一种或多种症状,抑制所述一种或多种症状的进展,或预防所述一种或多种症状。
“治疗(Treatment)”是指如上文刚刚所定义的“治疗”的行为。
“药物”、“药物物质”、“活性药物成分”等是指可以用于治疗需要治疗的受试者的化合物(例如,式1的化合物,包括亚属化合物和说明书中具体命名的化合物)。
药物的“有效量”、药物的“治疗有效量”等是指可以用于治疗受试者的药物量并且可能取决于受试者的重量和年龄以及施用途径等。
“赋形剂”是指用于药物的任何稀释剂或媒介物。
“药物组合物”是指一种或多种药物物质和一种或多种赋形剂的组合。
“药品”、“药物剂型”、“剂型”、“最终剂型”等是指适合于治疗需要治疗的受试者并且通常可以呈片剂、胶囊、含有粉末或颗粒的药囊、液体溶液或悬浮液、贴片、膜等形式的药物组合物。
“与MetAP2有关的病状”和类似短语是关于受试者的疾病、病症或病状,对于所述疾病、病症或病状来说,对MetAP2的抑制可以提供治疗性或预防性益处。
在说明书中可以使用以下缩写词:Ac(乙酰基);ACN(乙腈);AIBN(偶氮-双异丁腈);API(活性药物成分);aq(水性);Boc(叔丁氧羰基);Cbz(苄氧羰基);dba(二亚苄基丙酮);DCC(1,3-二环己基碳化二亚胺);DCE(1,1-二氯乙烷);DCM(二氯甲烷);DIPEA(N,N-二异丙基乙胺、胡尼格氏碱(Hünig's Base));DMA(N,N-二甲基乙酰胺);DMAP(4-二甲基氨基吡啶);DMARD(改善病情的抗风湿药物);DME(1,2-二甲氧基乙烷);DMF(N,N-二甲基甲酰胺);DMSO(二甲亚砜);dppf(1,1'-双(二苯基膦)二茂铁);DTT(二硫苏糖醇);EC50(半数最大反应时的有效浓度);EDA乙氧基化十二烷醇,35);EDC(N-(3-二甲基氨基丙基)-N'-乙基碳化二亚胺);EDTA(乙二胺四乙酸);ee(对映异构体过量);eq(当量);Et(乙基);Et3N(三乙基-胺);EtOAc(乙酸乙酯);EtOH(乙醇);HATU(六氟磷酸2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基脲鎓(V));HEPES(4-(2-羟基乙基)哌嗪-1-乙烷磺酸);AcOH(乙酸);HOBt(1H-苯并[d][1,2,3]三唑-1-醇);IC50(50%抑制时的浓度);IPA(异丙醇);IPAc(乙酸异丙酯);IPE(异丙醚);LDA(二异丙基氨基锂);LiHMDS(双(三甲基甲硅烷基)氨基锂);mCPBA(间氯过氧苯甲酸);Me(甲基);MeOH(甲醇);MTBE(甲基叔丁醚);mp(熔点);NaOt-Bu(叔丁醇钠);NMM(N-甲基吗啉);OTf(三氟甲磺酸盐);PE(石油醚);Ph(苯基);pIC50(-log10(IC50),其中IC50是以摩尔(M)单位给出);Pr(丙基);i-Pr(异丙基);PTFE(聚四氟乙烯);RT(室温,约20℃至25℃);TCEP(三(2-羧乙基)膦);TFA(三氟乙酸);TFAA(2,2,2-三氟乙酸酐);THF(四氢呋喃);TMS(三甲基甲硅烷基);以及Tris缓冲液(2-氨基-2-羟基甲基-丙-1,3-二醇缓冲液)。
如下文所描述的,本公开是关于式1的化合物和其药学上可接受的盐。本公开还关于用于制备式1的化合物的材料和方法,含有其的药物组合物,以及式1的化合物和其药学上可接受的盐(任选地与其它药理学活性剂的组合)用于治疗与MetAP2有关的肥胖和其它疾病、病症或病状的用途。
除实施例中的特定化合物以外,式1的化合物还包括那些化合物,其中:(i)R1和R2各自独立地选自苯基和C3-5杂芳基,并且每个苯基和C3-5杂芳基独立地经0至3个Ra取代;(ii)每个R1和R2独立地选自苯基和C3-5杂芳基,每个C3-5杂芳基具有5个环原子,其中每个苯基和C3-5杂芳基独立地经0至3个Ra取代;(iii)每个R1和R2独立地选自苯基和C3-5杂芳基,每个C3-5杂芳基具有6个环原子,其中每个苯基和C3-5杂芳基独立地经0至3个Ra取代;或(iv)每个R1和R2独立地选自苯基和C3-5杂芳基,每个C3-5杂芳基是吡啶基,并且每个苯基和C3-5杂芳基独立地经0至3个Ra取代。
式1的化合物还包括那些化合物,其中:(v)每个R1和R2独立地选自苯基和C3-5杂芳基,并且每个C3-5杂芳基独立地选自吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、异噁唑基、噁唑基、异噻唑基、噻唑基、吡啶基、哒嗪基、嘧啶基和吡嗪基,其中每个苯基和C3-5杂芳基独立地经0至3个Ra取代。
除先前段落中的实施方案(i)至(v)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(vi)R1和R2都是C3-5杂芳基,并且每个C3-5杂芳基独立地经0至3个Ra取代。
式1的化合物还包括那些化合物,其中(vii)R1和R2都是苯基,并且每个苯基独立地经0至3个Ra取代。
除先前段落中的实施方案(i)至(vii)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(viii):
每个Ra独立地选自卤基、-CN、R3和R4;
每个R3独立地选自-OR4、-N(R4)R5、-NR4C(O)R6和-C(O)N(R4)R5;
每个R4和R5独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C6-14芳基-(CH2)m-,其经0至3个Rc取代;
每个R6独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C6-14芳基-(CH2)m-,其经0至3个Rd取代;
每个Rb独立地选自卤基、-CN和R7;
每个Rc和Rd独立地选自
(a)卤基、-CN和R7,以及
(b)C1-6烷基,其经0至3个Rb取代;
每个R7独立地选自-OR8、-N(R8)R9、-NR8C(O)R9和-C(O)N(R8)R9;并且
每个R8和R9独立地选自C1-6烷基和C3-8环烷基-(CH2)m-,各自经0至3个独立地选自卤基和-CN的取代基取代。
除先前段落中的实施方案(i)至(vii)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(ix):
每个Ra独立地选自卤基、-CN、R3和R4;
每个R3独立地选自-OR4和-N(R4)R5;
每个R4和R5独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C6-14芳基-(CH2)m-,其中所述C6-14芳基部分是经0至3个独立地选自Rb和C1-6烷基的取代基取代的苯基,并且每个C1-6烷基独立地经0至3个Rb取代;
每个Rb独立地选自卤基、-CN和R7;
每个Rc独立地选自
(a)卤基、-CN和R7,以及
(b)C1-6烷基,其经0至3个Rb取代;
每个R7独立地选自-OR8和-N(R8)R9;并且
每个R8和R9独立地选自C1-6烷基和C3-8环烷基-(CH2)m-,各自经0至3个独立地选自卤基和-CN的取代基取代。
除先前段落中的实施方案(i)至(vii)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(x):
每个Ra独立地选自卤基、-CN、R3和R4;
每个R3独立地选自-OR4和-N(R4)R5;
每个R4和R5独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C6-14芳基-(CH2)m-,其中所述C6-14芳基部分是经0至3个独立地选自Rb和C1-6烷基的取代基取代的苯基,并且每个C1-6烷基独立地经0至3个Rb取代;
每个Rb独立地选自卤基和-CN;并且
每个Rc独立地选自卤基、-CN和经0至3个Rb取代的C1-6烷基。
除先前段落中的实施方案(i)至(vii)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xi):
每个Ra独立地选自卤基、-CN、R3和R4;
每个R3独立地选自-OR4和-N(R4)R5;
每个R4和R5独立地选自经0至3个Rb取代的C1-6烷基;并且
每个Rb独立地选自卤基和-CN。
除先前段落中的实施方案(i)至(vii)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xii)Ra不存在。
式1的化合物还包括那些化合物,其中(xiii)R1和R2各自独立地是-OR4或-N(R4)R5;(xiv)R1和R2都是-OR4;或(xv)R1和R2都是-N(R4)R5。
除前述段落中的实施方案(xiii)至(xv)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xvi):
每个R4和R5独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C6-14芳基-(CH2)m-,其经0至3个Rc取代;
每个Rb独立地选自卤基、-CN和R7;
每个Rc独立地选自
(a)卤基、-CN和R7,以及
(b)经0至3个Rb取代的C1-6烷基;
每个R7独立地选自-OR8、-N(R8)R9、-NR8C(O)R9和-C(O)N(R8)R9;并且
每个R8和R9独立地选自C1-6烷基和C3-8环烷基-(CH2)m-,各自经0至3个独立地选自卤基和-CN的取代基取代。
除前述段落中的实施方案(xiii)至(xv)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xvii):
每个R4和R5独立地选自
(a)经0至3个Rb取代的C1-6烷基,以及
(b)C6-14芳基-(CH2)m-,其中所述C6-14芳基部分是经0至3个Rc取代的苯基;
每个Rb独立地选自卤基、-CN和R7;
每个Rc独立地选自
(a)卤基、-CN和R7,以及
(b)经0至3个Rb取代的C1-6烷基;
每个R7独立地选自-OR8和-N(R8)R9;并且
每个R8和R9独立地选自C1-6烷基和C3-8环烷基-(CH2)m-,各自经0至3个独立地选自卤基和-CN的取代基取代。
除前述段落中的实施方案(xiii)至(xv)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xviii):
每个R4和R5独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C6-14芳基-(CH2)m-,其中所述C6-14芳基部分是经0至3个Rc取代的苯基;
每个Rb独立地选自卤基和-CN;并且
每个Rc独立地选自卤基、-CN和C1-6烷基,其经0至3个Rb取代。
除前述段落中的实施方案(xiii)至(xv)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xix):
每个R4和R5独立地选自经0至3个Rb取代的C1-6烷基;并且
每个Rb独立地选自卤基和-CN。
除前述段落中的实施方案(xiii)至(xv)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xx):
每个R4和R5独立地选自经0至3个Rb取代的C1-3烷基;并且
每个Rb独立地选自卤基和-CN。
除前述段落中的实施方案(xiii)至(xv)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xxi):
每个R4和R5独立地选自甲基和乙基,各自经0至3个Rb取代;并且
每个Rb独立地选自卤基和-CN。
除前述段落中的实施方案(xiii)至(xv)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xxii):
每个R4和R5独立地是经0至3个Rb取代的甲基;并且
每个Rb独立地选自卤基和-CN。
除前述段落中的实施方案(xiii)至(xv)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xxiii):
每个R4和R5独立地是经0至3个Rb取代的乙基;并且
每个Rb独立地选自卤基和-CN。
除先前段落中的实施方案(i)至(viii)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xxiv)Rd不存在。
除先前段落中的实施方案(i)至(x)、(xiii)至(xviii)和(xxiv)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xxv)m是0、1、2或3;(xxvi)m是0、1或2;(xxvii)m是0或1;或(xxviii)m是0。
除先前段落中的实施方案(i)至(x)、(xiii)至(xviii)和(xxiv)至(xxviii)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xxix)Rc不存在。
除先前段落中的实施方案(i)至(xxix)中的一种以外或作为其的替代方法,式1的化合物包括那些化合物,其中(xxx)Rb不存在。
式1的化合物包括先前段落中所描述的实施方案(i)至(xxx)以及上文和实施例中具体命名的所有化合物,并且可以盐、复合物、溶剂合物、水合物和液晶的形式存在。同样,作为盐的式1的化合物可以复合物、溶剂合物、水合物和液晶的形式存在。
式1的化合物可以形成药学上可接受的复合物、盐、溶剂合物和水合物。这些盐包括酸加成盐(包括二酸)和碱盐。药学上可接受的酸加成盐包括从无机酸衍生而来的盐,所述无机酸诸如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、氢氟酸和亚磷酸;以及从有机酸衍生而来的无毒性盐,诸如脂族单羧酸和二羧酸、经苯基取代的链烷酸、羟基链烷酸、链烷二酸、芳族酸、脂族和芳族磺酸等。所述盐包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐、碳酸盐、硫酸氢盐、硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨基磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐(hibenzate)、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、焦谷氨酸盐、蔗糖酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐以及羟萘甲酸盐(xinofoate)。
药学上可接受的碱盐包括从碱衍生而来的盐,包括金属阳离子,诸如碱或碱土金属阳离子,以及胺。合适的金属阳离子的实例包括钠、钾、镁、钙、锌和铝。合适的胺的实例包括精氨酸、N,N'-二苄基乙二胺、氯普鲁卡因(chloroprocaine)、胆碱、二乙胺、二乙醇胺、二环己基胺、乙二胺、甘氨酸、赖氨酸、N-甲基葡萄糖胺、乙醇胺、2-氨基-2-羟基甲基-丙-1,3-二醇以及普鲁卡因。关于适用的酸加成盐和碱盐的讨论,参见S.M.Berge等人,J.Pharm.Sci.(1977)66:1-19;还参见Stahl和Wermuth,Handbook of PharmaceuticalSalts:Properties,Selection,and Use(2002)。
药学上可接受的盐可以使用各种方法来制备。举例来说,可以使式1的化合物与适当的酸或碱反应以产生所需的盐。或者,可以使式1的化合物的前体与酸或碱反应以除去酸或碱不稳定保护基或打开前体的内酯或内酰胺基团。另外,可以通过用适当的酸或碱处理或通过与离子交换树脂接触来将式1的化合物的盐转化成另一种盐(或游离形式)。在反应之后,如果所述盐从溶液中沉淀出来,那么可以通过过滤来将其分离,或通过蒸发回收盐来将其分离。盐的电离程度可以在完全电离至几乎非电离的范围内变化。
式1的化合物可以在范围为完全非晶至完全结晶的连续固态存在。术语“非晶”是指物质在分子水平上缺乏长程有序性并且视温度可展现固体或液体的物理性质的一种状态。通常,所述物质不会产生独特的X射线衍射图案并且当展现固体性质时更正式地被描述成液体。当加热后,发生了固体变成液体性质,它的特征是状态的变化,通常是第二级(“玻璃化转变”)。术语“结晶”是指物质在分子水平上具有规则有序的内部结构并且产生具有确定的峰的独特的X射线衍射图案的固相。所述物质在充分加热时也会展现液体性质,但从固体变成液体的特征是相变,通常是第一级(“熔点”)。
式1的化合物也可以未溶剂化和溶剂化形式存在。术语“溶剂合物”描述了包含化合物和一种或多种药学上可接受的溶剂分子(例如,乙醇)的分子复合物。术语“水合物”是溶剂为水的溶剂合物。药学上可接受的溶剂合物包括那些化合物,其中所述溶剂可以经同位素取代(例如,D2O、丙酮-d6、DMSO-d6)。
用于有机化合物的溶剂合物和水合物的目前公认的分类系统是在分离位点、通道和金属-离子配位的溶剂合物和水合物之间进行区分。参见例如K.R.Morris(H.G.Brittain编)Polymorphism in Pharmaceutical Solids(1995)。分离位点的溶剂合物和水合物是通过干预有机化合物的分子而使溶剂(例如,水)分子从相互直接接触中分离的那些。在通道溶剂合物中,溶剂分子位于晶格通道中,在所述通道中它们与其它溶剂分子相邻。在金属-离子配位的溶剂合物中,溶剂分子与金属离子结合。
当溶剂或水紧密结合时,复合物将具有不依赖于湿度的充分明确的化学计量。然而,当溶剂或水弱结合时,如在通道溶剂合物中和在吸湿性化合物中,水或溶剂含量将取决于湿度和干燥条件。在所述情况下,通常将观察到非化学计量。
式1的化合物也可以多组分复合物(除盐和溶剂合物以外)形式存在,其中所述化合物(药物)和至少一种其它组分是以化学计量或非化学计量量存在。这种类型的复合物包括包合物(药物-主体包合复合物)和共晶。后者通常被定义为中性分子成分的结晶复合物,其是通过非共价相互作用结合在一起,但也可以是中性分子与盐的复合物。可以通过熔融结晶,通过从溶剂再结晶,或通过将组分物理研磨在一起来制备共晶。参见例如O.Almarsson和M.J.Zaworotko,Chem.Commun.(2004)17:1889-1896。关于多组分复合物的一般性综述,参见J.K.Haleblian,J.Pharm.Sci.(1975)64(8):1269-88。
当经历合适的条件时,式1的化合物可以介晶态(中间相或液晶)形式存在。介晶态处于真的结晶态与真的液态(熔体或溶液)之间。因温度变化而产生的介晶性被描述成“热致性”,而因添加第二种组分(诸如水或另一种溶剂)而产生的介晶性被描述成“溶致性”。具有形成溶致性中间相的可能性的化合物被描述成“两亲性”并且包括具有极性离子性部分(例如,-COO-Na+、-COO-K+、-SO3 -Na+)或极性非离子性部分(诸如-N-N+(CH3)3)的分子。参见例如N.H.Hartshorne和A.Stuart,Crystals and the Polarizing Microscope(第4版,1970)。
每一种式1的化合物可以多晶型物、立体异构体、互变异构体或其一些组合的形式存在,可以进行同位素标记,可以因施用前药而产生,或在施用之后形成代谢物。
“前药”是指具有极少或无药理学活性的化合物,当在体内代谢时其会经历向具有所需的药理学活性的化合物的转化。可以通过用如例如H.Bundgaar,Design of Prodrugs(1985)中所描述的“前部分”替换药理学活性化合物中存在的适当的官能团来制备前药。前药的实例包括分别具有羧酸、羟基或氨基官能团的式1的化合物的酯、醚或酰胺衍生物。关于前药的进一步讨论,参见例如T.Higuchi和V.Stella“Pro-drugs as Novel DeliverySystems,”ACS Symposium Series 14(1975)和E.B.Roche编,Bioreversible Carriers inDrug Design(1987)。
“代谢物”是指在施用药理学活性化合物后体内所形成的化合物。实例包括分别具有甲基、烷氧基、叔氨基、仲氨基、苯基和酰胺基团的式1的化合物的羟基甲基、羟基、仲氨基、伯氨基、酚和羧酸衍生物。
式1的化合物可以因存在一个或多个立体异构中心、一个或多个双键或两者而产生的立体异构体形式存在。所述立体异构体可以是纯的、基本上纯的或混合物。所述立体异构体也可以由酸加成盐或碱盐产生,其中抗衡离子具有光学活性,例如当抗衡离子是D-乳酸盐或L-赖氨酸时。
式1的化合物可以互变异构体形式存在,所述互变异构体是由互变异构化产生的异构体。互变异构体性异构现象包括例如亚胺-烯胺、酮-烯醇、肟-亚硝基和酰胺-亚胺酸互变异构现象。
式1的化合物可以展现不止一种类型的异构现象。
可以通过诸如色谱和分级结晶的常规技术来分离几何(顺/反)异构体。
用于制备或分离具有特定立体化学构型的化合物的常规技术包括由合适的光学纯的前体进行手性合成或使用例如手性高压液相色谱(HPLC)对外消旋体(或盐或衍生物的外消旋体)进行解析。或者,可以使外消旋体(或外消旋前体)与合适的光学活性化合物(例如醇)反应,或在式1的化合物含有酸性或碱性部分、酸或碱(诸如酒石酸或1-苯基乙胺)的情况下反应。所得的非对映异构性混合物可以通过色谱、分级结晶等来分离,并且适当的非对映异构体转化成具有必需的立体化学构型的化合物。关于用于分离立体异构体的技术的进一步讨论,参见E.L.Eliel和S.H.Wilen,Stereochemistry of Organic Compounds(1994)。
式1的化合物可以具有同位素变化,其中至少一个原子由具有相同原子数目、但原子质量不同于通常在自然界中所发现的原子质量的原子替换。适合于包含在式1的化合物中的同位素包括例如氢的同位素,诸如2H和3H;碳的同位素,诸如11C、13C和14C;氮的同位素,诸如13N和15N;氧的同位素,诸如15O、17O和18O;硫的同位素,诸如35S;氟的同位素,诸如18F;氯的同位素,诸如36Cl;以及碘的同位素,诸如123I和125I。同位素变化(例如,氘、2H)的使用可以提供由较大代谢稳定性所产生的某些治疗优势,例如体内半衰期延长或剂量需求减少。另外,所公开化合物的某些同位素变化可以结合放射性同位素(例如,氚、3H或14C),其可适用于药物和/或底物组织分布研究。经正电子发射同位素(诸如11C、18F、15O和13N)取代可适用于正电子发射计算机断层扫描术(PET)研究以用于检查底物受体占用。可以通过类似于本公开中其它地方所描述的那些方法的方法,使用适当的同位素标记试剂替代非标记试剂来制备同位素标记的化合物。
式1的化合物可以使用下文所描述的技术来制备。流程和实施例中的一些可以省略常见反应的细节,这些常见反应包括氧化、还原等等,分离技术(萃取、蒸发、沉淀,色谱、过滤、研磨、结晶化等),以及分析程序,这些反应是有机化学领域技术人员所已知的。所述反应和技术的细节可见于许多论文中,包括Richard Larock,Comprehensive OrganicTransformations(1999),和由Michael B.Smith和其他人所编辑的大型丛书,Compendiumof Organic Synthetic Methods(1974以及下列等等)。起始物质和试剂可以从商业来源获得或可以使用文献方法来制备。一些反应流程可以忽略由化学转变所产生的次要产物(例如,来自酯水解反应的醇、来自二酸脱羧基反应的CO2等)。另外,在一些情况下,反应中间物可以用于后续步骤而无需分离或纯化(即,原位)。
在以下反应流程和实施例中的一些中,某些化合物可以使用保护基来制备,这防止了别的反应位点上的不合需要的化学反应。保护基也可以用于增强化合物的溶解性或另外改变物理性质。关于保护基策略的讨论,用于安装和除去保护基的材料和方法的描述,以及适用于常见官能团(包括胺、羧酸、醇、酮、醛等等)的保护基的汇编,参见T.W.Greene和P.G.Wuts,Protecting Groups in Organic Chemistry(1999)和P.Kocienski,ProtectiveGroups(2000)。
通常,在整个说明书中所描述的化学转变可以使用基本上化学计量量的反应物来进行,但某些反应可以由使用过量的一种或多种反应物而受益。另外,在整个说明书中所公开的许多反应可以在大约室温(RT)和周围温度下进行,但视反应动力学、产量等等而定,一些反应可以在高压下进行或使用较高温度(例如,回流条件)或较低温度(例如,-78℃至0℃)。在本公开和权利要求中对化学计量范围、温度范围、pH范围等的任何提及,无论是否明确地使用词语“范围”,都包括所指示的端点。
许多化学转变也可以使用一种或多种相容性溶剂,所述溶剂可能会影响反应速率和产量。视反应物的性质而定,一种或多种溶剂可以是极性质子性溶剂(包括水)、极性非质子性溶剂、非极性溶剂或一些组合。代表性溶剂包括饱和脂族烃(例如,正戊烷、正己烷、正庚烷、正辛烷、环己烷、甲基环己烷);芳族烃(例如,苯、甲苯、二甲苯);卤代烃(例如,二氯甲烷、氯仿、四氯化碳);脂族醇(例如,甲醇、乙醇、丙-1-醇、丙-2-醇、丁-1-醇、2-甲基-丙-1-醇、丁-2-醇、2-甲基-丙-2-醇、戊-1-醇、3-甲基-丁-1-醇、己-1-醇、2-甲氧基-乙醇、2-乙氧基-乙醇、2-丁氧基-乙醇、2-(2-甲氧基-乙氧基)-乙醇、2-(2-乙氧基-乙氧基)-乙醇、2-(2-丁氧基-乙氧基)-乙醇);醚(例如,二乙醚、二异丙醚、二丁醚、1,2-二甲氧基-乙烷、1,2-二乙氧基-乙烷、1-甲氧基-2-(2-甲氧基-乙氧基)-乙烷、1-乙氧基-2-(2-乙氧基-乙氧基)-乙烷、四氢呋喃、1,4-二噁烷);酮(例如,丙酮、甲基乙基酮);酯(乙酸甲酯、乙酸乙酯);含氮溶剂(例如,甲酰胺、N,N-二甲基甲酰胺、乙腈、N-甲基-吡咯烷酮、吡啶、喹啉、硝基苯);含硫溶剂(例如,二硫化碳、二甲亚砜、四氢-噻吩-1,1,-二氧化物);以及含磷溶剂(例如,六甲基磷三酰胺)。
在以下流程中,取代基标识符(例如,R1、R2、R3等)如上文对于式1所定义。然而,如先前所提到的,起始物质和中间物中的一些可以包括保护基,在最终产物之前除去所述保护基。在所述情况下,取代基标识符是指式1中所定义的部分和具有适当保护基的那些部分。举例来说,流程中的起始物质或中间物可以包括具有潜在反应性胺的R2取代基。在所述情况下,R2将包括如Boc或Cbz基团连接于胺或无Boc或Cbz基团连接于胺的部分。
流程A展示用于制备式1的化合物的通用方法。根据所述方法,使烟曲霉醇(A1)与以下物质反应:乙烯基膦氧化物(A2,其中R1和R2独立地是苯基或C3-5杂芳基,各自任选地经1-3个Ra取代),次膦酸对乙烯基酯或对乙烯基次膦酸酰胺(A2,其中分别R1和R2中的一个是苯基或C3-5杂芳基,各自任选地经取代,而另一个是-OR4或-N(R4)R5),膦酸对乙烯基酯或乙烯基膦酸二酰胺(A2,其中分别R1和R2都是-OR4或-N(R4)R5),或膦酰胺对乙烯基酯(A2,其中R1和R2中的一个是-OR4而另一个是-N(R4)R5)。在强碱(例如,KOH、NaOH、LiOH、NaH等)存在下和在一种或多种相容性溶剂(DMF、甲苯、甲基环己烷等)中,通常在室温下进行氧杂迈克尔加成(oxa-Michaeladdition)。烟曲霉醇(A1)可以通过烟曲霉素的碱水解反应来制备。举例来说,可以在室温下使以二环己基胺盐形式商购获得的烟曲霉素与氢氧化钠水溶液接触以产生A1。乙烯基反应物(A2)可以使用本领域中已知的方法来制备,例如通过使适当经取代的次膦酰氯、氯膦酸酯(phosphonochloridate)、膦酰氯(phosphonamidic chloride)、氯磷酸酯(phosphorochloridate)、次磷酰氯(phosphorodiamidic chloride)或磷酰氯(phosphoramidochloridate)与格氏试剂(Grignard reagent)(例如,CH2=CHMgBr)在相容性溶剂(例如,Et2O,THF)中反应以产生A2。
流程B展示用于制备流程A中的乙烯基反应物(A2)的另一种方法。根据所述方法,使乙烯基卤化物或三氟甲磺酸盐(B2,其中X=Br、I、OTf)与以下物质反应:必需的膦氧化物(B1,其中R1和R2独立地是苯基或C3-5杂芳基,各自任选地经取代),次膦酸酯或次膦酸酰胺(B1,其中R1和R2中的一个是苯基或C3-5杂芳基,各自任选地经取代,而另一个是-OR4或-N(R4)R5),膦酸酯或膦酸二酰胺(B1,其中R1和R2都是-OR4或-N(R4)R5),或膦酰胺酯(B1,其中R1和R2中的一个是-OR4而另一个是-N(R4)R5)。所述反应是在钯催化剂(例如,Pd(PPh3)4)和碱(Et3N、Na2CO3、K2CO3、Cs2CO3、K3PO4等)的存在下,在相容性溶剂(THF、DMF、二噁烷、甲苯等)中,通常在高温下进行。参见例如Xu等人,Synthesis 8:691-92(1986)(使二苯基膦氧化物和溴乙烯与Pd(Ph3P)4和Et3N在甲苯中在60℃下反应8小时,产生二苯基(乙烯基)膦氧化物);还参见Kalek等人,Organic Letters 10(20):4637-40(2008)(使膦酸二乙酯和溴乙烯与Pd(Ph3P)4和Cs2CO3在THF中在120℃下在微波反应器中反应10分钟,产生乙烯基膦酸二乙酯)。
流程中所叙述的方法可以按需要改变。举例来说,可以添加或除去保护基并且可以通过例如烷基化、酰化、水解、氧化、还原、酰胺化、磺酸化、炔基化等来进一步加工产物,以产生所需的最终产物。此外,包含立体异构体混合物的任何中间物或最终产物可以任选地通过手性柱色谱(例如,超临界流体色谱)或通过用如上文所描述的光学纯的试剂进行衍生来纯化,以产生所需的立体异构体。
应对包括上文所命名的化合物和其药学上可接受的复合物、盐、溶剂合物和水合物的式1的化合物评估其生物药学性质,诸如在pH范围内的溶解性和溶液稳定性、渗透性等,以选择适当的剂型和施用途径。意图用于药学用途的化合物可以结晶或非晶产物形式施用,并且可以例如通过诸如沉淀、结晶化、冷冻干燥、喷雾干燥、蒸发干燥、微波干燥或射频干燥的方法以固体栓塞、粉末或膜形式获得。
式1的化合物可以单独施用或相互组合或与不同于式1的化合物的一种或多种药理学活性化合物组合施用。通常,这些化合物中的一种或多种是以药物组合物(制剂)形式与一种或多种药学上可接受的赋形剂结合施用。赋形剂的选择取决于特定施用模式、赋形剂对溶解性和稳定性的作用以及剂型性质等。适用的药物组合物和其制备方法可例如见于A.R.Gennaro(编),Remington:The Science and Practice of Pharmacy(第20版,2000)。
式1的化合物可以经口施用。经口施用可以涉及吞咽,在这种情况下化合物通过胃肠道进入血流。或者或另外,经口施用可以涉及经粘膜施用(例如,经颊、舌下、舌上施用)以使得化合物通过口腔粘膜进入血流。
适合于经口施用的制剂包括固体、半固体和液体系统,诸如片剂;含有多颗粒或纳米颗粒、液体或粉末的软或硬胶囊;可填充有液体的锭剂;咀嚼片;凝胶;快速分散剂型;膜;卵形剂(ovules);喷雾;以及经颊或粘膜粘性贴片。液体制剂包括悬浮液、溶液、糖浆和酏剂。所述制剂可以用作软或硬胶囊(例如由明胶或羟丙基甲基纤维素制成)中的填充剂并且通常包含载剂(例如,水、乙醇、聚乙二醇、丙二醇、甲基纤维素、或合适的油)和一种或多种乳化剂、助悬剂或两者。液体制剂也可以通过对固体(例如,来自药囊)进行复水来制备。
式1的化合物也可以用于快速溶解、快速崩解剂型,诸如Liang和Chen,ExpertOpinion in Therapeutic Patents(2001)11(6):981-986中所描述的那些剂型。
对于片剂剂型来说,视剂量而定,活性药物成分(API)可以占剂型的约1wt%至约80wt%或更通常是剂型的约5wt%至约60wt%。除API以外,片剂可以包括一种或多种崩解剂、粘结剂、稀释剂、表面活性剂、助流剂、润滑剂、抗氧化剂、着色剂、调味剂、防腐剂和掩味剂。崩解剂的实例包括羧甲基淀粉钠(sodium starch glycolate)、羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲基纤维素钠、交联聚维酮、聚乙烯基吡咯烷酮、甲基纤维素、微晶纤维素、经C1-6烷基取代的羟丙基纤维素、淀粉、预胶凝化淀粉和海藻酸钠。通常,崩解剂将占剂型的约1wt%至约25wt%或约5wt%至约20wt%。
粘结剂通常用于赋予片剂制剂凝聚特质。合适的粘结剂包括微晶纤维素、明胶、糖、聚乙二醇、天然和合成树胶、聚乙烯基吡咯烷酮、预胶凝化淀粉、羟丙基纤维素和羟丙基甲基纤维素。片剂也可以含有稀释剂,诸如乳糖(单水合物、喷雾干燥的单水合物、无水)、甘露糖醇、木糖醇、右旋糖、蔗糖、山梨糖醇、微晶纤维素、淀粉和二元磷酸钙二水合物。
片剂还可以包括诸如月桂基硫酸钠和聚山梨醇酯80的表面活性剂,和诸如二氧化硅和滑石的助流剂。当存在时,表面活性剂可以占片剂的约0.2wt%至约5wt%,并且助流剂可以占片剂的约0.2wt%至约1wt%。
片剂也可以含有润滑剂,诸如硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酰富马酸钠以及硬脂酸镁与月桂基硫酸钠的混合物。润滑剂可以占片剂的约0.25wt%至约10wt%或约0.5wt%至约3wt%。
片剂掺合物可以直接压制或通过辊压来形成片剂。在制成片剂之前片剂掺合物或掺合物的部分可以可选地为湿式、干式或熔融制粒,熔融凝固,或挤压。必要时,在掺合组分中的一种或多种之前,可以通过筛选或研磨或两者来确定尺寸。最终剂型可以包含一个或多个层并且可以包衣,未包衣,或经过囊封。示例性片剂可以含有高达约80wt%API、约10wt%至约90wt%粘结剂、约0wt%至约85wt%稀释剂、约2wt%至约10wt%崩解剂和约0.25wt%至约10wt%润滑剂。关于掺合、制粒、研磨、筛选、制片、包衣的讨论,以及用于制备药品的替代性技术的描述,参见A.R.Gennaro(编),Remington:The Science and Practiceof Pharmacy(第20版,2000);H.A.Lieberman等人(编),Pharmaceutical Dosage Forms:Tablets,第1-3卷(第2版,1990);和D.K.Parikh和C.K.Parikh,Handbook ofPharmaceutical Granulation Technology,第81卷(1997)。
用于人或兽医学用途的可消耗口服膜是柔软的水溶性或遇水膨胀性薄膜剂型,其可以快速溶解或具有粘膜粘性。除API以外,典型的膜包括一种或多种膜形成聚合物、粘结剂、溶剂、保湿剂、增塑剂、稳定剂或乳化剂、粘度改变剂和溶剂。其它膜成分可以包括抗氧化剂、着色剂、调味剂和风味增强剂、防腐剂、唾液刺激剂、冷却剂、共溶剂(包括油)、软化剂、膨松剂、消泡剂、表面活性剂以及掩味剂。制剂的一些组分可以执行一种以上功能。
除给药需求以外,膜中API的量可以取决于其溶解性。如果具有水溶性,则API通常将占膜中非溶剂组分(溶质)的约1wt%至约80wt%或膜中溶质的约20wt%至约50wt%。难溶性API可以占组合物的较大比例,通常高达膜中非溶剂组分的约88wt%。
膜形成聚合物可以选自天然多糖、蛋白质或合成水胶体并且通常占膜的约0.01wt%至约99wt%或约30wt%至约80wt%。
通常通过对包覆于可剥离的背衬支持物或纸上的薄水性膜进行蒸发干燥来制备膜剂型,这可以在烘炉或烘道中(例如,在组合型包衣-干燥设备中),在冻干装置中,或在真空烘箱中进行。
适用于经口施用的固体制剂可以包括立即释放制剂和改良释放制剂。改良释放制剂包括延迟、持续、脉冲、控制、标靶和程序化释放。关于合适的改良释放制剂的一般描述,参见美国专利申请No.6,106,864。关于其它适用的释放技术的细节,诸如高能分散和渗透性和包衣颗粒,参见Verma等人,Pharmaceutical Technology On-line(2001)25(2):1-14。
式1的化合物也可以直接施用于受试者的血流、肌肉或内脏中。适合于肠胃外施用的技术包括静脉内、动脉内、腹腔内、鞘内、心室内、尿道内、胸骨内、颅内、肌肉内、滑膜内和皮下施用。适合于肠胃外施用的装置包括针注射器,包括微针注射器、无针注射器和输液装置。
肠胃外制剂通常是水性溶液,其可以含有诸如盐、碳水化合物和缓冲剂(例如,约3至约9的pH)的赋形剂。然而,对于一些应用来说,式1的化合物可能更适合配制成无菌非水性溶液或干燥形式以与合适的媒介物(诸如无菌、无热原水)结合使用。在无菌条件下(例如,通过冻干)制备肠胃外制剂可以容易地使用标准药学技术来实现。
用于制备肠胃外溶液的化合物的溶解性可以通过适当的配制技术来提高,诸如并入溶解性增强剂。用于肠胃外施用的制剂可以配制成立即或改良释放。改良释放制剂包括延迟、持续、脉冲、控制、靶向和程序化释放。因此,式1的化合物可以配制成悬浮液、固体、半固体或触变性液体以用于以植入式储存器形式施用,从而提供活性化合物的改良释放。所述制剂的实例包括涂有药物的支架和包含载有药物的聚(DL-乳酸-共乙醇)酸(PGLA)微球的半固体和悬浮液。
式1的化合物也可以局部、皮内或经皮施用于皮肤或粘膜。用于这种目的的典型的制剂包括凝胶、水凝胶、洗液、溶液、乳膏、软膏、撒布粉、敷料、泡沫、膜、皮肤贴片、薄片、植入物、海绵、纤维、绷带和微乳液。也可以使用脂质体。典型的载剂可以包括醇、水、矿物油、液体矿脂、白矿脂、甘油、聚乙二醇和丙二醇。局部用制剂还可以包括渗透增强剂。参见例如Finnin和Morgan,J.Pharm.Sci.88(10):955-958(1999)。
局部施用的其它方式包括通过电穿孔、离子电渗法、声波导入法、超声波导入法和微针或无针(例如PowderjectTM和BiojectTM)注射来递送。用于局部施用的制剂可以如上文所描述的配制成立即或改良释放。
式1的化合物也可以经鼻或通过吸入来施用,通常以干粉、气溶胶喷雾或滴鼻剂形式。吸入器可以用于施用干粉,其包含单独API,API与稀释剂(诸如乳糖)的粉末掺合物,或包括API和磷脂(诸如磷脂酰胆碱)的混合组分颗粒。对于经鼻使用来说,粉末可以包括生物粘附剂,例如壳聚糖或环糊精。增压容器、泵、喷洒器、雾化器或喷雾器可以用于由包含以下物质的溶液或悬浮液产生气溶胶喷雾:API,一种或多种用于分散、溶解API(例如,含水或不含水的EtOH)或延长其释放的试剂,一种或多种充当推进剂的溶剂(例如,1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷),以及任选的表面活性剂(诸如脱水山梨醇三油酸酯、油酸或寡乳酸)。使用电水动力学的雾化器可以用于产生细雾。
在用于干粉或悬浮液制剂之前,通常将药品粉碎成适合于通过吸入递送的粒度(通常,以体积计90%的颗粒具有小于5微米的最大尺寸)。这可以通过任何适当的尺寸缩减方法来实现,诸如螺旋气流研磨、流化床气流研磨、超临界流体处理、高压均质化或喷雾干燥。
用于吸入器或吹入器的胶囊、泡罩和药筒(例如由明胶或羟丙基甲基纤维素制成)可以配制成含有活性化合物、合适的粉末基质(诸如乳糖或淀粉)和性能改良剂(诸如L-亮氨酸、甘露糖醇或硬脂酸镁)的粉末混合物。乳糖可以是无水或单水合物。其它合适的赋形剂包括葡聚糖、葡萄糖、麦芽糖、山梨糖醇、木糖醇、果糖、蔗糖和海藻糖。
适合用于使用电水动力学来产生细雾的雾化器的溶液制剂可以含有每驱动一次约1μg至约20mg API并且驱动体积可以在约1μL至约100μL范围内变化。典型的制剂可以包含一种或多种式1的化合物、丙二醇、无菌水、EtOH和NaCl。可用来替代丙二醇的替代性溶剂包括甘油和聚乙二醇。
用于吸入施用、经鼻施用或两者的制剂可以使用例如PGLA来配制成立即或改良释放。合适的诸如薄荷醇和左薄荷脑(levomenthol)的香味剂或诸如糖精或糖精钠的甜味剂可以添加至意图用于吸入/经鼻施用的制剂中。
在干粉吸入器和气溶胶的情况下,借助于递送所计量的量的阀门来确定剂量单位。通常将单位安排成施用所计量的剂量或含有约10μg至约1000μg API的“一喷”。总日剂量通常将在约100μg至约10mg范围内,这可以单次剂量施用或更通常在一整天内以分次剂量施用。
活性化合物可以经直肠或经阴道施用,例如以栓剂、阴道栓剂或灌肠剂的形式。可可脂是一种传统的栓剂基质,但可以酌情使用各种替代物。用于经直肠或阴道施用的制剂可以如上文所描述的配制成立即或改良释放。
式1的化合物也可以直接施用于眼睛或耳朵,通常以微粉化悬浮液或溶液于等张、经过pH调节的无菌生理盐水中的滴剂的形式。适合于经眼和经耳施用的其它制剂包括乳膏、凝胶、生物可降解性植入物(例如可吸收性凝胶海绵、胶原蛋白)、非生物可降解性植入物(例如硅酮)、薄片、晶体和颗粒或囊泡系统(诸如类脂囊泡(niosomes)或脂质体)。制剂可以包括一种或多种聚合物和防腐剂,诸如苯扎氯铵。典型的聚合物包括交联聚丙烯酸、聚乙烯基醇、透明质酸、纤维素聚合物(例如,羟丙基甲基纤维素、羟乙基纤维素、甲基纤维素)和杂多糖聚合物(例如,结冷胶(gelan gum))。所述制剂也可以通过离子电渗法来递送。用于经眼或经耳施用的制剂可以如上文所描述的配制成立即或改良释放。
为改良其溶解性、溶解速率、掩味、生物利用度或稳定性,可以将式1的化合物与可溶性大分子实体组合,包括环糊精和其衍生物以及含有聚乙二醇的聚合物。举例来说,API-环糊精复合物通常适用于大多数剂型和施用途径。可以使用包合与非包合复合物。作为与API直接复合的替代方法,可以使用环糊精作为辅助添加剂,即作为载剂、稀释剂或增溶剂。α-、β-和γ-环糊精常用于这些目的。参见例如WO 91/11172、WO 94/02518和WO 98/55148。
如上文所指出,一种或多种式1的化合物,包括上文具体命名的化合物和其药学活性复合物、盐、溶剂合物和水合物,可以相互组合或与一种或多种其它活性药学活性化合物组合以治疗各种疾病、病状和病症。在所述情况下,活性化合物可以如上文所描述的组合成单一剂型或可以试剂盒形式提供,所述试剂盒适合于组合物的共施用。试剂盒包括(1)两种或更多种不同药物组合物,其中至少一种含有式1的化合物;以及(2)用于分开保存两种药物组合物的装置,诸如分次瓶或分次铝箔包。所述试剂盒的实例是用于片剂或胶囊包装的熟悉的泡罩包装。试剂盒适合于施用不同类型的剂型(例如,口服和肠胃外)或以独立的给药时间间隔施用不同药物组合物,或相互滴定不同的药物组合物。为了在患者顺应性上给予帮助,试剂盒通常包括施用指导并且可以提供记忆辅助。
对于向人患者施用来说,所要求保护和所公开的化合物的总日剂量通常在约0.1mg至约3000mg范围内,这取决于施用途径。举例来说,经口施用可能需要约1mg至约3000mg的总日剂量,而静脉内剂量可能只需要约0.1mg至约300mg的总日剂量。总日剂量可以单次或分次剂量施用并且在医师的指导下可以在上文所给出的典型范围外。尽管这些剂量是基于具有约60kg至约70kg质量的人受试者平均值,但医师仍将能够确定用于质量在这一重量范围外的患者(例如,婴儿)的适当剂量。
如上文所指出,式1的化合物可以用于治疗指示MetAP2的抑制的疾病、病症和病状。所述疾病、病症和病状通常与受试者的任何不健康或反常状态有关,对于所述状态,MetAP2的抑制提供了一种治疗性益处。更具体来说是,式1的化合物可以用于治疗受试者的肥胖或超重病状,或治疗与肥胖或超重病状有关的疾病、病症或病状,包括心血管疾病、高血压、糖尿病、高血糖症、胰岛素抗性、X代谢综合征、葡萄糖耐受不良、非酒精性肝脂肪变性、血脂异常(包括高总胆固醇或高甘油三酯水平)、动脉粥样硬化、中风、睡眠呼吸暂停、骨关节炎、不孕不育、多囊卵巢综合征和普拉德-威利综合征。
根据2000年由美国国家心肺血研究所(National Heart,Lung,and BloodInstitute)公布的The Practical Guide:Identification,Evaluation,and Treatmentof Overweight and Obesity in Adults,基于受试者的身体质量指数(BMI),可以将成年人类分类为超重或肥胖。通过将受试者的质量(以kg计)除以受试者身高(以米计)的平方来计算BMI。根据Guide,将25-29.9kg/m2的BMI分类为超重,并且将30-34.9kg/m2、35-39.9kg/m2和≥40kg/m2的身体质量指数分别分类为1类肥胖、2类肥胖和3类(极度)肥胖。
可以将所要求保护和所公开的化合物与一种或多种其它药理学活性化合物或疗法组合以治疗一种或多种指示MetAP2的病症、疾病或病状,包括肥胖。举例来说,式1的化合物,包括上文具体命名的化合物和其药学上可接受的复合物、盐、溶剂合物和水合物,可以与一种或多种化合物或疗法组合同时、依序或分开施用以用于治疗心血管疾病、高血压、糖尿病、高血糖症、胰岛素抗性、X代谢综合征、葡萄糖耐受不良、非酒精性肝脂肪变性、血脂异常、动脉粥样硬化、中风、睡眠呼吸暂停、骨关节炎、不孕不育、多囊卵巢综合征和普拉德-威利综合征。所述组合可以提供显著治疗优势,包括极少副作用、治疗底层患者群体的能力得到提高或协同作用活性。
举例来说,可以将式1的化合物与一种或多种用于治疗肥胖、糖尿病、高血糖症、胰岛素抗性、X代谢综合征、葡萄糖耐受不良和非酒精性肝脂肪变性的药剂组合。这些药剂包括胰脂肪酶抑制剂(例如,奥利司他(orlistat));胰岛素;胰岛素敏化剂,包括双胍(例如,丁双胍(buformin)、二甲双胍(metformin)和苯乙双胍(phenformin))和格列酮(glitazone)(例如,吡格列酮(pioglitazone)和罗格列酮(rosiglitazone));胰岛素促分泌物,包括磺酰脲(例如,醋磺环己脲(acetohexamide)、氯磺丙脲(chlorpropamide)、妥拉磺脲(tolazamide)、甲苯磺丁脲(tolbutamide)、格列齐特(gliclazide)、格列美脲(glimepiride)、格列吡嗪(glipizide)和格列本脲(glyburide))和美格列奈(meglitinide)(例如,那格列奈(nateglinide)和瑞格列奈(repaglinide));α-葡萄糖苷酶抑制剂(例如,阿卡波糖(acarbose)和米格列醇(miglitol));胰高血糖素样肽类似物和激动剂(例如,艾塞那肽(exenatide)、利拉鲁肽(liraglutide)和他司鲁肽(taspoglutide));二肽基肽酶-4抑制剂(例如,阿洛利停(alogliptin)、利拉利汀(linagliptin)、沙克列汀(saxagliptin)、西他列汀(sitagliptin)和维格列汀(vildagliptin));以及胰淀素(amylin)类似物(例如,普兰林肽(pramlinitide))。
另外,式1的化合物可以与一种或多种用于治疗骨关节炎的药剂组合,包括非类固醇消炎药(NSAID)(例如,阿扎丙宗(apazone)、阿司匹林(aspirin)、塞来昔布(celecoxib)、双氯芬酸(diclofenac)(含和不含米索前列醇(misoprostol))、双氟尼酸(diflunisal)、依托度酸(etodolac)、非诺洛芬(fenoprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚美辛(indomethacin)、酮洛芬(ketoprofen)、甲氯芬那酸钠(meclofenamate sodium)、甲芬那酸(mefenamic acid)、美洛昔康(meloxicam)、萘丁美酮(nabumetone)、萘普生(naproxen)、奥沙普秦(oxaprozin)、保泰松(phenylbutazone)、吡罗昔康(piroxicam)、水杨酸胆碱和水杨酸镁、双水杨酸酯(salsalate)和舒林酸(sulindac));止痛药(例如,扑热息痛(acetaminophen)和硫酸吗啡),以及可待因(codeine)、氢可酮(hydrocodone)、羟考酮(oxycodone)、丙氧酚(propoxyphene)和曲马多(tramadol),全部都含或不含扑热息痛);皮质类固醇(例如,倍他米松(betamethasone)、乙酸可的松(cortisone acetate)、地塞米松(dexamethasone)、氢化可的松(hydrocortisone)、甲泼尼龙(methylprednisolone)、氢化泼尼松(prednisolone)和泼尼松(prednisone));以及骨质疏松药(例如,阿仑膦酸盐(alendronate)、氯膦酸盐(clodronate)、依替膦酸盐(etidronate)、伊班膦酸盐(ibandronate)、奈立膦酸盐(neridronate)、奥帕膦酸盐(olpadronate)、帕米膦酸盐(pamidronate)、利塞膦酸盐(risedronate)、替鲁膦酸盐(tiludronate)和唑来膦酸盐(zoledronate))。
式1的化合物也可以与一种或多种用于治疗心血管疾病、高血压、血脂异常、动脉粥样硬化和中风的药剂组合,包括钙通道阻断剂(例如,氨氯地平(amlodipine)、阿雷地平(aranidipine)、阿折地平(azelnidipine)、巴尼地平(barnidipine)、苄普地尔(bepridil)、贝尼地平(benidipine)、西尼地平(cilnidipine)、氯维地平(clevidipine)、硫氮卓酮(diltiazem)、伊拉地平(isradipine)、依福地平(efonidipine)、非洛地平(felodipine)、芬地林(fendiline)、氟司必林(fluspirilene)、拉西地平(lacidipine)、乐卡地平(lercanidipine)、马尼地平(manidipine)、米贝拉地尔(mibefradil)、尼卡地平(nicardipine)、硝苯地平(nifedipine)、尼伐地平(nilvadipine)、尼莫地平(nimodipine)、尼索地平(nisoldipine)、尼群地平(nitrendipine)、普拉地平(pranidipine)和维拉帕米(verapamil));他汀(statin)(例如,阿托伐他汀(atorvastatin)、氟伐他汀(fluvastatin)、洛伐他汀(lovastatin)、美伐他汀(mevastatin)、匹伐他汀(pitavastatin)、普伐他汀(pravastatin)、瑞舒伐他汀(rosuvastatin)和辛伐他汀(simvastatin));PPARα活化剂(例如,贝特(fibrate),诸如苯扎贝特(bezafibrate)、环丙贝特(ciprofibrate)、氯贝特(clofibrate)、非诺贝特(fenofibrate)和吉非罗齐(gemfibrozil));胆酸螯合剂(例如,消胆胺(cholestyramine)、考来维仑(colesevelam)和考来替泊(colestipol));其它降脂药(例如,烟酸(niacin)和依替米贝(ezetimibe));β-阻断剂(例如,阿普洛尔(alprenolol)、阿替洛尔(atenolol)、倍他洛尔(betaxolol)、比索洛尔(bisoprolol)、布新洛尔(bucindolol)、卡替洛尔(carteolol)、卡维地洛(carvedilol)、塞利洛尔(celiprolol)、艾司洛尔(esmolol)、杜仲(eucommia bark)、拉贝洛尔(labetalol)、美托洛尔(metoprolol)、纳多洛尔(nadolol)、奈必洛尔(nebivolol)、氧烯洛尔(oxprenolol)、喷布洛尔(penbutolol)、品多洛尔(pindolol)、普萘洛尔(propranolol)、索他洛尔(sotalol)和噻吗洛尔(timolol));血管紧张素转化酶(ACE)抑制剂(贝那普利(benazepril)、卡托普利(captopril)、依那普利(enalapril)、咪达普利(imidapril)、赖诺普利(lisinopril)、培哚普利(perindopril)、喹那普利(quinapril)、雷米普利(ramipril)、群多普利(trandolapril)和佐芬普利(zofenopril));以及血小板聚集抑制剂(阿昔单抗(abciximab)、阿司匹林、西洛他唑(cilostazol)、氯吡格雷(clopidogrel)、双嘧达莫(dipyridamole)、双嘧达莫、依替巴肽(eptifibatide)、伊菲曲班(ifetroban)、匹考他胺(picotamide)、普拉格雷(prasugrel)、特鲁曲班(terutroban)、替卡格雷(ticagrelor)、噻氯匹定(ticlopidine)和替罗非班(tirofiban))。
生物学活性
式1的化合物的生物学活性可以使用各种体外和体内方法来确定。以下体外测定测量测试化合物抑制MetAP2的能力。体内测定测量测试化合物诱导体重减轻或降血糖活性的能力。
MetAP2蛋白纯化
编码人MetAP2酶的全长序列的DNA通过PCR扩增并且克隆至pFastBac表达载体(Invitrogen)中。通过使用Bac-to-Bac系统(Invitrogen)进行转座来产生合并了MetAP2构建体的重组杆状病毒。通过在5L波动生物反应器(Wave Bioreactors)(Wave Biotech)中进行草地贪夜蛾(Spodoptera frugiperda)Sf9细胞(Invitrogen)的感染来进行重组蛋白的表达。通过与SP Hitrap Fast Flow或SP Sepharose(Sigma)柱结合来从细胞提取物中分离出重组蛋白,并且使用NaCl梯度洗脱所述蛋白。通过AKTA FPLC在Superdex-200柱(GE)上进一步纯化MetAP2的部分纯化提取物。在变性SDS-PAGE凝胶上确定MetAP2蛋白的纯度。将纯化的MetAP2蛋白浓缩至17mg/mL或2.5mg/mL的最终浓度。将蛋白在-78℃下贮存于含有10mMHEPES(pH 7.4)、150mM NaCl和1mM CoCl2的缓冲液中或含有20mM HEPES(pH 7.4)、120mMNaCl和5mM MnCl2的缓冲液中。
酶测定:MetAP2的抑制
使用黑色384孔板格式在以下反应条件下确定MetAP2的抑制:50mM Hepes(pH7.5)、100mM NaCl、10μM MnCl2或10μM CoCl2、0.005%1mM TCEP、1%DMSO。为了开始所述测定,将4μL 5至50nM MetAP2酶溶液(酶最终浓度是2至20nM)添加至每一个孔中,随后添加在含有5%DMSO的缓冲溶液中的2μL测试化合物(2.5倍连续稀释液,用于各测试化合物的11个数据点)。接着,将4μL底物溶液(2.5x Km Met-AMC)添加至所述板的每一个孔中(在Km值下的最终底物浓度)。通过使用荧光板读取器在460nm下用330nm激发波长读取荧光监测反应速率,历时10至30分钟。将每一个孔的结果表示为抑制百分比并使用以下等式进行计算:
其中是在测试化合物不存在下板上所有速率的平均值,是使用10μM工具化合物的速率(MetAP2活性是100%得到抑制),并且x是在测试化合物存在下的速率(原始数据)。通过使用标准4参数等式拟合抑制百分比数据来获得各测试化合物的IC50并且报道成pIC50,即-log(IC50),其中IC50是50%抑制时的摩尔浓度。
MetAP2细胞活性:NMet-14-3-3γ的蛋白质印迹(western blotting)
将HUVEC细胞(Lonza)接种于96孔组织培养微板中并且培养24小时,随后添加测试化合物(11点系列的连续稀释液)或DMSO媒介物。24小时后,通过在含有蛋白酶和磷酸酶抑制剂(Calbiochem)的细胞提取缓冲液(CellSignaling)中溶解细胞来制备全细胞提取物。通过离心除去不溶性物质并稀释样品以及在SDS-PAGE缓冲液中煮沸。通过SDS-PAGE解析蛋白并且转移至PVDF膜上。对膜进行封闭,接着与适当的一抗、NMet-14-3-3γ(Novus)和β-肌动蛋白(Sigma)一起孵育,随后与IRDye 680-或800CW-缀合的二抗(Li-Cor)一起孵育。在Odyssey(Li-Cor)上对膜进行扫描并且使用LiCor软件对对应于N-Met14-3-3γ和β-肌动蛋白的信号进行定量。通过使用XLfit4 Microsoft Excel曲线拟合软件对未加工的N-Met14-3-3γ蛋白信号相对于β-肌动蛋白蛋白信号的比率进行曲线拟合来获得化合物EC50并且报道成pEC50,即-log(EC50),其中EC50是50%有效(最大)反应时的摩尔浓度。
体重减轻
从商业供应商获得十至十二周龄雄性C57bl/6小鼠,并且使其处于高脂肪饮食(60%千卡脂肪)至少15周。当平均体重达到约50g时开始用MetAP2抑制剂处理。在0.5%甲基纤维素水溶液中配制MetAP2抑制剂并且通过口服管饲法来施用。对照动物接受等体积的不含MetAP2抑制剂的0.5%甲基纤维素水溶液。每日记录体重(BW)和食物摄入,并且单独地将功效计算成相对于处理前值的BW减轻百分比。视研究设计而定,处理持续12、14或28天。在一些研究中,在处理结束时确定间接测热法或身体组成。
降血糖活性
从商业供应商获得六周龄雄性KKAy小鼠并且使其处于标准饲料。在适应环境8天后,开始用MetAP2抑制剂处理。在0.5%甲基纤维素水溶液中配制MetAP2抑制剂,通过口服管饲法将其每日施用一次。用等体积的不含所述化合物的0.5%甲基纤维素水溶液处理对照动物。4周后,从每一只小鼠的尾静脉收集血液。使用Tosoh HLC-723G8自动糖化血红蛋白分析仪来测量糖化血红蛋白水平,并且使用Hitachi型号7180自动葡萄糖分析仪来测量血浆葡萄糖水平。对于MetAP2抑制剂的降血糖活性的评估,使用威廉姆斯单尾检验(one-tailed Williams test)分析对照组与化合物处理组之间的统计学差异。
实施例
以下实施例意图是说明性和非限制性的,并且代表本发明的特定实施方案。
在以下实施例中对于许多化合物获得1H核磁共振(NMR)光谱。特征性化学位移(δ)以处于四甲基硅烷低磁场的百万分之份数给出,使用常规缩写词来指示主要峰值,包括s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、m(多重峰)和br(宽峰)。对于常见溶剂使用以下缩写词:CDCl3(氘代氯仿)、DMSO-d6(氘代二甲亚砜)、CD3OD(氘代甲醇)、CD3CN(氘代乙腈)和THF-d8(氘代四氢呋喃)。使用电喷雾电离(ESI-MS)或大气压力化学电离(APCI-MS)质谱法来记录质谱(对于[M+H]+是m/z)。
当有所指示时,通过质量触发HPLC(泵:WatersTM 2525;MS:ZQTM;软件:MassLynxTM)、快速色谱或制备型薄层色谱(TLC)来纯化某些制备和实施例的产物。通常在柱(例如,GeminiTM 5μC18 110A,AxiaTM,30x75mm,5μ)上,在酸性条件下(“酸模式”),分别用含有0.035%和0.05%三氟乙酸(TFA)的CH3CN和水流动相洗脱,或在碱性条件下(“碱性模式”),用都含有10mMNH4HCO3的水和20/80(v/v)水/乙腈流动相洗脱来进行反相色谱。通常在硅胶60F254板上进行制备型TLC。通过色谱分离后,除去溶剂并且通过在离心蒸发器(例如,GeneVacTM)、旋转蒸发器、真空烧瓶等中干燥来获得产物。通常在约1个大气压(14.7psi)的压力下在惰性(例如,氮气)或反应性(例如,H2)气氛中进行反应。
制备1:(3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-醇
向1-L 3颈圆底烧瓶中装入1.5M NaOH水溶液(263mL,395mmol),随后是(2E,4E,6E,8E)-10-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)-10-氧代癸-2,4,6,8-四烯酸二环己基胺(79g,123mmol)。在室温下搅拌所得混合物过夜,在此期间形成棕色固体沉淀物。TLC显示标题化合物是主要产物。添加乙酸乙酯(200mL)并在室温下搅拌混合物10分钟。在添加期间形成黄色沉淀物并将所聚集的固体破碎成较小颗粒。添加氯化钠(35.6g,609mmol)并再搅拌混合物10分钟。过滤混合物并用EtOAc(160mL)洗涤滤饼。分离有机层和水层并用EtOAc(2x200mL)萃取水层。合并有机层并接着用水(96mL)、0.4N H2SO4(含硫酸铵,13g/L)(2x200mL)和盐水(160mL)洗涤。经Na2SO4干燥有机相,过滤,并使用旋转蒸发器浓缩。用丙酮(2x40mL)稀释残余物并在旋转蒸发器中浓缩至干,产生呈淡橘色糖浆状的粗产物。用丙酮(4.0mL)和3%NaHCO3水溶液(72mL)依序稀释残余物并接着在冰浴中冷却。用上一批的产物对混合物进行接种并在冰浴中搅拌2小时。过滤混合物并用冰水(100mL)洗涤滤饼。将滤饼风干4小时并接着在室温下在高度真空下干燥过夜,产生呈灰白色固体状的标题化合物(21.8g,62.5%)。C16H27O4的[M+H]+计算值,283.19;实验值283.3。
制备2:二苯基(乙烯基)膦氧化物
在装备有磁性搅拌棒的500mL 3颈圆底烧瓶中,将二苯基膦氧化物(19.2g,95mmol)、溴乙烯(1M THF)(86mL,86mmol)、Et3N(39.7mL,285mmol)和Pd(Ph3P)4(4.99g,4.32mmol)混合于甲苯(150mL)中,产生黄色悬浮液。用氮气净化混合物并在N2下加热至60℃,历时24小时。接着冷却混合物并过滤。浓缩滤液并通过快速色谱(240g柱),用含50-100%EtOAc的庚烷洗脱来纯化。合并纯的级分并浓缩,产生呈淡黄色固体状的标题化合物(10g,51%)。C14H14OP的[M+H]+计算值,229.08;实验值229.1。
制备3:二对甲苯基(乙烯基)膦氧化物
在装备有磁性搅拌棒的40mL小瓶中,将二对甲苯基膦氧化物(930mg,4.04mmol)、溴乙烯(1M THF)(3.67mL,3.67mmol)、Et3N(1.689mL,12.12mmol)和Pd(Ph3P)4(424mg,0.367mmol)混合于甲苯(10mL)中,产生黄色悬浮液。用N2净化混合物,密封所述小瓶并加热至60℃,历时18小时。接着冷却混合物并过滤。浓缩滤液并通过快速色谱(25g柱),用含50-100%EtOAc的庚烷洗脱来纯化。合并纯的级分并浓缩,产生呈透明糖浆状的标题化合物(400mg,42.5%)。C16H18OP的[M+H]+计算值,257.11,实验值257.1。
制备4:双(4-(三氟甲基)苯基)(乙烯基)膦氧化物
在装备有磁性搅拌棒的40mL小瓶中,将双(4-(三氟甲基)苯基)膦氧化物(930mg,2.75mmol)、溴乙烯(1M THF)(2.500mL,2.500mmol)、Et3N(1.150mL,8.25mmol)和Pd(Ph3P)4(289mg,0.250mmol)混合于甲苯(10mL)中,产生黄色悬浮液。用N2净化混合物,密封所述小瓶并加热至80℃,历时18小时。接着冷却混合物并过滤。浓缩滤液并通过快速色谱(25g柱),用含50-100%EtOAc的庚烷洗脱来纯化。合并纯的级分并浓缩,产生呈棕色糖浆状的标题化合物(320mg,35.1%)。C16H12F6OP的[M+H]+计算值,365.05,实验值365.1。
实施例1:(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)二苯基膦氧化物
在装备有磁性搅拌棒的8mL小瓶中,将(3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-醇(250mg,0.885mmol)、二苯基(乙烯基)膦氧化物(202mg,0.885mmol)和KOH(24.84mg,0.443mmol)混合于甲苯(3mL)中,产生褐色溶液。在室温下使混合物搅拌1.5小时并接着过滤和浓缩。将少量Et2O(约1.5mL)添加至浓缩混合物中,将其涡旋直至它成为棕色溶液。用上一批的产物晶体对溶液进行接种。约1分钟后晶体开始形成。将小瓶盖上盖子并使其在室温下静置过夜。在早上,将残余Et2O用移液管移至一个单独的小瓶中并用Et2O(2x)冲洗晶体。所述单独小瓶中的Et2O显示晶体形成并将其添加回母瓶中,与另外一些Et2O一起涡旋,并且用移液管移出透明黄色Et2O溶液。在N2流下干燥剩余晶体。接着将水(约8mL)添加至小瓶中,并将混合物涡旋和过滤。用水将固体洗涤多次以除去任何残余KOH。用少量Et2O洗涤所得晶体并使其干燥。将晶体转移至小瓶中并在真空下干燥,产生呈褐色固体状的标题化合物(320mg,70.8%)。1H NMR(400MHz,CD3OD)δppm 0.66-0.74(m,1H),1.13(s,3H),1.41-1.55(m,1H),1.59-1.70(m,5H),1.77(s,4H),2.15-2.25(m,1H),2.25-2.36(m,1H),2.40(d,J=4.29Hz,1H),2.44-2.51(m,1H),2.69(ddt,1H),2.83(d,J=4.29Hz,1H),2.93(dtd,J=15.32,8.38,8.38,6.82Hz,1H),3.32-3.42(m,3H),3.42-3.50(m,1H),3.83-4.03(m,3H),5.21-5.27(m,1H),7.49-7.60(m,6H),7.72-7.86(m,4H)。C30H40O5P的[M+H]+计算值,511.26;实验值511.4。
实施例2:(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)二对甲苯基膦氧化物
在装备有磁性搅拌棒的50mL圆底烧瓶中,将(3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-醇(441mg,1.561mmol)、二对甲苯基(乙烯基)膦氧化物(400mg,1.561mmol)和KOH(26.3mg,0.468mmol)混合于甲苯(3mL)中,产生无色悬浮液。使混合物搅拌2小时。通过制备型HPLC,用含45-85%CH3CN的10mM NH4HCO3水溶液洗脱来纯化产物。合并纯的级分并浓缩,产生呈粘性白色泡沫状的标题化合物(225mg,27%)。1H NMR(400MHz,CD3OD)δppm 0.67-0.73(m,1H),1.13(s,3H),1.18(t,J=7.07Hz,1H),1.43-1.53(m,1H),1.58-1.67(m,2H),1.69(s,3H),1.77(s,3H),1.79-1.85(m,1H),2.17-2.25(m,1H),2.29-2.36(m,1H),2.36-2.42(m,7H),2.42-2.47(m,1H),2.58-2.68(m,1H),2.82-2.85(m,1H),2.85-2.91(m,1H),3.37(s,3H),3.46-3.49(m,1H),3.49-3.52(m,1H),3.79-3.89(m,1H),3.93-4.02(m,2H),5.22-5.28(m,1H),7.31-7.36(m,4H),7.58-7.65(m,2H),7.65-7.72(m,2H)。C32H44O5P的[M+H]+计算值,539.29;实验值539.4。
实施例3:(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)双(4-(三氟甲基)苯基)膦氧化物
在装备有磁性搅拌棒的20mL圆底烧瓶中,将(3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-醇(248mg,0.879mmol)、双(4-(三氟甲基)苯基)(乙烯基)膦氧化物(320mg,0.879mmol)和KOH(14.79mg,0.264mmol)混合于甲苯(3mL)中,产生无色悬浮液。使混合物搅拌2小时。通过制备型HPLC,用含45-85%CH3CN的10mM NH4HCO3水溶液洗脱来纯化产物。合并纯的级分并冻干,产生呈白色松软固体状的标题化合物(127.6mg,22.46%)。1H NMR(400MHz,CD3OD)δppm0.64(d,J=13.14Hz,1H),1.13(s,3H),1.36(dd,J=13.52,4.17Hz,1H),1.44-1.53(m,2H),1.68(s,3H),1.75-1.81(m,4H),2.18(d,J=6.82Hz,1H),2.29-2.36(m,2H),2.36-2.41(m,1H),2.75(s,1H),2.81(d,J=4.29Hz,1H),3.06-3.16(m,1H),3.39(s,3H),3.49(dd,J=11.37,2.53Hz,1H),3.91-4.12(m,3H),5.19-5.25(m,1H),7.85(dt,J=5.56,2.78Hz,4H),8.00(dd,J=11.37,8.08Hz,2H),8.09(dd,J=11.49,7.96Hz,2H)。C32H38F6O5P的[M+H]+计算值,647.24;实验值647.4。
实施例4:(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)膦酸二甲酯
在装备有磁性搅拌棒的20mL小瓶中,将(3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-醇(835mg,2.96mmol)、乙烯基膦酸二甲酯(523mg,3.84mmol)和KOH(1161mg,20.70mmol)混合于DMF中,产生无色悬浮液。在室温下使混合物搅拌20分钟。将产物从未溶解的KOH中轻轻倒出并在水(70mL)与乙酸乙酯(75mL)之间分配。分离各层并用乙酸乙酯(75mL)重新萃取水层。合并有机层,用盐水(30mL)洗涤,并浓缩有机层,产生黄色糖浆。通过制备型HPLC,用含35-75%CH3CN的10mM NH4HCO3水溶液洗脱来纯化产物。合并纯的级分并用Et2O(2x200mL)萃取。浓缩合并的有机萃取物,产生黄色液体,将其溶解于CH3CN/水(1:1)中并接着冻干,产生呈灰白色吸湿性固体状的标题化合物(380mg,30.7%)。1H NMR(400MHz,CD3OD)δppm 0.92-0.98(m,1H),1.18(s,3H),1.61-1.68(m,4H),1.75(s,3H),1.99-2.05(m,2H),2.11-2.26(m,4H),2.26-2.35(m,1H),2.52(d,J=4.29Hz,1H),2.60(t,J=6.32Hz,1H),2.94(d,J=4.04Hz,1H),3.36-3.45(m,3H),3.48(s,1H),3.59(dd,J=11.24,2.40Hz,1H),3.74(dd,J=10.99,1.64Hz,6H),3.77-3.84(m,2H),4.11(br s,1H),5.21-5.26(m,1H)。C20H36O7P的[M+H]+计算值,419.22;实验值419.3。
实施例5:(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)膦酸二乙酯
在装备有磁性搅拌棒的干燥100mL圆底烧瓶中,将(3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-醇(6.55g,23.20mmol)混合于DMF(50mL)中,产生无色溶液。添加乙烯基膦酸二乙酯(4.28mL,27.8mmol)和KOH(3.90g,69.6mmol)并在室温下使反应混合物搅拌30分钟。接着将产物从未溶解的KOH中轻轻倒出,用水(200mL)稀释并用EtOAc(2x300mL)萃取。浓缩合并的萃取物并通过制备型HPLC,用含35-75%CH3CN的10mM NH4OH水溶液洗脱来纯化。合并纯的级分,浓缩至约原始体积的一半,并接着用Et2O(2x500mL)萃取。用水洗涤有机物并浓缩,产生呈粘稠透明油状物的标题化合物(5g,48%)。1H NMR(400MHz,CD3OD)δppm 0.90-1.03(m,1H),1.19(s,3H),1.32(td,J=7.07,1.26Hz,6H),1.62-1.69(m,4H),1.76(s,3H),1.97-2.08(m,2H),2.12-2.25(m,4H),2.31(d,J=7.07Hz,1H),2.53(d,J=4.29Hz,1H),2.60(t,J=6.32Hz,1H),2.95(d,J=4.29Hz,1H),3.44(s,3H),3.60(dd,J=11.12,2.53Hz,1H),3.74-3.89(m,2H),4.07-4.16(m,5H),5.20-5.27(m,1H)。C22H40O7P的[M+H]+计算值,447.25;实验值447.4。
表1列出了实施例中所示的一些化合物的MetAP2抑制,其中较大pIC50和pEC50值表示较高效力。根据说明书中从第35页开始所描述的酶测定(pIC50),其中MetAP2酶与钴或锰离子复合,并且根据说明书中从第36页开始所描述的细胞测定(pEC50)来测试表1中所示的化合物。
表1:MetAP2抑制
表2列出了在用实施例中所示的一些化合物处理后小鼠的体重减轻(BWL)。根据说明书中从第36页开始所描述的BWL方案,使用表格中所指示的剂量、给药方案(频率)和处理持续时间来测试表2中所示的化合物。
表2:小鼠的体重减轻(BWL)
实施例编号 | 剂量 | 频率 | 持续时间 | BWL% |
1 | 3mg/kg | 每天一次 | 28天 | 18 |
5 | 1mg/kg | 每天一次 | 28天 | 18 |
表3列出了在用实施例1中所示的化合物处理4周后KKAy小鼠的糖化血红蛋白(GHb)和血浆葡萄糖(PG)水平。根据说明书中从第37页开始所描述的方案,使用表格中所指示的剂量来进行研究。通过每组8只动物的平均值±标准偏差来指示各值。
表3:小鼠的降血糖活性
根据威廉姆斯单尾检验,相对于对照组p<0.025。
如本说明书和随附权利要求中所使用,除非上下文另外明确指出,否则诸如“一个(a)”、“一个(an)”和“所述”的单数冠词可以指单一物体或多种物体。因此,举例来说,对含有“化合物”的组合物的提及可以包括单一化合物或两种或更多种化合物。以上描述意图是说明性的并且无限制性。许多实施方案将为本领域的技术人员在阅读以上描述后所显而易见。因此,本发明的范围应参考随附权利要求来确定并且包括所述权利要求享有权利的等效物的完整范围。本公开中所引用的所有文章和参考文献(包括专利、专利申请和出版物)的公开内容都以引用的方式并且出于所有目的整体并入本文中。
Claims (39)
1.一种式1的化合物,
其立体异构体或所述化合物或立体异构体的药学上可接受的盐,其中:
R1和R2各自独立地选自苯基、C3-5杂芳基、-OR4和-N(R4)R5,其中每个苯基和C3-5杂芳基独立地经0至3个Ra取代,并且每个C3-5杂芳基具有5或6个环原子,其中1或2个是独立地选自N、O和S的杂原子;
每个Ra独立地选自卤基、-CN、R3和R4;
每个R3独立地选自-OR4、-N(R4)R5、-NR4C(O)R6、-NR4C(O)OR5、-C(O)OR4、-C(O)N(R4)R5、-C(O)N(R4)OR5、-C(O)N(R4)S(O)2R6、-N(R4)S(O)2R6、-SR4、-S(O)R6、-S(O)2R6和-S(O)2N(R4)R5;
每个R4和R5独立地选自
(a)C1-6烷基、C2-6烯基和C2-6炔基,各自经0至3个Rb取代,以及
(b)C3-8环烷基-(CH2)m-、C2-6杂环基-(CH2)m-、C6-14芳基-(CH2)m-和C1-9杂芳基-(CH2)m-,各自经0至3个Rc取代;
每个R6独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C3-8环烷基-(CH2)m-、C2-6杂环基-(CH2)m-、C6-14芳基-(CH2)m-和C1-9杂芳基-(CH2)m-,各自经0至3个Rd取代;
每个Rb独立地选自卤基、-CN和R7;
每个Rc独立地选自
(a)卤基、-CN和R7,以及
(b)C1-6烷基、C2-6烯基和C2-6炔基,各自经0至3个Rb取代;
每个Rd独立地选自
(a)卤基、-CN和R7,以及
(b)C1-6烷基,其经0至3个Rb取代;
每个R7独立地选自-OR8、-N(R8)R9、-NR8C(O)R9、-NR8C(O)OR9、-C(O)OR8、-C(O)N(R8)R9、-C(O)N(R8)OR9、-C(O)N(R8)S(O)2R9、-N(R8)S(O)2R9、-SR8、-S(O)R8、-S(O)2R8和-S(O)2N(R8)R9;
每个R8和R9独立地选自C1-6烷基、C3-8环烷基-(CH2)m-和C2-6杂环基-(CH2)m-,各自经0至3个独立地选自卤基和-CN的取代基取代;并且
每个m独立地选自0、1、2、3和4;
其中R4、R5和R6中所列的每个杂芳基部分独立地具有1至4个独立地选自N、O和S的杂原子,并且R4、R5、R6和R8中所列的每个杂环基部分独立地具有1至4个独立地选自N、O和S的杂原子。
2.根据权利要求1所述的化合物、立体异构体或药学上可接受的盐,其中R1和R2各自独立地选自苯基和C3-5杂芳基,并且每个苯基和C3-5杂芳基独立地经0至3个Ra取代。
3.根据权利要求1所述的化合物、立体异构体或药学上可接受的盐,其中每个R1和R2独立地选自苯基和C3-5杂芳基,每个C3-5杂芳基具有5个环原子,其中每个苯基和C3-5杂芳基独立地经0至3个Ra取代。
4.根据权利要求1所述的化合物、立体异构体或药学上可接受的盐,其中每个R1和R2独立地选自苯基和C3-5杂芳基,每个C3-5杂芳基具有6个环原子,其中每个苯基和C3-5杂芳基独立地经0至3个Ra取代。
5.根据权利要求1和2中任一项所述的化合物、立体异构体或药学上可接受的盐,其中每个R1和R2独立地选自苯基和C3-5杂芳基,每个C3-5杂芳基是吡啶基,并且每个苯基和C3-5杂芳基独立地经0至3个Ra取代。
6.根据权利要求1至5中任一项所述的化合物、立体异构体或药学上可接受的盐,其中R1和R2都是C3-5杂芳基,并且每个C3-5杂芳基独立地经0至3个Ra取代。
7.根据权利要求1所述的化合物、立体异构体或药学上可接受的盐,其中R1和R2都是苯基,并且每个苯基独立地经0至3个Ra取代。
8.根据权利要求1至7中任一项所述的化合物、立体异构体或药学上可接受的盐,其中:
每个Ra独立地选自卤基、-CN、R3和R4;
每个R3独立地选自-OR4、-N(R4)R5、-NR4C(O)R6和-C(O)N(R4)R5;
每个R4和R5独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C6-14芳基-(CH2)m-,其经0至3个Rc取代;
每个R6独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C6-14芳基-(CH2)m-,其经0至3个Rd取代;
每个Rb独立地选自卤基、-CN和R7;
每个Rc和Rd独立地选自
(a)卤基、-CN和R7,以及
(b)C1-6烷基,其经0至3个Rb取代;
每个R7独立地选自-OR8、-N(R8)R9、-NR8C(O)R9和-C(O)N(R8)R9;并且
每个R8和R9独立地选自C1-6烷基和C3-8环烷基-(CH2)m-,各自经0至3个独立地选自卤基和-CN的取代基取代。
9.根据权利要求1至7中任一项所述的化合物、立体异构体或药学上可接受的盐,其中:
每个Ra独立地选自卤基、-CN、R3和R4;
每个R3独立地选自-OR4和-N(R4)R5;
每个R4和R5独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C6-14芳基-(CH2)m-,其中所述C6-14芳基部分是经0至3个独立地选自Rb和C1-6烷基的取代基取代的苯基,并且每个C1-6烷基独立地经0至3个Rb取代;
每个Rb独立地选自卤基、-CN和R7;
每个Rc独立地选自
(a)卤基、-CN和R7,以及
(b)C1-6烷基,其经0至3个Rb取代;
每个R7独立地选自-OR8和-N(R8)R9;并且
每个R8和R9独立地选自C1-6烷基和C3-8环烷基-(CH2)m-,各自经0至3个独立地选自卤基和-CN的取代基取代。
10.根据权利要求1至7中任一项所述的化合物、立体异构体或药学上可接受的盐,其中:
每个Ra独立地选自卤基、-CN、R3和R4;
每个R3独立地选自-OR4和-N(R4)R5;
每个R4和R5独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C6-14芳基-(CH2)m-,其中所述C6-14芳基部分是经0至3个独立地选自Rb和C1-6烷基的取代基取代的苯基,并且每个C1-6烷基独立地经0至3个Rb取代;
每个Rb独立地选自卤基和-CN;并且
每个Rc独立地选自卤基、-CN和经0至3个Rb取代的C1-6烷基。
11.根据权利要求1至7中任一项所述的化合物、立体异构体或药学上可接受的盐,其中:
每个Ra独立地选自卤基、-CN、R3和R4;
每个R3独立地选自-OR4和-N(R4)R5;
每个R4和R5独立地选自经0至3个Rb取代的C1-6烷基;并且
每个Rb独立地选自卤基和-CN。
12.根据权利要求1至7中任一项所述的化合物、立体异构体或药学上可接受的盐,其中Ra不存在。
13.根据权利要求1所述的化合物、立体异构体或药学上可接受的盐,其中R1和R2各自独立地选自-OR4和-N(R4)R5。
14.根据权利要求1所述的化合物、立体异构体或药学上可接受的盐,其中R1和R2都是-OR4。
15.根据权利要求13和14中任一项所述的化合物、立体异构体或药学上可接受的盐,其中:
每个R4和R5独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C6-14芳基-(CH2)m-,其经0至3个Rc取代;
每个Rb独立地选自卤基、-CN和R7;
每个Rc独立地选自
(a)卤基、-CN和R7,以及
(b)经0至3个Rb取代的C1-6烷基;
每个R7独立地选自-OR8、-N(R8)R9、-NR8C(O)R9和-C(O)N(R8)R9;并且
每个R8和R9独立地选自C1-6烷基和C3-8环烷基-(CH2)m-,各自经0至3个独立地选自卤基和-CN的取代基取代。
16.根据权利要求13和14中任一项所述的化合物、立体异构体或药学上可接受的盐,其中:
每个R4和R5独立地选自
(a)经0至3个Rb取代的C1-6烷基,以及
(b)C6-14芳基-(CH2)m-,其中所述C6-14芳基部分是经0至3个Rc取代的苯基;
每个Rb独立地选自卤基、-CN和R7;
每个Rc独立地选自
(a)卤基、-CN和R7,以及
(b)经0至3个Rb取代的C1-6烷基;
每个R7独立地选自-OR8和-N(R8)R9;并且
每个R8和R9独立地选自C1-6烷基和C3-8环烷基-(CH2)m-,各自经0至3个独立地选自卤基和-CN的取代基取代。
17.根据权利要求13和14中任一项所述的化合物、立体异构体或药学上可接受的盐,其中:
每个R4和R5独立地选自
(a)C1-6烷基,其经0至3个Rb取代,以及
(b)C6-14芳基-(CH2)m-,其中所述C6-14芳基部分是经0至3个Rc取代的苯基;
每个Rb独立地选自卤基和-CN;并且
每个Rc独立地选自卤基、-CN和C1-6烷基,其经0至3个Rb取代。
18.根据权利要求13和14中任一项所述的化合物、立体异构体或药学上可接受的盐,其中:
每个R4和R5独立地选自经0至3个Rb取代的C1-6烷基;并且
每个Rb独立地选自卤基和-CN。
19.根据权利要求13和14中任一项所述的化合物、立体异构体或药学上可接受的盐,其中:
每个R4和R5独立地选自经0至3个Rb取代的C1-3烷基;并且
每个Rb独立地选自卤基和-CN。
20.根据权利要求13和14中任一项所述的化合物、立体异构体或药学上可接受的盐,其中:
每个R4和R5独立地选自甲基和乙基,各自经0至3个Rb取代;并且
每个Rb独立地选自卤基和-CN。
21.根据权利要求13和14中任一项所述的化合物、立体异构体或药学上可接受的盐,其中:
每个R4和R5独立地是经0至3个Rb取代的甲基;并且
每个Rb独立地选自卤基和-CN。
22.根据权利要求13和14中任一项所述的化合物、立体异构体或药学上可接受的盐,其中:
每个R4和R5独立地是经0至3个Rb取代的乙基;并且
每个Rb独立地选自卤基和-CN。
23.根据权利要求1至8中任一项所述的化合物、立体异构体或药学上可接受的盐,其中Rd不存在。
24.根据权利要求1至10、13至17和23中任一项所述的化合物、立体异构体或药学上可接受的盐,其中m是0。
25.根据权利要求1至10、13至17、23和24中任一项所述的化合物、立体异构体或药学上可接受的盐,其中Rc不存在。
26.根据权利要求1至25中任一项所述的化合物、立体异构体或药学上可接受的盐,其中Rb不存在。
27.根据权利要求1所述的化合物,其选自以下化合物:
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)二苯基膦氧化物;
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)二对甲苯基膦氧化物;
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)双(4-(三氟甲基)苯基)膦氧化物;
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)膦酸二甲酯;
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)膦酸二乙酯;
前述化合物中任一种的立体异构体;以及
前述化合物或立体异构体中任一种的药学上可接受的盐。
28.根据权利要求1所述的化合物,其选自以下化合物:
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)二苯基膦氧化物;
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)二对甲苯基膦氧化物;
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)双(4-(三氟甲基)苯基)膦氧化物;
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)膦酸二甲酯;
(2-(((3R,4S,5S,6R)-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基丁-2-烯-1-基)环氧乙烷-2-基)-1-氧杂螺[2.5]辛-6-基)氧基)乙基)膦酸二乙酯;以及
前述化合物中任一种的药学上可接受的盐。
29.根据权利要求1所述的化合物,其由以下结构表示:
30.根据权利要求1所述的化合物,其由以下结构表示:
31.根据权利要求1所述的化合物,其由以下结构表示:
32.根据权利要求1所述的化合物,其由以下结构表示:
33.根据权利要求1所述的化合物,其由以下结构表示:
34.一种药物组合物,其包含:
根据如权利要求1-33中任一项所定义的化合物、立体异构体或药学上可接受的盐;以及
药学上可接受的赋形剂。
35.如权利要求1-33中任一项所定义的化合物、立体异构体或药学上可接受的盐,其用作药物。
36.如权利要求1-33中任一项所定义的化合物、立体异构体或药学上可接受的盐,其用于治疗选自高血糖症、糖尿病、血脂异常、肥胖、胰岛素抗性、X代谢综合征、葡萄糖耐受不良、多囊卵巢综合征、心血管疾病、非酒精性肝脂肪变性、动脉粥样硬化和普拉德-威利综合征的疾病、病症或病状。
37.一种治疗受试者的疾病、病症或病状的方法,所述方法包括向所述受试者施用如权利要求1-33中任一项所定义的化合物、立体异构体或药学上可接受的盐,其中所述疾病、病症或病状选自高血糖症、糖尿病、血脂异常、肥胖、胰岛素抗性、X代谢综合征、葡萄糖耐受不良、多囊卵巢综合征、心血管疾病、非酒精性肝脂肪变性、动脉粥样硬化和普拉德-威利综合征。
38.一种组合,其包含如权利要求1-33中任一项所定义的化合物、立体异构体或药学上可接受的盐,以及至少一种额外的药理学活性剂。
39.根据权利要求38所述的组合,其中所述额外的药理学活性剂选自胰岛素、丁双胍、二甲双胍、苯乙双胍、吡格列酮、罗格列酮、醋磺环己脲、氯磺丙脲、妥拉磺脲、甲苯磺丁脲、格列齐特、格列美脲、格列吡嗪、格列本脲、那格列奈、瑞格列奈、阿卡波糖、米格列醇、艾塞那肽、利拉鲁肽、他司鲁肽、阿洛利停、利拉利汀、沙克列汀、西他列汀、维格列汀、普兰林肽、奥利司他、阿伐他汀、氟伐他汀、洛伐他汀、美伐他汀、匹伐他汀、普伐他汀、瑞舒伐他汀、辛伐他汀、烟酸、苯扎贝特、环丙贝特、氯贝特、非诺贝特、吉非罗齐、消胆胺、考来维仑、考来替泊和依替米贝。
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TW201636342A (zh) | 2014-12-19 | 2016-10-16 | 武田藥品工業有限公司 | 煙黴醇衍生物 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1301260A (zh) * | 1998-05-15 | 2001-06-27 | 株式会社钟根堂 | 烟曲霉醇衍生物及其制备方法 |
US20040242681A1 (en) * | 2001-09-27 | 2004-12-02 | Cheol-Kyu Han | Fumagillol derivatives and preparing method thereof |
CN101142210A (zh) * | 2005-01-26 | 2008-03-12 | 株式会社钟根堂 | 烟曲霉醇衍生物或制备烟曲霉醇衍生物的方法、以及包含该衍生物的药物组合物 |
CN103096874A (zh) * | 2010-04-15 | 2013-05-08 | 华盛顿大学 | 前药组合物、前药纳米粒子及其使用方法 |
CN103534244A (zh) * | 2011-03-08 | 2014-01-22 | 扎夫根股份有限公司 | 氧杂螺[2.5]辛烷衍生物及类似物 |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PH26256A (en) | 1988-08-12 | 1992-04-01 | Fujisawa Pharmaceutical Co | Oxaspiro [2,5] octane derivative |
KR0138530B1 (ko) | 1988-09-01 | 1998-05-15 | 우메모또 요시마사 | 푸마길롤 유도체 |
KR0166088B1 (ko) | 1990-01-23 | 1999-01-15 | . | 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도 |
US5376645A (en) | 1990-01-23 | 1994-12-27 | University Of Kansas | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
GB9518953D0 (en) | 1995-09-15 | 1995-11-15 | Pfizer Ltd | Pharmaceutical formulations |
JPH1081631A (ja) * | 1996-07-17 | 1998-03-31 | Takeda Chem Ind Ltd | 癌転移または再発抑制剤 |
GB9711643D0 (en) | 1997-06-05 | 1997-07-30 | Janssen Pharmaceutica Nv | Glass thermoplastic systems |
WO1998056372A1 (en) | 1997-06-09 | 1998-12-17 | Massachusetts Institute Of Technology | TYPE 2 METHIONINE AMINOPEPTIDASE (MetAP2) INHIBITORS AND USES THEROF |
EP1024801B1 (en) | 1997-10-31 | 2004-06-23 | Children's Medical Center Corporation | Method for regulating size and growth of vascularized normal tissue |
KR100357541B1 (ko) | 1998-05-15 | 2002-10-18 | 주식회사종근당 | 5-데메톡시 푸마질롤 유도체 및 그 제조방법 |
BR0115109A (pt) | 2000-11-01 | 2005-10-18 | Praecis Pharm Inc | Agentes terapêuticos e métodos de uso dos mesmos para a modulação da angiogênese |
US7332523B2 (en) | 2002-04-11 | 2008-02-19 | Children's Medical Center Corporation | TNP-470 polymer conjugates and use thereof |
KR100552043B1 (ko) | 2004-02-28 | 2006-02-20 | 주식회사종근당 | 푸마질롤 유도체를 포함하는 비만치료용 조성물 |
FR2886855B1 (fr) | 2005-06-08 | 2009-07-17 | Agronomique Inst Nat Rech | Utilisation de la fumagilline et de ses derives pour augmenter la biodisponibilite des lactones macrocyliques |
CN101990441A (zh) | 2007-11-28 | 2011-03-23 | 默萨那治疗学股份有限公司 | 生物相容的生物可降解的烟曲霉素类似物轭合物 |
US8299067B2 (en) | 2008-03-27 | 2012-10-30 | Versitech Limited | 5-demethoxyfumagillol and derivatives thereof |
WO2010065877A2 (en) | 2008-12-04 | 2010-06-10 | Zafgen Corporation | Methods of treating an overweight or obese subject |
US8642650B2 (en) | 2008-12-04 | 2014-02-04 | Zafgen, Inc. | Methods of treating an overweight or obese subject |
US20130210821A1 (en) | 2010-05-27 | 2013-08-15 | James E. Vath | Methods for Treating Obesity |
FR2973376B1 (fr) | 2011-03-28 | 2013-05-10 | Atlanthera | Derives utiles dans le traitement ou la prevention de tumeurs osseuses |
TW201636342A (zh) | 2014-12-19 | 2016-10-16 | 武田藥品工業有限公司 | 煙黴醇衍生物 |
-
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- 2015-12-18 EP EP15820800.9A patent/EP3233870B1/en active Active
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- 2017-07-18 CO CONC2017/0007189A patent/CO2017007189A2/es unknown
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1301260A (zh) * | 1998-05-15 | 2001-06-27 | 株式会社钟根堂 | 烟曲霉醇衍生物及其制备方法 |
US20040242681A1 (en) * | 2001-09-27 | 2004-12-02 | Cheol-Kyu Han | Fumagillol derivatives and preparing method thereof |
CN101142210A (zh) * | 2005-01-26 | 2008-03-12 | 株式会社钟根堂 | 烟曲霉醇衍生物或制备烟曲霉醇衍生物的方法、以及包含该衍生物的药物组合物 |
CN103096874A (zh) * | 2010-04-15 | 2013-05-08 | 华盛顿大学 | 前药组合物、前药纳米粒子及其使用方法 |
CN103534244A (zh) * | 2011-03-08 | 2014-01-22 | 扎夫根股份有限公司 | 氧杂螺[2.5]辛烷衍生物及类似物 |
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MX2017007926A (es) | 2017-09-27 |
EP3233870B1 (en) | 2018-10-31 |
ES2702026T3 (es) | 2019-02-27 |
PE20171141A1 (es) | 2017-08-09 |
JP2018500329A (ja) | 2018-01-11 |
SG11201704985VA (en) | 2017-07-28 |
BR112017012965A2 (pt) | 2018-01-09 |
US20180050051A1 (en) | 2018-02-22 |
AR103078A1 (es) | 2017-04-12 |
EA201791398A1 (ru) | 2017-10-31 |
DOP2017000138A (es) | 2017-07-31 |
CL2017001602A1 (es) | 2018-03-09 |
CR20170332A (es) | 2017-10-05 |
CO2017007189A2 (es) | 2017-10-20 |
PH12017501134A1 (en) | 2017-11-27 |
AU2015364477A1 (en) | 2017-07-13 |
IL252908A0 (en) | 2017-08-31 |
CA2971282A1 (en) | 2016-06-23 |
KR20170099973A (ko) | 2017-09-01 |
UY36450A (es) | 2016-07-29 |
EA032431B1 (ru) | 2019-05-31 |
US9827255B2 (en) | 2017-11-28 |
US10328089B2 (en) | 2019-06-25 |
EP3233870A1 (en) | 2017-10-25 |
WO2016100778A1 (en) | 2016-06-23 |
ECSP17045054A (es) | 2017-10-31 |
TN2017000254A1 (en) | 2018-10-19 |
TW201636342A (zh) | 2016-10-16 |
US20160175332A1 (en) | 2016-06-23 |
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