CN109422727A - 泊马度胺衍生物及其制备方法 - Google Patents
泊马度胺衍生物及其制备方法 Download PDFInfo
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- CN109422727A CN109422727A CN201810951914.4A CN201810951914A CN109422727A CN 109422727 A CN109422727 A CN 109422727A CN 201810951914 A CN201810951914 A CN 201810951914A CN 109422727 A CN109422727 A CN 109422727A
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- substituted
- methyl
- propyl
- radicals
- pharmaceutically acceptable
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical class O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 title abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- -1 amino, hydroxyl Chemical group 0.000 claims description 100
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 29
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 150000002431 hydrogen Chemical class 0.000 claims description 25
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 12
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 12
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000001544 thienyl group Chemical class 0.000 claims description 12
- 125000002971 oxazolyl group Chemical group 0.000 claims description 11
- 125000005493 quinolyl group Chemical group 0.000 claims description 11
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 10
- 150000001768 cations Chemical class 0.000 claims description 10
- 125000002541 furyl group Chemical group 0.000 claims description 10
- 125000003226 pyrazolyl group Chemical class 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 9
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- MCSJGXLZPITMIH-UHFFFAOYSA-N 2-aminobutane-1,1,1-triol Chemical class CCC(N)C(O)(O)O MCSJGXLZPITMIH-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229910001415 sodium ion Inorganic materials 0.000 claims description 7
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 claims description 6
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910001425 magnesium ion Inorganic materials 0.000 claims description 6
- 229910001414 potassium ion Inorganic materials 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 5
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical class C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 229910001424 calcium ion Inorganic materials 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 229950002366 nafoxidine Drugs 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 1
- 239000011575 calcium Substances 0.000 claims 1
- 229910052791 calcium Inorganic materials 0.000 claims 1
- 150000003217 pyrazoles Chemical class 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 150000003233 pyrroles Chemical class 0.000 claims 1
- 229960000688 pomalidomide Drugs 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 2
- 231100001231 less toxic Toxicity 0.000 abstract description 2
- 229940002612 prodrug Drugs 0.000 abstract description 2
- 239000000651 prodrug Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 54
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 36
- 239000002585 base Substances 0.000 description 33
- 238000003756 stirring Methods 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 238000001914 filtration Methods 0.000 description 12
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 11
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
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- 238000000926 separation method Methods 0.000 description 7
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 5
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- 241000790917 Dioxys <bee> Species 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
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- 229940125782 compound 2 Drugs 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- 125000005936 piperidyl group Chemical group 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
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- 229910052717 sulfur Inorganic materials 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
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- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
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- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
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- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
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- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明涉及泊马度胺衍生物及其制备方法,特别涉及一种式(Ⅰ)所示的化合物或其药学上可接受的盐,其中R1、R2、R3、R4、R5、R6和R7、m和n如说明书中所定义,本发明实现了一种新颖的具有高稳定性,良好溶解度,改善生物利用度,低毒副作用或具备长效潜力的泊马度胺前体药物。
Description
技术领域
本发明涉及泊马度胺衍生物或其药学上可接受的盐,及其在制备治疗癌症的药物中的应用。
背景技术
泊马度胺(式A结构)由美国赛尔基因公司研发,并于2013年2月首次在美国获准上市。泊马度胺是继沙利度胺,来那度胺后第三个上市的同类免疫调节剂,能够增强T细胞和自然杀伤细胞介导的免疫反应,同时抑制单核细胞产生促炎性细胞因子(如TNF-α、IL-6等)。此外,泊马度胺能够抑制肿瘤细胞增生并诱导细胞凋亡,对来那度胺耐药的多发性骨髓瘤细胞株亦具有较强的增殖抑制作用。
泊马度胺常见的不良反应有中性粒细胞减少,疲乏虚弱,贫血,便秘,腹泻,血小板减少,上呼吸道感染,背痛发热,还可能引起血栓,且可能导致胎儿出现严重的出生缺陷。
根据文献报道,泊马度胺属于难溶性药物,测定其在纯化水,PH6.8磷酸盐缓冲液,PH4.5醋酸盐缓冲液和0.1mol/L盐酸中的溶解度,结果分别是17.8,17.0,18.7和18.9μg/mL。泊马度胺的低溶解度不仅增加了制剂工艺的难度,也限制了活性成分在胃肠道的溶出和吸收过程,进而影响口服生物利用度。
目前上市的泊马度胺口服胶囊剂,商品名为POMALYST,其为了增加药物的溶出度,在其处方中添加了表面活性剂十二烷基硫酸钠,但十二烷基硫酸钠有一定的胃肠道刺激性。
发明内容
本发明的目的在于提供一种新颖的具有高稳定性,良好溶解度,改善生物利用度,低毒副作用或具备长效潜力的泊马度胺前体药物。
在一方面,本发明公开一种式(Ⅰ)所示的化合物(包括其立体异构体)或其药学上可接受的盐,
其中:
R1选自H,取代或非取代的C1-6烷基,取代或非取代的C1-6烷氧基,取代或非取代的C2-6烯基,取代或非取代的C2-6炔基,其中前述取代的取代基选自C1-6烷基,C1-6烷氧基;
R2选自H,-OR3,-SR3,-NHR3,取代或非取代的C3-10杂环基,取代或非取代的C3-10杂环芳基,取代或非取代的C3-10环烷基,其中前述取代的取代基选自C1-6烷基,C1-6烷氧基,羰基,羧基,氨基,羟基;
R3选自-C(O)(R4)(R5),-P(O)(OR6)(OR7),-P(O)2(OR6)M,-P(O)3MY;
R4选自氢,氨基,羟基,卤素,C1-6烷基;
R5选自氢,取代或非取代的C1-16烷基,取代或非取代的C1-6烷氧基,取代或非取代的C3-10杂环基,取代或非取代的C3-10杂环芳基,取代或非取代的C3-10环烷基,苯基,苄基,-(CH2)nSCH3,-(CH2)mNHCH3,-(CH2)mN(CH3)2,其中前述取代的取代基选自氨基,羟基,羧基,-SH,-C(O)NH2,C1-6烷基;
R6和R7各自独立的选自氢,C1-6烷基;M和Y各自独立选自单价阳离子,或者MY为一个二价阳离子;且
m和n各自独立的选自1,2,3,4,5,6。
在一实施例中,R1选自H,取代或非取代的甲基,取代或非取代的乙基,取代或非取代的丙基,取代或非取代的丁基,取代或非取代的戊基,取代或非取代的己基,其中前述取代的取代基选自甲基,乙基或丙基。
在一实施例中,R2选自H,-OR3,取代或非取代的四氢呋喃基,取代或非取代的四氢吡咯基,取代或非取代的呋喃基,取代或非取代的噻吩基,取代或非取代的吡咯基,取代或非取代的咪唑基,取代或非取代的吡唑基,取代或非取代的噻唑基,取代或非取代的噁唑基,取代或非取代的吡啶基,取代或非取代的嘧啶基,取代或非取代的哒嗪基,取代或非取代的吡嗪基,取代或非取代的嘌呤基,取代或非取代的喹啉基,取代或非取代的异喹啉基,取代或非取代的吲哚基,取代或非取代的环丙基,取代或非取代的环己基,取代或非取代的环丁基,取代或非取代的环戊基,其中前述取代的取代基选自甲基,乙基,丙基,羰基,羧基,氨基,羟基。
在一优选实施例中,R3选自-C(O)(R4)(R5),其中R4选自氢,氨基,甲基,乙基,丙基;R5选自氢,取代或非取代的四氢呋喃基,取代或非取代的四氢吡咯基,取代或非取代的呋喃基,取代或非取代的噻吩基,取代或非取代的吡咯基,取代或非取代的咪唑基,取代或非取代的吡唑基,取代或非取代的噻唑基,取代或非取代的噁唑基,取代或非取代的吡啶基,取代或非取代的嘧啶基,取代或非取代的哒嗪基,取代或非取代的吡嗪基,取代或非取代的嘌呤基,取代或非取代的喹啉基,取代或非取代的异喹啉基,取代或非取代的吲哚基,取代或非取代的环丙基,取代或非取代的环己基,取代或非取代的环丁基,取代或非取代的环戊基,苯基,苄基,-(CH2)nSCH3,-(CH2)mNHCH3,-(CH2)mN(CH3)2,其中前述取代的取代基选自氨基,羟基,羧基,-SH,-C(O)NH2,甲基,乙基,丙基。
在一更优选实施例中,n选自1,2或3,m选自1,2,3,4或5。
在一实施例中,R3选自-P(O)(OR6)(OR7),-P(O)2(OR6)M,-P(O)3MY,其中R6和R7各自独立的选自氢,甲基,乙基,丙基,丁基,戊基,己基,M和Y各自独立选自钠离子,钾离子,或者MY为一个二价阳离子,选自钙离子,镁离子。
在一实施例中,R1选自H,甲基,乙基或丙基;R2选自H,-OR3,取代或非取代的呋喃基,取代或非取代的噻吩基,取代或非取代的吡咯基,取代或非取代的咪唑基,取代或非取代的吡唑基,取代或非取代的噻唑基,取代或非取代的噁唑基,取代或非取代的吡啶基,取代或非取代的嘧啶基,取代或非取代的哒嗪基,取代或非取代的吡嗪基,取代或非取代的嘌呤基,取代或非取代的喹啉基,取代或非取代的异喹啉基,取代或非取代的吲哚基,其中前述取代的取代基选自甲基,乙基,丙基;
R3选自-C(O)(R4)(R5),-P(O)(OR6)(OR7),-P(O)2(OR6)M,-P(O)3MY;
R4选自氢,氨基,甲基,乙基,丙基;
R5选自氢,甲基,乙基,丙基,丁基,戊基,己基,庚基,辛基,壬基,癸基,四氢呋喃基,四氢吡咯基,呋喃基,噻吩基,吡咯基,咪唑基,吡唑基,噻唑基,噁唑基,吡啶基,嘧啶基,哒嗪基,吡嗪基,嘌呤基,喹啉基,异喹啉基,吲哚基,苯基,苄基,-(CH2)nSCH3,-(CH2)mNHCH3,-(CH2)mN(CH3)2;
R6和R7各自独立的选自氢,甲基,乙基,丙基;M和Y各自独立选自钠离子,钾离子,或者MY为一个二价阳离子,选自钙离子,镁离子;且
m和n各自独立的选自1,2,3,4,5,6。
在一优选实施例中,其中:
R1选自H,甲基;
R2选自H,-OR3,其中取代基选自甲基,乙基,丙基;
R3选自-C(O)(R4)(R5),-P(O)(OR6)(OR7),-P(O)2(OR6)M,-P(O)3MY;
R4选自氢,氨基;
R5选自氢,甲基,乙基,丙基,丁基,戊基,己基,庚基,辛基,壬基,癸基,四氢呋喃基,四氢吡咯基,呋喃基,噻吩基,吡咯基,咪唑基,吡唑基,噻唑基,噁唑基,吡啶基,嘧啶基,哒嗪基,吡嗪基,嘌呤基,喹啉基,异喹啉基,吲哚基,苯基,苄基,-(CH2)nSCH3,-(CH2)mNHCH3,-(CH2)mN(CH3)2;
R6和R7为氢;M和Y各自独立选自钠离子,钾离子,或者MY为一个二价阳离子,选自钙离子,镁离子;且
m和n各自独立的选自1,2,3,4,5,6。
根据本发明,通式为式(Ⅰ)的化合物,其优选化合物包括:
本发明中所述的药学上可接受的盐包括但不限于盐酸盐或氨丁三醇盐。
另一方面,本发明提供一种药物组合物,其包含有治疗有效剂量的如前述的化合物(包括其立体异构体)或其药学上可接受的盐,以及药学上可接受的载体和/或赋形剂。
又一方面,本发明提供如前述的化合物(包括其立体异构体)或其药学上可接受的盐在制备治疗癌症的药物中的用途。所述癌症包括但不限于前列腺癌,多发性骨髓瘤。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述的式(Ⅰ)所示的化合物包括其立体异构体。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素,任选地进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又称为重氢)、氚(T,又称为超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指直链和支链的饱和脂肪族烃基团,主链包括1至20个碳原子,优选为1至12个碳原子,进一步优选为1至8个碳原子,更优选为1至6个碳原子,再进一步优选1至4个碳原子的直链与支链基团,最优选1至2个碳原子;烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,2-二甲基己基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基和正癸基。
“烷氧基”是指-O-烷基,其中烷基如本文上述定义。烷氧基可以是取代的或未取代的,烷氧基实施例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基和正己氧基。
“烯基”是指至少含一个碳-碳双键组成的如本文上述定义的烷基,优选含有2至20个碳原子,进一步优选2至12个碳原子,更优选在主链上有2至8个碳原子,烯基可以是取代的或未取代的;非限制性实施例包括乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯、1,4-己二烯、3-十一烯基、4-十二烯基和4,8,12-十四碳三烯基。
“炔基”是指包含至少一个碳-碳三键组成的如本文上述定义的烷基,优选含有2至20个碳原子,进一步优选2至8个碳原子,更优选在主链上有2至4个碳原子的炔基;炔基可以是取代的或未取代的;非限制性实施例包括乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基、4-癸炔基、3-十一炔基和4-十二炔基。
“环烷基”是指全部为碳的单环、稠合、螺环或桥环的环,非限制性地包括环丙烷、环丁烷、环戊烷、螺[3.4]辛烷、二环[3.1.1]己烷等。
“杂环”或“杂环基”是指取代的或未取代的饱和或不饱和的至少含有1至5个选自N、O、S、S(=O)或S(=O)2原子或基团的非芳香环系统,非芳香环系统包含3至20个环原子,优选3至10个环原子,更优选3至8个环原子;杂环基环中选择性取代的N、S可被氧化成各种氧化态;非限制性实施例包括氧杂环丙烷基、氧杂环丁基、氧杂环戊基、氧杂环己基、氧杂环己基、氧杂环辛基、氮杂环丙烷基、氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环丙烯基、1,3二氧环戊基、1,4-二氧环戊基、1,3-二氧环戊基、1,3-二氧环己基、1,3-二硫环己基、氮杂环庚烯基、吗啉基、哌嗪基、吡啶基、呋喃基、噻吩基、吡咯基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、硫代吗啉基、二氢吡喃、噻二唑基、噁唑基、噁二唑基、吡唑基、1,4-二氧杂环己二烯基、2H-1,2-噁嗪基或2,5-二氢噻吩基等。
“杂芳基”是指取代或未取代的5至14元芳香环,且含有1至5个选自N、O或S(=O)n原子或基团,优选5至10元杂芳香环,进一步优选5至6元;杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉、硫代吗啉、1,3-二噻烷、苯并咪唑、哌叮基、苯并咪唑、苯并吡啶、吡咯并吡啶;所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。
“取代”是指基团中一个或多个氢原子被其它基团取代的情形,如果所述的基团被氢原子取代,形成的基团与被氢原子取代的基团相同。
“取代或非取代的”是指基团可以被取代或不被取代的情形,若在本发明中没有指出基团可以被取代,则表示该基团为未取代的情形。
“各自独立的选自”是指各取代基可以相同或不同,甚至在同一实施方案中用同一取代基符号表示的不同取代基也可以相同或不同。
“药学上可接受的盐”指的是保持游离酸或游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或有机碱,或所述的游离酸通过与无毒的无机酸或有机酸反应获得的那些盐。
附图说明
图1显示了各组化合物给药大鼠后血浆中药物浓度和时间的关系,其中分别显示了SD大鼠单次口服2.95mg/kg化合物1的盐酸盐、2.8mg/kg化合物11的氨丁三醇盐和2.0mg/kg泊马度胺药时曲线图。
具体实施方式
下面将结合实施例对本发明作进一步说明,可以使本领域技术人员更全面地理解本发明,但不以任何方式限制本发明。
实施例1
化合物1的制备
步骤1:氮气保护下,向1000mL三颈反应瓶中加入S.M.B(20g,73.2mmol,1.00eq)和DMF(400ml),电磁搅拌。随后缓慢加入氢化钠(3.5g,87.5mmol,1.2eq),继续搅拌30min后,加入碘化钾(12g,72.2mmol,0.99eq)和TBAB(四丁基溴化铵)(3.52g,10.9mmol,0.15eq),搅拌15min后,将S.M.1(23.8g,72.8mmol,0.99eq)加入,搅拌12h。停止反应,将反应体系倒入2L水中,搅拌1h,有固体析出,过滤,得到黄色固体滤饼,滤饼以500ml DCM(二氯甲烷)洗涤,分液,取有机相减压浓缩,柱层析(PE:EA=1.5:1),得13.20g黄色固体产品,收率35.8%。
步骤2:氮气保护下,向100ml三颈反应瓶中加入Int 1-01(500mg,1mmol,1.00eq),DCM 5ml,室温搅拌10min后,一次性加入HCl/EA(10ml,10mmol,10.0eq),继续搅拌40min。停止反应,过滤干燥得380mg黄色固体产物,收率86.9%。
HPLC:97.05%
LCMS:403.2(M+H-HCl)
1H NMR(400MHz,DMSO)δ8.56-8.51(d,3H),7.51-7.47(dd,1H),7.06–7.04(d,1H),7.01-7.02(d,1H),6.56(bs,2H),5.91-5.85(dd,1H),5.74-5.69(t,1H),5.28-5.23(m,1H),3.92(s,1H),2.25(m,1H),2.88-2.84(d,1H),2.61-2.51(m,1H),2.16-2.10(m,2H),0.96-0.92(m,6H)。
实施例2
化合物2的制备
步骤1:向2000mL三颈反应瓶中加入S.M.2(50g,285.4mmol,1.00eq),H2O(1000ml),碳酸氢钠(95.9g,1141.6mmol,4.00eq),搅拌30min后,加入DCM和Bu4NHSO4(9.7g,28.5mmol,0.1eq),继续搅拌20min后,加入S.M.A(56.5g,342.5mmol,1.2eq),搅拌反应15h。停止反应,分液,取得有机相减压浓缩得60g无色油状物,收率93.8%。
步骤2:氮气保护下,向100ml单口反应瓶中加入S.M.B(5.0g,18.3mmol,1.00eq),DMF 50ml,冰水浴搅拌10min,随后一次性加入NaH(0.9g,22.0mmol,1.2eq),继续搅拌20min后,加入TBAB(0.6g,1.8mmol,0.1eq),和KI(3.0g,18.3mmol,1.00eq)加入,冰水浴下反应10min,将Int.2-01(6.2g,27.5mmol,1.50eq)加入,室温搅拌过夜。停止反应,分液,有机相减压浓缩,柱层析(DCM:EA=5:1)得1.5g产品。
步骤3:氮气保护下,向25ml三口反应瓶中加入Int 2-02(0.1g,0.2mmol,1.00eq),盐酸/二氧六环20ml,室温搅拌过夜。停止反应,过滤干燥得73mg黄色固体产物,收率92.4%。
HPLC:96.24%
LCMS:361.1(M+H+)
1H NMR(400MHz,DMSO)δ=8.50(s,2H),7.49(t,1H),7.04(dd,2H),5.79(q,J=9.7,2H),
5.24(dd,4.5,1H),3.82(d,2H),3.57(s,1H),3.14–3.01(m,1H),2.85(d,1H),2.60(d,1H)。
实施例3
化合物3的制备
步骤1:向500mL三颈反应瓶中加入S.M.1(6g,31.7mmol,1.00eq),H2O(130ml),碳酸氢钠(10.6g,126.8mmol,4.00eq)加入,搅拌30min,随后加入DCM和Bu4NHSO4(1.08g,3.2mmol,0.1eq),搅拌20min;将S.M.A(6.3g,38.0mmol,1.2eq)加入,搅拌反应15h。停止反应,分液,有机相减压浓缩得7.2g无色油状物,收率95.5%。
步骤2:向250mL单口反应瓶中加入Int 2-02(5.0g,18.3mmol,1.00eq),NaI(18g,121mmol),MeCN(75ml),室温搅拌过夜。停止反应,分液,有机相减压浓缩得9.2g无色油状产物,收率92.2%。
步骤3:氮气保护下,向250ml三口反应瓶中加入S.M.B(3g,10.98mmol,1.00eq),DMF 65mL,将反应体系温度冷却至-20℃以下,滴加LiHMDS(11ml,11mmol,1.00eq),搅拌10min后,加入Int.3-02(4.34g,13.17mmol,1.20eq)的DMF溶液,继续搅拌。停止反应,将反应体系倒入1%的NH4Cl(300ml)冰水溶液中,搅拌析出固体,过滤,滤饼溶于EtOAc中,减压浓缩,柱层析(PE/EtOAc=10:1-2:1)得1.6g产品,收率30%。
步骤4:氮气保护下,向25ml三口反应瓶中加入Int 3-03(0.5g,1.05mmol,1.00eq),盐酸/二氧六环20ml,室温搅拌过夜。停止反应,过滤,干燥得235mg黄色固体产物,收率54.2%。
HPLC:96.4%
LCMS:375.1(M+H+)
1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),7.48(t,J=7.8Hz,1H),7.05(d,J=8.4Hz,1H),7.01(d,J=7.1Hz,1H),5.86(t,J=9.1Hz,1H),5.74(d,J=9.5Hz,1H),5.24(dd,J=13.0,5.3Hz,1H),4.11–4.02(m,3H),3.11–3.03(m,3H),2.87–2.74(m,1H),2.68–2.57(m,1H),2.14–2.08(m,1H),1.38(d,J=7.0Hz,3H)。
实施例4
化合物4的制备
步骤1:向500mL三颈反应瓶中加入S.M.4(6.3g,25.27mmol,1.00eq),H2O(110ml),将碳酸氢钠(8.48g,101.08mmol,4.00eq)加入,搅拌10min,随后加入DCM和Bu4NHSO4(0.86g,2.52mmol,0.1eq),搅拌10min后,冰浴条件下,滴加S.M.A(5g,30.32mmol,1.2eq),室温搅拌反应15h。停止反应,分液,取得有机相减压浓缩得7.4g无色油状物,收率98.4%。
步骤2:氮气保护下,向250ml三口反应瓶中加入S.M.B(2.7g,9.88mmol,1.00eq),DMF 70ml,反应体系冷却至-20℃以下,滴加LiHMDS(9.88ml,9.88mmol,1.00eq)继续搅10min,随后加入Int.4-01(3.8g,12.84mmol,1.3eq)的DMF溶液,保持低温搅拌。停止反应,将反应体系倒入1%的NH4Cl(315ml)冰水溶液中,搅拌析出固体,过滤,滤饼以EA溶解,减压浓缩,柱层析(PE:EA=2:1)得800mg产品,收率15%。
步骤3:氮气保护下,向25ml三口反应瓶中加入Int 4-02(0.2g,0.37mmol,1.00eq),2N盐酸/EA 4ml,室温搅拌过夜。停止反应,过滤,干燥得80mg黄色固体产物,收率50%。
HPLC:98.24%.
LCMS:417.4(M+H+)
1H NMR(400MHz,DMSO)δ8.43(s,2H),7.50(t,J=7.7Hz,1H),7.09–6.95(m,2H),6.55(s,2H),5.87(d,J=9.6Hz,1H),5.74(d,J=9.8Hz,1H),5.24(d,J=12.9Hz,1H),4.00(s,1H),3.09(t,J=15.2Hz,1H),2.86(d,J=18.2Hz,1H),1.76–1.64(m,1H),1.57(dd,J=14.0,6.9Hz,2H),1.24(s,2H),0.89(d,J=6.2Hz,6H)。
实施例5
化合物5的制备
步骤1:制备方法同实施例4的步骤1,不同之处在于,将S.M.4改为S.M.5。制备获得7.6g无色油状物,收率99.2%。
步骤2:制备方法同实施例4的步骤2,不同之处在于,将Int.4-01改为Int.5-01。制备获得800mg产品,收率15%。
步骤3:制备方法同实施例4的步骤3,不同之处在于,将Int.4-02改为Int.5-02。制备得到83.6mg黄色固体产物,收率52%。
HPLC:99.5%
LCMS:417.4(M+H+)
1H NMR(400MHz,DMSO)δ8.47(s,3H),7.49(s,1H),7.05(d,J=8.5Hz,2H),6.52(s,2H),5.87(d,J=9.8Hz,1H),5.71(dd,J=9.7,4.3Hz,1H),5.29–5.16(m,1H),3.97(s,1H),3.08(ddd,J=18.7,12.7,6.1Hz,1H),2.86(d,J=17.5Hz,1H),2.63(dd,J=26.7,13.6Hz,1H),2.20–2.05(m,1H),1.41(dt,J=13.3,6.6Hz,1H),1.32–1.07(m,2H),0.93–0.70(m,6H)。
实施例6
化合物6的制备
步骤1:制备方法同实施例4的步骤1,不同之处在于,将S.M.4改为S.M.6。制备得6.3g无色油状物,收率94.2%。
步骤2:制备方法同实施例4的步骤2,不同之处在于,将Int.4-01改为Int.6-01。制备获得100mg产品,收率2%。
步骤3:制备方法同实施例4的步骤3,不同之处在于,将Int.4-02改为Int.6-02。制备得到45mg黄色固体产物,收率56.2%。
HPLC:96.53%。
LCMS:401.4(M+H+)
1H NMR(400MHz,DMSO)δ10.00(s,1H),9.00(s,1H),7.48(s,1H),7.03(dd,J=11.8,7.8Hz,2H),6.53(s,2H),5.86(s,2H),5.24(dd,J=13.0,5.2Hz,1H),4.40(s,1H),3.16(d,J=32.7Hz,2H),3.13–2.98(m,1H),2.91–2.78(m,1H),2.22(dd,J=14.8,7.1Hz,1H),2.16–2.04(m,1H),1.91(s,4H),0.85(s,0H)。
实施例7
化合物7的制备
步骤1:制备方法同实施例4的步骤1,不同之处在于,将S.M.4改为S.M.7。制备得7g无色油状物,收率88.6%。
步骤2:制备方法同实施例4的步骤2,不同之处在于,将Int.4-01改为Int.7-01。制备得到2.1g产品,收率40.2%。
步骤3:制备方法同实施例4的步骤3,不同之处在于,将Int.4-02改为Int.7-02。制备得到45mg黄色固体产物,收率56.2%。
HPLC:96.41%
LCMS:451.4(M+H+)
1H NMR(400MHz,DMSO)δ8.64(s,3H),7.48(dd,J=10.3,4.3Hz,1H),7.38–7.15(m,5H),7.14–6.92(m,2H),5.94–5.78(m,1H),5.66(dd,J=9.6,3.1Hz,1H),5.20(d,J=13.0Hz,1H),4.33(s,1H),3.09(dt,J=21.8,11.7Hz,3H),2.86(d,J=16.2Hz,1H),2.77–2.51(m,1H),2.12(d,J=6.2Hz,1H)。
实施例8
化合物8的制备
氮气保护下,向250ml三口反应瓶中加入S.M.B(2.5g,9.15mmol,1.00eq),DMF65mL,反应体系温度冷却至-20℃以下,滴加LiHMDS(9.15ml,9.15mmol,1.00eq),继续低温搅拌10min,随后加入S.M.8(2.72g,11.89mmol,2.00eq)的DMF溶液,冰浴下反应。停止反应,将反应体系倒入1%的NH4Cl(300mL)冰水溶液中,搅拌析出固体,过滤,滤饼溶于EtOAc,减压浓缩,柱层析(PE:EtOAc=2:1)得290mg产品。
HPLC:82.4%
LCMS:386.1(M+H+)
1H NMR(400MHz,DMSO)δ8.64(s,3H),7.48(dd,J=10.3,4.3Hz,1H),7.38–7.15(m,5H),7.14–6.92(m,2H),5.94–5.78(m,1H),5.66(dd,J=9.6,3.1Hz,1H),5.20(d,J=13.0Hz,1H),4.33(s,1H),3.09(dt,J=21.8,11.7Hz,3H),2.86(d,J=16.2Hz,1H),2.77–2.51(m,1H),2.12(d,J=6.2Hz,1H)。
实施例9
化合物9的制备
步骤1:氮气保护下,向100mL三口反应瓶中加入S.M.B(1g,3.66mmol,1.00eq),DMF25mL,将反应体系温度冷却至-20℃以下,滴加LiHMDS(3.66ml,3.66mmol,1.00eq),搅拌10min,随后加入S.M.9(1.21g,5.49mmol,1.20eq)的DMF溶液,冰水浴下反应。停止反应,将反应体系倒入1%的NH4Cl(120mL)冰水溶液中,搅拌析出固体,过滤,滤饼以EtOAc溶解,减压浓缩,柱层析(PE:EA=2:1)得310mg产品,收率18.3%。
HPLC:98.2%
LCMS:480.2(M+Na+)
1H NMR(400MHz,DMSO)δ7.48(t,J=7.7Hz,1H),7.02(t,J=8.1Hz,2H),6.53(s,2H),5.64(d,J=2.3Hz,2H),5.23(dd,J=13.0,5.3Hz,1H),3.05(td,J=13.9,13.4,6.9Hz,1H),2.82(dt,J=17.8,3.2Hz,1H),2.72–2.51(m,2H),2.27(t,J=7.3Hz,2H),2.15–2.02(m,1H),1.49(t,J=7.1Hz,2H),1.22(s,1H),0.84(t,J=6.6Hz,3H)。
实施例10
化合物10的制备
步骤1:氮气保护下,向500mL三颈反应瓶中加入S.M.10(15g,107.9mmol,1.00eq),DCM(150ml),DMF(4滴),冰浴条件下,继续滴加草酰氯(15.07g,118.74mmol,1.1eq),室温搅拌2h。停止反应,将反应液减压浓缩得14.56g油状物,收率86.1%。
步骤2:向100ml单口反应瓶中加入Int.10-01(14.56g,92.06mmol,1.00eq),多聚甲醛(2.78g,92.06mmol,1.00eq),氯化锌(2.52g,18.41mmol,0.2eq),将反应体系温度升高至90℃搅拌。停止反应,反应液减压浓缩,柱层析得4.3g产品,收率24.7%。
步骤3:氮气保护下,向250ml三口反应瓶中加入S.M.B(4.48g,16.4mmol,1.00eq),DMF 65ml,将反应体系温度冷却至-20℃以下;滴加LiHMDS(16.4ml,16.4mmol,1.00eq),搅拌10min后,加入Int.10-02(4.0g,21.3mmol,1.3eq)的DMF溶液,冰浴下搅拌。将反应体系倒入1%的NH4Cl(360ml)冰水溶液中,搅拌析出固体,过滤,滤饼以EA溶解,减压浓缩,柱层析(DCM:EA=50:1~30:1)得3.3g产品,收率47.5%。
步骤4:向250ml三口反应瓶中加入Int.10-03(3.33g,7.85mmol,1.00eq),THF66ml,二甲胺(1.41g,31.4mmol,4.00eq),KI(33mg),常温搅拌。停止反应,将体系直接以减压泵旋干以少量EA溶解后再以3N的HCl/EA成盐析出,过滤得500mg产品,收率15%。
HPLC:98.6%
LCMS:451.4(M+H+)
1H NMR(400MHz,DMSO)δ10.78(s,0H),7.48(dd,J=8.4,7.1Hz,1H),7.04(dd,J=21.7,7.6Hz,2H),6.59(s,2H),5.81(q,J=9.7Hz,1H),5.26(dd,J=13.0,5.4Hz,1H),3.61–3.18(m,1H),2.83(s,3H),2.51(dt,J=3.8,1.9Hz,1H),2.22–1.98(m,1H)。
实施例11
化合物11的制备
步骤1:向100mL三颈反应瓶中加入S.M.11(2.50g,10mmol,1.00eq),碳酸氢钠(3.78g,45mmol,4.50eq),四丁基硫酸氢铵(169mg,0.5mmol,0.05eq),水(12ml),乙酸异丙酯(14ml),搅30min后,滴加S.M.A(2.97g,18mmol,1.80eq),搅拌反应约13h。停止反应,分液,取得有机相减压浓缩得到无色液体2.20g,收率85.2%。
步骤2:氮气保护下,向100ml三口反应瓶中加入泊马度胺(1.00g,3.66mmol,1.00eq),DMF 10ml,搅拌1h后,加入氢化钠(60%)(175mg,4.39mmol,1.20eq),继续搅拌40min;随后加入Int.11.01(0.95g,3.66mmol,1.00eq),继续搅拌27h。停止反应,将体系倒入5%的氯化铵(200ml)溶液中,搅拌析出固体,过滤,滤饼以200ml DCM溶解,减压浓缩,柱层析(PE:EA=1.5:1)得到650mg黄色固体产物。收率35.9%。
步骤3:氮气保护下,向100ml三口反应瓶中加入Int11.02(490mg,1mmol,1.00eq),DCM 20ml,室温搅拌10min后,加入HCl/EA(20ml,20mmol,20.0eq),继续搅拌45min。停止反应,以水泵将反应体系中盐酸真空抽20min,然后氮气氛下抽滤,得到黄色固体产物,直接以10ml甲醇溶解,用作下一步原料。氮气保护下,向100ml三口反应瓶中加入上述中间体的甲醇溶液,室温搅拌下滴加三丁胺醇(243mg,2mmol,2.00eq)的20ml甲醇溶液,搅拌10min,将25ml丙酮滴加入体系中,体系有大量固体析出,搅拌40min。过滤得到滤饼,真空干燥,得到170mg黄色固体产物,收率27.2%。
HPLC:99.73
LCMS:382(M-H-2tris)
1H NMR(400MHz,DMSO),.δ7.52-7.48(t,1H),7.05-7.03(t,2H),5.92(m,2H),5.16-5.11(dd,1H),3.37(s,12H),3.03-2.95(m,1H),2.82-2.78(d,1H),2.64-2.53(m,1H),2.10-2.03(m,1H)。
实施例12
本发明化合物的溶解度测定
将1mg化合物1与1ml水混合,室温搅拌,完全溶解,取上清液作为供试样品溶液。通过HPLC测定供试样品溶液,结果如表1所示。
将50mg化合物的盐酸盐或氨丁三醇盐与150μl水混合,室温搅拌,完全溶解,取上清液作为供试样品溶液。通过HPLC测定供试样品溶液,结果如表1所示。
表1
样品 | 室温下水中的最低溶解度(mg/ml) |
化合物1 | 1 |
化合物1的盐酸盐 | >300 |
化合物2的盐酸盐 | >300 |
化合物3的盐酸盐 | >300 |
化合物4的盐酸盐 | >300 |
化合物5的盐酸盐 | >300 |
化合物6的盐酸盐 | >300 |
化合物7的盐酸盐 | >300 |
化合物10的盐酸盐 | >300 |
化合物11的氨丁三醇盐 | >300 |
本试验未测定样品的饱和溶解度,而是采用选取适量样品,判断样品的溶解能力。由试验得出,本发明化合物(1mg)或盐(300mg)能完全溶解在1ml水中,化合物溶解度不小于1mg/ml,其盐溶解度不小于300mg/ml。而泊马度胺在水中的溶解度约为0.01mg/ml,远低于本发明化合物或其盐的溶解能力。
实施例13
本发明化合物的稳定性测定
取适量样品各自独立的放置于不同环境条件下,测定0天,5天,10天或30天时样品的百分含量,评价样品的稳定性。
表2
样品 | 化合物1盐酸盐 | 化合物2盐酸盐 | 化合物11氨丁三醇盐 |
0天 | 97.1% | 96.1% | 99.9% |
5天/RT/75%RH/避光 | / | / | 79.8% |
5天/RT/92.5%RH/避光 | / | / | 78.4% |
5天/40℃/60%RH/避光 | / | / | 92.8% |
5天/60℃/75%RH/避光 | / | / | 15.6% |
5天/光照 | / | / | 99.5% |
10天/RT/75%RH/避光 | 96.8% | / | / |
10天/RT/92.5%RH/避光 | 95.5% | 93.3% | / |
10天/40℃/60%RH/避光 | 96.9% | 43.5% | / |
10天/60℃/75%RH/避光 | 96.4% | 13.3% | / |
10天/光照 | 96.7% | / | / |
30天/RT/75%RH/避光 | 96.1% | / | / |
30天/RT/92.5%RH/避光 | 93.3% | / | / |
30天/40℃/60%RH/避光 | 95.1% | / | / |
30天/60℃/75%RH/避光 | 94.7% | / | / |
30天/光照 | 95.0% | / | / |
注:RT=室温,RH=相对湿度
实施例14
药动学数据
本实施例中所使用的为雄性SD大鼠(SPF级),体重250~330g,购自北京维通利华实验动物技术有限公司,大于8周龄,动物群养在装有垫料的聚碳酸酯笼具里(最多5只动物/性别/笼)。自由饮水,每日自由采食合格饲料5CC4(同5CR4,PMI NutritionInternational LLC,美国)。
采用随机区组设计的分组,对试验用SD大鼠进行分组,分为化合物1的盐酸盐组、化合物11的氨丁三醇盐组、泊马度胺组。各组以灌胃(i.g.)的方式给药,给药剂量设为2mg/kg(以泊马度胺计)。
试验方法:给药前,给药后0.25、0.5、1、2、3、4、6、8、12、24、36和48小时采集血样,采入含有EDTA-2K的抗凝管中的全血于湿冰上存放,并在30分钟内于3500rpm,4℃下离心5分钟来获得血浆样品。分离取得的血浆样品立即放在干冰中暂存然后转移至-60至-80℃冰箱中。血浆中的化合物1的盐酸盐、化合物11的氨丁三醇盐和泊马度胺分析采用LC/MS/MS进行检测,采用软件WinNonlin的非室模型计算大鼠给药后的药代动力学参数。
数据结果:大鼠给予泊马度胺(2mg/kg)等摩尔剂量的各化合物后血浆中泊马度胺浓度随时间变化的药代动力学参数如下表所示:
表3
化合物 | 化合物1的盐酸盐 | 化合物11的氨丁三醇盐 | 泊马度胺 |
剂量(mg/kg) | 2.95 | 2.8 | 2 |
T<sub>max</sub>(h) | 0.58±0.38 | 0.33±0.14 | 2.33±0.58 |
C<sub>max</sub>(ng/mL) | 1100±214 | 1240±383 | 366±62 |
t<sub>1/2</sub>(h) | 2.69±0.53 | 2.09±0.27 | 2.62±0.28 |
AUC<sub>last</sub>(h*ng/mL) | 4660±249 | 4510±1420 | 2570±383 |
结论:由上述试验结果可知,各组给药后,在体内均只检出泊马度胺,说明它们进入体内后均迅速代谢为泊马度胺。在2mg/kg的剂量下,给药后,本发明化合物相比泊马度胺,Cmax值升高3倍以上,AUClast升高2倍以上,化合物1和化合物11的Cmax表明本发明化合物与泊马度胺相比具有更好的口服生物利用度。
Claims (13)
1.一种式(Ⅰ)所示的化合物或其药学上可接受的盐,
其中:
R1选自H,取代或非取代的C1-6烷基,取代或非取代的C1-6烷氧基,取代或非取代的C2-6烯基,取代或非取代的C2-6炔基,其中前述取代的取代基选自C1-6烷基,C1-6烷氧基;
R2选自H,-OR3,-SR3,-NHR3,取代或非取代的C3-10杂环基,取代或非取代的C3-10杂环芳基,取代或非取代的C3-10环烷基,其中前述取代的取代基选自C1-6烷基,C1-6烷氧基,羰基,羧基,氨基,羟基;
R3选自-C(O)(R4)(R5),-P(O)(OR6)(OR7),-P(O)2(OR6)M,-P(O)3MY;
R4选自氢,氨基,羟基,卤素,C1-6烷基;
R5选自氢,取代或非取代的C1-16烷基,取代或非取代的C1-6烷氧基,取代或非取代的C3-10杂环基,取代或非取代的C3-10杂环芳基,取代或非取代的C3-10环烷基,苯基,苄基,-(CH2)nSCH3,-(CH2)mNHCH3,-(CH2)mN(CH3)2,其中前述取代的取代基选自氨基,羟基,羧基,-SH,-C(O)NH2,C1-6烷基;
R6和R7各自独立的选自氢,C1-6烷基;M和Y各自独立选自单价阳离子,或者MY为一个二价阳离子;且
m和n各自独立的选自1,2,3,4,5,6。
2.如权利要求1所述的式(Ⅰ)所示的化合物或其药学上可接受的盐,其中R1选自H,取代或非取代的甲基,取代或非取代的乙基,取代或非取代的丙基,取代或非取代的丁基,取代或非取代的戊基,取代或非取代的己基,其中前述取代的取代基选自甲基,乙基或丙基。
3.如权利要求1所述的式(Ⅰ)所示的化合物或其药学上可接受的盐,其中R2选自H,-OR3,取代或非取代的四氢呋喃基,取代或非取代的四氢吡咯基,取代或非取代的呋喃基,取代或非取代的噻吩基,取代或非取代的吡咯基,取代或非取代的咪唑基,取代或非取代的吡唑基,取代或非取代的噻唑基,取代或非取代的噁唑基,取代或非取代的吡啶基,取代或非取代的嘧啶基,取代或非取代的哒嗪基,取代或非取代的吡嗪基,取代或非取代的嘌呤基,取代或非取代的喹啉基,取代或非取代的异喹啉基,取代或非取代的吲哚基,取代或非取代的环丙基,取代或非取代的环己基,取代或非取代的环丁基,取代或非取代的环戊基,其中前述取代的取代基选自甲基,乙基,丙基,羰基,羧基,氨基,羟基。
4.如权利要求3所述的式(Ⅰ)所示的化合物或其药学上可接受的盐,其中R3选自-C(O)(R4)(R5),其中:
R4选自氢,氨基,甲基,乙基,丙基;且
R5选自氢,取代或非取代的四氢呋喃基,取代或非取代的四氢吡咯基,取代或非取代的呋喃基,取代或非取代的噻吩基,取代或非取代的吡咯基,取代或非取代的咪唑基,取代或非取代的吡唑基,取代或非取代的噻唑基,取代或非取代的噁唑基,取代或非取代的吡啶基,取代或非取代的嘧啶基,取代或非取代的哒嗪基,取代或非取代的吡嗪基,取代或非取代的嘌呤基,取代或非取代的喹啉基,取代或非取代的异喹啉基,取代或非取代的吲哚基,取代或非取代的环丙基,取代或非取代的环己基,取代或非取代的环丁基,取代或非取代的环戊基,苯基,苄基,-(CH2)nSCH3,-(CH2)mNHCH3,-(CH2)mN(CH3)2,其中前述取代的取代基选自氨基,羟基,羧基,-SH,-C(O)NH2,甲基,乙基,丙基。
5.如权利要求4所述的式(Ⅰ)所示的化合物或其药学上可接受的盐,其中n选自1,2或3,m选自1,2,3,4或5。
6.如权利要求1所述的式(Ⅰ)所示的化合物或其药学上可接受的盐,其中R3选自-P(O)(OR6)(OR7),-P(O)2(OR6)M,-P(O)3MY,其中R6和R7各自独立的选自氢,甲基,乙基,丙基,丁基,戊基,己基,M和Y各自独立选自钠离子,钾离子,或者MY为一个二价阳离子,选自钙离子,镁离子。
7.如权利要求1所述的式(Ⅰ)所示的化合物或其药学上可接受的盐,其中:
R1选自H,甲基,乙基或丙基;
R2选自H,-OR3,取代或非取代的呋喃基,取代或非取代的噻吩基,取代或非取代的吡咯基,取代或非取代的咪唑基,取代或非取代的吡唑基,取代或非取代的噻唑基,取代或非取代的噁唑基,取代或非取代的吡啶基,取代或非取代的嘧啶基,取代或非取代的哒嗪基,取代或非取代的吡嗪基,取代或非取代的嘌呤基,取代或非取代的喹啉基,取代或非取代的异喹啉基,取代或非取代的吲哚基,其中前述取代的取代基选自甲基,乙基,丙基;
R3选自-C(O)(R4)(R5),-P(O)(OR6)(OR7),-P(O)2(OR6)M,-P(O)3MY;
R4选自氢,氨基,甲基,乙基,丙基;
R5选自氢,甲基,乙基,丙基,丁基,戊基,己基,庚基,辛基,壬基,癸基,四氢呋喃基,四氢吡咯基,呋喃基,噻吩基,吡咯基,咪唑基,吡唑基,噻唑基,噁唑基,吡啶基,嘧啶基,哒嗪基,吡嗪基,嘌呤基,喹啉基,异喹啉基,吲哚基,苯基,苄基,-(CH2)nSCH3,-(CH2)mNHCH3,-(CH2)mN(CH3)2;
R6和R7各自独立的选自氢,甲基,乙基,丙基;M和Y各自独立选自钠离子,钾离子,或者MY为一个二价阳离子,选自钙离子,镁离子;且
m和n各自独立的选自1,2,3,4,5,6。
8.如权利要求7所述的式(Ⅰ)所示的化合物及其立体异构体或药学上可接受的盐,其中,
R1选自H,甲基;
R2选自H,-OR3,其中取代基选自甲基,乙基,丙基;
R3选自-C(O)(R4)(R5),-P(O)(OR6)(OR7),-P(O)2(OR6)M,-P(O)3MY;
R4选自氢,氨基;
R5选自氢,甲基,乙基,丙基,丁基,戊基,己基,庚基,辛基,壬基,癸基,四氢呋喃基,四氢吡咯基,呋喃基,噻吩基,吡咯基,咪唑基,吡唑基,噻唑基,噁唑基,吡啶基,嘧啶基,哒嗪基,吡嗪基,嘌呤基,喹啉基,异喹啉基,吲哚基,苯基,苄基,-(CH2)nSCH3,-(CH2)mNHCH3,-(CH2)mN(CH3)2;
R6和R7为氢;M和Y各自独立选自钠离子,钾离子,或者MY为一个二价阳离子,选自钙离子,镁离子;且
m和n各自独立的选自1,2,3,4,5,6。
9.如权利要求1所述的式(Ⅰ)所示的化合物或其药学上可接受的盐,其中该化合物具有下列的结构之一:
10.如权利要求1-9任一项所述的式(Ⅰ)所示的化合物或其药学上可接受的盐,其中该药学上可接受的盐为盐酸盐或氨丁三醇盐。
11.一种药物组合物,包含有治疗有效剂量的如权利要求1-9中任一项所述的化合物或其药学上可接受的盐,以及药学上可接受的载体和/或赋形剂。
12.如权利要求1-9中任一项所述的化合物或其药学上可接受的盐在制备治疗癌症的药物中的用途。
13.如权利要求12所述的用途,其中所述的癌症为前列腺癌,多发性骨髓瘤。
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