CN110267964B - 作为IL-12、IL-23及/或IFNα响应调节剂的经取代的杂芳基氧化膦化合物 - Google Patents
作为IL-12、IL-23及/或IFNα响应调节剂的经取代的杂芳基氧化膦化合物 Download PDFInfo
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- CN110267964B CN110267964B CN201780086194.3A CN201780086194A CN110267964B CN 110267964 B CN110267964 B CN 110267964B CN 201780086194 A CN201780086194 A CN 201780086194A CN 110267964 B CN110267964 B CN 110267964B
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- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 108010038745 tryptophylglycine Proteins 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 230000010472 type I IFN response Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/650905—Six-membered rings having the nitrogen atoms in the positions 1 and 2
Abstract
本发明涉及具有下式I的化合物或其立体异构体或药学上可接受的盐,其中所有取代基如本文所定义,其可用于通过作用于Tyk‑2以引起信号转导抑制来调节IL‑12、IL‑23及/或IFNα。
Description
相关申请的交叉参考
本申请要求2016年12月13日提交的第62/433,470号美国临时申请的权益,其公开内容以全文引用的方式并入本文中。
技术领域
本发明涉及可用于通过作用于Tyk-2以引起信号转导抑制来调节IL-12、IL-23及/或IFNα的化合物。本文提供化合物、包含此类化合物的组合物及其使用方法。本发明进一步涉及含有至少一种本发明化合物的药物组合物,其可用于治疗哺乳动物中与调节IL-12、IL-23及/或IFNα相关的病状。
背景技术
共用常见p40亚基的杂二聚体细胞因子白介素IL-12及IL-23通过活化抗原递呈细胞制得且在Th1及Th17细胞的分化及增殖中十分关键,所述Th1及Th17细胞为在自身免疫中起关键作用的两种效应子T细胞谱系。IL-23由p40亚基以及特有p19亚基构成。经由由IL-23R及IL-12Rβ1构成的杂二聚体受体起作用的IL-23为Th17细胞存活及增殖所必需,所述Th17细胞会产生促炎性细胞因子,诸如IL-17A、IL-17F、IL-6及TNF-α(McGeachy,M.J.等人,“The link between IL-23and Th17 cell-mediated immune pathologies”,Semin.Immunol.,19:372-376(2007))。这些细胞因子在介导多种自身免疫性疾病,包括类风湿性关节炎、多发性硬化、炎性肠病及狼疮的病理学中十分关键。与IL-23相同,IL-12除p40亚基以外还含有p35亚基且经由由IL-12Rβ1及IL-12Rβ2构成的杂二聚体受体起作用。IL-12为Th1细胞发育及分泌IFNγ所必需,IFNγ为通过刺激MHC表达、将B细胞类别转换至IgG亚类及活化巨噬细胞而在免疫中关键起作用的细胞因子(Gracie,J.A.等人,“Interleukin-12induces interferon-gamma-dependent switching of IgGalloantibody subclass”,Eur.J.Immunol.,26:1217-1221(1996);Schroder,K.等人,“Interferon-gamma:an overview of signals,mechanisms and functions”,J.Leukoc.Biol.,75(2):163-189(2004))。
自身免疫中含p40的细胞因子的重要性通过以下发现来证明:保护缺乏p40、p19、或IL-23R的小鼠免受多发性硬化、类风湿性关节炎、炎性肠病、狼疮及牛皮癣以及其他疾病的模型中的疾病(Kyttaris,V.C.等人,“Cutting edge:IL-23receptor deficiencyprevents the development of lupus nephritis in C57BL/6-lpr/lpr mice”,J.Immunol.,184:4605-4609(2010);Hong,K.等人,“IL-12,independently of IFN-gamma,plays a crucial role in the pathogenesis of a murine psoriasis like skindisorder”,J.Immunol.,162:7480-7491(1999);Hue,S.等人,“Interleukin-23drivesinnate and T cell-mediated intestinal inflammation”,J.Exp.Med.,203:2473-2483(2006);Cua,D.J.等人,“Interleukin-23rather than interleukin-12is the criticalcytokine for autoimmune inflammation of the brain”,Nature,421:744-748(2003);Murphy,C.A.等人,“Divergent pro-and anti-inflammatory roles for IL-23and IL-12in joint autoimmune inflammation”,J.Exp.Med.,198:1951-1957(2003))。
在人类疾病中,在牛皮癣性病变中已测量到p40及p19的高表达,且在来自MS患者的大脑的活性病变中及在患有活性克罗恩病患者的肠粘膜中已鉴别出Th17细胞(Lee,E.等人,“Increased expression of interleukin 23p19 and p40 in lesional skin ofpatients with psoriasis vulgaris”,J.Exp.Med.,199:125-130(2004);Tzartos,J.S.等人,“Interleukin-17production in central nervous system infiltrating T cellsand glial cells is associated with active disease in multiple sclerosis”,Am.J.Pathol.,172:146-155(2008))。还展示活性SLE患者中p19、p40及p35的mRNA水平明显比非活性SLE患者中那些mRNA水平更高(Huang,X.等人,“Dysregulated expression ofinterleukin-23and interleukin-12 subunits in systemic lupus erythematosuspatients”,Mod.Rheumatol.,17:220-223(2007)),且来自狼疮患者的T细胞具有主要Th1表型(Tucci,M.等人,“Overexpression of interleukin-12and T helper 1predominancein lupus nephritis”,Clin.Exp.Immunol.,154:247-254(2008))。
此外,全基因组关联研究已鉴别多个与慢性炎性及自身免疫性疾病相关的基因座,所述基因座编码在IL-23及IL-12途径中起作用的因子。这些基因包括IL23A、IL12A、IL12B、IL12RB1、IL12RB2、IL23R、JAK2、TYK2、STAT3及STAT4(Lees,C.W.等人,“New IBDgenetics:common pathways with other diseases”,Gut,60:1739-1753(2011);Tao,J.H.等人,“Meta-analysis of TYK2 gene polymorphisms association withsusceptibility to autoimmune and inflammatory diseases”,Mol.Biol.Rep.,38:4663-4672(2011);Cho,J.H.等人,“Recent insights into the genetics ofinflammatory bowel disease”,Gastroenterology,140:1704-1712(2011))。
实际上,已展示在包括牛皮癣、克罗恩病及牛皮癣性关节炎的疾病中抑制IL-12与IL-23的抗p40治疗以及IL-23特异性抗p19疗法在自身免疫的治疗中有效(Leonardi,C.L.等人,“PHOENIX 1study investigators.Efficacy and safety of ustekinumab,a humaninterleukin-12/23monoclonal antibody,in patients with psoriasis:76-weekresults from a randomized,double-blind,placebo-controlled trial(PHOENIX 1)”,Lancet,371:1665-1674(2008);Sandborn,W.J.等人,“Ustekinumab Crohn's DiseaseStudy Group.A randomized trial of Ustekinumab,a human interleukin-12/23monoclonal antibody,in patients with moderate-to-severe Crohn's disease”,Gastroenterology,135:1130-1141(2008);Gottlieb,A.等人,“Ustekinumab,a humaninterleukin 12/23monoclonal antibody,for psoriatic arthritis:randomized,double-blind,placebo-controlled,crossover trial”,Lancet,373:633-640(2009))。因此,可预期抑制IL-12及IL-23的作用的药剂在人类自身免疫病症中具有治疗益处。
包括IFNα成员以及IFNβ、IFNε、IFNκ及IFNω的I型干扰素(IFN)群组经由杂二聚体IFNα/β受体(IFNAR)起作用。I型IFN在先天与后天免疫***中具有多种作用,包括活化细胞与体液免疫响应以及增强自身抗原的表达及释放(Hall,J.C.等人,“Type I interferons:crucial participants in disease amplification in autoimmunity”,Nat.Rev.Rheumatol.,6:40-49(2010))。
在患有全身性红斑性狼疮(SLE)(一种可能致命的自身免疫性疾病)的患者中,已证明在大多数患者中在末梢血液单核细胞中及在受影响的器官中血清干扰素(IFN)α(I型干扰素)水平增加或I型IFN调节的基因(所谓IFNα特征)的表达增加(Bennett,L.等人,“Interferon and granulopoiesis signatures in systemic lupus erythematosusblood”,J.Exp.Med.,197:711-723(2003);Peterson,K.S.等人,“Characterization ofheterogeneity in the molecular pathogenesis of lupus nephritis fromtranscriptional profiles of laser-captured glomeruli”,J.Clin.Invest.,113:1722-1733(2004)),且若干研究已展示血清IFNα水平与疾病活性与严重程度相关(Bengtsson,A.A.等人,“Activation of type I interferon system in systemic lupuserythematosus correlates with disease activity but not with antiretroviralantibodies”,Lupus,9:664-671(2000))。IFNα在狼疮的病理学中的直接作用通过向患有恶性或病毒性疾病的患者给药IFNα可诱导狼疮样综合征的观察结果来证明。此外,易感狼疮的小鼠中缺乏IFNAR提供高度保护以免于自身免疫、疾病严重程度及死亡(Santiago-Raber,M.L.等人,“Type-I interferon receptor deficiency reduces lupus-likedisease in NZB mice”,J.Exp.Med.,197:777-788(2003)),且全基因组关联研究已鉴别出与狼疮相关的基因座,其编码在I型干扰素途径中起作用的因子,包括IRF5、IKBKE、TYK2及STAT4(Deng,Y.等人,“Genetic susceptibility to systemic lupus erythematosus inthe genomic era”,Nat.Rev.Rheumatol.,6:683-692(2010);Sandling,J.K.等人,“Acandidate gene study of the type I interferon pathway implicates IKBKE andIL8 as risk loci for SLE”,Eur.J.Hum.Genet.,19:479-484(2011))。除狼疮以外,有迹象表明I型干扰素介导的途径的异常活化在诸如干燥综合征( syndrome)及硬皮病的其他自身免疫性疾病的病理学中十分重要(U.等人,“Activation of the typeI interferon system in primary syndrome:a possible etiopathogenicmechanism”,Arthritis Rheum.,52:1185-1195(2005);Kim,D.等人,“Induction ofinterferon-alpha by scleroderma sera containing autoantibodies totopoisomerase I:association of higher interferon-alpha activity with lungfibrosis”,Arthritis Rheum.,58:2163-2173(2008))。因此,可预期抑制I型干扰素响应的作用的药剂在人类自身免疫病症中具有治疗益处。
酪氨酸激酶2(Tyk2)为非受体酪氨酸激酶的Janus激酶(JAK)家族的成员,且已展示在调节以下两者中IL-12、IL-23及I型干扰素的受体的信号转导级联下游中十分关键:小鼠(Ishizaki,M.等人,“Involvement of Tyrosine Kinase-2in Both the IL-12/Th1 andIL-23/Th17 Axes In vivo”,J.Immunol.,187:181-189(2011);Prchal-Murphy,M.等人,“TYK2 kinase activity is required for functional type I interferon responsesin vivo”,PLoS One,7:e39141(2012))及人类(Minegishi,Y.等人,“Human tyrosinekinase 2deficiency reveals its requisite roles in multiple cytokine signalsinvolved in innate and acquired immunity”,Immunity,25:745-755(2006))。Tyk2介导转录因子的STAT家族成员的受体诱导的磷酸化,其为一种导致STAT蛋白质二聚及STAT依赖型促炎性基因转录的必要信号。缺乏Tyk2的小鼠对结肠炎、牛皮癣及多发性硬化的实验模型具有抗性,表明Tyk2介导的信号传导在自身免疫及相关病症中的重要性(Ishizaki,M.等人,“Involvement of Tyrosine Kinase-2in Both the IL-12/Th1 and IL-23/Th17 AxesIn vivo”,J.Immunol.,187:181-189(2011);Oyamada,A.等人,“Tyrosine kinase 2playscritical roles in the pathogenic CD4 T cell responses for the development ofexperimental autoimmune encephalomyelitis”,J.Immunol.,183:7539-7546(2009))。
在人类中,表达Tyk2的无活性变异体的个体经保护以免发生多发性硬化及可能的其他自身免疫病症(Couturier,N.等人,“Tyrosine kinase 2variant influences Tlymphocyte polarization and multiple sclerosis susceptibility”,Brain,134:693-703(2011))。全基因组关联研究已展示Tyk2的其他变体与诸如克罗恩病、牛皮癣、全身性红斑性狼疮及类风湿性关节炎的自身免疫病症有关,进一步表明Tyk2在自身免疫中的重要性(Ellinghaus,D.等人,“Combined Analysis of Genome-wide Association Studies forCrohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci”,Am.J.Hum.Genet.,90:636-647(2012);Graham,D.等人,“Association of polymorphismsacross the tyrosine kinase gene,TYK2 in UK SLE families”,Rheumatology(Oxford),46:927-930(2007);Eyre,S.等人,“High-density genetic mappingidentifies new susceptibility loci for rheumatoid arthritis”,Nat.Genet.,44:1336-1340(2012))。
鉴于所述病状可受益于涉及细胞因子及/或干扰素调节的治疗,能够调节诸如IL-12、IL-23及/或IFNα的细胞因子及/或干扰素的新颖化合物及使用这些化合物的方法可对多个有需要患者提供实质性治疗益处。
发明内容
本发明涉及式I化合物,其通过抑制Tyk2-介导的信号转导可用作IL-12、IL-23及/或IFNα的调节剂。
本发明还提供制备本发明化合物的方法及中间体。
本发明还提供包含药学上可接受的载体及至少一种本发明化合物的药物组合物。
本发明还提供一种通过抑制Tyk-2介导的信号转导调节IL-12、IL-23及/或IFNα的方法,其包括向需要此类治疗的宿主给药治疗有效量的至少一种本发明化合物。
本发明还提供一种治疗增殖性疾病、代谢性疾病、过敏性疾病、自身免疫性疾病及炎性疾病的方法,其包括向需要此类治疗的宿主给药治疗有效量的至少一种本发明化合物。
一个实施方案为一种治疗炎性疾病及自身免疫性疾病的方法。出于本发明的目的,炎性及自身免疫性疾病或病症包括具有炎性或自身免疫性组分的任何疾病。
另一实施方案为一种治疗包括2型糖尿病及动脉粥样硬化的代谢性疾病的方法。
本发明还提供本发明化合物用于制备用以治疗癌症的药物的用途。
本发明还提供用于治疗的本发明化合物。
具体实施方式
在本发明的第一方面,提供式(I)化合物
其中:
X为-N-或-CH-;
Y为-N-或-CH-;
R1为CD3、C1-3烷基或C3-6环烷基;
R2为CO-C3-6环烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,其经0-4个R2a取代;
R2a在每次出现时独立地为氢、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基、卤基C1-6烷基、羟基C1-6烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,该芳基或杂环基经0-2个Ra取代;
Ra为氢、卤素或C1-4烷基;
R3为P(O)-(C1-4烷基)2;
或其立体异构体或药学上可接受的盐。
在本发明的第二方面,提供式II化合物,
其中:
X为-N-或-CH-;
R1为CD3、C1-3烷基或C3-6环烷基;
R2为CO-C3-6环烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,其经0-4个R2a取代;
R2a在每次出现时独立地为氢、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基、卤基C1-6烷基、羟基C1-6烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,该芳基或杂环基经0-2个Ra取代;
Ra为氢、卤素或C1-4烷基;
R3为P(O)-(C1-4烷基)2;
或其立体异构体或药学上可接受的盐。
在本发明的第三方面,提供下式化合物,
其中:
X为-N-或-CH-;
R1为CD3、C1-3烷基或C3-6环烷基;
R2为CO-C3-6环烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,其经0-4个R2a取代;
R2a在每次出现时独立地为氢、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基、卤基C1-6烷基、羟基C1-6烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,该芳基或杂环基经0-2个Ra取代;
Ra为氢、卤素或C1-4烷基;
R3为P(O)-(C1-4烷基)2;
或其立体异构体或药学上可接受的盐。
在本发明的第四方面,提供下式化合物,
其中:
X为-N-或-CH-;
R1为CD3、C1-3烷基或C3-6环烷基;
R2为CO-C3-6环烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,其经0-4个R2a取代;
R2a在每次出现时独立地为氢、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基、卤基C1-6烷基、羟基C1-6烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,该芳基或杂环基经0-2个Ra取代;
Ra为氢、卤素或C1-4烷基;
或其立体异构体或药学上可接受的盐。
在本发明的第五方面,提供如上文所述的化合物,其中
R1为CD3或C1-3烷基;
R2为CO-C3-6环烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,其经0-4个R2a取代;
R2a在每次出现时独立地为氢、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基、卤基C1-6烷基、羟基C1-6烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,该芳基或杂环基经0-2个Ra取代;
Ra为氢、卤素或C1-4烷基;
或其立体异构体或药学上可接受的盐。
在本发明的第六方面,提供如上文所述的化合物,其中
R1为CD3;
R2为CO-C3-6环烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,其经0-4个R2a取代;
R2a在每次出现时独立地为氢、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基、卤基C1-6烷基、羟基C1-6烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,该芳基或杂环基经0-2个Ra取代;
Ra为氢、卤素或C1-4烷基;
或其立体异构体或药学上可接受的盐。
在本发明的第七方面,提供下式化合物,
其中:
R1为CD3、C1-3烷基或C3-6环烷基;
R2为CO-C3-6环烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,其经0-4个R2a取代;
R2a在每次出现时独立地为氢、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基、卤基C1-6烷基、羟基C1-6烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,该芳基或杂环基经0-2个Ra取代;
Ra为氢、卤素或C1-4烷基;
R3为P(O)-(C1-4烷基)2;
或其立体异构体或药学上可接受的盐。
在本发明的第八方面,提供下式化合物,
其中:
R1为CD3、C1-3烷基或C3-6环烷基;
R2为CO-C3-6环烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,其经0-4个R2a取代;
R2a在每次出现时独立地为氢、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基、卤基C1-6烷基、羟基C1-6烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,该芳基或杂环基经0-2个Ra取代;
Ra为氢、卤素或C1-4烷基;
R3为P(O)-(C1-4烷基)2;
或其立体异构体或药学上可接受的盐。
在另一方面,提供一种选自第一方面范围内的例示实施例的化合物,或其药学上可接受的盐、互变异构体或立体异构体。
在另一方面,提供一种选自任何上述方面的范围内的化合物的任何子集清单的化合物。
在另一实施方案中,提供一种包含一或多种式I化合物及药学上可接受的载体或稀释剂的药物组合物。
本发明还涉及可用于通过作用于Tyk-2以引起信号转导抑制来治疗与调节IL-12、IL-23及/或IFNα相关的疾病的药物组合物,其包含式I化合物、或其药学上可接受的盐、及药学上可接受的载体或稀释剂。
本发明进一步涉及治疗与调节IL-12、IL-23及/或IFNα相关的疾病的方法,其包括向需要此类治疗的患者给药治疗有效量的式I化合物。
本发明还提供一种治疗增殖性疾病、代谢性疾病、过敏性疾病、自身免疫性疾病及炎性疾病的方法(或本发明化合物用于制备用以治疗这些疾病的药物的用途),其包括向需要此类治疗的宿主给药治疗有效量的至少一种本发明化合物。
本发明还提供一种治疗炎性疾病或自身免疫性疾病的方法(或本发明化合物用于制备用以治疗这些疾病的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物。
本发明还提供一种治疗疾病的方法(或本发明化合物用于制备用以治疗这些疾病的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物,其中该疾病为类风湿性关节炎、多发性硬化、全身性红斑性狼疮(SLE)、狼疮性肾炎、皮肤狼疮、炎性肠病、牛皮癣、克罗恩病、牛皮癣性关节炎、干燥综合征、全身性硬皮病、溃疡性结肠炎、格雷夫斯病、盘状红斑狼疮、成年发作型斯蒂尔病、全身发作型青少年特发性关节炎、痛风、痛风性关节炎、I型糖尿病、胰岛素依赖性糖尿病、败血症、败血性休克、志贺杆菌病、胰腺炎(急性或慢性)、肾小球肾炎、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性嗜中性白细胞减少症、血小板减少、异位性皮肤炎、重症肌无力、胰腺炎(急性或慢性)、强直性脊柱炎、寻常天疱疮、古德帕斯彻病、抗磷脂综合征、特发性血小板减少、ANCA相关的血管炎、天疱疮、川崎病、慢性炎性脱髓鞘多发性神经病(CIDP)、皮肌炎、多发性肌炎、葡萄膜炎、格林-巴利综合征、自身免疫性肺炎、自身免疫性甲状腺炎、自身免疫性炎性眼睛病及慢性脱髓鞘多发性神经病。
本发明还提供一种治疗炎性疾病或自身免疫性疾病的方法(或本发明化合物用于制备用以治疗所述疾病的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物,其中该疾病选自全身性红斑性狼疮(SLE)、狼疮性肾炎、皮肤狼疮、克罗恩病、溃疡性结肠炎、I型糖尿病、牛皮癣、类风湿性关节炎、全身发作型青少年特发性关节炎、强直性脊柱炎及多发性硬化。
本发明还提供一种治疗类风湿性关节炎的方法(或本发明化合物用于制备用以治疗类风湿性关节炎的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物。
另外,本发明还提供一种治疗病状的方法(或本发明化合物用于制备用以治疗这些病状的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物,其中该病状选自急性骨髓性白血病、慢性骨髓性白血病、转移性黑素瘤、卡波西肉瘤、多发性骨髓瘤、实体肿瘤、眼部血管再生及婴儿血管瘤、B细胞淋巴瘤、全身性红斑性狼疮(SLE)、类风湿性关节炎、牛皮癣性关节炎、多发性血管炎、特发性血小板减少性紫癜(ITP)、重症肌无力、过敏性鼻炎、多发性硬化(MS)、移植排斥、I型糖尿病、膜性肾炎、炎性肠病、自身免疫性溶血性贫血、自身免疫性甲状腺炎、冷及温凝集素疾病、伊文氏综合征、溶血尿毒综合征/血栓性血小板减少性紫癫(HUS/TTP)、类肉瘤病、干燥综合征、周边神经病、寻常天疱疮及哮喘。
本发明还提供一种治疗IL-12、IL-23及/或介导的疾病的方法(或本发明化合物用于制备用以治疗这些疾病的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物。
本发明还提供一种治疗IL-12、IL-23及/或IFNα介导的疾病的方法(或本发明化合物用于制备用以治疗这些疾病治疗药剂的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物,其中IL-12、IL-23及/或IFNα介导的疾病为通过IL-12、IL-23及/或IFNα调节的疾病。
本发明还提供一种治疗疾病的方法,其包括向需要此类治疗的患者给药治疗有效量的式I化合物以及其他治疗剂。
本发明还提供用于治疗的本发明化合物。
在另一实施方案中,式I化合物选自例示化合物或例示化合物或本文中其他实施方案的组合。
本发明可在不背离其精神或基本属性的情况下以其他特定形式来实施。本发明涵盖本文中所提及的本发明的优选方面及/或实施方案的所有组合。应了解,本发明的任何及所有实施方案均可结合任何一或多种其他实施方案来描述本发明的额外更优选实施方案。还应了解,优选实施方案的各个别元素为其自身独立的优选实施方案。此外,一实施方案的任何要素意欲与任何实施方案的任何及所有其他要素组合以描述另一实施方案。
定义
以下为本说明书及随附权利要求书中所用的术语的定义。除非另外指明,否则对于本文的基团或术语提供的初始定义适用于本说明书及权利要求书通篇中的个别或作为另一基团的一部分的基团或术语。
本发明化合物可具有一或多个不对称中心。除非另外指明,否则在本发明中包括本发明化合物的所有手性(对映异构及非对映异构)及外消旋形式。烯烃的许多几何异构体、C=N双键及其类似物也可存在于化合物中,且本发明中涵盖所有此类稳定异构体。描述本发明化合物的顺式及反式几何异构体且可以异构体混合物或以分开的异构形式分离。本发明化合物可以光学活性或外消旋形式分离。本领域熟知如何制备光学活性形式,诸如通过拆分外消旋形式或通过自光学活性起始物质合成。除非特别指定特定立体化学或异构形式,否则欲为结构的所有手性、(对映异构及非对映异构)及外消旋形式及全部几何异构形式。
当任何变量(例如R3)在化合物的任何组成部分或式中出现一次以上时,其在每次出现时的定义独立于其在其他每次出现时的定义。因此,举例而言,若展示基团经0至2个R3取代,则该基团可任选经多达两个R3基团取代且R3在每次出现时独立地选自R3的定义。此外,取代基及/或变量的组合仅在此类组合产生稳定化合物时是容许的。
当展示连至取代基的键与连接环中的两个原子的键交叉时,则此类取代基可键合至该环上的任何原子。若所列取代基未指示此类取代基键合至指定化学式的化合物的其余部分的原子,则此类取代基可经此类取代基中的任何原子键合。取代基及/或变量的组合仅在此类组合产生稳定化合物时是容许的。
在本发明化合物上存在氮原子(例如胺)的情况下,这些氮原子可通过用氧化剂(例如MCPBA及/或过氧化氢)处理而转化成N-氧化物,得到本发明的其他化合物。因此,认为所展示及所要求保护的所有氮原子涵盖所示氮及其N-氧化物(N→O)衍生物。
不在两个字母或符号之间的虚线“-”用于指示取代基的连接点。举例而言,-CONH2经由碳原子连接。
关于式I化合物的特定部分的术语“任选经取代的”(例如任选经取代的杂芳基)是指具有0、1、2或更多个取代基的部分。举例而言,如下文所定义的“任选经取代的烷基”涵盖“烷基”与“经取代的烷基”。本领域技术人员应了解,对于含有一或多个取代基的任何基团,此类基团不意欲引入空间上不切实际、合成上不可行及/或本身不稳定的任何取代或取代模式。
如本文所使用,术语“至少一个化学实体”可与术语“化合物”互换。
如本文中所使用,术语“烷基”或“亚烷基”意欲包括具有指定数目的碳原子的支链与直链饱和脂族烃基。举例而言,“C1-10烷基”(或亚烷基)意欲包括C1、C2、C3、C4、C5、C6、C7、C8、C9及C10烷基。另外,举例而言,“C1-C6烷基”表示具有1至6个碳原子的烷基。烷基可未经取代或经取代以使得其氢中的一或多者经另一化学基团置换。实例烷基包括(但不限于)甲基(Me)、乙基(Et)、丙基(例如正丙基及异丙基)、丁基(例如正丁基、异丁基、叔丁基)、戊基(例如正戊基、异戊基、新戊基)及其类似基团。
“烯基”或“亚烯基”意欲包括呈直链或支链构型且具有一或多个可存在于沿链的任何稳定点的碳-碳双键的烃链。举例而言,“C2-6烯基”(或亚烯基)意欲包括C2、C3、C4、C5及C6烯基。烯基的实例包括(但不限于)乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基、4-甲基-3-戊烯基及其类似基团。
“炔基”或“亚炔基”意欲包括呈直链或支链构型且具有一或多个可存在于沿链的任何稳定点的碳-碳三键的烃链。举例而言,“C2-6炔基”(或亚炔基)意欲包括C2、C3、C4、C5及C6炔基;诸如乙炔基、丙炔基、丁炔基、戊炔基、己炔基及其类似基团。
当术语“烷基”与另一基团一起使用,诸如用于“芳基烷基”中时,此组合更明确定义经取代的烷基所含有的至少一个取代基。举例而言,“芳基烷基”是指如上所定义的经取代的烷基,其中至少一个取代基为芳基,诸如苯甲基。因此,术语芳基(C0-4)烷基包括具有至少一个芳基取代基的经取代的低碳烷基,且还包括直接键合至另一基团的芳基,即芳基(C0)烷基。术语“杂芳基烷基”是指如上所定义的经取代的烷基,其中至少一个取代基为杂芳基。
当提及经取代的烯基、炔基、亚烷基、亚烯基或亚炔基时,这些基团经一至三个如上针对经取代的烷基所定义的取代基取代。
术语“烷氧基”是指经如本文所定义的烷基或经取代的烷基取代的氧原子。举例而言,术语“烷氧基”包括基团-O-C1-6烷基,诸如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、戊氧基、2-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基、3-甲基戊氧基及其类似基团。”低碳烷氧基”是指具有一至四个碳的烷氧基。
应了解,通过本领域技术人员选择所有基团,包括例如烷氧基、硫代烷基及氨基烷基以提供稳定化合物。
如本文所用,“经取代的”意谓指定原子或基团上的任何一或多个氢经选自指定基团置换,其限制条件为不超出指定原子的正常价数。若取代基为氧代(oxo)或酮基(即=O),则置换原子上的2个氢。酮基取代基不存在于芳族部分上。除非另外规定,否则取代基依核心结构命名。举例而言,应了解,当列出(环烷基)烷基为可能的取代基时,此取代基与核心结构的连接点位于烷基部分中。如本文所使用,环双键是在两个相邻环原子之间所形成的双键(例如C=C、C=N或N=N)。
取代基及/或变量的组合仅在此类组合可以产生稳定化合物或有用的合成中间体时才容许。稳定化合物或稳定结构意谓化合物足够稳固以承受自反应混合物中分离得到可用纯度且随后配制成为有效治疗剂。目前所述的化合物优选不含有N-卤基、S(O)2H或S(O)H基团。
术语“环烷基”是指环化烷基,包括单环状、二环状或多环状环***。C3-7环烷基意欲包括C3、C4、C5、C6及C7环烷基。实例环烷基包括(但不限于)环丙基、环丁基、环戊基、环己基、降冰片烷基及其类似基团。如本文所用,“碳环”或“碳环基团”欲意意谓任何稳定3、4、5、6或7员单环状或双环状、或7、8、9、10、11、12或13员双环状或三环状环,其中任一者可为饱和、部分不饱和、不饱和或芳族环。此类碳环的实例包括(但不限于)环丙基、环丁基、环丁烯基、环戊基、环戊烯基、环己基、环庚烯基、环庚基、环庚烯基、金刚烷基、环辛基、环辛烯基、环辛二烯基、[3.3.0]二环辛烷、[4.3.0]二环壬烷、[4.4.0]二环癸烷、[2.2.2]二环辛烷、芴基、苯基、萘基、茚满基、金刚烷基、蒽基及四氢萘基(萘满)。如上文所示,桥接环也包括于碳环定义中(例如[2.2.2]二环辛烷)。除非另外规定,否则优选的碳环为环丙基、环丁基、环戊基、环己基及苯基。当使用术语“碳环”时,意欲包括“芳基”。当一或多个碳原子键联两个非相邻碳原子时,产生桥接环。优选的桥键为一或两个碳原子。应注意,一个桥键总是将单环转变成三环。当环桥接时,该环中所述取代基还可存在于桥键上。
术语“芳基”是指环部分中具有6至12个碳原子的单环或双环芳族烃基,诸如苯基及萘基,其各可经取代。
因此,在式I化合物中,术语“环烷基”包括环丙基、环丁基、环戊基、环己基、环庚基、二环辛基等,以及以下环***:
术语“卤基”或“卤素”是指氯、溴、氟及碘。
术语“卤烷基”意谓具有一或多个卤基取代的经取代的烷基。举例而言,“卤烷基”包括单、二及三氟甲基。
术语“卤代烷氧基”意谓具有一或多个卤基取代基的烷氧基。举例而言,“卤代烷氧基”包括OCF3。
因此,芳基的实例包括:
术语“杂环(heterocycle)”、“杂环烷基”、“杂环(heterocyclo)”、“杂环(heterocyclic)”或“杂环基(heterocyclyl)”可互换使用且是指经取代及未经取代的3至7员单环基团、7至11员二环基团及10至15员三环基团,其中该等环中的至少一者具有至少一个杂原子(O、S或N),该含杂原子的环优选具有1、2或3个选自O、S及N的杂原子。此类含有杂原子的基团的各环可含有一或两个氧或硫原子及/或一至四个氮原子,其限制条件为各环中杂原子的总数为四或更小,且其他限制条件为环含有至少一个碳原子。氮及硫原子可任选经氧化且氮原子可任选经季铵化。包括二环及三环基团的稠合环可仅含有碳原子,且可为饱和、部分饱和或完全不饱和的。杂环基可在任何可用氮或碳原子处连接。如本文所用,术语“杂环(heterocycle)”、“杂环烷基”、“杂环(heterocyclo)”、“杂环(heterocyclic)”及“杂环基(heterocyclyl)”包括如下所定义的“杂芳基”。
除下文所述杂芳基之外,例示性单环杂环基团包括氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、咪唑啉基、噁唑烷基、异噁唑啉基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂基、氮杂基、1-吡啶酮基、4-哌啶酮基、四氢吡喃基、吗啉基、硫吗啉基、硫吗啉基亚砜、硫吗啉基砜、1,3-二氧杂环戊烷及四氢-1,1-二氧代噻吩基及其类似基团。例示性二环杂环基包括奎宁环基。其他单环杂环基包括及
术语“杂芳基”是指经取代及未经取代的芳族5或6员单环基团、9或10员二环基团及11至14员三环基团,其在至少一个环中具有至少一个杂原子(O、S或N),该含杂原子环优选具有1、2或3个选自O、S及N的杂原子。含杂原子的杂芳基的各环可含有一或两个氧或硫原子及/或一至四个氮原子,其限制条件为各环中杂原子的总数为四个或更小且各环具有至少一个碳原子。包括二环及三环基团的稠合环可仅含有碳原子,且可为饱和、部分饱和或不饱和的。氮及硫原子可任选经氧化且氮原子可任选经季铵化。二环或三环杂芳基必须包括至少一个完全芳族环,但其他稠合环可为芳族或非芳族环。杂芳基可在任何环的任何可用的氮或碳原子处进行连接。价数允许时,若该其他环为环烷基或杂环,则其另外任选经=O(氧代)取代。
例示性单环杂芳基包括吡咯基、吡唑基、吡唑啉基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、噻吩基、噁二唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基及其类似基团。
例示性双环杂芳基包括吲哚基、苯并噻唑基、苯并二氧杂环戊烯基、苯并噁唑基、苯并噻吩基、喹啉基、四氢异喹啉基、异喹啉基、苯并咪唑基、苯并吡喃基、吲嗪基、苯并呋喃基、色酮基、香豆素基、苯并吡喃基、噌啉基、喹喔啉基、吲唑基、吡咯并吡啶基、呋喃并吡啶基、二氢异吲哚基、四氢喹啉基及其类似基团。
例示性三环杂芳基包括咔唑基、苯并吲哚基、菲啉基、吖啶基、菲啶基、呫吨基及其类似基团。
在式I化合物中,优选的杂芳基包括:
除非另外指明,否则当提及特定命名的芳基(例如苯基)、环烷基(例如环己基)、杂环(例如吡咯烷基、哌啶基及吗啉基)或杂芳基(例如四唑基、咪唑基、吡唑基、***基、噻唑基及呋喃基)时,如果适用,该提及意欲包括具有0至3个、优选0至2个选自以上针对芳基、环烷基、杂环及/或杂芳基所述取代基的取代基的环。
术语“碳环基”或“碳环状”是指饱和或不饱和单环或二环,其中所有环的所有原子均为碳。因此,术语包括环烷基及芳基环。单环碳环具有3至6个环原子,更通常具有5或6个环原子。二环碳环具有7至12个环原子,例如配置为二环[4,5]、[5,5]、[5,6]或[6,6]***,或9或10个环原子,配置为二环[5,6]或[6,6]。单及二环碳环的实例包括环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、苯基及萘基。碳环可经取代,在此情况下所述取代基选自上文针对环烷基及芳基所述的那些基团。
术语“杂原子”应包括氧、硫及氮。
当术语“不饱和”在本文中用以指环或基团时,该环或基团可为完全不饱和或部分不饱和的。
在整个本说明书中,其基团及取代基可通过本领域技术人员选择,以提供稳定部分及化合物及适用作药学上可接受的化合物的化合物及/或可用于制备药学上可接受的化合物的中间体化合物。
式I化合物可以游离形式存在(在无电离之情况下)或可形成还在本发明范围内的盐。除非另外指明,否则提及本发明化合物应理解为包括提及游离形式及其盐。术语“盐”表示与无机及/或有机酸及碱形成的酸性及/或碱性盐。另外,例如当式I化合物含有碱性部分(诸如胺或吡啶或咪唑环)与酸性部分(诸如甲酸)时,术语“盐”可包括两性离子(内盐)。药学上可接受的(即无毒的生理学上可接受的)盐优选为诸如可接受的金属及胺盐,其中阳离子并不明显促进盐的毒性或生物活性。然而,其他盐可用于例如可在制备期间所用的分离或纯化步骤中,且因此涵盖在本发明的范围内。式I化合物的盐例如可由使式I化合物与一定量(诸如等量)的酸或碱在介质(诸如使盐析出的介质)中或在水性介质中反应,继而冻干来形成。
例示性酸加成盐包括乙酸盐(诸如由乙酸或三卤乙酸(例如三氟乙酸)形成的那些盐)、己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、富马酸盐、葡糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、氢氯酸盐(由盐酸形成)、氢溴酸盐(由溴化氢形成)、氢碘酸盐、2-羟基乙烷磺酸盐、乳酸盐、马来酸盐(由马来酸形成)、甲烷磺酸盐(由甲烷磺酸形成)、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐(诸如由硫酸形成的那些盐)、磺酸盐(诸如本文中提及的那些盐)、酒石酸盐、硫氰酸盐、甲苯磺酸盐(toluenesulfonate)(诸如甲苯磺酸盐(tosylate))、十一烷酸盐及其类似盐。
例示性碱性盐包括铵盐,碱金属盐,诸如钠盐、锂盐及钾盐;碱土金属盐,诸如钙盐及镁盐;钡盐、锌盐及铝盐;由有机碱(例如有机胺)形成的盐,诸如三烷基胺(诸如三乙胺)、普鲁卡因、二苯甲胺、N-苯甲基-β-苯乙胺、1-二苯羟甲胺、N,N'-二苯甲基乙二胺、去氢松香胺、N-乙基哌啶、苯甲胺、二环己胺或类似药学上可接受的胺,及由氨基酸(诸如精氨酸、赖氨酸及类似物)形成的盐。碱性含氮基团可由试剂季铵化,诸如低碳烷基卤化物(例如甲基、乙基、丙基及丁基氯化物、溴化物及碘化物)、二烷基硫酸盐(例如二甲基、二乙基、二丁基及二戊基硫酸盐)、长链卤化物(例如癸基、十二烷基、十四烷基及十八烷基氯化物、溴化物及碘化物)、芳基烷基卤化物(例如苯甲基及苯乙基溴化物)及其他试剂。优选的盐包括单盐酸盐、硫酸氢盐、甲烷磺酸盐、磷酸盐或硝酸盐。
短语“药学上可接受的”在本文中用于指在合理医学判断范围内,适用于与人类及动物的组织接触而无过度毒性、刺激、过敏响应或其他问题或并发症、与合理益处/风险比相匹配的化合物、物质、组合物及/或剂型。
如本文所使用,“药学上可接受的盐”是指本发明化合物的衍生物,其中母体化合物通过制备其酸盐或碱盐而经修饰。药学上可接受的盐的实例包括(但不限于)碱性基团(诸如胺)的无机酸盐或有机酸盐;以及酸性基团(诸如羧酸)的碱盐或有机盐。药学上可接受的盐包括由例如无毒的无机酸或有机酸形成的母体化合物的常规无毒盐或季铵盐。举例而言,此类常规无毒盐包括那些衍生自无机酸的盐,所述无机酸为诸如盐酸、氢溴酸、硫酸、氨磺酸、磷酸及硝酸;及自有机酸制备的盐,所述有机酸为诸如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、双羟萘酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲烷磺酸、乙烷二磺酸、草酸及羟乙基磺酸及其类似物。
本发明的药学上可接受的盐可通过常规化学方法由含有碱性或酸性部分的母体化合物合成。一般而言,这些盐可通过使这些化合物的游离酸或碱形式与化学计量量的适当碱或酸在水中或在有机溶剂中或在两者的混合物中反应来制备;一般而言,优选非水性介质(如***、乙酸乙酯、乙醇、异丙醇或乙腈)。适合的盐的清单见于Remington'sPharmaceutical Sciences,第18版,Mack Publishing Company,Easton,PA(1990)中,其公开内容特此以引用的方式并入。
涵盖呈掺合物或纯或大体上纯形式的本发明化合物的所有立体异构体。立体异构体可包括经由拥有一或多个手性原子而成为光学异构体的化合物,以及借助于一或多个键周围之受限旋光性而成光学异构体(阻转异构体)的化合物。本发明化合物的定义涵盖所有可能的立体异构体及其混合物。具体涵盖外消旋形式及具有指定活性的分离的光学异构体。外消旋形式可通过物理方法拆分,诸如非对映异构体衍生物的分步结晶、分离或结晶,或通过手性柱色谱分离。单个光学异构体可由常规方法(诸如与光活性酸形成盐继之以结晶)自外消旋体获得。
本发明意欲包括存在于本发明化合物中的原子的所有同位素。同位素包括原子数相同但质量数不同的那些原子。作为一般实例且非限制性地,氢的同位素包括氘及氚。碳的同位素包括13C及14C。本发明的同位素标记化合物一般可通过本领域技术人员已知的常规技术或通过类似于本文所述的方法,使用适当同位素标记试剂代替另外使用的非标记试剂来制备。
还涵盖本发明化合物的前药及溶剂合物。术语”前药”表示向受试者给药时通过代谢或化学方法经历化学转化产生式I化合物及/或其盐及/或溶剂合物的化合物。将在体内转化以提供生物活性药剂(即式I化合物)的任何化合物为本发明的范围及精神内的前药。举例而言,含有羧基的化合物可形成生理学上可水解的酯,其充当前药通过在体内水解产生式I化合物本身。此类前药优选经口给药,因为许多情况下水解主要在消化酶的影响下发生。在酯本身具有活性的情况下或在水解发生于血液中的那些情况下,可使用肠胃外给药。式I化合物的生理学上可水解的酯的实例包括C1-6烷基苯甲基、4-甲氧基苯甲基、茚满基、苯二甲酰基、甲氧基甲基、C1-6烷酰氧基-C1-6烷基(例如乙酰氧基甲基、特戊酰氧基甲基或丙酰氧基甲基)、C1-6烷氧基羰氧基-C1-6烷基(例如甲氧基羰氧基甲基或乙氧基羰氧基甲基、甘氨酰基氧基甲基、苯基甘氨酰基氧基甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)-甲基),及用于例如青霉素及头孢菌素领域中的其他熟知的生理学上可水解的酯。此类酯可通过本领域已知的常规技术来制备。
各种形式的前药是本领域熟知的。关于此类前药衍生物的实例,参见:
a)Bundgaard,H.编,Design of Prodrugs,Elsevier(1985),及Widder,K.等人编,Methods in Enzymology,112:309-396,Academic Press(1985);
b)Bundgaard,H.,第5章,“Design and Application of Prodrugs”,Krosgaard-Larsen,P.等人编,A Textbook of Drug Design and Development,第113-191页,HarwoodAcademic Publishers(1991);及
c)Bundgaard,H.,Adv.Drug Deliv.Rev.,8:1-38(1992),各文献以引用的方式并入本文中。
式I化合物及其盐可以互变异构形式存在,其中氢原子转置至分子的其他部分且分子的原子之间的化学键因此发生重排。应了解,所有互变异构体形式,只要其可存在,均包括于本发明内。另外,本发明化合物可具有反式及顺式异构体。
进一步应了解,式I化合物的溶剂合物(例如水合物)还在本发明的范围内。溶剂化方法一般为本领域已知的。
实用性
本发明化合物调节IL-23刺激及IFNα刺激的细胞功能,包括基因转录。可通过本发明化合物调节的其他类型的细胞功能包括(但不限于)IL-12刺激响应。
因此,式I化合物通过对Tyk2起作用来介导信号转导而在治疗与调节IL-23或IFNα的功能,且尤其选择性抑制IL-23、IL-12及/或IFNα的功能相关的病状中具有实用性。此类病状包括IL-23、IL-12或IFNα相关疾病,其中致病机制通过这些细胞因子介导。
如本文所使用,术语”治疗(treating/treatment)”涵盖治疗哺乳动物,尤其人类中的疾病病况,且包括:(a)预防或延迟哺乳动物疾病病况的出现,当此类哺乳动物易患该疾病病况但又尚未诊断患有该疾病病况时尤其如此;(b)抑制疾病病况,即遏制其显现;及/或(c)实现症状或疾病病况的全部或部分还原,及/或缓解、改善、减轻或治愈疾病或病症及/或其症状。
鉴于其作为IL-23、IL-12及IFNα刺激的细胞响应的调节剂的活性,式I化合物适用于治疗IL-23、IL-12或IFNα相关疾病,分别包括(但不限于)炎性疾病,诸如克罗恩病、溃疡性结肠炎、哮喘、移植物抗宿主疾病、同种异体移植物排斥、慢性阻塞性肺病;自身免疫性疾病,诸如格雷夫斯病、类风湿性关节炎、全身性红斑狼疮、皮肤狼疮、狼疮性肾炎、盘状红斑狼疮、牛皮癣;自身炎性疾病,包括CAPS、TRAPS、FMF、成年发作型斯蒂尔病、全身发作型青少年特发性关节炎、痛风、痛风性关节炎;代谢性疾病,包括2型糖尿病、动脉粥样硬化、心肌梗塞;破坏性骨骼病症,诸如骨骼再吸收疾病、骨关节炎、骨质疏松、多发性骨髓瘤相关的骨骼病症;增殖性病症,诸如急性骨髓性白血病、慢性骨髓性白血病;血管生成病症,诸如包括实体肿瘤、眼部血管再生及婴儿血管瘤的血管生成病症;传染病,诸如败血症、败血性休克及志贺杆菌病;神经退化性疾病,诸如阿尔兹海默病、帕金森病、大脑缺血或由创伤性损伤所产生的神经退化性疾病、致癌性及病毒性疾病,诸如转移性黑素瘤、卡波西肉瘤、多发性骨髓瘤及HIV感染及CMV视网膜炎、AIDS。
更特定言之,可用本发明化合物处理的特异性病状或疾病包括(但不限于)胰腺炎(急性或慢性)、哮喘、过敏、成人呼吸窘迫综合征、慢性阻塞性肺病、肾小球肾炎、类风湿性关节炎、全身性红斑狼疮、皮肤狼疮、狼疮性肾炎、盘状红斑狼疮、硬皮病、慢性甲状腺炎、格雷夫斯病、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性嗜中性白细胞减少症、血小板减少、异位性皮肤炎、慢性活性肝炎、重症肌无力、多发性硬化、炎性肠病、溃疡性结肠炎、克罗恩病、牛皮癣、移植物抗宿主疾病、通过内毒素诱导的炎性反应、肺结核、动脉粥样硬化、肌肉退化症、恶病质、牛皮癣性关节炎、莱特综合征、痛风、创伤性关节炎、风疹性关节炎、急性关节膜炎、胰腺β细胞疾病;以大规模嗜中性白细胞浸润为特征的疾病;类风湿性脊柱炎、痛风性关节炎及其他关节炎病状、大脑疟疾、慢性肺部炎性疾病、硅肺、肺部类肉瘤病、骨骼再吸收疾病、同种异体移植物排斥、归因于感染的发热及肌痛、继发于感染的恶病质、瘢痕瘤形成、疤组织形成、溃疡性结肠炎、发热、流感、骨质疏松、骨关节炎、急性骨髓性白血病、慢性骨髓性白血病、转移性黑素瘤、卡波西肉瘤、多发性骨髓瘤、败血症、败血性休克及志贺杆菌病;阿尔兹海默病、帕金森病、大脑缺血或由创伤性损伤所产生的神经退化性疾病;血管生成病症,包括实体肿瘤、眼部血管再生及婴儿血管瘤;病毒性疾病,包括急性肝炎感染(包括甲型肝炎、乙型肝炎及丙型肝炎)、HIV感染及CMV视网膜炎、AIDS、ARC或恶性病、及疱疹;中风、心肌缺血、中风性心脏病发作中的缺血、器官缺氧[此应视为低氧]、血管增生、心脏及肾脏再灌注损伤、血栓形成、心脏肥大、凝血酶诱导的血小板凝集、内毒素血症及/或毒性休克综合征、与***素内过氧化酶合酶-2相关的病状及寻常天疱疮。优选的治疗方法为其中病状选自克罗恩病、溃疡性结肠炎、同种异体移植物排斥、类风湿性关节炎、牛皮癣、强直性脊柱炎、牛皮癣性关节炎及寻常天疱疮的那些方法。或者优选的治疗方法为其中病状选自包括由中风产生的脑缺血再灌注损伤及由心肌梗塞产生的心脏缺血再灌注损伤的缺血再灌注损伤的那些方法。另一优选的治疗方法为其中病状为多发性骨髓瘤的治疗方法。
当本文使用术语“IL-23、IL-12及/或IFNα相关的病状”或“IL-23、IL-12及/或IFNα相关的疾病或病症”时,各者意欲涵盖所有上文所鉴别的病状,如同其详细重复一般,以及受IL-23、IL-12及/或IFNα影响的任何其他病状。
本发明因此提供用于治疗此类病状的方法,其包括向有需要的受试者给药治疗有效量的至少一种式I化合物或其盐。“治疗有效量”意欲包括当单独或组合给药以抑制IL-23、IL-12及/或IFNα功能及/或治疗疾病时有效的本发明化合物的量。
治疗IL-23、IL-12及/或IFNα相关病状的方法可包含单独给药或彼此及/或与可用于治疗此类病状的其他适合的治疗剂组合给药式I化合物。因此,“治疗有效量”还意欲包括有效抑制IL-23、IL-12及/或IFNα功能及/或治疗与IL-23、IL-12及/或IFNα相关的疾病所要求的化合物的组合的量。
示例性此类其他治疗剂包括皮质类固醇、咯利普兰(rolipram)、钙磷酸蛋白、抑制细胞因子的消炎药(CSAID)、白介素-10、糖皮质激素、水杨酸盐、氧化氮及其他免疫抑制剂;核易位抑制剂,诸如去氧斯匹胍素(deoxyspergualin,DSG);非甾体抗炎药(NSAID),诸如布洛芬(ibuprofen)、塞来昔布(celecoxib)及罗非昔布(rofecoxib);类固醇,诸如***(prednisone)或***(dexamethasone);抗病毒剂,诸如阿巴卡韦(abacavir);抗增殖剂,诸如甲氨蝶呤(methotrexate)、来氟米特(leflunomide)、FK506(他克莫司(tacrolimus)、);抗疟疾药,诸如羟基氯喹(hydroxychloroquine);细胞毒性药物,诸如硫唑嘌呤(azathiprine)及环磷酰胺(cyclophosphamide);TNF-α抑制剂,诸如替尼达普(tenidap)、抗TNF抗体或可溶性TNF受体及雷帕霉素(rapamycin)(西罗莫司(sirolimus)或)或其衍生物。
以上其他治疗剂在与本发明化合物组合使用时可例如以Physicians'DeskReference(PDR)中所示或如原本通过本领域普通技术人员确定的那些量使用。在本发明方法中,此类其他治疗剂可在给药本发明化合物之前、同时或之后给药。本发明还提供能够通过抑制Tyk2介导的信号转导治疗IL-23、IL-12或IFNα相关病状(包括如上文所述IL-23、IL-12及/或IFNα介导之疾病)的药物组合物。
制剂/药物组合物
本发明组合物可含有如上文所述的其他治疗剂且可根据技术,诸如药物制剂领域中熟知的那些技术,例如通过采用常规固体或液体媒介物或稀释剂以及类型适于所需给药模式的药物添加剂(例如赋形剂、粘合剂、防腐剂、稳定剂、调味剂等)来配制。
因此,本发明进一步包括包含一或多种式I化合物及药学上可接受的载体的组合物。
“药学上可接受的载体”是指用于将生物活性剂递送至动物,尤其哺乳动物的领域中普遍接受的介质。药学上可接受的载体根据本领域普通技术人员范围内的多个因素配制。这些因素包括(但不限于)所配制的活性剂的类型及性质;给药含该药剂的组合物的受试者;组合物的预期给药途径;及所靶向的治疗适应症。药学上可接受的载体包括水性及非水性液体介质,以及多种固体及半固体剂型。除活性剂以外,此类载体可包括多种不同成分及添加剂,此类额外成分出于本领域普通技术人员熟知的多种原因(例如使活性剂、粘合剂稳定等)包括于制剂中。适合的药学上可接受的载体的描述及涉及其选择的因素见于多种容易获得的来源中,诸如Remington's Pharmaceutical Sciences,第17版(1985),其以全文引用的方式并入本文中。
式I化合物可通过适用于待治疗的病状的任何手段给药,其可取决于位点特异性治疗需要或待递送药物的量。对于皮肤相关疾病而言,通常优选局部给药,且对于癌或癌前病状而言,优选全身治疗,但还涵盖其他递送模式。举例而言,化合物可经口递送,诸如呈片剂、胶囊、颗粒、粉末或液体制剂(包括糖浆)形式;局部递送,诸如呈溶液、悬浮液、凝胶或软膏形式;舌下、颊内、肠胃外递送,诸如通过皮下、静脉内、肌肉内或胸骨内注射或输注技术(例如呈无菌可注射水性或非水性溶液或悬浮液形式);经鼻递送,诸如通过吸入喷雾;局部递送,诸如呈乳膏或软膏形式;经直肠递送,诸如呈栓剂形式;或经脂质体递送。可给药含有无毒的药学上可接受的媒介物或稀释剂的剂量单位制剂。化合物可以适用于立即释放或延长释放的形式给药。立即释放或延长释放可由适合的药物组合物实现,或尤其在延长释放的情况下用诸如皮下植入物或渗透泵的装置实现。
用于经口给药的例示性组合物包括悬浮液,其可含有例如微晶纤维素用于赋予松散的海藻酸或海藻酸钠作为悬浮剂、作为粘度增强剂的甲基纤维素及甜味剂或调味剂(诸如本领域已知的那些);及立即释放片剂,其可含有例如微晶纤维素、磷酸二钙、淀粉、硬脂酸镁及/或乳糖及/或其他赋形剂、粘合剂、增量剂、崩解剂、稀释剂及润滑剂(诸如本领域已知的那些)。本发明化合物还可例如以模制、压缩或冻干片剂的形式通过舌下及/或经颊给药来经口递送。例示性组合物可包括快速溶解稀释剂,诸如甘露糖醇、乳糖、蔗糖及/或环糊精。此类制剂中还可包括高分子量赋形剂,诸如纤维素或聚乙二醇(PEG);用以辅助粘膜粘附噁赋形剂,诸如羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(SCMC)及/或马来酸酐共聚物(例如);及用以控制释放的试剂,诸如聚丙烯酸共聚物(例如)。还可添加润滑剂、助流剂、调味剂、着色剂及稳定剂以便易于制备及使用。
用于经鼻气雾剂或吸入给药的例示性组合物包括溶液,其可含有例如苯甲醇或其他适合的防腐剂、用以增强吸收及/或生物利用度的吸收促进剂及/或其他溶解剂或分散剂,诸如本领域已知的那些。
用于肠胃外给药的例示性组合物包括可注射溶液或悬浮液,其可含有例如适合的无毒肠胃外可接受的稀释剂或溶剂,诸如甘露糖醇、1,3-丁二醇、水、林格氏溶液、等张氯化钠溶液或其他适合的分散剂或润湿剂及悬浮剂(包括合成的单甘油酯或二甘油酯)及脂肪酸(包括油酸)。
用于经直肠给药的例示性组合物包括栓剂,其可含有例如适合的无刺激性赋形剂,诸如可可脂、合成的甘油酯或聚乙二醇,其在常温为固体但在直肠腔内液化及/或溶解以释放药物。
本发明化合物的治疗有效量可由本领域普通技术人员确定,且包括用于哺乳动物的例示性剂量每天每kg体重约0.05至1000mg;1-1000mg;1-50mg;5-250mg;250-1000mg的活性化合物,其可以单次剂量或以个别分次剂量形式给药,诸如每天1至4次。应了解,任何特定受试者的特定剂量水平及剂量频率可以是变化的且其将取决于多种因素,所述因素包括所采用的特定化合物的活性;该化合物的代谢稳定性及作用时长;受试者的物种、寿命、体重、一般健康状况、性别及饮食;给药模式及时间;***速率;药物组合;及特定病状的严重程度。治疗的优选受试者包括动物,最佳为哺乳动物物种,诸如人类及家养动物,诸如狗、猫、马及其类似动物。因此,当本文使用”患者”时,此术语意欲包括由调节IL-23、IL-12及/或IFNα介导的功能影响的所有受试者,最优选哺乳动物物种。
制备方法
本发明化合物可通过有机化学领域技术人员可得的多种方法合成。下文描述用于制备本发明化合物的一般合成方案。这些方案为说明性的且不意欲限制本领域技术人员可用于制备本文所披露化合物的可能技术。制备本发明化合物的不同方法对于本领域技术人员显而易见。另外,合成中的多个步骤可以替代次序进行以得到一或多种所需化合物。下文所述的制备及实施例部分中给出通过一般方案中所述的方法制备的本发明化合物的实施例。纯手性实施例的制备可通过本领域技术人员已知的技术来进行。举例而言,纯手性化合物可通过手性相制备型HPLC分离外消旋产物来制备。或者,实施例化合物可通过已知得到对映异构性富集产物的方法来制备。
此部分中描述的反应及技术在适于所用试剂及材料且适合所进行的转化的溶剂中进行。另外,在下述合成方法的说明中,应了解,所提出的所有反应条件(包括溶剂选择、反应气氛、反应温度、实验持续时间及后处理操作)均经选择为本领域技术人员容易识别的该反应的标准条件。有机合成技术人员应了解,分子的各个部分上所存在的官能基须与所提出的试剂及反应相容。这些与反应条件相容的取代基限制对于本领域技术人员显而易见,然后必需再采用替代方法。有时需要判断,以修改合成步骤次序或选择一种特定方法方案而非另一种,从而获得所需本发明化合物。还将了解,在本领域中规划任何合成路线时的另一主要考虑因素为审慎选择用于保护本发明所述化合物中存在的反应性官能团的保护基。可为有经验的操作人员说明多种替代方案的权威文献为Greene等人(ProtectiveGroups in Organic Synthesis,第3版,Wiley and Sons(1999))。
方案中所用的取代基不一定对应于权利要求书中所用的取代基。
本发明的实施例化合物可使用中间体A制备,该中间体可如WO 2014674661中所述制备。使用诸如双(三甲基甲硅烷基)氨基锂(LHMDS)的强碱使A与(2-氨基苯基)二甲基氧化膦缩合,得到中间体B(X=CH)。与胺或伯甲酰胺的钯催化交叉偶联得到实施例化合物C(X=CH)。或者,A可在诸如LHMDS的适合的碱存在下,使用中间体D处理,得到B(X=N)。随后在催化性钯来源存在下与胺或酰胺偶联,得到实施例化合物C(X=N)。中间体D可通过2-氨基-3-碘吡啶与二甲基氧化膦的钯催化交叉偶联来制备。
实施例
式(I)化合物及用于制备式(I)化合物的中间体可使用以下实施例中所示的操作及相关操作制备。用于这些实施例中的方法及条件及这些实施例中制备的实际化合物并不意欲为限制性的,但意欲表明可如何制备式(I)化合物。当未通过本文所描述的操作制备时,用于这些实施例中的起始物质及试剂通常为市售的或在化学文献中报道或可通过使用化学文献中所描述的操作来制备。
在给定实施例中,短语“干燥且浓缩”通常是指经硫酸钠或硫酸镁对于有机溶剂中的溶液进行干燥,之后自滤液过滤且移除溶剂(通常在减压下且在适合于所制备物质的稳定性的温度)。使用中压色谱设备(Teledyne Corporation),利用预装填的硅胶管柱,用所指示的溶剂或溶剂混合物洗脱进行柱色谱。使用大小适于待分离物质的量反相柱(WatersSunfire C18、Waters XBridge C18、Axia C18、YMC S5 ODS或其类似管柱),通常用还含有0.05%或0.1%三氟乙酸或10mM乙酸铵的递增浓度的甲醇或乙腈/水梯度洗脱,以适合于管柱大小及待实现的分离的洗脱速率进行制备型高效液相色谱(HPLC)。使用ChemDraw Ultra,9.0.5版(CambridgeSoft)确定化学名称。使用以下缩写:
制备型HPLC方法及条件:
经由制备型LC/MS使用以下条件纯化粗物质:柱:XBridge C18,19×200mm,5μm颗粒;流动相A:含0.1%三氟乙酸的5:95的乙腈:水;流动相B:含0.1%三氟乙酸的95:5的乙腈:水;梯度:5-45%B,经20分钟,随后在100%B保持4分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥。
分析型HPLC方法条件:
分析型HPLC经Shimadzu LC10AS液相色谱进行:柱,Waters Acquity BEH C18,1.7μm 2.0×50mm;梯度洗脱,0-100%,梯度时间1.5分钟,且分析时间2分钟(溶剂A,90%水/10%MeOH/0.1%TFA;溶剂B,90%MeOH/10%水/0.1%TFA);流速,1mL/min;220nm,检测波长。
制备1
在室温经5分钟向(2-氨基苯基)二甲基氧化膦(0.5g,2.96mmol)及A(0.606g,2.90mmol;如WO 2014/074661中所述制备)于四氢呋喃(10mL)中的溶液中添加双(三甲基硅烷基)氨基锂(7.24ml,7.24mmol)。在室温搅拌所得混合物1小时。接着用水(5mL)淬灭反应物。用1N HCl溶液将混合物调节至pH 9-10,且进一步用水(40mL)稀释。收集析出产物B(0.65g,1.902mmol,产率65.6%)且真空干燥。该物质以原样用于下一反应。1H NMR(500MHz,DMSO-d6)δ10.80-10.57(m,1H),9.14(br s,1H),7.92-7.84(m,1H),7.74-7.67(m,1H),7.62-7.55(m,1H),7.51-7.45(m,1H),1.68(s,3H),1.66(s,3H)。LC保留时间0.86分钟。MS(E+)m/z:342(MH+)。
实施例1的制备:
向MY:A0F8C-061(25mg,0.073mmol)于二噁烷(1.0mL)中的溶液中添加4-环丙基吡啶-2-胺(12.76mg,0.095mmol)、Pd2(dba)3(6.70mg,7.32μmol)、Xantphos(8.47mg,0.015mmol)、Cs2CO3(31.0mg,0.095mmol)且用氮吹扫5分钟。将反应物置放于经预加热130℃的加热块中2小时。用DMSO稀释反应混合物,过滤且使用制备型HPLC纯化,得到11.5mg实施例1(产率36%)。1H NMR(500MHz,DMSO-d6)δ10.61-10.53(m,1H),9.93-9.86(m,1H),9.04(s,1H),7.90-7.82(m,2H),7.74-7.63(m,2H),7.60-7.52(m,1H),7.46-7.38(m,1H),7.33-7.25(m,1H),6.63-6.53(m,1H),1.88-1.81(m,1H),1.72(s,3H),1.68(s,3H),1.07-1.00(m,2H),0.75-0.68(m,2H)。LC保留时间0.88分钟。MS(E+)m/z:440(MH+)。
使用与实施例1的合成中所述类似的操作制备以下表1中所示的实施例。
表1.C系列的分析型HPLC及质谱结果。
制备2
步骤1:
向3-碘吡啶-2-胺(600mg,2.73mmol)、二甲基氧化膦(255mg,3.27mmol)于5mL1,4-二噁烷中的溶液中添加K3PO4(637mg,3.00mmol)、二乙酰氧基钯(61.2mg,0.273mmol)及Xantphos(189mg,0.327mmol),用N2吹扫混合物且在130℃搅拌16,LC-MS指示所需产物。混合物流经Isco柱用MeOH/DCM(0-15%,梯度时间=20分钟)洗脱,得到化合物D,产率56%(260mg,1.528mmol)。1H NMR(499MHz,三氯甲烷-d)δ8.19(dt,J=4.7,2.1Hz,1H),7.37(ddd,J=13.8,7.5,1.8Hz,1H),6.65(ddd,J=7.3,5.1,1.9Hz,1H),6.15(br.s.,2H),1.79(s,3H),1.77(s,3H)。LC保留时间0.13分钟。MS(E+)m/z:171.35(MH+)。
步骤2:
在0℃经5分钟向4,6-二氯-N-三氘甲基哒嗪-3-甲酰胺(A,307mg,1.469mmol;如WO2014/074661中所述制备)及(2-氨基吡啶-3-基)二甲基氧化膦(D,250mg,1.469mmol)于四氢呋喃(5mL)中的溶液中添加于THF(3.67mL,3.67mmol)中的双(三甲基硅烷基)氨基锂。在0℃搅拌所得混合物2小时。用水(2mL)淬灭反应物。真空浓缩混合物且用isco柱(24g,MeOH/DCM=0-15%,梯度时间=20min)纯化残余物得到化合物E(回收氧化膦)。1H NMR(400MHz,DMSO-d6)δ11.75(s,1H),9.18(s,1H),8.80(s,1H),8.60-8.54(m,1H),8.14(ddd,J=13.1,7.7,1.9Hz,1H),7.28(dd,J=6.5,4.8Hz,1H),1.85(s,3H),1.82(s,3H)。LC保留时间0.83分钟。MS(E+)m/z:343(MH+)。
实施例9的制备:
用氮吹扫E(15mg,0.044mmol)、环丙烷甲酰胺(7.45mg,0.088mmol)、Xantphos(3.80mg,6.56μmol)、Pd2(dba)3(3.01mg,3.28μmol)及Cs2CO3(28.5mg,0.088mmol)于二噁烷(0.7mL)中的混合物2分钟,且接着130℃搅拌3小时。用DMSO稀释粗产物且过滤,之后使用制备型HPLC纯化,得到5.5mg(产率32%)实施例9。1H NMR(500MHz,DMSO-d6)δ11.40-11.30(m,1H),9.32-9.22(m,1H),9.17-9.00(m,1H),8.51-8.42(m,1H),8.20-8.06(m,1H),7.28-7.19(m,1H),1.86-1.70(m,6H),1.20-1.08(m,1H),0.90-0.77(m,4H).LC保留时间0.77分钟。MS(E+)m/z:392(MH+)。
使用与实施例9的合成中所述类似的操作制备以下表2中所示的实施例:
表2.F系列的分析型HPLC及质谱结果。
表3.实施例1-26的1H NMR数据。
生物测定
探针置换测定(HTRF格式)
向10μL于测定缓冲液(20mM Hepes pH 7.5,150mM NaCl、10mM MgCl2、2mM DTT、50μg/mL BSA及0.015%Brij 35)中的26nM荧光素标记的探针加0.2nM抗6×His-铽标记的抗体(Medarex,labeled by Cisbio)中添加10μL重组人类带His标签的Tyk2假激酶域(His-TVMV-Tyk2,575-869)达最终浓度为0.5nM。在室温1小时之后,经Envision盘读取器测量HTRF信号(520nm处荧光素受体及495nm处铽供体的发射波长的荧光强度的比率)。通过比较无抑制剂的对照与无蛋白质的对照计算抑制百分比。产生剂量响应曲线以测定抑制50%信号所需的浓度(EC50)。
重组带His标签的Tyk2的蛋白质序列(575-869):
结合数据
Kit225T细胞测定
将具有稳定整合的STAT依赖性荧光素酶报告基因的Kit225T细胞接种于含有10%热不活化FBS(Gibco)及100U/mL PenStrep(Gibco)的RPMI(Gibco)中。接着用20ng/mL人类重组IL-23或200U/mL人类重组IFNα(PBL InterferonSource)刺激细胞5-6小时。荧光素酶表达使用荧光素酶测定***(Promega)根据制造商的说明来测量。抑制数据通过比较0%抑制的无抑制剂对照孔与100%抑制的非刺激对照孔来计算。产生剂量响应曲线以确定抑制50%细胞响应所需的浓度(IC50),如通过非线性回归分析所得出。
Kit225T细胞抑制数据
序列表
<110> 百时美施贵宝公司
<120> 作为IL-12、IL-23及/或IFNα响应调节剂的经烷基酰胺取代的杂芳基氧化膦化合物
<130> 12824-WO
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 317
<212> PRT
<213> 智人
<400> 1
Met Gly Ser Ser His His His His His His Ser Ser Gly Glu Thr Val
1 5 10 15
Arg Phe Gln Gly His Met Asn Leu Ser Gln Leu Ser Phe His Arg Val
20 25 30
Asp Gln Lys Glu Ile Thr Gln Leu Ser His Leu Gly Gln Gly Thr Arg
35 40 45
Thr Asn Val Tyr Glu Gly Arg Leu Arg Val Glu Gly Ser Gly Asp Pro
50 55 60
Glu Glu Gly Lys Met Asp Asp Glu Asp Pro Leu Val Pro Gly Arg Asp
65 70 75 80
Arg Gly Gln Glu Leu Arg Val Val Leu Lys Val Leu Asp Pro Ser His
85 90 95
His Asp Ile Ala Leu Ala Phe Tyr Glu Thr Ala Ser Leu Met Ser Gln
100 105 110
Val Ser His Thr His Leu Ala Phe Val His Gly Val Cys Val Arg Gly
115 120 125
Pro Glu Asn Ile Met Val Thr Glu Tyr Val Glu His Gly Pro Leu Asp
130 135 140
Val Trp Leu Arg Arg Glu Arg Gly His Val Pro Met Ala Trp Lys Met
145 150 155 160
Val Val Ala Gln Gln Leu Ala Ser Ala Leu Ser Tyr Leu Glu Asn Lys
165 170 175
Asn Leu Val His Gly Asn Val Cys Gly Arg Asn Ile Leu Leu Ala Arg
180 185 190
Leu Gly Leu Ala Glu Gly Thr Ser Pro Phe Ile Lys Leu Ser Asp Pro
195 200 205
Gly Val Gly Leu Gly Ala Leu Ser Arg Glu Glu Arg Val Glu Arg Ile
210 215 220
Pro Trp Leu Ala Pro Glu Cys Leu Pro Gly Gly Ala Asn Ser Leu Ser
225 230 235 240
Thr Ala Met Asp Lys Trp Gly Phe Gly Ala Thr Leu Leu Glu Ile Cys
245 250 255
Phe Asp Gly Glu Ala Pro Leu Gln Ser Arg Ser Pro Ser Glu Lys Glu
260 265 270
His Phe Tyr Gln Arg Gln His Arg Leu Pro Glu Pro Ser Cys Pro Gln
275 280 285
Leu Ala Thr Leu Thr Ser Gln Cys Leu Thr Tyr Glu Pro Thr Gln Arg
290 295 300
Pro Ser Phe Arg Thr Ile Leu Arg Asp Leu Thr Arg Leu
305 310 315
Claims (13)
5.权利要求4的化合物
其中:
R1为CD3或C1-3烷基;
R2为CO-C3-6环烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,其经0-4个R2a取代;
R2a在每次出现时独立地为氢、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基、卤基C1-6烷基、羟基C1-6烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,该芳基或杂环基经0-2个Ra取代;
Ra为氢、卤素或C1-4烷基;
或其药学上可接受的盐。
6.权利要求5的化合物
其中:
R1为CD3;
R2为CO-C3-6环烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,其经0-4个R2a取代;
R2a在每次出现时独立地为氢、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基、卤基C1-6烷基、羟基C1-6烷基、C5-8芳基或含有1至4个选自N、O及S的杂原子的5至7员杂环基,该芳基或杂环基经0-2个Ra取代;
Ra为氢、卤素或C1-4烷基;
或其药学上可接受的盐。
11.一种药物组合物,其包含一或多种权利要求1至10中任一项的化合物或其药学上可接受的盐及药学上可接受的载体或稀释剂。
12.权利要求1至10中任一项的化合物或其药学上可接受的盐在制备用于治疗疾病的药物中的用途,其中该疾病为炎性疾病或自身免疫性疾病。
13.权利要求12的用途,其中该炎性疾病或自身免疫性疾病为多发性硬化、类风湿性关节炎、炎性肠病、全身性红斑性狼疮、牛皮癣、牛皮癣性关节炎、克罗恩病、干燥综合征或硬皮病。
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