CN117940166A - 用于治疗疼痛的sos1抑制剂和ras抑制剂 - Google Patents
用于治疗疼痛的sos1抑制剂和ras抑制剂 Download PDFInfo
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- CN117940166A CN117940166A CN202280038585.9A CN202280038585A CN117940166A CN 117940166 A CN117940166 A CN 117940166A CN 202280038585 A CN202280038585 A CN 202280038585A CN 117940166 A CN117940166 A CN 117940166A
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Abstract
本申请描述了用于治疗疼痛的新靶标和鉴别了用于本发明的适宜的化合物。
Description
本发明描述了与无七之子同源物1受体(Son of Sevenless homolog 1receptor,SOS1)蛋白和大鼠肉瘤(RAS)结合、从而抑制级联途径、导致疼痛减轻的化合物的用途。
仍然需要用于治疗疼痛的新治疗。许多最有效且经常开具的疼痛治疗是阿片样物质。这些药物滥用和成瘾的可能性很高。然而,迄今为止,没有具有相当功效的治疗来代替它们作为一线治疗。为了提供疼痛治疗的典范转移,需要识别体内的新靶标和途径。
本申请描述了在治疗疼痛的适宜途径中SOS-Ras的鉴定和利用。
最近,已经鉴定出SOS1抑制剂能够介导一些病症:
WO2019/122129描述了作为SOS1抑制剂的苄基氨基取代的吡啶并嘧啶,其可用于治疗肿瘤学中的癌性生长。
WO2018/115380描述了作为SOS1抑制剂的苄基氨基取代的喹唑啉,其类似地可用于治疗肿瘤学中的癌性生长。
WO2018/172250描述了用于治疗过度增殖性疾病的一类2-甲基喹唑啉。
WO2019/201848描述了用于治疗过度增殖性疾病的另一类2-甲基喹唑啉。
WO2020/173935教导了作为RAS抑制剂的新的异二氢吲哚酮取代的吲哚。
另外的SOS1抑制剂在《美国国家科学院院刊》(Proceedings of the NationalAcademy of Sciences of the United States of America),(2019),116(7),2551-2560中有教导。
最近还鉴别了各种RAS抑制剂,包括称为KRAS的RAS抑制剂子集。WO2018/068017、WO2018/140513、WO2018/140514和WO2020/173938都教导了具有作为RAS抑制剂治疗癌症的活性的新化合物。新的Ras抑制剂及其临床状态的概述可以在RSC Med.Chem.,2020,11,760中找到。
令人惊奇的是,现在已经发现,可以利用SOS1/RAS途径治疗疼痛。
因此,本发明提供了用于治疗疼痛的SOS1抑制剂。
本发明还提供了用于治疗疼痛的RAS抑制剂。
附图
图1A.导致疼痛的NGF信号转导途径及验证该途径的临床药物。NGF与TrkA结合,随后的信号转导最终导致神经元中二磷酸化细胞外信号调节激酶(dppERKnuc)的核积累,上调疼痛基因。
图2.靶标的临床遗传验证。在NF1中,患者在神经元间隙蛋白(NF1)中具有突变。该突变导致功能丧失,阻止RASGTP上的GTP正常转换为GDP,进而增加RASGTP的浓度和导致过度信号传导、肿瘤和疼痛。
图3.BI3406抑制PC-12细胞系中神经生长因子(NGF)刺激的磷酸-细胞外调节激酶1和2(pERK1/2)活化的结果图。
图4.该图显示了在BI3406给药后1小时和他尼珠单抗(Tanezumab)施用后+1小时、+9小时、+25小时和+33小时使用承重(WB)评估的25mg/kg BI3406(10mL/kg,p.o.,am和pm给药,2天)联合0.1、0.3和1mg/kg单剂量他尼珠单抗(10mL/kg,i.p.,t=0)的组合和3mg/kg单独他尼珠单抗(10mL/kg,i.p.,T=0)的效力。
发明概述
本申请描述了SOS-Ras靶标作为用于治疗疼痛的适当途径的鉴定和利用。
已知Ras蛋白是维持肿瘤的关键要素,因此该靶标长期以来在肿瘤学中被认为是有吸引力的。然而,直到最近,SOS1-Ras才被视为不可成药性靶标。Ras的典型特性是小的GTP酶,其通常在GTP结合的活化状态和GDP结合的非活化状态之间循环,部分地通过GTP酶活化蛋白(GAP)刺激GTP水解来促进(图2)。然而,当Ras蛋白被突变激活时,受损的GAP刺激有利于持续GTP结合的Ras的形成。这种关键性的生物化学缺陷促进最早努力靶向于突变Ras。通过类似于作为蛋白激酶的有效拮抗剂的ATP-竞争性抑制剂,已经尝试了鉴定Ras的GTP-竞争性抑制剂。然而,尽管ATP以低微摩尔亲和力结合蛋白激酶,但是GTP以皮摩尔亲和力结合Ras蛋白,阻止了有效抑制剂的发现。
随着适宜的SOS1抑制剂和Ras抑制剂的发现,已经有可能研究除癌症之外的其它适应症的途径。令人惊讶的是,现在,详细的研究已经揭示了能够通过使用SOS1抑制剂和Ras抑制剂对疼痛具有积极作用。本发明提供了用于治疗疼痛的SOS1抑制剂。
SOS1抑制剂的活性可以在Hillig等人,PNAS|2019年2月12日|第116卷|第7期|2551–2560中描述的HTRF结合测定中测量。
其它SOS1测定是本领域技术人员熟知的,包括诸如FRET/SPR结合的测定。
适用于本发明的SOS1抑制剂在HTRF结合测定中具有小于或等于5微摩尔的IC50。
特别适宜的SOS1抑制剂在HTRF结合测定中具有小于100纳摩尔的IC50。
在一个特别优选的实施方案中,SOS1抑制剂在HTRF结合测定中具有1纳摩尔或更小的IC50。
本发明的SOS1抑制剂还显示出对SOS1相对于其它靶标的选择性。适宜地,本发明的SOS1抑制剂相对于一种或多种以下靶标显示出大于或等于100倍的选择性:MEK 1、MEK2、TrkA激酶、TrkB激酶、TrkC激酶、C-Raf、B-Raf、PI3激酶、AKT和ERK。
当确定本发明的化合物对于SOS1的选择性是否超过其它靶标的100倍时,可以使用以下测定和方法:
MEK 1和2可以使用MEK测定试剂盒(产品代码CS0490,Sigma,St Louis,USA)测定。
Trk受体激酶活性可以如Wang等人,Curr Chem Genomics.2008;1:27–33中所述测定。
B-Raf可以使用B-Raf激酶测定试剂盒(产品代码17-359,Sigma,St Louis,USA)测定。
C-Raf可以使用BPS生物科学测定试剂盒(目录号79570,San Diego,CA 92121.美国)测定。
PI3激酶可以经由Fry,Methods Mol Biol,2009;462:345-62中描述的方法测定。
AKT可以使用abcam试剂盒Akt激酶活性测定试剂盒(ab139436)(abcam plc,Cambridge,USA)测定。
ERK可以使用Promega ERK2激酶试剂盒(目录号V1961,Promega corporation,Madison,USA)测定。
适宜的SOS1抑制剂包括WO2019/122129、WO2018/115380和WO2018/172250、WO2019/201848和WO2020/173935中公开的那些。
另外的SOS1抑制剂在《美国国家科学院院刊》(Proceedings of the NationalAcademy of Sciences of the United States of America),(2019),116(7),2551-2560中有教导。
如ACS Med Chem Lett 9(9),941-946(2018)中所述的吲哚类。
如J Med Chem 61(19),8875-8894(2018)中所述的吲哚类。
如J Med Chem 61(19),8875-8894(2018);Cancer Discovery,2020年8月19日;CD-20-0142.doi:10.1158/2159-8290.CD-20-0142;Lu等人,Chem MedChem 2016,11,814–821中所述的苯并咪唑类。
特别适宜的化合物是:
BI 3406(N-[(1R)-1-[3-氨基-5-(三氟甲基)苯基]乙基]-7-甲氧基-2-甲基-6-[(3S)-氧杂环戊烷-3-基]氧基喹唑啉-4-胺);该分子的合成公开在WO2018115380中;
Bay 293(6,7-二甲氧基-2-甲基-N-[(1R)-1-[4-[2-(甲基氨基甲基)苯基]噻吩-2-基]乙基]喹唑啉-4-胺)。合成公开在PNAS2019 116(7)2551-2560中;
4-[[(1R)-1-(3,3-二氟-2H-1-苯并呋喃-7-基)乙基]氨基]-6-[1-(二氟甲基)环丙基]-2-甲基吡啶并[4,3-d]嘧啶-7-酮。合成公开在WO2019122129中;
合成公开在WO2020180770中;
合成公开在WO2020180768中;
(R)-环丙基(4-(1-甲基-4-((1-(2-甲基-3-(三氟苯基)苯基)乙基)氨基)酞嗪-6-基)哌嗪-1-基)甲酮。合成公开在WO2021127429中。
(R)-5-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-8,9-二氢-7H-环戊二烯并[h]喹唑啉-6-基)-1-甲基吡啶-2(1H)-酮。合成公开在WO2021105960中;
(R)-4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-2,6,8,8-四甲基-6,8-二氢-7H-吡咯并[2,3-g]喹唑啉-7-酮。合成公开在WO2021130731中;和BI-170963,公开在WO2019122129中。
特别适宜的化合物是
在NGF刺激的PC12测定中,在疼痛的体外模型中测试了SOS1抑制剂(Sasagawa等人,NATURE CELL BIOLOGY第7卷,第4期,2005年4月,365-373)。所测试的化合物在模型中显示出强大的功效。特别地,BI3406显示与疼痛候选药物他尼珠单抗相当的功效。
SOS1抑制剂作为疼痛治疗具有许多优点;它们不具有阿片类药物的成瘾可能性,并且它们显示出强大的功效。它们也没有显示出具有使他尼珠单抗和其它抗NGFs几乎不能以治疗有效剂量使用的副作用。
本发明提供了用于治疗疼痛的Ras抑制剂。
Ras抑制剂的活性可以在Kessler等人,Proc Natl Acad Sci USA.2019年8月6日;116(32):15823–15829描述的结合测定中测量。
适用于本发明的Ras抑制剂在结合测定中具有小于或等于5000nM的IC50。
特别适宜的Ras抑制剂具有小于100纳摩尔的IC50。
在一个特别优选的实施方案中,Ras抑制剂具有1纳摩尔或更小的IC50。
本发明的Ras抑制剂还显示出对SOS1相对于其它靶标的选择性。适宜地,本发明的Ras抑制剂相对于一种或多种以下靶标显示出大于或等于100倍的选择性:MEK 1、MEK 2、TrkA激酶、TrkB激酶、TrkC激酶、C-Raf、B-Raf、PI3激酶、AKT和ERK。
目前有多种Ras抑制剂处于开发中;Araxes化合物ARS-3248、ARS-1620&ARS-853、Amgen的AMG-510、Mirati的MRTX-849和BridgeBio的BBP-454都已经作为癌症药物进行了研究。这类Ras抑制剂将适用于本发明。
其它Ras抑制剂包括:
它们的合成可以在J.M.Ostrem,U.Peters,M.L.Sos,J.A.Wells和K.M.Shokat,Nature,2013,503,548–551;和M.P.Patricelli,M.R.Janes,L.S.Li,R.Hansen,U.Peters,L.V.Kessler,Y.Chen,J.M.Kucharski,J.Feng,T.Ely,J.H.Chen,S.J.Firdaus,A.Babbar,P.Ren和Y.Liu,Cancer Discovery,2016,6,316–329中找到。
特别适宜的Ras抑制剂包括:
BI-2852
(3S)-5-羟基-3-[2-[[[1-[(1-甲基咪唑-4-基)甲基]吲哚-6-基]甲基氨基]甲基]-1H-吲哚-3-基]-2,3-二氢吲哚-1-酮
ARS-3248/JNJ74699157
ARS-1620
M.R.Janes,J.Zhang,L.S.Li,R.Hansen,U.Peters,X.Guo,Y.Chen,A.Babbar,S.J.Firdaus,L.Darjania,J.Feng,J.H.Chen,S.Li,S.Li,Y.O.Long,C.Thach,Y.Liu,A.Zarieh,T.Ely,J.M.Kucharski,L.V.Kessler,T.Wu,K.Yu,Y.Wang,Y.Yao,X.Deng,P.P.Zarrinkar,D.Brehmer,D.Dhanak,M.V.Lorenzi,D.Hu-Lowe,M.P.Patricelli,P.Ren和Y.Liu,Cell,2018,172,578–589.e517
ARS-853
M.P.Patricelli,M.R.Janes,L.S.Li,R.Hansen,U.Peters,L.V.Kessler,Y.Chen,J.M.Kucharski,J.Feng,T.Ely,J.H.Chen,S.J.Firdaus,A.Babbar,P.Ren和Y.Liu,CancerDiscovery,2016,6,316–329.
AMG-510
J.Canon,K.Rex,A.Y.Saiki,C.Mohr,K.Cooke,D.Bagal,K.Gaida,T.Holt,C.G.Knutson,N.Koppada,B.A.Lanman,J.Werner,A.S.Rapaport,T.San Miguel,R.Ortiz,T.Osgood,J.R.Sun,X.Zhu,J.D.McCarter,L.P.Volak,B.E.Houk,M.G.Fakih,B.H.O'Neil,T.J.Price,G.S.Falchook,J.Desai,J.Kuo,R.Govindan,D.S.Hong,W.Ouyang,H.Henary,T.Arvedson,V.J.Cee和J.R.Lipford,Nature,2019,575,217–223。
MRTX-849
J.Hallin,L.D.Engstrom,L.Hargis,A.Calinisan,R.Aranda,D.M.Briere,N.Sudhakar,V.Bowcut,B.R.Baer,J.A.Ballard,M.R.Burkard,J.B.Fell,J.P.Fischer,G.P.Vigers,Y.Xue,S.Gatto,J.Fernandez-Banet,A.Pavlicek,K.Velastagui,R.C.Chao,J.Barton,M.Pierobon,E.Baldelli,E.F.Patricoin 3rd,D.P.Cassidy,M.A.Marx,I.I.Rybkin,M.L.Johnson,S.I.Ou,P.Lito,K.P.Papadopoulos,P.A.Janne,P.Olson和J.G.Christensen,Cancer Discovery,2020,10,54–71.
J.B.Fell,J.P.Fischer,B.R.Baer,J.F.Blake,K.Bouhana,D.M.Briere,K.D.Brown,L.E.Burgess,A.C.Burns,M.R.Burkard,H.Chiang,M.J.Chicarelli,A.W.Cook,J.J.Gaudino,J.Hallin,L.Hanson,D.P.Hartley,E.J.Hicken,G.P.Hingorani,R.J.Hinklin,M.J.Mejia,P.Olson,J.N.Otten,S.P.Rhodes,M.E.Rodriguez,P.Savechenkov,D.J.Smith,N.Sudhakar,F.X.Sullivan,T.P.Tang,G.P.Vigers,L.Wollenberg,J.G.Christensen和M.A.Marx,J.Med.Chem.,2020,DOI:10.1021/acs.jmedchem.9b02052.
和BBP-454。
另外的Ras抑制剂描述在RSC Med.Chem.,2020,11,760中。
在本发明的另一个实施方案中,已经发现当与抗NGF抗体组合施用时,SOS1抑制剂特别适用于治疗疼痛。
在本发明的另一个实施方案中,已经发现当与抗NGF抗体组合施用时,Ras抑制剂特别适用于治疗疼痛。
本发明提供了一种通过施用治疗有效量的SOS1抑制剂与抗NGF抗体的组合治疗疼痛的方法。
他尼珠单抗是抗NGF抗体的实例。其是一种有前途且高效的疼痛疗法,但是患者在足以提供疼痛缓解的剂量水平下经常遭受令人不愉快的副作用。
该组合提供了协作水平的功效,其优点是抗NGF抗体可以以足以提供疼痛缓解的剂量水平施用,并且不会达到可以看到不良事件的水平。在协作系统中,两种独立的药物能够显示出相当于所述药物之一在高得多的剂量下的活性水平。令人惊讶地发现,两种药物组合具有这样的效果。
科学文献教导了他尼珠单抗在10mg/kg在大鼠中显示出功效。(Miyagi等人,Efficacy of nerve growth factor antibody in a knee osteoarthritis pain modelin mice,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670727/,抗NGF的最大有效剂量是10mg/kg小鼠,Ghilardi等人,Neuroplasticity of Sensory and SympatheticNerve Fibers in the Painful Arthritic Joint,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386465/,抗NGF的最大有效剂量是10mg/kg小鼠,Shelton等人,Nervegrowth factor mediates hyperalgesia and cachexia in auto-immune arthritishttps://pubmed.ncbi.nlm.nih.gov/15927377/,抗NGF的最大有效剂量是10mg/kg小鼠)。
已经证明BI3406在10mg/kg的剂量在小鼠疼痛模型中具有功效。
已经证明以25mg/kg给予SOS1抑制剂BI3406在疼痛模型中几乎没有至没有功效。
令人惊奇的是,低剂量的SOS1(25mg/kg)BI3406与0.3mg/kg他尼珠单抗的组合具有显著的镇痛作用。低剂量的SOS1(25mg/kg)BI3406与1.0mg他尼珠单抗的组合具有显著的镇痛作用。固定剂量的SOS1的镇痛作用的增加与他尼珠单抗的剂量相关(即功效是剂量相关性的)。
这些数据表明,应当能够降低他尼珠单抗在人中的剂量并因此降低限制这类药物使用的副作用的倾向。与单独使用更高剂量的他尼珠单抗相比,SOS1抑制与通过单克隆抗体如他尼珠单抗进行的NGF阻断的组合将递送增加的疼痛功效和减少的副作用。
SOS抑制剂与NGF单克隆抗体或NGF途径的其它阻断剂/调节剂的组合具有递送更强的疼痛功效且副作用减少的潜力,导致在病症如骨关节炎中的疼痛的改善和增强治疗。因此,本发明提供了SOS1抑制剂与抗NGF组合的用途,其中一种或两种组分以用于治疗疼痛的亚治疗剂量施用。
术语亚治疗剂量用于描述这样的剂量:其低于组分作为单一疗法显示出功效的剂量。
该组合的其它优点包括口服给药代替静脉内或皮下给药的潜力。该组合还可以导致较低的治疗成本和提供较低的免疫原性风险。
特别适宜的抗NGF抗体包括他尼珠单抗、法司努单抗(Fasinumab)、福拉奴单抗(Fulranumab)和MEDI735。
特别适宜的抗NGF抗体是他尼珠单抗和福拉奴单抗。
在一个优选的实施方案中,抗NGF抗体是他尼珠单抗。在另一个优选的实施方案中,抗NGF抗体是法司努单抗。
在一个特别优选的实施方案中,本发明提供了SOS1抑制剂与亚治疗剂量的他尼珠单抗的组合用于治疗疼痛的用途。任选地,SOS1抑制剂和他尼珠单抗均以亚治疗剂量施用。
术语亚治疗剂量用于描述这样的剂量:其低于组分作为单一疗法显示出功效的剂量。
适用于本发明的SOS1抑制剂在HTRF结合测定中具有小于或等于5微摩尔的IC50。
特别适宜的SOS1抑制剂具有小于100纳摩尔的IC50。
在一个特别优选的实施方案中,SOS1抑制剂具有1纳摩尔或更小的IC50。
本发明的SOS1抑制剂还显示出对SOS1相对于其它靶标的选择性。适宜地,本发明的SOS1抑制剂相对于一种或多种以下靶标显示出大于或等于100倍的选择性:MEK 1、MEK2、TrkA激酶、TrkB激酶、TrkC激酶、C-Raf、B-Raf、PI3激酶、AKT和ERK。
适用于与抗NGF抗体、特别是他尼珠单抗或法司努单抗组合的其它SOS1抑制剂是:
BI 3406(N-[(1R)-1-[3-氨基-5-(三氟甲基)苯基]乙基]-7-甲氧基-2-甲基-6-[(3S)-氧杂环戊烷-3-基]氧基喹唑啉-4-胺);该分子的合成公开在WO2018115380中;
Bay 293(6,7-二甲氧基-2-甲基-N-[(1R)-1-[4-[2-(甲基氨基甲基)苯基]噻吩-2-基]乙基]喹唑啉-4-胺)。合成公开在PNAS2019 116(7)2551-2560中。
4-[[(1R)-1-(3,3-二氟-2H-1-苯并呋喃-7-基)乙基]氨基]-6-[1-(二氟甲基)环丙基]-2-甲基吡啶并[4,3-d]嘧啶-7-酮。合成公开在WO2019122129中。
合成公开在WO2020180770中。
合成公开在WO2020180768中。
(R)-环丙基(4-(1-甲基-4-((1-(2-甲基-3-(三氟苯基)苯基)乙基)氨基)酞嗪-6-基)哌嗪-1-基)甲酮。合成公开在WO2021127429中。
(R)-5-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-8,9-二氢-7H-环戊二烯并[h]喹唑啉-6-基)-1-甲基吡啶-2(1H)-酮。合成公开在WO2021105960中。
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(R)-4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-2,6,8,8-四甲基-6,8-二氢-7H-吡咯并[2,3-g]喹唑啉-7-酮。合成公开在WO2021130731中。
特别适用于与他尼珠单抗组合使用的SOS-1抑制剂是BI 3406(N-[(1R)-1-[3-氨基-5-(三氟甲基)苯基]乙基]-7-甲氧基-2-甲基-6-[(3S)-氧杂环戊烷-3-基]氧基喹唑啉-4-胺)和Bay 293(6,7-二甲氧基-2-甲基-N-[(1R)-1-[4-2-(甲基氨基甲基)苯基]噻吩-2-基]乙基]喹唑啉-4-胺)。
特别适用于与法司努单抗组合使用的SOS-1抑制剂是BI 3406(N-[(1R)-1-[3-氨基-5-(三氟甲基)苯基]乙基]-7-甲氧基-2-甲基-6-[(3S)-氧杂环戊烷-3-基]氧基喹唑啉-4-胺)和Bay 293(6,7-二甲氧基-2-甲基-N-[(1R)-1-[4-2-(甲基氨基甲基)苯基]噻吩-2-基]乙基]喹唑啉-4-胺)。
适用于本发明的Ras抑制剂在结合测定中具有小于或等于5000nM的IC50。
特别适宜的Ras抑制剂具有小于100纳摩尔的IC50。
在一个特别优选的实施方案中,Ras抑制剂具有1纳摩尔或更小的IC50。
适宜的Ras抑制剂包括:
BI-2852
(3S)-5-羟基-3-[2-[[[1-[(1-甲基咪唑-4-基)甲基]吲哚-6-基]甲基氨基]甲基]-1H-吲哚-3-基]-2,3-二氢吲哚-1-酮
ARS-3248/JNJ74699157
ARS-1620
ARS-853
AMG-510
MRTX-849
和BBP-454。
特别适用于与法司努单抗组合使用的Ras抑制剂是BI 2852(3S)-5-羟基-3-[2-[[[1-[(1-甲基咪唑-4-基)甲基]吲哚-6-基]甲基氨基]甲基]-1H-吲哚-3-基]-2,3-二氢吲哚-1-酮。
特别适用于与他尼珠单抗(Tanazumab)组合使用的Ras抑制剂是BI 2852(3S)-5-羟基-3-[2-[[[1-[(1-甲基咪唑-4-基)甲基]吲哚-6-基]甲基氨基]甲基]-1H-吲哚-3-基]-2,3-二氢吲哚-1-酮。
不受理论的束缚,据信SOS1抑制剂和Ras抑制剂以下述方式治疗疼痛:
神经生长因子(NGF)是与NGF受体(TrkA)结合导致参与伤害感觉的基因上调的蛋白质。已知NGF是慢性疼痛发展的重要贡献因素。NGF与TrkA的结合和随后的信号转导最终导致神经元中二磷酸化细胞外信号调节激酶(dppERKnuc)的核积累,上调疼痛基因,如图1所示。
SOS和受其下游影响的分子如Ras的水平进入该级联,SOS和RAS的水平越高,则导致bRAF和MEK的水平就越高,导致二磷酸化细胞外信号调节激酶(dppERKnuc)的积累,导致更高水平的疼痛。通过抑制该途径,能够控制RAS GTP的形成。通过降低RAS GTP的水平,疼痛被减轻。
术语疼痛包括但不限于:急性疼痛;慢性疼痛;炎性疼痛;伤害性疼痛;神经性疼痛;痛觉过敏;异常性疼痛;中枢性疼痛;癌症疼痛;术后疼痛;内脏痛;肌肉骨骼疼痛;心脏或血管疼痛;头痛,包括偏头痛;口颌面痛(orofacialpain),包括牙痛;和背痛。
更详细地,适于治疗的疼痛包括但不限于:
(a)急性疼痛和/或自发性疼痛,
(b)慢性疼痛和/或持续性疼痛,
(c)炎性疼痛,包括关节炎疼痛、由骨关节炎或类风湿性关节炎引起的疼痛、由炎性肠病、银屑病和湿疹引起的疼痛中的任一种,
(d)伤害性疼痛,
(e)神经性疼痛,包括痛性糖尿病性神经病变或与疱疹后神经痛相关的疼痛,
(f)痛觉过敏,
(g)异常性疼痛,
(h)中枢性疼痛、中枢性中风后疼痛、由多发性硬化引起的疼痛、由脊髓损伤引起的疼痛或由帕金森病或癫痫引起的疼痛,
(i)癌症疼痛,
(j)术后疼痛,
(k)内脏疼痛,包括消化性内脏疼痛和非消化性内脏疼痛、归因于胃肠(GI)障碍的疼痛、由功能性肠病(FBD)引起的疼痛、由炎性肠病(IBD)引起的疼痛、由痛经、骨盆疼痛、膀胱炎、间质性膀胱炎或胰腺炎引起的疼痛,
(l)肌肉骨骼疼痛、肌痛、纤维肌痛、脊椎炎、血清阴性(非类风湿性)关节病、非关节风湿病、抗肌萎缩蛋白病(dystrophinopathy)、糖原分解、多肌炎、脓性肌炎,
(m)心脏或血管疼痛、归因于心绞痛、心肌梗塞、二尖瓣狭窄、心包炎、雷诺现象(Raynaud’s phenomenon)、硬化病(scleredoma)、硬化病或骨骼肌缺血的疼痛,
(n)头痛,包括偏头痛、有先兆偏头痛、无先兆偏头痛、丛集性头痛、紧张型头痛;
(o)口颌面痛,包括牙痛、颞下颌肌筋膜疼痛或耳鸣,或
(p)背痛、滑囊炎、月经痛、偏头痛、牵涉痛、三叉神经痛、超敏、由脊柱创伤和/或变性或中风引起的疼痛。
疼痛的治疗包括但不限于预防疼痛、改善疼痛、控制疼痛、降低疼痛的发生率或延迟疼痛的发展或进展。
特别适宜的疼痛适应症包括骨关节炎和癌症疼痛。
在另一个实施方案中,适宜的适应症是骨关节炎。
根据本发明的另一个方面,提供了本发明的化合物,其用于在与第二药理学活性化合物的组合中分开、顺序或同时使用。优选地,组合的第二药理学活性化合物可以包括但不限于:
·阿片类镇痛剂,例如吗啡、氢吗啡酮、羟吗啡酮、左啡诺、左洛啡烷、美沙酮、麦啶、芬太尼、可待因、二氢可待因、羟考酮、氢可酮、丙氧芬、纳美芬、纳洛芬、纳洛酮、纳曲酮、丁丙诺啡、布托啡诺、纳布啡或喷他佐辛;
·非甾体抗炎药(NSAID),例如阿司匹林、双氯芬酸、二氟尼柳(diflusinal)、依托度酸、芬布芬、非诺洛芬、氟苯柳、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮咯酸、甲氯芬那酸、甲芬那酸、美洛昔康、萘丁美酮、萘普生、尼美舒利、硝基氟吡洛芬、奥沙拉嗪、奥沙普秦、保泰松、吡罗昔康、柳氮磺吡啶、舒林酸、托美丁或佐美酸;
·巴比妥类镇静剂,例如异戊巴比妥、阿普比妥、仲丁巴比妥、布他比妥(butabital)、甲基苯巴比妥、美沙比妥、美索比妥、戊巴比妥、苯巴比妥(phenobartital)、司可巴比妥、他布比妥、theamylal或硫喷妥;
·具有镇静作用的苯二氮类,例如利眠宁、氯氮/>地西泮、氟西泮、劳拉西泮、奥沙西泮、替马西泮或三唑仑;
·具有镇静作用的H1拮抗剂,例如苯海拉明、美吡拉敏、异丙嗪、氯苯那敏或氯环利嗪;
·镇静剂,例如格鲁米特、甲丙氨酯、甲喹酮或氯醛比林;
·骨骼肌松弛剂,例如巴氯芬、卡立普多、氯唑沙宗、环苯扎林、美索巴莫或奥芬那君;
·NMDA受体拮抗剂,例如右美沙芬((+)-3-羟基-N-甲基吗啡喃)或其代谢物右羟吗喃((+)-3-羟基-N-甲基吗啡喃)、氯胺酮、美金刚、吡咯并喹啉奎宁(pyrroloquinolinequinine)、顺式-4(膦酰基甲基)-2-哌啶甲酸、布地品、EN-3231(吗啡和右美沙芬的组合制剂)、托吡酯、奈拉美生(neramexane)或培净福太(perzinfotel),包括NR2B拮抗剂,例如艾芬地尔、曲索罗地(traxoprodil)或(-)-(R)-6-{2-[4-(3-氟苯基)-4-羟基-1-哌啶基]-1-羟乙基-3,4-二氢-2(1H)-喹啉酮;
·α-肾上腺素能药,例如多沙唑嗪、坦索洛新、可乐定、胍法辛、右美托咪定(dexmetatomidine)、莫达非尼或4-氨基-6,7-二甲氧基-2-(5-甲烷亚磺酰氨基-1,2,3,4-四氢异喹啉-2-基)-5-(2-吡啶基)喹唑啉;
·三环抗抑郁药,例如地昔帕明、丙米嗪、阿米替林或去甲替林;
·抗惊厥药,例如卡马西平、拉莫三嗪、托吡酯(topiratmate)或丙戊酸盐;
·速激肽(NK)拮抗剂,特别是NK-3、NK-2或NK-1拮抗剂,例如(αR,9R)-7-[3,5-双(三氟甲基)苄基]-8,9,10,11-四氢-9-甲基-5-(4-甲基苯基)-7H-[1,4]二氮杂环辛间四烯并[2,1-g][1,7]-萘啶-6-13-二酮(TAK-637)、5-[[(2R,3S)-2-[(1R)-1-[3,5-双(三氟甲基)苯基]乙氧基-3-(4-氟苯基)-4-吗啉基]-甲基]-1,2-二氢-3H-1,2,4-三唑-3-酮(MK-869)、阿瑞吡坦(aprepitant)、拉奈匹坦、达匹坦或3-[[2-甲氧基-5-(三氟甲氧基)苯基]-甲基氨基]-2-苯基哌啶(2S,3S);
·毒蕈碱拮抗剂,例如奥昔布宁、托特罗定、丙哌维林、曲司氯铵(tropsiumchloride)、达非那新、索利那新、替米维林和异丙阿托品;
·COX-2选择性抑制剂,例如塞来考昔、罗非考昔、帕瑞考昔、伐地考昔、地拉考昔、艾托考昔或芦米考昔;
·煤焦油镇痛剂(coal-tar analgesic),特别是扑热息痛;
·精神安定药,例如氟哌利多、氯丙嗪、氟哌啶醇、奋乃静、硫利达嗪、美索达嗪、三氟拉嗪、氟奋乃静、氯氮平、奥氮平、利培酮、齐拉西酮、喹硫平、舍吲哚、阿立哌唑、索奈哌唑、布南色林、伊潘立酮、哌罗匹隆、雷氯必利、佐替平、联苯芦诺(bifeprunox)、阿塞那平(asenapine)、鲁拉西酮(lurasidone)、氨磺必利、巴拉哌酮(balaperidone)、帕林多尔(palindore)、依利色林、奥沙奈坦、利莫那班、麦克林坦(meclinertant)、或沙立佐坦;/>
·香草素受体激动剂(例如树脂毒素(resinferatoxin))或拮抗剂(例如辣椒平(capsazepine));
·β-肾上腺素能药,例如普萘洛尔;
·局部麻醉剂,例如美西律;
·皮质类固醇,例如地塞米松;
·5-HT受体激动剂或拮抗剂,特别是5-HT1B/1D激动剂,例如依利曲坦、舒马曲坦、那拉曲坦、佐米曲普坦或利扎曲坦;
·5-HT2A受体拮抗剂,例如R(+)-α-(2,3-二甲氧基-苯基)-1-[2-(4-氟苯基乙基)]-4-哌啶甲醇(MDL-100907);
·胆碱能(烟碱)镇痛剂,例如ispronicline(TC-1734)、(E)-N-甲基-4-(3-吡啶基)-3-丁烯-1-胺(RJR-2403)、(R)-5-(2-氮杂环丁烷基甲氧基)-2-氯吡啶(ABT-594)或烟碱;
·
·PDEV抑制剂,例如5-[2-乙氧基-5-(4-甲基-1-哌嗪基-磺酰基)苯基]-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(西地那非)、(6R,12aR)-2,3,6,7,12,12a-六氢-2-甲基-6-(3,4-亚甲二氧基苯基)-吡嗪并[2′,1′:6,1]-吡啶并[3,4-b]吲哚-1.4-二酮(IC-351或他达拉非)、2-[2-乙氧基-5-(4-乙基-哌嗪-1-基-1-磺酰基)-苯基]-5-甲基-7-丙基-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(伐地那非)、5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁烷基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮、5-(5-乙酰基-2-丙氧基-3-吡啶基)-3-乙基-2-(1-异丙基-3-氮杂环丁烷基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮、5-[2-乙氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-[2-甲氧基乙基]-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮、4-[(3-氯-4-甲氧基苄基)氨基]-2-[(2S)-2-(羟基甲基)吡咯烷-1-基]-N-(嘧啶-2-基甲基)嘧啶-5-甲酰胺、3-(1-甲基-7-氧代-3-丙基-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)-N-[2-(1-甲基吡咯烷-2-基)乙基]-4-丙氧基苯磺酰胺;
·大麻素;
·代谢型谷氨酸亚型1受体(mGluR1)拮抗剂;
·血清素再摄取抑制剂,例如舍曲林、舍曲林代谢物去甲基舍曲林、氟西汀、诺氟西汀(氟西汀去甲基代谢物)、氟伏沙明、帕罗西汀、西酞普兰、西酞普兰代谢物去甲基西酞普兰、依他普仑、d,l-芬氟拉明、非莫西汀、伊福西汀、氰基度硫平(cyanodothiepin)、利托西汀、达泊西汀、奈法唑酮、西立氯胺和曲唑酮;
·去甲肾上腺素(降肾上腺素)再摄取抑制剂,例如马普替林、洛非帕明、米氮平(mirtazapine)、羟丙替林、非唑拉明、托莫西汀、米安色林、安非他酮(buproprion)、安非他酮代谢物羟基安非他酮、诺米芬辛和维洛沙嗪尤其是选择性去甲肾上腺素再摄取抑制剂,例如瑞波西汀,特别是(S,S)-瑞波西汀;
·双重血清素-去甲肾上腺素再摄取抑制剂,例如文拉法辛、文拉法辛代谢物O-去甲基文拉法辛、氯米帕明、氯米帕明代谢物去甲基氯米帕明、度洛西汀、米那普仑和丙米嗪;
·诱导型一氧化氮合酶(iNOS)抑制剂,例如S-[2-[(1-亚氨基乙基)氨基]乙基]-L-高半胱氨酸、S-[2-[(1-亚氨基乙基)-氨基]乙基]-4,4-二氧代-L-半胱氨酸、S-[2-[(1-亚氨基乙基)氨基]乙基]-2-甲基-L-半胱氨酸、(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸、2-[[(1R,3S)-3-氨基-4-羟基-1-(5-噻唑基)-丁基]硫基]-5-氯-3-吡啶甲腈;2-[[(1R,3S)-3-氨基-4-羟基-1-(5-噻唑基)丁基]硫基]-4-氯苯甲腈,(2S,4R)-2-氨基-4-[[2-氯-5-(三氟甲基)苯基]硫基]-5-噻唑丁醇、2-[[(1R,3S)-3-氨基-4-羟基-1-(5-噻唑基)丁基]硫基]-6-(三氟甲基)-3-吡啶甲腈、2-[[(1R,3S)-3-氨基-4-羟基-1-(5-噻唑基)丁基]硫基]-5-氯苯甲腈、N-[4-[2-(3-氯苄基氨基)乙基]苯基]噻吩-2-甲脒或胍基乙基二硫化物;
·乙酰胆碱酯酶抑制剂,例如多奈哌齐;
·前列腺素E2亚型4(EP4)拮抗剂,例如N-[({2-[4-(2-乙基-4,6-二甲基-1H-咪唑并[4,5-c]吡啶-1-基)苯基]乙基}氨基)-羰基]-4-甲基苯磺酰胺或4-[(1S)-1-({[5-氯-2-(3-氟苯氧基)吡啶-3-基]羰基}氨基)乙基]苯甲酸;
·白三烯B4拮抗剂;例如1-(3-联苯基-4-基甲基-4-羟基-色满-7-基)-环戊烷甲酸(CP-105696)、5-[2-(2-羧乙基)-3-[6-(4-甲氧基苯基)-5E-己烯基]氧基苯氧基]-戊酸(ONO-4057)或DPC-11870;
·5-脂氧化酶抑制剂,例如齐留通、6-[(3-氟-5-[4-甲氧基-3,4,5,6-四氢-2H-吡喃-4-基])苯氧基-甲基]-1-甲基-2-喹诺酮(ZD-2138),或2,3,5-三甲基-6-(3-吡啶基甲基)、1,4-苯醌(CV-6504);
·钠通道阻断剂,例如利多卡因;或
·5-HT3拮抗剂,例如昂丹司琼;
及其可药用盐和溶剂化物。
本发明还提供了药物制剂,其包含如上定义的式I化合物或其可药用盐或溶剂化物,以及可药用佐剂、稀释剂或载体。药物制剂可以进一步包含一种或多种用于治疗上述病症的另外的活性剂。
本发明还提供了药物盒,其包含如上文所定义的式I化合物或其可药用盐或溶剂合物,以及一种或多种另外的活性剂,作为组合制剂用于在治疗上述病症中分开、同时或依次施用。
本发明还提供了治疗哺乳动物(尤其是人)的上述病症的方法,该方法包括向需要该治疗的哺乳动物施用治疗有效量的如上定义的式I化合物或其可药用盐或溶剂化物。
旨在用于药物用途的本发明的化合物可以作为结晶或无定形产物施用。它们可以例如通过诸如沉淀、结晶、冷冻干燥、喷雾干燥或蒸发干燥的方法以固体塞、粉末或膜获得。微波或射频干燥可用于此目的。
它们可以单独施用或与一种或多种本发明的其它化合物组合或与一种或多种其它药物组合(或作为其任意组合)施用。通常,它们将作为与一种或多种可药用赋形剂联合的制剂施用。术语“赋形剂”在本文中用于描述除本发明的化合物之外的任意成分。赋形剂的选择将在很大程度上取决于多种因素,例如具体施用模式、赋形剂对溶解度和稳定性的影响以及剂型的性质。
适于递送本发明化合物的药物组合物及其制备方法对于本领域技术人员来说是显而易见的。这类组合物及其制备方法可以在例如Remington’s Pharmaceutical Sciences,第19版(Mack Publishing Company,1995)中找到。
口服施用
本发明的化合物可以口服施用。口服施用可以包括吞咽,使得化合物进入胃肠道,或者可以采用化合物直接从口腔进入血流的口腔或舌下施用。
适于口服施用的制剂包括固体制剂,例如片剂,含颗粒、液体或粉末的胶囊剂,锭剂(包括液体填充的),咀嚼剂,多颗粒和纳米颗粒,凝胶,固体溶液,脂质体,膜剂,珠剂(ovules),喷雾剂和液体制剂。
液体制剂包括混悬剂、溶液、糖浆和酏剂。这类制剂可以用作软胶囊或硬胶囊中的填充剂,通常包含载体,例如水、乙醇、聚乙二醇、丙二醇、甲基纤维素或适宜的油,以及一种或多种乳化剂和/或助悬剂。液体制剂也可以通过由固体、例如来自小药囊的固体进行重构来制备。
本发明的化合物还可以以快速溶解、快速崩解剂型使用,例如Liang和Chen的Expert Opinion in Therapeutic Patents,11(6),981-986,(2001)中所述的那些。
对于片剂剂型,根据剂量,药物可以占剂型的1重量%至80重量%,更典型地占剂型的5重量%至60重量%。除了药物之外,片剂通常含有崩解剂。崩解剂的实例包括羟乙酸淀粉钠、羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲基纤维素钠、交聚维酮、聚乙烯吡咯烷酮、甲基纤维素、微晶纤维素、低级烷基取代的羟丙基纤维素、淀粉、预胶化淀粉和藻酸钠。通常,崩解剂将占剂型的1重量%至25重量%,优选5重量%至20重量%。
粘合剂通常用于给片剂制剂赋予内聚性质。适宜的粘合剂包括微晶纤维素、明胶、糖、聚乙二醇、天然和合成树胶、聚乙烯吡咯烷酮、预胶化淀粉、羟丙基纤维素和羟丙基甲基纤维素。片剂还可以含有稀释剂,例如乳糖(一水合物、喷雾干燥的一水合物、无水物等)、甘露醇、木糖醇、右旋糖、蔗糖、山梨醇、微晶纤维素、淀粉和磷酸氢钙二水合物。
片剂还可以任选地包含表面活性剂,例如十二烷基硫酸钠和聚山梨酯80,以及助流剂,例如二氧化硅和滑石粉。当存在时,表面活性剂可以占片剂的0.2重量%至5重量%,助流剂可以占片剂的0.2重量%至1重量%。
片剂通常还含有润滑剂,例如硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酰富马酸钠以及硬脂酸镁与十二烷基硫酸钠的混合物。润滑剂通常占片剂的0.25重量%至10重量%,优选0.5重量%至3重量%。
其它可能的成分包括抗氧化剂、着色剂、矫味剂、防腐剂和掩味剂。
示例性的片剂含有高达约80%的药物、约10重量%至约90重量%的粘合剂、约0重量%至约85重量%的稀释剂、约2重量%至约10重量%的崩解剂和约0.25重量%至约10重量%的润滑剂。
片剂混合物可直接压制或通过辊压制形成片剂。或者,片剂混合物或部分混合物可以在压片之前湿法造粒、干法造粒或熔融造粒、熔融凝结或挤出。最终制剂可以包含一个或多个层,并且可以是包衣的或未包衣的;其甚至可以被包封。
片剂的配方在H.Lieberman和L.Lachman的Pharmaceutical Dosage Forms: Tablets,第1卷(Marcel Dekker,纽约,1980)中有讨论。
用于人或兽医用途的可消耗口服膜通常是柔韧的水溶性或水溶胀性薄膜剂型,其可以快速溶解或粘膜粘附,并且通常包含式I化合物、成膜聚合物、粘合剂、溶剂、保湿剂、增塑剂、稳定剂或乳化剂、粘度调节剂和溶剂。制剂的一些组分可以执行多于一种功能。
本发明的化合物可以是水溶性的或不溶性的。水溶性化合物通常占溶质的1重量%至80重量%,更通常20重量%至50重量%。溶解性较低的化合物可以占组合物的较大比例,通常高达溶质的88重量%。或者,本发明的化合物可以是多微粒珠粒的形式。
成膜聚合物可以选自天然多糖、蛋白质或合成水胶体,通常以0.01至99重量%的范围、更通常以30至80重量%的范围存在。
其它可能的成分包括抗氧化剂、着色剂、矫味剂和增味剂、防腐剂、唾液刺激剂、冷却剂、共溶剂(包括油)、软化剂、填充剂、消泡剂、表面活性剂和掩味剂。
根据本发明的膜通常通过蒸发干燥涂覆在可剥离背衬载体或纸上的水性薄膜来制备。这可以在干燥烘箱或通道中进行,通常是组合的涂覆干燥器,或通过冷冻干燥或抽真空进行。
用于口服施用的固体制剂可以配制成立即释放和/或改变释放。改变释放制剂包括延迟释放、持续释放、脉冲释放、控制释放、靶向释放和程序化释放。
适用于本发明目的的改变释放制剂描述在美国专利号6,106,864中。其它适宜的释放技术如高能分散体和渗透和包衣颗粒的细节可以在Verma等人的Pharmaceutical Technology On-line,25(2),1-14,(2001)中找到。在WO 00/35298中描述了使用咀嚼胶来实现控释。
肠胃外施用
本发明的化合物还可以直接施用到血流中、肌肉中或内脏器官中。适用于肠胃外施用的方法包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内和皮下。适用于肠胃外施用的装置包括针(包括微针)注射器、无针注射器和输注技术。
肠胃外制剂通常是水溶液,其可以含有赋形剂,例如盐、碳水化合物和缓冲剂(优选至pH为3至9),但是对于一些应用,它们可以更适宜地配制成无菌非水溶液或干燥形式以与适宜的载体如无菌无热原水结合使用。
在无菌条件下制备肠胃外制剂,例如通过冷冻干燥,可以使用本领域技术人员熟知的标准药学技术容易地完成。
用于制备肠胃外溶液的本发明的化合物的溶解度可以通过使用适当的配制技术来提高,例如掺入溶解度增强剂。
用于肠胃外施用的制剂可以配制成立即释放和/或改变释放。改变释放制剂包括延迟释放、持续释放、脉冲释放、控制释放、靶向释放和程序化释放。因此,本发明的化合物可以配制成固体、半固体或触变液体,用于作为植入储库施用,提供活性化合物的改变释放。这类制剂的实例包括药物涂覆支架和聚(dl-乙交酯-丙交酯共聚物)(PGLA)微球。
局部施用
本发明的化合物也可以局部施用于皮肤或粘膜,即经皮肤或透皮。用于该目的的典型制剂包括凝胶、水凝胶、洗剂(lotions)、溶液、乳膏、软膏、扑粉、敷料、泡沫、膜剂、皮肤贴剂、糯米纸囊剂、植入剂、海绵、纤维、绷带和微乳液。也可以使用脂质体。典型的载体包括醇、水、矿物油、液体凡士林、白凡士林、甘油、聚乙二醇和丙二醇。可以掺入渗透增强剂-参见例如Finnin和Morgan的J Pharm Sci,88(10),955-958(1999年10月)。
局部施用的其它方式包括通过电穿孔、离子导入法、超声透入法(phonophoresis)、超声促渗法(sonophoresis)和微针或无针(例如PowderjectTM,BiojectTM,etc.)注射递送。
用于局部施用的制剂可以配制成立即释放和/或改变释放。改变释放制剂包括延迟释放、持续释放、脉冲释放、控制释放、靶向释放和程序化释放。
吸入/鼻内施用
本发明的化合物也可以经鼻内或通过吸入施用,通常以来自干粉吸入器的干粉形式(单独,作为混合物,例如与乳糖的干混物,或作为混合组分颗粒,例如与磷脂如磷脂酰胆碱混合)或者作为来自加压容器、泵、喷雾器、雾化器(优选使用电流体动力学产生细雾的雾化器)或雾化吸入器的气溶胶喷雾剂,使用或不使用适宜的抛射剂,如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷。对于鼻内使用,粉末可以包含生物粘附剂,例如壳聚糖或环糊精。
加压容器、泵、喷雾器、雾化器或雾化吸入器含有本发明的化合物的溶液或混悬液,所述溶液或混悬液包含例如乙醇、含水乙醇或适用于分散、溶解或延长活性物质释放的替代试剂、作为溶剂的抛射剂和任选的表面活性剂如山梨坦三油酸酯、油酸或低聚乳酸。
在用于干粉或混悬液配制之前,将药物产品微粉化至适于通过吸入递送的尺寸(通常小于5微米)。这可以通过任意适宜的粉碎方法实现,例如螺旋喷射研磨、流化床喷射研磨、超临界流体加工以形成纳米颗粒、高压均化或喷雾干燥。
用于吸入器或吹入器的胶囊(例如由明胶或羟丙基甲基纤维素制成)、泡罩和药筒可以配制成含有本发明的化合物、适宜的粉末基质(例如乳糖或淀粉)和性能改性剂(例如l-亮氨酸、甘露醇或硬脂酸镁)的粉末混合物。乳糖可以是无水的或一水合物的形式,优选后者。其它适宜的赋形剂包括葡聚糖、葡萄糖、麦芽糖、山梨醇、木糖醇、果糖、蔗糖和海藻糖。
适用于使用电流体动力学产生细雾的雾化器中的溶液制剂每次致动可含有1μg至20mg的本发明的化合物,致动体积可以在1μl至100μl之间变化。典型的制剂可以包含式I化合物、丙二醇、无菌水、乙醇和氯化钠。可以代替丙二醇使用的替代溶剂包括甘油和聚乙二醇。
可以将适宜的矫味剂(例如薄荷醇和左薄荷醇)或甜味剂(例如糖精或糖精钠)加入到旨在用于吸入/鼻内施用的本发明的那些制剂中。
用于吸入/鼻内施用的制剂可以使用例如PGLA配制成立即释放和/或改变释放。改变释放制剂包括延迟释放、持续释放、脉冲释放、控制释放、靶向释放和程序化释放。
在干粉吸入器和气雾剂的情况下,剂量单位通过递送计量的阀来确定。根据本发明的单位通常被安排成施用含有1至10,000μg的本发明的化合物的计量剂量或“一喷”。总日剂量通常在1μg至10mg的范围,其可以在一天中以单剂量或更通常以分开剂量施用。
直肠/阴道内施用
本发明的化合物可以经直肠或阴道施用,例如以栓剂、阴道环或灌肠剂的形式。可可脂是传统的栓剂基质,但是可以根据需要使用各种替代物。
用于直肠/阴道施用的制剂可以配制成立即释放和/或改变释放。改变释放制剂包括延迟释放、持续释放、脉冲释放、控制释放、靶向释放和程序化释放。
眼/耳施用
本发明的化合物也可以直接施用于眼或耳,通常以等渗的、pH调节的无菌盐水中的微粉化混悬液或溶液的滴剂形式。适用于眼和耳施用的其它制剂包括软膏、可生物降解的(例如可吸收的凝胶海绵、胶原)和不可生物降解的(例如硅酮)植入物、糯米纸囊剂、透镜和颗粒或囊泡系统,例如泡囊或脂质体。聚合物如交联聚丙烯酸、聚乙烯醇、透明质酸、纤维素聚合物(例如羟丙基甲基纤维素、羟乙基纤维素或甲基纤维素)或杂多糖聚合物(例如结冷胶)可以与防腐剂(如苯扎氯铵)一起掺入。这类制剂也可以通过离子导入法递送。
用于眼/耳施用的制剂可以配制成立即释放和/或改变释放。改变释放制剂包括延迟释放、持续释放、脉冲释放、控制释放、靶向释放或程序化释放。
其它技术
本发明的化合物可以与可溶性大分子实体组合,例如环糊精及其适宜的衍生物或含聚乙二醇的聚合物,以改善其溶解度、溶出速率、掩味、生物利用度和/或稳定性,用于任一种上述施用方式。
例如,发现药物-环糊精复合物通常可用于大多数剂型和施用途径。可以使用包合复合物和非包合复合物。作为与药物直接复合的替代方案,环糊精可以用作辅助添加剂,即用作载体、稀释剂或增溶剂。最常用于这些目的的是α-、β-和γ-环糊精,其实例可以在国际专利申请号WO 91/11172、WO 94/02518和WO 98/55148中找到。
成套药盒
由于可能期望施用活性化合物的组合,例如为了治疗特定疾病或病症的目的,因此在本发明的范围内,两种或更多种药物组合物(其中至少一种含有本发明的化合物)可以方便地组合成适于共同施用组合物的药盒形式。
因此,本发明的药盒包含两种或更多种单独的药物组合物,其中至少一种含有根据本发明的式I化合物,以及用于单独保存所述组合物的装置,例如容器、分开的瓶子或分开的箔包。这种药盒的实例是用于包装片剂、胶囊等的熟悉的泡罩包装。
本发明的药盒特别适合于施用不同的剂型,例如口服和肠胃外,用于以不同的剂量间隔施用单独的组合物,或用于相对于另一种逐渐增加单独的组合物。为了有助于依从性,药盒通常包含施用说明书,并且可以提供有所谓的记忆辅助。
剂量
对于施用于人类患者,本发明的化合物的总日剂量通常在0.5mg至3000mg的范围,当然这取决于施用方式。例如,口服施用可要求3mg至3000mg的总日剂量,而静脉内剂量可能仅要求0.5mg至500mg。总日剂量可以以单剂量或分开剂量施用,并且可以根据医师的判断落在本文给出的典型范围之外。
这些剂量是基于体重约60kg至70kg的平均人类对象。医师将能够容易地确定体重超出该范围的对象(例如婴儿和老年人)的剂量。
为了避免疑义,本文提及的“治疗”包括对治愈性、姑息性和预防性治疗的称谓。
实验
材料和方法
SOS1抑制剂的鉴定:
以下方法是基于Hillig等人,PNAS,2019年2月12日,第116卷,第7期,2551–2560中描述的HTRF结合测定。
抑制数据的测量和评估、IC50值的计算
使用HTRF模块(激发:337nm,发射1:620nm,发射2:665nm),用PHERAstar读数器(BMG,德国)测量均匀时间分辨荧光(HTRF)。665和620nm处的发射比用作进一步评估的特定信号。使用对照将数据标准化:DMSO=0%抑制,具有抑制剂对照溶液的抑制对照孔=100%抑制。在多达11个浓度(例如20μM、5.7μM、1.6μM、0.47μM、0.13μM、38nM、11nM、3.1nM、0.89nM、0.25nM和0.073nM)一式两份测试化合物。使用商业软件包(Genedata Screener,瑞士)、使用四参数拟合计算了IC50值。通过SOS1cat测定(“On-assay”)的KRASG12C活化。该测定定量了SOS1cat介导的KRASG12C–GDP的荧光GTP类似物的负载。通过测量从与GST-KRASG12C结合的抗GST-铽(FRET供体)到负载的荧光GTP类似物(FRET受体)的共振能量转移实现了成功负载的检测。荧光GTP类似物EDA–GTP–DY-647P1[用DY-647P1标记的2'/3'-O-(2-氨基乙基-氨甲酰基鸟苷-5'-三磷酸酯(Dyomics GmbH,德国))]由Jena Bioscience(德国)合成,以1mM水溶液提供。在含有100nM GST-KRASG12C和2nM抗GST-铽(Cisbio,法国)的测定缓冲液[10mM HEPES pH 7.4(AppliChem)、150mM NaCl(Sigma)、5mM MgCl2(Sigma)、1mM DTT(Thermo Fisher)、0.05%BSA Fraction V pH 7.0(ICN Biomedicals)、0.0025%(v/v)Igepal(Sigma)]中制备KRASG12C工作溶液。在含有20nM SOS1cat和200nM EDA–GTP–DY-647P1的测定缓冲液中制备SOS1cat工作溶液。在不含SOS1cat的含有200nM EDA-GTP-DY-647P1的测定缓冲液中制备抑制剂对照溶液。测定的所有步骤都在20℃进行。使用Multidrop分配器(Thermo LabSystems)将2.5μL体积的KRASG12C工作溶液加入测试板的所有孔中。10分钟后,向除了抑制剂对照溶液孔之外的所有孔中加入2.5μL的SOS1cat工作溶液。培养30分钟后,测量了HTRF。
Ras抑制剂的鉴定
使用以下来自Kessler等人,Proc Natl Acad Sci U S A.,2019年8月6日;116(32):15823–15829的测定鉴定了Ras抑制剂。
α筛选测定;一种测量SOS:RAS相互作用的体外无细胞方法。
使用Perkin Elmer开发的Alpha筛选技术进行了各种蛋白质-蛋白质相互作用的测量。重组Ras蛋白质(H-、N-、K-RAS变体;所有KRAS变体都是基于KRAS同工型4B(uniprotid P01116-2);KRAS(G12D)1-169,N-末端6His-标签,C-末端avi-标签,来自XtalBioStructures,Inc.,KRAS(G12C)1-169,C-末端avi-标签,生物素化,突变:C51S,C80L,C118S,NRAS(wt)1-172,C-末端avi-标签,生物素化;HRAS(wt)1-166,C-末端avi-标签,生物素化)。如制造商(Avidity LLC,Aurora,Colorado,USA)所推荐,用重组BirA生物素-蛋白质连接酶在体外进行生物素化。相互作用蛋白,例如SOS1(564-1049,N-末端GST-标签,TEV切割位点)、cRaf(1-303,N-末端GST-标签,TEV切割位点)和PI3KA-RBD(160-317,N-末端-HIS_GST-标签),表达为谷胱甘肽S转移酶(GST)融合。因此,α筛选珠是谷胱甘肽包被的αLisa受体珠(Perkin Elmer AL 109R)和α筛选链霉亲和素缀合供体珠(Perkin Elmer 6760002L)。核苷酸购自Sigma(GTP#G8877,GDP#G7127),吐温-20来自Biorad(#161-0781)。所有相互作用测定均在含有0.1%牛血清白蛋白、0.05%吐温-20和10μM相应核苷酸的PBS中进行。在白色ProxiPlate-384 Plus板(Perkin Elmer#6008280)中以20μL终体积进行测定。简言之,将生物素化Ras蛋白质(终浓度10nM)和GST-SOS1、GST-PI3K或GST-CRAF(终浓度10nM)与谷胱甘肽受体珠(终浓度5μg/ml)在缓冲液中混合,所述缓冲液含有相应的核苷酸(对于含SOS1的测定为GDP或GTP,对于含PI3K或CRAF的相互作用测定仅为GTP),并且在室温下培养30分钟。在绿光下加入链霉亲和素供体珠(终浓度5μg/mL)后,将混合物于室温在暗处进一步培养60min。根据生产商的推荐,在Enspire多模式读板器(Perkin Elmer)上测量单氧诱导的荧光。使用GraphPad Prism Data软件分析数据。
基于NGF刺激的PC12测定,使用以下测定测定了SOS1抑制剂和Ras抑制剂治疗疼痛的能力(Sasagawa等人,NATURE CELL BIOLOGY第7卷,第4期,2005年4月,365-373)。
BI3406抑制PC-12细胞系中神经生长因子(NGF)刺激的磷酸-细胞外调节激酶1和2(pERK1/2)活化
均相时间分辨荧光(HTRF)测定:
在不同NGF刺激物浓度下的BI-3406抑制:
在NGF激活后,经由测量ERK1/2磷酸化的HTRF读数监测了选择性小分子大鼠肉瘤:无七之子1(RAS:SOS1)抑制剂BI-3406(Selleck Chemicals)的抑制作用。所有测定都是在大鼠肾上腺PC-12细胞(Merck)中进行,所述细胞在补充有1%热灭活马血清(Merck)、0.5%热灭活胎牛血清(FBS)、1%青霉素-链霉素和2mM L-谷氨酰胺的RPMI-1640生长培养基(Gibco)中血清饥饿24小时,另有说明除外。根据制造商的指示制备来自HTRF商业试剂盒(Cisbio)的试剂。
测定程序:
从常规细胞培养物中分离PC-12细胞,在血清饥饿条件下以适当的细胞密度在384孔板(通常每孔25,000个细胞)中铺板24小时。在培养后,用工作浓度的BI-3406在适当的浓度响应范围内预处理PC-12细胞30分钟(37℃/5%CO2)。在每个测定的NGF(Merck)浓度下建立BI-3406的一式两份浓度响应曲线。在30分钟的化合物预培养后,用NGF处理PC-12细胞(测试从250ng/mL至10ng/mL的NGF滴定),随后培养5分钟(37℃/5%CO2)。在NGF处理5分钟后,将来自商业HTRF试剂盒的裂解缓冲液应用于PC-12细胞用于培养30分钟,同时振荡(20℃,600rpm)。每孔收获适当体积的裂解物并转移到单独的384孔Proxiplate(PerkinElmer)中,向其中每个裂解物样品孔中分配5X浓缩的HTRF试剂盒抗体混合物。于室温培养2小时,然后使用微板读数器(PHERAstar FSX,BMG Labtech)测定荧光信号。
分析
i.针对NGF活化的BI-3406IC50图:
通过将样品数据相对于每个板内使用的高和低对照(分别为+/-25ng/mL NGF)标准化,计算每个化合物浓度的抑制百分比数值。将来自每个一式两份BI-3406浓度响应曲线的抑制百分比数值进行平均,以提供每个浓度的数据点。然后,使用四参数逻辑拟合,其中y=A xnH/(EC50nH+xnH),其中x和y分别表示测试物质浓度和%细胞pERK信号,使用平均抑制百分比数值确定50%抑制浓度(IC50)和最大%功效(抑制)(最大%功效BI3406/由-NGF对比+NGF差异给出的最大%功效)。参数EC50是半数最大输出的测试物质浓度,A是最大抑制(功效),而nH是希尔系数(GraphPad Prism)。然后,将响应数据针对每个BI-3406化合物浓度的摩尔对数以及确定的拟合结果作图,用于显示目的。误差条表示一个标准偏差。
ii.BI-3406IC50对比NGF浓度:
按照第‘i’部分中所述的分析,在NGF浓度250ng/mL、200ng/mL、150ng/mL、100ng/mL、50ng/mL、25ng/mL和10ng/mL计算了BI-3406的IC50值。随后,将得到的每个NGF浓度(x轴)的IC50值(y轴)的几何平均值绘制在单独的图中。误差条表示由2-8个单独的IC50平行测定计算的一个标准偏差。
iii.最大功效百分比对比NGF浓度:
按照第‘i’部分中所述,在适当的BI-3406浓度响应范围内计算每个化合物浓度的抑制百分比数值。由2-8次平行测定计算了对每个NGF浓度测试的BI-3406化合物的最高浓度计算的平均抑制百分比数值,随后绘制在单独的图中,以显示最大功效百分比(y轴)相对于NGF浓度(x轴)。误差条表示一个标准偏差。
结果图示于图3中。
组合研究:抗NGF和BI-3406抑制的协作
经由测量由NGF活化引起的ERK1/2磷酸化的HTRF读数,监测了选择性小分子RAS:SOS抑制剂BI-3406(Selleck Chemicals)和已知的基于抗体的NGF抑制剂抗NGF的组合抑制作用。所有测定在已经在补充有1%热灭活马血清(Merck)、0.5%热灭活胎牛血清(FBS)、1%青霉素-链霉素和2mM L-谷氨酰胺的RPMI-1640生长培养基(Gibco)中血清饥饿24小时的大鼠肾上腺PC-12细胞(Merck)中进行,另有说明除外。根据制造商的指示制备了来自HTRF商业试剂盒(Cisbio)的试剂。
测定程序:
从常规细胞培养物中分离出PC-12细胞,在血清饥饿条件下以适当的细胞密度(通常每孔25,000个细胞)在384孔板中铺板24小时。在血清饥饿培养基中制备不同抗-NGF(Abcam)浓度和固定NGF浓度的工作制备物,预培养30分钟(37℃/5%CO2)。同时,用工作浓度的BI-3406预处理PC-12细胞30分钟(37℃/5%CO2)。对测试的每个抗-NGF:NGF组合建立BI-3406的一式两份浓度响应曲线。在预培养30分钟后,用适当的抗-NGF:NGF组合处置PC-12细胞(针对固定的250ng/mL浓度的NGF,测试从30μg/mL到0μg/mL范围的抗-NGF的递增),随后培养5分钟(37℃/5%CO2)。在抗NGF:NGF处理5分钟后,将来自商业HTRF试剂盒的裂解缓冲液应用于PC-12细胞,在振荡(20℃,600rpm)下培养30分钟。每孔收集适当体积的裂解物,转移到单独的384-孔Proxiplate(Perkin Elmer)中,向其中向每个裂解物样品孔中分配5x浓缩的HTRF试剂盒抗体混合物。于室温培养2小时,然后在微板读数器(PHERAstarFSX,BMG Labtech)中测量荧光信号。
分析
i.针对抗-NGF:NGF攻击的BI-3406百分比功效图
通过将样品数据相对于每个板内使用的高和低对照(分别为+/-250ng/mL NGF)标准化,计算每个化合物浓度的抑制百分比数值。将来自每个一式两份BI-3406浓度响应曲线的抑制百分比数值进行平均,以提供每个浓度的数据点。然后,使用四参数逻辑拟合,其中y=A xnH/(EC50nH+xnH),其中x和y分别表示测试物质浓度和%细胞pERK信号,使用平均抑制百分比数值确定50%抑制浓度(IC50)和最大抑制(功效)(最大%抑制(功效)BI3406/由-NGF给出的最大%抑制(功效))。参数EC50是半数最大作用的测试物质浓度,A是最大输出(功效),而nH是希尔系数(GraphPad Prism)。然后,将响应数据针对每个BI-3406化合物浓度的摩尔对数以及确定的拟合结果作图,用于显示目的。误差条表示一个标准偏差。提取针对每个抗-NGF:NGF组合测试的BI-3406化合物的顶部和底部浓度计算的平均抑制百分比数值,以表格形式在测试的不同抗-NGF:NGF组合之间进行比较。
蛋白质印迹:
针对BI-3406抑制的NGF攻击:
通过测量NGF活化引起的ERK1/2磷酸化的基于蛋白质印迹的读数(Jess,ProteinSimple),监测了选择性小分子Ras:SOS抑制剂BI-3406(Selleck Chemicals)的抑制作用。所有测定在已经在补充有1%热灭活马血清(Merck)、0.5%热灭活胎牛血清(FBS)、1%青霉素-链霉素和2mM L-谷氨酰胺的RPMI-1640生长培养基(Gibco)中血清饥饿24小时的大鼠肾上腺PC-12细胞(Merck)中进行,另有说明除外。根据制造商的指示制备了来自JessSeparation Module商业试剂盒(Protein Simple)的试剂。
测定程序:
从常规细胞培养物中分离出PC-12细胞,在血清饥饿条件下以适当的细胞密度在6孔板中铺板24小时。在培养后,用工作浓度的BI-3406预处理PC-12细胞30分钟(37℃/5%CO2)。在每个测定的NGF(Merck)浓度下建立BI-3406的一式两份浓度响应曲线。在30分钟的化合物预培养后,用适当浓度的NGF处理PC-12细胞,随后培养5分钟(37℃/5%CO2)。在NGF处理5分钟后,将PC-12细胞混悬液转移到falcon管中并离心(4℃,300xg,5分钟)。弃去细胞上清液,用冰冷的PBS洗涤剩余的细胞沉淀。重复3次PBS洗涤,然后将含有蛋白酶和磷酸酶抑制剂的冰冷裂解缓冲液加入到干燥的细胞沉淀中。随后,将管超声处理30秒,在冰上储存15分钟,定期倒置以确保细胞裂解完成。在裂解后,将样品离心(4℃,13,000xg,5分钟),提取上清液以制备用于蛋白质印迹分析。根据制造商的指示制备上清液样品用于加载到Jess毛细管盒中。在相同的运行中加载每个测试的BI-3406浓度的一式两份样品。如i中所述分析数据。
细胞培养和生长因子处理
PC-12细胞(1)购自美国典型培养物保藏中心(Rockville,MD),在含有10%马血清(Life Technologies,Grand Island,NY)和5%胎牛血清(Hyclone,Logan,UT)的RPMI-1640(Biowhittaker,Walkersville,MD)中培养。通过台盼蓝染料排除法评估细胞活力。在测定之前,将细胞在DMEM中饥饿16小时,然后用神经生长因子(NGF-β;小鼠颌下腺,Sigma,St.Louis,MO)刺激,所述神经生长因子以20ng/μl的浓度溶于RPMI-1640中,然后在使用前稀释至适当的浓度。
免疫荧光测定
将细胞铺板在聚-L-赖氨酸包被的盖玻片或格栅玻璃底培养皿上,血清饥饿并用指定浓度的NGF刺激。将细胞于室温用4%多聚甲醛固定10分钟,于室温在0.2%Triton X-100中透化10分钟或者于-20℃在100%甲醇中透化10分钟,然后于室温用1%BSA封闭30分钟。然后,将细胞与初级抗体抗磷酸-ERK1/2(1:200)抗体于室温培养1-2小时,接着与二级抗体(Alexa Fluor 647抗小鼠IgG(1:500))抗体于室温培养1小时。所有抗体均由CellSignalling Technology,Danvers,MA,USA提供。在平衡后,洗涤细胞,使用荧光分光光度计(Molecular Devices Spectramax,San Jose,CA 95134USA)测量荧光。
测试化合物
抗NGF单克隆抗体由Abcam(Cambridge,MA,USA)提供。BI-3406由MedchemExpress,NJ,USA提供。
数据分析
使用GraphPad Prism分析了数据。
结果
在PC-12细胞系测定中,针对适宜的对照,在神经生长因子(NGF)刺激的磷酸细胞外调节激酶1和2(pERK1/2)活化的抑制中测试了多种结构不同的SOS1抑制剂,包括BI3406。在SOS1测定中,所有测试化合物具有低于5的IC50。
所有化合物都显示出在40-70%之间的功效水平。
BI-3406具有10-20nM的IC50。
在相同的测定中测试了Ras抑制剂。其显示出在40-70%之间的功效水平。
在PC-12细胞系测定中,在神经生长因子(NGF)刺激的磷酸细胞外调节激酶1和2(pERK1/2)活化的抑制中测量了NGF抑制剂他尼珠单抗与SOS1抑制剂BI-3406组合治疗疼痛的能力。
在200nM的浓度,他尼珠单抗具有100%的功效。
在50nM的浓度,他尼珠单抗具有90%的功效。
浓度为500nM的BI-3406具有40%的功效。
浓度为50nM的他尼珠单抗与浓度为500nM的BI-3406的组合具有~96%的功效。
在测定中还测量了NGF抑制剂他尼珠单抗与Ras抑制剂的组合治疗疼痛的能力。
在200nM的浓度,他尼珠单抗具有100%的功效。
在50nM的浓度,他尼珠单抗具有90%的功效。
浓度为500nM的BI-3406具有40%的功效。
浓度为50nM的他尼珠单抗与Ras抑制剂的组合具有~97%的功效。
标题:在C57Bl6小鼠中采用承重考察了25mg/kg BI3406与单剂量的他尼珠单抗组合对CFA-(完全弗氏佐剂)诱导的超敏反应的作用。
研究目的:为了考察25mg/kg(10mL/kg,口服,am和pm给药,2天)的BI3406与单剂量的他尼珠单抗0.1、0.3和1mg/kg(10mL/kg,i.p.,T=0)的组合和单独的他尼珠单抗3mg/kg(10mL/kg,i.p.,T=0)的作用,采用承重(WB)评估,在BI3406给药后1小时和他尼珠单抗施用后+1小时、+9小时、+25小时和+33小时。
动物:n=50只雄性C57/BL6小鼠20.1g-26.0g(Charles River Order#4650568)。
环境条件:将动物以每组5只圈养在标准笼子中,自由取食和饮水,12小时/12小时光照/黑暗循环(在上午7:00开灯)。
测试化合物:
·BI3406,25mg/kg(10mL/kg,i.p.,BID,2天)
·他尼珠单抗,0.1、0.3、1&3mg/kg(10mL/kg,i.p.,T=0)
对照组:溶媒,0.5%羟甲基纤维素(10mL/kg,p.o.,BID,2天)
研究时间表:
在CFA给药前3天:熟悉WB装置,采集基线读数一次。
给药前24小时:向左后爪足底内注射20μl的CFA 1.5mg/ml。
给药前1小时:采集WB的CFA后读数。
在第1天:施用化合物
·0.1、0.3、1&3mg/kg他尼珠单抗(10mL/kg,i.p.)。
·25mg/kg的BI3406(10mL/kg,i.p.,BID,2天)。
在第1天和第2天,在每个剂量的BI3406之后1小时进行载重测量(参见上述时间表)。
第3天,给动物施用BI3406,在每个时间点每组处死3只动物用于收集血液。时间点是BI3406最后给药后1小时、2小时和8小时。通过时间表1方法处死动物,通过心脏穿刺将血液收集到EDTA管中,于4℃以1500×g离心10分钟。取出所得血浆,分成2个等分试样。将样品储存在-80℃直至装运。
研究评估:承重
未经处理的动物将它们的体重平均分配在两只后爪之间。然而,当对一个后爪施加疼痛攻击(即,坐骨神经收缩或CFA足底内注射)时,重量被重新分配,使得较少的重量施加在受影响的爪上(在受损的爪上承受的重量减少)。将动物置于失能测试仪(incapacitance tester)(Linton Instruments,UK)中,后爪在分开的传感器上。历经2s记录由左后肢和右后肢施加的平均力。对左后爪和右后爪两者进行承重读数。计算了同侧/对侧的比例,以%(平均值±s.e.m.)表示。
结果
统计学:双向RM混合模型(处理x重复因子:时间)(InVivoStat v3.7.0.0)
*p<0.05、**p<0.01和***p<0.001,当在相同时间点与溶媒组相比时具有显著性差异(每组n=9-10)。###p<0.001,当与相同药物组内的基线相比时具有显著性差异。
分析
亚镇痛剂量的SOSi(BI3406,25mg/kg po)本身没有有限的镇痛作用,但是当与NGF单克隆抗体(他尼珠单抗)组合时,观察到增强的镇痛响应。当与SOSi(BI3406,25mg/kg po)组合时,他尼珠单抗的增强的镇痛作用是剂量相关的。当与SOSi(BI3406,25mg/kg)组合时,用0.3mg/kg和1.0mg/kg的他尼珠单抗观察到镇痛响应的统计学上显著的增强。组合研究产生了与较高剂量的他尼珠单抗单独给药时相当的镇痛作用。
Claims (16)
1.用于治疗疼痛的SOS1抑制剂和Ras抑制剂。
2.权利要求1的用途,其中所述SOS1抑制剂在测定中具有小于或等于5微摩尔的IC50。
3.权利要求1的用途,其中所述SOS1抑制剂具有小于100纳摩尔的IC50。
4.权利要求1的用途,其中所述SOS1抑制剂具有1纳摩尔或更小的IC50。
5.权利要求1的用途,其中所述Ras抑制剂在测定中具有小于或等于500纳摩尔的IC50。
6.权利要求1的用途,其中所述Ras抑制剂具有小于100纳摩尔的IC50。
7.权利要求1的用途,其中所述Ras抑制剂具有1纳摩尔或更小的IC50。
8.权利要求1-7的用途,其中本发明的SOS1抑制剂和Ras抑制剂相对于一种或多种以下靶标显示出大于或等于100倍的选择性:MEK 1、MEK 2、TrkA激酶、TrkB激酶、TrkC激酶、C-Raf、B-Raf、PI3激酶、AKT和ERK。
9.根据权利要求1的用途,其中所述SOS1抑制剂选自:
BI 3406(N-[(1R)-1-[3-氨基-5-(三氟甲基)苯基]乙基]-7-甲氧基-2-甲基-6-[(3S)-氧杂环戊烷-3-基]氧基喹唑啉-4-胺)
Bay 293(6,7-二甲氧基-2-甲基-N-[(1R)-1-[4-[2-(甲基氨基甲基)苯基]噻吩-2-基]乙基]喹唑啉-4-胺)
4-[[(1R)-1-(3,3-二氟-2H-1-苯并呋喃-7-基)乙基]氨基]-6-[1-(二氟甲基)环丙基]-2-甲基吡啶并[4,3-d]嘧啶-7-酮
和BI-170963。
10.根据权利要求1的用途,其中所述SOS1抑制剂选自(N-[(1R)-1-[3-氨基-5-(三氟甲基)苯基]乙基]-7-甲氧基-2-甲基-6-[(3S)-氧杂环戊烷-3-基]氧基喹唑啉-4-胺)(BI-3406)和(6,7-二甲氧基-2-甲基-N-[(1R)-1-[4-2-(甲基氨基甲基)苯基]噻吩-2-基]乙基]喹唑啉-4-胺)(BAY-293)。
11.根据权利要求1的用途,其中所述Ras抑制剂选自:
12.根据权利要求1的用途,其中所述Ras抑制剂是(3S)-5-羟基-3-[2-[[[1-[(1-甲基咪唑-4-基)甲基]吲哚-6-基]甲基氨基]甲基]-1H-吲哚-3-基]-2,3-二氢异吲哚-1-酮(BI-2852)。
13.如权利要求1-12中所述的SOS1抑制剂或Ras抑制剂,当与抗NGF抗体组合施用时用于治疗疼痛。
14.权利要求13的用途,其中所述抗-NGF抗体是他尼珠单抗。
15.权利要求1-14的用途,其中所述疼痛包括:急性疼痛;慢性疼痛;炎性疼痛;伤害性疼痛;神经性疼痛;痛觉过敏;异常性疼痛;中枢性疼痛;癌症疼痛;术后疼痛;内脏痛;肌肉骨骼疼痛;心脏或血管疼痛;头痛,包括偏头痛;口颌面痛,包括牙痛;和背痛。
16.权利要求1-14的用途,其中所述疼痛包括:
(a)急性疼痛和/或自发性疼痛,
(b)慢性疼痛和/或持续性疼痛,
(c)炎性疼痛,包括关节炎疼痛、由骨关节炎或类风湿性关节炎引起的疼痛、由炎性肠病、银屑病和湿疹引起的疼痛中的任一种,
(d)伤害性疼痛,
(e)神经性疼痛,包括痛性糖尿病性神经病变或与疱疹后神经痛相关的疼痛,
(f)痛觉过敏,
(g)异常性疼痛,
(h)中枢性疼痛、中枢性中风后疼痛、由多发性硬化引起的疼痛、由脊髓损伤引起的疼痛或由帕金森病或癫痫引起的疼痛,
(i)癌症疼痛,
(j)术后疼痛,
(k)内脏疼痛,包括消化性内脏疼痛和非消化性内脏疼痛、归因于胃肠(GI)障碍的疼痛、由功能性肠病(FBD)引起的疼痛、由炎性肠病(IBD)引起的疼痛、由痛经、骨盆疼痛、膀胱炎、间质性膀胱炎或胰腺炎引起的疼痛,
(l)肌肉骨骼疼痛、肌痛、纤维肌痛、脊椎炎、血清阴性(非类风湿性)关节病、非关节风湿病、抗肌萎缩蛋白病、糖原分解、多肌炎、脓性肌炎,
(m)心脏或血管疼痛、归因于心绞痛、心肌梗塞、二尖瓣狭窄、心包炎、雷诺现象、硬化病、硬化病或骨骼肌缺血的疼痛,
(n)头痛,包括偏头痛、有先兆偏头痛、无先兆偏头痛、丛集性头痛、紧张型头痛;
(o)口颌面痛,包括牙痛、颞下颌肌筋膜疼痛或耳鸣,或
(p)背痛、滑囊炎、月经痛、偏头痛、牵涉痛、三叉神经痛、超敏、由脊柱创伤和/或变性或中风引起的疼痛。
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