CN1307993C - 含有大环内酯的药物组合物 - Google Patents
含有大环内酯的药物组合物 Download PDFInfo
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- CN1307993C CN1307993C CNB028211588A CN02821158A CN1307993C CN 1307993 C CN1307993 C CN 1307993C CN B028211588 A CNB028211588 A CN B028211588A CN 02821158 A CN02821158 A CN 02821158A CN 1307993 C CN1307993 C CN 1307993C
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明涉及药物复合物,其包含式I化合物和可药用的2-氨基-1,3-丙二醇以及一种或多种可药用的赋形剂。
Description
本发明涉及药物组合物,例如用于病理状况的治疗,包括联合施用具有药物活性的活性剂。治疗包括预防和/或治疗。
一方面,本发明提供了式I的药物活性化合物,
如EP 427680所公开的化合物(实施例66a中的33-表-33-氯-FR 520),和2-氨基-1,3-丙二醇以及一种或多种可药用的赋形剂。
一种或多种可药用的赋形剂例如包括一种或多种可药用的助剂、载体、稀释剂。2-氨基-1,3-丙二醇可包括一种或多种2-氨基-1,3-丙二醇。
已知式I化合物对于治疗各种病症/疾病具有活性,如例如炎性状况、免疫介导的病症,或自身免疫疾病,例如血管炎、肾小球肾炎(glomerulonephritides)、特应性皮炎、过敏(例如特应性接触性湿疹、哮喘)、银屑病、系统性红斑狼疮、类风湿性关节炎、炎性肠病(例如局限性回肠炎、溃疡性结肠炎)、多发性硬化症、胰岛素依赖型糖尿病、干燥综合征、内源性后葡萄膜炎(uveitide)(尤其是贝赫切特病)、桥本甲状腺炎,并预防异种移植物或同种异体移植物、例如包括心脏、肾脏、肝脏或骨髓移植物引起的排斥;移植血管疾病或移植物抗宿主病。
此处提及的2-氨基-1,3-丙二醇包括式II化合物,
其中:
R1为任选取代的直链或支链(C12-22)碳链,例如烷基链,其任选被取代或未取代的亚苯基间隔,且R2、R3、R4和R5彼此独立地为H或低级烷基。当R1所指的碳链被取代时,其优选被卤素、硝基、氨基、羟基或羧基取代。当碳链被任选取代的苯基间隔时,碳链优选为未取代的。当亚苯基部分被取代时,其优选被卤素、硝基、氨基、甲氧基、羟基或羧基取代。“低级烷基”包括(C1-4)烷基。这些化合物例如公开于EP 627406、EP778263、EP1002792或WO 02/06268中,其相关内容、尤其是有关所述化合物的内容在此引入作为参考。
优选的化合物包括式II化合物,其中R1为直链或支链、优选直链的(C13-20)碳链,任选被硝基、卤素、氨基、羟基或羧基取代,且更优选式II化合物,其中R1为任选被卤素取代的苯基烷基,例如其中烷基为任选被羟基取代的(C1-6)烷基,且其中苯基被直链或支链(C6-14)烷基取代且任选被卤素取代。更优选地,R1为苯基(C1-6)烷基,其中的苯基被直链或支链、优选直链(C6-14)烷基取代,如(C6-14)烷基-苯基-(C1-6)烷基。如果R1为苯基烷基,其中的苯基被直链或支链(C6-14)烷基取代,则苯基可以被烷基在邻位、间位或对位、优选在对位取代。优选R2至R5的每一个均为H。
药物组合物可包含式I化合物和2-氨基-丙醇,例如EP 778263中所述的一种2-氨基-丙醇,以及一种或多种可药用的赋形剂。
在另一个优选实施方案中,2-氨基-1,3-丙二醇或2-氨基-丙醇为具有淋巴细胞归巢性质的化合物。这种性质可按照如例如以下的试验鉴别:将供试化合物或赋形剂通过强饲口服施用于大鼠。在施用后2、6、24、48和72小时取尾血用于血液学监测,于第11天取尾血以给出基线个体值。淋巴细胞归巢剂是这样一种化合物:例如在施用小于5mg/kg、优选小于3mg/kg的剂量后,其6小时使外围血液淋巴细胞减少超过50%。
仍然更优选的式II化合物为式IIa化合物,
例如2-氨基-2[2-(4-辛基苯基)乙基]丙烷-1,3-二醇盐酸盐。基于观察到的活性,例如EP 627406中所述,2-氨基-1,3-丙二醇例如式II化合物可用作免疫调节剂,例如在治疗同种异体移植物排斥中的例如免疫抑制剂。例如如WO 98/22100所述,例如式II的2-氨基-1,3-丙二醇可抑制移植血管疾病并特别适用于预防或治疗移植器官的慢性排斥,此外可抑制异种移植物排斥。
根据本发明,2-氨基-1,3-丙二醇或2-氨基-丙醇具有药物活性且是药学可接受的。
只要存在所述形式,式I化合物和2-氨基-1,3-丙二醇包括任何形式的化合物,例如游离形式、盐形式、溶剂化物形式和盐与溶剂化物形式。游离形式的本发明化合物可转化成相应的盐形式的化合物;溶剂化物形式的游离形式或盐形式的本发明化合物可转化为相应的非溶剂化物形式的游离形式或盐形式的化合物,反之亦然。
游离形式的化合物的药物活性与盐/溶剂化物形式的化合物的活性在类似的范围内。溶剂化物包括水合物。盐包括可药用的盐。
例如式II化合物的可药用盐包括式II化合物与酸形成的盐,所述酸例如包括无机酸,如盐酸、氢溴酸和硫酸,并包括有机酸,如乙酸、富马酸、马来酸、苯甲酸、柠檬酸、苹果酸、甲磺酸和苯磺酸,并且如果存在羧基,还包括与以下物质形成的盐:
—金属如钠、钾、钙和铝,
—胺如三乙胺,和
—氨基二酸如赖氨酸。
在一个优选的实施方案中,式II化合物或那些EP 1002792所述的化合物包括所述化合物的磷酸盐。
式I化合物和式II化合物可以以异构形式存在,且本发明包括任何异构形式的本发明的式I化合物和2-氨基-1,3-丙二醇以及任何异构混合物。例如如果本发明的式I化合物和2-氨基-1,3-丙二醇在分子中具有一个或多个不对称中心,则本发明包括各种光学异构体形式的化合物,以及外消旋体、非对映异构体和其混合物。
我们现已惊讶地发现:在其中式I化合物或2-氨基-1,3-丙二醇可显示药物活性的实验性自身免疫葡萄膜炎(EVU)的动物模型中,当以例如次优剂量联合施用式I化合物和2-氨基-1,3-丙二醇例如式II化合物时,获得了增强的活性。联合施用的化合物的增强的活性显著高于在例如次优剂量水平下所测试的每种单一化合物的活性。据信相同的规律也适用于其中式I化合物或2-氨基-1,3-丙二醇显示药物活性的所有疾病,例如包括炎性状况、免疫介导的病症,或自身免疫疾病,例如血管炎、肾小球肾炎、特应性皮炎、过敏(例如特应性接触性湿疹、哮喘)、银屑病、系统性红斑狼疮、类风湿性关节炎、炎性肠病(例如局限性回肠炎、溃疡性结肠炎)、多发性硬化症、胰岛素依赖型糖尿病、干燥综合征、内源性后葡萄膜炎(尤其是贝赫切特病)、桥本甲状腺炎,并预防异种移植物或同种异体移植物例如包括心脏、肾脏、肝脏或骨髓移植物引起的排斥;移植血管疾病或移植物抗宿主病。
另一方面,本发明提供了一种包装,其包含式I化合物以及一种或多种可药用赋形剂的药物组合物,且包含用于同时或依次施用2-氨基-1,3-丙二醇的说明书。
另一方面,本发明提供了一种包装,其包含2-氨基-1,3-丙二醇以及一种或多种可药用赋形剂的药物组合物,且包含用于同时或依次施用式I化合物的说明书。
另一方面,本发明提供了药物包,例如一种包装,其在同一个包装中包含式I化合物以及一种或多种可药用赋形剂的药物组合物,以及2-氨基-1,3-丙二醇以及一种或多种可药用赋形剂的药物组合物。
另一方面,本发明提供了提高如前所述的式I化合物的药物活性的方法,该方法包括向需要用式I化合物和/或2-氨基-1,3-丙二醇治疗的对象联合施用式I化合物和2-氨基-1,3-丙二醇。
式I化合物和2-氨基-1,3-丙二醇可以以不同的方式联合施用:
a)以固定组合的形式,包含处于同一药物组合物中的式I化合物和具有药物活性的2-氨基-1,3-丙二醇;
b)以(药物)包的形式,其中式I化合物和2-氨基-1,3-丙二醇以分开的药物组合物形式存在,例如与用于联合施用的说明书在同一包装中出售。
c)以自由组合的形式,其中式I化合物与2-氨基-1,3-丙二醇例如以药物组合物的形式分别包装,其中每个包装均包括用于同时或依次施用的说明书。
式I化合物与2-氨基-1,3-丙二醇的最有效比例可取决于例如待治疗的适应症。适宜的剂量和剂量范围当然将根据例如所使用的本发明的活性化合物、宿主、施用方式和所治疗病症的性质和严重性而变化。但是,一般而言,为了在较大的哺乳动物例如人体中取得满意的结果,适用的日剂量为大环内酯如药物活性的式I化合物和药物活性的2-氨基-1,3-丙二醇的已知剂量,例如低于这些最佳剂量,例如以分剂量、例如每天不超过4次施用。通常,在全身获得满意的结果所需要的日剂量为约0.5mg/kg至约15mg/kg、优选1mg/kg至约15mg/kg动物/人体重的式I化合物,和约0.005mg/kg至0.1mg/kg、优选0.01mg/kg至0.1mg/kg的式II化合物。优选的化合物I和II的比例为约3000至10、优选500至10。
本发明的活性化合物可通过任何常规的途径施用,例如通过全身,例如口服,例如以片剂或胶囊的形式施用;或通过胃肠外,例如以注射用溶液或混悬液的形式施用;以及局部施用如表皮、鼻内、气管内施用。
另一方面,本发明提供了治疗其中式I化合物和/或2-氨基-1,3-丙二醇具有药物活性的疾病的方法,所述疾病例如包括炎性状况、免疫介导的病症或自身免疫疾病,例如血管炎、肾小球肾炎、特应性皮炎、过敏(例如特应性接触性湿疹、哮喘)、银屑病、系统性红斑狼疮、类风湿性关节炎、炎性肠病(例如局限性回肠炎、溃疡性结肠炎)、多发性硬化症、胰岛素依赖型糖尿病、干燥综合征、内源性后葡萄膜炎(尤其是贝赫切特病)或桥本甲状腺炎,并预防异种移植物或同种异体移植物例如包括心脏、肾脏、肝脏或骨髓移植物引起的排斥;移植血管疾病或移植物抗宿主病,所述方法包括向需要这种治疗的对象施用有效量的式I化合物和2-氨基-1,3-丙二醇,例如以以下形式施用:
—固定组合,例如药物组合物的形式;
—(药物)包,例如处于同一个包装中的式I化合物的药物组合物和2-氨基-1,3-丙二醇的药物组合物的形式;
—一种包装,包含例如药物组合物形式的式I化合物或2-氨基-1,3-丙二醇,并包含用于同时或依次联合施用的说明书。
在本发明的一个优选实施方案中,式I化合物与式IIa化合物联合施用。
式I化合物和2-氨基-1,3-丙二醇可作为唯一的成分或与免疫调节方案中的其它药物或其它抗炎剂一起施用。例如所述化合物可与以下药物组合使用:环孢菌素、雷帕霉素或其它子囊霉素,或它们的免疫抑制类似物,例如环孢菌素A、环孢菌素G、FK-506、雷帕霉素、40-O-(2-羟基)乙基-雷帕霉素等;皮质类固醇;环磷酰胺;硫唑嘌呤;甲氨喋呤;白瑞夸尔;来氟洛米;咪唑立宾;霉酚酸;霉酚酸酯;15-脱氧斯潘格宁;免疫抑制单克隆抗体,例如针对白细胞受体例如MHC、CD2、CD3、CD4、CD7、CD25、CD28、B7、CD40、CD45或CD58或针对它们的配体的单克隆抗体;或其它免疫调节化合物例如CTLA4-1g。
用于测定式I化合物和2-氨基-1,3-丙二醇的活性的试验法是已知的。可使用例如Clin.Immunol.Immunopathol.1986,39:329-336,McAllister等人所述的实验性自身免疫葡萄膜炎(EAU)模型。
另一方面,本发明提供了例如同时或依次施用的式I化合物以及2-氨基-1,3-丙二醇作为药物的用途;以及式I化合物与2-氨基-1,3-丙二醇的组合在制备用于治疗疾病的药物中的用途,所述疾病中式I化合物或2-氨基-1,3-丙二醇具有药物活性。治疗包括预防和/或治疗。
附图简介
图1显示在大鼠中进行的实验性自身免疫葡萄膜炎(EAU)试验的结果。
用以下物质每日一次口服治疗大鼠,为期14天,
-◆-:对照(安慰剂,即药物赋形剂/水),
-■-:式IIa化合物(0.1mg),
-▲-:式I化合物(15mg),或
式IIa化合物(0.1mg)+式I化合物(15mg)。
以mg计的重量表示为mg/kg体重/天。双眼损害的评分均值在免疫后20天内如实施例所述进行测定。
图2显示在大鼠中进行的实验性自身免疫葡萄膜炎(EAU)试验的结果。用以下物质每日一次口服治疗大鼠,为期14天,
-◆-:对照(安慰剂,即药物赋形剂/水),
-■-:式IIa化合物(0.1mg),
-▲-:式I化合物(15mg),
式I化合物(15mg)+式IIa化合物(0.1mg),14天,或
-*-:式I化合物(15mg)+式IIa化合物(0.1mg),28天。
其它参数如图1所述。
实施例
实施例1:EAU试验系统
实验性自身免疫葡萄膜炎(EAU)
所使用的EAU模型类似于McAllister等人(1986)先前所述的模型(McAllister CG、Vistica BP、Sekura R、Kuwabara T、Gery l.“百日咳毒素对实验性自身免疫葡萄膜炎的诱导与转移的效果”Clin ImmunolImmunopathol 1986;39:329-336)。在第一天于醚麻醉下向动物(每组5只大鼠)的右脚垫注射50μg纯化的牛视网膜S-抗原并经腹膜注射1μg百日咳毒素(Difco)。抗原以磷酸盐缓冲的盐水稀释并以1∶1的比例与弗氏完全佐剂和Bacto M肺结核H37RA(Difco)混合。注射体积为0.1ml,含有50μl完全佐剂和1.14mg结核分支杆菌。该操作在所有动物中均诱发爆发性(fulimant)疾病,其可于免疫后最初的9至10天观察到。未治疗动物的眼睛损害在几乎所有动物中均发展至严重性分级的第4级(见“EAU评价”部分)。
治疗、剂量
以强饲法对动物进行治疗,使用日剂量为单独的15mg/kg式I化合物或0.1mg/kg的式IIa化合物,或使用相同剂量水平的两种化合物的组合。治疗在免疫前2小时开始,并连续14天每日进行一次。对照动物以单独的安慰剂/水(安慰剂:单独的药物赋形剂)类似地进行治疗。
EAU评价
于免疫后的第7天开始,以检眼镜(Heine,Beta 200)每日检查动物的炎症变化,直至第20天。眼部炎症的程度以0至4的分级(对于一只眼睛)进行半定量评价:
0:正常;
1:虹膜充血;
2:虹膜充血,伴血管扩张;
3:在前房有早期纤维蛋白渗出物和中度虹膜细胞浸润;和
4:在前房有大面积纤维蛋白凝块或纤维蛋白堵塞瞳孔以及严重的虹膜细胞浸润。
结果
用0.1mg/kg的式IIa化合物或15mg/kg/天的式I化合物经口服治疗的动物(LEWIS大鼠)在疾病的进程和强度方面与安慰剂对照组无显著不同(参见例如表1和图1)。
与此相反,以相同剂量水平施用两种化合物使疾病的发作显著延迟(较对照组晚6天)且炎症的强度显著较弱。在第19天,治疗动物的最高平均评分为4.4,相比之下对照组第11天的评分为8.0。
表1
试验组 | 剂量 | EAUPOS | EAU 10 | EAU 1s1 | SCORE MAX | |
评分 | 天 | |||||
对照 | 0.0 | 5/5 | 5/5 | 10.0(0.0) | 8.0(0.0) | 11 |
Cpd IIa | 0.1 | 4/4*) | 2/5 | 10.5(0.6) | 8.0(0.0) | 13 |
Cpd I | 15 | 5/5 | 1/5 | 11.8(1.3) | 6.8(1.3) | 14 |
Cpd IIa+Cpd I | 0.1+15 | 4/5 | 0/5 | 16(1.4) | 4.4(3.3) | 19 |
*)一只试验动物在第11天由于强饲所致创伤而脱落。
在表1的“EAU POS”和“EAU 10”项下分别显示了直至研究结束(EAU POS)和第10天(EAU 10)时的每组患病动物数/动物数。使用了以下缩略语:
Cpd I:式I化合物
Cpd IIa:式IIa化合物
对照:安慰剂(药物赋形剂/水)
剂量:口服,以mg/kg/天计
EAU POS:EAU阳性大鼠数
EAU 10:第10天EAU的发病率
EAU 1st:首发EAU症状的日子(均值±SD)
SCORE MAX:最高评分(双眼损害的均值±SD)
EAU-试验(用作实验实施例)的结果显示:次优剂量的式I化合物与次优剂量的式IIa化合物的组合在抗EAU活性方面显著优于分别单独使用次优剂量的式I化合物或次优剂量的式IIa化合物(表1和图1)。该效果认可了次优剂量的式I化合物加次优剂量的式IIa化合物的使用。
实施例2:
如实施例1所述、以表2给出的剂量治疗动物(每组6只大鼠)。如表2和图2所示,联合治疗显示出优于用单一化合物治疗的结果。在第14天用两种化合物治疗的动物中,在第16天于一只动物中观察到首发临床症状。在4周的治疗期间还观察到症状被完全抑制。症状最早于第34天,即末次治疗后6天出现于一只动物中。
表2
试验组 | 剂量 | EAU POS | EAU10 | EAU 1st | SCORE MAX | |
评分 | 天 | |||||
对照组 | - | 6/6 | 6/6 | 9.3(0.5) | 8.0(0.0) | 12 |
Cpd IIa | 0.1 | 6/6 | 0/6 | 11.2(1.0) | 8.0(0.0) | 14 |
Cpd I | 15 | 6/6 | 2/6 | 11.5(0.8) | 6.0(2.5) | 14 |
Cpd I+Cpd IIa | 15+0.1(14x) | 6/6 | 0/6 | 18.0(1.1) | 8.0(0.0) | 21 |
Cpd I+Cpd IIa | 15+0.1(28x) | 6/6 | 0/6 | 34.8(0.4) | 7.2(1.3) | 37 |
含义同表1的说明。
EAU试验的结果(用作实验实施例)表明:当在免疫开始时以化合物I和IIa的组合进行4周治疗时,可防止疾病的发生。
Claims (9)
1.药物组合物,其包含式I化合物,
和式II的2-氨基-1,3-丙二醇,
其中R1为任选地被卤素、硝基、氨基、羟基或羧基取代的直链或支链(C12-22)碳链,其任选地被未取代或被卤素、硝基、氨基、甲氧基、羟基或羧基取代的亚苯基间隔,且R2、R3、R4和R5彼此独立地为H或C1-4烷基,以及一种或多种可药用的赋形剂。
2.权利要求1所述的药物组合物,其中式II化合物具有以下结构式:
3.药物包,其包含处于同一包装中的权利要求1所定义的式I化合物以及一种或多种可药用赋形剂的药物组合物,和权利要求1所定义的式II的2-氨基-1,3-丙二醇以及一种或多种可药用赋形剂的药物组合物。
4.权利要求3所述的药物包,其中式II化合物具有以下结构式:
5.权利要求1所定义的式I化合物与权利要求1所定义的式II的2-氨基-1,3-丙二醇的组合在制备用于治疗炎性状况、免疫介导的病症或自身免疫疾病或用于预防异种移植物或同种异体移植物引起的排斥的药物中的用途。
6.权利要求5所述的用途,其中所述炎性状况、免疫介导的病症和自身免疫疾病选自血管炎、肾小球肾炎、特应性皮炎、过敏、银屑病、系统性红斑狼疮、类风湿性关节炎、炎性肠病、多发性硬化症、胰岛素依赖型糖尿病、干燥综合征、内源性后葡萄膜炎、桥本甲状腺炎、移植血管疾病和移植物抗宿主病。
7.权利要求6所述的用途,其中所述炎性状况、免疫介导的病症和自身免疫疾病选自特应性接触性湿疹、哮喘、局限性回肠炎、溃疡性结肠炎和贝赫切特病。
8.权利要求5所述的用途,其中所述的异种移植物或同种异体移植物引起的排斥选自心脏、肾脏、肝脏或骨髓移植物引起的排斥。
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