CN1097735A - 脂肪酸衍生物和含有脂肪酸衍生物的药物组合物 - Google Patents
脂肪酸衍生物和含有脂肪酸衍生物的药物组合物 Download PDFInfo
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- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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Abstract
纯的多不饱和脂肪酸衍生物是通过部分纯化和
部分合成制备的。其是大麻素受体的配位体。这些
衍生物具有广泛的生理活性，因此可在药物组合物中
作为活性成分。所述生理活性有：抗炎，止喘，止吐，
抗偏头痛和镇痛。它们也可用作治疗青光眼的有效
药。另外，这些衍生物还可使情绪兴奋并缓解许多硬
化症状。
Description
对于大麻素（cannabinoid）受体的内生配体目前仍然没有确定。一种新的名为anandamide的花生四烯酸衍生物，花生四烯酰基乙醇酰胺（Arachidonylethanolamide）是从猪脑中分离的。其结构是通过质谱分析和核磁共振谱法确定的并通过合成被证实。它以典型的竞争性配体的方式抑制标记大麻素探测剂与突触体膜的特殊结合，并产生与浓度有关的对小鼠脉管输送的电引起的抽搐反应的抑制，即影响精神的大麻素的特征效果。类似的化合物已经合成，其药理特性经过试验。
大麻的对精神起显著作用的成分，△9-四氢大麻醇（△9-THC）在大脑中与特殊G-蛋白偶联的受体结合。虽然大麻素受体在大鼠中和人体中已经克隆化，但其生理功能仍是未知的。建立得很好的THC的行为效果以及大脑中受体的分布量和解剖定位表明受体与其它活性物一起在控制运动、记忆、情绪和缓解痛疼方面具有作用。
受体的存在及对大麻素活性的大结构要求表明可能存在特殊的内生大麻素配体。
为鉴别内生大麻素化合物，采用离心放射性配体结合测定法试验来自大脑的馏分。用具有45PM的K0的氚化HU-243（11-羟基六氢大麻醇-3-二甲基庚基同系物）作为大鼠突触体膜中的探测剂。首先按照用于类脂类分离的标准方法对猪脑的有机可溶性提取液进行色谱分离。将猪脑在氯仿和/或甲醇中均匀化并以13，000Xg离心分离，在硅石（Kieselgel60，70-230筛）上分馏有机可溶性提取液，然后采用洗脱方法分离大多数类脂[C.C.Sweeley，Methodg Enzyol，14，254（1969）;J.C.Dittmer和M.A.Wells.ibid.P.482]。许多从猪脑中分离的初始馏分抑制了[3H]HU-243与大麻素受体的结合。特别要注意[3H]HU-243与用于在其中进行测定的硅化聚丙烯微驱除管（microfuge tubes）的结合。通常，加入的[3H]HU-243大约有15～20%粘到微驱除管上，当未标记的大麻素药物从受体中替换放射性配体时该数量略有增加。当监测突触体受体、溶液和微驱除管三者中的[3H]HU-243三向平衡时，我们观察到所有抑制[3H]HU-243与受体结合的粗脑馏分也抑制放射性配体与微驱除管结合。用低压和中压柱色谱法以及薄层色谱法（TLC）将数个期望的馏分提纯。采用正相与反相系统的组合。薄层色谱法：在分析RP-18平板上（Merck）Rf为0.65，用比例为4∶1的甲醇与二氯甲烷洗脱∶展开二次-第一展开剂前沿：3.1cm，第二展开剂前沿：7.4cm。[W.A.Devane，L.Hanug，Mechoulam，Proceed.第五届北欧神经科学会议，Publ.Univ.Kuopio Med.P.198（1991）]。将anandamide用甲醇：氯仿（2∶98）通过硅胶柱（Kieselgel60，40-63μm，Merck）洗脱，用甲醇∶水（88∶12）通过反相柱（RP-C，40-63μm，Sigma）洗脱。
回收到一种名为anandamide的化合物（0.6mg，从4.5Kg脑中分离出），该化合物在薄层色谱法上表现为一个色谱斑，而流出物在用质谱仪探测仪的气相色谱（GC）上主要以一个波峰的形式。anandamide以典型的具有KD为52+1.8nM（n＝3）的竞争性配体的方式抑制[3H]HU-243与突触体膜的特殊结合（图1）。在该系统中KD为46+3nM。
从前面的试验，我们比较了（+）和（-）-11-羟基-δ-8-四氢大麻醇的1，1-二甲基庚基同系物对小鼠脉管输送的电引起的抽搐反应的抑制效果，其结果表明该制剂适合于作为测试影响精神的大麻素作用方式的模型。R.G.Partwee，L.A.Stevengon，D.B.Elrick，R，Mechoulam，A.D.Corbett，Brit.J.Pharmacol，105，980（1992）。anandamide产生与浓度有关的抽搐反应的抑制作用（图2）。该抑制作用不被纳洛酮（300nM）逆转。抑制程度可以与和受体的结合的那些抑制程度比较。
anandamide的结构通过质谱法（MS）和核磁共振（NMR）谱法确定。附加数据从该物质的三甲基硅（TMS）衍生物的GC-MS和CID测定法得到。结果表明anandamide是一种四烯C20脂肪酸的乙醇酰胺。
上述结构的证据是anandamide在GC-MS条件下的特性中发现的。
在电离（EI）条件下，热脱水产生了m/Z为329M+和在C1下的m/Z为330MH+，带Cl的m/Z330MH+和m/E329M+两者都是在一个离子捕集仪器中在EI条件下形成的（图3）。这些脱水产物的裂解图谱与anandamide和棕榈基乙醇酰胺：m/Z85（麦克拉佛特重排离子）和m/Z98（γ-裂解产物）两者在EI质谱的低质量范围是相似的（图4）。脱水棕榈基乙醇酰胺的EI质谱显示与δ裂解碎片相对应的一种m/Z112离子。在anandamide的GC-MS分析中得到的EI质谱中没有这种离子，表明在四烯酸的5位置上存在第一个双键（正如在不希望产生δ-裂解产物的花生四烯酰基乙醇酰胺中）（图4）。
记录1H NMR谱。由双键质子（δ，5.30-5.45，多重峰）产生的峰与具有双烯丙基质子（δ，2.75-2.90，多重峰）的化学位移的质子产生的那些峰相偶合。这种双烯丙基质子一般存在于许多天然形成的全部顺式（allcis）、非共轭、多不饱和脂肪酸中，例如亚油酸和花生四烯酸。在δ2.01-2.27之间观察到的三对质子，我们认为这是2个烯丙基的亚甲基和1个亚甲基α连到羰基部分上所引起的。只观察到一个甲基（0.88，t）。对于在3.42（N-CH，t）的两个质子，在3.72（0-CH2，t）的两个质子和在2.20（COCH2，t）所观察到的峰在化学位移和自旋偶合方式方面与在合成的棕榈基乙醇酰胺的NMR谱中所观察到的峰相似。N-CH2和O-CH2的峰是偶合的。
上面分析数据的并列使我们断定anandamide的结构是花生四烯酰基乙醇酰胺（arachidonyl ethanolamide）[5，8，11，14-二十碳四烯酰胺，（N，-2-羟乙基）-（全-E）]，一种新的化学个体。该结论通过合成被证实。将在二氯甲烷中的由花生四烯酸和草酰氯制备的花生四烯酰氯在0℃，氮气氛条件下加到在二氯甲烷中的乙醇酰胺（在10倍摩尔超量下）中。15分钟后用水洗涤反应物，干燥，并用硅胶柱色谱法（用氯仿中的2%的甲醇洗脱）提纯反应产物得到纯度为97%（经GC-MS）的油性花生四烯酰基乙醇酰胺。根据tlc，NMR（300MH2）和GC-MS（保留时间和裂解方式）可判定合成的花生四烯酰基乙醇酰胺与得到的产物是相同的（图3）。合成的anandamide与大麻素受体KI＝39±5.0nM（n＝3）结合。
这种新的纯化的化合物anandamide看来是作为脑的成分存在，该化合物能够以与其它化合物的配合物形式或以任何其它形式存在，但是按照本发明已经确定本文定义为anandamide的化合物是以本文所述的性质为特征的。本文所定义的类似化合物以基本相同的性质为特征，并且这些类似化合物也是本发明的一部分。
本发明还涉及可用于各种研究项目和测定的该化合物的标记形式。
本发明进一步涉及含有有效量的本文所定义的这些化合物中的一种化合物的药物组合物。
按照所描述的用于花生四烯酰基乙醇酰胺的合成方法，制备下列不饱脂肪酸的乙醇酰胺。
学名 俗名 速记符号
9,12十八碳二烯酸★ 亚油酸 18:2(n-6)
6,9,12-十八碳三烯酸 γ-亚麻酸 18:3(n-6)
8,11,14-二十碳三烯酸 高-γ-亚麻酸 20:3(n-6)
4,7,10,13,16-二十碳五烯酸 - 20:5(n-6)
9,12,15,-十八碳三烯酸 α-亚麻酸 18:3(n-3)
5,8,11,14,17-二十碳五烯酸 - 20:5(n-3)
4,7,10,13,16,19-
二十二碳六烯酸 - 22:6(n-3)
5,8,11-二十碳三烯酸 - 20:3(n-9)
★每个例子中双键构型是顺式的。
这些乙醇酰胺衍生物具有消炎止痛、抗青光眼和止吐活性（见生物结果）。为了得到在生物研究中是重要的14C标记化合物，用14C-标记花生四烯酸重复上述合成步骤得到50mci/mmol14C-花生四烯酰基乙醇酰胺。用3H-花生四烯酸我们得到3H-花生四烯酰基乙醇酰胺150Ci/mmol。当使用14C-标记乙醇酰胺时获得50mci/mmol14C-花生四烯酰基乙醇酰胺。
生物结果
止痛、将新化合物在标准热平皿试验中测试。
有代表性的结果在表1中给出。
将化合物溶解在洗涤剂（磷乳）：乙醇：盐水为（5∶5∶90）的溶液中并以0.1ml/10g体重的注射量静脉注射入尾部静脉。
止吐活性
按照在Feigenbaum等人，Eur.J.Pharmacol.169，159-165（1989）中描述的方法在鸽子中对化合物进行防止由antieoplastic药（二氨二氯络铂）引起的呕吐的试验。有代表性的结果在表1中给出。
将化合物按上面所述溶解用于止痛试验，按1.0ml/Kg体重的注射量进行皮下注射。
抗青光眼活性
按照R.Mechoulam等人在“大麻的治疗可能性”（eds S.Cohen
按照R.Mechoulam等人在“大麻的治疗可能性”（eds S.Cohen.R.C.stillman）Plenum press，New York，1975，PP.35-48）中关于某此大麻素的治疗可能性中所详细描述的方法，通过将α-胰凝乳蛋白酶注射入眼中使兔子引起稳定青光眼病，在这些兔子中试验化合物的抗青光眼活性。这种化合物与毛果芸香碱（一种标准的抗青光眼药）的0.01%水溶液相比降低了眼内压（I.O.P.）并使原I.O.P.的半时间（half time）的恢复延长了约30小时。
向眼中注射的0.1%的脂肪酸乙醇酰胺溶液的活性比毛果芸香碱低，并使原I.O.P.的半时间的恢复延长2至10小时。
如对止痛所述的方法将这些化合物溶解，并用盐水进一步稀释得到所需浓度。
消炎活性
将化合物用W.Calhoun等人在“试剂和作用”，21，306-a309（1987）中报导的方法进行试验。用水作为取代介质代替汞。将在盐水中的50μ15%的乙醇中溶解的PAF（1.0Mg）或花生四烯酸（1.0mg）皮下注射到雌小鼠（20-25g）的右后爪的足底表面。在该过程中小鼠处在乙醚麻醉状态中。在治疗前和PAF注射后15分钟或花生四烯酸注射后30分钟用水置换法测量右爪的体积得到外踝的量。计算每个小鼠爪体积的变化。两个试验的乙醇酰胺的结果在表Ⅱ中给出。
剂量
对人的有效剂量为每天共1-100mg，可以注射或口服。
表Ⅰ
止痛和呕吐的减轻
化合物 止痛 呕吐的减轻
ED50(mg/Kg)-(50%)=(mg/Kg)
花生四烯酰基乙醇酰胺 4.2 2.5
5,8,11,14,17-二十碳五烯酰基 5.2 3.6
乙醇酰胺
4,7,10,13,16,19-二十二碳 6.1 4.8
六烯酰基乙醇酰胺
5,8,11,-二十碳三烯酰基乙醇酰胺 7.6 6.2
-在小鼠中,详细的给药方法见讲义
=在鸽子中,详细的给药方法见讲义
表Ⅱ
花生四烯酸对引起爪浮肿的抑制作用三
剂量(mg/kg)
花生四烯酰基乙醇酰胺 4,7,10,13,16,19二十二
碳六烯酰基乙醇酰胺
0.010 56.2 -
0.025 58.4 -
0.050 74.2 52.4
0.100 98.0 66.8
0.250 100.0 72.0
三 给出的这些值是与媒介物治疗对照试验相比时对爪浮肿的抑制百分数。通过ANOVA95%是显著的。N＝5只小鼠/组。
给对照小鼠口服花生油（50μl）。爪体积增加＝38+4μl。
从脑中分离和合成的化合物。
化合物的名称 Ki
顺-7，10，13，16-二十二碳四烯酰基 34.4±3.2nM
乙醇酰胺
anandamide 39.0±5.0nM
高-γ-亚麻酰基乙醇酰胺 53.4±5.5nM
合成的化合物，制备及试验
化合物的名称 Ki
N-丙基-5，8，11，14，-二十碳四烯酰基酰胺 11.7±2.6nM
N-乙基-5，8，11，14，-二十碳四烯酰基酰胺 34.0±2.7nM
N-甲基-5，8，11，14，-二十碳四烯酰基酰胺 60.0±7.4nM
花生四烯酰基-β-二甲基乙醇酰胺 161.8±34.1nM
含有有效量的作为活性组分的本发明化合物的药物组合物具有各种药理作用。这些作用中有提到的消炎、止喘、止痛、抗青光眼、止偏头疼及镇痉作用。它们也可以使情绪兴奋以及改善多种硬化症状。单位剂量的形式根据化合物和医疗用途而改变，一般，其范围在大约1mg之间至大约100mg之间。优选每单位剂量形式约5至25mg
下面参考附图说明本发明，其中：
图1表示用天然anandamide的[3H]HU-243结合的竞争性的抑制作用;
图2表示用天然anandamide的脉管输送抽搐反应的抑制作用;
图3是anandamide的GC-MS谱;
图4表示所述的一些化合物的结构;
图5是脱水高-γ-亚麻酰基乙醇酰胺（5）的EIGC-MS谱。
图6是脱水二十二碳四烯酰基乙醇酰胺，化合物（6）的EIGC-MS谱;
图7是高-γ-亚麻酰基乙醇酰胺（5）和二十二碳四烯酰基乙醇酰胺的EIGC-MS谱（上曲线和下曲线）。
图8表示用化合物（5）（方块）和化合物（6）（三角）的[3H]HU-243的竞争性结合。
图9是本发明一些化合物的结构图。
图例
图1.用天然anandamide的[3H]HU-243结合的竞争性抑制作用。突触体膜是由鼠的整个脑除去脑干（Sprague-Dawley雄性，430-470g）而制备的。用指定浓度的anandamide或单独的媒介物（无脂肪酸的牛血清白蛋白，最终浓度-0.5mg/ml）在30℃下将[3H]HU-243（45-55PM）与突触体膜（蛋白含量3-4μg）培育90分钟。用离心法将结合的和游离的放射性配体分离（见对于该试验的全部说明的参考8）。将这些数据归一化至100%的特殊结合，其用50nM来标记的HU-243测定。特殊结合的量是与该膜结合的总放射性的77-82%。数据点（□，△）表示两个独立试验中重复三次测定得到的平均值。K数值（平均值+SE，n＝3）是用配体程序确定的;K＝52+18nM。
图2.用天然anandamide的脉管输送抽搐反应的抑制作用。将从MFI老鼠中获得的脉管输精管固定在起始张力为0.5g的4ml硅化器官浴槽中。浴槽中含有保持在37℃的Mg++-游离克雷伯（Krebs）溶液并用95%的O2和5%的CO2豉泡。用三个脉冲的0.5S序列（群频0.11Hz：脉宽0.5ms）超大程度地刺激组织。记录等长收缩。将天然anandamide分散到Tween80和盐水中（见参考12）并加入40μl。Tween80在使用的最大浴浓度（0.63μg/mL;n＝6）下不抑制抽搐反应。
图3.anandamide在离子捕集仪器上的GC-MS谱。在这些条件（见说明书）下对anandamide进行热脱水，因此实际上上面的GC-MS谱是对应的2-噁唑啉的M+离子的GC-MS谱。
图4.这些脂肪酸乙醇酰胺在GC-MS条件（见讲义）下进行热脱水后形成的anandamide、棕榈基乙醇酰胺以及二氢和四氢噁唑离子碎片的结构。m/Z112离子只从棕榈基乙醇酰胺形成。
Claims (9)
1、基本纯的下列通式化合物及其酸加成盐和配合物
其中R是含有16至28个碳原子、带有2至6个双键(优选都是顺式构型)的多不饱和脂肪酸的链烯基部分，第一个双链是在从分子的非羧基部分算起的C-3、C-6或C-9位置上，其中R″是-H、低级烷基、-OH或-(CH2)n-OH，其中n是小的整数，以及当R″是氢时，R′是低级烷基，或-(CH2)m-OH，其中m是小的整数，
当R″是低级烷基时，R′是-(CH2)p-OH，其中P是小的整数，
当R″是-OH时，R′是-(CH2)q-OH，其中q是小的整数，
或R′和R″两者各是-(CH2)n-OH，其中n是小的整数。
2、根据权利要求1的化合物，其中链烯基部分是十八碳二烯、十八碳三烯、二十碳五烯、二十二碳六烯、二十碳三烯或二十碳四烯部分。
3、根据权利要求1的化合物，其选自花生四烯酰基乙醇酰胺、顺-7，10，13，16-二十二碳四烯酰基乙醇酰胺、高-γ-亚麻酰基乙醇酰胺、N-丙基-5，8，11，14-二十碳四烯酰基酰胺、N-乙基-5，8，11，14-二十碳四烯酰基酰胺、N-甲基-5，8，11，14-二十碳四烯酰基酰胺、花生四烯酰基-β-二甲基乙醇酰胺。
4、一种消炎、止喘、止痛、止吐、抗青光眼、止偏头疼、镇痉挛、情绪兴奋以及改善多种硬化症状的药物组合物，其含有作为活性组分的有效量的权利要求1，2或3中所定义的化合物。
5、根据权利要求4的组合物，其中的活性成分是权利要求3中定义的化合物。
6、根据权利要求4或5的组合物，其中给人服用的单位剂量是约1mg至100mg活性化合物。
7、权利要求1，2或3中定义的化合物是以放射性标记形式。
8、根据权利要求7的化合物，其中标记是3H或14C。
9、一种用于在脑中与大麻素受体结合的组合物，含有有效量的权利要求1，2或3之任一项中所定义的化合物。
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| CN93121715A Pending CN1097735A (zh) | 1992-11-30 | 1993-11-30 | 脂肪酸衍生物和含有脂肪酸衍生物的药物组合物 |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0670826B1 (zh) |
| JP (1) | JPH08504195A (zh) |
| CN (1) | CN1097735A (zh) |
| AU (1) | AU5733494A (zh) |
| CZ (1) | CZ136195A3 (zh) |
| DE (1) | DE69328492T2 (zh) |
| ES (1) | ES2145118T3 (zh) |
| HU (1) | HUT73177A (zh) |
| IL (1) | IL103932A (zh) |
| PL (1) | PL309051A1 (zh) |
| SK (1) | SK70895A3 (zh) |
| WO (1) | WO1994012466A1 (zh) |
| ZA (1) | ZA938947B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103877100A (zh) * | 2013-05-21 | 2014-06-25 | 成都旗美生物科技有限公司 | 亚麻酸酰基乙醇胺的联合医用和保健用药物 |
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|---|---|---|---|---|
| EP0777415A4 (en) * | 1994-07-11 | 1999-06-16 | David W Pate | COMPOSITIONS CONTAINING AN ANANDAMIDE ANALOG AND METHOD FOR TREATING INCREASED EYE PRESSURE USING IT |
| US5631297A (en) * | 1994-07-11 | 1997-05-20 | Pate; David W. | Anandamides useful for the treatment of intraocular hypertension, ophthalmic compositions containing the same and methods of use of the same |
| IT1271267B (it) * | 1994-12-14 | 1997-05-27 | Valle Francesco Della | Ammidi di acidi mono e bicarbossilici con amminoalcoli,selettivamente attive sul recettore periferico dei cannabinoidi |
| DE19544635A1 (de) * | 1995-11-30 | 1997-06-05 | Boehringer Mannheim Gmbh | Neue Aminoalkoholderivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
| DE19706903A1 (de) * | 1997-02-21 | 1998-08-27 | Bayer Ag | Verwendung von bekannten Agonisten des zentralen Cannabinoid-Rezeptors CB 1 |
| AU765670B2 (en) | 1998-04-03 | 2003-09-25 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Synthetic endogenous cannabinoids analogues and uses thereof |
| EP1645270B1 (en) * | 1998-05-29 | 2010-04-28 | Neurosciences Research Foundation Inc. | Control of pain with ANANDAMIDE |
| US7589220B2 (en) | 1998-06-09 | 2009-09-15 | University Of Connecticut | Inhibitors of the anandamide transporter |
| US7897598B2 (en) | 1998-06-09 | 2011-03-01 | Alexandros Makriyannis | Inhibitors of the anandamide transporter |
| AU5198199A (en) * | 1998-08-17 | 2000-03-06 | Senju Pharmaceutical Co., Ltd. | Preventives/remedies for glaucoma |
| AU1833600A (en) * | 1998-11-24 | 2000-06-19 | Andreas Goutopoulos | Cannabimimetic lipid amides as useful medications |
| US7161016B1 (en) | 1998-11-24 | 2007-01-09 | University Of Connecticut | Cannabimimetic lipid amides as useful medications |
| US7276613B1 (en) | 1998-11-24 | 2007-10-02 | University Of Connecticut | Retro-anandamides, high affinity and stability cannabinoid receptor ligands |
| GB9923738D0 (en) | 1999-10-07 | 1999-12-08 | Nestle Sa | Nutritional composition |
| US7119108B1 (en) | 1999-10-18 | 2006-10-10 | University Of Connecticut | Pyrazole derivatives as cannabinoid receptor antagonists |
| US6974568B2 (en) | 2000-05-23 | 2005-12-13 | The Regents Of The University Of California | Treatment for cough |
| NO20006008L (no) * | 2000-11-28 | 2002-05-29 | Thia Medica As | Fettsyreanaloger for behandling av inflammatoriske og autoimmune sykdommer |
| US8449908B2 (en) | 2000-12-22 | 2013-05-28 | Alltranz, Llc | Transdermal delivery of cannabidiol |
| JP2004526745A (ja) | 2001-03-27 | 2004-09-02 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 体脂肪を減らし脂肪酸の代謝を変調する方法、化合物および組成物 |
| WO2003008632A1 (en) * | 2001-07-16 | 2003-01-30 | Hoegestaett Edward | Fatty acid conjugation as a method for screening of potentially bioactive substances |
| CA2478338A1 (en) | 2002-03-08 | 2003-09-18 | Signal Pharmaceuticals, Inc. | Combination therapy for treating, preventing or managing proliferative disorders and cancers |
| JP2006517194A (ja) | 2002-06-06 | 2006-07-20 | イッサム リサーチ ディベロップメント カンパニー オブ ザ ヘブリュー ユニバーシティ オブ エルサレム | 骨成長を調節するための方法、組成物および製造物 |
| ITMI20030210A1 (it) * | 2003-02-07 | 2004-08-08 | Res & Innovation Soc Coop A R L | Composti endocannabinoido-simili e loro impiego |
| US7276608B2 (en) | 2003-07-11 | 2007-10-02 | Bristol-Myers Squibb Company | Tetrahydroquinoline derivatives as cannabinoid receptor modulators |
| US7326706B2 (en) | 2003-08-15 | 2008-02-05 | Bristol-Myers Squibb Company | Pyrazine modulators of cannabinoid receptors |
| IL160420A0 (en) | 2004-02-16 | 2004-07-25 | Yissum Res Dev Co | Treating or preventing diabetes with cannabidiol |
| JP2009538827A (ja) * | 2006-05-01 | 2009-11-12 | イースタン バージニア メディカル スクール | カンナビノイドおよび使用方法 |
| US20080175902A1 (en) * | 2006-11-30 | 2008-07-24 | University Of Plymouth | Methods for slowing the progression of multiple sclerosis |
| WO2009018389A1 (en) | 2007-07-30 | 2009-02-05 | Alltranz Inc. | Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same |
| WO2009109973A2 (en) * | 2008-03-04 | 2009-09-11 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Compounds and methods of treating obesity |
| WO2010013240A1 (en) | 2008-07-31 | 2010-02-04 | Dekel Pharmaceuticals Ltd. | Compositions and methods for treating inflammatory disorders |
| JP5796909B2 (ja) * | 2009-11-25 | 2015-10-21 | サイトメティックス、インコーポレイテッド | アラキドン酸類縁体、及びそれによる鎮痛治療 |
| AU2020260090C9 (en) * | 2019-04-15 | 2023-08-31 | Metagenics LLC | Novel hemp and PEA formulation and its use |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE306730B (zh) * | 1963-02-06 | 1968-12-09 | Sumitomo Chemical Co | |
| SE353319B (zh) * | 1964-08-15 | 1973-01-29 | Sumitomo Chemical Co | |
| US4619938A (en) * | 1984-03-21 | 1986-10-28 | Terumo Kabushiki Kaisha | Fatty acid derivatives of aminoalkyl nicotinic acid esters and platelet aggregation inhibitors |
| NZ216751A (en) * | 1985-07-05 | 1990-01-29 | Cird | Eicosatriynoic acid esters and amides,pharmaceutical compositions and process for preparing eicosatriynoic acid |
-
1992
- 1992-11-30 IL IL10393292A patent/IL103932A/xx not_active IP Right Cessation
-
1993
- 1993-11-30 ZA ZA938947A patent/ZA938947B/xx unknown
- 1993-11-30 JP JP6513466A patent/JPH08504195A/ja active Pending
- 1993-11-30 CN CN93121715A patent/CN1097735A/zh active Pending
- 1993-11-30 CZ CZ951361A patent/CZ136195A3/cs unknown
- 1993-11-30 SK SK708-95A patent/SK70895A3/sk unknown
- 1993-11-30 PL PL93309051A patent/PL309051A1/xx unknown
- 1993-11-30 ES ES94903364T patent/ES2145118T3/es not_active Expired - Lifetime
- 1993-11-30 AU AU57334/94A patent/AU5733494A/en not_active Abandoned
- 1993-11-30 EP EP94903364A patent/EP0670826B1/en not_active Expired - Lifetime
- 1993-11-30 DE DE69328492T patent/DE69328492T2/de not_active Expired - Fee Related
- 1993-11-30 WO PCT/US1993/011625 patent/WO1994012466A1/en active IP Right Grant
- 1993-11-30 HU HU9501561A patent/HUT73177A/hu unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103877100A (zh) * | 2013-05-21 | 2014-06-25 | 成都旗美生物科技有限公司 | 亚麻酸酰基乙醇胺的联合医用和保健用药物 |
| CN103877100B (zh) * | 2013-05-21 | 2016-08-10 | 成都旗美健康食品有限公司 | 亚麻酸酰基乙醇胺的联合医用和保健用药物 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5733494A (en) | 1994-06-22 |
| WO1994012466A1 (en) | 1994-06-09 |
| PL309051A1 (en) | 1995-09-18 |
| JPH08504195A (ja) | 1996-05-07 |
| DE69328492D1 (de) | 2000-05-31 |
| ZA938947B (en) | 1994-08-02 |
| EP0670826A4 (en) | 1996-08-14 |
| ES2145118T3 (es) | 2000-07-01 |
| HUT73177A (en) | 1996-06-28 |
| SK70895A3 (en) | 1995-09-13 |
| EP0670826B1 (en) | 2000-04-26 |
| IL103932A0 (en) | 1993-04-04 |
| DE69328492T2 (de) | 2000-09-07 |
| CZ136195A3 (en) | 1995-11-15 |
| EP0670826A1 (en) | 1995-09-13 |
| IL103932A (en) | 1997-02-18 |
| HU9501561D0 (en) | 1995-07-28 |
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