CN101326156A - 二苯基脲衍生物 - Google Patents
二苯基脲衍生物 Download PDFInfo
- Publication number
- CN101326156A CN101326156A CNA2006800466448A CN200680046644A CN101326156A CN 101326156 A CN101326156 A CN 101326156A CN A2006800466448 A CNA2006800466448 A CN A2006800466448A CN 200680046644 A CN200680046644 A CN 200680046644A CN 101326156 A CN101326156 A CN 101326156A
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- Prior art keywords
- compound
- trifluoromethyl
- treatment
- pharmaceutical composition
- anaerobic gram
- Prior art date
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- GWEHVDNNLFDJLR-UHFFFAOYSA-N 1,3-diphenylurea Chemical class C=1C=CC=CC=1NC(=O)NC1=CC=CC=C1 GWEHVDNNLFDJLR-UHFFFAOYSA-N 0.000 title description 2
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- DOSNEYGVIOOHLN-UHFFFAOYSA-N 1-[3-bromo-5-(trifluoromethyl)phenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound FC(F)(F)C1=CC(Br)=CC(NC(=O)NC=2C=C(C(Cl)=CC=2)C(F)(F)F)=C1 DOSNEYGVIOOHLN-UHFFFAOYSA-N 0.000 claims description 3
- GMQBWHLZFNAKSO-UHFFFAOYSA-N 1-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound FC(F)(F)C1=CC(Cl)=CC(NC(=O)NC=2C=C(C(Cl)=CC=2)C(F)(F)F)=C1 GMQBWHLZFNAKSO-UHFFFAOYSA-N 0.000 claims description 3
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- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OVENUGPMQDFGLE-UHFFFAOYSA-N 3-chloro-5-(trifluoromethyl)aniline Chemical compound NC1=CC(Cl)=CC(C(F)(F)F)=C1 OVENUGPMQDFGLE-UHFFFAOYSA-N 0.000 description 1
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
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- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Ophthalmology & Optometry (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Materials For Medical Uses (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及新的特别由三氟甲基和卤素取代的1，3－二苯基脲，以及它们在药物组合物的制备中作为活性成分的用途。本发明还涉及该化合物制备方法、含一种或多种所述化合物的药物组合物，并特别涉及它们作为抗感染药物的用途。
Description
本发明涉及其中苯基环特别由三氟甲基和卤素取代的新的1，3-二苯基脲，还涉及包含该化合物的药物组合物，并涉及该化合物在治疗和/或预防细菌感染中的用途。
在现有技术中，某些1，3-二苯基脲由于其杀虫特性(美国专利说明书US 2745874)或针对昆虫、真菌和寄生植物的一般杀灭活性(英国专利说明书GB 1 326 481)申请了专利保护。在一个实例中，1，3-二苯基脲的杀虫特性侧面显示出可能的杀菌作用，例如已描述的抗金黄色葡萄球菌(S.aureus)和杀菌活性(美国专利说明书US2745874)。此外，某些1，3-二苯基脲已经被描述成RNA-聚合酶细菌的抑制剂，且该特性通常转化为抗有氧革兰氏阳性和革兰氏阴性病原体的抗菌活性申请了专利保护，例如，抗金黄色葡萄球菌(S.aureus)和大肠细菌(TolC)(WO 01/51456)。
已经发现一小组新的具有独立的卤素/三氟甲基取代的1，3-二苯基脲特别的抗细菌活性，且几乎没有抗真菌的活性，而且这些新的1，3-二苯基脲抗大量的有氧和无氧革兰氏阳性病原体非常有效，包括，尤其是多抗药的葡萄球菌，例如金黄色葡萄球菌(S.aureus)和表皮葡萄球菌(S.epidermidis)、肠道球菌，例如粪肠球菌(E.faecalis)、链球菌，例如肺炎链球菌(S.pneumoniae)、化脓性链球菌(S.pyogenes)、草绿色链球菌(S.viridans)。这些特性使得这些化合物可以很好的用于治疗人类和动物的革兰氏阳性细菌感染，和/或这些病原体在非集群位置上寄生，和/或预防在集群位置上细菌的传播和可能引起的细菌感染。本发明优选的应用是有关的局部/定位治疗人类和动物感染，以及任何非集群和/或预防任何集群位置上杀灭细菌，或该位置上的细菌接种量减少到防止细菌传播到其他位置和引起感染。这些应用的实例是治疗皮肤、粘膜、眼睛、牙齿、胃肠道和上呼吸道感染，非集群和/或预防细菌集群，特别是皮肤、眼睛、鼻孔、口腔、粘膜、胃肠道、上呼吸道、假肢器官和表面，通常细菌可以在那里存活并复制，例如在外科实施以前和/或通常在任何情况下非集群和/或预防细菌(该细菌可以传染和移植)蔓延到其他位置是必须的。
因此，本发明涉及通式I的新型化合物
式I
其中
R1和R2独立地表示氯和溴；
X表示氧或硫；
及其药学上可接受的盐。
优选的式I化合物中R2表示氯。
另外优选的化合物中X表示氧。
本发明最优选的化合物是：
1-(3-氯-5-三氟甲基-苯基)-3-(4-氯-3-三氟甲基-苯基)-脲，
1-(3-溴-5-三氟甲基-苯基)-3-(4-氯-3-三氟甲基-苯基)-脲，
及其药学上可接受的盐。
“药学上可接受的盐”包括与强碱的盐，例如强碱或碱土碱，如氢氧化钠、氢氧化钾、氢氧化钙等，或者例如胆碱等。
由于本发明的化合物抑制有氧和无氧的革兰氏阳性细菌的能力，因此可以用于治疗人类和动物的疾病，该疾病一般与一种或多种该病原体有关，和/或非集群和/或预防一种或多种该类细菌的集群。这使得本发明的化合物成为重要的抗菌剂。
所述的化合物可以按本领域熟知的途径给药，例如，包括口服、静脉、局部、直肠给药、阴道给药、舌下给药，通过吸入或任何局部投药，该位置取决于作为传播或感染因子的细菌的定位。
应用实例包括胶囊、片剂、口服悬浮液或溶剂、栓剂、注射液、滴眼液、膏剂、气雾剂/喷雾剂或表面/局部给药形式。局部形式的实例以及适合于局部投药的形式可以有，特别是凝胶剂、乳膏、膏剂、糊剂、药水、溶液、/喷雾剂、锭剂、片剂、胶囊、粉、悬浮液、栓剂、胚珠(ovules)、涂料(lacquers)、胶粘剂等，其取决于打算治疗和/或到达和/或保护的集群，例如皮肤、粘膜、眼睛、耳朵、口腔、鼻孔、胃肠道部分、上呼吸道部分、假肢器官。
该描述的化合物还可以并入胶粘剂和/或一部分假肢器官中，其可以释放以阻止细菌集群。
优选的应用是口服、局部和滴眼液。
使用的剂量取决于特效活性成分的类型、人类或动物、给药方式，如果用于人类，还取决于年龄和患者的条件。通常每天剂量在0.01～50mg/kg体重，可以一次或每天分2-4剂服用。对于液体或半凝固制剂，例如溶液、膏剂、凝胶剂或乳膏，制剂适当的量是活性成分和赋形剂之间的比例为0.01％～5％。该剂量优选应每天等量服用1～4剂。通常，儿童应当接收适应于他们的体重和年龄的较低剂量。
制备式I的化合物可以包含惰性赋形剂或抗菌活性的赋形剂。片剂和颗粒，例如何以包含大量的粘合剂、填充赋形剂、载体物或稀释剂。
该上述组合物可以是经肠道给药、口服形式或局部形式，例如片剂、糖锭剂、凝胶胶囊、乳剂、溶液、乳膏、膏剂、或悬浮液，经鼻给药形式如喷雾剂、或者栓剂形式的直肠给药形式。这些化合物还可以是非肠道、肌肉注射或静脉形式给药，例如血管注射剂溶液的形式。
这些药物组合物可以包含式I化合物以及它们的药学上可接受的盐与制药工业中常见的无机和/或有机赋形剂，例如乳糖、玉米或其衍生物、硬脂酸或这些材料的盐的组合。
对于胶囊剂而言，可以使用植物油、蜡、脂肪、液体或半液体多元醇等。对于溶液和糖浆制剂而言，使用例如水、多元醇、蔗糖、葡萄糖等。血管注射剂是使用例如水、多元醇、醇、甘油、植物油、卵磷脂、脂质体等来制备的。栓剂是使用天然或氢化的油、蜡、脂肪酸(脂肪)、液体或半液体醇来制备的。用于表面和/或局部应用的乳膏、凝胶剂、膏剂等是使用例如多元醇、油剂、洗涤剂、渗透增强剂、填充剂等根据本领域熟练的技术人员所熟知的方法来制备。
该组合物另外还可包含防腐剂、稳定性改性剂、粘度改善剂或调节剂、溶解度改善剂、甜味剂、染料、味道改善剂、用于改变该渗透压的盐、缓冲剂、抗氧化剂等。
通式1的化合物还与一种或多种其他有疗效的物质组合使用，例如与其他抗感染类试剂来增强/补充其抗感染作用的范围，例如青霉素和头孢菌素、糖肽、喹诺酮、四环素、氨基糖苷类、大环内酯、磺酰胺等，或抗真菌药、抗原生动物(antiprotozals)等。
该发明的化合物还可以并入清洁剂和/或洗涤液和/或敷料和/或涂层和/或漆层和/或胶粘剂和/或一部分假肢器官用于非集群和/或预防细菌集群，在该位置上细菌可以存活最终复制并引起潜在的感染危险。
式I的化合物通常可以通过下述的流程1进行合成：4-卤素-5-(三氟甲基)-异氰酸苯酯或相应的苯基-硫基异氰酸酯(IIa)与3-卤素-5-三氟甲基-苯胺(IIIa)(参考实验部分)。另外，4-卤素-5-(三氟甲基)-苯胺(IIb)与3-卤素-5-(三氟甲基)-异氰酸苯酯或3-卤素-5-(三氟甲基)-苯基-硫基异氰酸酯(IIIb)合成得到通式I的衍生物。
流程1：
实施例
缩写：
DMF：N，N-二甲基甲酰胺
DMSO：二甲基亚砜
EtOAc：乙酸乙酯
MS：质谱
NMR：核磁共振谱
TBME：叔丁基甲基醚
THF：四氢呋喃
环己烷：环己烷
sat.：饱和的
rt：室温
r.m.：反应混合物
实施例1
1-(3-溴-5-三氟甲基-苯基)-3-(4-氯-3-三氟甲基-苯基)-脲
在室温下，向3-溴-5-三氟甲基-苯胺(743μl，5.25mmol、1.05eq.)的干燥二氯甲烷(20ml)溶液中加入4-氯-3-(三氟甲基)-异氰酸苯酯(1.11g，5.0mmol)并搅拌一整夜。然后将反应混合物浓缩至原来体积的约1/3，并滤出沉淀物。在TBME/环己烷重结晶得到772mg白色粉末的纯净产物(33％)。
MS(ES-)：460.8
实施例2
1-(3-氯-5-三氟甲基-苯基)-3-(4-氯基-3-三氟甲基-苯基)-脲
向3-氯-5-三氟甲基-苯胺(425μl，3.1mmol、1.03eq.)的干燥THF(15ml)溶液中加入4-氯-3-(三氟甲基)-异氰酸苯酯(665mg，3.0mmol)。在室温下搅拌一整夜后，用环己烷(100ml)稀释混合物，用2N HCl洗涤两次，用饱和的NaHCO3和盐水(各100ml)洗涤1次，并在真空中吸附于硅藻土上。在二氧化硅和环己烷/TBME(4∶1～2∶1)上层析纯化得到952mg白色粉末的产物(76％)。
1H NMR(DMSO)δ9.43(s，2H)，8.10(d，J＝2.5Hz，1H)，7.84(m，2H)，7.69(dd，J＝9.0，2.5Hz，1H)，7.64(d，J＝9.0Hz，1H)，7.45(s).MS(ES-)：414.9。
实施例3
1-(3-溴-5-三氟甲基-苯基)-3-(4-氯-3-三氟甲基-苯基)-硫脲
根据实施例2使用的步骤，用3-溴-5-(三氟甲基)-苯胺和4-氯-3-(三氟甲基)-异硫氰酸苯酯合成标题化合物。产量：86mg(36％)。
MS(ES-)：474.8，476.8。
实施例4
生物结果
根据临床和实验室标准协会(CLSI)进行抗菌敏感性测试。
临床和实验室标准协会(CLSI；从前是NCCLS)：针对有氧成长细菌的稀释抗菌敏感性测试方法；许可标准-第七版(2006)。临床和实验室标准协会文件M7-A7。
根据CLSI的方法测试链球菌(肺炎链球菌、化脓性链球菌、草绿色链球菌)但Todd Hewitt Broth中没有使用血液。根据CLSI(从前是NCCLS)指南测试厌氧菌(痤疮丙酸杆菌P.acnes、吉氏类杆菌B.distasonis)但在WilkinsChalgren Broth中使用microbroth稀释。美国国家实验室安全委员会(NCCLS)。厌氧菌的抗菌敏感性测试方法；许可标准-第六版(2004)。NCCLS文件M11-A6。
A)化合物抗代表性病原体鼻集群的抗菌活性实验(最低抑菌浓度(MIC)微克/毫升)
| 实施例 | 金黄色葡萄球菌ATCC 25923 | 金黄色葡萄球菌MRSA 101 | 金黄色葡萄球菌MRSA 39 | 表皮葡萄球菌MRSE 70 |
| 1 | 0.5 | 0.125 | 0.25 | 0.25 |
| 2 | 0.25 | 0.125 | 0.25 | 0.25 |
| 3 | 0.125 | 0.5 | 0.25 | 0.25 |
B)化合物抗代表性病原体眼睛感染的抗菌活性实验(最低抑菌浓度(MIC)微克/毫升)
| 实施例 | 金黄色葡萄球菌25923 | 金黄色葡萄球菌MRSA 101 | 金黄色葡萄球菌MRSA 39 | 表皮葡萄球菌MRSE 70 | 肺炎链球菌1/1 | 化脓性链球菌GAS-1 |
| 1 | 0.5 | 0.125 | 0.25 | 0.25 | 0.125 | 0.25 |
| 2 | 0.25 | 0.125 | 0.25 | 0.25 | 0.06 | 0.25 |
| 3 | 0.125 | 0.5 | 0.25 | 0.25 | 0.25 | 0.25 |
C)化合物抗代表性病原体皮肤感染的抗菌活性实验(最低抑菌浓度(MIC)微克/毫升)
| 实施例 | 金黄色葡萄球菌MRSA 39 | 表皮葡萄球菌MRSE 70 | 化脓性链球菌GAS-1 | 粪肠球菌VanB E80-8 | 痤疮丙酸杆菌6390 |
| 1 | 0.25 | 0.25 | 0.25 | 2 | ≤0.03 |
| 2 | 0.25 | 0.25 | 0.25 | 1 | ≤0.03 |
| 3 | 0.25 | 0.25 | 0.25 | 1 | ≤0.03 |
D)化合物抗代表性病原体胃肠*或牙齿**感染的抗菌活性实验(最低抑菌浓度(MIC)微克/毫升)
| 实施例 | 粪肠球菌*VanB E80-8 | 吉氏类杆菌*5770 | 草绿色链球菌**UHC 7 |
| 1 | 2 | 0.5 | 0.5 |
| 2 | 1 | 1 | 0.5 |
| 3 | 1 | 1 | 1 |
Claims (14)
1、通式I的化合物
式I
其中
R1和R2独立地表示氯和溴；
X表示氧或硫；
及其药学上可接受的盐。
2、根据权利要求1的式I的化合物，其中R2表示氯。
3、根据权利要求1或2的化合物，其中X表示氧。
4、根据权利要求1～3任一项的化合物
1-(3-氯-5-三氟甲基-苯基)-3-(4-氯-3-三氟甲基-苯基)-脲，
1-(3-溴-5-三氟甲基-苯基)-3-(4-氯-3-三氟甲基-苯基)-脲，
及其药学上可接受的盐。
5、用于治疗感染的药物组合物，包含如权利要求1～4任一项所述的化合物以及常见的载体材料和辅助剂。
6、用于治疗由有氧和无氧革兰氏阳性和无氧革兰氏阴性病原体感染的药物组合物，包含如权利要求1～4任一项所述的化合物以及常见的载体材料和辅助剂。
7、如权利要求1～4任一项所述的化合物用作药物治疗感染的用途。
8、如权利要求1～4任一项所述的化合物用作药物治疗由有氧和无氧革兰氏阳性和无氧革兰氏阴性病原体感染的用途。
9、如权利要求1～4任一项所述的一种或多种化合物作为活性成分来制备用于治疗感染的药物组合物的用途。
10、如权利要求1～4任一项所述的一种或多种化合物作为活性成分来制备用于治疗由有氧和无氧革兰氏阳性和无氧革兰氏阴性病原体感染的药物组合物的用途。
11、如权利要求1～4任一项所述的一种或多种化合物作为活性成分用于治疗细菌引起的鼻、眼睛、牙齿、胃肠或皮肤感染的用途。
12、如权利要求1～4任一项所述的一种或多种化合物作为活性成分来制备药物组合物的用途，该药物组合物用于杀菌、卫生、抗菌、消毒、非集群或预防皮肤、胃肠道或鼻、眼睛或牙齿部位或任何类型的假肢器官的集群。
13、用于制备治疗感染的药物组合物的方法，该组合物包含一种或多种如权利要求1～4任一项所述的化合物作为活性成分，该方法包括一种或多种活性成分与药学上可接受的赋形剂使用本身已知的方式混合。
14、用于制备治疗由有氧和无氧革兰氏阳性和无氧革兰氏阴性病原体感染的药物组合物的方法，该组合物包含一种或多种如权利要求1～4任一项所述的化合物作为活性成分，该方法包括一种或多种活性成分与药学上可接受的赋形剂使用本身已知的方式混合。
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| US2745874A (en) * | 1953-06-18 | 1956-05-15 | Geigy Ag J R | Insecticidal derivatives of diphenyl urea |
| CH431491A (de) * | 1962-04-05 | 1967-03-15 | Ciba Geigy | Verfahren zur Herstellung neuer Thiocarbanilide |
| SE370866B (zh) * | 1968-03-21 | 1974-11-04 | Ciba Geigy Ag | |
| CH533421A (de) * | 1970-02-02 | 1973-02-15 | Ciba Geigy Ag | Biozides Mittel |
| EP0318431B1 (de) * | 1987-11-24 | 1993-03-03 | Ciba-Geigy Ag | Motten- und Käferschutzmittel |
| EP1140840B1 (en) * | 1999-01-13 | 2006-03-22 | Bayer Pharmaceuticals Corp. | -g(v)-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| WO2001051456A2 (en) * | 2000-01-13 | 2001-07-19 | Tularik Inc. | Antibacterial agents |
-
2006
- 2006-12-08 CA CA002632925A patent/CA2632925A1/en not_active Abandoned
- 2006-12-08 BR BRPI0619793A patent/BRPI0619793A2/pt not_active IP Right Cessation
- 2006-12-08 CN CNA2006800466541A patent/CN101326157A/zh active Pending
- 2006-12-08 KR KR1020087016948A patent/KR20080080176A/ko not_active Withdrawn
- 2006-12-08 AU AU2006326354A patent/AU2006326354A1/en not_active Abandoned
- 2006-12-08 BR BRPI0619783A patent/BRPI0619783A2/pt not_active IP Right Cessation
- 2006-12-08 CA CA002632930A patent/CA2632930A1/en not_active Abandoned
- 2006-12-08 JP JP2008544826A patent/JP2009519269A/ja active Pending
- 2006-12-08 AU AU2006326355A patent/AU2006326355A1/en not_active Abandoned
- 2006-12-08 WO PCT/EP2006/011794 patent/WO2007068394A2/en active Application Filing
- 2006-12-08 US US12/097,191 patent/US20090023813A1/en not_active Abandoned
- 2006-12-08 JP JP2008544825A patent/JP2009519268A/ja active Pending
- 2006-12-08 CN CNA2006800466448A patent/CN101326156A/zh active Pending
- 2006-12-08 US US12/096,831 patent/US7696249B2/en not_active Expired - Fee Related
- 2006-12-08 KR KR1020087016947A patent/KR20080086502A/ko not_active Withdrawn
- 2006-12-08 WO PCT/EP2006/011795 patent/WO2007068395A1/en active Application Filing
- 2006-12-08 RU RU2008128365/04A patent/RU2008128365A/ru not_active Application Discontinuation
- 2006-12-08 RU RU2008128350/04A patent/RU2008128350A/ru not_active Application Discontinuation
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2008
- 2008-06-11 IL IL192060A patent/IL192060A0/en unknown
- 2008-06-11 IL IL192061A patent/IL192061A0/en unknown
- 2008-06-12 ZA ZA200805167A patent/ZA200805167B/xx unknown
- 2008-06-12 ZA ZA2008/05166A patent/ZA200805166B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| KR20080080176A (ko) | 2008-09-02 |
| BRPI0619783A2 (pt) | 2016-11-16 |
| ZA200805167B (en) | 2010-08-25 |
| RU2008128365A (ru) | 2010-01-20 |
| KR20080086502A (ko) | 2008-09-25 |
| AU2006326354A1 (en) | 2007-06-21 |
| US20090005452A1 (en) | 2009-01-01 |
| IL192061A0 (en) | 2008-12-29 |
| WO2007068395A1 (en) | 2007-06-21 |
| IL192060A0 (en) | 2009-02-11 |
| WO2007068394A8 (en) | 2008-09-25 |
| BRPI0619793A2 (pt) | 2016-08-23 |
| WO2007068394A3 (en) | 2007-08-02 |
| CN101326157A (zh) | 2008-12-17 |
| ZA200805166B (en) | 2011-10-26 |
| CA2632925A1 (en) | 2007-06-21 |
| US7696249B2 (en) | 2010-04-13 |
| JP2009519269A (ja) | 2009-05-14 |
| AU2006326355A1 (en) | 2007-06-21 |
| JP2009519268A (ja) | 2009-05-14 |
| WO2007068394A2 (en) | 2007-06-21 |
| CA2632930A1 (en) | 2007-06-21 |
| AU2006326354A8 (en) | 2008-12-18 |
| RU2008128350A (ru) | 2010-01-20 |
| US20090023813A1 (en) | 2009-01-22 |
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