CN1394204A - 二苯并[b,f]吖庚因中间体 - Google Patents
二苯并[b,f]吖庚因中间体 Download PDFInfo
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- 239000000543 intermediate Substances 0.000 title abstract 3
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 title description 3
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 title 1
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- 229910052751 metal Inorganic materials 0.000 claims description 7
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- -1 methoxyl group Chemical group 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
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- PWMWNFMRSKOCEY-UHFFFAOYSA-N 1-Phenyl-1,2-ethanediol Chemical compound OCC(O)C1=CC=CC=C1 PWMWNFMRSKOCEY-UHFFFAOYSA-N 0.000 description 1
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
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- 229940043279 diisopropylamine Drugs 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 229940061414 trileptal Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
- C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
- C07D223/26—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a double bond between positions 10 and 11
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
- C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
- C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
- C07D223/28—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a single bond between positions 10 and 11
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- Organic Chemistry (AREA)
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Epoxy Compounds (AREA)
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明涉及制备药用卡巴西亚肟的新方法，以及由所述方法制备或用于所述方法中的新中间体(I)、(V)、(VI)、(VII)、(IX)，以及所述中间体的制备方法，其中R1、R3、R4＝C1－4烷基，R2＝C1－4烷基或苯基。
Description
本发明涉及新的二苯并[b，f]吖庚因衍生物和其制备方法。本发明的化合物用作用于制备药物的中间体。
更具体地，本发明提供了式I的化合物其中，R1为(C1-4)烷基和R2为(C1-4)烷基或苯基。
式I的化合物可用作式IV(见下面)的药物卡巴西亚肟(Trileptal)的原料，所述药物用作抗惊厥剂，如用于治疗癫痫症。
卡巴西亚肟可按照下述反应路线由式I的化合物制得：
反应a、b和c可按照公知方法进行，例如在实施例的步骤f-h中所述的方法。
另一方面，本发明提供了一种式I化合物的制备方法，使式V的化合物与式R1OH或(R1O)3CH反应，
其中，R2如前定义，R1如前定义。
该反应可以公知方式进行，例如，在实施例的步骤d、d′和d″中所述的方法。
式V的化合物在现有文献中从未描述过，它们也是本发明的一部分，其制备方法也是如此。
按照本发明，式V的化合物可通过使式VI或VII的化合物进行闭环制得其中，R2如前定义，R3和R4彼此独立地为(C1-4)烷基。
式VI化合物的闭环反应适宜在酸性条件下进行，例如，实施例的步骤c2中所述。如果制备式V的化合物用于制备式I的化合物，优选不进行分离而就地反应形成式I化合物，如实施例的步骤e所述。
令人惊奇地发现，该环化反应导致生成式V的化合物，不会通过-COOR2的断裂而形成式VIII的5元环内酰胺
如下述文献所预期的那样：J.W.Schulenberg等，J.Amer.Chem.Soc.82，2035(1960)，考虑到-COOR2基团的吸电子特性。
式VII化合物的闭环反应适宜地在强碱性条件下进行，如实施例的步骤c1中所述。
式VI的化合物及式VII的化合物(其中，当R3和R4均为异丙基时，R2不为叔丁基)也是新的和本发明的一部分，其制备方法也是如此。
按照本发明，式VI的化合物可通过使式VIII的化合物在强碱条件下与式X-COOR2反应制备，R2如前定义，X为氯或甲氧基。反应可以常规方式进行，如实施例的步骤a2所述。
根据本发明，式VII的化合物可通过使式IX的化合物与式Cl-COOR2的化合物反应获得，其中，R3和R4如前定义，R2如前定义，但当R3和R4均为异丙基时，R2不为叔丁基。该反应可以常规方式进行，如实施例步骤b所述。
式IX的化合物也是新的和本发明的一部分。它们可通过使式X的化合物与式R3-NH-R4的化合物反应获得，R3和R4如前定义，所述反应以常规方式进行，如实施例步骤a1所述。
式VIII和X的原料为已知原料。
另一方面，本发明提供了通过使式II的化合物进行氨基甲酰化反应来生产式III化合物的改进方法，式II化合物(其中，R为甲基)的氨基甲酰化反应在WO96/21649中有述。按照该文献，采用在无机酸或相对强羧酸和溶剂存在下的金属氰酸盐。
令人惊奇地发现，这种氨基甲酰化反应也可在温和的条件下进行，其中采用乙酸。无需存在强酸和附加的溶剂。考虑到式II化合物相对较低的稳定性，不存在强酸是特别有利的。结果，收率得到显著提高。
本发明提供了一种生产式III化合物的方法，是使式II的化合物用金属氰酸盐进行氨基甲酰化处理，从而该反应采用乙酸进行，存在实质上过量的金属氰酸盐且不存在其它溶剂。
金属氰酸盐优选为氰酸钠或氰酸钾。“实质上过量”的金属氰酸盐是指至少0.2当量，优选0.2-0.5当量。这种过量是与公知的氨基甲酰化方法相比收率得到改善的反应的基本条件。该反应例如在实施例步骤g中所述。
下述实施例用于说明本发明。
实施例a1)
N，N-二甲基-2-邻甲苯基氨基-苯甲酰胺
将2-邻甲苯基氨基-苯甲酸(101g，0.444mol)悬浮于甲苯(800mL)中，并加热至58℃。在20分钟内，向其中加入亚硫酰氯(57.6g，0.484mol，1.1当量)的甲苯(100mL)溶液。将混合物缓慢地加热至82℃(1小时)，进行真空浓缩。将甲苯(800mL)加至蒸发残余物中，再将溶液进行真空浓缩。将粗的酰氯溶解于甲苯(500mL)中，将溶液冷却至3℃。在45分钟内，加入二甲胺(61.3mL，40％水溶液，1.1当量)，氢氧化钠(77g，30％水溶液，1.3当量)和水(240mL)。将获得的悬浮液在3℃下搅拌30分钟，然后升温至30℃。进行相分离，将水相用甲苯萃取(100mL)。合并后的有机相用水(200mL)洗涤两次，蒸发至干，并在真空下脱气1小时(30mbar，60℃)。获得产物，其为一种油，在放置后固化(104.7g，93.5％收率)。最后，将所获得的标题化合物在环己烷中进行重结晶。b)
(2-二甲基氨基甲酰基-苯基)-邻甲苯基氨基甲酸甲酯
将N，N-二甲基-2-邻甲苯基氨基-苯甲酰胺(104.7g，0.412mol，1当量)溶解于甲苯(800mL)中，并将其冷却至-8℃。缓慢地加入正丁基锂的己烷溶液(257mL，1.6M溶液，1当量)，以保持温度低于0℃(1小时)。将获得的有机悬浮液在-8℃下搅拌30分钟，并在30分钟内加入氯代甲酸甲酯(42.8g，1.1当量)。将悬浮液在5℃下搅拌1小时，然后用碳酸氢钠(500mL饱和水溶液)中止反应。进行相分离，水相用甲苯(200mL)萃取。合并后的有机相用水(200mL洗涤两次)，蒸发至干，并在真空下脱气1小时(30mbar，60℃)。在50℃下，将粗产物(133.8g)溶解于乙酸乙酯(240mL)中，并加入己烷(990mL)。再将溶液冷却至25℃(30分钟)，从而开始结晶。将悬浮液在25℃下搅拌1小时，冷却至3℃，再在该温度下搅拌4小时。过滤后，将固体用冷己烷洗涤，真空下干燥16小时(50℃，50mbar)。获得标题化合物，为一种浅黄色固体(98.0g，70.5％总收率，以2-邻甲苯基氨基-苯甲酸计)。c1)
10-氧代-10，11-二氢-二苯并[b，f]吖庚因-5-甲酸甲酯
将二异丙基胺(11.66g，0.115mol，1.2当量)溶解于THF(150mL)中，将溶液冷却至-10℃。缓慢地加入正丁基锂的己烷溶液(72mL，1.6M溶液，1.2当量)，以保持温度低于0℃(40分钟)。在45分钟内向获得的溶液中加入(2-二甲基氨基甲酰基-苯基)-邻甲苯基氨基甲酸甲酯(30.2g，0.096mol，1当量)的THF(80mL)溶液。将反应混合物在-5℃下搅拌1小时，然后通过加入水(30mL)使反应停止。将混合物进行真空浓缩，向油状残余物中加入水(220mL)和乙酸乙酯(220mL)。对两相进行快速搅拌，然后使其分离。将有机相用硫酸(300mL，1M溶液)洗涤，再用水(300mL)洗涤两次。将有机相蒸发至干，得到23.0g(89.5％收率)的标题化合物，为一种橙色油，放置后固化。a2)
[2-(甲氧基羰基-苯基-氨基)-苯基]-乙酸
将1-苯基-1，3-二氢-吲哚-2-酮(80g，382mmol)、氢氧化钠(16.06g，402mmol)和四氢呋喃(113mL)的混合物加热回流(67℃)5小时。将溶液用另一部分四氢呋喃(169mL)稀释，并冷却至-10℃。在该温度下加入20％丁基锂的环己烷溶液(122.3g，382mmol)，再加入碳酸二甲酯(51.7g，573mmol)。此后，再将溶液在-10℃下搅拌2小时。加入浓盐酸(38mL)和水(125mL)，减压蒸出有机溶剂。在向悬浮液中加入甲苯(345mL)后，用盐酸(34mL)将水相的pH值调节至1.5。在75℃下进行相分离后，将有机相用另一部分水(120mL)洗涤，减压浓缩，在0℃下结晶，得到81.2g的纯标题化合物(75％)。d)
10-甲氧基-二苯并[b，f]吖庚因-5-甲酸甲酯
在50℃下，将粗的10-氧代-10，11-二氢-二苯并[b，f]吖庚因-5-甲酸甲酯(22.3g，0.083mol，1当量)溶解于甲醇(112mL)中。加入催化量的对甲苯磺酸(0.445mg)，再加入原甲酸三甲酯(11.5mL，1.25当量)。将混合物反应5小时，然后将甲醇蒸出。新的甲醇连续加入以代替馏出物。当馏出100mL的甲醇时，将混合物在1小时内冷却至25℃。再将悬浮液在20分钟内冷却至3℃，在该温度下搅拌1小时，过滤。将固体用冷的甲醇洗涤，真空下干燥15小时(50℃，50mbar)。获得纯的标题化合物，为一种浅黄色粉末(18.02g，80.8％收率)。c2)
10-氧代-10，11-二氢-二苯并[b，f]吖庚因-5-甲酸甲酯
将[2-(甲氧基羰基-苯基-氨基)-苯基]-乙酸(16g，55.5mmol)和多磷酸(29g，167mmol，以P2O5计)的混合物在100℃下加热4小时。在搅拌和冷却下，向反应混合物中滴加入85-100℃的水(41mL)。在65℃下，加入甲苯(41mL)，将混合物搅拌30分钟。将两相分离，洗涤。将有机相浓缩，在0℃下结晶，得到12g的纯标题化合物(80％)。d′)
10-甲氧基-二苯并[b，f]吖庚因-5-甲酸甲酯
将10-氧代-10，11-二氢-二苯并[b，f]吖庚因-5-甲酸甲酯(15g，56mmol)在甲醇(75mL)中的悬浮液加热至60℃，加入催化量的对甲苯磺酸(0.213g，1.1mmol)。在加入原甲酸三甲酯(6.25g，58.9mmol)后，将溶液在60-70℃下搅拌4小时。在反应过程中，产物沉淀出来，为一种白色结晶。将混合物冷却至室温，过滤和干燥，得到15.5g的纯标题化合物(98％)。d″)
10-乙氧基-二苯并[b，f]吖庚因-5-甲酸甲酯
将10-氧代-10，11-二氢-二苯并[b，f]吖庚因-5-甲酸甲酯(15g，56mmol)在乙醇(75mL)中的悬浮液加热至60℃，加入催化量的对甲苯磺酸(0.213g，1.1mmol)。在加入原甲酸三乙酯(8.73g，58.9mmol)后，将溶液在60-70℃下搅拌4小时。在反应过程中，产物沉淀出来，为一种白色结晶。将混合物冷却至室温，过滤和干燥，得到16.0g的纯标题化合物(97％)。e)
10-甲氧基-二苯并[b，f]吖庚因-5-甲酸甲酯
将[2-(甲氧基羰基-苯基-氨基)-苯基]-乙酸(16g，55.5mmol)和多磷酸(29g，167mmol，以P2O5计)的混合物在100℃下加热4小时。在搅拌下，于65℃向反应混合物中滴加入甲醇(50mL)。将形成的悬浮液冷却至室温，过滤，用甲醇(40mL)洗涤。将白色的结晶干燥，得到12.2g的纯标题化合物(80％)。f)
10-甲氧基-5H-二苯并[b，f]吖庚因
将10-甲氧基-二苯并[b，f]吖庚因-5-甲酸甲酯(19g，67.5mmol)，聚乙二醇200(20mL)和氢氧化钠溶液50％(13mL，246mmol)的混合物在100℃下加热4小时。加入水(30mL)，将悬浮液冷却至20℃，过滤。将滤饼用水洗涤，在60℃/30mbar下干燥，得到14.7g的纯标题化合物(98％)。g)
10-甲氧基-二苯并[b，f]吖庚因-5-甲酰胺
在氮气氛及室温下，将乙酸(150mL)滴加至搅拌中的10-甲氧基-5H-二苯并[b，f]吖庚因(25.0g，112mmol)和NaOCN(9.25g，142mmol)的混合物中。在搅拌7小时后，将形成的标题化合物(由HPLC确定，＞95％区域的化合物)的黄色悬浮液用于合成10-氧代-10，11-二氢-二苯并[b，f]吖庚因-5-甲酰胺。通过加入1N的氢氧化钠以使pH值≥8，再用甲苯进行萃取而分离出标题化合物。将合并后的有机层干燥，真空浓缩，得到标题化合物，为一种浅黄色固体(收率≥75％)。h)
10-氧代-10，11-二氢-二苯并[b，f]吖庚因-5-甲酰胺
向g)中获得的乙酸混合物中加入水(12.5mL，694mmol)和100％的硫酸(约7.5mL，140 mmol)，直至pH值≤1。在搅拌17小时后，加入水(275mL)。将沉淀出的标题化合物过滤，真空干燥(以10-甲氧基-5H-二苯并[b，f]吖庚因计的总收率≥78％)。
Claims (12)
1.一种通过用金属氰酸盐对式II的化合物进行氨基甲酰化处理来制备式III化合物的方法，其中，R1为(C1-4)烷基，
其中R1如前定义，其中该反应采用乙酸，在实质上过量的金属氰酸盐存在下且不存在其它溶剂下进行。
2.一种式V的化合物的制备方法其中，R2为(C1-4)烷基或苯基，该方法包括使式VI的化合物闭环其中，R2如前定义。
3.根据权利要求2的式V化合物的制备方法，该方法包括使式VII的化合物闭环其中，R2如权利要求2定义，R3和R4分别为(C1-4)烷基。
4.根据权利要求2定义的式V的化合物。
5.式I的化合物其中，R1如权利要求1定义，R2如权利要求2定义。
6.如权利要求5定义的式I化合物的制备方法，该方法包括使权利要求2定义的式V化合物与式R1OH或(R1O)3CH的化合物反应，其中，R1如权利要求1定义。
7.式VI的化合物其中，R2如权利要求2定义。
8.如权利要求7定义的式VI化合物的制备方法，该方法包括在强碱性条件下，使式VIII化合物与式X-COOR2的化合物反应，
其中，R2如权利要求2定义，X为氯或甲氧基。
9.式VII的化合物
其中，R2如权利要求2定义，R3和R4如权利要求3定义，条件是，当R3和R4均为异丙基时，R2不为叔丁基。
10.如权利要求9定义的式VII化合物的制备方法，该方法包括使式IX的化合物与式ClCOOR2的化合物反应，其中，R3和R4如权利要求9定义，其中，R2如权利要求2定义，但当R3和R4均为异丙基时，R2不为叔丁基。
11.式IX的化合物
其中，R3和R4如权利要求9定义。
12.如权利要求11定义的式IX化合物的制备方法，该方法包括使式X的化合物与式R3-NH-R4的化合物反应，R3和R4如权利要求9定义。
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| CA2486560A1 (en) | 2002-06-14 | 2003-12-24 | Taro Pharmaceuticals U.S.A., Inc. | Method of preparing a 5h-dibenz[b,f]azepine-5-carboxamide |
| ITMI20040452A1 (it) | 2004-03-09 | 2004-06-09 | Clariant Lsm Italia Spa | Processo per la preparazione di oxcarbazepina |
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| CA2726588C (en) | 2008-06-03 | 2019-04-16 | Karl Kossen | Compounds and methods for treating inflammatory and fibrotic disorders |
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