(9ci)-5-异硫代氰酰基异喹啉 | 62855-11-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 中文名称: (9ci)-5-异硫代氰酰基异喹啉
• 英文名称: 5-isothiocyanatoisoquinoline
• CAS: 62855-11-2
• 化学式: C₁₀H₆N₂S
• 分子量: 186.237
• InChiKey: AMDNKJRTCIBIMK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  57.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (9ci)-5-异硫代氰酰基异喹啉 在 盐酸 、 水 、 sodium hydride 作用下， 以 四氢呋喃 、 甲醇 、 mineral oil 为溶剂， 反应 22.5h， 生成 (±)-trans-O-(4-phenylpyrrolidin-3-yl)isoquinolin-5-ylcarbamothioate
  参考文献：
  名称：

  [EN] HETEROCYCLIC COMPOUNDS FOR MODULATING NR2F6
  [FR] COMPOSÉS HÉTÉROCYCLIQUES POUR LA MODULATION DE NR2F6

  摘要：

  本公开涉及能够调节NR2F6活性的化合物。本公开的化合物可用于预防及/或治疗与调节NR2F6活性相关疾病和障碍的方法。

  公开号：

  WO2021170658A1
• 作为产物：
  描述：

  5-硝基异喹啉 在 palladium 10% on activated carbon 、 四丁基溴化铵 、 氢气 、 sodium carbonate 、 sulfur 作用下， 以 水 为溶剂， 反应 6.0h， 生成 (9ci)-5-异硫代氰酰基异喹啉
  参考文献：
  名称：

  化合物、制备方法及其用途

  摘要：

  本发明涉及药物化学领域，特别涉及化合物、制备方法及其用途。本发明涉及通式Ⅰ所示化合物及其盐，这类化合物为TRPV1拮抗剂，有较好的镇痛作用，本发明还涉及该类化合物的制备方法及含有它们的药物制剂，以及该类化合物和其药用组合物在治疗疼痛中的应用。

  公开号：

  CN105906564B

文献信息

• Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment
  作者：Lukas Hroch、Patrick Guest、Ondrej Benek、Ondrej Soukup、Jana Janockova、Rafael Dolezal、Kamil Kuca、Laura Aitken、Terry K. Smith、Frank Gunn-Moore、Dominykas Zala、Rona R. Ramsay、Kamil Musilek

  DOI：10.1016/j.bmc.2016.12.029

  日期：2017.2

  thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range

  阿尔茨海默氏病（AD）是一种神经退行性疾病，与淀粉样β肽（Aβ）的过度积累有关。基于AD的多因素性质，制备多靶标定向配体提供了一个可行的选择，可以一次解决更多的病理事件。已经设计并合成了新型的不对称双取代的吲哚基硫脲类，以与单胺氧化酶（MAO）和/或淀粉样蛋白结合醇脱氢酶（ABAD）相互作用。该设计结合了已知的MAO抑制剂支架（例如雷沙吉兰或拉多斯吉尔）和具有与ABAD相互作用潜力的芬替唑部分的功能。针对MAO的评估确定了几种在低至中等微摩尔范围内具有抑制作用的化合物。最有前途的化合物（19）抑制人MAO-A和MAO-B的IC 50值分别为6.34μM和0.30μM。ABAD活性评估未显示任何高效化合物，但该化合物系列可用于鉴定结构特征，以协助ABAD抑制剂的未来开发。最后，发现其中的几种化合物是辣根过氧化物酶（HRP）的有效抑制剂，从而阻止了使用Amplex™Red分析法检测MAO产生的
• COMPOUNDS FOR INHIBITING AGC KINASE AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME
  申请人：Industrial Technology Research Institute

  公开号：US20190194137A1

  公开（公告）日：2019-06-27

  A compound of formula (I) or a pharmaceutically acceptable salt thereof is provided. In formula (I), Ar is indazole, 5-isoquinoline, 6-isoquinoline, or their N-oxide. X is —C(═Z)—, wherein Z is N—CN, NH, NR 4 , NCOR 4 , NCONR 4 R 5 , NCO-aryl, S, or O. Y and J are independently H, alkyl, aryl, aminoalkyl, —NH 2 , —CN, —OH, —O-alkyl, —O-aryl, —COOH, —COOR 4 , —CONHR 4 , —CONHCH 2 -aryl, —CONR 4 CH 2 -aryl, —NHCOR 4 , halogen, halogened alkyl, -alkyl-OR 4 , -alkyl-ONO 2 , alkyl-ONO 2 , —OCOOR 4 , —O(C═O)-aryl, —CHR 4 OH, —CH 2 OH, —CH 2 O(C═O)-aryl, —CH 2 O(C═O)—R 4 , —CHR 4 O(C═O)-aryl, —CHR 4 O(C═O)—R 4 , unsaturated carboxylic ester, substituted alkynyl, —NHSO 2 R 4 , —SO 2 R 4 , —SO 2 NHR 4 , or —SO 2 NR 4 R 5 , or Y and J bond together to form a carbocylic or aromatic ring, wherein R 4 and R 5 are independently H, substituted C1-C6 alkyl, substituted aryl, cycloalkyl, alkylaryl, -alkyl-NR 6 R 7 , —S(O) 0-2 -(alkyl-NR 6 R 7 ). R 1 , R 2 and R 3 are H, C1-C6 alkyl, cycloalkyl, aryl, alkylaryl, alkylheteroaryl, alkylheterocycle, wherein any one thereof is optionally substituted with one or more of OH, NO 2 , or NR 8 R 9 .

  提供公式(I)的化合物或其药用盐。在公式(I)中，Ar是吲唑，5-异喹啉，6-异喹啉或它们的N-氧化物。X为—C(═Z)—，其中Z为N—CN，NH，NR4，NCOR4，NCONR4R5，NCO-芳基，S或O。Y和J独立地为H，烷基，芳基，氨基烷基，—NH2，—CN，—OH，—O-烷基，—O-芳基，—COOH，—COOR4，—CONHR4，—CONHCH2-芳基，—CONR4CH2-芳基，—NHCOR4，卤素，卤代烷基，-烷基-OR4，-烷基-ONO2，烷基-ONO2，—OCOOR4，—O(C═O)-芳基，—CHR4OH，—CH2OH，—CH2O(C═O)-芳基，—CH2O(C═O)—R4，—CHR4O(C═O)-芳基，—CHR4O(C═O)—R4，不饱和羧酸酯，取代炔烃基，—NHSO2R4，—SO2R4，—SO2NHR4或—SO2NR4R5，或Y和J结合在一起形成环，其中R4和R5独立地为H，取代的C1-C6烷基，取代的芳基，环烷基，烷基芳基，-烷基-NR6R7，—S(O)0-2-(烷基-NR6R7)。R1，R2和R3为H，C1-C6烷基，环烷基，芳基，烷基芳基，烷基杂芳基，烷基杂环，其中任意一个可以选择地取代一个或多个OH，NO2或NR8R9。
• Thiazolothienopyridines and anti-viral compositions thereof
  申请人：Rhone-Poulenc Industries

  公开号：US04261999A1

  公开（公告）日：1981-04-14

  Thienopyridine derivatives of the formula: ##STR1## wherein the symbol A represents pyrid-3-yl, isoquinol-5-yl, or a 3-alkylisoquinol-5-yl group in which the alkyl radical is of 1 through 10 carbon atoms, and one of the symbols X and Y represents a single bond and the other represents the vinylene radical, are new compounds possessing useful pharmacological properties. They are particularly useful as anti-viral agents and, in certain cases, as analgesics, anti-inflammatory agents and anti-pyretics.

  式子为：##STR1## 的噻唑吡啶衍生物，其中符号A代表吡啶-3-基、异喹啉-5-基或3-烷基异喹啉-5-基，其中烷基基团为1到10个碳原子，符号X和Y中的一个代表单键，另一个代表乙烯基团，是具有有用药理特性的新化合物。它们特别适用于抗病毒剂，并在某些情况下作为镇痛剂，抗炎剂和退热剂。
• Thiazolo[3,4-b]isoquinoline derivatives and pharmaceutical compositions
  申请人：Rhone-Poulenc Industries

  公开号：US04064247A1

  公开（公告）日：1977-12-20

  Thiazolo[3,4-b]isoquinoline derivatives of the general formula: ##STR1## wherein A represents 3-pyridyl, 4-pyridyl or 5-isoquinolyl and, when A represents 3-pyridyl, X.sub.1 represents hydrogen, halogen, dimethylamino or cyano, X.sub.2 represents hydrogen or fluorine and X.sub.3 represents hydrogen or nitro, at least two of X.sub.1, X.sub.2 and X.sub.3 representing hydrogen, or X.sub.1 X.sub.2 together represent methylenedioxy and X.sub.3 represents hydrogen, and when A represents 4-pyridyl or 5-isoquinolyl, X.sub.1, X.sub.2 and X.sub.3 each represent hydrogen, and non-toxic pharmaceutically acceptable acid addition salts thereof, possess useful pharmacodynamic properties, in particular analgesic and antipyretic activity. This invention relates to new therapeutically useful thiazolo[3,4-b]isoquinoline derivatives, to processes for their preparation and to pharmaceutical compositions containing them. The new thiazolo[3,4-b]isoquinoline derivatives of the present invention are those of the general formula: ##STR2## wherein A represents a heterocyclic radical containing one nitrogen atom, selected from 3-pyridyl, 4-pyridyl and 5-isoquinolyl and, when A represents a 3-pyridyl radical, X.sub.1 represents a hydrogen or halogen atom, or a dimethylamino or cyano radical, X.sub.2 represents a hydrogen or fluorine atom and X.sub.3 represents a hydrogen atom or a nitro radical, at least two of X.sub.1, X.sub.2 and X.sub.3 representing hydrogen atoms, or X.sub.1 and X.sub.2 together represent a methylenedioxy radical and X.sub.3 represents a hydrogen atom, and when A represents a 4-pyridyl or 5-isoquinolyl radical X.sub.1, X.sub.2 and X.sub.3 each represent a hydrogen atom, and acid addition salts thereof. The compounds of general formula I can exist in (R)- and (S)- forms and the invention includes both such forms and mixtures thereof. According to a feature of the present invention the thiazolo[3,4-b]isoquinoline derivatives of general formula I are prepared by one of the following processes: 1. Compounds of general formula I wherein A represents a 3-pyridyl or 5-isoquinolyl radical and when A represents a 3-pyridyl radical, X.sub.1 represents a hydrogen or halogen atom, X.sub.2 represents a hydrogen or fluorine atom, X.sub.3 represents a hydrogen atom or a nitro radical, at least two of X.sub.1, X.sub.2 and X.sub.3 representing hydrogen atoms, or X.sub.1 and X.sub.2 together represent a methylenedioxy radical and X.sub.3 represents a hydrogen atom, and when A represents a 5-isoquinolyl radical, X.sub.1, X.sub.2 and X.sub.3 represent hydrogen atoms, are prepared by cyclisation of a 1,2,3,4-tetrahydroisoquinoline derivative of the general formula: ##STR3## wherein A.sub.1 represents a 3-pyridyl or 5-isoquinolyl radical and, when A.sub.1 represents a 3-pyridyl radial, X.sub.4 represents a hydrogen or halogen atom, X.sub.5 represents a hydrogen or fluorine atom, X.sub.6 represents a hydrogen atom or a nitro radical, at least two of X.sub.4, X.sub.5 and X.sub.6 representing hydrogen atoms, or X.sub.4 and X.sub.5 togther represent a methylenedioxy radical and X.sub.6 represents a hydrogen atom, and when A.sub.1 represents a 5-isoquinolyl radical X.sub.4, X.sub.5 and X.sub.6 represent hydrogen atoms. The reaction is generally carried out by heating in an acid medium. It is particularly advantageous to carry out the reaction at a temperature from 65.degree. to 100.degree. C. in an aqueous inorganic acid, for example in hydrochloric acid. The 1,2,3,4-tetrahydroisoquinoline derivatives of general formula II can be obtained by reacting an isothiocyanate of the general formula: S.dbd.C.dbd.N--A.sub.1 III (wherein A.sub.1 is as hereinbefore defined), with a 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline derivative of the general formula: ##STR4## wherein X.sub.4, X.sub.5 and X.sub.6 are as hereinbefore defined. The reaction is generally carried out in an organic solvent such as an alcohol, for example ethanol, at a temperature from 15.degree. to 70.degree. C. The isothiocyanate of general formula III wherein A.sub.1 represents a 3-pyridyl radical can be prepared in accordance with the method described by J. C. Jochims, Chem. Ber. 101, 1746 (1968). The isothiocyanate of general formula III wherein A.sub.1 represents a 5-isoquinolyl radical can be obtained by condensing carbon disulphide with 5-aminoisoquinoline, followed by addition of dicyclohexylcarbodiimide. The condensation is generally carried out in the presence of a base such as a tertiary amine, for example triethylamine. The reaction is advantageously carried out in an organic solvent, such as pyridine, at a temperature from -10.degree. to 25.degree. C. The 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline derivatives of general formula IV can be obtained by reduction of a 1,2,3,4-tetrahydroisoquinoline derivative of the general formula: ##STR5## (wherein R represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms and X.sub.4, X.sub.5 and X.sub.6 are as hereinbefore defined) or of an acid addition salt thereof. When R in general formula V represents a hydrogen atom, the reduction is preferably carried out using lithium aluminium hydride, in tetrahydrofuran, at a temperature from 20.degree. to 70.degree. C. When R in general formula V represents an alkyl radical containing from 1 to 4 carbon atoms, the reduction is preferably caried out by means of an alkali metal borohydride, such as sodium borohydride, in an organic solvent or an aqueous-organic medium, such as an ethanol-water mixture, and at a temperature from 10.degree. C. to the reflux temperature of the reaction mixture. When a product of general formula IV in which X.sub.6 represents a nitro radical is required it is preferable to use an ester of general formula V (R = alkyl), the reduction of which takes place under conditions which do not affect the nitro radical. The 1,2,3,4-tetrahydroisoquinoline derivatives of general formula V, wherein R represents an alkyl radical containing 1 to 4 carbon atoms, can be obtained by esterification of a 1,2,3,4-tetrahydroisoquinoline derivative of general formula V, wherein R represents a hydrogen atom, by known methods for the conversion of an acid into an ester without affecting the rest of the molecule. By the term "known methods" as used in this Specification and accompanying claims is meant methods heretofore used or described in the chemical literature. The 1,2,3,4-tetrahydroisoquinoline derivatives of general formula V wherein R represents a hydrogen atom, X.sub.4 and X.sub.5 are as hereinbefore defined and X.sub.6 represents a hydrogen atom can be obtained from a phenylalanine derivative of the general formula: ##STR6## (wherein X.sub.4 and X.sub.5 are as hereinbefore defined) by application of the method described by A. Pictet and Th. Spengler, Chem. Ber., 44, 2030 (1911). When the L-form of a phenylalanine derivative of general formula VI is used, the product of general formula I obtained via the compound of general formula V is in the (S)-form. When a phenylalanine derivative of general formula VI in the D-form is used the product of general formula I is obtained in the (R)-form. When a mixture of the D- and L-forms of the phenylalanine derivative of general formula VI is used, the product of general formula I is obtained in the (R,S)-form. The compounds of general formulae II, IV and V wherein the symbol X.sub.6 represents a nitro radical can be obtained by nitration of a compound of general formula II, IV or V wherein X.sub.6 represent a hydrogen atom. The nitration is generally carried out by means of a mixture of nitric and sulphuric acid at a temperature of about -20.degree. C. or with a mixture of sodium nitrate and trifluoroacetic acid at a temperature of about 20.degree. C., followed, if desired, by separation of the isomers obtained. 2. Compounds of general formula I wherein X.sub.1 represents a hydrogen or halogen atom or a cyano radical and A, X.sub.2 and X.sub.3 are as hereinbefore defined are prepared by reaction of an amine of the general formula: H.sub.2 N -- A VII (wherein A is as hereinbefore defined) with a salt of the general formula: ##STR7## wherein X.sub.7 represents a hydrogen or halogen atom or a cyano radical, R.sub.1 represents a chloride atom, an alkylthio radical containing 1 to 4 carbon atoms (preferably a methylthio radical) or a benzylthio radical, A.sub.2.sup.- represents an anion, such as a chloride, iodide, sulphate, tetrafluoroborate or fluorosulphonate ion, and X.sub.2 and X.sub.3 are as hereinbefore defined. When R.sub.2 represents a chlorine atom, A.sub.2.sup.- represents a chloride ion. When R.sub.1 represents an alkylthio or benzylthio radical A.sub.2.sup.- represents an anion such as an iodide, sulphate tetrafluoroborate or fluorosulphonate ion. When R.sub.1 represents a chlorine atom and A.sub.1.sup.- represents a chloride ion, the reaction is preferably carried out in an organic solvent, such as acetonitrile, in the presence of an alkaline condensation agent, such as triethylamine, at a temperature of about 20.degree. C. When R.sub.1 represents an alkylthio or benzylthio radical and A.sub.2.sup.- represents an iodide, sulphate, tetrafluoroborate or fluorosulphonate ion, the reaction is preferably carried out in a basic organic solvent, such as pyridine, at a temperature of about 20.degree. C. The salt of general formula VIII wherein R.sub.1 represents a chlorine atom and A.sub.2.sup.- represents a chloride ion can be obtained by the reaction of a chlorinating agent, such as phosgene, phosphorus pentachloride, thionyl chloride or oxalyl chloride on a thiazolo[3,4-b]isoquinoline-3-thione derivative of the general formula: ##STR8## wherein X.sub.2, X.sub.3 and X.sub.7 are as hereinbefore defined. The reaction is generally carried out in an organic solvent or a mixture of organic solvents, such as a mixture of toluene and tetrahydrofuran, at a temperature from 0.degree. to 70.degree. C. The salts of general formula VIII wherein R.sub.1 represents an alkylthio or benzylthio radical and A.sub.2.sup.- represents an iodide, sulphate, tetrafluoroborate or fluorosulphonate ion can be obtained by the reaction of a reactive ester of the general formula: R.sub.2 -- A.sub.2 X (wherein R.sub.2 represents an alkyl radical containing from 1 to 4 carbon atoms or a benzyl radical and A.sub.2 represents the residue of a reactive ester such as an iodine atom, or an alkoxysulphonyloxy radical) or of triethyloxonium tetrafluoroborate or methyl fluorosulphonate and a compound of general formula IX. The reaction is generally effected, optionally in the presence of an organic solvent such as methylene chloride, at a temperature of about 20.degree. C. The thiazolo[3,4-b]isoquinoline-3-thione derivatives of general formula IX wherein X.sub.2, X.sub.3 and X.sub.7 are as hereinbefore defined (with the exception of those derivatives wherein X.sub.7 represents a cyano radical) can be obtained by the reaction of carbon disulphide, in a basic medium, with an isoquinoline derivative of the general formula: ##STR9## wherein X.sub.8 represents a hydrogen or halogen atom, E represents a halogen, e.g. bromine or chlorine, atom or a hydroxysulphonyloxy radical, and X.sub.2 and X.sub.3 are as hereinbefore defined. The reaction is generally carried out in the presence of sodium or potassium hydroxide at a temperatue of about 20.degree. C. Compounds of general formula XI can be obtained by the action of an inorganic acid on a 3-hydroxymethylisoquinoline derivative of general formula IV wherein X.sub.5 and X.sub.6 are as hereinbefore defined and X.sub.4 represents a hydrogen or halogen atom. Compounds of general formula XI wherein E represents a hydroxysulphonyloxy radical are generally prepared by treatment of the derivative of general formula IV with sulphuric acid in an aqueous medium at a temperature of about 100.degree. C., or in an organic solvent (such as dimethylformamide) in the presence of dicyclohexylcarbodiimide at a temperature of about 20.degree. C. Compounds of general formula XI wherein E represents a bromine atom are generally prepared by treatment of the derivative of general formula IV with aqueous hydrobromic acid (48% w/v) at the reflux temperature of the reaction medium, and isolating the product of general formula XI as its hydrobromide. Compounds of general formula XI wherein E represents a chlorine atom, are generally prepared by treatment of the derivative of general formula IV with thionyl chloride in an organic solvent, such as chloroform, saturated with hydrogen chloride gas, and at the reflux temperature of the reaction mixture and isolating the product of general formula XI as its hydrochloride. Compounds of general formula IX or XI, wherein X.sub.3 represents a nitro radical, can also be obtained by nitration of a compound of general formula IX or XI wherein X.sub.3 represents a hydrogen atom. The nitration is generally carried out with a mixture of nitric and sulphuric acid at a temperature of about -20.degree. C., or with nitronium fluoroborate in acetonitrile at a temperature of about 20.degree. C., or with sodium nitrate in trifluoroacetic acid at a temperature of about 20.degree. C., followed, if desired, by separation of the isomers obtained. The compounds of general formula IX wherein X.sub.7 represents a cyano radical and X.sub.2 and X.sub.3 are as hereinbefore defined, can be obtaned from a compound of general formula IX wherein X.sub.7 is replaced by a nitro radical, i.e. from a compound of the general formula: ##STR10## (wherein X.sub.2 and X.sub.3 are as hereinbefore defined) by known methods for the conversion of a nitro radical to a cyano radical, via the corresponding amine intermediate. Compounds of general formula XII can be obtained from a compound of general formula IX wherein X.sub.1 represents a hydrogen atom in accordance with the method hereinbefore described for the preparation of compounds of general formula IX wherein X.sub.3 represents a nitro radical from compounds of general formula IX wherein X.sub.3 represents a hydrogen atom. 3. Compounds of general formula I wherein A represents a 3-pyridyl radical, X.sub.1 represents a hydrogen or halogen atom or a dimethylamino or cyano radical, X.sub.2 represents a hydrogen or fluorine atom and X.sub.3 represents a hydrogen atom, (wherein X.sub.1 and X.sub.2 are different and one of them represents a hydrogen atom) are prepared by reducing by methods known per se the nitro radical in a compound of the general formula: ##STR11## (wherein A.sub.3 represents a 3-pyridyl radical, and one of X.sub.9 and X.sub.10 represents a nitro radical and the other represents a hydrogen atom) to obtain a corresponding amino compound of the general formula: ##STR12## (wherein A.sub.3 is as hereinbefore defined and one of X.sub.11 and X.sub.12 represents an amino radical and the other represents a hydrogen atom), and conversion of the amino radical in the compound of general formula XIV by methods known per se to a halogen atom, or to a dimethylamino or cyano radical. The reduction of the nitro radical to the amino radical is advantageously carried out in an acid medium (for example hydrochloric acid) in the presence of a metal, such as tin, at a temperature from 10.degree. to 40.degree. C. Compounds of general formula I wherein X.sub.1 represents a chlorine atom, are generally prepared from the compound of general formula XIV obtained as hereinbefore described, by preparation in situ of a diazonium salt in an aqueous medium at a temperture from -5.degree. to +5.degree. C. using sodium nitrite in the presence of an acid (such as hydrochloric acid), and decomposition of the diazonium salt using cuprous chloride at a temperature from 20.degree. to 70.degree. C. Compounds of general formula I wherein X.sub.1 or X.sub.2 represents a fluorine atom are generally prepared by decomposition of the diazonium salt prepared as hereinbefore described, at a temperature of about -10.degree. C., using hexafluorophosphoric acid. Compounds of general formula I wherein X.sub.1 represents a cyano radical are generally prepared by decomposition of the diazonium salt prepared as hereinbefore described, using potassium cyanide and copper sulphate. The reaction is advantageously carried out in an aqueous organic medium, for example in a water/toluene mixture, at a temperature from 0.degree. to 50.degree. C. Compounds of general formula I wherein X.sub.1 represents a dimethylamino radical can be obtained from a compound of general formula XIV by treatment with formaldehyde in the presence of a reducing agent. Advantageously sodium cyanoborohydride is used as reducing agent in the presence of an acid such as acetic acid, at a temperature of about 20.degree. C., in an aqueous-organic medium, such as a mixture of water and acetonitrile. Compounds of general formula XIII wherein X.sub.9 and X.sub.10 are as hereinbefore defined can be obtained from a compound of general formula I wherein A represents a 3-pyridyl radical and X.sub.1, X.sub.2 and X.sub.3 represent hydrogen atoms, by application of the methods hereinbefore described for the preparation of a compound of general formula I wherein A, X.sub.1 and X.sub.2 are as hereinbefore defined and X.sub.3 represents a nitro radical. The thiazolo[3,4-b]isoquinoline derivatives of general formula I obtained by the aforementioned processes can be purified by physical methods such as crystallisation or chromatography, or by chemical methods such as the formation of salts, crystallisation of the salts and decomposition of them in an alkaline medium. In carrying out the said chemical method the nature of the anion of the salt is immaterial, the only requirement being that the salt must be well-defined and readily crystallisable. The thiazolo[3,4-b]isoquinoline derivatives of general formula I may be converted by known methods into acid addition salts. The acid addition salts may be obtained by the action of acids on the thiazolo[3,4-b]isoquinoline derivatives in appropriate solvents. As organic solvents there may be used alcohols, ketones, ethers or chlorinated hydrocarbons. The salt which is formed is precipitated, if necessary after concentrating the solution, and is isolated by filtration or by decantation. The thiazolo[3,4-b]isoquinoline derivatives of general formula I and their acid addition salts possess useful pharmacodynamic properties. They are particularly active as analgesics and antipyretics. They exhibit a slight antiinflammatory activity. In rats they have proved active as analgesics at doses from 2 to 50 mg./kg., by oral administration, according to the technique of L. O. Randall and J. J. Selitto, Arch. Int. Pharmacodyn. 111, 409 (1957), modified by K. F. Swingle et al., Proc. Soc. Exp. Biol. Med., 137, 536 (1971). The majority of the derivatives have also proved active in mice at doses from 20 to 200 mg./kg., by oral administration, according to the technique of E. Siegmund, Proc. Soc. Exp. Biol. Med. 95, 729 (1957). The antipyretic activity of the thiazolo[3,4-b]isoquinoline derivatives of general formula I is demonstrated in rats at doses from 5 to 50 mg./kg., by oral administration, according to the technique of J.J. Loux et al., Toxicol. Appl. Pharmacol., 22, 674 (1972). The anti-inflammatory activity is demonstrated in rats for most of the derivatives at doses from 5 to 50 mg./kg., by oral administration, according to the technique of K. F. Benitz and L. M. Hall, Arch. Int. Pharmacodyn., 144, 185 (1963). In addition, the thiazolo[3,4-b]isoquinoline derivatives of general formula I have low toxicity. The LD.sub.50 is between 300 mg./kg. and a dose greater than 3,000 mg./kg. Of particular interest are those thiazolo[3,4-b]isoquinoline derivatives of general formula I wherein A represents a 3-pyridyl, 4-pyridyl or 5-isoquinolyl radical, and X.sub.1, X.sub.2 and X.sub.3 represent a hydrogen atom, in the (R)-and (S)-forms and mixtures thereof, and acid addition salts thereof, more particularly (S)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline, (R)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline, (R,S)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinolin e, (S)-3-(pyrid-4-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline, (S)-3-(isoquinol-5-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolin e and (R)-3-(isoquinol-5-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoli ne and acid addition salts thereof. For therapeutic purposes, the thiazolo[3,4-b]isoquinoline derivatives of general formula I may be employed as such or in the form of non-toxic acid addition salts, i.e. salts containing anions which are relatively innocuous to the animal organism in therapeutic doses of the salts (such as hydrochlorides, sulphates, nitrates, phosphates, acetates, propionates, succinates, benzoates, fumarates, maleates, tartrates, theophyllinacetates, salicylates, phenolphthalinates and methylene-bis-.beta.-hydroxynaphthoates) so that the beneficial physiological properties inherent in the bases are not vitiated by side effects ascribable to the anions.

  本发明涉及一种新的治疗性有用的噻唑并[3,4-b]异喹啉衍生物，它们具有有用的药理动力学特性，特别是镇痛和退热作用。本发明还涉及制备它们的方法以及包含它们的制药组合物。本发明的新的噻唑并[3,4-b]异喹啉衍生物是以下通式的化合物：其中A代表3-吡啶基、4-吡啶基或5-异喹啉基，当A代表3-吡啶基时，X1代表氢、卤素、二甲基氨基或氰基，X2代表氢或氟，X3代表氢或硝基，至少有两个X1、X2和X3代表氢，或X1和X2一起代表亚甲二氧基，X3代表氢，当A代表4-吡啶基或5-异喹啉基时，X1、X2和X3各自代表氢，并且它们的无毒药用酸盐具有有用的药理动力学特性，特别是镇痛和退热作用。这些化合物可以通过不同的方法制备，包括环化、还原、硝化和重氮化等方法。这些化合物的酸盐可以通过酸在适当的溶剂中作用于这些化合物来获得。这些化合物具有低毒性和良好的药理特性，特别是(S)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline，(R)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline，(R,S)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline，(S)-3-(pyrid-4-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline，(S)-3-(isoquinol-5-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline和(R)-3-(isoquinol-5-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline及其酸盐。
• Piperazines as P2X7 antagonists
  申请人：Betschmann Patrick

  公开号：US20080076924A1

  公开（公告）日：2008-03-27

  Novel compounds of Formula (I) or pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof of Formula (I) wherein the substituents are as defined herein, which are useful as therapeutic agents.

  化合物I式的新型化合物或其药学上可接受的盐、代谢物、异构体、对映体或前药，其中取代基如本文所定义，这些化合物可用作治疗剂。