1,2,3,4-四氢异喹啉-3-羧酸乙酯盐酸盐 | 57980-74-2

• 物质功能分类: 医药中间体 - 杂环化合物
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 1,2,3,4-四氢异喹啉-3-羧酸乙酯盐酸盐
• 英文名称: ethyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride
• 英文别名: 3-Ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride；ethyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate;hydrochloride
• CAS: 57980-74-2
• 化学式: C₁₂H₁₅NO₂*ClH
• 分子量: 241.718
• InChiKey: GKLWWGAFDIKVQY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.62
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  38.3
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 危险等级：
  IRRITANT
• 危险品标志：
  Xi
• 海关编码：
  2933499090

反应信息

• 作为反应物：
  描述：

  1,2,3,4-四氢异喹啉-3-羧酸乙酯盐酸盐 在 水 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 tert-butyl ((5S)-6-((4-chloro-3-methylphenyl)amino)-5-(2-(4-(4-fluorophenyl)-4-oxobutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)-6-oxohexyl)carbamate
  参考文献：
  名称：

  [EN] CXCR3 RECEPTOR AGONISTS
  [FR] AGONISTES DU RÉCEPTEUR CXCR3

  摘要：

  提供具有以下式I结构的化合物：其中R、R1、R2、R3a和R3b如本文所述定义。还提供了包含这些化合物的药物组合物，以及与它们的制造和使用相关的方法。

  公开号：

  WO2018045246A1
• 作为产物：
  描述：

  3-(氯甲基)异喹啉盐酸盐 、 2-氨基联苯 在 盐酸 、 聚合甲醛 、 potassium carbonate 作用下， 以 水 为溶剂， 生成 1,2,3,4-四氢异喹啉-3-羧酸 、 1,2,3,4-四氢异喹啉-3-羧酸乙酯盐酸盐
  参考文献：
  名称：

  Heterocycles for use as inhibitors of leukotrienes

  摘要：

  该发明涉及式I的杂环##STR1##其中Q是一个可选择地取代的含有一个或两个氮原子的6元单环或10元双环杂环基团；A是(1-6C)烷基、(3-6C)烯基、(3-6C)炔基或环(3-6C)烷基；X是氧、硫、亚砜基、磺酰基或亚胺基；Ar是苯基，可以选择性地带有一个或两个取代基，或Ar是一个可选择地取代的含有最多三个氮原子的6元杂环基团；R.sup.1是氢、(1-6C)烷基、(3-6C)烯基、(3-6C)炔基、氰基-(1-4C)烷基或(2-4C)烷酰基，或可选择地取代的苯甲酰基；而R.sup.2和R.sup.3一起形成一个式--A.sup.2--X.sup.2--A.sup.3--的基团，与A.sup.2和A.sup.3连接的碳原子一起定义具有4到7个环原子的环，其中A.sup.2和A.sup.3，可以相同也可以不同，每个是(1-4C)烷基，而X.sup.2是氧、硫、亚砜基、磺酰基或亚胺基；或其药学上可接受的盐。该发明的化合物是5-脂氧合酶的抑制剂。

  公开号：

  US05134148A1

文献信息

• T-TYPE CALCIUM CHANNEL BLOCKER
  申请人：Nissan Chemical Industries, Ltd.

  公开号：EP3053917A1

  公开（公告）日：2016-08-10

  It is an object to provid a novel compound that has an excellent T-type calcium channel inhibitory activity and is specifically useful for prevention or treatment of pain, chronic kidney disease and atrial fibrillation. The present invention provides a novel triazinone compound of Formula (I): where each substituent in the formula is defined in detail in the description, and R1 means a hydrogen atom, or a C1-6 alkyl group, etc., E means a 7 to 14-membered non-aromatic fused heterocyclic group, L3 means a C1-6 alkylene group, etc., D means a C6-14 aryyl group or a 5 to 10-membered heteroaryl group each of which is optionally substituted, etc., a tautomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

  本发明提供一种新颖的化合物，具有优异的T型钙通道抑制活性，特别适用于预防或治疗疼痛、慢性肾脏疾病和心房颤动。该新颖的三氮杂酮化合物的化学式如下（I）：其中公式中的每个取代基在描述中有详细定义，R1表示氢原子，或者C1-6烷基等，E表示一个由非芳香性融合杂环组成的7到14成员环，L3表示C1-6烷基链等，D表示一个C6-14芳基或者一个5到10成员杂环基，每个基都可以选择性取代等，化合物的互变异构体，或其药学上可接受的盐，或其溶剂化合物。
• 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.

  本发明涉及新型治疗用噻唑并[3,4-b]异喹啉衍生物，其一般式为：##STR1## 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，X.sub.1代表氢、卤素、二甲基氨基或氰基，X.sub.2代表氢或氟，X.sub.3代表氢或硝基，至少两个X.sub.1、X.sub.2和X.sub.3代表氢，或X.sub.1X.sub.2一起代表亚甲二氧基，X.sub.3代表氢，当A代表4-吡啶基或5-异喹啉基时，X.sub.1、X.sub.2和X.sub.3各自代表氢，以及其非毒性药物可接受的酸盐。这些新的噻唑并[3,4-b]异喹啉衍生物具有有用的药理作用，特别是镇痛和退热作用。本发明涉及新的治疗用噻唑并[3,4-b]异喹啉衍生物、其制备方法和含有它们的制药组合物。
• Tetrahydroisoquinoline amides
  申请人：Boehringer Ingelheim Pharmaceuticals, Inc.

  公开号：US05232928A1

  公开（公告）日：1993-08-03

  Tetrahydroisoquinoline amides having the general structure ##STR1## are disclosed, the substituents defined hereinbelow, which amides are useful in inhibiting human leukocyte and neutrophil elastaes.

  本发明揭示了具有一般结构##STR1##的四氢异喹啉酰胺，所述取代基如下所定义，这些酰胺对抑制人类白细胞和中性粒细胞弹性蛋白酶具有用处。
• T-TYPE CALCIUM CHANNEL INHIBITOR
  申请人：NISSAN CHEMICAL INDUSTRIES, LTD.

  公开号：US20160237071A1

  公开（公告）日：2016-08-18

  A novel compound that has an excellent T-type calcium channel inhibitory activity and is specifically useful for prevention or treatment of pain, chronic kidney disease and atrial fibrillation. The novel triazinone compound of Formula (I): where each substituent in the formula is defined in detail in the description, and R 1 could be a hydrogen atom, or a C 1-6 alkyl group, etc., E could be a 7 to 14-membered non-aromatic fused heterocyclic group, L 3 could be a C 1-6 alkylene group, etc., D could be a C 6-14 aryl group or a 5 to 10-membered heteroaryl group each of which is optionally substituted, etc., a tautomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

  一种新型化合物，具有出色的T型钙通道抑制活性，特别适用于预防或治疗疼痛、慢性肾脏疾病和心房颤动。该新型三嗪酮化合物的化学式为（I），其中公式中的每个取代基在描述中都有详细定义，R1可以是氢原子或C1-6烷基等，E可以是7-14个成员的非芳香融合杂环基，L3可以是C1-6亚烷基等，D可以是C6-14芳基或5-10个成员的杂环芳基，每个基团都可以有选择性地取代等，该化合物的互变异构体或药学上可接受的盐或溶剂化物。
• Heterocycles with inhibitory activity of 5-lipoxygenase
  申请人：ZENECA LIMITED

  公开号：EP0385662A2

  公开（公告）日：1990-09-05

  The invention concerns a heterocycle of the formula I wherein Q is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms; A is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene or cyclo(3-6C)alkylene; X is oxy, thio, sulphinyl, sulphonyl or imino; Ar is phenylene which may optionally bear one or two substituents or Ar is an optionally substituted 6-membered heterocyclene moiety containing up to three nitrogen atoms; R¹ is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or optionally substituted benzoyl; and R² and R³ together form a group of the formula -A²-X²-A³- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 4 to 7 ring atoms, wherein A² and A³, which may be the same or different, each is (1-4C)alkylene and X² is oxy, thio, sulphinyl, sulphonyl or imino; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.

  本发明涉及式 I 的杂环 其中 Q 是含有一个或两个氮原子的任选取代的 6 元单环或 10 元双环杂环分子； A是(1-6C)亚烷基、(3-6C)烯基、(3-6C)炔基或环(3-6C)亚烷基； X 是氧基、硫代、亚砜基、磺酰基或亚氨基； Ar 是亚苯基，可任选带有一个或两个取代基，或者 Ar 是任选被取代的含有最多三个氮原子的 6 元杂环分子； R¹是氢、(1-6C)烷基、(3-6C)烯基、(3-6C)炔基、氰基-(1-4C)烷基或(2-4C)烷酰基，或任选取代的苯甲酰基； 与 R² 和 R³ 一起形成式 -A²-X²-A³- 的基团，该基团与 A² 和 A³ 所连接的碳原子一起定义了一个具有 4 至 7 个环原子的环，其中 A² 和 A³ 可以相同或不同，各自为 (1-4C)烷基，X² 为氧基、硫基、亚砜基、磺酰基或亚氨基； 或其药学上可接受的盐。 本发明的化合物是 5-脂氧合酶的抑制剂。

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