11-chloro-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine | 77633-82-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并环庚烷吡啶
• 英文名称: 11-chloro-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine
• 英文别名: 2-chloro-16-ethyl-15,16,18-triazatetracyclo[9.7.0.03,8.013,17]octadeca-1(11),3,5,7,12,14,17-heptaene
• CAS: 77633-82-0
• 化学式: C₁₇H₁₆ClN₃
• 分子量: 297.787
• InChiKey: LZZLFFVKSIEPDF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  30.7
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  11-chloro-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine 、 N,N-二甲基-1,3-二氨基丙烷 反应 5.5h， 以(76%) of oily N-[3-(dimethylamino)propyl]-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]-cyclohepta-[1,2-b]pyrazolo[4,3-e]pyridin-11-amine are obtained的产率得到N-[3-(dimethylamino)propyl]-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]-cyclohepta-[1,2-b]pyrazolo[4,3-e]pyridin-11-amine
  参考文献：
  名称：

  1,5,6,11-Tetrahydro[5,6]cyclohepta-[1,2,-b]pyrazolo[4,3-e]pyridine

  摘要：

  本发明涉及新的1,5,6,11-四氢苯并[5,6]环庚[1,2-b]吡唑并[4,3-e]吡啶衍生物及其盐，其化学式为##STR1##其中R.sub.1为低碳基、苯基或苯基-低碳基；R.sub.2为氢、低碳基或苯基；R.sub.3为氢、卤素或低烷氧基；R.sub.4为氢、##STR2##烷基；R.sub.5为氢或低烷氧基；R.sub.6为氢、##STR3##n为2至6的整数；R.sub.7和R.sub.8相同或不同，每个为低碳基或R.sub.7和R.sub.8与它们附着的N原子形成的杂环的化学式为##STR4##其中R.sub.9为氢或低碳基；R.sub.10和R.sub.11相同或不同，每个为氢或低碳基或R.sub.10和R.sub.11与它们附着的N原子形成的杂环的化学式为##STR5##其中R.sub.9如上所述。这些化合物具有有用的抗炎活性以及精神活性。

  公开号：

  US04111940A1
• 作为产物：
  描述：

  无水氯化钙 、 1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-ol 、 盐酸 在 苯 、 乙醚 、 甲烷 作用下， 以 苯 为溶剂， 反应 31.0h， 生成 11-chloro-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine
  参考文献：
  名称：

  1,5,6,11-Tetrahydro[5,6]cyclohepta-[1,2,-b]pyrazolo[4,3-e]pyridine

  摘要：

  本发明涉及新的1,5,6,11-四氢苯并[5,6]环庚[1,2-b]吡唑并[4,3-e]吡啶衍生物及其盐，其化学式为##STR1##其中R.sub.1为低碳基、苯基或苯基-低碳基；R.sub.2为氢、低碳基或苯基；R.sub.3为氢、卤素或低烷氧基；R.sub.4为氢、##STR2##烷基；R.sub.5为氢或低烷氧基；R.sub.6为氢、##STR3##n为2至6的整数；R.sub.7和R.sub.8相同或不同，每个为低碳基或R.sub.7和R.sub.8与它们附着的N原子形成的杂环的化学式为##STR4##其中R.sub.9为氢或低碳基；R.sub.10和R.sub.11相同或不同，每个为氢或低碳基或R.sub.10和R.sub.11与它们附着的N原子形成的杂环的化学式为##STR5##其中R.sub.9如上所述。这些化合物具有有用的抗炎活性以及精神活性。

  公开号：

  US04111940A1

文献信息

• 1,5,6,11-Tetrahydro[5,6]cyclohepta-[1,2,-b]pyrazolo[4,3-e]pyridine
  申请人：E. R. Squibb & Sons, Inc.

  公开号：US04111940A1

  公开（公告）日：1978-09-05

  Various 1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]-pyrazolo[4,3-e]pyridine derivatives and their salts of the formulas ##STR1## wherein R.sub.1 is lower alkyl, phenyl, or phenyl-lower alkyl; R.sub.2 is hydrogen, lower alkyl or phenyl; R.sub.3 is hydrogen, halogen, or lower alkoxy; R.sub.4 is hydrogen, ##STR2## ALKYL; R.sub.5 is hydrogen or lower alkoxy; R.sub.6 is hydrogen, ##STR3## n is an integer from 2 to 6; R.sub.7 and R.sub.8 are the same or different and each is lower alkyl or R.sub.7 and R.sub.8 taken together with the N-atom form a heterocyclic ring of the formula ##STR4## wherein R.sub.9 is hydrogen or lower alkyl; R.sub.10 and R.sub.11 are the same or different and each is hydrogen or lower alkyl or R.sub.10 and R.sub.11 taken together with the N-atom form a heterocyclic ring of the formula ##STR5## wherein R.sub.9 is as defined above; are disclosed. These compounds possess useful antiinflammatory activity as well as psychotropic activity. SUMMARY OF THE INVENTION This invention relates to new 1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine derivatives and their salts of the formulas ##STR6## R.sub.1 is hydrogen, lower alkyl, phenyl, or phenyl-lower alkyl. R.sub.2 is hydrogen, lower alkyl, or phenyl. R.sub.3 is hydrogen, halogen or lower alkoxy. R.sub.4 is hydrogen, ##STR7## R.sub.5 is hydrogen or lower alkoxy. R.sub.6 is hydrogen, ##STR8## n is a integer from 2 to 6. R.sub.7 and R.sub.8 are the same or different and each is lower alkyl or R.sub.7 and R.sub.8 taken together with the N-atom to which they are attached form a heterocyclic ring of the formula ##STR9## wherein R.sub.9 is hydrogen or lower alkyl. R.sub.10 and R.sub.11 are independently selected from hydrogen and lower alkyl or R.sub.10 and R.sub.11 taken together with the N-atom to which they are attached form a heterocyclic ring of the formula ##STR10## wherein R.sub.9 is as defined above. Preferred embodiments of this invention are the compounds of formula I and their pharmaceutically acceptable salts wherein: R.sub.1 is lower alkyl, especially ethyl. R.sub.2 is hydrogen. R.sub.3 is hydrogen, Cl, Br, or lower alkoxy, especially hydrogen, Cl, or methoxy. R.sub.4 is hydrogen, ##STR11## wherein n is a integer from 2 to 4, especially wherein n is 3, and R.sub.7 and R.sub.8 are the same and each is methyl or ethyl, especially wherein R.sub.7 and R.sub.8 are both methyl. Also, preferred embodiments of this invention are the compound of formula II and their pharmaceutically acceptable salts wherein: R.sub.1 is lower alkyl, especially ethyl. R.sub.2 is hydrogen. R.sub.5 is hydrogen or methoxy, especially hydrogen. R.sub.6 is a heterocyclic of the formula ##STR12## or ##STR13## wherein R.sub.9 is hydrogen or methyl, especially ##STR14## or R.sub.6 is a substituted amine of the formula ##STR15## wherein R.sub.12 is lower alkyl, n is an integer from 2 to 4, especially n is 3, and R.sub.7 and R.sub.8 are the same and each is methyl or ethyl, especially wherein R.sub.7 and R.sub.8 are both methyl. DETAILED DESCRIPTION OF THE INVENTION The term "lower alkyl" as used throughout this specification is meant to include straight or branched chain hydrocarbon groups having from 1 to 4 carbon atoms, i.e., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. Similarly, the term "lower alkoxy" is meant to include such alkyl groups linked to an oxygen atom, i.e. methoxy, ethoxy, t-butoxy, etc. The term "phenyllower alkyl" includes such alkyl group linked to a phenyl ring, i.e. benzyl, phenethyl which are preferred. The term "halogen" represents the four common halogens, Cl, Br, I, and F, preferably Cl and Br, especially Cl. The compounds of formula I wherein R.sub.3 is halogen or lower alkoxy and ##STR16## alkyl are prepared by reacting a ketone of the formula ##STR17## wherein R.sub.1 and R.sub.2 are as defined above and R.sub.13 is halogen or lower alkoxy with a Grignard reagent of the formula ##STR18## in an inert solvent such as diethyl ether or tetrahydrofuran. The reaction is performed by heating at about reflux temperature for from about 3 to about 8 hours. The compounds of formula I wherein R.sub.3 is hydrogen and R.sub.4 is ##STR19## can be prepared by catalytic hydrogenation of the corresponding compound of formula I wherein R.sub.3 is halo, preferably Cl, with palladium on charcoal to remove the 4-halo substituent. The compounds of formula I wherein R.sub.3 is halogen or lower alkoxy and R.sub.4 is hydrogen are prepared by reduction of the ketone of formula III such as by reaction with an aluminum alkoxide and the corresponding alcohol; i.e. aluminum isopropoxide and isopropanol, or by catalytic hydrogenation of the ketone of formula III such as by treatment with palladium on charcoal at about room temperature for several hours. The compounds of formula I wherein both R.sub.3 and R.sub.4 are hydrogen are prepared by the catalytic hydrogenation of the ketone of formula III wherein R.sub.3 is halo, preferably Cl, by treatment with palladium on charcoal at an elevated temperature, i.e. from about 50.degree. to about 55.degree. C, for several hours. Also, the compounds of formula I wherein R.sub.3 is lower alkoxy and R.sub.4 is hydrogen can be prepared by reducing the ketone of formula III wherein R.sub.3 is halo and reacting with an alcohol in a single step, i.e. treatment of the ketone with sodium and an alcohol such as butanol. Treatment of the compound of formula I wherein R.sub.3 is hydrogen or lower alkoxy and R.sub.4 is hydrogen with gaseous hydrogen chloride in the presence of calcium chloride yields the intermediate of the formula ##STR20## Treatment of the 11-chloro intermediate of formula VI with an amine of the formula ##STR21## or the formula ##STR22## yields the compounds of formula II wherein R.sub.6 is ##STR23## The compounds of formula II wherein R.sub.5 is lower alkoxy and R.sub.6 is hydrogen, ##STR24## are prepared by catalytic hydrogenation of the corresponding compound of formula I wherein R.sub.3 is lower alkoxy and R.sub.4 is hydrogen ##STR25## with palladium on charcoal for several hours at about room temperature. The compounds of formula II wherein R.sub.5 is hydrogen and R.sub.6 is hydrogen, ##STR26## are prepared by catalytic hydrogenation of the corresponding compound of formula I wherein R.sub.3 is hydrogen or halogen and R.sub.4 is hydrogen, ##STR27## The ketones of formula III are prepared by the following method. A 5-aminopyrazole of the formula ##STR28## [prepared according to the procedure described in Z. F. Chemie 10, 386-388 (1970)] is reacted with a 2-(2-phenylethyl)-acetoacetic acid ester of the formula ##STR29## [prepared according to the procedure described in Annalen der Chemie 395 (1913)], by heating at a temperature of about 140.degree. C. in the presence of polyphosphoric acid producing a compound of the formula ##STR30## This intermediate of formula XI is oxidized with an oxidizing agent such as selenium dioxide in a solvent such as diethyleneglycol dimethyl ether or pyridine at about 140.degree. C to yield a compound of the formula ##STR31## which in most cases contain, besides some unreacted compound of formula XI, the aldehyde of the formula ##STR32## as impurities. Both can be separated by conventional methods. The methyl compound of formula XI can be used again in the oxidation step while the aldehyde of formula XIII is converted to the acid of the formula XII by means of H.sub.2 O.sub.2 in acetic acid. The compound of formula XII is then cyclized by heating at a temperature of about 210.degree. C using polyphosphoric acid as the ring closure agent, to produce a product of the formula ##STR33## The tetracyclic heterocycle of the formula XIV is treated with an inorganic acid halide such as phosphorus oxychloride, thionyl chloride, thionyl bromide, hydrogen iodide, etc., to yield the ketone of formula III wherein R.sub.3 is halo. The ketone compounds of formula III wherein R.sub.13 is lower alkoxy can be prepared by alkylating the hydroxy derivative of formula XIV with a lower alkyl halide, preferably a lower alkyl chloride or bromide, in the presence of a base such as potassium carbonate. Alternatively, the ketone of formula III wherein R.sub.13 is halo can be treated with an appropriate metal alcoholate, i.e., sodium ethoxide, potassium methoxide, etc., to yield the corresponding ketone wherein R.sub.3 is lower alkoxy. The compounds of formulas I and II form salts which are also part of this invention. The salts include acid addition salts, particularly the non-toxic, physiologically acceptable members. These salts are formed by reaction with one or moe equivalents of any of a variety of inorganic and organic acids providing acid addition salts including, for example, hydrohalides (especially hydrochloride and hydrobromide), sulfate, nitrate, borate, phosphate, oxalate, tartrate, maleate, citrate, acetate, ascorbate, succinate or aryl- or alkanesulfonates such as benzenesulfonate, methanesulfonate, cyclohexanesulfamate and toluenesulfonate. The acid addition salts frequently provide a convenient means for isolating the product, e.g., by forming and precipitating a salt (which is not necessarily non-toxic) in an appropriate medium in which the salt is insoluble, then after separation of the salt, neutralizing with a base such as barium hydroxide or sodium hydroxide, to obtain the free base of formula I or II. Other salts can then be formed from the free base by reaction with one or more equivalents of acid containing the desired anion. The compounds of formulas I and II as well as their pharmaceutically acceptable salts possess antiinflammatory activity. Thus, these compounds can be used for the treatment of inflammation in various mammalian species such as mice, dogs, cats, monkeys, etc., to relieve joint tenderness and stiffness in conditions such as rheumatoid arthritis. Formulation of these compounds can be carried out according to accepted pharmaceutical practice in oral dosage forms such as tablets, capsules, elixers or powders, or in injectable form in a sterile vehicle. The compounds of this invention can be administered in amounts of about 1 to 25 mg. per kilogram per day, preferably 2 to 20 mg. per kilogram per day, in one or more doses. The compounds of this invention are also psychotropic agents and can be used as ataractic agents for the relief of anxiety and tension states, for example, in mice, cats, rats, dogs and other mammalian species. For this purpose a compound or mixture of compounds of formula I and II, or a non-toxic, physiologically acceptable salt thereof, is administered orally or parenterally in amounts of about 10 to about 100 mg. per kilogram per day, preferably about 5 to about 25 mg. per kilogram per day, in one or more doses. Again, these compounds are formulated according to accepted pharmaceutical practice. The following examples are illustrative of the invention. All temperatures are in degrees centigrade.

  本发明涉及新的1,5,6,11-四氢苯并[5,6]环庚[1,2-b]吡唑并[4,3-e]吡啶衍生物及其盐的公式，其中R.sub.1为低碳基、苯基或苯基-低碳基；R.sub.2为氢、低碳基或苯基；R.sub.3为氢、卤素或低烷氧基；R.sub.4为氢、##STR2##烷基；R.sub.5为氢或低烷氧基；R.sub.6为氢、##STR3##，n为2至6的整数；R.sub.7和R.sub.8相同或不同，每个为低碳基，或R.sub.7和R.sub.8与它们连接的N原子形成的杂环环为##STR4##，其中R.sub.9为氢或低碳基；R.sub.10和R.sub.11相同或不同，每个为氢或低碳基，或R.sub.10和R.sub.11与它们连接的N原子形成的杂环环为##STR5##，其中R.sub.9如上所定义。这些化合物具有有用的抗炎活性和精神活性。
• US4111940A
  申请人：——

  公开号：US4111940A

  公开（公告）日：1978-09-05
• US4179564A
  申请人：——

  公开号：US4179564A

  公开（公告）日：1979-12-18
• 1,5,6,11-Tetrahydro[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine
  申请人：E. R. Squibb & Sons, Inc.

  公开号：US04179564A1

  公开（公告）日：1979-12-18

  Various 1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine derivatives and their salts of the formulas ##STR1## wherein R.sub.1 is lower alkyl, phenyl, or phenyl-lower alkyl; R.sub.2 is hydrogen, lower alkyl or phenyl; R.sub.3 is hydrogen, halogen, or lower alkoxy; R.sub.4 is hydrogen, ##STR2## R.sub.5 is hydrogen or lower alkoxy; R.sub.6 is hydrogen, ##STR3## n is an integer from 2 to 6; R.sub.7 and R.sub.8 are the same or different and each is lower alkyl or R.sub.7 and R.sub.8 taken together with the N-atom form a heterocyclic ring of the formula ##STR4## wherein R.sub.9 is hydrogen or lower alkyl; R.sub.10 and R.sub.11 are the same or different and each is hydrogen or lower alkyl or R.sub.10 and R.sub.11 taken together with the N-atom form a heterocyclic ring of the formula ##STR5## wherein R.sub.9 is as defined above; are disclosed. These compounds possess useful anti-inflammatory activity as well as psychotropic activity.

  本文介绍了各种1,5,6,11-四氢苯并[5,6]环庚[1,2-b]吡唑并[4,3-e]吡啶衍生物及其盐的公式，其中R.sub.1是低碳基，苯基或苯基-低碳基; R.sub.2是氢，低碳基或苯基; R.sub.3是氢，卤素或低烷氧基; R.sub.4是氢，##STR2## R.sub.5是氢或低烷氧基; R.sub.6是氢，##STR3## n是从2到6的整数; R.sub.7和R.sub.8相同或不同，每个都是低碳基，或者R.sub.7和R.sub.8与N原子一起形成公式的杂环环 ##STR4## 其中R.sub.9是氢或低碳基; R.sub.10和R.sub.11相同或不同，每个都是氢或低碳基，或者R.sub.10和R.sub.11与N原子一起形成公式的杂环环 ##STR5## 其中R.sub.9如上所定义; 这些化合物具有有用的抗炎活性以及精神活性。