1-ethyl-4-methylamino-5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-one | 65679-45-0

• 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: 1-ethyl-4-methylamino-5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-one
• 英文别名: 1-ethyl-5,6-dihydro-4-(methylamino)benzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one；16-Ethyl-12-(methylamino)-15,16,18-triazatetracyclo[9.7.0.03,8.013,17]octadeca-1(11),3,5,7,12,14,17-heptaen-2-one
• CAS: 65679-45-0
• 化学式: C₁₈H₁₈N₄O
• 分子量: 306.367
• InChiKey: AJDZOQMEWZOHNL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  59.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  甲烷 、 (1-ethyl-4-methylamino-5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-ylidene)-methyl-amine 在 氨 作用下， 以 硫酸 、 水 为溶剂， 生成 1-ethyl-4-methylamino-5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-one
  参考文献：
  名称：

  Derivatives of

  摘要：

  新的5,6-二氢苯并[5,6]环庚[1,2-b]吡唑并[4,3-e]吡啶-11(1H)-酮和亚胺及其盐是一种用于精神药理学和抗炎症药物的新衍生物。这些新化合物的一般式为##STR1## R.sup.1 为较低的烷基、苯基或苯基-较低的烷基；R.sup.2 为氢、较低的烷基或苯基；R.sup.3 为羟基、较低的烷氧基、卤素或胺基。胺基是一个非环状基团##STR2##其中R.sup.5和R.sup.6分别为氢、较低的烷基或苯基，或R.sup.5和R.sup.6与氮原子结合形成一个5或6成员的单环氮杂环，其中可能存在额外的氮、氧或硫原子。R.sup.4为氧(.dbd.O)或取代亚胺(.dbd.NR)；R为较低的烷基或苯基。本发明还涉及这些新化合物的制备方法。这些化合物和它们的盐可以用于制备药物。

  公开号：

  US04062858A1

文献信息

• US4062858A
  申请人：——

  公开号：US4062858A

  公开（公告）日：1977-12-13
• US4128717A
  申请人：——

  公开号：US4128717A

  公开（公告）日：1978-12-05
• Derivatives of
  申请人：E. R. Squibb & Sons, Inc.

  公开号：US04062858A1

  公开（公告）日：1977-12-13

  New derivatives of 5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-ones and imines, respectively, have the general formula ##STR1## They and the salts thereof are useful as psychotropic and antiinflammatory agents. SUMMARY OF THE INVENTION This invention relates to new derivatives of 5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]-pyridin-11(1H)-ones and imines and salts thereof. These new compounds have the general formula ##STR2## R.sup.1 is lower alkyl, phenyl or phenyl-lower alkyl; R.sup.2 is hydrogen, lower alkyl or phenyl; R.sup.3 is hydroxy, lower alkoxy, halogen or an amine group. The amine group is either an acyclic group ##STR3## wherein R.sup.5 and R.sup.6 each is hydrogen, lower alkyl or phenyl or R.sup.5 and R.sup.6 taken together with the nitrogen form a monocyclic nitrogen heterocyclic of 5 or 6 members in which an additional nitrogen, oxygen or sulfur may be present. R.sup.4 is oxygen (.dbd.O) or substituted imine (.dbd.NR) R is lower alkyl or phenyl. DETAILED DESCRIPTION OF THE INVENTION This invention relates to new compounds which are substituted 5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]-pyrazolo[4,3-e]pyridines and are useful as psychotropic and antiinflammatory agents. After the ring system has been produced, treatment with various reagents sequentially or alternately as described more fully below yields the derivatives having the uses described. These derivatives are more particularly 5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11 (1H)-ones and 5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)imines which are substituted in the 1- and 4-positions and optionally substituted in the 3-position. The new class of compounds have the general formula ##STR4## This class is characterized by two principal substituent groups, i.e., R.sup.4 is oxo or R.sup.4 is a substituted imine group, and these compounds have the following formulas, respectively: ##STR5## The various derivatives are described in greater detail in the description of the method of synthesis and in the specific examples which follow. All of these compounds are within the scope of this invention. The symbols have the following meanings which are the same throughout this specification. R.sup.1 is lower alkyl, phenyl or phenyl-lower alkyl. The lower alkyl groups are straight or branched chain hydrocarbon groups having up to seven carbon atoms like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and the like. The phenyl-lower alkyl groups are of the same type having a phenyl substituent attached to the alkyl chain. In each instance, the C.sub.1 -C.sub.4 alkyl groups and especially the C.sub.1 -C.sub.2 alkyl groups are preferred. R.sup.2 is hydrogen, lower alkyl or phenyl. The lower alkyl groups represented by R.sup.2 are of the same kind as described above with the same preferences for C.sub.1 -C.sub.4 and C.sub.1 -C.sub.2 members. R.sup.3 is hydroxy, lower alkoxy, halo or an amine group ##STR6## The lower alkoxy groups are of the same type as the lower alkyl groups having such lower alkyl groups linked to an oxygen atom, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like. The C.sub.1 -C.sub.4 and especially the C.sub.1 -C.sub.2 lower alkoxy groups are similarly preferred. The halogens represented by R.sup.3 include the four common halogens, preferably chlorine and bromine, especially chlorine. The amine group ##STR7## represented by R.sup.3 is an acyclic amine group wherein R.sup.5 is hydrogen, lower alkyl or phenyl and R.sup.6 is lower alkyl or phenyl or R.sup.5 and R.sup.6 join with the nitrogen to form a monocyclic heterocyclic having 5 or 6 members in which there may be an additional hetero atom which is oxygen, sulfur or nitrogen, the remaining atoms being carbon. The heterocyclic is unsubstituted or substituted with a lower alkyl or hydroxy-lower alkyl group. The acyclic amine groups represented by ##STR8## include, for example, lower alkylamino, e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, t-butylamino and the like or phenylamino, di(lower alkyl)-amino, e.g., dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino and the like, anilino, etc. The preferences for C.sub.1 -C.sub.4 and especially C.sub.1 -C.sub.2 alkyl groups apply in this instance also. Only one of R.sup.5 and R.sup.6 is phenyl. The heterocyclic substituents represented by the group ##STR9## include particularly piperidino, morpholino, thiamorpholino and piperazino each of which can bear a lower alkyl or hydroxy-lower alkyl group, i.e., R.sup.7 -hetero in which the "hetero" is one of those heterocyclics named and R.sup.7 is hydrogen when unsubstituted and lower alkyl or hydroxy-lower alkyl when substituted. 4-Methylpiperidino, 4-methylpiperazino and 4-hydroxyethylpiperazino are exemplary substituted members and preferred. R.sup.4 is oxo (.dbd.O) or substituted imino (.dbd.NR). R is lower alkyl of the type described above or phenyl. Especially preferred compounds are those compounds of formula Ia wherein R.sup.1 is lower alkyl, particularly ethyl; R.sup.2 is hydrogen; and R.sup.3 is hydroxy, lower alkoxy, particularly methoxy and ethoxy, or lower alkylamino particularly methylamino and butylamino; and those compounds of formula Ib wherein R.sup.1 is lower alkyl particularly ethyl; R.sup.2 is hydrogen; R.sup.3 is lower alkylamino, particularly methylamino and butylamino and R is lower alkyl, particularly methyl and butyl. The new compounds of this invention are prepared by the following series of reactions. A 5-aminopyrazole of the formula ##STR10## [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 ##STR11## [prepared according to the procedure described in Annalen der Chemie 395, 95 (1913)], by heating at a temperature of about 140.degree. C. in the presence of polyphosporic acid producing a compound of the formula ##STR12## This intermediate of formula IV is oxidized with an oxidizing agent like selenium dioxide in a solvent like diethyleneglycol dimethyl ether or pyridine at about 140.degree. C to yield a compound of the formula ##STR13## which in most cases contain, besides some unreacted compound of formula IV, the aldehyde of the formula ##STR14## as impurities. Both can be separated by conventional methods. The methyl compound of formula IV can be used again in the oxidation step while the aldehyde of the formula VI is converted to the acid of the formula V by means of H.sub.2 O.sub.2 in acetic acid. The compound of formula V is then cyclized by heating at a temperature of about 210.degree. using polyphosphoric acid as the ring closure agent, to produce a product of the formula ##STR15## The tetracyclic heterocycle of the formula VII is treated with an inorganic acid chloride or bromide such as phosphorus oxychloride, thionyl chloride, etc., to yield a compound of the formula ##STR16## wherein X is chlorine or bromine. Treatment of the compound of formula VIII with a primary amine of the formula R--NH.sub.2 (IX) produces the amino derivative of the formula ##STR17## which can be hydrolyzed by means of aqueous acid like sulfuric acid to a compound of the formula ##STR18## When a compound of formula VIII is made to react with a secondary amine of the formula ##STR19## a product of the formula ##STR20## is obtained. Compounds wherein R.sup.3 is lower alkoxy, according to the formula ##STR21## wherein R.sup.8 is lower alkyl, are prepared by alkylating the hydroxy derivative of formula VII with a lower alkyl halide in the presence of a base like potassium carbonate. The halide is preferably the chloride or bromide. Alternatively, a compound of the formula VIII can be treated with an appropriate alcoholate, e.g., a metal alcoholate like sodium ethoxide, potassium methoxide or the like to yield the same product. The new compounds of formula I 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 more 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 like benzenesulfonate, methanesulfonate, cyclohexanesulfamate and toluenesulfonate. The acid addition salts frequently provide a convenient means for isolating the product, e.g., by forming an 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. Other salts can then be formed from the free base by reaction with one or more equivalents of acid containing the desired anion. Certain members, e.g., those compounds of formula I wherein R.sup.3 is hydroxy, form salts with metals, e.g., alkali metals like sodium, alkaline earth metals like calcium and magnesium, etc. R.sub.3 then becomes --O--Met--, wherein Met represents the metal ion. The alkali metals, sodium and potassium in particular, are preferred in this instance. These salts can be used to form soluble derivatives or as intermediates. Additional experimental details are found in the examples. The new compounds of this invention have anti-inflammatory properties and are useful as anti-inflammatory agents, for example, to reduce local inflammatory conditions such as those of an edematous nature or resulting from proliferation of connective tissue in various mammalian species such as rats, dogs and the like when given orally in dosages of about 1 to 25 mg. per kilogram per day, preferably 2 to 20 mg. per kilogram per day, in single or 2 to 4 divided doses, as indicated by the carageenan edema assay in rats. The new 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, or non-toxic, physiologically acceptable salt thereof, is preferably administered orally, but parenteral routes such as subcutaneously, intramuscularly, intravenously or intraperitoneally can also be employed. A single dose, or preferably 2 to 4 divided daily doses, provided on a basis of about 10 to 100 mg. per kilogram per day, preferably about 5 to 25 mg. per kilogram per day, is appropriate. The compounds of the invention can be utilized by formulating in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. About 10 to 500 mg. of a compound or mixture of compounds of formula I or physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained. The following examples are illustrative of the invention and constitute preferred embodiments. They also serve as models for the preparation of other members of the group which can be produced by suitable substitution of starting materials. All temperatures are in degrees celsius.

  新的5,6-二氢苯并[5,6]环庚[1,2-b]吡唑并[4,3-e]吡啶-11(1H)-酮和亚胺及其盐是一种用于精神药理学和抗炎症药物的新衍生物。这些新化合物的一般式为##STR1## R.sup.1 为较低的烷基、苯基或苯基-较低的烷基；R.sup.2 为氢、较低的烷基或苯基；R.sup.3 为羟基、较低的烷氧基、卤素或胺基。胺基是一个非环状基团##STR2##其中R.sup.5和R.sup.6分别为氢、较低的烷基或苯基，或R.sup.5和R.sup.6与氮原子结合形成一个5或6成员的单环氮杂环，其中可能存在额外的氮、氧或硫原子。R.sup.4为氧(.dbd.O)或取代亚胺(.dbd.NR)；R为较低的烷基或苯基。本发明还涉及这些新化合物的制备方法。这些化合物和它们的盐可以用于制备药物。