1-环戊基-3-乙基-1,4,5,6-四氢-7H-吡唑并[3,4-c]吡啶-7-酮 | 162142-14-5

• 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-环戊基-3-乙基-1,4,5,6-四氢-7H-吡唑并[3,4-c]吡啶-7-酮
• 英文名称: 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine
• 英文别名: 1-cyclopentyl-3-ethyl-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-one；1-cyclopentyl-3-ethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one；1-Cyclopentyl-3-ethyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-C]pyridin-7-one；1-cyclopentyl-3-ethyl-5,6-dihydro-4H-pyrazolo[3,4-c]pyridin-7-one
• CAS: 162142-14-5
• 化学式: C₁₃H₁₉N₃O
• 分子量: 233.313
• InChiKey: QJLZPHIDOKBEGS-UHFFFAOYSA-N

物化性质

• 熔点：
  145-146 °C
• 沸点：
  501.8±49.0 °C(Predicted)
• 密度：
  1.34±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  46.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-环戊基-3-乙基-1,4,5,6-四氢-7H-吡唑并[3,4-c]吡啶-7-酮 在 tetraphosphorus decasulfide 作用下， 以 1,4-二氧六环 为溶剂， 反应 12.0h， 以87%的产率得到7H-吡唑并[3,4-c]吡啶-7-硫酮,1-环戊基-3-乙基-1,4,5,6-四氢-
  参考文献：
  名称：

  SAR of a Series of 5,6-Dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-α]pyridines as Potent Inhibitors of Human Eosinophil Phosphodiesterase

  摘要：

  The potency and physical properties of a previously reported 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine series of human eosinophil phosphodiesterase inhibitors were improved by tying the lactam moiety into a triazolo ring. The resulting 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine series provided nonionizable analogs with melting point properties suitable for micronization. Substitution at the 3-position of the 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine tricycle led to a 2-thienyl analog, 19 (tofimilast), a potent PDE4 inhibitor with low oral bioavailability and no emesis-associated behaviors in ferrets at plasma concentrations up to 152 ng/mL.

  DOI：

  10.1021/jm060904g
• 作为产物：
  描述：

  γ-己内酯 在 sodium hypochlorite 、 ammonium cerium (IV) nitrate 、 2,2,6,6-四甲基哌啶氧化物 、 水 、 sodium ethanolate 、 三乙酰氧基硼氢化钠 、 二异丁基氢化铝 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 乙腈 为溶剂， 生成 1-环戊基-3-乙基-1,4,5,6-四氢-7H-吡唑并[3,4-c]吡啶-7-酮
  参考文献：
  名称：

  Process Research and Large-Scale Synthesis of a Novel 5,6-Dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine PDE-IV Inhibitor

  摘要：

  An efficient synthesis of the PDE IV inhibitor, 9H.-cyclopentyl.. 7-ethyl-3-(thiophen-2-yl)-pyrazolo[3,4-c]-1,2,4-triazolo-,5,6-dihydro-[4,3-a]pyridine I is described. Starting from commercially available gamma -caprolactone, the synthesis was carried out in 10 steps. Key transformations were the selective O-methylation of diketone, 3-hydroxy-1-(4-methoxybenzyl)-4-propionyl-5,6-dihydro-1H-pyridin-2-one, with dimethyl sulfate and cesium carbonate in dimethylformamide, a one-pot pyrazole formation with subsequent acidic deprotection to provide lactam, 1-cyclopentyl-3-ethyl-1,4,5,6-tetrahydropyrazolo[3,4,c]pyridin-7- one, and finally the utilization of imidate, 1-cyclopentyl-7-ethoxy-3-ethyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine for the introduction of the triazole moiety. This process avoided the use of harsh reaction conditions, undesirable reagents and overcame the environmental concerns in the original synthesis.

  DOI：

  10.1021/op010222x

文献信息

• Process for preparing 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4h-1,2,3a,7,8-pentaaza-as-indacenes and intermediates useful therein
  申请人：——

  公开号：US20010039347A1

  公开（公告）日：2001-11-08

  The invention concerns a method of preparing an 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacene compound of Formula (1.0.0): 1 and pharmaceutically acceptable salt forms thereof, where R 1 is hydrogen; alkyl; alkoxy; alkoxyalkyl; alkenyl; cycloalkyl, cycloalkylalkyl; a saturated or unsaturated heterocyclic-(CH 2 ) n — group; or a group of Formula (1.1.0): 2 wherein all of said substituents are defined in more detail in the instant specification; comprising (a) subjecting a solventless reaction mixture of &ggr;-caprolactone and p-methoxybenzylamine to heating whereby there is produced an amide compound N-protected by p-methoxybenzyl, of Formula (2.0.0): 3 (b) reducing said amide compound of Formula (2.0.0) whereby there is produced an amino alcohol compound N-protected by p-methoxybenzyl, of Formula (3.0.0): 4 (c) acylating said aminoalcohol compound of Formula (3.0.0) with ethyl oxalyl chloride whereby there is produced an oxalamic acid ethyl ester compound N-protected by p-methoxybenzyl, of Formula (4.0.0): 5 (f) oxidizing said oxalamic acid ethyl ester compound of Formula (4.0.0) whereby there is produced an oxalamide ketone compound N-protected by p-methoxybenzyl, of Formula (5.0.0): 6 (e) ring closing said oxalamide ketone compound of Formula (5.0.0) whereby there is produced a pyridinone compound N-protected by p-methoxybenzyl, of Formula (6.0.0): 7 (f) O-methylating said pyridinone compound of Formula (6.0.0) whereby there is produced a 3-methoxy-pyridinone compound N-protected by p-methoxybenzyl, of Formula (7.0.0): 8 (g) treating said 3-methoxy-pyridinone compound of Formula (7.0.0) with cyclopentylhydrazine, whereby there is produced a pyrazolopyridinone compound N-protected by p-methoxybenzyl, of Formula (8.0.0) 9 (h) deprotecting said pyrazolopyridinone compound of Formula (8.0.0) by removing said p-methoxybenzyl group therefrom, whereby there is produced a lactam compound of Formula (9.0.0): 10 (i) esterifying said lactam compound of Formula (9.0.0) whereby there is produced a corresponding imino ester (imidate) compound of Formula (10.0.0): 11 (j) treating said imino ester (imidate) compound of Formula (10.0.0) with a carboxylic hydrazide compound of Formula (11.0.0): 12 where R 1 has the same meaning as set out further above; whereby there is produced said 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacene compound of Formula (1.0.0).

  本发明涉及一种制备8-环戊基-6-乙基-3-[取代]-5,8-二氢-4H-1,2,3a,7,8-五氮杂-茚化合物及其药学可接受的盐形式的方法，其中R1为氢；烷基；烷氧基；烷氧基烷基；烯基；环烷基，环烷基烷基；饱和或不饱和的杂环-(CH2)n-基；或式(1.1.0)的基团：其中所有的取代基在本说明书中有更详细的定义；包括(a)将&ggr;-己内酯和对甲氧基苯甲胺无溶剂反应混合物加热，从而生成一种由对甲氧基苯甲基保护的酰胺化合物，式(2.0.0)：(b) 还原式(2.0.0)的酰胺化合物，从而生成一种由对甲氧基苯甲基保护的氨基醇化合物，式(3.0.0)：(c) 用乙酰乙酸乙酯酰化式(3.0.0)的氨基醇化合物，从而生成一种由对甲氧基苯甲基保护的草酸乙酯化合物，式(4.0.0)：(d) 氧化式(4.0.0)的草酸乙酯化合物，从而生成一种由对甲氧基苯甲基保护的草酰胺酮化合物，式(5.0.0)：(e) 环合式(5.0.0)的草酰胺酮化合物，从而生成一种由对甲氧基苯甲基保护的吡啶酮化合物，式(6.0.0)：(f) 用O-甲基化式(6.0.0)的吡啶酮化合物，从而生成一种由对甲氧基苯甲基保护的3-甲氧基吡啶酮化合物，式(7.0.0)：(g) 用环戊基肼处理式(7.0.0)的3-甲氧基吡啶酮化合物，从而生成一种由对甲氧基苯甲基保护的吡唑吡啶酮化合物，式(8.0.0)：(h) 去除式(8.0.0)的p-甲氧基苯甲基保护基团，从而得到一种内酰胺化合物，式(9.0.0)：(i) 酯化式(9.0.0)的内酰胺化合物，从而生成一种相应的亚胺酯(亚胺)化合物，式(10.0.0)：(j) 用式(11.0.0)的羧酸肼化合物处理式(10.0.0)的亚胺酯(亚胺)化合物，其中R1的含义与上述相同；从而得到所述的8-环戊基-6-乙基-3-[取代]-5,8-二氢-4H-1,2,3a,7,8-五氮杂-茚化合物，式(1.0.0)。
• [EN] BICYCLIC TETRAHYDRO PYRAZOLOPYRIDINES AND THEIR USE AS MEDICAMENTS<br/>[FR] TETRAHYDROPYRAZOLOPYRIDINES BICYCLIQUES ET LEUR EMPLOI COMME MEDICAMENTS
  申请人：PFIZER INC.

  公开号：WO1996012720A1

  公开（公告）日：1996-05-02

  (EN) Compounds of formula (I) wherein R1, R2, R3 and X are as defined. The compounds of formula (I) and the pharmaceutically acceptable salts thereof are useful in inhibiting phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) and in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF.(FR) L'invention concerne des composés de formule (I) où R1, R2, R3 et X sont tels que définis. Les composés de cette formule (I) ainsi que leurs sels acceptables du point de vue pharmaceutique s'avèrent efficaces comme inhibiteurs de la phosphodiestérase (PDE) de type IV et de la production du facteur de nécrose des tumeurs (TNF) ainsi que dans le traitement de l'asthme, de l'arthrite, de la bronchite, des maladies chroniques obstructives des voies respiratoires, du psoriasis, des rhinites allergiques, des dermatites et autres maladies inflammatoires, du syndrome d'immuno-déficience acquise, du choc septique et d'autres affections donnant lieu à une production de TNF.

  化合物的公式（I），其中R1，R2，R3和X如定义。该公式（I）的化合物及其在抑制磷酸二酯酶（PDE）IV型和肿瘤坏死因子（TNF）的产生以及治疗哮喘，关节炎，支气管炎，慢性阻塞性呼吸道疾病，牛皮癣，过敏性鼻炎，皮炎和其他炎症性疾病，艾滋病，脓毒症休克和其他涉及TNF产生的疾病中的药物可接受的盐是有用的。
• [EN] BICYCLIC TETRAHYDRO PYRAZOLOPYRIDINES<br/>[FR] TETRAHYDRO PYRAZOLOPYRIDINES BICYCLIQUES
  申请人：PFIZER INC.

  公开号：WO1995001980A1

  公开（公告）日：1995-01-19

  (EN) Compounds of formula (I) wherein R1, R2, R3 and X are as defined. The compounds of formula (I) and the pharmaceutically acceptable salts thereof are useful in inhibiting phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) and in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF.(FR) Composés de la formule (I) dans laquelle R1, R2, R3 et X sont tels que définis dans le descriptif. Les composés de la formule (I) et leurs sels pharmaceutiquement acceptables conviennent à l'inhibition de la phosphodiestérase (PDE) de type IV et de la production du facteur de nécrose tumorale (TNF), ainsi qu'au traitement de l'asthme, de l'arthrite, de la bronchite, des affections chroniques et obstructives des voies aériennes, du psoriasis de la rhinite allergique, de la dermatite et d'autres maladies inflammatoires, du SIDA, du choc septique et d'autres maladies impliquant la production de TNF.

  化合物的化学式为(I)，其中R1、R2、R3和X的定义如所述。化合物(I)和其药学上可接受的盐在抑制磷酸二酯酶(PDE) IV型和肿瘤坏死因子(TNF)的产生方面有用，并在哮喘、关节炎、支气管炎、慢性阻塞性肺病、银屑病、过敏性鼻炎、皮炎和其他炎症性疾病、艾滋病、脓毒症休克和其他涉及TNF产生的疾病的治疗中有用。
• [EN] TRICYCLIC 5,6-DIHYDRO-9H-PYRAZOLO[3,4-c]-1,2,4-TRIAZOLO[4,3- alpha ]PYRIDINES<br/>[FR] 5,6-DIHYDRO-9H-PYRAZOLO[3,4-c]-1,2-4-TRIAZOLO[4,3- alpha ]PYRIDINES TRICYCLIQUES
  申请人：PFIZER INC.

  公开号：WO1996039408A1

  公开（公告）日：1996-12-12

  (EN) A compound of formula (I), wherein R1, R2, R3, R9 and R10 are as defined in the description. The compound of formula (I) and the pharmaceutically acceptable salts thereof are useful in inhibiting phosphodiesterase (PDE) Type IV and the production of tumor necrosis factor (TNF) and in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases characterized by phosphodiesterase (PDE) Type IV activity as well as AIDS, sepsis, septic shock and other diseases, such as cachexia, involving the production of TNF.(FR) L'invention concerne un composé de la formule (I) dans laquelle R1, R2, R3, R9 et R10 ont la signification donnée dans la description. Ledit composé et ses sels pharmaceutiquement acceptables peuvent être utilisés pour inhiber la phosphodiestérase (PDE) de type IV et la production du facteur de nécrose tumorale (TNF) et pour traiter l'asthme, l'arthrite, la bronchite, une maladie obstructive chronique des voies aériennes supérieures, le psoriasis, la rhinite allergique, la dermatite et d'autres maladies inflammatoires caractérisées par l'activité de la phosphodiestérase (PDE) de type IV, ainsi que le SIDA, la septicémie, un choc septique et d'autres maladies, telles que la cachéxie, impliquant la production du facteur de nécrose tumorale.

  一种化合物的公式(I)，其中R1、R2、R3、R9和R10如描述中所定义。公式(I)化合物及其药学上可接受的盐在抑制磷酸二酯酶(PDE) IV型和肿瘤坏死因子(TNF)的产生方面有用，并用于治疗哮喘、关节炎、支气管炎、慢性阻塞性呼吸道疾病、牛皮癣、过敏性鼻炎、皮炎和其他以磷酸二酯酶(PDE) IV型活性为特征的炎症性疾病，以及艾滋病、败血症、感染性休克和其他涉及TNF产生的疾病，如消耗症。
• Process for preparing 8-cyclopentyl-6-ethyl-3-&lsqb;substituted&rsqb;-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacenes and intermediates useful therein
  申请人：Pfizer Inc.

  公开号：US06326495B2

  公开（公告）日：2001-12-04

  The invention concerns a method of preparing an 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacene compound of the formula: and pharmaceutically acceptable salt forms thereof, where R1 is hydrogen; alkyl; alkoxy; alkoxyalkyl; alkenyl; cycloalkyl; cycloalkylalkyl; a saturated or unsaturated heterocyclic-(CH2)n—group; or a group of the formula —(Y)b—(Z)c-phenyl-(R5)a; comprising: (a) subjecting a solventless reaction mixture of &ggr;-caprolactone and p-methoxybenzylamine to heating whereby there is produced an amide compound N-protected by p-methoxybenzyl; (b) reducing said amide compound whereby there is produced an amino alcohol compound N-protected by p-methoxybenzyl; (c) acylating said aminoalcohol compound with ethyl oxalyl chloride whereby there is produced an oxalamic acid ethyl ester compound N-protected by p-methoxybenzyl; (d) oxidizing said oxalamic acid ethyl ester compound whereby there is produced an oxalamide ketone compound N-protected by p-methoxybenzyl, of the formula: (e) ring closing said oxalamide ketone compound whereby there is produced a pyridinone compound N-protected by p-methoxybenzyl, of the formula: (f) O-methylating said pyridinone compound whereby there is produced a 3-methoxy-pyridinone compound N-protected by p-methoxybenzyl; (g) treating said 3-methoxy-pyridinone compound with cyclopentylhydrazine, whereby there is produced a pyrazolopyridinone compound N-protected by p-methoxybenzyl; (h) deprotecting said pyrazolopyridinone compound by removing said p-methoxybenzyl group therefrom, whereby there is produced a lactam compound of the formula: (i) esterifying said lactam compound whereby there is produced a corresponding imino ester (imidate) compound of the formula: and (j) treating said imino ester (imidate) compound with a carboxylic hydrazide compound of the formula: R1—C(═O)—NH—NH2, where R1 has the same meaning as set out further above; whereby there is produced said 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacene.

  本发明涉及一种制备8-环戊基-6-乙基-3-［取代］-5,8-二氢-4H-1,2,3a,7,8-五氮杂萘化合物及其药学上可接受的盐形式的方法，其中R1为氢; 烷基; 烷氧基; 烷氧基烷基; 烯基; 环烷基; 环烷基烷基; 饱和或不饱和的杂环-(CH2)n-基团; 或式为-(Y)b-(Z)c-苯基-(R5)a的基团; 包括：(a)将&ggr;-己内酯和对甲氧基苯甲胺的无溶剂反应混合物加热，从而产生一种受对甲氧基苯甲基保护的酰胺化合物; (b)还原所述酰胺化合物，从而产生一种受对甲氧基苯甲基保护的氨基醇化合物; (c)用草酰氯乙酯酰化所述氨基醇化合物，从而产生一种受对甲氧基苯甲基保护的草酰胺乙酯化合物; (d)氧化所述草酰胺乙酯化合物，从而产生一种受对甲氧基苯甲基保护的草酰胺酮化合物，其式为：(e)环合所述草酰胺酮化合物，从而产生一种受对甲氧基苯甲基保护的吡啶酮化合物，其式为：(f)用甲基碘化物甲基化所述吡啶酮化合物，从而产生一种受对甲氧基苯甲基保护的3-甲氧基吡啶酮化合物; (g)用环戊基肼处理所述3-甲氧基吡啶酮化合物，从而产生一种受对甲氧基苯甲基保护的吡唑吡啶酮化合物; (h)去除所述吡唑吡啶酮化合物中的p-甲氧基苯甲基团，从而去保护，产生一种内酰胺化合物，其式为：(i)酯化所述内酰胺化合物，从而产生一种相应的亚胺酯(亚胺)化合物，其式为：(j)用式为R1-C(═O)-NH-NH2的羧酸肼化合物处理所述亚胺酯(亚胺)化合物，其中R1具有上述相同的含义; 从而产生所述8-环戊基-6-乙基-3-［取代］-5,8-二氢-4H-1,2,3a,7,8-五氮杂萘化合物。