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Indezole bioisostere replacement of catechol in therafeutically active compounds

A biological isosteric and compound technology, applied in the fields of organic active ingredients, drug combinations, organic chemistry, etc., can solve the problems that the types of treatments do not conform to direct prediction and lack of structural similarity.

Inactive Publication Date: 2001-02-21
PFIZER PRODS ETAT DE CONNECTICUT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the present invention, such structural similarity is completely lacking, and the large number of different therapeutic classes in which this indazole-p-catechol bioisostere displacement can be successfully performed does not conform to any direct prediction

Method used

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  • Indezole bioisostere replacement of catechol in therafeutically active compounds

Examples

Experimental program
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preparation example Construction

[0733] The preparation of the compound of formula (I-ii) is further described in Example 23 below. The compound can also be prepared according to the synthetic methods described in the above scheme 2 and scheme 3, using the compound (represented by formula (9.53)) prepared by the method described in the following example 20 as the starting material:

[0734] Preferred compounds of the above formula (9.51) can be prepared following the synthetic methods described in Scheme 1, Scheme 2, and Scheme 3 above and in more detail in the Examples below. Additional preferred methods for the preparation of said compounds are also available and are shown in the following Synthetic Scheme 5, which is a more general representation of the methods for the preparation of the above-mentioned preferred compounds of the present invention.

[0735] Process 5

[0736] As shown above, the starting material of formula XXVIII is reacted with hydrazine of formula ...

Embodiment 1

[0793] A. 5-Benzyloxy-4-methoxy-2-{1[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethyleneamino}benzonitrile

[0794] Phosphorus oxychloride (0.81ml, 0.0086mol) was added to 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane (4.02g, 0.0157mol) in dichloromethane (25ml) solution and the mixture was stirred at room temperature for 30 minutes. Then a solution of 2-amino-5-benzyloxy-4-methoxybenzonitrile (2 g, 0.0078 mol) in dichloromethane (25 ml) was added thereto, and the reaction was stirred at 40°C for 18 hours. After cooling, the reaction mixture was carefully poured into ice / water (100ml) and extracted with dichloromethane (2 x 100ml). The combined organic layers were washed with MgSO 4 Dry, filter, and distill under reduced pressure to obtain a brown oil. The crude product was purified on a silica gel column eluting with a gradient of methanol:dichloromethane (2:98 to 10:90 v / v) to afford the title compound. R f 0.67 (0.880 ammonia:methanol:dichloromethane 1:7:92, v / v). MS...

Embodiment 2

[0799] Contraction response of rabbit aorta

[0800] Rabbit aortic tissue was cut into rings and suspended under a resting tension of 1.5 g in an organ bath of Krebs Ringer bicarbonate (mM) of the following composition: NaCl (119), KCl (4.7), CaCl 2 (2.5), KH 2 PO 4 (1.2), MgSO 4 (1.2), NaHCO 3 (25), glucose (11), and use 95% / O 2 / 5%CO 2 saturation. The solution also contained 1 mM propanol, 0.5 mM idazoxan, 10 mM cocaine and 10 mM corticosterone. Tissues were exposed to two sensitizing doses of methoxyamine (100 mM) and washed over 1 hour. Control curves in all tissues were obtained from isotonic contraction in response to increased accumulation of methoxyamine. Further curves were obtained in the presence and absence of antagonist (1 hour incubation). Antagonist affinity estimates (pK b ), pK b =-log[A] / (DR-1) where the dose ratio (DR), relative to the corresponding control group, can be generated by the concentration of antagonist [A] alone which is assumed to be...

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Abstract

The invention discloses a therapeutically active compositions of matter and member species thereof which comprise indazole-containing compounds, said compounds and their therapeutic activity resulting directly from an indazole-for-catechol bioisostere replacement of a catechol-containing compound having the same therapeutic activity, where non-catechol substituents are the same or homologous before and after said replacement, and wherein said compositions of matter comprise a compound of Formula (I<1>) or (I<2>), or a pharmaceutically acceptable salt thereof, wherein in a preferred embodiment R is hydrogen; R is cyclohexyl; and R is ethyl. Ra and Rb are each individually and independently hydrogen or non-catechol substituents of said compounds resulting directly from an indazole-for-catechol bioisotere replacement of said catechol-containing compound having said therapeutic activity, where said non-catechol substituents are the same or homologous before and after said replacement, provided that both of Ra and Rb cannot be hydrogen at the same time. The therapeutic activity involved may comprise cholinesterase inhibitory activity, adrenergic alpha 1-antagonist and beta 1-agonist activity, calcium channel inhibitory activity, antineoplastic activity, and phosphodiesterase type IV inhibitor activity.

Description

[0001] Pending applications and other references to related applications [0002] References to catechol-containing protein tyrosine kinase receptor antagonists for use in the treatment of transitional proliferative disorders include U.S. Application No. 08 / 653,786 (attorney number PC8836B), filed May 28, 1996, The current U.S. Patent 5,747,498, the date of approval is May 5, 1998; the application date is International Application No.PCT / IB95 / 00436 on June 6, 1995, which designates the United States (the agency number is PC8836A), and in 1996 Publication No. WO96 / 30347 published on October 3; U.S. Application No. 60 / 020491 (Proxy No. 9365), filed on June 24, 1996, has been abandoned, and filed on June 11, 1997 as an international Application, Application No. PCT / IB97 / 675, assigned US (Attorney No. PC9365A) and published as WO 97 / 49688 on December 31, 1997; the entirety of the above publication is incorporated herein by reference. [0003] Reference is also made to U.S. Applicat...

Claims

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Application Information

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IPC IPC(8): A61K31/416A61P9/02A61P9/06A61P9/10A61P9/12A61P11/06A61P43/00C07D231/56
CPCC07D231/56A61P11/06A61P43/00A61P9/02A61P9/06A61P9/10A61P9/12
Inventor 安东尼·马法特
Owner PFIZER PRODS ETAT DE CONNECTICUT
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