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Paradoximes as HIV reverse transcriptase inhibitor as well as preparation method and purpose thereof

A technology of compounds and medicinal salts, which is applied in the field of preparation of anti-HIV drugs, can solve the problems of easy drug resistance and high frequency of daily doses, etc.

Inactive Publication Date: 2010-06-02
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the main problem is that it is prone to drug resistance or the number of daily doses is too high

Method used

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  • Paradoximes as HIV reverse transcriptase inhibitor as well as preparation method and purpose thereof
  • Paradoximes as HIV reverse transcriptase inhibitor as well as preparation method and purpose thereof
  • Paradoximes as HIV reverse transcriptase inhibitor as well as preparation method and purpose thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0156] According to a preferred embodiment of the present invention, X is -O-.

[0157] According to a preferred embodiment of the present invention, the compound of formula I of the present invention has the following formula Ia:

[0158]

[0159] or a pharmaceutically acceptable salt thereof,

[0160] in,

[0161] R 1 and R 3 each independently -NO 2 , -NH 2 , halogen, -OH, -CN or -N(R) 2 ;

[0162] R 2 for -H;

[0163] R 7 -CN, -HC=CH-CN, halogen, -CH 3 、-OCH 3 , -NH 2 、-CH 2 -NHR', -OH, -NO 2 、-CF 3 , -CH=CH 2 , -C≡CH, -C≡CR', -CH=CHR', -CH=CHCOR', -CHO, -C≡CR", -CH=CHR", -C≡C-CN, containing 1-3 A five-membered heteroaryl group of heteroatoms selected from N, O, S, and optionally with aldehyde, ketone, cyano, α, β unsaturated cyano, alkene, alkyne, aldehyde in its ring structure or a substituent of a keto group;

[0164] R' is H or C 1-6 Hydrocarbyl; R" is NO 2 , NH 2 , or N 3 ;

[0165] X is -O-, -NH-, or -NCOR-; and

[0166] R is C 1-4 Hydroc...

preparation Embodiment 1

[0257] Preparation Example 1 : the preparation of 6-chloro-2-(4-cyanoanilino)-3-nitropyridine (IV-1)

[0258] 2,6-dichloro-3-nitropyridine (II-1, 193mg, 1mmol) and p-cyanoaniline (III-1, 236mg, 2mmol) were dissolved in N,N-dimethylformamide (DMF, 3mL ). After cooling in an ice-water bath, potassium tert-butoxide (224 mg, 2 mmol) was added in batches, and then reacted at room temperature for 2 h. The reaction solution was poured into ice water, the pH value was adjusted to 5-6 with dilute HCl, and stirred for 30 minutes to precipitate a solid. The solid was filtered out, washed with water until neutral, dried, and separated on a silica gel column (dichloromethane as the eluent) to obtain compound IV-11 (186 mg, 68%) as a pale yellow solid, mp 175-178°C. 1 H NMR (CDCl 3 )δ10.47 (1H, br s, NH), 8.53 (1H, d, J=8.4Hz, ArH-4), 7.86 (2H, d, J=8.8Hz, ArH-2', 6'), 7.70 (2H, d, J=8.8Hz, ArH-3', 5'), 6.96 (1H, d, J=8.4Hz, ArH-5); MS (m / z): 275 (M + ).

preparation Embodiment 2

[0259] Preparation Example 2 : Preparation of 2-anilino-6-chloro-3-nitropyridine (IV-2)

[0260]Add 2,6-dichloro-3-nitropyridine (II-1, 193 mg, 1 mmol), aniline (III-2, 93 mg, 1 mmol) and sodium bicarbonate (84 mg, 1 mmol) into 10 mL of absolute ethanol, Reaction at room temperature for 24h. The reaction solution was poured into ice water, the pH value was adjusted to 5-6 with dilute HCl, and stirred for 30 minutes to precipitate a solid. The solid was filtered off, washed with water until neutral, and dried. Compound IV-2 (219mg, 88g) was obtained as a red solid, mp 95-98°C. 1 H NMR (CDCl 3 )δ10.28 (1H, b s, NH), 8.47 (1H, d, J=8.4Hz, ArH-4), 7.66 (2H, d, J=8.0Hz, ArH-2', 6'), 7.42( 2H, t, J=8.0Hz, ArH-3', 5'), 7.21 (1H, t, J=7.2Hz, ArH-4'), 6.81 (1H, d, J=8.4Hz, ArH-5) ; MS (m / z): 250 (M + ).

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Abstract

The invention relates to 2-(4-substituted phenylamino group) polysubstitution paradoximes as HIV reverse transcriptase inhibitors, and a preparation method and purpose thereof, in particular to I type compounds or medicinal salt thereof, wherein the definitions of the R1, R2, R3, R4, R5, R6, R7 and X are stated as the specification. The I type compounds of the invention are anti-HIV activity compounds having a novel framework structure.

Description

technical field [0001] The invention relates to 2-(4-substituted anilino) polysubstituted pyridine compounds with anti-HIV activity, a preparation method thereof, a pharmaceutical composition containing them and an application for preparing anti-HIV medicaments. Background technique [0002] HIV (HIV) is an RNA virus. The surface of the virus is a double lipid membrane. Two single-stranded RNAs and some important enzymes (such as reverse transcriptase, proteolytic enzyme, integrase) and structural proteins (p24, p17, p7, etc.) are wrapped in the membrane. There are two very important glycoproteins gp120 and gp41 on the membrane surface of the virus. gp120 is on the outside of the membrane, and gp41 spans the double lipid membrane and forms a complex with gp120. Their main function is to recognize and attack cells with CD4 surface receptors in the human immune system, such as lymphocytes (T cells), macrophages, etc. HIV cannot reproduce outside the body and must rely on h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/74A61K31/44A61P31/18
Inventor 谢蓝田兴涛李国雄
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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