Chiral tricyclic compounds with anti-histamine activity, preparation method and application

A compound, antihistamine technology, applied in the direction of organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc., can solve the problem of unreported synthesis of chiral derivatives, and achieve the effect of strong antihistamine activity

Inactive Publication Date: 2010-07-28
TIANJIN UNIV
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  • Abstract
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  • Claims
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AI Technical Summary

Problems solved by technology

[0004] Although many derivatives of tricyclic antihistamines have been synthesized, including the very active desloratadine, the synthesis of chiral derivatives has not been reported

Method used

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  • Chiral tricyclic compounds with anti-histamine activity, preparation method and application
  • Chiral tricyclic compounds with anti-histamine activity, preparation method and application
  • Chiral tricyclic compounds with anti-histamine activity, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] (1) Add methyl acrylate (11.33g, 0.13mol) to a dry 100mL four-neck flask, slowly add (R)-2-amino-1-propanol (3.76g, 0.05mol) dropwise under stirring at room temperature, drop After the completion, the oil bath was heated to 40°C, and the reaction was stopped after about 12 hours. The excess methyl acrylate was evaporated under reduced pressure to obtain a light yellow oil. The crude product was separated and purified by silica gel column chromatography to obtain 6.55 g of the addition product. The molar yield was 53.0%, [α] D 20 -73.6° (c 1.0, MeOH).

[0055] Its structural formula is

[0056]

[0057] 1 HNMR (CDCl 3 , 500MHz) δ: 3.67(s, 6H), 3.38(t, J=10.5Hz, 1H), 3.33(q, J=4.8Hz, 1H), 2.84~2.90(m, 3H), 2.56~2.60(m , 2H), 2.38~2.52(m, 4H), 0.88(d, J=7.0Hz, 3H);

[0058] 13 C NMR (CDCl 3 , 125MHz) δ: 173.25, 63.19, 57.08, 51.82, 44.91, 33.80, 9.29.

[0059] (2) Add 200mL of toluene to a 500mL four-neck flask with mechanical stirring, heat up to reflux, then ...

Embodiment 2

[0070] (1) Add methyl acrylate (8.60g, 0.1mol) to a dry 100mL four-neck flask, slowly add (S)-2-amino-1-propanol (3.76g, 0.05mol) dropwise under stirring at room temperature, drop After the completion, the oil bath was heated to 80°C, and the reaction was stopped after about 14 hours. The excess methyl acrylate was evaporated under reduced pressure to obtain a light yellow oil. The crude product was separated and purified by silica gel column chromatography to obtain 7.73 g of the addition product, and the molar yield was 62.5%, [α] D 20 +69.5° (c 1.0, MeOH).

[0071] Its structural formula is

[0072]

[0073] 1 H NMR (CDCl 3 , 500MHz) δ: 3.67(s, 6H), 3.37(t, J=10.5Hz, 1H), 3.33(q, J=5.3Hz, 1H), 2.84~2.90(m, 3H), 2.56~2.60(m , 2H), 2.46~2.52(m, 2H), 2.38~2.43(m, 2H), 0.88(d, J=6.5Hz, 3H);

[0074] 13 C NMR (CDCl 3 , 125MHz) δ: 173.06, 62.96, 56.86, 51.63, 44.69, 33.57, 9.07.

[0075] (2) Add 230mL tetrahydrofuran in a 500mL four-necked flask with mechanical stirri...

Embodiment 3

[0086] (1) Add methyl acrylate (2.15g, 0.025mol) to a dry 100mL four-neck flask, slowly add (R)-2-amino-1-butanol (0.89g, 0.01mol) dropwise under stirring at room temperature, and heat up to 35°C, stop the reaction for about 20 hours, distill off methanol and excess methyl acrylate to obtain a crude product, and separate the residue by silica gel column chromatography to obtain 1.29 g of an addition product with a molar yield of 49.7%, [α] D 20 +20.2° (c 1.0, MeOH).

[0087] Its structural formula is

[0088]

[0089] 1 H NMR (CDCl 3 , 300MHz) δ: 3.74(s, 6H), 3.59(q, J=5.7Hz, 1H), 3.38(t, J=10.4Hz, 1H), 2.92~2.97(m, 2H), 2.71~2.75(m , 3H), 2.50~2.61(m, 4H), 1.57~1.68(m, 1H), 1.18~1.34(m, 1H), 0.97(t, J=7.5Hz, 3H);

[0090] 13 C NMR (CDCl 3 , 75MHz) δ: 172.99, 63.99, 60.80, 51.60, 45.35, 33.89, 18.39, 11.90.

[0091] (2) Add 220mL of dioxane into a 500mL four-neck flask with mechanical stirring, heat up to reflux, then add potassium tert-butoxide (9.76g, 0.087mol) to...

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Abstract

The invention discloses chiral tricyclic compounds with anti-histamine activity, a preparation method and application. The chiral tricyclic compounds with the anti-histamine activity have a structural formula, wherein when R1 is phenyl or hydroxyalkyl, ester alkyl or carboxyalkyl of C1 to C11, R2 is straight-chain alkyl of C1 to C7; R3 is hydrogen or alkyl of C1 to C4; R4 is hydrogen or alkyl of C1 to C4; R5 is hydrogen or alkyl of C1 to C4; and R6 is hydrogen or alkyl of C1 to C4. Experiments prove that the chiral tricyclic compounds with the anti-histamine activity can be competitively combined with the body H1 receptor to block the action of the histamine and the H1 receptor so as to restrain the biological effect of the histamine and play a role in allergic resistance. The experiments show that the compounds have stronger anti-histamine activity compared with a positive contrast chlorpheniramine group.

Description

technical field [0001] The invention relates to a tricyclic compound with antihistamine activity, a preparation method and application. Background technique [0002] Tricyclines are the second generation H 1 An important branch of receptor antagonists, which is composed of ethylenediamines, aminoalkyl ethers and propylamines H 1 The two aromatic rings of receptor antagonists are connected by different groups in the ortho position to form a tricyclic structure, and then modified by bioelectronic isosteres to form a class of antiallergic drugs. [0003] h 1 Receptor antagonists can compete with H 1 Receptor binding to block histamine and H 1 The role of receptors, thereby inhibiting the biological effects of histamine and playing an anti-allergic effect. h 1 Receptor antagonists can be roughly divided into two generations. The first generation is called traditional antihistamine drugs. They easily pass through the blood-brain barrier and have affinity reactions with rela...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61K31/4545A61P37/08
Inventor 王东华陈立功李阳闫喜龙王玥王娟林艳
Owner TIANJIN UNIV
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