Lymph-absorbable aryl substituted imidazole derivatives

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

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514398, 514399, 514400, 514341, 5483205, 5483211, 5483225, 5483231, 5483235, 5483345, 5483411, 5483415, C07D23384, C07D23358, A61K 31415

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active

060545917

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to imidazole derivatives which are effectively absorbed from the intestinal tract to the lymphatic system and transferred to the lymph node in a high concentration and to pharmaceutical compositions comprising them, particularly anti-AIDS agents.


BACKGROUND ART

As agents for treating acquired immunodeficiency syndrome (AIDS), some of nucleoside derivatives (AZT, ddI, ddC, D4T, 3TC) are being used clinically. Studies have been focused also on non-nucleoside derivatives (Nevirapine, HEPT derivatives, TIBO derivatives, and the like) which are different from the nucleoside derivatives in the mechanisms of action, act specifically against HIV-1, and do not show cross resistance to them. It has been reported that a series of imidazole derivatives as one of the non-nucleoside derivatives show anti-HIV activity other than AZT and the like (JP-A 5-255270, WO 96/10019, and the like).
In recent years, as an attractive phenomenon, it has been made clear that HIV viruses keep propagating actively in the infected lymph node in asymptomatic patients who have been thought to be in the conditions of latent infection (Multifactorial nature of human immunodeficiency virus disease: Implications for therapy, Science, 262, 1011-1018 (1993), Anthony Fauci.).
In order to increase efficiency of anti-AIDS agents, it has been suggested that the concentration in the lymph node should be elevated. There is a report that some nucleoside derivatives such as AZT and the like satisfy the above object (Antiviral Chemistry & Chemotherapy (1995) 6 (4), 230). However, there is not such a report on the non-nucleoside derivatives such as the above imidazole derivatives and the like.


DISCLOSURE OF INVENTION

The present inventors found it important to elevate concentrations of anti-AIDS agents in the lymph node in order to increase their efficiency and intensively studied lymphotropic agents. As a result they found that the compound of the formula (I): ##STR2## wherein X and Y each is independently hydrogen, lower alkyl, halogen or nitro; ##STR3## wherein R.sup.1 is optionally substituted lower alkyl; R.sup.2 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkylalkyl, optionally substituted lower aroylalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl or optionally substituted carbamoyloxyalkyl;
2) acyloxyalkyl,
3) --CR.sup.4 R.sup.5 (OR.sup.6) substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or taken together form optionally substituted cyclic alkyl or o-biphenylenemethane together with the adjacent carbon atom; and R.sup.6 is optionally substituted alkyl,
4) --C(.dbd.CR.sup.7 R.sup.8)R.sup.9 optionally substituted alkyl, or R.sup.7 and R.sup.9 form optionally substituted cyclic alkenyl taken together with the adjacent carbon atom,
5) --COR.sup.10 substituted aralkyl, or --B--COOR.sup.11 --CH(CH.sub.2 OCOR.sup.12).sub.2 wherein R.sup.12 is hydrogen or alkyl, or optionally substituted heteroarylalkyl,
6) --COOR.sup.13 substituted aralkyl, or optionally substituted heteroarylalkyl,
7) --CONHCOR.sup.14 substituted aryl, optionally substituted aralkyl, or optionally substituted heteroarylalkyl,
8) --CONHCOOR.sup.15 aryl, optionally substituted aralkyl, or optionally substituted heteroarylalkyl, or
9) --CONHCH.sub.2 NR.sup.16 R.sup.17 alkyl, optionally substituted aralkyl, or form an optionally substituted heterocyclic ring taken together with the adjacent nitrogen atom, salt thereof, or hydrate thereof (referred to as the compound of the present invention) is effectively absorbed from the intestinal tract to the lymphatic system and can be transferred to the lymph node in a high concentration.
After the compound of the present invention is absorbed in the lymph, it shows its activity with the structure unchanged or changed by the in vivo hydrolysis conversion into the active compound.


BEST MODE FOR CARRYING OUT THE INVENTION

Preferred examples of the present invention are exemplifi

REFERENCES:
patent: 5326780 (1994-07-01), Sugimoto et al.
patent: 5472965 (1995-12-01), Sugimoto et al.
Ichihashi et al, Pharmaceutical Research, vol. 8, No. 10, pp. 1302-1306, 1991.
Ichihashi et al, Pharmaceutical Research, vol. 11, No. 4, pp. 508-512, 1994 .

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