Japan Energy Corporation

Other

Johns Hopkins University

Takeda Chemical Industries, Inc.

Dainippon Sumitomo Pharma Co., Ltd.

Yoshiaki Kiso

Tsutomu Mimoto

Ryohei Kato

Naoko Morohashi

Tominaga Fukazawa

Makoto Shintani

Yuuichi Nagano

Naoko Hattori

Osamu Takahashi

Masahiko Fujino

Ernesto Freire

Haruo Takaku

Satoshi Nojima

Naoya Kinomura

Sumitsugu Kisanuki

Keisuke Terashima

Azin Nezami

A novel compound represented by the formula (1) below which has &#x3b2;-secretase inhibitory activity, its pharmaceutically acceptable salt or a prodrug thereof.  

Compound having &#x3b2;-secretase inhibitory activity

The present invention relates to a compound of the formula (1): wherein Ris group of the formula (2): (wherein X is nitrogen atom or C(R), Y is nitrogen atom or C(R), Rand Rare each independently hydrogen atom, etc.) etc., m is 1 to 6, Lis single bond, etc., Ris hydrogen atom, substituted or unsubstituted alkyl group, etc., Ris hydrogen atom, etc., Lis single bond, etc., Ris hydrogen atom, substituted or unsubstituted aryl group, etc., or pharmaceutically acceptable salt thereof, being useful for preventing or treating Alzheimer's disease.

&#x3b2; secretase inhibitor

Compounds and methods for the inhibition of anti-malarial target aspartyl protease plasmepsins (e.g. Plasmepsin I, Plasmepsin II, Plasmepsin IV and HAP) are provided. The compounds are based on allophenylnorstatine substituted at positions R1-R4, such that R1 is isoquinoline, carboxyl, naphtalene, phenyl, phenol, benzene, an amino acid, and derivatives thereof; R2 and R3 are aliphatic groups; and R4 is indan, naphthalene, benzylamine, phenyl, phenol, cyclopentane, tert-butylamine, or derivatives thereof. The compounds may be used to inhibit Plasmepsin II, to kill malarial parasites, and to treat malaria in a patient. Certain of the substituted allophenylnorstatine-based compounds also exhibit inhibitory activity against Cathepsin D.

Inhibitors of plasmepsins

Provided are excellent &#x3b2;-secretase inhibitors, that is, compounds represented by the general formula (1) or prodrugs thereof: wherein A is amino or protected amino; Band Bare each a single bond, alkylene of 1 to 3 carbon atoms, or the like; D is a single bond, &#x2014;NHCO, or the like; E is &#x2014;COOH, tetrazole ring, or the like; n is an integer of 1 to 3; m is an integer of 1 to 3; G is hydroxyl, a group represented by the general formula (2), or the like:  in which Z is &#x2014;NH, -Asp-Ala-NH&#x2014;, -Asp-Ala-, -Asp-NH&#x2014;, or the like; L is a 5-to 10-membered ring optionally containing a heteroatom and/or unsaturated bond; X is &#x2014;COOH, tetrazole ring, or the like; Y is hydrogen, &#x2014;COOH, or the like; and k is an integer of 1 to 4; and R, R, and Rare each alkyl of 1 to 6 carbon atoms, or the like.

Peptide derivatives having &#x3b2;-secretase inhibitory activity

The present invention is to provide a multiple-agents-binding compound comprising a compound having anti-HIV activity and having no affinity for cell surface protein bound together with a same or different kind of at least one compound having anti-HIV activity and having no affinity for cell surface protein, or a salt thereof, and a pharmaceutical composition for the prevention or treatment of infectious diseases of HIV or AIDS comprising said multiple-agents-binding compound.

Multiple-agents-binding compound, production and use thereof

&bgr;-Amino-&agr;-hydroxycarboxylic acid derivatives represented by the following formula and salts thereof which are useful as human immunodeficiency virus (HIV) protease inhibitors:

&bgr;-amino-&agr;-hydroxycarboxylic acid derivatives and HIV protease inhibitors

A novel tripeptide compound represented by the following general formula (I) exhibiting superior HIV protease inhibition activity, and an anti-AIDS medicine comprising this compound as an effective component and a pharmaceutically acceptable salt thereof.

Tripeptide compounds and anti-AIDS medicine

The present invention provides synthetic methodology to produce novel dipeptide compounds and pharmaceutically acceptable salts thereof which exhibit excellent HIV protease inhibitory activity and excellent bioavailability from digestive tracts. Methods of using the dipeptide compounds and pharmaceutically acceptable salts thereof also are provided. A non-limiting example of a dipeptide compound of the invention has the general formula (IA):

Methods of preparing novel dipeptide compounds or pharmaceutically acceptable salts thereof

The present invention provides a novel dipeptide compound or pharmaceutically acceptable salt thereof which exhibits an excellent HIV protease inhibitory activity and an excellent bioavailability from digestive tracts, and an anti-AIDS agent comprising said dipeptide compound as an effective ingredient. ##STR1## (wherein R.sub.1 represents 5-membered or 6-membered monocyclic hydrocarbon group or heterocyclic group wherein more than one carbon atom of said monocyclic hydrocarbon group is substituted with hetero atom. X represents methylene group (--CH.sub.2 --), chloromethylene group(--CH(Cl)--), oxygen atom sulfur atom or sulfonyl group (--SO.sub.2 --). R.sub.21 and R.sub.22 each represents hydrogen atom or aliphatic hydrocarbon group having 1-6 carbons. R.sub.3 represents aliphatic hydrocarbon group or monovalent group derived from aromatic monocyclic hydrocarbon having 1-6 carbons.)

Methods for preparing novel dipeptide compounds or pharmacuetically

The present invention provides a novel dipeptide compound or pharmaceutically acceptable salt thereof which exhibits an excellent HIV protease inhibitory activity and an excellent bioavailability from digestive tracts, and an anti-AIDS agent comprising said dipeptide compound as an effective ingredient. General formula (I): ##STR1## (wherein R.sub.1 represents 5-membered or 6-membered monocyclic hydrocarbon group or heterocyclic group wherein more than one carbon atom of said monocyclic hydrocarbon group is substituted with hetero atom. X represents methylene group (--CH.sub.2 --), chloromethylene group(--CH(Cl)--), oxygen atom sulfur atom or sulfonyl group (--SO.sub.2 --). R.sub.21 and R.sub.22 each represents hydrogen atom or aliphatic hydrocarbon group having 1-6 carbons. R.sub.3 represents aliphatic hydrocarbon group or monovalent group derived from aromatic monocyclic hydrocarbon having 1-6 carbons.)

Dipeptide compound or pharmaceutically acceptable salt thereof and

A process for producing peptide derivatives of formula (1) or salts thereof: ##STR1## which comprises condensation of peptide derivative of formula (2): ##STR2## with carboxylic acid of formula (3): ##STR3## or condensation of a peptide derivative of formula (4): ##STR4## with a protected amino acid of formula (5'): ##STR5## wherein R.sup.1 and R.sup.2 are a lower alkyl group or hydrogen atom, R.sup.3 is a lower alkyl group, X is a methylthiomethyl, methanesulfonylmethyl, carbamoylmethyl, or a lower alkyl group, Ar is an aryl or heteroaryl group, and A.sup.4 is Ar--O--CH.sub.2 --CO. The peptide derivatives and salts thereof are useful as the human immunodeficiency virus (HIV) protease inhibitors.

Growing community of inventors

Ibaraki, Japan

Yoshiaki Kiso