Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-02-16
2001-09-18
Celsa, Bennett (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S019300, C530S300000, C530S331000, C424S185100
Reexamination Certificate
active
06291432
ABSTRACT:
FIELD OF TECHNOLOGY
The present invention relates to a novel tripeptide compounds exhibiting an action to inhibit an enzymatic activity of a protease which originates from human immunodeficiency virus (HIV). Moreover, the present invention relates to an anti-AIDS medicine which can control in vivo growth of HIV utilizing the inhibitive activity of this novel tripeptide compound against protease originating from HIV.
BACKGROUND OF THE INVENTION
Human immunodeficiency virus (HIV) which causes AIDS produces precursor proteins such as a reverse transcriptase or Gag protein used for production of the virus particles in host cells. These precursor proteins can exhibit their functions only when cut into a specific size by a protease of a virus origin (HIV protease). The HIV protease inhibitor which blocks formation and growth of infectious virus particles by inhibiting the enzymatic activity of the HIV protease can be used as an anti-virus agent. Several HIV protease inhibitors have already been reported. One of them is a transition state mimetic which is a compound something like a synthetic peptide (see, for example, T. Robins, J. Plattner, J. Acquir. Immun. Defic. Syndr., 6, 162 (1993)). For example, a hydroxyethylamine derivative such as Ro31-8959 (N. A. Roberts et al., Science 248, 358-361 (1990)) which contains a phenylalanine &phgr;[CH(OH)CH
2
N] decahydroisoquinolinecarboxylic acid skeleton similar to an amino acid sequence which is selectively cleaved by an HIV protease, such as -Tyr . . . Pro or -Phe . . . Pro, and a hydroxymethylcarboxamide derivative such as a peptide derivative including a norstati skeleton such as phenylalanine &phgr;[CH(OH)C(O)N]proline (T. F. Tam et al., J. Med. Chem. 35, 1318-1320 (1992)) are useful as an HIV protease inhibitor. Clinical application of these substances is being actively promoted.
Specifically, like a transition state mimetic these compounds utilize an HIV protease inhibition activity to control production of the virus particles in host cells, whereby growth and infection of HIV can be controlled and AIDS can be prevented. Clinical application of these compounds as the anti-AIDS medicines is being adopted (Nakajima et al., The Pharmaceuticals monthly, Vol. 35, 2983-2989 (1993)). These transition state mimetics are expected to become next generation anti-AIDS medicines succeeding nucleic acid derivative-type reverse transcriptase inhibitors such as AZT (azidothymidine), DDC (dideoxycytidine), and DDI (dideoxyinosine) which are already clinically used as anti-AIDS drugs.
The present inventors have also discovered that a group of synthetic peptide compounds which are transition state mimetics including a 3-amino-2-hydroxy-4-phenylbutanoic acid residue exhibit a strong HIV protease inhibitive action and are useful as anti-AIDS medicines. The inventors have filed a patent application relating to the HIV protease inhibitor (Japanese Patent Application Laid-open No. 170722/1993). The inventors of the present invention continued the studies in which the inventors have synthesized various peptide compounds and determined chemical structures of novel compounds, including novel compounds exhibiting superior inhibition activity against HIV protease (Japanese Patent Application Laid-open No. 185631/1996, European Patent Publication EP 751145 A2).
However, hydroxymethylcarboxamide derivatives having superior HIV protease inhibition activity among these peptide-type compounds require a comparatively high dose to clinically exhibit a certain effect in many cases. Because anti-AIDS medicines are continuously administered for a long period of time, development of a compound possessing a high HIV protease inhibition activity which can provide a certain effect by oral administration at a small dose is desired. Specifically, development of a compound possessing a novel structure which is capable of tightly binding with HIV protease and exhibits a high treatment effect at a lower plasma concentration is desired.
DISCLOSURE OF THE INVENTION
The present invention was completed in view of this situation and has an object of providing a novel tripeptide compound showing a high HIV protease inhibition activity as compared with an HIV protease inhibitor consisting of a transition-state mimetic peptide compound which has been proposed as a conventional anti-AIDS medicine and exhibiting superior anti-HIV virus activity accompanied by this high HIV protease inhibition activity. Another object of the present invention is to provide an anti-AIDS medicine comprising this novel tripeptide compound as an active component and exhibiting a treatment effect with a smaller dose.
In an effort to solve these problems, the present inventors have made extensive improvement in conventional transition-state mimetic substance and, as a result, the inventors have designed and prepared a novel tripeptide compound. More specifically, the inventors of the present invention have found that a tripeptide compound having a skeleton similar to an amino acid sequence which is selectively cleared by an HIV protease, such as -Tyr . . . Pro or -Phe . . . Pro, particularly a hydroxymethylcarbamide derivative including a norstatin skeleton such as phenylalanine &phgr;[(CH(OH)C(O)N] proline, or a hydroxyethylamine derivative including phenylalanine &phgr;[CH(OH)CH
2
N] decahydroisoquinolinecarboxylic acid, exhibits a high HIV protease inhibition activity and a high action of suppressing growth of HIV viruses, particularly when a novel structure is introduced in the C-terminal amide structure. This finding has led to the completion of the present invention. The inventors have further found that another novel tripeptide produced by replacing a substitution group on the N-terminal amino group with an acyl group having a specific structure exhibits a high HIV protease inhibition activity and a high action of suppressing growth of HIV viruses. This finding has led to the completion of another feature of the present invention.
The above object can be achieved in the present invention by a novel tripeptide compound represented by the following formula (I),
wherein A is —NH—, —NR— (wherein R represents an alkyl group having 6 or less carbon atoms), —O—CH
2
—, —CH
2
—O— or a single bond; B is —CO— or —SO
2
—; D is —CO— or —CH
2
—; E represents a divalent hydrocarbon group which may form a 5 to 7 member ring together with the adjacent nitrogen atom and carbon atom or a divalent hydrocarbon group with one or more carbon atoms therein being replaced by one or more hetero atoms, wherein said ring may form a condensed ring together with another 5 to 7 member ring or may have 3 or less substituents on that ring; R
1
is a hydrogen atom, an alkyl group having 6 or less carbon atoms, or an aromatic group or heterocyclic group having 10 or less carbon atoms, wherein the said alkyl group may possess an alkyloxy group having 4 or less carbon atoms as an substituent, said aromatic group or heterocyclic group may be substituted by an alkyl group having 4 or less carbon atoms, alkyloxy group, mono or dialkyl-substituted amino group, halogeno group, hydroxyl group, amino group, or an alkyl or alkenyl group having 3 or less carbon atoms which may be substituted by a monocyclic aromatic group or monocyclic heteroaromatic group; R
2
is an aliphatic hydrocarbon group having 1-7 carbon atoms or an aromatic hydrocarbon group, provided that the aliphatic hydrocarbon group may have either a linear or branched structure and the carbon atom forming the skeleton of said aliphatic hydrocarbon group or aromatic hydrocarbon group may be replaced by a hetero atom, or the hydrogen atom thereon may be substituted by a carbamoyl group, carboxyl group or halogeno group; R
3
is an aryl group, arylthio group or aryloxy group, and may contain a substituent on the aromatic ring; and R
4
, R
5
, R
6
, R
7
, and R
8
respectively represent a hydrogen atom, alkyl group having 3 or less carbon atoms, halogeno group, amino group, hydroxyl group, aminomethyl group, hydroxymethyl group, or an amino group s
Kiso Yoshiaki
Mimoto Tsutomu
Nojima Satoshi
Takaku Haruo
Terashima Keisuke
Celsa Bennett
Japan Energy Corporation
Testa Hurwitz & Thibeault LLP
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