Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1994-05-20
2001-11-06
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S016700, C514S017400, C514S019300, C530S329000, C530S330000, C530S331000, C530S332000
Reexamination Certificate
active
06313094
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to &bgr;-Amino-&agr;-hydroxycarboxylic acid derivatives and salts thereof which are useful as human immunodeficiency virus (HIV) protease inhibitors and/or as intermediates for synthesizing the inhibitors.
2. Description of the Related Art
Heretofore, various efforts for the therapy of acquired immunodeficiency syndrome (AIDS) and the prevention of infection of the human immunodeficiency virus (HIV) by inhibiting the HIV protease have been performed. Some peptide derivatives have been proposed as the inhibitor, for example, Japanese Unexamined Patent Publication Nos. 117615, 209854, 202898, 202899, 204475 (1990) and Review:
J. Med. Chem.,
34, 2305 (1991). Some HIV protease inhibitors involve the use of hydroxy amino acid isosteres, and in addition, a formation of hydrogen bond between the hydroxy group and Asp25 in the active site of HIV protease was proposed.
Also, a renin inhibitor having a &bgr;-amino-&agr;-hydroxycarboxylic residue shown by the following general formula (6) as an amino acid isostere in a peptide chain was proposed, for example, in Japanese Unexamined Patent Publication No. 101098 (1990) and the preparation of said carboxylic acid was reported in relation to an anti-cancer agent, for example, in
J. Med. Chem.,
20, 510, (1977), ibid., 33, 2707 (1990).
Formula (6) has the following structure:
In the general formula (6), R
8
represents a straight or branched lower alkyl group, a cycloalkyl-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, an amino-lower alkyl group, or an aryl-lower alkyl group.
However, no &bgr;-amino-&agr;-hydroxy-carbocyclic acid mentioned above has been used as amino acid isostere in an HIV protease inhibitor.
Further, compounds having the following basic structure represented by general formula (3) and (3′) are not known.
wherein n represents 1 or 2, A represents a hydrogen atom or a peptide N-terminal protective group, B
1
, B
2
, B
3
, B
5
, and B
6
represents independently a single bond or an amino acid residue, optionally the amino group of said amino acid can be substituted with a hydrocarbon residue having 12 or less carbon atoms, B
7
represents a single bond or an amino acid residue represented by following formula (4) with a proviso that XR
2
R
3
represents the following general formula (4′) when B
7
is a single bond, X represents a nitrogen atom or an oxygen atom, R
1
represents a lower alkyl group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group or a heterocyclic group optionally substituted with an amino group, a mercapto group, a hydroxy group, a carboxy group, a carbamoyl group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group or a heterocyclic group, R
2
and R
3
each represents a hydrogen atom or an optionally substituted hydrocarbon group having 12 or less carbon atoms which form cycles by forming bonds between said carbon atoms which may optionally be replaced with an oxygen, nitrogen or sulfur atom with the proviso that no R
3
is present when X represents oxygen atom, R
4
represents a carbamoyl group, a carboxy group, a cyano group, an alkoxycarbonyl group, a hydroxy group, a lower alkoxy group, a lower alkylthio group, a lower alkanesulfonyl group, a sulfonyl group, a lower alkanesulfinyl group or a sulfamoyl group, R
5
represents an optionally substituted arylmethyl group, and R
6
has the same meaning as that in the following general formula (4):
wherein R
6
and R
7
represent a bivalent hydrocarbon group forming a 5-7 membered ring optionally substituted or fused with the other 5-7 membered ring, and a part of carbon atoms in said rings optionally replaced with hetero atoms.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel HIV protease inhibitors.
Another object of the invention is to provide novel compounds with excellent inhibitory action having a &bgr;-Amino-&agr;-hydroxycarboxylic acid residue as an amino acid isostere.
The object of the present invention has been attained by the following HIV protease inhibitors:
Human immunodeficiency virus (HIV) protease inhibitors comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:
wherein A represents a hydrogen atom or a peptide N-terminal protective group, B
1
, B
2
, B
3
, B
4
, B
5
, and B
6
represent independently a single bond or amino acid residue in which the amino group is optionally substituted with a hydrocarbon group having 12 or less carbon atoms, with a proviso that the presence of at least one of said B
1
through B
6
is necessary, R
1
represents a lower alkyl group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group or a heterocyclic group, each optionally substituted with an amino group, a mercapto group, a hydroxy group, a carboxy group, a carbamoyl group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group or a heterocyclic group, X represents a nitrogen atom or an oxygen atom, and R
2
and R
3
each represents a hydrogen atom or a hydrocarbon group having 12 or less carbon atoms which may form cycles of which carbon atoms may optionally be replaced with an oxygen, nitrogen or sulfur atom, with the proviso that no R
3
is present when X represents an oxygen atom.
Another object of the present invention has been attained by novel compounds represented by the following general formula (3) or (3′), and the HIV protease inhibitors containing said compound or pharmaceutically acceptable salt compounds thereof:
wherein n represents 1 or 2, A represents a hydrogen atom or a peptide N-terminal protective group, B
1
, B
2
, B
3
, B
5
, and B
6
represents independently a single bond or an amino acid residue, optionally the amino group of said amino acid can be substituted with a hydrocarbon residue having 12 or less carbon atoms, B
7
represents a single bond or an amino acid residue represented by the following formula (4), with a proviso that XR
2
R
3
represents the following general formula (4′) when B
7
is a single bond, X represents a nitrogen atom or an oxygen atom, R
1
represents a lower alkyl group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group or a heterocyclic group optionally substituted with an amino group, a mercapto group, a hydroxy group, a carboxy group, a carbamoyl group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group or a heterocyclic group, R
2
and R
3
each represents a hydrogen atom or an optionally substituted hydrocarbon group having 12 or less carbon atoms which form cycles by forming bonds between said carbon atoms which may optionally be replaced with an oxygen, nitrogen or sulfur atom, with the proviso that no R
3
is present when X represents an oxygen atom, R
4
represents a carbamoyl group, a carboxy group, a cyano group, an alkoxycarbonyl group, a hydroxy group, a lower alkoxy group, a lower alkylthio group, a lower alkanesulfonyl group, a sulfonyl group, a lower alkanesulfinyl group or a sulfamoyl group, R
5
represents an optionally substituted arylmethyl group, and R
6
has the same meaning as that in the following general formula (4):
wherein R
6
and R
7
represent a bivalent hydrocarbon group forming a 5-7 membered ring optionally substituted or fused with the other 5-7 membered ring, and a part of carbon atoms in said rings optionally replaced with hetero atoms.
REFERENCES:
patent: 4240975 (1980-12-01), Umezawa et al.
patent: 4656269 (1987-04-01), Iizuka et al.
patent: 4711958 (1987-12-01), Iizuka et al.
patent: 4841067 (1989-06-01), Iizuka et al.
patent: 4853463 (1989-08-01), Iizuka et al.
patent: 4857650 (1989-08-01), Iizuka et al.
patent: 4870183 (1989-09-01), Iizuka et al.
patent: 5342922 (1994-08-01), Marshall et al.
patent: 5932550 (1999-08-01), Kato et al.
patent: 5962640 (1999-10-01), Kato et al.
patent: 2015070 (1990-10-01), None
patent: 337714 (1989-10-01), None
patent: 357332 (1990-03-01), None
patent: 373497 (1990-06-01), None
patent: 373549 (1990-06-01), None
patent: 372537 (1990-06-01), None
Hattori Naoko
Kiso Yoshiaki
Mimoto Tsutomu
Nagano Yuuichi
Shintani Makoto
Japan Energy Corporation
Low Christopher S. F.
Lukton David
Testa Hurwitz & Thibeault LLP
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