Amine derivatives of oxo- and hydroxy- substituted hydrocarbons

Details Amine derivatives of oxo- and hydroxy- substituted hydrocarbons Amine derivatives of oxo- and hydroxy- substituted hydrocarbons

1999-05-27

2001-07-10

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S247000, C514S248000, C514S252030, C540S553000, C544S237000, C544S238000

Reexamination Certificate

active

06258806

ABSTRACT:

TECHNICAL FIELD
The invention relates to certain amine derivatives and their use in the inhibition of human immunodeficiency virus (HIV) proteases and thus in the treatment of HIV viral infections such as acquired immunodeficiency syndrome (AIDS).
BACKGROUND ART
Human immunodeficiency virus (HIV) is a pathogenic retrovirus causing AIDS and its related disorders. The development of antiviral chemotherapy against AIDS has been the subject of an intense research effort since the discovery of HIV. (For a recent review on molecular targets for AIDS therapy see Mitsua et al, Science, 1990, pp 1533-1544). The HIV Proteases (HIV PR), and aspartyl proteases, were first suggested as a potential target for AIDS therapy by Kramer et al. (
Science,
231, 1580, 1986). Since that time the potential usefulness of HIV PR inhibitors as effective agents in treatment of AIDS has been widely recognized (for a review of the HIV PR as a therapeutic target see Tomaselli et al.
Chimica Oggi
, May 1991, pp 6-27 and Huff J. R.,
J.Med.Chem.,
1991, 34, 2314-2327). Of the classical transition state mimics for aspartyl proteases, the hydroxyethylene, dihydroxyethylene, hydroxyethylamine and phosphinic acid isosteres appear to provide the greatest affinity for HIV PR. Many inhibitors of HIV PR have been shown to have an antiviral activity at concentrations in the nanomolar range in the different cell systems and are described as such in the patent literature.
SUMMARY OF THE INVENTION
The invention provides a new class of compounds which are useful as inhibitors of retroviral proteases, particularly aspartyl proteases and more particularly HIV proteases, and which are effective in treating conditions characterized by unwanted activity of these enzymes, in particular acquired immune deficiency syndrome.
A first embodiment of the invention is directed to compounds of the general formula (I):
or pharmaceutically acceptable salts thereof, wherein:
R
1
is a group R, wherein R is selected from the group consisting of hydrogen, —R′H, —R′C(O)OR″, —R′C(O)NH
2
, —R′C(O)NHR″, —R′C(O)NR″R′″, —R′NHC(O)R″, —R′NR′″C(O)R″ or —R′C(O)R″, where R″ and R′″ are independently optionally substituted (C
1
-C
18
)alkyl, typically (C
1
-C
12
)alkyl; (C
3
-C
18
)cycloalkyl, typically (C
3
-C
12
)cycloalkyl; (C
3
-C
18
)cycloalkyl(C
1
-C
18
)alkyl, typically (C
3
-C
12
)cycloalkyl(C
1
-C
6
)alkyl; (C
6
-C
24
)aryl, typically (C
6
-C
16
)aryl; (C
7
-C
25
)aralkyl, typically (C
7
-C
16
)aralkyl; (C
2
-C
18
)alkenyl, typically (C
2
-C
12
)alkenyl; (C
8
-C
26
)aralkenyl, typically (C
8
-C
16
)aralkenyl; (C
2
-C
18
)alkynyl, typically (C
2
-C
12
)alkynyl; (C
8
-C
26
)aralkynyl, typically (C
8
-C
16
)aralkynyl; or heterocyclic, and where R′ is an optionally substituted divalent radical derived from (C
1
-C
18
)alkyl, typically (C
1
-C
12
)alkyl; (C
3
-C
18
)cycloalkyl, typically (C
3
-C
12
)cycloalkyl; (C
3
-C
18
)cycloalkyl(C
1
-C
18
)alkyl, typically (C
3
-C
12
)cycloalkyl(C
1
-C
6
)alkyl; (C
6
-C
24
)aryl, typically (C
6
-C
16
)aryl; (C
7
-C
25
)aralkyl, typically (C
7
-C
16
)aralkyl; (C
2
-C
18
)alkenyl, typically (C
2
-C
12
)alkenyl; (C
8
-C
26
)aralkenyl, typically (C
8
-C
16
)aralkenyl; (C
2
-C
18
)alkynyl, typically (C
2
-C
12
)alkynyl; (C
8
-C
26
)aralkynyl, typically (C
8
-C
16
)aralkynyl; or heterocyclic,
or R
1
is
 where R
4
, R
5
and R
6
are independently a group R as defined above, or R
4
has the meaning of R as defined above and R
5
and R
6
taken together are ═O, ═S, ═NH or ═NR;
and R
2
is
 where R is as previously defined; D is O or S; Y is hydrogen, —R or —OR, where R is as previously defined, or is an amino acid, aza-amino acid or peptide residue in which any functional group present is optionally protected; and B is optionally absent or is (C
1
-C
6
)alkylidene, wherein any one or more —CH
2
— groups may be replaced by —NR—, —NH—, —O— or —S— or provided that the compound of Formula (I) does not contain a chain of three or more atoms which are not carbon, and wherein any H atom may be substituted by a group R as previously defined; and optionally N*, N, R
1
and R taken together form a cyclic diazaalkane of the formula:
 where p is 1 to 3, each R is independently as defined above and R
8
is R, —NH
2
, —NHR, —NR
2
, —COOH, —COOL, —CHO, —C(O)R, —CN, halo, —CF
3
, —OL, —SR, —S(O)R, —S(O)
2
R, —CONH
2
, —CONHR, —CONR
2
, —NHOH, —NHOL, —NO
2
, ═O, ═S or —NHNH
2
, wherein each R is independently as defined above and each L is independently R or a hydroxyl protecting group which is labile in vivo;
or R
2
, N* and R
4
together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinafter which may be additionally substituted by —C(O)Y, where Y is as previously defined
and R
3
is X—W—A′—Q—A—, wherein:
A′ and A independently are absent or (C
1
-C
8
)alkylidene, typically (C
1
-C
4
)alkylidene which may be substituted with one or more substituents R as previously defined;
Q is
 where L and each R, independently of the others, are as previously defined,
and optionally Q and A together, or Q and A′ together, or A′, Q and A together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinafter;
W is absent or is N(R), O or S, wherein R is as previously defined;
and X is hydrogen, or X
1
, where X
1
is Ra— or RbC(O)— or RbS(O)
z
—, where z is 1 or 2 and Ra and Rb are independently (C
1
-C
18
)alkyl, typically (C
1
-C
12
)alkyl; (C
3
-C
18
)cycloalkyl, typically (C
3
-C
12
)cycloalkyl; (C
3
-C
18
)cycloalkyl(C
1
-C
18
)alkyl, typically (C
3
-C
12
)cycloalkyl(C
1
-C
6
)alkyl; heterocyclic; (C
1
-C
18
)alkylheterocyclic, typically (C
1
-C
12
)alkylheterocyclic; heterocyclic(C
6
-C
24
)aryloxy, typically heterocyclic(C
6
-C
16
aryloxy; (C
1
-C
18
)alkoxy, typically (C
1
-
12
)alkoxy; (C
1
-C
18
)alkoxy(C
1
-C
18
)alkyl, typically (C
1
-C
12
)alkoxy(C
1
-C
12
)alkyl; (C
6
-C
24
)aryloxy(C
1
-C
18
)alkyl, typically (C
6
-C
16
)aryloxy(C
1
-C
12
)alkyl; (C
6
-C
24
)aryloxy(C
1
-C
18
)alkoxy, typically (C
6
-C
16
)aryloxy(C
1
-C
12
)alkoxy; (C
6
-C
24
)aryl, typically (C
6
-C
16
)aryl; (C
6
-C
24
)aryl(C
1
-C
18
)alkyl, typically (C
6
-C
16
)aryl(C
1
-C
12
)alkyl; (C
6
-C
24
)aryl(C
1
-C
18
)alkylheterocyclic, typically (C
6
-C
16
)aryl(C
1
-C
12
)alkylheterocyclic; heterocyclicoxy(C
1
-C
18
)alkyl, typically heterocyclicoxy(C
1
-C
12
)alkyl; (C
1
-C
18
)alkylamino, typically (C
1
-C
12
)alkylamino; di(C
1
-C
18
)alkylamino, typically di(C
1
-C
12
)alkylamino; (C
6
-C
24
)arylamino, typically (C
6
-C
16
)arylamino; di(C
6
-C
24
)arylamino, typically di(C
6
-C
16
)arylamino; (C
7
-C
25
)aralkylamino, typically (C
7
-C
12
)aralkylamino or di(C
7
-C
25
)aralkylamino, typically di(C
7
-C
12
)aralkylamino; any of which may be optionally substituted as hereinbelow defined-or substituted with a group Re, where Re is a group of the formula:
 where Z has the meaning of Ra or Rb or is an acylated amino acid, azaamino acid or peptide residue, and Rf is the side-chain of a natural amino acid in which any functional group present is optionally protected;
or X is Re as previously defined,
or X is an optionally protected amino acid, azaamino acid or peptide residue; or
when W is N(R), then X, N and the substituent R on N together may form a saturated or un,saturated cyclic, bicyclic or fused ring system as defined hereinbelow or N, A′ and the substituent R on N together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbelow.
Also included within the scope of the invention are compounds wherein two R substituents, not necessarily vicinal, taken together are optionally substituted (C
2
-C
18
)alkylidene, typically (C
2
-C
8
)alkylidene.
Also included within the scope of the invention are compounds wherein the Z—NH bond shown is replaced by a modified isosteric bond, such as CH
3
—NRa—, RaCH
2
—NRa—, CH
3
—CHRa—, HCH═CR

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