&agr;-hydroxyarylbutanamine inhibitors of aspartyl protease

Details &agr;-hydroxyarylbutanamine inhibitors of aspartyl protease &agr;-hydroxyarylbutanamine inhibitors of aspartyl protease

2001-10-22

2004-02-24

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S617000, C514S625000, C564S155000, C564S161000, C564S192000

Reexamination Certificate

active

06696494

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to acylated &agr;-hydroxyarylbutanamines and related sulfonamides, ureas and carbamates that inhibit aspartyl protease and to methods of treating diseases using these compounds.
BACKGROUND OF THE INVENTION
The human immunodeficiency virus (“HIV”) is the causative agent for acquired immunodeficiency syndrome (“AMDS”)—a disease characterized by the destruction of the immune system, particularly of CD4+ T-cells, with attendant susceptibility to opportunistic infections—and its precursor AIDS-related complex (“ARC”)—a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss. As in the case of several other retroviruses, HIV encodes the production of a protease which carries out post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions. A number of synthetic anti-viral agents have been designed to target various stages in the replication cycle of HIV. These agents include compounds which block viral binding to CD4+ T-lymphocytes (for example, soluble CD4), and compounds which interfere with viral replication by inhibiting viral reverse transcriptase (for example, didanosine and zidovudine (AZT)) and inhibit integration of viral DNA into cellular DNA. However, such agents, which are directed primarily to early stages of viral replication, do not prevent the production of infectious virions in chronically infected cells. Furthermore, administration of some of these agents in effective amounts has led to cell-toxicity and unwanted side effects, such as anemia and bone marrow suppression.
More recently, the focus of anti-viral drug design has been to create compounds which inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the action of virus-encoded proteases which are essential for replication. The anti-viral potential of HIV protease inhibition has been demonstrated using peptidal inhibitors. Such peptidal compounds, however, are typically large and complex molecules that tend to exhibit poor bioavailability and are not generally efficacious on oral administration. Accordingly, the need still exists for compounds that can effectively inhibit the action of viral proteases, particularly aspartyl proteases, for use as agents for preventing and treating chronic and acute viral infections.
In addition, aspartyl protease inhibitors are of interest for developing antimalarial drugs. Resistance to known antimalarial therapies is becoming an increasing problem, and new therapies are therefore desperately needed. Upon infecting a host, the malaria parasite avidly consumes the host hemoglobin as its source of nutrients. Plasmepsin I and II are proteases from
Plasmodium falciparum
that are necessary during the initial stages of hemoglobin hydrolysis and digestion.
It has been shown that inhibition of plasmepsin by a peptidomimetic inhibitor is effective in preventing malarial hemoglobin degradation and in killing the parasite. Thus, persons skilled in the art expect that plasmepsin inhibitors will provide effective antimalarial therapy.
Another aspartyl protease, cathepsin D, has been implicated in a variety of diseases, including connective tissue disease, muscular dystrophy, and breast cancer. The enzyme is also believed to be the protease which processes the beta-amyloid precursor protein (Dreyer, R. N. et al. Eur. J. Biochem (1994), 244, 265-271 and Ladror, U. S. et al. J. Biol. Chem. (1994), 269, 12422-18428) generating the major component of plaques in the brains of Alzheimer's patients. Consequently, persons of skill in the art expect that inhibitors of cathepsin D will be useful in treating Alzheimer's disease.
Other human aspartyl proteases, such as renin, are involved in the maintenance of blood pressure, and inhibitors of these proteases find use as treatments for hypertension. Inhibitors of aspartyl proteases that process endothelin precursors are similarly useful blocking vasoconstriction.
SUMMARY OF THE INVENTION
It has now been discovered that certain acylated &agr;-hydroxyarylbutanamines and related sulfonamides, ureas and carbamates and pharmaceutically acceptable salts thereof, are useful as inhibitors of aspartyl proteases, in particular, HIV aspartyl protease. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection. The compounds of this invention are capable of inhibiting HIV viral replication in human CD4+ T-cells and are useful as therapeutic and prophylactic agents to treat or prevent infection by HIV-1 and related viruses which may result in asymptomatic infection, AIDS-related complex (“ARC”), acquired immunodeficiency syndrome (“AIDS”), or similar disease of the immune system. Therefore, in one aspect, the present invention relates to compounds of formula
wherein
R
1
is chosen from the group consisting of C
1
-C
20
alkyl, substituted C
1
-C
20
alkyl, aryl, alkylaryl, substituted alkylaryl, C
3
-C
10
oxaalkyl, substituted aryl, heterocyclyl, and substituted heterocyclyl;
R
2
is chosen from the group consisting of C
1
-C
10
hydrocarbon, substituted aryl and heterocyclyl;
A is chosen from the group consisting of —SO
2
—, —NHSO
2
—, —SO
2
NHC(O)—
 wherein r→designates the point of attachment to R
1
and n→designates the point of attachment to N;
is monocyclic, bicyclic or tricyclic aryl or heteroaryl containing from 0 to 3 substituents chosen from lower alkyl, lower alkoxy, lower alkylthio, hydroxy, mercapto, cyano, carboxy, lower alkoxycarbonyl, (lower alkoxycarbonyl)lower alkoxy, lower alkylaminocarbonyl, amino, lower alkylamino, di(lower alkyl)amino, nitro, halo and haloalkyl;
R
5
is chosen from the group consisting of hydrogen, alkyl, aryl and substituted aryl;
R
6
and R
7
are chosen independently from the group consisting of hydrogen, halogen and lower alkyl;
D is —C(O)— or —NHC(O)—;
E is chosen from the group consisting of C
5
-C
8
alkyl, heterocyclyl, substituted heterocyclyl and NR
10
R
11
;
R
10
is hydrogen or lower alkyl;
R
11
is chosen from C
1
-C
10
hydrocarbon, substituted aryl and substituted alkyl; and
Y is —O—, —S—, —NH— or a direct bond.
In another aspect, the invention relates to a method of treating or preventing a protease-precipitated disease which comprises administering a therapeutically effective amount of a compound of the formula shown above.
In another aspect, the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula shown above, or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formulae
as described above. Preferred subgenera are those in which:
R
2
is C
1
-C
10
hydrocarbon;
A is chosen from the group consisting of —SO
2
—,
 is monocyclic or bicyclic aryl or containing from 0 to 3 substituents chosen from lower alkyl, hydroxy, alkoxy, (lower alkoxycarbonyl)lower alkoxy, nitro and halo;
R
10
is hydrogen; and
R
11
is chosen from C
1
-C
10
hydrocarbon and substituted alkyl.
Particularly preferred subgenera are those in which
(1) A is —SO
2
—;
 and
R
1
is chosen from the group consisting of C
1
-C
8
alkyl; phenyl; phenyl substituted with halo, methoxy, hydroxymethyl, allyl, carboxy, trifluoromethyl, anilino, benzoyl, dimethylamino, amino, nitro, cyano, and C
1
-C
6
alkyl; hydroxy C
1
-C
6
alkyl; naphthyl; nitrogenous heterocyclyl; and substituted nitrogenous heterocyclyl;
(2)
 is phenyl, substituted phenyl or naphthyl; most preferably naphthyl or
 wherein
R
12
is chosen from the group consisting of hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, nitro and [(lower alkoxy)carbonyl]loweralkoxy;
R
13
is chosen from the group consisting of hydrogen, halogen, lower alkyl,

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