HIV protease inhibitors

Details HIV protease inhibitors HIV protease inhibitors

2000-08-17

2003-01-28

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S192000, C549S292000

Reexamination Certificate

active

06512006

ABSTRACT:

BACKGROUND OF THE INVENTION
The HIV-protease enzyme is absolutely essential for the replication and dissemination of HIV throughout the body (Navia M. A. and McKeever B. M.,
Ann. New York Acad. Sci.,
1990; 616:73-85) and has become an extremely important target for the design and development of anti-HIV therapeutic agents (von der Helm K.,
Biol. Chem.
1996; 377:756-774). Several peptidomimetic HIV protease inhibitors have been successfully developed (such as indinavir, saquinavir, ritonavir, and nelfinavir), which demonstrate significant clinical success in lowering plasma viral load, reducing the onset to AIDS, and decreasing the frequency of opportunistic infections (Deeks S. G., Smith M., Holodniy M., and Kahn J. O.,
JAMA.
1997; 277:145-153).
Yet the current HIV protease inhibitors by their peptidomimetic nature have relatively poor solubility, high biliary excretion, limited bioavailabilities and significant liver metabolism. These drawbacks in turn increase the need for high doses of a drug, which increases the frequency of various side effects and multiple drug interactions (Barry M., Gibbons S., Back D., and Mulcahy F.,
Clin. Pharmacokinet.,
1997;32: 194-209). More importantly, resistance to the current HIV protease inhibitors has emerged (Shock H. B., Garsky V. M., and Kuo L.,
J. Biol. Chem.,
1996;271:31957-31963) resulting in treatment failures (Fatkenheuer G., Theisen A., Rockstroh J., Grabow T., et al., AIDS, 1997;11:F113-F116). From this discussion, it is apparent that while HIV protease is an excellent antiviral target for the treatment of HIV infection and AIDS, there is a need to identify non-peptide inhibitors with improved pharmacological properties and which are not cross resistant with the current drugs (Wallace R. W.,
DDT,
1997;2:83-84).
U.S. Pat. No. 5,789,440 recites non-peptidic HIV protease inhibitors of formula A
The patent is hereby incorporated by reference. Excellent HIV protease inhibition was achieved, but the antiviral activity at the cellular level was in some cases less than desired for an ideal therapeutic agent due to poor overall pharmacological properties (Tummino P. J., Vara Prasad J. V. N., Ferguson D., Nauhan C., et al.,
BioOrganic and Med Chem.,
1996;4:1401-1410). These efforts however led to a core structure B where R
1
and R
2
were alkyl groups filling the
S
1
′ and S
2
′ pockets, respectively, and the phenyl of the phenethyl group at C
6
filled the S
2
pocket very efficiently. This core structure was recognized as a valuable platform for additional study (Tait B. D., Hagen S., Domagala J. M., Ellsworth E. L., et al.,
J. Med. Chem.,
1997;40:3781-3792).
Additional dihydropyrones C were reported when it was unexpectedly discovered that certain groups which reduced lipophilicity judiciously placed at R
1
-R
5
led to greatly
improved antiviral cellular activity. See U.S. Pat. No. 5,834,506. The patent is hereby incorporated by reference. Among the preferred compounds were those where R
1
and R
5
were OH, NH
2
, or CH
2
OH. In such cases, the preferred R
4
included a small alkyl chain or ring and R
6
was methyl. In addition to improved cellular antiviral activity, the compounds also showed good pharmacokinetics in animals relative to the less-polar substituted compounds. These compounds were also not cross resistant with current HIV Protease inhibitors (Hagen S. E., Vara Prasad J. V. N., Boyer F. E., Domagala J. M ., et al.,
J. Med.,
1997;40:3707-3711; Vander Roest S., Wold S., and Saunders J., 37
th
Interscience Conference on Antimicrobial Agents and Chemotherapy,
Sep. 28-Oct. 1, 1997, Toronto, Canada. Abstract I-84; Domagala J. M., Boyer F., Ellsworth E., Gajda C., et al., 5
th
Conference on Retroviruses and Opportunistic Infections,
Feb. 1-5, 1998, Chicago, Ill. Abstract 638).
While the compounds C were notable for their improved pharmacological properties relative to the non-polar substituted core molecules B, these highly favorable properties were conferred directly by the use of OH, NH
2
and NR
2
groups placed on the lipophilic rings. The rings themselves were important for binding to the enzyme “pockets” and for holding the t-butyl group and the groups R
1
-R
3
and R
5
in their proper places within the enzyme's active site.
This hereby incorporates by reference 5888L1-01-TMC filed on even date herewith entitled “A Method of Making Dihydropyrone HIV Protease Inhibitors” by Victor Fedij et al.
SUMMARY OF THE INVENTION
The present invention relates to compounds or pharmaceutically acceptable salts thereof of formula I, shown below:
wherein:
R
1
is H, a straight or branched alkyl of 1-6 carbons or a carbocycle of 3-6 carbons,
R
2
is H, a straight or branched alkyl of 1-5 carbons or a carbocycle of 3-6 carbons;
R
3
is H [C(R
9
)
2
]
n
OR, [C(R
9
)
2
]
n
N(R)
2
, [C(R
9
)
2
]
n
N(R
9
)COR, [C(R
9
)
2
]
n
CO
2
R, [C(R
9
)
2
]
n
(O)COR, [C(R
9
)
2
]
n
CON(R)
2
, [C(R
9
)
2
]
n
OC(O)N(R)
2
, [C(R
9
)
2
R], [C(R
9
)
2
]
n
N(R
9
)CON(R)
2
, [C(R
9
)
2
]
n
N(R
9
)CO
2
R, [C(R
9
)
2
]
n
OSO
2
N(R)
2
, [C(R
9
)
2
]
n
N(R
9
)SO
2
OR, [C(R
9
)
2
]
n
N(R
9
)SO
2
N(R)
2
, [C(R
9
)
2
]
n
OSO
2
R, [C(R
9
)
2
]
n
N (R
9
)SO
2
R, [C(R
9
)
2
]
n
SO
p
R, [C(R
9
)
2
]
n
N(R
9
)CSN(R)
2
, [C(R
9
)
2
]
n
N(R
9
)C(═NR
9
)N(R)
2
, [C(R
9
)
2
]
n
SO
2
N(R)
2
, [C(R
9
)
2
]
n
C(NR
9
)N(R)
2
, [C(R
9
)
2
]
n
COR, O[C(R
9
)
2
]
m
OR, N(R)[C(R
9
)
2
]
m
OR, F, Cl, Br, CF
3
, CN, or ═O when Ar is Het;
R
4
, R
5
, and R
6
are independently H, a straight or branched alkyl of 1-6 carbons, a cycloalkyl of 3-6 carbons, [C(R
9
)
2
]
n
OR, [C(R
9
)
2
]
n
N(R)
2
, F, Cl, Br, CN, CF
3
, ═O when Ar is Het; [C(R
9
)
2
]
n
N(R
9
)COR, [C(R
9
)
2
]
n
SO
p
R, [C(R
9
)
2
]
n
R, [C(R
9
)
2
]
n
(O)COR, O[C(R
9
)
2
]
m
OR, N(R)[C(R
9
)
2
]
m
OR, [C(R
9
)
2
]
n
N(R
9
)CON(R)
2
, [C(R
9
)
2
]
n
(O)CON(R)
2
, [C(R
9
)
2
]
n
NR
9
CO
2
R, [C(R
9
)
2
]
n
COR, [C(R
9
)
2
]
n
CO
2
R, [C(R
9
)
2
]
n
CON(R)
2
, [C(R
9
)
2
]
n
N(R
9
)SO
2
R, [C(R
9
)
2
]
n
SO
2
N(R)
2
, [C(R
9
)
2
]
n
N(R
9
)SO
2
OR, [C(R
9
)
2
]
n
OSO
2
N(R)
2
, [C(R
9
)
2
]
n
N(R
9
)SO
2
N(R)
2
, [C(R
9
)
2
]
n
C(═NR
9
)N(R)
2
, [C(R
9
)
2
]
n
N(R
9
)C(═NR
9
)N(R)
2
, [C(R
9
)
2
]
n
Het;
any two of R
1
-R
3
or R
4
-R
6
may together form a ring of 5-6 total atoms which may contain 0-3 heteroatoms;
X is NH, NR
8
;
f is an integer of from 0 to 3;
n is an integer of from 0 to 3;
m is an integer of from 2 to 4;
p is an integer from 1 to 2;
R
7
is a straight or branched alkyl of 1-6 carbons or a carbocycle of 3-6 carbons;
R
8
is a straight or branched alkyl of 1-6 carbons, a carbocycle of 3-6 carbons, (CH
2
)
n
Ph, or a (CH
2
)
n
heterocycle of 5-6 atoms containing 1-4 heteroatoms and wherein the (R)
2
in N(R)
2
optionally forms a heterocycle containing the nitrogen, all optionally substituted by F, Ci, Br, OR
9
, CN, CO
2
R
9
, N(R
9
)
2
, NR
9
COR
9
, CF
3
, or ═O; or an alkyl group bearing polar functionalities, optionally including OH, NH
2
, CN;
R
1
and R
8
may together form a ring of 5-6 atoms;
R is independently H, a straight or branched alkyl of 1-6 carbons, (CH
2
)
n
Ph, or a (CH
2
)
n
heterocycle of 5-6 atoms containing 1-4 heteroatoms and wherein the (R)
2
in N(R)
2
optionally forms a heterocycle containing the nitrogen, all optionally substituted by F, Cl, Br, OR
9
, CN, CO
2
R
9
, N(R
9
)
2
, NR
9
COR
9
, CF
3
, or ═O;
R
9
is independently H, a straight or branched alkyl of 1-4 carbons, or phenyl;
R
10
is independently H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br, OR
9
or N(R
9
)
2
;
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
and R
10
may be alkene

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