Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-09
2002-04-23
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S255030, C514S256000, C544S238000, C544S241000, C544S297000, C544S322000, C544S333000, C544S359000, C544S392000, C544S403000
Reexamination Certificate
active
06376492
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds and pharmaceutically acceptable salts thereof and methods for treating infections by HIV and related viruses and/or the treatment of Acquired Immune Deficiency Syndrome (AIDS) Also disclosed are pharmaceutical compositions containing the compounds and the method of use of the present compounds alone or in combination with other agents, for the treatment and inhibition of ATDS and viral infection from HIV.
BACKGROUND OF THE INVENTION
A retrovirus designated Human Immunodeficiency Virus (HIV) is believed to be the causative agent of the complex disease termed Acquired Immune Deficiency Syndrome (AIDS) and is a member of the lentivirus family of retroviruses (M. A. Gonda, F. Wong-Staal N R. C. Gallo, “Sequence Homology and Morphological Similarity of HTLV III and Visna Virus, A Pathogenic Lentivirus”,
Science
, 227, 173, (1985); and P. Sonigo and N. Alizon, et al., “Nucleotide Sequence of the Visna Lentivirus: Relationship to the AIDS Virus”,
Cell
, 42, 369, (1985)). The HIV virus (also referred to as the AIDS virus) was previously known as or referred to as LAV, HTLV-III, or ARV, and is now designated by HIV-1. Other closely related variants of HIV-1 include HIV-2 and SIV (simian immunodeficiency virus), and mutants thereof. The complex disease AIDS includes progressive destruction of the immune system and degeneration of the central and peripheral nervous system. The HIV virus appears to preferentially attack helper T-cells (T-lymphocytes or OKT4-bearing T-cells) and also other human cells, e.g., certain cells within the brain. The helper T-cells are invaded by the virus and the T-cell becomes an HIV virus producer. The helper T-cells are quickly destroyed and their number in the human being is depleted to such an extent that the body's B-cells as well as other T-cells normally stimulated by helper T-cells no longer function normally or produce sufficient lymphokines and antibodies to destroy the invading virus or other invading microbes.
While the HIV virus does not necessarily cause death per se, it does cause the human's immune system to be so severely depressed that the human falls prey to various other diseases such as herpes,
Pneumocystis carinii
, toxoplasmosis, cytomegalovirus, Kaposi's sarcoma, and Epstein-Barr virus related lymphomas among others. These secondary infections are separately treated using other medications as is conventional. Early during infection, humans with HIV virus seem to live on with little or no symptoms, but have persistent infections. Later in the disease, humans suffer mild immune system depression with various symptoms such as weight loss, malaise, fever, and swollen lymph nodes. These syndromes have been called persistent generalized lymphadenopathy syndrome (PGL) and AIDS related complex (ARC) and develop into AIDS.
In all cases, those infected with the AIDS virus are believed to be persistently infective to others. Further, AIDS and AIDS related complex is after some time fatal.
A description of the mechanism by which the virus infects its host is given in an article by R. Yarchoan, and S. Broder, “Development of Antiretroviral Therapy for the Acquired Immunodeficiency Syndrome and Related Disorders”,
New England Journal of Medicine
, 316, 557-564 (Feb. 26, 1987).
Considerable efforts are being directed toward the control of HIV by means of inhibition of the reverse transcriptase of HIV, required for replication of thee virus. (V. Merluzzi et al., “Inhibition of the HIV-1 Replication by a Nonnucleoside Reverse Transcriptase Inhibitor”,
Science
, 25, 1411 (1990)). For example, a currently used therapeutic compound, AZT, is an inhibitor of the viral reverse transcriptase (U.S. Pat. No. 4,724,232). Unfortunately, many of the now used compounds suffer from toxicity problems, lack of bioavailability or are short lived in vivo, viral resistance, or combinations thereof. Therefore, new compounds are being investigated. For example, a PCT application published on Feb. 18, 1993, (WO 93/03022; International Application No. PCT/SE92/00533) discloses thiourea compounds which show promise in the treatment and inhibition of HIV and AIDS.
Certain compounds falling within the scope of the definition of the methods of the present invention have been published in roles other than for the treatment of HIV. These compounds are excluded by proviso from the compound claims. The Chemical Abstract registry numbers or sources for these compounds are as follows:
a)
i)
87977-01-3;
ii)
75808-56-9;
iii)
78329-62, 112822-56-7, -49-8, 51-2,
-48, 7, -48-6, -50-1 and -46-5;
iv)
65094-08-8;
v)
39960-40-2 and -10-6, 64442-48-2 and
-47-3;
vi)
U.S. Pat. No. 3,705,903;
vii)
85180-12-7;
viii)
55474-82-3;
ix)
49551-06-6, -08-8, -08-4, -81-7, -67-9,
-65-7, -58-8, -31-7, -63-3 and -60-2, and
49552-03-6;
x)
U.S. Pat. No. 4,057,636;
b)
100973-52-2, 92852-25-0;
c)
141403-37-4
Therefore, it is an object of the invention to provide compounds and pharmaceutically acceptable salts thereof to inhibit and/or treat HIV and AIDS.
Another object of the present invention is to provide therapeutic formulations that are of value in the inhibition and/or treatment of infection by HIV and the treatment or inhibition of the acquired immune deficiency syndrome.
Another object is to provide methods for the inhibition and/or treatment of infection by HIV and the resulting acquired immune deficiency syndrome.
Other objects, features, and advantages will become apparent to those skilled in the art from the following description and claims.
DESCRIPTION OF THE INVENTION
The present invention provides compounds useful for the inhibition and/or treatment of HIV and AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition Ingredients, whether or not in combination with other anti-virals, immunomodulators, antibiotics, or vaccines. Methods of treating or inhibiting AIDS, methods of inhibiting replication of HIV, and methods of treating or inhibiting HIV in humans are also disclosed.
The compounds used in the methods of the present invention are those of the formula (IA) below
wherein A is
wherein R
a
is H, OR
b
, CN, NO
2
, N(R
b
)
2
, SR
b
, SO
2
R
b
, SO
2
N(R
b
)
2
, COR
b
, CO
2
R
b
, CON(R
b
)
2
, PO(R
b
)2, PO(OR
b
)
2
, PO(NR
b
)
2
, wherein R
b
is hydrogen, C
1
-C
6
alkyl, C
1
-C
6
substituted alkyl, C
2
-C
6
alkenyl, C
2
-C
6
substituted alkenyl, C
2
-C
8
alkynyl, C
2
-C
8
substituted alkynyl, C
1
-C
6
alkoxy, C
1
-C
6
substituted alkoxy, C
4-10
aralkyl, C
1-10
alkaryl, C
1-10
alkylthio, C
4-10
aralkylthio, C
1-10
alkylsulfinyl, C
4-10
alkylsulfinyl, C
1-10
alkylsulfonyl, C
4-10
alkylsulfonyl, carboxy, C
1-10
alkylthiocarbonyl, C
4-10
aralkylcarbonyl, C
4-10
aralkylthiocarbonyl, C
4-10
aralkoxycarbonyl, C
4-10
aralkoxycarbonyl, C
1-4
alkyl, C
4-10
aralkoxy, C
1-12
dialkylamino-C
1-6
aralkanoylamino C
4-10
aralkylamino or C
1
-C
4
alkanoyloxy;
R
1
is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, O, and N; or R
1
is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, O, and N;
R
2
is a group of the formula
wherein R
5
is R
1
as defined above; or R
5
is a group of the formula
(R
10
)
y
—X—
wherein y is 1 or 2; X is N, S, O and R
10
is R
1
as defined; or R
10
is hydrogen, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, or C
2
-C
6
alkynyl, substituted C
1
-C
6
alkyl, substituted C
2
-C
6
alkenyl, or substituted C
2
-C
6
alkynyl; or R
5
is hydrogen, halo, cyano, carboxy, amino, thio, hydroxy, C
1
-C
6
alkoxy, C
1
-C
6
substituted alkoxy, C
1
-C
6
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, or C
2
-C
8
alkenoxy;
R
6
, R
7
, R
8
, and R
9
are independently C
3
-C
8
cycloalkyl, hydrogen, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, substituted C
1
-C
6
alkyl, substituted C
2
-C
6
alkenyl, or substituted C
2
-C
6
alkynyl, C
1
-C
6
s
Lind Peter Thomas
Morin John Michael
Noreen Rolf
Ternansky Robert John
Birch Stewart Kolasch & Birch, LLP.
Medivir AB
Raymond Richard L.
Truong Tamthom N.
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