Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-25
2001-06-05
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S118000
Reexamination Certificate
active
06242461
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to novel aryl substituted azabenzimidazoles and the pharmaceutically acceptable salts thereof, methods of preparing these compounds and the use of these compounds in the treatment of HIV, AIDS and AIDS related diseases and in slowing the progression of HIV infection into AIDS.
The human disease, Acquired Immune Deficiency Syndrome (AIDS), is caused by the Human Immunodeficiency Virus (HIV), particularly the strain known as HIV-1.
Like other viruses, HIV cannot replicate without commandeering the biosynthetic apparatus of the host cell it infects. HIV causes this biosynthetic apparatus to produce the structural proteins which make up the viral progeny. These proteins are coded for by the genetic material contained within the infecting virus particle, or virion. Being a retrovirus, however, the genetic material of HIV is RNA, not DNA as in the host cell's genome. Accordingly, the viral RNA must first be converted into DNA, and then integrated into the host cell's genome, in order for the host cell to produce the required viral proteins. The conversion of the RNA to DNA is accomplished through the use of enzyme reverse transcriptase (RT), which is included within the infecting virion along with the RNA. Reverse transcriptase has three enzymatic functions; it acts as an RNA-dependent DNA polymerase; as a ribonuclease; and as a DNA-dependent DNA polymerase. Acting first as an RNA-dependent DNA polymerase, RT makes a single-stranded DNA copy of the viral RNA. Next, acting as a ribonuclease, RT frees the DNA just produced from the original viral RNA and then destroys the original RNA. Finally, acting as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand, using the first DNA strand as a template. The two strands form double stranded DNA, which is integrated into the host cell's genome by another enzyme called an integrase.
Compounds which inhibit the enzymatic functions of HIV reverse transcriptase will inhibit replication of HIV in infected cells. There is a high medical need for better tolerated, conveniently administered agents to treat AIDS which is increasingly viewed as a chronic disease. These agents should ideally reverse the development and progression of AIDS, in HIV infected individuals, reduce susceptibility to secondary infections, and return the patient to as near a normal lifestyle as possible.
SUMMARY OF THE INVENTION
The present invention comprises compounds of the formula
or a pharmaceutically acceptable salt thereof wherein
n is an integer from 1 to 4;
X is CH or N;
R
1
is H, (C
1
-C
6
)alkyl or (C
1
-C
6
) alkyloxy;
R
2
is H, (C
1
-C
6
)alkyl or (C
1
-C
6
) alkyloxy;
each R
3
is independently selected from H, (C
1
-C
6
)alkyl, (C
1
-C
6
) alkyloxy, (C
1
-C
6
) alkylthio, halo, nitro, cyano, ethynyl, hydroxy and trifluoromethyl;
R
4
is H, (C
1
-C
6
)alkyl or (C
1
-C
6
) alkoxy;
R
5
is H, (C
1
-C
6
)alkyl or (C
1
-C
6
) alkoxy, trifluoromethyl; and
W is N or C;
Y is N(R
4
), N, S or O;
Z is R
4
,NR
4
H, O, or OH;
provided that when Y═NR
4
, W═C, and Z═O, there is a single bond between YW and a double bond between WZ; and
when Y=O or S, W═C, and Z═O, there is a single bond between YW and a double bond between WZ; and
when Y═N, W═C, Z═R
4
or NHR
4
, there is a double bond between YW and a single bond between WZ; and
when Y═N, W═N, there is a double bond between YW and Z does not exist.
The invention also includes a pharmaceutical composition for inhibiting the enzymatic functions of HIV-reverse transcriptase in a patient wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutical composition is also effective in treating AIDS, AIDS related complex, and related disorders.
The invention further includes a method for treating an HIV infection that comprises administering to a patient infected with HIV, a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof. The method of treating a patient infected with HIV, including an individual that is asymptomatic but tests positive for the HIV antigen, an individual who is symptomatically sick but does not have AIDS related diseases and an individual infected with the HIV virus who has AIDS related diseases. The method further includes treating patients infected by one or more strains of the HIV virus as determined by the presence of either a measurable viral antibody or antigen in the patient's serum, has a symptomatic AID's defining infection including disseminated histoplasmosis, isopsoriasis, bronchial and pulmonary candidiasis, including pneumocystic pneumonia, non Hodgkin's lymphoma and kaposi's sarcoma or has an absolute CD
4
lympocyte count of less than 200/cm
3
in the patient's peripheral blood. The administration of the compounds of Formula I is oral and an effective dose is from about 0.01 mg/kg/day to about 500 mg/kg/day. The method includes the compounds of Formula I selected from the group consisting of:
3-[4-(2-Methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
6-Fluoro-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
3-[4-(2-Ethyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
3-[4-(2-Isopropyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one; and
3-[4-(2-Methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzooxazol-2-one.
6-Methyl-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
6-Ethyl-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
6-Isopropyl-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
6-Trifluoromethyl-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
6-Methoxy-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
6-Chloro-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
6-Cyano-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
5-Methyl-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
5-Chloro-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
5-Cyano-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
5-Methoxy-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
5-Fluoro-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
5-Trifluoromethyl-3-[4-(2-methyl-imidazo[4, 5-c] pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
6-Chloro-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzooxazol-2-one;
6-Methoxy-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzooxazol-2-one;
6-Methyl-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzooxazol-2-one;
5-Chloro-3-[4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzooxazol-2-one;
5-Methyl-3-[4-(2-methyl-imidazo[4,5-c]pyrid in-1-yl)-benzyl]-3H-benzooxazol-2-one;
1-[4-(2-Methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-1,3-dihydro-benzoimidazol-2-one;
3-[6-(2-Methyl-imidazo[4, 5-c] pyridin-1-yl)-pyridin-3-ylmethyl]-3H-benzothiazol-2-one;
1-[4-(2-Methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-1H-benzotriazole;
2-Methyl-1-[4-(2-methyl-benzoimidazol-1-ylmethyl)-phenyl]-1H-imidazo[4,5-c]pyridine;
3-[2-Methyl-4-(2-methyl-imidazo[4,5-c]pyridin-1-yl)-benzyl]-3H-benzothiazol-2-one;
5,6-Difluoro-3-[4-(2-methyl-imidazo[4,5-c]pyr
Goldstein Steven W.
Sherer Brian A.
Stirtan William G.
Appleman Jolene W.
Dentz Bernard
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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