Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1995-02-01
2004-02-10
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S046000, C514S050000, C514S255030
Reexamination Certificate
active
06689761
ABSTRACT:
FIELD OF THE INVENTION
The combination in this invention is useful in the inhibition of HIV protease, the inhibition of HIV reverse transcriptase, the treatment of infection by HIV and in the treatment of AIDS and/or ARC (i.e., AIDS related complex), either as compounds, pharmaceutically acceptable salts or esters (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al.,
Proc. Nat'l Acad. Sci
., 85, 4686 (1988), demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al.,
Nature
, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al.,
EMBO J
., 4, 1267 (1985); Power, M. D. et al.,
Science
, 231, 1567 (1986); Pearl, L. H. et al.,
Nature
, 329, 351 (1987)].
The compound disclosed and referred to as “Compound J” in EPO 541,168, which published on May 12, 1993, is a potent inhibitor of HIV protease and is useful in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of AIDS or ARC, without significant side effects or toxicity:
or pharmaceutically acceptable salts thereof.
Compound J
One substantial and persistent problem in the treatment of AIDS has been the ability of the HIV virus to develop resistance to the individual therapeutic agents employed to treat the disease. To solve this problem, a combination therapy for AIDS has been discovered by applicants.
Applicants demonstrate that the combination of compounds of this invention is useful in the treatment of HIV infection.
In the present invention, applicants co-administer the potent HIV protease inhibitor Compound J with the nucleoside HIV reverse transcriptase inhibitor 3TC. Optionally, a third component which is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, ddI or ddC, is added to the combination. This combination therapy is a method to enhance the effectiveness in treating AIDS and to preclude the development of resistance to the individual therapeutic agents.
SUMMARY OF THE INVENTION
The present invention involves a combination of Compound J and the nucleoside analog HIV reverse transcriptase inhibitor 3TC, and, optionally, a nucleoside inhibitor of HIV reverse transcriptase selected from AZT, ddI or ddC, or a pharmaceutically acceptable salt or ester thereof.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
This invention is concerned with the combination of certain compounds, or pharmaceutically acceptable salts thereof, in the inhibition of HIV protease, the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). The combination is defined as follows:
A combination of compounds, which is Compound J and the nucleoside analog, HIV reverse transcriptase inhibitor 3TC, and, optionally a nucleoside inhibitor of HIV reverse transcriptase selected from AZT, ddI and ARC, or pharmaceutically acceptable salt or ester thereof.
One preferred combination involves the combination of Compound J and 3TC and AZT, administered simultaneously.
Another preferred combination involves the combination of Compound J, 3TC and AZT, administered alternatively.
Another preferred combination is compound J and the nucleoside inhibitor of HIV reverse transcriptase 3TC, or pharmaceutically acceptable salts thereof.
The HIV protease inhibitor Compound J is synthesized by the protocol of EP 0 541 168, published May 12, 1993. Compound J is N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N′-(t-butyl-carboxamido)-piperazinyl))-pentanemide, or pharmaceutically acceptable salt thereof.
The nucleoside analog 3TC has the structure
It is synthesized by the methods of C. K. Chu et al.,
J. Org. Chem
. 56, 6503 (1991); W. B. Choi et al.,
J. Am., Chem. Soc
. 113, 9377 (1991); L. Houng et al.,
J. Org. Chem
. 57, 5563 (1992); R. F. Schinazi et al.,
Antimicrob. Agents Chemother
. 36, 672 (1992); P. A. Furman et al.,
Antimicrob. Agents Chemother
. 36, 2686 (1992), EP 0494119 and WO 91/11186.
The pharmaceutically acceptable salts of the present invention (in the form of water- or oil-soluble or dispersible products) include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
The pharmaceutically acceptable salts of the combination of the instant invention include the combination wherein one of the individual components is in the form of a pharmaceutically acceptable salt, or the combination wherein all of the individual components are in the form of pharmaceutically acceptable salts, or a pharmaceutically acceptable salt of the combined components (i.e., a salt of the combination). In one embodiment of the present invention, the sulfate salt of the combination is utilized.
The pharmaceutically acceptable esters in the present invention refer to non-toxic esters, preferably the alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters, of which the methyl ester is preferred. However, other esters such as phenyl-C
1-5
alkyl may be employed if desired.
Esterification of alcohols, such as Compound J of the present invention, is performed by a variety of conventional procedures, including reacting the alcohol group with the app
Chodakewitz Jeffrey A.
Emini Emilio A.
Camara Valerie J.
Merck & Co. , Inc.
Travers Russell
Tribble Jack L.
Walton Kenneth R.
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