News Column

Patent Issued for Betulinic Acid Derivatives with Antiviral Activity

June 30, 2014



By a News Reporter-Staff News Editor at AIDS Weekly -- From Alexandria, Virginia, NewsRx journalists report that a patent by the inventors Liu, Zheng (Beacon Falls, CT); Meanwell, Nicholas A. (East Hampton, CT); Regueiro-Ren, Alicia (Middletown, CT), filed on September 20, 2012, was published online on June 17, 2014 (see also Bristol-Myers Squibb Company).

The patent's assignee for patent number 8754069 is Bristol-Myers Squibb Company (Princeton, NJ).

News editors obtained the following quote from the background information supplied by the inventors: "HIV-1 (human immunodeficiency virus -1) infection remains a major medical problem, with an estimated 45-50 million people infected worldwide at the end of 2010. The number of cases of HIV and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0 million new infections were reported, and 3.1 million people died from AIDS. Currently available drugs for the treatment of HIV include nucleoside reverse transcriptase (RT) inhibitors or approved single pill combinations: zidovudine (or AZT or RETROVIR.RTM.), didanosine (or VIDEX.RTM.), stavudine (or ZERIT.RTM.), lamivudine (or 3TC or EPIVIR.RTM.), zalcitabine (or DDC or HIVID.RTM.), abacavir succinate (or ZIAGEN.RTM.), Tenofovir disoproxil fumarate salt (or VIREAD.RTM.), emtricitabine (or FTC EMTRIVA.RTM.), COMBIVIR.RTM. (contains -3TC plus AZT), TRIZIVIR.RTM. (contains abacavir, lamivudine, and zidovudine), EPZICOM.RTM. (contains abacavir and lamivudine), TRUVADA.RTM. (contains VIREAD.RTM. and EMTRIVA.RTM.); non-nucleoside reverse transcriptase inhibitors: rilpivirine (or EDURANT.RTM.), nevirapine (or VIRAMUNE.degree.), delavirdine (or RESCRIPTOR.RTM.) and efavirenz (or SUSTIVA.degree.), ATRIPLA.RTM. (TRUVADA.RTM.+SUSTIVA.RTM.), COMPLERA.RTM. (TRUVADA.RTM.+EDURANT.RTM.), and etravirine, and peptidomimetic protease inhibitors or approved formulations: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, KALETRA.RTM. (lopinavir and Ritonavir), darunavir, atazanavir (REYATAZ.RTM.) and tipranavir (APTIVUS.RTM.), and integrase inhibitors such as raltegravir (ISENTRESS.RTM.), and entry inhibitors such as enfuvirtide (T-20) (FUZEON.RTM.) and maraviroc (SELZENTRY.RTM.).

"Each of these drugs can only transiently restrain viral replication if used alone. However, when used in combination, these drugs have a profound effect on viremia and disease progression. In fact, significant reductions in death rates among AIDS patients have been recently documented as a consequence of the widespread application of combination therapy. However, despite these impressive results, 30 to 50% of patients may ultimately fail combination drug therapies. Insufficient drug potency, non-compliance, restricted tissue penetration and drug-specific limitations within certain cell types (e.g. most nucleoside analogs cannot be phosphorylated in resting cells) may account for the incomplete suppression of sensitive viruses. Furthermore, the high replication rate and rapid turnover of HIV-1 combined with the frequent incorporation of mutations, leads to the appearance of drug-resistant variants and treatment failures when sub-optimal drug concentrations are present. Therefore, novel anti-HIV agents exhibiting distinct resistance patterns, and favorable pharmacokinetic as well as safety profiles are needed to provide more treatment options. Improved HIV fusion inhibitors and HIV entry coreceptor antagonists are two examples of new classes of anti-HIV agents further being studied by a number of investigators.

"HIV attachment inhibitors are a further subclass of antiviral compounds that bind to the HIV surface glycoprotein gp120, and interfere with the interaction between the surface protein gp120 and the host cell receptor CD4. Thus, they prevent HIV from attaching to the human CD4 T-cell, and block HIV replication in the first stage of the HIV life cycle. The properties of HIV attachment inhibitors have been improved in an effort to obtain compounds with maximized utility and efficacy as antiviral agents. In particular, U.S. Pat. No. 7,354,924 and US 2005/0209246 are illustrative of HIV attachment inhibitors.

"Another emerging class of compounds for the treatment of HIV are called HIV maturation inhibitors. Maturation is the last of as many as 10 or more steps in HIV replication or the HIV life cycle, in which HIV becomes infectious as a consequence of several HIV protease-mediated cleavage events in the gag protein that ultimately results in release of the capsid (CA) protein. Maturation inhibitors prevent the HIV capsid from properly assembling and maturing, from forming a protective outer coat, or from emerging from human cells. Instead, non-infectious viruses are produced, preventing subsequent cycles of HIV infection.

"Certain derivatives of betulinic acid have now been shown to exhibit potent anti-HIV activity as HIV maturation inhibitors. For example, U.S. Pat. No. 7,365,221 discloses monoacylated betulin and dihydrobetuline derivatives, and their use as anti-HIV agents. As discussed in the '221 reference, esterification of betulinic acid (1) with certain substituted acyl groups, such as 3',3'-dimethylglutaryl and 3',3'-dimethylsuccinyl groups produced derivatives having enhanced activity (Kashiwada, Y., et al., J. Med. Chem. 39:1016-1017 (1996)). Acylated betulinic acid and dihydrobetulinic acid derivatives that are potent anti-HIV agents are also described in U.S. Pat. No. 5,679,828. Esterification of the hydroxyl in the 3 carbon of betulin with succinic acid also produced a compound capable of inhibiting HIV-1 activity.

"Other references to the use of treating HIV infection with compounds derived from betulinic acid include US 2005/0239748 and US 2008/0207573, as well as WO2006/053255, WO2009/100532 and WO2011/007230.

"One HIV maturation compound that has been in development has been identified as Bevirimat or PA-457, with the chemical formula of C.sub.36H.sub.56O.sub.6 and the IUPAC name of 3.beta.-(3-carboxy-3-methyl-butanoyloxy) lup-20(29)-en-28-oic acid.

"Reference is also made herein to the applications by Bristol-Myers Squibb entitled 'MODIFIED C-3 BETULINIC ACID DERIVATIVES AS HIV MATURATION INHIBITORS' U.S. Ser. No. 13/151,706 filed on Jun. 2, 2011 (US 20120142707A1) and 'C-28 AMIDES OF MODIFIED C-3 BETULINIC ACID DERIVATIVES AS HIV MATURATION INHIBITORS' U.S. Ser. No. 13/151,722, filed on Jun. 2, 2011 (US20120142653A1). Reference is also made to the applications entitled 'C-28 AMINES OF C-3 MODIFIED BETULINIC ACID DERIVATIVES AS HIV MATURATION INHIBITORS' U.S. Ser. No. 13/359,680, filed on Jan. 27, 2012, and 'C-17 AND C-3 MODIFIED TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY' U.S. Ser. No. 13/359,727, filed on Jan. 27, 2012.

"What is now needed in the art are new compounds which are useful as HIV maturation inhibitors, as well as new pharmaceutical compositions containing these compounds."

As a supplement to the background information on this patent, NewsRx correspondents also obtained the inventors' summary information for this patent: "The present invention provides compounds of Formula I below, including pharmaceutically acceptable salts thereof, their pharmaceutical formulations, and their use in patients suffering from or susceptible to a virus such as HIV. The compounds of Formula I are effective antiviral agents, particularly as inhibitors of HIV. They are useful for the treatment of HIV and AIDS.

"One embodiment of the present invention is directed to a compound of Formula I, including pharmaceutically acceptable salts thereof:

"##STR00002## wherein a is 1 to 4; X is --O; R.sub.1 is --C(O)CH.sub.2C(CH.sub.3).sub.2COOH, --C(O)C(CH.sub.3).sub.2CH.sub.2COOH, or --C(O)CH.sub.2C(CH.sub.3).sub.2CH.sub.2COOH; R.sub.2 is selected from the group of --H, methyl, isopropenyl and isopropyl; R.sub.3 and R.sub.4 are independently selected from the group of --H, --C.sub.1-6 alkyl, --C.sub.1-6 alkylsubstituted alkyl and --C.sub.3-6 cycloalkyl; or R.sub.3 and R.sub.4 are taken together with the adjacent N to form a cycle selected from the group of:

"##STR00003## R.sub.5 is independently --H or --C.sub.1-6 alkyl; R.sub.6 is selected from the group of --SO.sub.2R.sub.7, --SO.sub.2NR.sub.8R.sub.9 R.sub.7 is selected from the group of --C.sub.1-6 alkyl, --C.sub.1-6 alkylsubstituted alkyl, --C.sub.3-6 cycloalkyl and aryl; and R.sub.8 and R.sub.9 are independently selected from the group of --H, --C.sub.1-6 alkyl, and --C.sub.1-6 alkylsubstituted alkyl.

"In a further embodiment, there is provided a method for treating mammals infected with a virus, especially wherein said virus is HIV, comprising administering to said mammal an antiviral effective amount of a compound of Formula I above, and one or more pharmaceutically acceptable carriers, excipients or diluents. Optionally, the compound of Formula I can be administered in combination with an antiviral effective amount of another AIDS treatment agent selected from the group consisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent; an immunomodulator; and (d) other HIV entry inhibitors.

"Another embodiment of the present invention is a pharmaceutical composition comprising an antiviral effective amount of a compound of Formula I, and one or more pharmaceutically acceptable carriers, excipients, and diluents; and optionally in combination with an antiviral effective amount of another AIDS treatment agent selected from the group consisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent; an immunomodulator; and (d) other HIV entry inhibitors.

"In another embodiment of the invention there is provided one or more methods for making the compounds of Formula I.

"Also provided herein are intermediate compounds useful in making the compounds of Formula I.

"The present invention is directed to these, as well as other important ends, hereinafter described."

For additional information on this patent, see: Liu, Zheng; Meanwell, Nicholas A.; Regueiro-Ren, Alicia. Betulinic Acid Derivatives with Antiviral Activity. U.S. Patent Number 8754069, filed September 20, 2012, and published online on June 17, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8754069.PN.&OS=PN/8754069RS=PN/8754069

Keywords for this news article include: Genetics, HIV/AIDS, Protease, Proteins, Proteomics, RNA Viruses, Retroviridae, HIV Infections, Vertebrate Viruses, Primate Lentiviruses, Enzymes and Coenzymes, Reverse Transcriptase, Bristol-Myers Squibb Company, Viral Sexually Transmitted Diseases.

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Source: AIDS Weekly


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