U.S. patent application number 15/224865 was filed with the patent office on 2016-11-24 for antiviral therapy.
This patent application is currently assigned to VIIV HEALTHCARE COMPANY. The applicant listed for this patent is VIIV HEALTHCARE COMPANY. Invention is credited to Mark Richard Underwood.
Application Number | 20160339033 15/224865 |
Document ID | / |
Family ID | 44319704 |
Filed Date | 2016-11-24 |
United States Patent
Application |
20160339033 |
Kind Code |
A1 |
Underwood; Mark Richard |
November 24, 2016 |
ANTIVIRAL THERAPY
Abstract
The present invention relates to combinations of compounds
comprising HIV integrase inhibitors and other therapeutic agents.
Such combinations are useful in the inhibition of HIV replication,
the prevention and/or treatment of infection by HIV, and in the
treatment of AIDS and/or ARC.
Inventors: |
Underwood; Mark Richard;
(Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
VIIV HEALTHCARE COMPANY |
Wilmington |
DE |
US |
|
|
Assignee: |
VIIV HEALTHCARE COMPANY
Wilmington
DE
|
Family ID: |
44319704 |
Appl. No.: |
15/224865 |
Filed: |
August 1, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14710952 |
May 13, 2015 |
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15224865 |
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13575380 |
Jul 26, 2012 |
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PCT/US2011/022219 |
Jan 24, 2011 |
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14710952 |
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61298589 |
Jan 27, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 31/18 20180101;
A61P 31/12 20180101; A61K 31/513 20130101; A61K 31/536 20130101;
A61K 9/0019 20130101; A61K 31/4985 20130101; A61K 31/52 20130101;
A61P 31/00 20180101; A61K 9/0014 20130101; A61K 31/5365 20130101;
A61P 43/00 20180101; A61K 45/06 20130101; A61K 31/675 20130101;
A61P 37/04 20180101; A61K 31/505 20130101; A61K 9/0053 20130101;
A61K 31/513 20130101; A61K 2300/00 20130101; A61K 31/5365 20130101;
A61K 2300/00 20130101 |
International
Class: |
A61K 31/5365 20060101
A61K031/5365; A61K 31/513 20060101 A61K031/513; A61K 31/52 20060101
A61K031/52 |
Claims
1. A combination comprising a compound of formula (I) ##STR00005##
or a pharmaceutically acceptable salt thereof, and abacavir, or a
pharmaceutically acceptable salt thereof.
2. The combination according to claim 1 wherein the
pharmaceutically acceptable salt of abacavir is a hemisulfate
salt.
3. The combination according to claim 1 wherein the
pharmaceutically acceptable salt of a compound of formula (I) is a
sodium salt.
4. The combination according to claim 1, further comprising
lamivudine or a pharmaceutically acceptable salt thereof.
5. The combination according to claim 4, wherein the
pharmaceutically acceptable salt of the compound of formula (I) is
a sodium salt, and wherein the pharmaceutically acceptable salt of
abacavir is a hemisulfate salt.
6. A combination comprising a compound of formula (I) ##STR00006##
or a pharmaceutically acceptable salt thereof, and abacavir, or a
pharmaceutically acceptable salt thereof, and lamivudine.
7. A method of treatment of HIV infection comprising administering
to a human, a compound of formula (I) ##STR00007## or a
pharmaceutically acceptable salt thereof, and abacavir, or a
pharmaceutically acceptable salt thereof.
8. The method according to claim 7 wherein the pharmaceutically
acceptable salt of abacavir is a hemisulfate salt.
9. The method according to claim 7 wherein the pharmaceutically
acceptable salt of a compound of formula (I) is a sodium salt.
10. The method according to claim 7, further comprising the
administration of lamivudine or a pharmaceutically acceptable salt
thereof.
11. The method according to claim 7, wherein the pharmaceutically
acceptable salt of the compound of formula (I) is a sodium salt,
and wherein the pharmaceutically acceptable salt of abacavir is a
hemisulfate salt.
12. A method of treatment of HIV infection comprising administering
to a human of the compound of formula (I) ##STR00008## or a
pharmaceutically acceptable salt thereof, and abacavir, or a
pharmaceutically acceptable salt thereof, and lamivudine.
13. A pharmaceutical composition comprising a compound of formula
(I) ##STR00009## or a pharmaceutically acceptable salt thereof, and
abacavir, or a pharmaceutically acceptable salt thereof, together
with a pharmaceutically acceptable carrier therefor.
14. The pharmaceutical composition according to claim 13 wherein
the pharmaceutically acceptable salt of abacavir is a hemisulfate
salt.
15. The pharmaceutical composition according to claim 13 wherein
the pharmaceutically acceptable salt of a compound of formula (I)
is a sodium salt.
16. The pharmaceutical composition according to claim 13 further
comprising lamivudine or a pharmaceutically acceptable salt
thereof.
17. The combination according to claim 1 wherein the combination is
administered simultaneously.
18. The combination according to claim 6 wherein the combination is
administered simultaneously.
19. The combination according to claim 1 wherein the combination is
administered sequentially.
20. The combination according to claim 6 wherein the combination is
administered sequentially.
21. A method of treatment according to claim 7 wherein the compound
of formula (I) or a pharmaceutically acceptable salt thereof, and
abacavir or a pharmaceutically acceptable salt thereof, are
administered simultaneously.
22. A method of treatment according to claim 12 wherein the
compound of formula (I) or a pharmaceutically acceptable salt
thereof, abacavir or a pharmaceutically acceptable salt thereof,
and lamivudine are administered simultaneously.
23. A method of treatment according to claim 7 wherein the compound
of formula (I) or a pharmaceutically acceptable salt thereof, and
abacavir or a pharmaceutically acceptable salt thereof, are
administered sequentially.
24. A method of treatment according to claim 12 wherein the
compound of formula (I) or a pharmaceutically acceptable salt
thereof, abacavir or a pharmaceutically acceptable salt thereof,
and lamivudine are administered sequentially.
25. A patient pack comprising a compound of formula (I) according
to claim 1 or a pharmaceutically acceptable salt thereof, and
abacavir or a pharmaceutically acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is filed as a continuation application of
U.S. Ser. No. 14/710,952 filed on JulyMay 13, 2015, which is a
continuation application of U.S. Ser. No. 13/575,380 filed on Jul.
26, 2012 which is a National Phase of International Application No.
PCT/US2011/022219, filed Jan. 24, 2011 which claims priority from
U.S. Provisional Application Ser. No. 61/298,589 filed Jan. 27,
2010, and the entire contents of each of the foregoing applications
are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The human immunodeficiency virus ("HIV") is the causative
agent for acquired immunodeficiency syndrome ("AIDS"), a disease
characterized by the destruction of the immune system, particularly
of CD4.sup.+ T-cells, with attendant susceptibility to
opportunistic infections, and its precursor AIDS-related complex
("ARC"), a syndrome characterized by symptoms such as persistent
generalized lymphadenopathy, fever and weight loss. HIV is a
retrovirus; the conversion of its RNA to DNA is accomplished
through the action of the enzyme reverse transcriptase. Compounds
that inhibit the function of reverse transcriptase inhibit
replication of HIV in infected cells. Such compounds are useful in
the prevention or treatment of HIV infection in humans.
[0003] In addition to CD4, HIV requires a co-receptor for entry
into target cells. The chemokine receptors function together with
CD4 as co-receptors for HIV. The chemokine receptors CXCR4 and CCR5
have been identified as the main co-receptors for HIV-1. CCR5 acts
as a major co-receptor for fusion and entry of macrophage-tropic
HIV into host cells. These chemokine receptors are thought to play
an essential role in the establishment and dissemination of an HIV
infection. Therefore, CCR5 antagonists are thought to be useful as
therapeutic agents active against HIV.
[0004] As in the case of several other retroviruses, HIV encodes
the production of a protease which carries out post-translational
cleavage of precursor polypeptides in a process necessary for the
formation of infectious virions. These gene products include pol,
which encodes the virion RNA-dependent DNA polymerase (reverse
transcriptase), an endonuclease, HIV protease, and gag, which
encodes the core-proteins of the virion.
[0005] One focus of anti-viral drug design has been to create
compounds which inhibit the formation of infectious virions by
interfering with the processing of viral polyprotein precursors.
Processing of these precursor proteins requires the action of
virus-encoded proteases which are essential for replication. The
anti-viral potential of HIV protease inhibition has been
demonstrated using peptidyl inhibitors.
[0006] A required step in HIV replication in human T-cells is the
insertion by virally-encoded integrase of proviral DNA into the
host cell genome. Integration is believed to be mediated by
integrase in a process involving assembly of a stable nucleoprotein
complex with viral DNA sequences, cleavage of two nucleotides from
the 3' termini of the linear proviral DNA and covalent joining of
the recessed 3' OH termini of the proviral DNA at a staggered cut
made at the host target site. The repair synthesis of the resultant
gap may be accomplished by cellular enzymes. Inhibitors of HIV
integrase can be effective in treating AIDS and inhibiting viral
replication.
[0007] Administration of combinations of therapeutic compounds in
the treatment of HIV infection and related conditions can result in
potentiated antiviral activity, reduced toxicity, delayed
progression to resistance, and increased drug efficacy.
Combinations administered in a single dosage unit can result in
increased patient compliance as the pill burden is reduced and
dosing schedules are simplified. However, not all compounds are
suitable for administration in combinations. Factors that influence
the feasibility of combinations include the chemical instability of
the compounds, size of the dosage unit, potential for antagonistic
or merely additive activities of the combined compounds, and
difficulties in achieving a suitable formulation.
[0008] There is continued need to find therapeutic agents suitable
for use in combination and feasible pharmaceutical compositions to
treat HIV infection. Due to their high potency and pharmacokinetic
profile, certain HIV integrase inhibitors are attractive as
components in combination therapy.
BRIEF DESCRIPTION OF THE FIGURES
[0009] FIG. 1: Inhibition of HIV-1.sub.IIIB by a compound of
formula (I), GSK1349572A, in combination with abacavir (ABC).
[0010] FIG. 2: Inhibition of HIV-1.sub.IIIB by a compound of
formula (I), GSK1349572A, in combination with efavirenz (EFV).
[0011] FIG. 3: Inhibition of HIV-1.sub.IIIB by a compound of
formula (I), GSK1349572A, in combination with lopinavir (LPV)
SUMMARY OF THE INVENTION
[0012] The present invention relates to combinations of compounds
comprising HIV integrase inhibitors and other therapeutic agents.
Such combinations are useful in the inhibition of HIV replication,
the prevention and/or treatment of infection by HIV, and in the
treatment of AIDS and/or ARC. The present invention also features
pharmaceutical compositions containing HIV integrase
inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The present invention relates to combinations comprising a
compound of the following formula (I), (II), or (III):
##STR00001##
or a pharmaceutically acceptable salt thereof, and one or more
therapeutic agents selected from the group consisting of nucleotide
reverse transcriptase inhibitors, nucleoside reverse transcriptase
inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors
(NNRTIs), protease inhibitors, CCR5 antagonists, CXCR4 antagonists,
fusion inhibitors, maturation inhibitors, and integrase
inhibitors.
[0014] The present invention relates to methods of treatment of HIV
infection, AIDS, and AIDS related conditions by administering to a
subject a compound of formula (I), (II), or (III) and one or more
therapeutic agents selected from the group consisting of nucleotide
reverse transcriptase inhibitors, nucleoside reverse transcriptase
inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors
(NNRTIs), protease inhibitors, CCR5 antagonists, CXCR4 antagonists,
fusion inhibitors, maturation inhibitors, and integrase
inhibitors.
[0015] A compound of formula (I) is also known as GSK1349572. A
chemical name of the compound of formula (I) is
(4R,12a5)-N-[2,4-flurophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-
-methyl-6,8-dioxo-2H-pyrido [1',2':4,5]pyrazino
[2,1-b][1,3]oxazine-9-carboxamide.
[0016] A chemical name of the compound of formula (II) is (3S,11
aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-m-
ethyl-5,7-dioxo-oxazolo [3,2-a] pyrido [1,2-d]
pyrazine-8-carboxamide.
[0017] A chemical name of the compound of formula (III) is
(4aS,13aR)-N-[2,4-difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9-
,11,13,13a-octahydro-1H-pyrido
[1,2-a]pyrrolo[1',2':3,4,]imidazo[1,2-d]pyrazine-8-carboxamide.
[0018] The term "pharmaceutically acceptable carrier or adjuvant"
refers to a carrier or adjuvant that may be administered to a
patient, together with a compound of this invention, and which does
not destroy the pharmacological activity thereof and is nontoxic
when administered in doses sufficient to deliver a therapeutic
amount of the antiviral agent.
[0019] The term "treatment" as used herein refers to the
alleviation of symptoms of a particular disorder in a patient, or
the improvement of an ascertainable measurement associated with a
particular disorder, and may include the suppression of symptom
recurrence in an asymptomatic patient such as a patient in whom a
viral infection has become latent. Treatment may include
prophylaxis which refers to preventing a disease or condition or
preventing the occurrence of symptoms of such a disease or
condition, in a patient. As used herein, the term "patient" refers
to a mammal, including a human.
[0020] As used herein, the term "subject" refers to a patient,
animal or a biological sample.
[0021] Pharmaceutically acceptable salts of the compounds according
to the invention include those derived from pharmaceutically
acceptable inorganic and organic acids and bases. Examples of
suitable acids include hydrochloric, hydrobromic, sulfuric, nitric,
perchloric, fumaric, maleic, phosphoric, glycollic, lactic,
salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric,
methanesulfonic, ethanesulfonic, formic, benzoic, malonic,
naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such
as oxalic, while not in themselves pharmaceutically acceptable, may
be employed in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their pharmaceutically
acceptable acid addition salts. Salts derived from appropriate
bases include alkali metal (e.g. sodium), alkaline earth metal
(e.g., magnesium), ammonium, NW.sub.4.sup.+ (wherein W is C.sub.1-4
alkyl) and other amine salts. An advantageous salt is sodium
salt.
[0022] Salts of the compounds of the present invention may be made
by methods known to a person skilled in the art. For example,
treatment of a compound of the present invention with an
appropriate base or acid in an appropriate solvent can yield the
corresponding salt.
[0023] The present invention relates to methods of treating or
preventing viral infection, for example an HIV infection, in a
human comprising administering to the human a therapeutically
effective amount of a compound of formula (I), (II), or (III) or a
pharmaceutically acceptable salt thereof in combination with one or
more therapeutic agents selected from the group consisting of
nucleotide reverse transcriptase inhibitors, nucleoside reverse
transcriptase inhibitors (NRTIs), non-nucleoside reverse
transcriptase inhibitors (NNRTIs), protease inhibitors, CCR5
antagonists, CXCR4 antagonists, fusion inhibitors, maturation
inhibitors, and integrase inhibitors. The combination may be
administered simultaneously or sequentially.
[0024] The compounds of formula (I), (II) and (III) are
particularly suited to the treatment or prophylaxis of HIV
infections and associated conditions. Reference herein to treatment
may extend to prophylaxis as well as the treatment of established
infections, symptoms, and associated clinical conditions such as
AIDS related complex (ARC), Kaposi's sarcoma, and AIDS
dementia.
[0025] Combination therapies comprise the administration of a
compound of the present invention or a pharmaceutically acceptable
salt thereof and another pharmaceutically active agent. The active
ingredient(s) and pharmaceutically active agents may be
administered simultaneously (i.e., concurrently) in either the same
or different pharmaceutical compositions or sequentially in any
order. The amounts of the active ingredient(s) and pharmaceutically
active agent(s) and the relative timings of administration will be
selected in order to achieve the desired combined therapeutic
effect.
[0026] Examples of such therapeutic agents include, but are not
limited to, agents that are effective for the treatment of viral
infections or associated conditions. Among these agents are
nucleotide reverse transcriptase inhibitors, acyclic nucleoside
phosphonates, for example
(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl) cytosine (HPMPC),
[[[2-(6-amino-9H-purin-9-yl)ethoxy] methyl]phosphinylidene]
bis(oxymethylene)-2,2-dimethyl propanoic acid (bis-POM PMEA,
adefovir dipivoxil), adefovir,
[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl] phosphonic
acid (tenofovir), tenofovir disoproxil fumarate, and
(R)-[[2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic
acid bis-(isopropoxycarbonyloxymethyl)ester (bis-POC-PMPA);
nucleoside reverse transcriptase inhibitors, for example
3'-azido-3'-deoxythymidine (AZT, zidovudine), 2',3'-dideoxycytidine
(ddC, zalcitabine), 2',3'-dideoxyadenosine, 2',3'-dideoxyinosine
(ddl, didanosine), 2',3'-didehydrothymidine (d4T, stavudine),
(-)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine
(lamivudine),
cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine
(FTC, emtricitabine),
(-)-cis-4-[2-amino-6-(cyclo-propylamino)-9H-purin-9-yl]-2-cyclopentene-1--
methanol (abacavir), fozivudine tidoxil, alovudine, amdoxovir,
elvucitabine, apricitabine, and festinavir (OBP-601); protease
inhibitors, for example indinavir, ritonavir, nelfinavir,
amprenavir, saquinavir, fosamprenavir, lopinavir, atazanavir,
tipranavir, darunavir, brecanavir, palinavir, lasinavir,
TMC-310911, DG-17, PPL-100, and SPI-256; non-nucleoside reverse
transcriptase inhibitors (NNRTIs), for example nevirapine,
delavirdine, efavirenz, GSK2248761 (IDX-12899), lersivirine
(UK-453,061), rilpivirine (TMC-278), etravirine, loviride,
immunocal, oltipraz, capravirine, and RDEA-806; integrase
inhibitors, for example raltegravir, elvitegravir, and JTK-656;
CCR5 and/or CXCR4 antagonists, for example, maraviroc, vicriviroc
(Sch-D), TBR-652 (TAK-779), TAK-449, PRO-140, GSK706769, and
SCH-532706; fusion inhibitors, for example enfuvirtide (T-20),
T-1249, PRO-542, ibalizumab (TNX-355), BMS-378806 (BMS-806),
BMS-488043, KD-247, 5-Helix inhibitors, and HIV attachment
inhibitors; and maturation inhibitors, for example, bevirimat
(PA-344 and PA-457).
[0027] The present invention features a combination comprising a
compound of formula (I)
##STR00002##
or a pharmaceutically acceptable salt thereof, and one or more
therapeutic agents selected from the group consisting of
lamivudine, abacavir, tenofovir, efavirenz, GSK2248761,
lersivirine, lopinavir, fosamprenavir, and atazanavir.
[0028] The present invention also features a combination comprising
a compound of formula (I) or a pharmaceutically acceptable salt
thereof, and one or more therapeutic agents selected from abacavir,
efavirenz, or lopinavir. The present invention features a
combination comprising of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, and abacavir.
[0029] The present invention features a method of treatment of HIV
infection comprising administering to a subject, a compound of
formula (I), or a pharmaceutically acceptable salt thereof, and one
or more therapeutic agents selected from the group consisting of
lamivudine, abacavir, tenofovir, efavirenz, GSK2248761,
lersivirine, lopinavir, fosamprenavir, and atazanavir.
[0030] The present invention features a method of treatment of HIV
infection comprising administering to a subject, a compound of
formula (I) or a pharmaceutically acceptable salt thereof, with one
or more therapeutic agents selected from the group consisting of
abacavir, efavirenz, and lopinavir. The present invention features
a method of treatment of HIV infection comprising administering to
a subject a compound of formula (I) or a pharmaceutically
acceptable salt thereof, and abacavir.
[0031] The present invention features a pharmaceutical composition
comprising a compound of formula (I) or a pharmaceutically
acceptable salt thereof, and one or more therapeutic agents
selected from the group consisting of: lamivudine, abacavir,
efavirenz, tenofovir, GSK2248761, lersivirine, lopinavir,
fosamprenavir, and atazanavir together with a pharmaceutically
acceptable carrier therefor.
[0032] The present invention features a pharmaceutical composition
comprising a compound of formula (I) or a pharmaceutically
acceptable salt thereof, and one or more therapeutic agents
selected from the group consisting of: abacavir, efavirenz, and
lopinavir, together with a pharmaceutically acceptable carrier
therefor. The present invention features a pharmaceutical
composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof, and abacavir together
with a pharmaceutically acceptable carrier therefor.
[0033] The present invention features a combination comprising a
compound of formula (II)
##STR00003##
or a pharmaceutically acceptable salt thereof, and one or more
therapeutic agents selected from the group consisting of
lamivudine, abacavir, tenofovir, efavirenz, GSK2248761,
lersivirine, lopinavir, fosamprenavir, and atazanavir
[0034] The present invention also features a combination comprising
a compound of formula (II) or a pharmaceutically acceptable salt
thereof, and one or more therapeutic agents selected from abacavir,
efavirenz, and lopinavir. The present invention features a
combination comprising of a compound of formula (II) or a
pharmaceutically acceptable salt thereof, and abacavir.
[0035] The present invention features a method of treatment of HIV
infection comprising administering to a subject, a compound of
formula (II) or a pharmaceutically acceptable salt thereof, and one
or more therapeutic agents selected from the group consisting of
lamivudine, abacavir, tenofovir, efavirenz, GSK2248761,
lersivirine, lopinavir, fosamprenavir, and atazanavir.
[0036] The present invention features a method of treatment of HIV
infection comprising administering to a subject, a compound of
formula (II) or a pharmaceutically acceptable salt thereof, with
one or more therapeutic agents selected from the group consisting
of abacavir, efavirenz, and lopinavir. The present invention
features a method of treatment of HIV infection comprising
administering to a subject a compound of formula (II) or a
pharmaceutically acceptable salt thereof, and abacavir.
[0037] The present invention features a pharmaceutical composition
comprising a compound of formula (II) or a pharmaceutically
acceptable salt thereof, and one or more therapeutic agents
selected from the group consisting of: lamivudine, abacavir,
tenofovir, efavirenz, GSK2248761, lersivirine, lopinavir,
fosamprenavir, and atazanavir together with a pharmaceutically
acceptable carrier therefor.
[0038] The present invention features a pharmaceutical composition
comprising a compound of formula (II) or a pharmaceutically
acceptable salt thereof, and one or more therapeutic agents
selected from the group consisting of: abacavir, efavirenz, and
lopinavir, together with a pharmaceutically acceptable carrier
therefor. The present invention features a pharmaceutical
composition comprising a compound of formula (II) or a
pharmaceutically acceptable salt thereof, and abacavir together
with a pharmaceutically acceptable carrier therefor.
[0039] The present invention features a combination comprising a
compound of formula (III)
##STR00004##
or a pharmaceutically acceptable salt thereof, and one or more
therapeutic agents selected from the group consisting of
lamivudine, abacavir, tenofovir, efavirenz, GSK2248761,
lersivirine, lopinavir, fosamprenavir, and atazanavir
[0040] The present invention also features a combination comprising
a compound of formula (III) or a pharmaceutically acceptable salt
thereof, and one or more therapeutic agents selected from abacavir,
efavirenz, and lopinavir. The present invention also features a
combination comprising a compound of formula (III) or a
pharmaceutically acceptable salt thereof, and abacavir.
[0041] The present invention features a method of treatment of HIV
infection comprising administering to a subject, a compound of
formula (III) or a pharmaceutically acceptable salt thereof, and
one or more therapeutic agents selected from the group consisting
of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761,
lersivirine, lopinavir, fosamprenavir, and atazanavir.
[0042] The present invention features a method of treatment of HIV
infection comprising administering to a subject, a combination of a
compound of formula (III) or a pharmaceutically acceptable salt
thereof, with one or more therapeutic agents selected from the
group consisting of abacavir, efavirenz, and lopinavir. The present
invention features a method of treatment of HIV infection
comprising administering to a subject a compound of formula (III)
or a pharmaceutically acceptable salt thereof, and abacavir.
[0043] The present invention features a pharmaceutical composition
comprising a compound of formula (III) or a pharmaceutically
acceptable salt thereof, and one or more therapeutic agents
selected from the group consisting of: lamivudine, abacavir,
tenofovir, efavirenz, GSK2248761, lersivirine, lopinavir,
fosamprenavir, and atazanavir together with a pharmaceutically
acceptable carrier therefor.
[0044] The present invention features a pharmaceutical composition
comprising a compound of formula (III) or a pharmaceutically
acceptable salt thereof, and one or more therapeutic agents
selected from the group consisting of: abacavir, efavirenz, and
lopinavir, together with a pharmaceutically acceptable carrier
therefor. The present invention features a pharmaceutical
composition comprising a compound of formula (III) or a
pharmaceutically acceptable salt thereof, and abacavir together
with a pharmaceutically acceptable carrier therefor.
[0045] The present invention features combinations, methods of
treatment, and pharmaceutical compositions as described above
wherein a pharmaceutically acceptable salt of a compound of formula
(I), (II) or (III) is a sodium salt.
[0046] The present invention features combinations, methods of
treatment, and pharmaceutical compositions as described above
wherein one or more therapeutic agents are a pharmaceutically
acceptable salt of said therapeutic agents, for example, abacavir
hemisulfate, fosamprenavir calcium, atazanavir sulfate, tenofovir
disoproxil sulfate, vicriviroc maleate or bevirimat
dimeglumine.
[0047] The present invention features methods of treatment as
described above wherein the subject is a human.
[0048] The present invention features combinations, methods of
treatment and pharmaceutical compositions as described above
wherein the combination is administered sequentially.
[0049] The present invention features combinations, methods of
treatment and pharmaceutical compositions as described above
wherein the combination is administered simultaneously or
concurrently.
[0050] Compounds of formula (I), (II), and (III) may be made by
methods disclosed in WO 2006/116764, U.S. 61/193,634
(WO2010/068253) or 61/193,636 (WO2010/068262), incorporated herein
by reference hereto.
[0051] Abacavir may be made by methods disclosed in U.S. Pat. Nos.
5,034,394; 5,089,500; 6,294,540; 5,641,889; 5,840,990; 5,919,941;
5,808,147; 6,392,085; 6,448,403; 5,917,041; 6,087,501; 5,917,042;
6,555,687; 6,552,193; 6,870,053; 6,294,540; 6,340,587; or
6,646,125.
[0052] Lamivudine may be made by methods disclosed in U.S. Pat.
Nos. 5,047,407; 7,119,202; 5,905,082; 5,696,254; 5,663,320;
5,693,787; 6,051,709; or 6,329,522.
[0053] Tenofovir may be made by U.S. Pat. Nos. 5,922,695;
5,935,946; 5,977,089; 6,043,230, 6,069,249.
[0054] Efavirenz may be made by may be made by methods disclosed in
U.S. Pat. Nos. 5,519,021; 5,663,169; 5,811,423; 6,555,133;
6,639,071; or 6,939,964.
[0055] GSK2248761 may be made by methods disclosed in U.S. Pat. No.
7,534,809.
[0056] Lersivirine may be made by methods disclosed in U.S. Pat.
No. 7,109,228.
[0057] Lopinavir may be made by methods disclosed in U.S. Pat. No.
5,914,332.
[0058] Fosamprenavir may be made by methods disclosed in U.S. Pat.
Nos. 6,436,989; 6,514,953; or 6,281,367.
[0059] Atazanavir may be made by methods disclosed in U.S. Pat. No.
5,849,911 or 6,087,383.
[0060] The therapeutic agents of the combinations may be made
according to published methods or by any method known to those
skilled in the art.
[0061] In an aspect of the invention, a compound of formula (I),
(II) or (III) or a pharmaceutically acceptable salt thereof may be
formulated into compositions together with one or more therapeutic
agents. The composition may be pharmaceutical composition, which
comprises a compound of formula (I), (II), or (III), one or more
therapeutic agents, and a pharmaceutically acceptable carrier,
adjuvant or vehicle. In one embodiment, the composition comprises
an amount of a combination of the present invention effective to
treat or prevent viral infection, for example an HIV infection, in
a biological sample or in a patient. In another embodiment,
combinations of the invention and pharmaceutical compositions
thereof, comprising an amount of a combination of the present
invention effective to inhibit viral replication or to treat or
prevent a viral infection or disease or disorder, for example an
HIV infection, and a pharmaceutically acceptable carrier, adjuvant
or vehicle, may be formulated for administration to a patient, for
example, for oral administration.
[0062] The present invention features combinations according to the
invention for use in medical therapy, for example for the treatment
or prophylaxis of a viral infection, for example an HIV infection
and associated conditions. The compounds according to the invention
are especially useful for the treatment of AIDS and related
clinical conditions such as AIDS related complex (ARC), progressive
generalized lymphadenopathy (PGL), Kaposi's sarcoma,
thromobocytopenic purpura, AIDS-related neurological conditions
such as AIDS dementia complex, multiple sclerosis or tropical
paraperesis, anti-HIV antibody-positive and HIV-positive
conditions, including such conditions in asymptomatic patients.
[0063] According to another aspect, the present invention provides
a method for the treatment or prevention of the symptoms or effects
of a viral infection in an infected patient, for example, a mammal
including a human, which comprises administering to said patient a
pharmaceutically effective amount of a combination according to the
invention. According to one aspect of the invention, the viral
infection is a retroviral infection, in particular an HIV
infection.
[0064] The present invention further includes the use of a
combination according to the invention in the manufacture of a
medicament for simultaneous (concurrent) or sequential
administration to a subject for the treatment of a viral infection,
in particular and HIV infection.
[0065] The present invention further provides a method for the
treatment of a clinical condition in a patient, for example, a
mammal including a human which clinical condition includes those
which have been discussed hereinbefore, which comprises treating
said patient with a pharmaceutically effective amount of a compound
according to the invention. The present invention also includes a
method for the treatment or prophylaxis of any of the
aforementioned diseases or conditions.
[0066] Compounds of the present invention may be administered with
an agent known to inhibit or reduce the metabolism of compounds,
for example ritonavir. Accordingly, the present invention features
a method for the treatment or prophylaxis of a disease as
hereinbefore described by administration of a compound of the
present invention in combination with a metabolic inhibitor. Such
combination may be administered simultaneously or sequentially.
[0067] In general a suitable dose for each of the above-mentioned
conditions will be in the range of 0.01 to 250 mg per kilogram body
weight of the recipient (e.g. a human) per day, in the range of 0.1
to 100 mg per kilogram body weight per day; in the range 1 to 30 mg
per kilogram body weight per day; in the range 0.5 to 20 mg per
kilogram body weight per day. Unless otherwise indicated, all
weights of active ingredients are calculated as the parent compound
of formula (I), (II), or (III) and other therapeutic agents. For
salts thereof, the weights would be increased proportionally. The
desired dose may be presented as one, two, three, four, five, six
or more sub-doses administered at appropriate intervals throughout
the day. In some cases the desired dose may be given on alternative
days. These sub-doses may be administered in unit dosage forms, for
example, containing 1 to 2000 mg; 5 to 500 mg; 10 to 400 mg, 20 to
300 mg of each active ingredient per unit dosage form.
[0068] The combinations may be administered to achieve peak plasma
concentrations of each active ingredient.
[0069] While it is possible for the active ingredients to be
administered alone, it is preferable to present it as a
pharmaceutical composition. The compositions of the present
invention comprise an active ingredient, as defined above, together
with one or more acceptable carriers thereof and one or more
additional therapeutic agents. Each carrier must be acceptable in
the sense of being compatible with the other ingredients of the
composition and not injurious to the patient.
[0070] Pharmaceutical compositions include those suitable for oral,
rectal, nasal, topical (including transdermal, buccal and
sublingual), vaginal or parenteral (including subcutaneous,
intramuscular, intravenous, intradermal, and intravitreal)
administration. The compositions may conveniently be presented in
unit dosage form and may be prepared by any methods well known in
the art of pharmacy. Such methods represent a further feature of
the present invention and include the step of bringing into
association the active ingredients with the carrier, which
constitutes one or more accessory ingredients. In general, the
compositions are prepared by uniformly and intimately bringing into
association the active ingredients with liquid carriers or finely
divided solid carriers or both, and then if necessary shaping the
product.
[0071] The present invention further includes a pharmaceutical
composition as hereinbefore defined wherein a compound of the
present invention or a pharmaceutically acceptable derivative
thereof and another therapeutic agent are presented separately from
one another as a kit of parts.
[0072] Compositions suitable for transdermal administration may be
presented as discrete patches adapted to remain in intimate contact
with the epidermis of the recipient for a prolonged period of time.
Such patches suitably contain the active compound 1) in an
optionally buffered, aqueous solution or 2) dissolved and/or
dispersed in an adhesive or 3) dispersed in a polymer. A suitable
concentration of the active compound is about 1% to 25%, preferably
about 3% to 15%. As one particular possibility, the active compound
may be delivered from the patch by electrotransport or
iontophoresis as generally described in Pharmaceutical Research
3(6), 318 (1986).
[0073] Pharmaceutical compositions of the present invention
suitable for oral administration may be presented as discrete units
such as capsules, caplets, cachets or tablets each containing a
predetermined amount of the active ingredients; as a powder or
granules; as a solution or a suspension in an aqueous or
non-aqueous liquid; or as an oil-in-water liquid emulsion or a
water-in-oil liquid emulsion. The active ingredient may also be
presented as a bolus, electuary or paste.
[0074] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active
ingredients in a free-flowing form such as a powder or granules,
optionally mixed with a binder (e.g. povidone, gelatin,
hydroxypropylmethyl cellulose), lubricant, inert diluent,
preservative, disintegrant (e.g. sodium starch glycollate,
cross-linked povidone, cross-linked sodium carboxymethyl cellulose)
surface-active or dispersing agent. Molded tablets may be made by
molding a mixture of the powdered compound moistened with an inert
liquid diluent in a suitable machine. The tablets may optionally be
coated or scored and may be formulated so as to provide slow or
controlled release of the active ingredients therein using, for
example, hydroxypropylmethyl cellulose in varying proportions to
provide the desired release profile. Tablets may optionally be
provided with an enteric coating, to provide release in parts of
the gut other than the stomach.
[0075] Pharmaceutical compositions suitable for topical
administration in the mouth include lozenges comprising the active
ingredients in a flavored base, usually sucrose and acacia or
tragacanth; pastilles comprising the active ingredient in an inert
basis such as gelatin and glycerin, or sucrose and acacia; and
mouthwashes comprising the active ingredient in a suitable liquid
carrier.
[0076] Pharmaceutical compositions suitable for vaginal
administration may be presented as pessaries, tampons, creams,
gels, pastes, foams or spray. Pharmaceutical compositions may
contain in addition to the active ingredient such carriers as are
known in the art to be appropriate.
[0077] Pharmaceutical compositions for rectal administration may be
presented as a suppository with a suitable carrier comprising, for
example, cocoa butter or a salicylate or other materials commonly
used in the art. The suppositories may be conveniently formed by
admixture of the active combination with the softened or melted
carrier(s) followed by chilling and shaping in molds.
[0078] Pharmaceutical compositions suitable for parenteral
administration include aqueous and nonaqueous isotonic sterile
injection solutions which may contain anti-oxidants, buffers,
bacteriostats and solutes which render the pharmaceutical
composition isotonic with the blood of the intended recipient; and
aqueous and non-aqueous sterile suspensions which may include
suspending agents and thickening agents; and liposomes or other
microparticulate systems which are designed to target the compound
to blood components or one or more organs. The pharmaceutical
compositions may be presented in unit-dose or multi-dose sealed
containers, for example, ampoules and vials, and may be stored in a
freeze-dried (lyophilized) condition requiring only the addition of
the sterile liquid carrier, for example water for injection,
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described.
[0079] Unit dosage pharmaceutical compositions include those
containing a daily dose or daily subdose of the active ingredients,
as hereinbefore recited, or an appropriate fraction thereof.
[0080] Pharmaceutical compositions of the present invention may be
presented as patient packs containing one or more courses of
treatment in a single package, for example, a blister pack. It will
be understood that the administration of the combination of the
invention by means of a single patient pack, or patient packs of
each composition, is an additional feature of the invention.
[0081] It should be understood that in addition to the ingredients
particularly mentioned above the pharmaceutical compositions of
this invention may include other agents conventional in the art
having regard to the type of pharmaceutical composition in
question, for example, those suitable for oral administration may
include such further agents as sweeteners, thickeners and flavoring
agents.
EXAMPLES
Example 1
Biological Activity
Assays
Method
[0082] Antiviral HIV activity was measured by means of a
tetrazolium-based colorimetric procedure in the human T-cell
leukemia virus (HTLV-1) transformed cell line MT-4. Aliquots of
test compound were diluted vertically across a deep-well master
assay plate, in medium (RPMI 1640, 10% vol./vol. fetal bovine serum
(FBS), and 10 .mu.g/mL gentamicin), at concentrations that were
approximately 40-fold higher than the final assay concentration.
Serial dilutions were made at either 1:2 or 1:3.16 ratios. HIV
inhibitors were diluted horizontally across master assay plates,
also in concentrations that were approximately 40-fold higher than
the final assay concentration. Small aliquots of both the
vertically-diluted and the horizontally-diluted compounds were
combined in daughter plates using an automated 96-well pipetting
system (RapidPlate-96, Zymark Corp.). Checkerboard style dilutions
were arranged so that every concentration of test compound was
tested in the presence and absence of every concentration of the
HIV inhibitors. Anti-HIV activity tests were performed in
triplicate assays, or more, of each combination. Exponentially
growing MT-4 cells were harvested and centrifuged at 1,000 rpm for
10 minutes in a Jouan centrifuge (Model CR 4 12). Cell pellets were
re-suspended in fresh medium (RPMI 1640, 20% vol./vol. FBS, 20%
vol./vol. IL-2, and 10 .mu.g/mL gentamicin) to a density of
1.25.times.10.sup.6 cells/mL. Cell aliquots were infected by the
addition of HIV-1 (strain IIIB) diluted to give a viral
multiplicity of infection (MOI) of 73 pfU per 1.times.10.sup.4
cells. A similar cell aliquot was diluted with medium to provide a
mock-infected control. Cell infection was allowed to proceed for 1
hour at 37.degree. C. in a tissue culture incubator with humidified
5% CO.sub.2 atmosphere. After the 1 hour incubation the virus/cell
suspension was added to each well of the plates containing
pre-diluted compounds. Plates were then placed in a tissue culture
incubator with humidified 5% CO.sub.2 for 5 days. At the end of the
incubation period, 40 .mu.L of CellTiter 96 MTS reagent (Promega
no. G3581) was added to each well of the incubation plate. Plates
were incubated at 37.degree. C. for 2 to 3 hours to allow for color
development. O.D. was measured at 492 nM using a microplate
absorbance reader (Tecan no. 20-300).
Virus Used
[0083] HIV-1 strain IIIB, wild-type laboratory strain, virus
titer=6.896 E4 TCID.sub.50/mL.
Data Analysis
[0084] Although some assay formats might theoretically miss
antagonism due to combination cytotoxicity, the approach described
here should not miss an antagonistic effect. The readout in the
MT-4 cell assay utilizes MTS, a tetrazolium-based staining reagent
where changes in optical density (O.D.) of the reagent are used to
estimate the total cell number remaining after treatment. Final
MT-4 cell numbers may decrease due to two effects. First, an
HIV-induced cytotoxicity may occur when HIV kills greater than 75%
of the MT-4 cells during the 5 days following infection. Second, a
compound-induced cytotoxicity may occur, where the compound either
directly kills the MT-4 cells or prevents cell growth (stasis) over
the 5 days in either infected or uninfected cells. In either of
these situations the O.D. is low as compared with infected cells
protected by anti-HIV-1 compounds or relative to untreated and
uninfected control cells. Since both cytotoxic effects and
antagonism of anti-HIV activity would lead to lower O.D. we should
not miss an antagonistic effect due to combination cytotoxicity,
but could underestimate synergistic combinations.
[0085] Within assay combination cytotoxicity was evaluated by
comparing wells containing the uninfected MT-4 cells from the assay
plates that contained the highest concentration of test compound or
the comparator compound, with wells containing HIV-1 infected MT-4
cells under the corresponding highest combination concentrations.
For each of these values there is one well per assay plate and thus
at least 3 wells per combination assay. Although they do not
comprise a formal combination cytotoxicity analysis, the ratio of
compound in combinations to compound alone provides a measure of
the compound combination cytotoxicity within the concentrations
examined.
[0086] The interaction of each pair of compound combinations was
analyzed by the methods described by Selleseth, D. W. et al. (2003)
Antimicrobial Agents and Chemotherapy 47:1468-71. Synergy and
antagonism are defined as deviations from dosewise additivity,
which results when two drugs interact as if they were the same
drug. Values for average deviation from additivity in the range of
-0.1 to -0.2 indicate weak synergy and values that approach -0.5
would indicate strong synergy of the interaction. Conversely,
positive values of 0.1 to 0.2 would indicate that a weak antagonism
exists between the treatments.
Results
[0087] A compound of formula (I) was found to be additive with
raltegravir, adefovir, and maraviroc and was not affected by the
presence of ribavirin. A compound of formula (I) was found to be
synergistic with stavudine, abacavir, efavirenz, nevirapine,
lopinavir, amprenavir, enfuvirtide.
* * * * *