U.S. patent application number 14/744501 was filed with the patent office on 2015-10-08 for combinations of a pyrimidine containing nnrti with rt inhibitors.
The applicant listed for this patent is JANSEN SCIENCES IRELAND UC. Invention is credited to Paul Stoffels.
Application Number | 20150283135 14/744501 |
Document ID | / |
Family ID | 34280181 |
Filed Date | 2015-10-08 |
United States Patent
Application |
20150283135 |
Kind Code |
A1 |
Stoffels; Paul |
October 8, 2015 |
Combinations Of A Pyrimidine Containing NNRTI With RT
Inhibitors
Abstract
The present invention concerns combinations of a pyrimidine
containing NNRTI with nucleoside reverse transcriptase inhibitors
and nucleotide reverse transcriptase inhibitors useful for the
treatment of HIV infected patients or for the prevention of HIV
transmission or infection.
Inventors: |
Stoffels; Paul;
(Hoogstraten, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JANSEN SCIENCES IRELAND UC |
Little Island |
|
IE |
|
|
Family ID: |
34280181 |
Appl. No.: |
14/744501 |
Filed: |
June 19, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14454045 |
Aug 7, 2014 |
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14744501 |
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12574881 |
Oct 7, 2009 |
8841310 |
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14454045 |
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10570228 |
Feb 28, 2006 |
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PCT/EP2004/052028 |
Sep 3, 2004 |
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12574881 |
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60508486 |
Oct 3, 2003 |
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60499771 |
Sep 3, 2003 |
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Current U.S.
Class: |
514/81 ;
514/263.4; 514/274; 514/275 |
Current CPC
Class: |
A61P 31/18 20180101;
A61K 31/513 20130101; A61K 31/505 20130101; A61P 37/04 20180101;
A61K 9/20 20130101; A61K 31/675 20130101; A61P 43/00 20180101; A61K
31/52 20130101; A61K 31/505 20130101; A61K 2300/00 20130101; A61K
31/513 20130101; A61K 2300/00 20130101; A61K 31/52 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 31/505 20060101
A61K031/505; A61K 31/513 20060101 A61K031/513; A61K 31/52 20060101
A61K031/52; A61K 31/675 20060101 A61K031/675 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 3, 2003 |
EP |
03103275.8 |
Sep 8, 2003 |
EP |
03103319.4 |
Sep 10, 2003 |
EP |
03103335.0 |
Oct 2, 2003 |
EP |
03103668.4 |
Claims
1. A combination comprising
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile, or a stereoisomeric form thereof or a
pharmaceutically acceptable salt thereof; a nucleoside reverse
transcriptase inhibitor; and a nucleotide reverse transcriptase
inhibitor; wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile, the nucleotide reverse transcriptase inhibitor,
and the nucleoside reverse transcriptase inhibitor are
therapeutically effective HIV inhibitors at a dose that can be
administered once daily.
2. The combination according to claim 1, wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile.
3. The combination according to claim 1, wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile hydrochloride.
4. The combination according to claim 1, wherein the nucleotide
reverse transcriptase inhibitor and/or the nucleoside reverse
transcriptase inhibitor select mutations in the reverse
transcriptase that do not cause resistance to
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile.
5. The combination according to claim 1, wherein the nucleotide
reverse transcriptase inhibitor is tenofovir or its prodrug
tenofovir disoproxil fumarate.
6. The combination according to claim 1 wherein the nucleoside
reverse transcriptase inhibitor is emtricitabine, racemic FTC,
lamivudine, abacavir, or a pharmaceutically acceptable salt
thereof.
7. The combination according to claim 1 wherein the nucleoside
reverse transcriptase inhibitor is emtricitabine.
8. The combination according to claim 1 wherein the nucleoside
reverse transcriptase inhibitor is lamivudine.
9. The combination according to claim 1 wherein the nucleoside
reverse transcriptase inhibitor is abacavir or a pharmaceutically
acceptable salt thereof.
10. The combination according to claim 1 wherein the combination
comprises
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimid-
inyl]-amino]-benzonitrile, or a stereoisomeric form thereof; or a
pharmaceutically acceptable salt thereof; tenofovir or its prodrug
tenofovir disoproxil fumarate, and lamivudine.
11. The combination according to claim 9, wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile.
12. The combination according to claim 9, wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile hydrochloride.
13. The combination according to claim 1 that comprises
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile, or a stereoisomeric form thereof; or a
pharmaceutically acceptable salt thereof; tenofovir or its prodrug
tenofovir disoproxil fumarate, and abacavir or a pharmaceutically
acceptable salt thereof.
14. The combination according to claim 13, wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile.
15. The combination according to claim 13, wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile hydrochloride.
16. The combination according to claim 1 that comprises
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile, or a stereoisomeric form thereof; or a
pharmaceutically acceptable salt thereof; lamivudine, and
emtricitabine.
17. The combination according to claim 16, wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile.
18. The combination according to claim 16, wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile hydrochloride.
19. The combination according to claim 1 that comprises
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile, or a stereoisomeric form thereof or a
pharmaceutically acceptable salt thereof; and abacavir, or a
pharmaceutically acceptable salt thereof; and emtricitabine.
20. The combination according to claim 19, wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile.
21. The combination according to claim 19, wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile hydrochloride.
22. The combination according to claim 1 that comprises
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile, or a stereoisomeric form thereof; or a
pharmaceutically acceptable salt thereof; lamivudine, and abacavir,
or a pharmaceutically acceptable salt thereof.
23. The combination according to claim 22, wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile.
24. The combination according to claim 22, wherein the
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is
E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-am-
ino]-benzonitrile hydrochloride.
25. The combination according to claim 1, wherein the weight ratio
of each couple of components of the combination vary in a range
from 1/10 to 10/1.
26. A product containing a combination as claimed in claim 1 in a
single unit dosage form.
27. A pharmaceutical formulation comprising a pharmaceutically
acceptable carrier and a combination as claimed in claim 1.
28. A kit comprising the combination of claim 1 packaged with
instructions for use.
29. A method of treating HIV infection in a patient comprising
administering to the patient a combination as claimed in claim 1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The application is a continuation of U.S. application Ser.
No. 14/454,045, filed Aug. 7, 2014, which is a continuation of U.S.
application Ser. No. 12/574,881, filed Oct. 7, 2009, which is a
continuation of U.S. application Ser. No. 10/570,228, filed Feb.
28, 2006, now abandoned, which is the National Stage Entry of
International Application No. PCT/EP2004/052028, filed Sep. 3,
2004, which claims the benefit of European Application Nos.
03103668.4 filed Oct. 2, 2003, 03103335.0, filed Sep. 10, 2003,
03103319.4, filed Sep. 8, 2003, and 03103275.8, filed Sep. 3, 2003
and U.S. Provisional Application Nos. 60/508,486, filed Oct. 3,
2003 and 60/499,771, filed Sep. 3, 2003.
FIELD OF THE INVENTION
[0002] The present invention concerns combinations of a pyrimidine
containing NNRTI with nucleoside reverse transcriptase inhibitors
and/or nucleotide reverse transcriptase inhibitors useful for the
treatment of HIV infected patients or for the prevention of HIV
transmission or infection.
BACKGROUND OF THE INVENTION
[0003] Despite the fact that significant progress has been made by
the introduction of HAART therapy (Highly Active Anti-Retroviral
Therapy), resistance of the HIV virus against nucleoside reverse
transcriptase inhibitors (NRTIs), non-nucleoside reverse
transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase
inhibitors (NtRTIs), protease inhibitors and even the more recent
fusion inhibitors is still a major cause of therapy failure. For
instance, half of the patients receiving anti-HIV combination
therapy do not respond fully to the treatment, mainly because of
resistance of the virus to one or more drugs used. Moreover, it has
been shown that resistant virus is carried over to newly infected
individuals, resulting in severely limited therapy options for
these drug-naive patients. On the International AIDS Conference in
Paris in July 2003, researchers released that the biggest study so
far of resistance to AIDS drugs finds that about 10 percent of all
newly infected people in Europe have drug-resistant strains.
Smaller tests to determine the spread of resistance have been done
in the high-risk city center of San Francisco. This test showed the
highest level of resistance at 27 percent.
[0004] The pharmacokinetic profile of many commercially available
antiretrovirals does not allow relatively low therapeutic doses.
Poor pharmacokinetic profiles often in combination with poor
solubility properties of the antiretrovirals cause the AIDS patient
to face a high pill burden which is particularly undesirable for
drug-naive patients or first line therapy. Moreover, as a
consequence of the AIDS virus even resisting antiretroviral
combination therapy, a physician will boost the plasma levels of
the active drugs in order for said antiretrovirals to regain
effectivity against the mutated HIV viruses, the consequence of
which is an even higher increase in pill burden. Boosting plasma
levels may also lead to an increased risk of non-compliance with
the prescribed therapy and to increased side-effects.
[0005] Several attempts have been made to date to design
combination regimens. For instance, the combination of lamivudine
(a nucleoside RT inhibitor also named 3TC) at a 150 mg dose and
zidovudine (a nucleotide RT inhibitor also named AZT) at a 300 mg
dose, formulated in an oral tablet and dosed twice daily, or the
combination of abacavir sulfate at a dose equivalent to 300 mg
abacavir (a nucleoside RT inhibitor), lamivudine at a 150 mg dose
and zidovudine at a 300 mg dose, formulated in an oral tablet and
dosed twice daily.
[0006] WO 93/23021 describes therapeutic combinations for the
treatment of HIV-infections comprising zidovudine and an agent
serving to enhance the antiviral activity against HIV populations
otherwise resistant to zidovudine.
[0007] WO 96/01110 describes a triple combination of zidovudine,
lamivudine and loviride, the latter being a non-nucleoside RT
inhibitor of the .alpha.-APA class.
[0008] An overview of new antiretroviral drugs is given in Clinical
Microbiology and Infection 2003, Vol. 9: 3, pp. 186-193.
[0009] WO 03/016306 specifically discloses more than 250 pyrimidine
derivative having HIV replication inhibiting properties that act as
non-nucleoside RT inhibitors (NNRTIs) having the ability to inhibit
the replication both wild-type and of mutant strains. One of said
NNRTIs is
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]amino-
]-benzonitrile (herein referred to as TMC278). WO 03/016306 also
discloses the methods to synthesize these compounds. It further
discloses combinations of said NNRTIs with other antiretrovirals,
i.e. suramine, pentamidine, thymopentin, castanospermine, dextran
(dextran sulfate), foscarnet-sodium (trisodium phosphono formate),
zidovudine (3'-azido-3'-deoxythymidine, AZT), didanosine
(2',3'-di-deoxyinosine; ddI), zalcitabine (dideoxycytidine, ddC),
lamivudine (2'-3'-dideoxy-3'-thiacytidine, 3TC), stavudine
(2',3'-didehydro-3'-deoxythymidine, d4T), abacavir, nevirapine
(11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido-[3,2-b:2',3'-e][1,4]dia-
zepin-6-one), efavirenz, delavirdine, TMC120, TMC125, tenofovir,
(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4-
,5,1-jk][1,4]benzodiazepine-2(1H)-thione,
.alpha.-[(2-nitrophenyl)amino]-2,6-dichloro-benzene-acetamide,
RO-5-3335, indinavir, ritonavir, saquinavir, lopinavir (ABT-378),
nelfinavir, amprenavir, TMC126, BMS-232632, VX-175, T-20, T-1249,
AMD-3100 and hydroxyurea.
[0010] Notwithstanding existing combination therapy, there is still
a need for improved antiretroviral therapy, more particularly AIDS
therapy. This need is particularly acute for therapy that is
effective not only on wild type HIV virus, but also on the
increasingly more common resistant HIV viruses. It is thus highly
desirable especially for first line therapy to design a combination
regimen with a low pill burden that limits or even suppresses the
recurrence of drug resistant virus and which can be used and
remains effective for a long term.
[0011] It is an object of the invention to provide combinations of
more than one therapeutically effective antiretroviral drug, which
combinations can be used as first line therapy in drug-naive
patients for a long period of time.
[0012] It is also an object of the invention to provide
combinations of more than one therapeutically effective
antiretroviral drug in which the antiretroviral drugs have a
complementary resistance profile thus creating a high resistance
barrier and thus allowing a drug-naive patient to take the
combinations for a long period of time.
[0013] Another object of the invention is to provide combinations
of more than one therapeutically active antiretroviral drug wherein
each of the active antiretroviral drugs of the combinations can be
administered once daily thus reducing the pill burden for the
patient.
[0014] A further object of the invention is to provide combinations
of more than one therapeutically active antiretroviral drug wherein
each of the active antiretroviral drugs of the combinations can be
co-formulated.
[0015] Yet a further object of the invention is to provide
combinations of more that one therapeutically active antiretroviral
drug wherein a therapeutically effective amount of each of the
active antiretroviral drugs of the combinations can be
co-formulated in one single pharmaceutical formulation.
[0016] Another object of the present invention is to provide
combinations of more than one active antiretroviral drug which
combinations can be used to prevent HIV transmission or infection
in humans.
[0017] All references cited herein are incorporated by
reference.
SUMMARY OF THE INVENTION
[0018] Thus in a first aspect, the present invention provides a
combination comprising (i) TMC278 or a stereoisomeric form thereof;
or a pharmaceutically acceptable salt thereof; or a prodrug
thereof; and (ii) a nucleoside reverse transcriptase inhibitor
and/or a nucleotide reverse transcriptase inhibitor; wherein TMC278
and the nucleotide reverse transcriptase inhibitor and/or the
nucleoside reverse transcriptase inhibitor are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily.
[0019] Thus in a second aspect, the present invention provides a
combination comprising (i) TMC278 or a stereoisomeric form thereof;
or a pharmaceutically acceptable salt thereof; or a prodrug
thereof; and (ii) a nucleoside reverse transcriptase inhibitor;
wherein TMC278 and the nucleoside reverse transcriptase inhibitor
are therapeutically effective HIV inhibitors at a dose that can be
administered once daily.
[0020] In a third aspect there is provided a combination comprising
(i) TMC278 or a stereoisomeric form thereof; or a pharmaceutically
acceptable salt thereof; or a prodrug thereof; and (ii) a
nucleotide reverse transcriptase inhibitor; wherein TMC278 and the
nucleotide reverse transcriptase inhibitor are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily.
[0021] In a fourth aspect there is provided a triple combination
comprising (i) TMC278 or a stereoisomeric form thereof; or a
pharmaceutically acceptable salt thereof; or a prodrug thereof; and
(ii) a nucleoside reverse transcriptase inhibitor; and (iii) a
nucleotide reverse transcriptase inhibitor; wherein TMC278 and the
nucleotide reverse transcriptase inhibitor and the nucleoside
reverse transcriptase inhibitor are therapeutically effective HIV
inhibitors at a dose that can be administered once daily.
[0022] In a fifth aspect there is provided a triple combination
comprising (i) TMC278 or a stereoisomeric form thereof; or a
pharmaceutically acceptable salt thereof; or a prodrug thereof; and
(ii) a nucleoside reverse transcriptase inhibitor; and (iii) a
second nucleoside reverse transcriptase inhibitor different from
the nucleoside reverse transcriptase inhibitor of (ii); wherein
TMC278 and the first and second nucleoside reverse transcriptase
inhibitors are therapeutically effective HIV inhibitors at a dose
that can be administered once daily.
[0023] In another aspect there is provided a pharmaceutical
formulation comprising a pharmaceutically acceptable carrier and a
combination as specified herein.
[0024] The invention also concerns the use of the combinations
specified herein as HIV inhibitors and the use thereof in the
treatment of HIV infected patients or in the prevention of HIV
transmission or infection.
[0025] The invention is based on the finding that TMC278 is a
potent reverse transcriptase inhibitor that has an extremely high
genetic barrier in combination with a favourable pharmacokinetic
profile allowing once daily dosing. It was surprising to discover
that TMC278 has all these properties together. This is unusual
because one cannot predict what mutations will be selected in the
HIV-1 genome by a given drug, whether the mutated virus will have
any chance of survival under the pressure of the drug, how much
drug is needed to limit or to suppress the recurrence of such
mutated virus, and at what frequency such drug has to be given to
maintain suppression of the development of a resistant virus that
can break through the genetic barrier of the drug.
DETAILED DESCRIPTION OF THE INVENTION
[0026] As used herein the term `therapeutically effective HIV
inhibitors at a dose that can be administered once daily` means
that the HIV inhibitors are suitable for dosing every 24 hours. The
`term suitable for dosing every 24 hours` means that the HIV
inhibitors are such that they can be administered every 24 hours
and give effective blood plasma concentrations of the active
ingredients such that they are effective to suppress HIV infection
over a period of 24 hours. The HIV inhibitors for use in the
invention can be dosed every 24 hours.
[0027] TMC278 or
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amin-
o]-benzonitrile is a known NNRTI, which can be prepared as
described in WO03/016306. TMC278 can be used in base form or, which
is preferred, as a suitable pharmaceutically acceptable salt form,
in particular as an acid addition salt form. The pharmaceutically
acceptable addition salts are meant to comprise the therapeutically
active non-toxic salt forms. The acid addition salt forms can be
obtained by treating the base form with appropriate acids as
inorganic acids, for example, hydrohalic acids, e.g. hydrochloric,
hydrobromic and the like; sulfuric acid; nitric acid; phosphoric
acid and the like; or organic acids, for example, acetic,
propanoic, hydroxyacetic, 2-hydroxy-propanoic, 2-oxopropanoic,
oxalic, malonic, succinic, maleic, fumaric, malic, tartaric,
2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic,
ethanesulfonic, benzene-sulfonic, 4-methylbenzenesulfonic,
cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and
the like acids. Preferred for use in the present invention are the
hydrohalic acid salts, in particular the hydrochloride salt.
[0028] TMC278 occurs in stereoisomeric forms, more in particular as
E- and Z-isomeric forms. Both isomers may be used in the
combinations of the present invention. Whenever reference is made
herein to TMC278, the E- and the Z-form as well as any mixture of
both forms are meant to be included.
[0029] A preferred form of TMC278 for use in the invention is the
E-isomer, i.e.
(E)-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]--
amino]-benzonitrile (hereinafter called E-TMC278). The Z-isomer of
TMC278, i.e.
(Z)-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidi-
nyl]-amino]-benzonitrile (hereinafter called compound Z-TMC278) can
also be used. It has relatively high potency against wild-type
HIV-1 but is less active against single and double mutants in
comparison to the E-isomer. Table 1 shows the IC.sub.50 value in nM
of the E and Z-isomer of TMC278.
TABLE-US-00001 TABLE 1 HIV RT mutation E-isomer Z-isomer Wild-type
0.4 0.6 100I 0.4 6.3 103N 0.3 1.6 181C 1.3 5.0 188L 2.0 32 227C 2.0
4.0 100I + 103N 7.9 790 103N + 181C 1.0 40 227L + 106A 1.0 4.0
[0030] Whenever reference is made herein to the E-form of TMC278
(i.e. E-TMC278), the pure E-isomer or any isomeric mixture of the
E- and the Z-forms wherein the E-form is predominantly present is
meant to be comprised, i.e. an isomeric mixture containing more
than 50% or in particular more than 80% of the E-form, or even more
than 90% of the E-form. Of particular interest is the E-form
substantially free of the Z-form. Substantially free in this
context refers to E-Z-mixtures with no or almost no Z-form, e.g.
isomeric mixtures containing as much as 90%, in particular 95% or
even 98% or 99% of the E-form. Equally, whenever reference is made
herein to the Z-form of TMC278 (i.e. Z-TMC278), the pure Z-isomer
or any isomeric mixture of the Z- and the E-forms wherein the
Z-form is predominantly present is meant to be comprised, i.e. an
isomeric mixture containing more than 50% or in particular more
than 80% of the Z-form, or even more than 90% of the Z-form. Of
particular interest is the Z-form substantially free of the E-form.
Substantially free in this context refers to E-Z-mixtures with no
or almost no E-form, e.g. isomeric mixtures containing as much as
90%, in particular 95% or even 98% or 99% of the Z-form.
[0031] Also meant to be included for use in this invention are
salts of the isomeric forms of TMC278, in particular the salts
mentioned above. Of particular interest are Z-TMC278 hydrochloride
and specifically E-TMC278 hydrochloride.
[0032] Advantageously, the nucleotide reverse transcriptase
inhibitor and the nucleoside reverse transcriptase inhibitor select
mutations in the reverse transcriptase that do not cause resistance
to TMC278. Of particular interest therefore is any combination
specified herein wherein (1) TMC278 and the nucleoside/nucleotide
reverse transcriptase inhibitor or inhibitors are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily and (2) the nucleoside/nucleotide reverse transcriptase
inhibitor or inhibitors select mutations in the reverse
transcriptase that do not cause resistance to TMC278.
[0033] Specifically, in one embodiment, a combination is provided
comprising (i) TMC278 or its stereoisomeric form or
pharmaceutically acceptable salt or its prodrug, and (ii) a
nucleoside reverse transcriptase inhibitor, wherein (1) TMC278 and
the nucleoside reverse transcriptase inhibitor are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily and (2) the nucleoside reverse transcriptase inhibitor
selects mutations in the reverse transcriptase that do not cause
resistance to TMC278. In another embodiment, a combination is
provided comprising (i) TMC278 or its stereoisomeric form or
pharmaceutically acceptable salt or its prodrug, and (ii) a
nucleotide reverse transcriptase inhibitor, wherein (1) TMC278 and
the nucleotide reverse transcriptase inhibitor are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily and (2) the nucleotide reverse transcriptase inhibitor
selects mutations in the reverse transcriptase that do not cause
resistance to TMC278.
[0034] In a preferred embodiment, a triple combination is provided
comprising (i) TMC278 or its stereoisomeric form or
pharmaceutically acceptable salt or its prodrug, and (ii) a
nucleoside reverse transcriptase inhibitor, and (iii) a nucleotide
reverse transcriptase inhibitor, wherein (1) TMC278 and the
nucleotide reverse transcriptase inhibitor and the nucleoside
reverse transcriptase inhibitor are therapeutically effective HIV
inhibitors at a dose that can be administered once daily and (2)
the nucleotide reverse transcriptase inhibitor and the nucleoside
reverse transcriptase inhibitor select mutations in the reverse
transcriptase that do not cause resistance to TMC278.
[0035] In another preferred embodiment, a triple combination is
provided comprising (i) TMC278 or its stereoisomeric form or
pharmaceutically acceptable salt or its prodrug, and (ii) a
nucleoside reverse transcriptase inhibitor, and (iii) a second
nucleoside reverse transcriptase inhibitor different from the
nucleoside reverse transcriptase inhibitor of (ii); wherein (1)
TMC278 and the nucleoside reverse transcriptase inhibitors are
therapeutically effective HIV inhibitors at a dose that can be
administered once daily and (2) the nucleoside reverse
transcriptase inhibitors select mutations in the reverse
transcriptase that do not cause resistance to TMC278.
[0036] Preferred nucleotide reverse transcriptase inhibitors that
can be used in the combinations subject of this invention include
tenofovir and its prodrug tenofovir disoproxil fumarate.
[0037] Tenofovir is an adenosine nucleotide analogue currently
commercially available with activity against retroviruses.
Tenofovir disoproxil fumarate (tenofovir DF) is a once-daily,
orally administered prodrug of tenofovir. For antiviral activity,
tenofovir DF needs to be hydrolysed to the ANP analogue and then
phosphorylated to the active diphosphate moiety [Arimilli et al
Antiviral Chemistry and Chemotherapy 1997, 8: 6 (557-564); Fridland
et al. Antiviral Research 1997, 34]. After entry in to lymphocytes
or macrophages, the prodrug is quantitatively converted to the
parent analogue, tenofovir, and phosphorylated to mono- and
diphosphate metabolites. The cellular enzymes that are responsible
for phosphorylation of this drug are adenylate kinase and
nucleoside diphosphate kinase [Robbins et al. Antimicrobial Agents
and Chemotherapy 1995, 39: 10 (2304-2308); Robbins et al.
Antimicrobial Agents and Chemotherapy 1998, 42: 3 (612-617)].
Unlike other nucleoside analogues, such as zidovudine or stavudine,
both of whose phosphorylation is cell cycle-dependent, tenofovir is
efficiently phosphorylated in resting as well as cycling peripheral
blood lymphocytes [Robbins et al. 1998]. Tenofovir can inhibit
HIV-1 replication in different cell types that may target HIV,
including primary human blood lymphocytes and macrophages [Perno et
al. Antiviral Research 1992 (289-304); Perno et al. Molecular
Pharmacology 1996, 50: 2 (359-366)]. The primary target of
tenofovir diphosphate is reverse transcriptase (RT). Tenofovir
diphosphate is a competitive inhibitor for the incorporation of
deoxyadenosine triphosphate into nascent proviral DNA chains.
Inhibition of HIV-1 RT by tenofovir diphosphate has an inhibition
constant of approximately 0.9 .mu.M, and if the analogue is
incorporated into the growing viral DNA chain it may terminate
further chain elongation. Tenofovir inhibits viral RT much more
effectively than it inhibits cellular DNA polymerases [Suo et al
Journal of Biological Chemistry 1998, 273: 42 (2750-2758)]. The
concentration required to inhibit the replication of various HIV-1
strains by 50% (EC50) in lymphocyte and macrophage cell types
(MT-2, CEM, ACH8) ranges from 0.2 to 10 .mu.M. The antiviral effect
is achieved at non-toxic doses of tenofovir (selectivity index
ranging from 100 to 2000). Tenofovir DF is currently available as
300 mg tablets to be taken once daily.
[0038] Viral resistance to tenofovir in vitro emerges slowly. A
recombinant virus expressing the K65R mutation showed a 3-fold
decreased susceptibility to tenofovir in vitro [Cherrington et al.
Interscience Conference on Antimicrobial Agents and Chemotherapy
1997, 37th]. Notably, clinical HIV strains expressing the M184V
lamivudine-associated resistance mutation on RT show wild-type or
increased susceptibility to tenofovir in vitro, independent of
changes in Ki for the mutant enzyme [Miller et al. Interscience
Conference on Antimicrobial Agents and Chemotherapy 1998,].
Long-term treatment (5 to 15 weeks) of newborn rhesus macaques with
tenofovir (doses of 30 mg/kg) starting 3 weeks after inoculation
with simian immunodeficiency virus, resulted in emergence of SIV
with approximately 5-fold decreased susceptibility to tenofovir
[Van Rompay et al. Antimicrobial Agents and Chemotherapy 1996, 40:
11 (2586-2591)]. This low level of resistance was associated with
the appearance of the K65R mutation.
[0039] In a preferred embodiment, a combination is provided
comprising (i) TMC278 or its stereoisomeric form or
pharmaceutically acceptable salt or its prodrug, and (ii) tenofovir
or its prodrug tenofovir disoproxil fumarate, wherein TMC278 and
tenofovir or its prodrug tenofovir disoproxil fumarate are
therapeutically effective HIV inhibitors at a dose that can be
administered once daily.
[0040] In another preferred embodiment, a triple combination is
provided comprising (i) TMC278 or its stereoisomeric form or
pharmaceutically acceptable salt or its prodrug, and (ii) a
nucleoside reverse transcriptase inhibitor, and (iii) tenofovir
disoproxil fumarate; wherein TMC278 and the nucleoside reverse
transcriptase inhibitor and tenofovir disoproxil fumarate are
therapeutically effective HW inhibitors at a dose that can be
administered once daily.
[0041] Preferred nucleoside reverse transcriptase inhibitors that
can be used in the combinations of this invention include abacavir
or a pharmaceutically acceptable salt thereof, emtricitabine,
racemic FTC and lamivudine (also named 3TC).
[0042] Emtricitabine or (-)-FTC is the left (-) rotatory
enantiomeric form of racemic FTC or
(.+-.)-cis-4-amino-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1-
H)-pyrimidinone (FTC). It is a commercially available nucleoside
analogue and exhibits activity against HIV-1 [Hoong et al. Journal
of Organic Chemistry 1992 (5563-5565); Jeong et al Journal of
Medicinal Chemistry 1993, 36: 2 (181-195); Van Roey et al.
Antiviral Chemistry and Chemotherapy 1993, 4: 6 (369-375]. The in
vitro anti-HIV-1 activity of (-)-beta-enantiomer of FTC was
reported to be 20-fold more than the (+)-beta-enantiomer, and the
(+)-enantiomer was significantly more toxic than the (-)-enantiomer
to myeloid progenitor cells [Schinazi et al Antimicrobial Agents
and Chemotherapy 1992, 36: 11 (2423-2431)]. The potential for HIV-1
resistance to FTC was evaluated by serial passage of the virus in
human PBMCs and MT-2 cells in the presence of increasing drug
concentrations. Highly drug-resistant HIV-1 variants dominated the
replicating virus population after two or more cycles of infection.
RT derived from drug-resistant viral particles was 15- to 50-fold
less susceptible to the 5'-triphosphate of FTC compared with the
enzyme from parental drug susceptible virus. DNA sequence analysis
of the RT gene amplified from resistant viruses consistently
identified mutations at codon 184 from Met (ATG) to Val (GTG or
GTA) [Schinazi et al Antimicrobial Agents and Chemotherapy 1993,
37: 4 (875-881); Tisdale et al Antiviral Research 1993, 20: Suppl
1; Smith et al Journal of Virology 1997, 71: 3 (2357-2362); Harrer
et al Journal of Infectious Diseases 1996, 173: 2 (476-479);
Tisdale et al Proceedings of the National Academy of Sciences of
the United States of America 1993, 90: 12 (5653-5656)]. Due to this
observed single mutation in the YMDD of reverse transcriptase in
the HIV-infected patients, (-)-FTC is not suitable for monotherapy
and needs to be administered in combination with other
antiretroviral agents to effectively treat patients infected with
HIV. Emtricitabine is available as 200 mg capsules to be taken once
a day.
[0043] Lamivudine has the chemical name
(-)-2',3'-dideoxy-3'-thiacytidine and is described for instance in
EP-382 526 as an antiviral nucleoside analogue. It is also a well
established and useful antiretroviral which is commercially
available for instance as 150 mg oral tablets. Lamivudine is also
commercially available in combination with zidovudine (300 mg
zidovudine/150 mg lamivudine), and in combination with lamivudine
and abacavir sulfate (300 mg zidovudine/150 mg
lamivudine/equivalent of 300 mg abacavir).
[0044] Abacavir is a well established and useful antiretroviral
which is commercially available for instance as an oral solution of
abacavir sulfate in a strength equivalent to 20 mg abacavir
base/ml, or as an oral tablet of abacavir sulfate in a strength
equivalent to 300 mg abacavir base. Abacavir sulfate is also
commercially available in combination with lamivudine and
zidovudine (300 mg zidovudine/150 mg lamivudine/equivalent of 300
mg abacavir).
[0045] Abacavir is a carbocyclic nucleoside with potent and
selective anti-HIV activity. Abacavir in its optically active form
is disclosed in EP-434 450. The cis-isomer of abacavir with
unspecified absolute stereochemical configuration is described in
EP-349 242. Abacavir is one of the most potent NRTI developed to
date. An average reduction in viral load of more than 1.4 log10 RNA
copies/ml is observed after a short course of abacavir monotherapy.
In vitro, resistant virus is not rapidly selected by abacavir. A
significant decrease in susceptibility to abacavir in wild-type or
zidovudine-resistant HIV-1 strains was not observed until after
eight to ten passages in MT-4 cells. A set of resistance mutations
at HIV reverse transcriptase (RT) codons, 65R, 74V, 115F and/or
184V, are selected during in vitro passage with abacavir, and a
combination of these mutations was required to confer a 10-fold
reduction in abacavir susceptibility in a laboratory strain of HIV.
The first mutation detected upon passage of HIV-1 in an increasing
concentration of abacavir is M184V, which confers only a 3-fold
decrease in HIV-1 susceptibility. Phenotype resistance to 3TC
and/or the presence of the 184V mutation does not prevent viral
load response to abacavir therapy. Resistance to multiple
nucleosides is associated with a decreased or absent response to
abacavir [Kumar et al Antimicrobial Agents and Chemotherapy 1999,
43:3 (603-608); Lanier et al International Conference on
Retroviruses and Opportunistic Infections 1998, 5th:Chicago; posted
on 16 Apr. 1999].
[0046] In a preferred embodiment, a combination is provided
comprising (i) TMC278 or a stereoisomeric form thereof; or a
pharmaceutically acceptable salt thereof; or a prodrug thereof, and
(ii) emtricitabine, wherein TMC278 and emtricitabine are
therapeutically effective HIV inhibitors at a dose that can be
administered once daily.
[0047] In a preferred embodiment, a combination is provided
comprising (i) TMC278 or a stereoisomeric form thereof; or a
pharmaceutically acceptable salt thereof; or a prodrug thereof; and
(ii) lamivudine, wherein TMC278 and lamivudine are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily.
[0048] In another preferred embodiment, a combination is provided
comprising (i) TMC278 or a stereoisomeric form thereof; or a
pharmaceutically acceptable salt thereof; or a prodrug thereof; and
(ii) abacavir or a pharmaceutically acceptable salt thereof,
characterized in that, TMC278 and abacavir are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily.
[0049] In another preferred embodiment, a combination is provided
comprising (i) TMC278 or a stereoisomeric form thereof; or a
pharmaceutically acceptable salt thereof; or a prodrug thereof; and
(ii) abacavir sulfate, characterized in that, TMC278 and abacavir
sulfate are therapeutically effective HIV inhibitors at a dose that
can be administered once daily.
[0050] In another preferred embodiment, a triple combination is
provided comprising (i) TMC278 or a stereoisomeric form thereof; or
a pharmaceutically acceptable salt thereof; or a prodrug thereof;
and (ii) emtricitabine, and (iii) a nucleotide reverse
transcriptase inhibitor, wherein TMC278 and the nucleotide reverse
transcriptase inhibitor and emtricitabine are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily.
[0051] In another preferred embodiment, a triple combination is
provided comprising (i) TMC278 or or a stereoisomeric form thereof;
or a pharmaceutically acceptable salt thereof; or a prodrug
thereof; and (ii) lamivudine, and (iii) a nucleotide reverse
transcriptase inhibitor, wherein TMC278 and the nucleotide reverse
transcriptase inhibitor and lamivudine are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily.
[0052] In another preferred embodiment, a triple combination is
provided comprising (i) TMC278 or a stereoisomeric form thereof; or
a pharmaceutically acceptable salt thereof; or a prodrug thereof;
and (ii) abacavir or a pharmaceutically acceptable salt thereof, or
preferably abacavir sulfate, and (iii) a nucleotide reverse
transcriptase inhibitor, wherein TMC278 and the nucleotide reverse
transcriptase inhibitor and abacavir or a pharmaceutically
acceptable salt thereof, or preferably abacavir sulphate, are
therapeutically effective HIV inhibitors at a dose that can be
administered once daily.
[0053] In another preferred embodiment, a triple combination is
provided comprising (i) TMC278 or a stereoisomeric form thereof; or
a pharmaceutically acceptable salt thereof; or a prodrug thereof;
and (ii) emtricitabine, and (iii) tenofovir or its prodrug
tenofovir disoproxil fumarate, wherein TMC278 and emtricitabine and
tenofovir or its prodrug tenofovir disoproxil fumarate are
therapeutically effective HIV inhibitors at a dose that can be
administered once daily.
[0054] In another preferred embodiment, a triple combination is
provided comprising (i) TMC278 or a stereoisomeric form thereof; or
a pharmaceutically acceptable salt thereof; or a prodrug thereof;
and (ii) lamivudine and (iii) tenofovir or its prodrug tenofovir
disoproxil fumarate, wherein TMC278 and lamivudine and tenofovir or
its prodrug tenofovir disoproxil fumarate are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily.
[0055] In another preferred embodiment, a triple combination is
provided comprising (i) TMC278 or a stereoisomeric form thereof; or
a pharmaceutically acceptable salt thereof; or a prodrug thereof;
and (ii) abacavir or a pharmaceutically acceptable salt form
thereof, preferably abacavir sulfate; and (iii) tenofovir or its
prodrug tenofovir disoproxil fumarate, wherein TMC278 and abacavir
or a pharmaceutically acceptable salt form thereof, preferably
abacavir sulfate and tenofovir or its prodrug tenofovir disoproxil
fumarate are therapeutically effective HIV inhibitors at a dose
that can be administered once daily.
[0056] The following preferred triple combinations are also
included [0057] (a) TMC278 or a stereoisomeric form thereof; or a
pharmaceutically acceptable salt thereof; or a prodrug thereof;
with emtricitabine and tenofovir disoproxil fumarate; [0058] (b)
TMC278 or a stereoisomeric form thereof; or a pharmaceutically
acceptable salt thereof; or a prodrug thereof; with lamivudine and
tenofovir disoproxil fumarate. [0059] (c) TMC278 or a
stereoisomeric form thereof; or a pharmaceutically acceptable salt
thereof; or a prodrug thereof; with abacavir sulfate and tenofovir
disoproxil fumarate. [0060] (d) TMC278 or a stereoisomeric form
thereof; or a pharmaceutically acceptable salt thereof; or a
prodrug thereof; with emtricitabine and lamivudine; [0061] (e)
TMC278 or a stereoisomeric form thereof; or a pharmaceutically
acceptable salt thereof; or a prodrug thereof; emtricitabine and
abacavir or a pharmaceutically acceptable salt thereof, preferably
abacavir sulfate. [0062] (f) TMC278 or a stereoisomeric form
thereof; or a pharmaceutically acceptable salt thereof; or a
prodrug thereof; abacavir or a pharmaceutically acceptable salt
thereof, preferably abacavir sulfate and lamivudine.
[0063] In particular, in each of the combinations (a)-(f) the
active ingredients, in particular TMC278, emtricitabine,
lamivudine, abacavir or a pharmaceutically acceptable salt form
thereof, preferably abacavir sulfate, and tenofovir or its prodrug
tenofovir disoproxil fumarate, are therapeutically effective HIV
inhibitors at a dose that can be administered once daily.
[0064] The double combinations of the present invention may contain
one or more additional active ingredients, which can be agents
useful for treating HIV infected patients or other active agents.
The triple combinations of the present invention may equally
contain one or more additional active ingredients, which can be
agents useful for treating HIV infected patients or other active
agents. Preferably any of these additional agents are
therapeutically effective at a dose that can be administered once
daily.
[0065] The active ingredients of the combinations of the present
invention may be administered simultaneously, concurrently or
sequentially. Simultaneous administration may be done by employing
a unitary pharmaceutical formulation or separate pharmaceutical
formulations. In general, the combinations may be administered by
topical, oral, rectal, intravenous, subcutaneous or intramuscular
routes. For first line therapy of HIV infection, simultaneous
administration employing a unitary pharmaceutical formulation is
preferred.
[0066] Thus, in another aspect there is provided a product
containing a combination as specified herein as a combined
preparation for simultaneous, separate or sequential use against
HIV infection.
[0067] The invention also provides a product containing (i) TMC278
or a stereoisomeric form thereof; or a pharmaceutically acceptable
salt thereof; or a prodrug thereof; and (ii) a nucleoside reverse
transcriptase inhibitor and/or a nucleotide reverse transcriptase
inhibitor; wherein TMC278 and the nucleotide reverse transcriptase
inhibitor and/or the nucleoside reverse transcriptase inhibitor are
therapeutically effective HIV inhibitors at a dose that can be
administered once daily; as a combined preparation for
simultaneous, separate or sequential use against HIV infection.
[0068] In a further aspect there is provided a product containing
(i) TMC278 or a stereoisomeric form thereof; or a pharmaceutically
acceptable salt thereof; or a prodrug thereof; and (ii) a
nucleoside reverse transcriptase inhibitor; wherein TMC278 and the
nucleoside reverse transcriptase inhibitor are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily; as a combined preparation for simultaneous, separate or
sequential use against HIV infection.
[0069] In another aspect there is provided a product containing (i)
TMC278 or a stereoisomeric form thereof; or a pharmaceutically
acceptable salt thereof; or a prodrug thereof; and (ii) a
nucleotide reverse transcriptase inhibitor, wherein TMC278 and the
nucleotide reverse transcriptase inhibitor are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily; as a combined preparation for simultaneous, separate or
sequential use against HIV infection.
[0070] In another aspect there is provided a product containing (i)
TMC278 or a stereo-isomeric form thereof; or a pharmaceutically
acceptable salt thereof; or a prodrug thereof; and (ii) a
nucleoside reverse transcriptase inhibitor; and (iii) a nucleotide
reverse transcriptase inhibitor; wherein TMC278 and the nucleotide
reverse transcrip-tase inhibitor and the nucleoside reverse
transcriptase inhibitor are therapeutically effective HIV
inhibitors at a dose that can be administered once daily; as a
combined preparation for simultaneous, separate or sequential use
against HIV infection.
[0071] In another aspect there is provided a product containing (i)
TMC278 or a stereoisomeric form thereof; or a pharmaceutically
acceptable salt thereof; or a prodrug thereof; and (ii) a
nucleoside reverse transcriptase inhibitor; and (iii) a second
nucleoside reverse transcriptase inhibitor other than the
nucleoside reverse transcriptase inhibitor of (ii); wherein TMC278
and the nucleoside reverse transcriptase inhibitors are
therapeutically effective HIV inhibitors at a dose that can be
administered once daily; as a combined preparation for
simultaneous, separate or sequential use against HIV infection.
[0072] The active ingredients in the products of the invention are
present in therapeutically effective amounts, the latter meaning an
amount that is sufficient to exert a sufficient HIV inhibitory
effect during a certain time period, i.e. the time period between
each intake of the formulations, preferably for about 24 hours.
[0073] Particular embodiments are products as specified above
containing one or more of the specific active ingredients mentioned
herein such as emtricitabine, racemic FTC, lamivudin, tenofovir and
its prodrug tenofovir disoproxil fumarate.
[0074] The products as mentioned above may contain separate
formulations of the active ingredients, or two or where applicable
more of the active ingredients may be co-formulated.
[0075] In still a further aspect the invention provides
pharmaceutical formulations containing a combination as specified
herein and a suitable carrier.
[0076] In another aspect there is provided a pharmaceutical
formulation comprising a pharmaceutically acceptable carrier and as
active ingredients (i) TMC278 or a stereoisomeric form thereof; or
a pharmaceutically acceptable salt thereof; or a prodrug thereof;
and (ii) a nucleoside reverse transcriptase inhibitor and/or a
nucleotide reverse transcriptase inhibitor; wherein TMC278 and the
nucleoside reverse transcriptase inhibitor and/or the nucleotide
reverse transcriptase inhibitor are therapeutically effective HIV
inhibitors at a dose that can be administered once daily.
[0077] The invention further provides a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and as active
ingredients (i) TMC278 or a stereoisomeric form thereof; or a
pharmaceutically acceptable salt thereof; or a prodrug thereof; and
(ii) a nucleoside reverse transcriptase inhibitor; wherein TMC278
and the nucleoside reverse transcriptase inhibitor are
therapeutically effective HIV inhibitors at a dose that can be
administered once daily.
[0078] In still another aspect there is provided a pharmaceutical
formulation comprising a pharmaceutically acceptable carrier and as
active ingredients (i) TMC278 or a stereoisomeric form thereof; or
a pharmaceutically acceptable salt thereof; or a prodrug thereof;
and (ii) a nucleotide reverse transcriptase inhibitor, wherein
TMC278 and the nucleoside reverse transcriptase inhibitor and the
nucleotide reverse transcriptase inhibitor are therapeutically
effective HIV inhibitors at a dose that can be administered once
daily.
[0079] In still another aspect there is provided a pharmaceutical
formulation comprising a pharmaceutically acceptable carrier and as
active ingredients (i) TMC278 or a stereoisomeric form thereof; or
a pharmaceutically acceptable salt thereof; or a prodrug thereof;
and (ii) a nucleoside reverse transcriptase inhibitor; and (iii) a
nucleotide reverse transcriptase inhibitor; wherein TMC278 and the
nucleoside reverse transcriptase inhibitor and the nucleotide
reverse transcriptase inhibitors are therapeutically effective HIV
inhibitors at a dose that can be administered once daily.
[0080] In still another aspect there is provided a pharmaceutical
formulation comprising a pharmaceutically acceptable carrier and as
active ingredients (i) TMC278 or a stereoisomeric form thereof; or
a pharmaceutically acceptable salt thereof; or a prodrug thereof;
and (ii) a nucleoside reverse transcriptase inhibitor; and (iii) a
second nucleoside reverse transcriptase inhibitor different from
the nucleoside reverse transcriptase inhibitor of (ii); wherein
TMC278 and the nucleoside reverse transcriptase inhibitors are
therapeutically effective HIV inhibitors at a dose that can be
administered once daily.
[0081] The active ingredients in the pharmaceutical formulations of
the invention are present in therapeutically effective amounts, the
latter meaning an amount that is sufficient to exert a sufficient
HIV inhibitory effect during a certain time period, i.e. the time
period between each intake of the formulations, preferably for
about 24 hours.
[0082] Particular embodiments are pharmaceutical formulations as
specified above containing one or more of the specific active
ingredients mentioned herein such as emtricitabine, racemic FTC,
lamivudin, tenofovir and its prodrug tenofovir disoproxil
fumarate.
[0083] The pharmaceutical formulations of the present invention may
be formulated into various forms for different types of
administration. To prepare the pharmaceutical formulations of this
invention, effective amounts of the active ingredients, optionally
in addition salt form, is combined in intimate admixture with a
pharmaceutically acceptable carrier, which carrier may take a wide
variety of forms depending on the form of preparation desired for
administration. The pharmaceutical formulations of the invention
are preferably formulated in unitary dosage form suitable,
particularly, for administration orally, rectally, percutaneously,
or by parenteral injection. For example, in preparing the
formulations in oral dosage form, any of the usual pharmaceutical
media may be employed such as, for example, water, glycols, oils,
alcohols and the like in the case of oral liquid preparations such
as suspensions, syrups, elixirs, emulsions and solutions; or solid
carriers such as starches, sugars, kaolin, diluents, lubricants,
binders, disintegrating agents and the like in the case of powders,
pills, capsules, and tablets. Because of their ease in
administration, tablets and capsules represent the most
advantageous oral dosage unit forms, in which case solid
pharmaceutical carriers are obviously employed. For parenteral
compositions, the carrier will usually comprise sterile water, at
least in large part, though other ingredients, for example, to aid
solubility, may be included. Injectable solutions, for example, may
be prepared in which the carrier comprises saline solution, glucose
solution or a mixture of saline and glucose solution. Injectable
suspensions may also be prepared in which case appropriate liquid
carriers, suspending agents and the like may be employed.
[0084] In one aspect of the invention, the present combinations can
be formulated in an oral tablet form further comprising
pharmaceutically acceptable excipients having a weight ranging
between 150 mg and 600 mg, suitable ranging between 200 and 400 mg.
Convenient oral tablet forms containing the active ingredients
according to the present invention have a total nominal weight
ranging between 200 mg and 1500 mg, suitably between 500 mg and
1250 mg, more suitable between 600 and 1100 mg.
[0085] An advantage of the pharmaceutical formulations of the
invention resides in the fact that each of the ingredients of the
present combinations can be co-formulated in one pharmaceutical
formulation and do not have to be administered separately. The
daily therapeutic antiretroviral amount of the ingredients of the
present combinations of such co-formulated single pharmaceutical
form preferably is administered in a single unit dosage form but,
if desired, also multiple unit dosage forms, such as two, three,
four, five or even more unit dosage forms may be administered. A
physician will be able to determine the exact dosage to be given
taking into account the severity of the patient's condition as well
as the patient's weight, gender and possibly other parameters such
as individual differences in absorption, biodistribution,
metabolism and excretion rates for each drug as well as other
factors known to those skilled in the art.
[0086] This invention also provides a method of treating HIV
infected patients said method comprising administering a
combination as specified herein.
[0087] Furthermore there is provided a method of treating HIV
infected patients, said method comprising administering TMC278 or
its stereoisomeric form or pharmaceutically acceptable salt or its
prodrug, in combination with a nucleoside reverse transcriptase
inhibitor and/or a nucleotide reverse transcriptase inhibitor, in
which method a therapeutically effective amount of TMC278 and the
nucleoside reverse transcriptase inhibitor and/or nucleotide
reverse transcriptase inhibitor can be administered once daily.
[0088] Furthermore there is provided a method of treating HIV
infected patients, said method comprising administering TMC278 or
its stereoisomeric form or pharmaceutically acceptable salt or its
prodrug, in combination with a nucleoside reverse transcriptase
inhibitor, in which method a therapeutically effective amount of
TMC278 and the nucleoside reverse transcriptase inhibitor can be
administered once daily.
[0089] In a further aspect of this invention concerns a method of
treating HIV infected patients said method comprising administering
TMC278 or its stereoisomeric form or pharmaceutically acceptable
salt or its prodrug, and a nucleotide reverse transcriptase
inhibitor, in which method a therapeutically effective amount of
TMC278 and the nucleotide reverse transcriptase inhibitor can be
administered once daily.
[0090] Still a further aspect of this invention comprises a method
of treating HIV infected patients said method comprising
administering TMC278 or its stereoisomeric form or pharmaceutically
acceptable salt or its prodrug, in combination with a nucleoside
reverse transcriptase inhibitor, and a nucleotide reverse
transcriptase inhibitor, in which method a therapeutically
effective amount of TMC278, the nucleotide reverse transcriptase
inhibitor and the nucleoside reverse transcriptase inhibitor can be
administered once daily.
[0091] Still a further aspect of this invention comprises a method
of treating HIV infected patients said method comprising
administering TMC278 or its stereoisomeric form or pharmaceutically
acceptable salt or its prodrug, in combination with a nucleoside
reverse transcriptase inhibitor, and a second nucleoside reverse
transcriptase inhibitor different from the former nucleoside
reverse transcriptase inhibitor, in which method a therapeutically
effective amount of TMC278, the nucleoside reverse transcriptase
inhibitors can be administered once daily.
[0092] The active ingredients in the methods of the invention are
administered in therapeutically effective amounts, the latter
meaning an amount that is sufficient to exert a sufficient HIV
inhibitory effect during a certain time period, i.e. the time
period between each intake of the formulations, preferably for
about 24 hours.
[0093] Particular embodiments are methods as specified above
wherein one or more of the specific active ingredients mentioned
herein such as emtricitabine, racemic FTC, lamivudin, tenofovir and
its prodrug tenofovir disoproxil fumarate, are administered.
[0094] One embodiment of the present invention relates to the
present combinations for use as a medicine. Another embodiment
relates to the combinations of the present invention for use in the
manufacture of a medicament to treat HIV infected patients.
[0095] Of particular interest are any of the combinations as
specified herein, or any of the products, pharmaceutical
formulations, unit dosage forms, methods and uses being based on
said combinations, wherein TMC278 is E-TMC287, or preferably TMC278
hydrochloride salt or more preferably E-TMC278 hydrochloride
salt.
[0096] The combinations of this invention are especially useful for
the treatment of AIDS and related clinical conditions such as AIDS
related complex (ARC), progressive generalised lymphadenopathy
(PGL) or AIDS related neurological conditions such as multiple
sclerosis. The present triple combination may be particularly
useful for the treatment of drug-naive HIV infected patients.
[0097] The combinations of the invention are also useful for the
prevention of HIV transmission or infection in humans, in
particular sexual transmission. Thus, the present invention relates
to the use of combinations according to the present invention for
the manufacture of a medicament for the prevention of HIV infection
or transmission via sexual intercourse or related intimate contact
between partners. The invention also relates to a method of
preventing HIV infection or transmission via sexual intercourse or
related intimate contact between partners comprising administering
to a subject in need thereof an effective amount of any of the
combinations according to the present invention.
[0098] The respective daily dose for each of the active ingredients
of a combination according to the present invention may range
between 10 mg and 800 mg, preferably between 50 and 400 mg, more
preferably between 50 and 300 mg, or between 100 and 300 mg. In
particular, the daily dose for TMC278 may range between 10 mg and
500 mg, preferably between 10 and 300, more preferably between 50
and 250 mg, still more preferably between 50 and 200 mg, e.g. about
100 mg.
[0099] The weight ratio of each couple of components of the triple
combination taken on a daily basis may vary in a range from 1/10 to
10/1. Suitably, the weight ratio of each couple varies between 1/6
and 6/1, more suitably 1/4 and 4/1, preferably between 1/3 and 3/1,
and more preferably between 1/2 and 2/1.
TABLE-US-00002 Table 2 lists some examples of the daily dose for
each of the active ingredients in combinations of compound
E-TMC278, emtricitabine and tenofovir. Combination no. E-TMC278
Emtricitabine Tenofovir 1 50 mg 200 mg -- 2 50 mg -- 300 mg 3 100
mg 200 mg -- 4 100 mg -- 300 mg 5 200 mg 200 mg -- 6 200 mg -- 300
mg 7 50 mg 200 mg 300 mg 8 100 mg 200 mg 300 mg 9 200 mg 200 mg 300
mg
TABLE-US-00003 Table 3 lists some examples of the daily dose for
each of the active ingredients in combinations of TMC278, abacavir
and lamivudine wherein the dose mentioned in the table for abacavir
sulfate is the equivalent dose of abacavir base. Combination
Abacavir no. E-TMC278 Lamivudine sulfate 1 50 mg 150 mg 300 mg 2
100 mg 150 mg 300 mg 3 200 mg 150 mg 300 mg
[0100] Thus, an interesting combination according to the present
invention comprises compound E-(A) in a daily dose ranging between
10 mg and 500 mg, a daily dose of 150 mg lamivudine and a daily
dose of an equivalent of 300 mg abacavir base. Suitably, such
combination is formulated in a single pharmaceutical form.
[0101] Another interesting combination according to the present
invention comprises compound E-(A) in a daily dose ranging between
50 mg and 250 mg, a daily dose of 150 mg lamivudine and a daily
dose of an equivalent of 300 mg abacavir base. Suitably, such
combination is formulated in a single pharmaceutical form.
[0102] The present invention also relates to a pharmaceutical
composition in a form adapted to be applied to a site where sexual
intercourse or related intimate contact can take place, such as the
genitals, rectum, mouth, hands, lower abdomen, upper thighs,
especially the vagina and mouth, comprising a pharmaceutically
acceptable carrier and as active ingredients an effective amount of
a combination according to the present invention. As appropriate
special adapted compositions there may be cited all compositions
usually employed for being applied to the vagina, rectum, mouth and
skin such as for example gels, jellies, creams, ointments, films,
sponges, foams, intravaginal rings, cervical caps, suppositories
for rectal or vaginal application, vaginal or rectal or buccal
tablets, mouthwashes. To prepare such pharmaceutical compositions,
an effective amount of each of the particular compounds of the
triple combination as the active ingredients is combined in
intimate admixture with a pharmaceutically acceptable carrier,
which carrier may take a wide variety of forms depending on the
form of administration. In order to increase the residence time of
such pharmaceutical composition at the site of administration, it
may be advantageous to include in the composition a bioadhesive, in
particular a bioadhesive polymer. A bioadhesive may be defined as a
material that adheres to a live biological surface such as for
example a mucus membrane or skin tissue.
[0103] Thus, the present invention also relates to a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and as
active ingredients an effective amount of each of the compounds of
the present triple combination characterized in that the
pharmaceutical composition is bioadhesive to the site of
application. Preferably, the site of application is the vagina,
rectum, mouth or skin, most preferred is the vagina.
[0104] Otten R A et al in Journal of Virology (2000), 74(20),
9771-9775 and Witvrouw M et al in Antiviral Research (2000), 46(3),
215-221 disclose the ability of tenofovir to delay HIV viral
breakthrough after high-risk sexual exposure.
[0105] Pani A et al in Antiviral Chemistry & Chemotherapy
(2001), 12(Suppl. 1), 51-59 describe the ability of lamivudine to
delay viral breakthrough.
[0106] The ability of TMC278 to prevent HIV infection via sexual
intercourse or related intimate contact between partners can be
demonstrated in the following test Immature monocyte derived
dendritic cells (immMO-DC) represent a good model for interstitial
dendritic cells, which are early targets during sexual HIV
transmission and important initiators of the immune response. These
immMO-DC were used in "in vitro" models to test the prevention of
HIV infection via sexual intercourse or related intimate contact
between partners. One such model is described in the experimental
part and indicates that the TMC278 potently inhibits HIV
replication in MO-DC/CD4(+) T cell co-cultures.
EXAMPLES
Example 1
Pharmacokinetics of E-TMC278
[0107] A double-blind, randomized, placebo-controlled Phase I trial
was designed to evaluate safety, tolerability, and ex-vivo
pharmacokinetics of single doses of compound E-TMC278 in healthy
male volunteers. Oral doses of 12.5, 25, and 50 mg were formulated
in PEG 400 and taken with a standard meal. The pharmacokinetic
results are shown in Table 4.
[0108] The pharmacokinetic results of another double-blind,
randomized, placebo-controlled Phase I study with 4 dosing sessions
to evaluate the safety, tolerability, pharmaco-kinetics and ex-vivo
pharmacodynamics of single 100 mg and 200 mg oral doses of compound
E-TMC278 in healthy male subjects are also reported in Table 4.
Randomization was such that for each session 6 subjects received
the same dose of compound E-TMC278 and 3 subjects received placebo.
There was a time interval of about 14 days between each dosing
session
[0109] Table 4 shows that high and dose-proportional exposures were
obtained. The correlation coefficient for the 5 C.sub.max
datapoints is 0.9897 and for the area under the curve values
between 0 and 48 hours (AUC.sub.0-48 hr) 0.9952. Half-life of
plasma concentrations ranged between 37 and 39 hours. The compound
was well tolerated by the volunteers. No relevant adverse effects
of the drug were noted.
TABLE-US-00004 TABLE 4 Parameter 12.5 mg 25 mg 50 mg 100 mg 200 mg
C.sub.max 73 .+-. 14 149 .+-. 32 267 .+-. 27 482 .+-. 121 807 .+-.
207 (ng/ml) T.sub.max (hr) 4.0 .+-. 0 4.0 .+-. 1.3 4.0 .+-. 1.3 4.3
.+-. 0.8 4.3 .+-. 0.8 AUC.sub.0-48 hr 1337 .+-. 310 2805 .+-. 496
5094 .+-. 509 8162 .+-. 2251 15592 .+-. 2746 (nghr/ml)
AUC.sub.0-.infin. 2210 .+-. 473 4637 .+-. 1164 8872 .+-. 1342 15844
.+-. 4592 (nghr/ml) T.sub.1/2 (hr) 37.1 38.7 45 .+-. 9 55 .+-.
18
Example 2
Virological Profile of Compound E-TMC278
[0110] Compound E-TMC278 was tested in a cell-based assay, using
natural host cells of HIV. MT-4 cells (a cell line of human T
cells) were infected with HIV-1 (wild type or mutants) and exposed
to different concentrations of antiviral compound in the presence
of 10% fetal calf serum. Cytotoxicity was determined in parallel
with the antiviral activity so that the selectivity of the
antiviral effect could be assessed. Active compounds have to
penetrate the cell membrane in order to interfere with replication
steps inside the cell.
[0111] After four days of incubation at 37.degree. C., the
viability of the HIV and mock-infected cells was assessed by an
automated tetrazolium-based colorimetric assay. This method enabled
the calculation of both the 50% inhibitory concentration for
inhibition of viral cytopathicity (IC50), the IC90, and the 50%
cytotoxic concentration (CC50). The ratio CC50/IC50, also called
the selectivity index, is an indication of the specificity of the
antiviral effect. Tested HIV strains included: Wild type (wt)
HIV-1; a panel of single and double mutants, obtained by
site-directed mutagenesis (SDM), and a panel of clinical isolates,
selected for resistance against NNRTIs.
[0112] Activity Towards Wild Type and SDM Mutants
[0113] A limited panel of HIV-1 mutants was constructed using
site-directed mutagenesis (SDM) and homologous recombination
techniques. Compound E-TMC278 was tested against an extended panel
of single and double mutants known to be resistant against
commercially available NNRTIs. Nevirapine (NVP) and efavirenz (EFV)
were included as controls.
[0114] The results are shown in Table 5 (values presented are IC50
values in nM). For wild type virus, the obtained IC50 was 0.4 nM
(0.15 ng/ml) and the IC90 1.3 nM (0.48 ng/ml). The HIV strain with
the lowest sensitivity against compound E-TMC278 within this
selection was the double mutant 100I+103N, with an IC50 of about 8
nM and an IC90 of about 16 nM.
TABLE-US-00005 TABLE 5 Compound NVP EFV E-TMC278 wild type 81 1.4
0.4 100I 597 35 0.4 101E 547 5 1.6 103N 2,879 28 0.3 106A 2,983 23
0.2 108I -- 2 0.3 138K 64 1.3 0.4 179D 161 6 0.6 179E 158 5 0.4
181C 10,000 2 1.3 188C 3,764 5 0.1 188H 241 9 0.2 188L 10,000 78
2.0 190A 4,101 8 0.3 190S 10,000 275 0.1 225H 171 2 0.3 227C 1,816
36 2.0 227L 78 0.3 0.3 234I 45 NT 0.3 236L 41 1 0.3 100I + 103N
10,000 10,000 7.9 101E + 103N 7,033 84 0.5 103N + 181I 10,000 37
1.0 227L + 106A 10,000 8 1.0
[0115] Development of Resistance In Vitro
[0116] NNRTIs are highly selective inhibitors of HIV-1 but their
current clinical use is limited by the rapid emergence of NNRTI
(cross-) resistance. The rate of resistance emergence against
compound E-TMC278 and the first generation NNRTIs nevirapine and
efavirenz was compared in vitro.
[0117] MT4 cells were infected with wild type HIV-1 at high
multiplicity of infection (>1 infectious virus per cell, to
maximize the genetic diversity of the virus population) in the
presence of various concentrations of compound E-TMC278 (40, 200,
1000 and 5000.times.IC50), and were monitored twice a week for
virus replication. Emerging virus was collected for pheno- and
genotyping. Cultures without evidence of virus replication were
further sub-cultivated in the presence of the same concentration of
inhibitor for a total duration of 30 days (10 passages).
[0118] Resistance to nevirapine emerged within 3-6 days, at all
tested concentrations. Breakthrough virus harboured the typical
Y181C mutation. The same experiments with efavirenz resulted in the
selection of G190E at all concentrations (up to 5 .mu.M) within 3
to 7 days. Compound E-TMC278 did not select for resistant virus
within 30 days using wild-type virus. If a double resistant mutant
K103N+Y181C (IC50 0.8 nM) was used instead of wild type virus,
resistance did emerge at all tested concentrations. Starting from
the single mutants Y181C (IC50 1.3 nM) or 103N (IC50 0.3 nM), virus
breakthrough did not occur at 40 and 200 nM, but did occur at 10
nM.
[0119] In this experimental setting of high genetic diversity,
HIV-1, resistant to first generation NNRTIs, was selected very
rapidly. Resistant viruses harboured only one mutation. In
contrast, emergence of HIV-1, resistant to compound E-TMC278 was
delayed or did not occur.
[0120] Cardiovascular and pulmonary safety of compound E-TMC278
Compound E-TMC278 had little or no effect on cardiovascular and
pulmonary parameters in vivo at plasma levels covering and
exceeding the targeted plasma levels in man and at concentrations
in vitro covering or exceeding the anti-viral concentration in
vitro.
Example 3
In Vitro Models to Test the Ability of Compound E-TMC278 to Prevent
HIV Infection Via Sexual Intercourse or Related Intimate Contact
Between Partners
[0121] For instance, in one model, monocyte-derived dendritic cells
(MO-DC) were infected for 2 hours with the monotropic HIV strain
Ba-L at a multiplicity of infection (MOI) of 10.sup.-3. After
infection, cells were washed 6 times and resuspended in 10% BCS at
400.000 cells/ml. Autologous CD4(+) T cells were purified out of
the lymphocyte fraction of the same elutration as the MO-DC and
used at a concentration of 2.times.10.sup.6 cells/ml ((ratio
MO-DC/CD4(+) T:1/5).
[0122] A serial dilution of a compound of formula (I) (test
compound) was added to the MO-DC/CD4(+) T cell co-cultures. Each
experiment was done in 96-well plates, in which each cup contained
50 .mu.l of MO-DC, 50 .mu.l of CD4(+) T cells and 100 .mu.l of test
compound. Half of the culture medium, with test compound, was
refreshed twice weekly.
[0123] Supernatants were analysed in ELISA after 14 days of
culture. To determine antiviral activity, the test compound
concentration able to suppress 50% of the viral replication at the
end of the primary cultures (EC50) was measured. For compound
E-TMC278, the EC50 value was 0.55 nM.
Example 4
Formulations
[0124] Tablet formulation of the following composition:
TABLE-US-00006 Emtricitabine 300 mg Tenofovir diisoproxyl fumarate
300 mg E-TMC278 hydrochloride salt 110 mg HPMC 2910 15 mPa s 24 mg
Polysorbate 20 6 mg Crosspolyvidone 18 mg Lactose monohydrate 43 mg
Magnesium stearate 3 mg Talcum 6 mg
[0125] The active ingredients and lactose are fluidised and sprayed
with a solution of HPMC and polysorbate in water (at an equivalent
of 120 ml/tablet). Subsequently crosspolyvidone is added, while
still being fluidised, followed by magnesium stearate and talcum.
The thus obtained granulate is compressed into 13 mm cylindrical
tablets using standard compressing equipment.
* * * * *