U.S. patent application number 10/352279 was filed with the patent office on 2003-12-25 for indole, azaindole and related heterocyclic pyrrolidine derivatives.
Invention is credited to Kadow, John F., Meanwell, Nicholas A., Wang, Tao, Xue, Qiufen May, Zhang, Zhongxing.
Application Number | 20030236277 10/352279 |
Document ID | / |
Family ID | 27734713 |
Filed Date | 2003-12-25 |
United States Patent
Application |
20030236277 |
Kind Code |
A1 |
Kadow, John F. ; et
al. |
December 25, 2003 |
Indole, azaindole and related heterocyclic pyrrolidine
derivatives
Abstract
This invention provides compounds having drug and bio-affecting
properties, their pharmaceutical compositions and method of use. In
particular, the invention is concerned with amido piperazine
derivatives. These compounds possess unique antiviral activity,
whether used alone or in combination with other antivirals,
antiinfectives, immunomodulators or HIV entry inhibitors. More
particularly, the present invention relates to the treatment of HIV
and AIDS.
Inventors: |
Kadow, John F.;
(Wallingford, CT) ; Xue, Qiufen May; (Glastonbury,
CT) ; Wang, Tao; (Middletown, CT) ; Zhang,
Zhongxing; (Madison, CT) ; Meanwell, Nicholas A.;
(East Hampton, CT) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
27734713 |
Appl. No.: |
10/352279 |
Filed: |
January 27, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60356977 |
Feb 14, 2002 |
|
|
|
Current U.S.
Class: |
514/300 ;
514/414; 546/113; 548/465 |
Current CPC
Class: |
C07D 471/04 20130101;
C07D 403/14 20130101; C07D 403/04 20130101; A61P 31/18 20180101;
C07D 403/06 20130101; C07D 403/12 20130101; A61P 31/12
20180101 |
Class at
Publication: |
514/300 ;
514/414; 546/113; 548/465 |
International
Class: |
C07D 471/02; C07D 43/02;
A61K 031/4745; A61K 031/405 |
Claims
What is claimed is:
1. A compound of Formula I, including pharmaceutically acceptable
salts thereof 105Q is selected from the group consisting of:
106R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5, are
independently selected from the group consisting of hydrogen,
halogen, cyano, nitro, COOR.sup.8, XR.sup.57, and B; m is 1 or 2;
R.sup.7 is (CH.sub.2).sub.nR.sup.44 wherein n is 0-6; R.sup.6 is O
or does not exist; ----represents a carbon-carbon bond or does not
exist; A is selected from the group consisting of C.sub.1-6alkoxy,
phenyl and D; wherein D is selected from the group consisting of
pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl,
pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl,
benzoimidazolyl and benzothiazolyl; wherein said phenyl and D are
independently optionally substituted with one or two of the same or
different amino, halogen or trifluoromethyl; 107B is selected from
the group consisting of (C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl,
C(O)NR.sup.40R.sup.41, phenyl and heteroaryl; wherein said
(C.sub.1-6)alkyl, phenyl and heteroaryl are independently
optionally substituted with one to three same or different halogens
or from one to three same or different substituents selected from
F; F is selected from the group consisting of (C.sub.1-6)alkyl,
phenyl, hydroxy, (C.sub.1-6)alkoxy, halogen, benzyl,
--NR.sup.42C(O)--(C.sub.1-6)alkyl, --NR.sup.42R.sup.43, COOR.sup.54
and --CONR.sup.42; wherein said (C.sub.1-6)alkyl is optionally
substituted with one to three same or different halogen; R.sup.8 is
selected from the group consisting of hydrogen and
(C.sub.1-6)alkyl; R.sup.9 is selected from the group consisting of
hydrogen and methyl; X is selected from the group consisting of
NR.sup.9, O and S; R.sup.40 and R.sup.41 are independently selected
from the group consisting of hydrogen, (C.sub.1-6)alkyl,
(C.sub.1-6)alkoxy, phenyl and heteroaryl; wherein said phenyl and
heteroaryl are independently optionally substituted with one to
three same or different halogen, methyl, or CF.sub.3 groups;
R.sup.42 and R.sup.43 are independently selected from the group
consisting of hydrogen and (C.sub.1-6)alkyl; R.sup.44 is selected
from the group consisting of H, (C.sub.1-6)alkyl,
CO(C.sub.1-6)alkyl, C(O)-phenyl and --CONR.sub.aR.sub.b; R.sub.a
and R.sub.b are each independently H, (C.sub.1-6)alkyl or phenyl;
R.sup.54 is selected from the group consisting of hydrogen and
(C.sub.1-6)alkyl; R.sup.57 is (C.sub.1-6)alkyl; and heteroaryl is
selected from the group consisting of pyridinyl, pyrazinyl,
pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl,
thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl,
imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,
1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl,
pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl.
2. The compound of claim 1, including pharmaceutically acceptable
salts thereof of formula 108wherein: Z is 109A is selected from the
group consisting of phenyl and D; wherein D is selected from the
group consisting of pyridinyl, furanyl and thienyl; wherein phenyl
and D are independently optionally substituted with one or two of
the same or different amino or halogen; W is selected from the
group consisting of 110R.sup.1 is hydrogen; and Q is a member
selected from groups (A) and (B) consisting of 111provided R.sup.2
and R.sup.3 are each independently hydrogen, methoxy or halogen;
and R.sup.4 and R.sup.5 are selected from the group consisting of
hydrogen, halogen, cyano, COOR.sup.8, C(O)NHCH.sub.3,
C(O)NHheteroaryl, and heteroaryl; and 112provided R.sup.2 is
hydrogen, methoxy or halogen; R.sup.3 and R.sup.4 are selected from
the group consisting of hydrogen, halogen, methoxy, cyano,
COOR.sup.8, C(O)NHCH.sub.3, C(O)NHheteroaryl and heteroaryl; and
R.sup.6 does not exist; and ----represents a carbon-carbon bond in
(A) and (B).
3. A pharmaceutical composition which comprises an antiviral
effective amount of a compound of Formula I, including
pharmaceutically acceptable salts thereof, as claimed in any of
claims 1-2, and one or more pharmaceutically acceptable carriers,
excipients or diluents.
4. The pharmaceutical composition of claim 3, useful for treating
infection by HIV, which additionally comprises an antiviral
effective amount of an AIDS treatment agent selected from the group
consisting of: (a) an AIDS antiviral agent; (b) an anti-infective
agent; (c) an immunomodulator; and (d) HIV entry inhibitors.
5. A method for treating a mammal infected with a virus comprising
administering to said mammal an antiviral effective amount of a
compound of Formula I, including pharmaceutically accceptable salts
thereof, as claimed in any of claims 1-2, and one or more
pharmaceutically acceptable carriers, excipients or diluents.
6. The method of claim 5, comprising administering to said mammal
an antiviral effective amount of a compound of Formula I in
combination with an antiviral effective amount of an AIDS treatment
agent selected from the group consisting of: an AIDS antiviral
agent; an anti-infective agent; an immunomodulator; and an HIV
entry inhibitor.
7. The method of claim 5 wherein said virus is HIV.
8. The method of claim 6 wherein said virus is HIV.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Serial No. 60/356,977 filed Feb. 14, 2002.
FIELD OF THE INVENTION
[0002] This invention provides compounds having drug and
bio-affecting properties, their pharmaceutical compositions and
method of use. In particular, the invention is concerned with new
heterocyclic amidopiperazine derivatives that possess unique
antiviral activity. More particularly, the present invention
relates to compounds useful for the treatment of HIV and AIDS.
BACKGROUND ART
[0003] HIV-1 (human immunodeficiency virus-1) infection remains a
major medical problem, with an estimated 33.6 million people
infected worldwide. The number of cases of HIV and AIDS (acquired
immunodeficiency syndrome) has risen rapidly. In 1999, 5.6 million
new infections were reported, and 2.6 million people died from
AIDS. Currently available drugs for the treatment of HIV include
six nucleoside reverse transcriptase (RT) inhibitors (zidovudine,
didanosine, stavudine, lamivudine, zalcitabine and abacavir), three
non-nucleoside reverse transcriptase inhibitors (nevirapine,
delavirdine and efavirenz), and six peptidomimetic protease
inhibitors (saquinavir, indinavir, ritonavir, nelfinavir,
amprenavir and lopinavir). Each of these drugs can only transiently
restrain viral replication if used alone. However, when used in
combination, these drugs have a profound effect on viremia and
disease progression. In fact, significant reductions in death rates
among AIDS patients have been recently documented as a consequence
of the widespread application of combination therapy. However,
despite these impressive results, 30 to 50% of patients ultimately
fail combination drug therapies. Insufficient drug potency,
non-compliance, restricted tissue penetration and drug-specific
limitations within certain cell types (e.g. most nucleoside analogs
cannot be phosphorylated in resting cells) may account for the
incomplete suppression of sensitive viruses. Furthermore, the high
replication rate and rapid turnover of HIV-1 combined with the
frequent incorporation of mutations, leads to the appearance of
drug-resistant variants and treatment failures when sub-optimal
drug concentrations are present (Larder and Kemp; Gulick;
Kuritzkes; Morris-Jones et al; Schinazi et al; Vacca and Condra;
Flexner; Berkhout and Ren et al; (Ref. 6-14)). Therefore, novel
anti-HIV agents exhibiting distinct resistance patterns, and
favorable pharmacokinetic as well as safety profiles are needed to
provide more treatment options.
[0004] Currently marketed HIV-1 drugs are dominated by either
nucleoside reverse transcriptase inhibitors or peptidomimetic
protease inhibitors. Non-nucleoside reverse transcriptase
inhibitors (NNRTIs) have recently gained an increasingly important
role in the therapy of HIV infections (Pedersen & Pedersen, Ref
15). At least 30 different classes of NNRTI have been described in
the literature (De Clercq, Ref. 16) and several NNRTIs have been
evaluated in clinical trials. Dipyridodiazepinone (nevirapine),
benzoxazinone (efavirenz) and bis(heteroaryl) piperazine
derivatives (delavirdine) have been approved for clinical use.
However, the major drawback to the development and application of
NNRTIs is the propensity for rapid emergence of drug resistant
strains, both in tissue cell culture and in treated individuals,
particularly those subject to monotherapy. As a consequence, there
is considerable interest in the identification of NNRTIs less prone
to the development of resistance (Pedersen & Pedersen, Ref 15).
A recent overview of non-nucleoside reverse transcriptase
inhibitors: perspectives on novel therapeutic compounds and
strategies for the treatment of HIV infection. has appeared
(Buckheit , reference 99). A review covering both NRTI and NNRTIs
has appeared (De clercq, reference 100). An overview of the current
state of the HIV drugs has been published (De clercq, reference
101)
[0005] Several indole derivatives including indole-3-sulfones,
piperazino indoles, pyrazino indoles, and
5H-indolo[3,2-b][1,5]benzothiazepine derivatives have been reported
as HIV-1 reverse transciptase inhibitors (Greenlee et al, Ref. 1;
Williams et al, Ref. 2; Romero et al, Ref. 3; Font et al, Ref. 17;
Romero et al, Ref. 18; Young et al, Ref. 19; Genin et al, Ref. 20;
Silvestri et al, Ref. 21). Indole 2-carboxamides have also been
described as inhibitors of cell adhesion and HIV infection
(Boschelli et al, U.S. Pat. No. 5,424,329, Ref. 4). 3-substituted
indole natural products (Semicochliodinol A and B,
didemethylasterriquinone and isocochliodinol) were disclosed as
inhibitors of HIV-1 protease (Fredenhagen et al, Ref. 22).
[0006] Structurally related aza-indole amide derivatives have been
disclosed previously (Kato et al, Ref. 23; Levacher et al, Ref. 24;
Dompe Spa, WO-09504742, Ref. 5(a); SmithKline Beecham PLC,
WO-09611929, Ref. 5(b); Schering Corp., US-05023265, Ref. 5(c)).
However, these structures differ from those claimed herein in that
they are aza-indole mono-amide rather than unsymmetrical aza-indole
piperazine diamide derivatives, and there is no mention of the use
of these compounds for treating viral infections, particularly HIV.
Indole and azaindole piperazine containing derivatives have been
disclosed in three different PCT patent applications (Reference
93-95) None of these applications discloses pyrrolidine compounds
such as described in this invention.
[0007] Nothing in these references can be construed to disclose or
suggest the novel compounds of this invention and their use to
inhibit HIV infection.
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SUMMARY OF THE INVENTION
[0112] The present invention comprises compounds of Formula I,
their pharmaceutical formulations, and their use in patients
suffering from or susceptible to a virus such as HIV. The compounds
of Formula I, which include nontoxic pharmaceutically acceptable
salts and/or hydrates thereof, have the formula and meaning as
described below. Each embodiment of a particular aspect of the
invention depends from the preceding embodiment unless otherwise
stated.
SUMMARY DESCRIPTION OF THE INVENTION
[0113] The present invention comprises compounds of Formula I, or
pharmaceutically acceptable salts thereof, which are effective
antiviral agents, particularly as inhibitors of HIV.
[0114] A first embodiment of a first aspect of the invention are
compounds of Formula I, including pharmaceutically acceptable salts
thereof, 1
[0115] wherein:
[0116] Z is 2
[0117] Q is selected from the group consisting of: 3
[0118] R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5, are
independently selected from the group consisting of hydrogen,
halogen, cyano, nitro, COOR.sup.8, XR.sup.57, and B;
[0119] m is 1 or 2;
[0120] R.sup.7 is (CH.sub.2).sub.nR.sup.44 wherein n is 0-6;
[0121] R.sup.6 is O or does not exist;
[0122] ----represents a carbon-carbon bond or does not exist;
[0123] A is selected from the group consisting of C.sub.1-6alkoxy,
phenyl and D; wherein D is selected from the group consisting of
pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl,
pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl,
benzoimidazolyl and benzothiazolyl; wherein said phenyl and D are
independently optionally substituted with one or two of the same or
different amino, halogen or trifluoromethyl;
[0124] --W-- is 4
[0125] B is selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.3-6)cycloalkyl, C(O)NR.sup.40R.sup.41, phenyl and
heteroaryl; wherein said (C.sub.1-6)alkyl, phenyl and heteroaryl
are independently optionally substituted with one to three same or
different halogens or from one to three same or different
substituents selected from F; F is selected from the group
consisting of (C.sub.1-6)alkyl, phenyl, hydroxy, (C.sub.1-6)alkoxy,
halogen, benzyl, --NR.sup.42C(O)--(C.sub.1-6)alkyl,
--NR.sup.42R.sup.43, COOR.sup.54 and --CONR.sup.42; wherein said
(C.sub.1-6)alkyl is optionally substituted with one to three same
or different halogen;
[0126] R.sup.8 is selected from the group consisting of hydrogen
and (C.sub.1-6)alkyl;
[0127] R.sup.9 is selected from the group consisting of hydrogen
and methyl;
[0128] X is selected from the group consisting of NR.sup.9, O and
S;
[0129] R.sup.40 and R.sup.41 are independently selected from the
group consisting of hydrogen, (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy,
phenyl and heteroaryl; wherein said phenyl and heteroaryl are
independently optionally substituted with one to three same or
different halogen, methyl, or CF.sub.3 groups;
[0130] R.sup.42 and R.sup.43 are independently selected from the
group consisting of hydrogen and (C.sub.1-6)alkyl;
[0131] R.sup.44 is selected from the group consisting of H,
(C.sub.1-6)alkyl, CO(C.sub.1-6)alkyl, C(O)-phenyl and
--CONR.sub.aR.sub.b;
[0132] R.sub.a and R.sub.b are each independently H,
(C.sub.1-6)alkyl or phenyl;
[0133] R.sup.54 is selected from the group consisting of hydrogen
and (C.sub.1-6)alkyl;
[0134] R.sup.57 is (C.sub.1-6)alkyl; and
[0135] heteroaryl is selected from the group consisting of
pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl,
benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,
isoxazolyl, imidazolyl, benzoimidazolyl,
1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-- 2-yl,
oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl,
triazinyl and triazolyl.
[0136] A more preferred embodiment of a first aspect of the
invention are compounds of Formula I, including pharmaceutically
acceptable salts thereof, 5
[0137] wherein:
[0138] Z is 6
[0139] A is selected from the group consisting of phenyl and D;
wherein D is selected from the group consisting of pyridinyl,
furanyl and thienyl; wherein phenyl and D are independently
optionally substituted with one or two of the same or different
amino or halogen;
[0140] W is selected from the group consisting of 7
[0141] R.sup.1 is hydrogen; and
[0142] Q is a member selected from groups (A) and (B) consisting of
8
[0143] provided R.sup.2 and R.sup.3 are each independently
hydrogen, methoxy or halogen; and R.sup.4 and R.sup.5 are selected
from the group consisting of hydrogen, halogen, cyano, COOR.sup.8,
C(O)NHCH.sub.3, C(O)NHheteroaryl, and heteroaryl; and 9
[0144] provided R.sup.2 is hydrogen, methoxy or halogen;
[0145] R.sup.3 and R.sup.4 are selected from the group consisting
of hydrogen, halogen, methoxy, cyano, COOR.sup.8, C(O)NHCH.sub.3,
C(O)NHheteroaryl and heteroaryl; and R.sup.6 does not exist;
[0146] and ----represents a carbon-carbon bond in (A) and (B).
[0147] Another embodiment of the present invention is a method for
treating mammals infected with a virus, wherein said virus is HIV,
comprising administering to said mammal an antiviral effective
amount of a compound of Formula I, and one or more pharmaceutically
acceptable carriers, excipients or diluents; optionally the
compound of Formula I can be administered in combination with an
antiviral effective amount of an AIDS treatment agent selected from
the group consisting of: (a) an AIDS antiviral agent; (b) an
anti-infective agent; (c) an immunomodulator; and (d) HIV entry
inhibitors.
[0148] Another embodiment of the present invention is a
pharmaceutical composition comprising an antiviral effective amount
of a compound of Formula I and one or more pharmaceutically
acceptable carriers, excipients, diluents and optionally in
combination with an antiviral effective amount of an AIDS treatment
agent selected from the group consisting of: (a) an AIDS antiviral
agent; (b) an anti-infective agent; (c) an immunomodulator; and (d)
HIV entry inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
[0149] Since the compounds of the present invention, may possess
asymmetric centers and therefore occur as mixtures of diastereomers
and enantiomers, the present invention includes the individual
diastereoisomeric and enantiomeric forms of the compounds of
Formula I in addition to the mixtures thereof.
Definitions
[0150] The term "C.sub.1-6 alkyl" as used herein and in the claims
(unless specified otherwise) mean straight or branched chain alkyl
groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, amyl, hexyl and the like.
[0151] "Halogen" refers to chlorine, bromine, iodine or
fluorine.
[0152] An "aryl" group refers to an all carbon monocyclic or
fused-ring polycyclic (i.e., rings which share adjacent pairs of
carbon atoms) groups having a completely conjugated pi-electron
system. Examples, without limitation, of aryl groups are phenyl,
napthalenyl and anthracenyl. The aryl group may be substituted or
unsubstituted. When substituted the substituted group(s) is
preferably one or more selected from alkyl, cycloalkyl, aryl,
heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,
heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy,
thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,
carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,
O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,
amino and --NR.sup.xR.sup.y, wherein R.sup.x and R.sup.y are
independently selected from the group consisting of hydrogen,
alkyl, cycloalkyl, aryl, carbonyl, C-carboxy, sulfonyl,
trihalomethyl, and, combined, a five- or six-member heteroalicyclic
ring.
[0153] As used herein, a "heteroaryl" group refers to a monocyclic
or fused ring (i.e., rings which share an adjacent pair of atoms)
group having in the ring(s) one or more atoms selected from the
group consisting of nitrogen, oxygen and sulfur and, in addition,
having a completely conjugated pi-electron system. It should be
noted that the term heteroaryl is intended to encompass an N-oxide
of the parent heteroaryl if such an N-oxide is chemically feasible
as is known in the art. Examples, without limitation, of heteroaryl
groups are furyl, thienyl, benzothienyl, thiazolyl, imidazolyl,
oxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, triazolyl,
tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl,
tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl,
isoquinolinyl, purinyl, carbazolyl, benzoxazolyl, benzimidazolyl,
indolyl, isoindolyl, pyrazinyl. diazinyl, pyrazine,
triazinyltriazine, tetrazinyl, and tetrazolyl. When substituted the
substituted group(s) is preferably one or more selected from alkyl,
cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy,
aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy,
thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,
carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,
O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,
amino, and --NR.sup.xR.sup.y, wherein R.sup.x and R.sup.y are as
defined above.
[0154] As used herein, a "heteroalicyclic" group refers to a
monocyclic or fused ring group having in the ring(s) one or more
atoms selected from the group consisting of nitrogen, oxygen and
sulfur. The rings may also have one or more double bonds. However,
the rings do not have a completely conjugated pi-electron system.
Examples, without limitation, of heteroalicyclic groups are
azetidinyl, piperidyl, piperazinyl, imidazolinyl, thiazolidinyl,
3-pyrrolidin-1-yl, morpholinyl, thiomorpholinyl and
tetrahydropyranyl. When substituted the substituted group(s) is
preferably one or more selected from alkyl, cycloalkyl, aryl,
heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,
heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy,
thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano,
halogen, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido,
C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido,
trihalomethanesulfonamido, trihalomethanesulfonyl, silyl, guanyl,
guanidino, ureido, phosphonyl, amino and --NR.sup.xR.sup.y, wherein
R.sup.x and R.sup.y are as defined above.
[0155] An "alkyl" group refers to a saturated aliphatic hydrocarbon
including straight chain and branched chain groups. Preferably, the
alkyl group has 1 to 20 carbon atoms (whenever a numerical range;
e.g., "1-20", is stated herein, it means that the group, in this
case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3
carbon atoms, etc. up to and including 20 carbon atoms). More
preferably, it is a medium size alkyl having 1 to 10 carbon atoms.
Most preferably, it is a lower alkyl having 1 to 4 carbon atoms.
The alkyl group may be substituted or unsubstituted. When
substituted, the substituent group(s) is preferably one or more
individually selected from trihaloalkyl, cycloalkyl, aryl,
heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,
heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy,
thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halo,
nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido,
C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido,
trihalomethanesulfonamido, trihalomethanesulfonyl, and combined, a
five- or six-member heteroalicyclic ring.
[0156] A "cycloalkyl" group refers to an all-carbon monocyclic or
fused ring (i.e., rings which share and adjacent pair of carbon
atoms) group wherein one or more rings does not have a completely
conjugated pi-electron system. Examples, without limitation, of
cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane,
cyclopentene, cyclohexane, cyclohexadiene, cycloheptane,
cycloheptatriene and adamantane. A cycloalkyl group may be
substituted or unsubstituted. When substituted, the substituent
group(s) is preferably one or more individually selected from
alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,
heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy,
thioaryloxy, thioheteroarylloxy, thioheteroalicycloxy, cyano, halo,
nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido,
C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido,
trihalo-methanesulfonamido, trihalomethanesulfonyl, silyl, guanyl,
guanidino, ureido, phosphonyl, amino and --NR.sup.xR.sup.y with
R.sup.x and R.sup.y as defined above.
[0157] An "alkenyl" group refers to an alkyl group, as defined
herein, consisting of at least two carbon atoms and at least one
carbon-carbon double bond.
[0158] An "alkynyl" group refers to an alkyl group, as defined
herein, consisting of at least two carbon atoms and at least one
carbon-carbon triple bond.
[0159] A "hydroxy" group refers to an --OH group.
[0160] An "alkoxy" group refers to both an --O-alkyl and an
--O-cycloalkyl group as defined herein.
[0161] An "aryloxy" group refers to both an --O-aryl and an
--O-heteroaryl group, as defined herein.
[0162] A "heteroaryloxy" group refers to a heteroaryl-O-- group
with heteroaryl as defined herein.
[0163] A "heteroalicycloxy" group refers to a heteroalicyclic-O--
group with heteroalicyclic as defined herein.
[0164] A "thiohydroxy" group refers to an --SH group.
[0165] A "thioalkoxy" group refers to both an S-alkyl and an
--S-cycloalkyl group, as defined herein.
[0166] A "thioaryloxy" group refers to both an --S-aryl and an
--S-heteroaryl group, as defined herein.
[0167] A "thioheteroaryloxy" group refers to a heteroaryl-S-- group
with heteroaryl as defined herein.
[0168] A "thioheteroalicycloxy" group refers to a
heteroalicyclic-S-- group with heteroalicyclic as defined
herein.
[0169] A "carbonyl" group refers to a --C(.dbd.O)--R" group, where
R" is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl (bonded through a
ring carbon) and heteroalicyclic (bonded through a ring carbon), as
each is defined herein.
[0170] An "aldehyde" group refers to a carbonyl group where R" is
hydrogen.
[0171] A "thiocarbonyl" group refers to a --C(.dbd.S)--R" group,
with R" as defined herein.
[0172] A "Keto" group refers to a --CC(.dbd.O)C-- group wherein the
carbon on either or both sides of the C.dbd.O may be alkyl,
cycloalkyl, aryl or a carbon of a heteroaryl or heteroaliacyclic
group.
[0173] A "trihalomethanecarbonyl" group refers to a
Z.sub.3CC(.dbd.O)-- group with said Z being a halogen.
[0174] A "C-carboxy" group refers to a --C(.dbd.O)O--R" groups,
with R" as defined herein.
[0175] An "O-carboxy" group refers to a R"C(--O)O-group, with R" as
defined herein.
[0176] A "carboxylic acid" group refers to a C-carboxy group in
which R" is hydrogen.
[0177] A "trihalomethyl" group refers to a --CZ.sub.3, group
wherein Z is a halogen group as defined herein.
[0178] A "trihalomethanesulfonyl" group refers to an
Z.sub.3CS(.dbd.O).sub.2-- groups with Z as defined above.
[0179] A "trihalomethanesulfonamido" group refers to a
Z.sub.3CS(.dbd.O).sub.2NR.sup.x-- group with Z and R.sup.X as
defined herein.
[0180] A "sulfinyl" group refers to a --S(.dbd.O)--R" group, with
R" as defined herein and, in addition, as a bond only; i.e.,
--S(O)--.
[0181] A "sulfonyl" group refers to a --S(.dbd.O).sub.2R" group
with R" as defined herein and, in addition as a bond only; i.e.,
--S(O).sub.2--.
[0182] A "S-sulfonamido" group refers to a
--S(.dbd.O).sub.2NR.sup.XR.sup.- Y, with R.sup.X and R.sup.Y as
defined herein.
[0183] A "N-Sulfonamido" group refers to a
R"S(.dbd.O).sub.2NR.sub.X-- group with R.sub.x as defined
herein.
[0184] A "O-carbamyl" group refers to a --OC(.dbd.O)NR.sup.xR.sup.y
as defined herein.
[0185] A "N-carbamyl" group refers to a R.sup.xOC(.dbd.O)NR.sup.y
group, with R.sup.x and R.sup.y as defined herein.
[0186] A "O-thiocarbamyl" group refers to a
--OC(.dbd.S)NR.sup.xR.sup.y group with R.sup.x and R.sup.y as
defined herein.
[0187] A "N-thiocarbamyl" group refers to a
R.sup.xOC(.dbd.S)NR.sup.y-- group with R.sup.x and R.sup.y as
defined herein.
[0188] An "amino" group refers to an --NH.sub.2 group.
[0189] A "C-amido" group refers to a --C(.dbd.O)NR.sup.xR.sup.y
group with R.sup.x and R.sup.y as defined herein.
[0190] A "C-thioamido" group refers to a --C(.dbd.S)NR.sup.xR.sup.y
group, with R.sup.x and R.sup.y as defined herein.
[0191] A "N-amido" group refers to a R.sup.xC(.dbd.O)NR.sup.y--
group, with R.sup.x and R.sup.y as defined herein.
[0192] An "ureido" group refers to a
--NR.sup.xC(.dbd.O)NR.sup.yR.sup.y2 group with R.sup.x and R.sup.y
as defined herein and R.sup.y2 defined the same as R.sup.x and
R.sup.y.
[0193] A "guanidino" group refers to a
--R.sup.xNC(.dbd.N)NR.sup.yR.sup.y2 group, with R.sup.x, R.sup.y
and R.sup.y2 as defined herein.
[0194] A "guanyl" group refers to a R.sup.xR.sup.yNC(.dbd.N)--
group, with R.sup.x and R.sup.Y as defined herein.
[0195] A "cyano" group refers to a --CN group.
[0196] A "silyl" group refers to a --Si(R").sub.3, with R" as
defined herein.
[0197] A "phosphonyl" group refers to a P(.dbd.O)(OR.sup.x).sub.2
with R.sup.x as defined herein.
[0198] A "hydrazino" group refers to a --NR.sup.xNR.sup.yR.sup.y2
group with R.sup.x, R.sup.y and R.sup.y2 as defined herein.
[0199] Any two adjacent R groups may combine to form an additional
aryl, cycloalkyl, heteroaryl or heterocyclic ring fused to the ring
initially bearing those R groups.
[0200] It is known in the art that nitogen atoms in heteroaryl
systems can be "participating in a heteroaryl ring double bond",
and this refers to the form of double bonds in the two tautomeric
structures which comprise five-member ring heteroaryl groups. This
dictates whether nitrogens can be substituted as well understood by
chemists in the art. The disclosure and claims of the present
invention are based on the known general principles of chemical
bonding. It is understood that the claims do not encompass
structures known to be unstable or not able to exist based on the
literature.
[0201] Physiologically acceptable salts and prodrugs of compounds
disclosed herein are within the scope of this invention. The term
"pharmaceutically acceptable salt" as used herein and in the claims
is intended to include nontoxic base addition salts. Suitable salts
include those derived from organic and inorganic acids such as,
without limitation, hydrochloric acid, hydrobromic acid, phosphoric
acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric
acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric
acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid,
and the like. The term "pharmaceutically acceptable salt" as used
herein is also intended to include salts of acidic groups, such as
a carboxylate, with such counterions as ammonium, alkali metal
salts, particularly sodium or potassium, alkaline earth metal
salts, particularly calcium or magnesium, and salts with suitable
organic bases such as lower alkylamines (methylamine, ethylamine,
cyclohexylamine, and the like) or with substituted lower
alkylamines (e.g. hydroxyl-substituted alkylamines such as
diethanolamine, triethanolamine or
tris(hydroxymethyl)-aminomethane), or with bases such as piperidine
or morpholine.
[0202] In the method of the present invention, the term "antiviral
effective amount" means the total amount of each active component
of the method that is sufficient to show a meaningful patient
benefit, i.e., healing of acute conditions characterized by
inhibition of the HIV infection. When applied to an individual
active ingredient, administered alone, the term refers to that
ingredient alone. When applied to a combination, the term refers to
combined amounts of the active ingredients that result in the
therapeutic effect, whether administered in combination, serially
or simultaneously. The terms "treat, treating, treatment" as used
herein and in the claims means preventing or ameliorating diseases
associated with HIV infection.
[0203] The present invention is also directed to combinations of
the compounds with one or more agents useful in the treatment of
AIDS. For example, the compounds of this invention may be
effectively administered, whether at periods of pre-exposure and/or
post-exposure, in combination with effective amounts of the AIDS
antivirals, immunomodulators, antiinfectives, or vaccines, such as
those in the following table.
1 Drug Name Manufacturer Indication ANTIVIRALS 097 Hoechst/Bayer
HIV infection, AIDS, ARC (non-nucleoside reverse trans- criptase
(RT) inhibitor) Amprenivir Glaxo Wellcome HIV infection, 141 W94
AIDS, ARC GW 141 (protease inhibitor) Abacavir (1592U89) Glaxo
Wellcome HIV infection, GW 1592 AIDS, ARC (RT inhibitor) Acemannan
Carrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIV
infection, AIDS, ARC, in combination with AZT AD-439 Tanox
Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV
infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV
infection AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive,
AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in
combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427
(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced
Biotherapy AIDS, ARC Neutralizes pH Concepts Labile alpha aberrant
(Rockville, MD) Interferon AR177 Aronex Pharm HIV infection, AIDS,
ARC Beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases
BMS-232623 Bristol-Myers Squibb/ HIV infection, (CGP-73547)
Novartis AIDS, ARC (protease inhibitor) BMS-234475 Bristol-Myers
Squibb/ HIV infection, (CGP-61755) Novartis AIDS, ARC (protease
inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead
Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI
Pharma USA HIV infection Cytomegalovirus MedImmune CMV retinitis
Immune globin Cytovene Syntex Sight threatening Ganciclovir CMV
peripheral CMV retinitis Delaviridine Pharmacia-Upjohn HIV
infection, AIDS, ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem.
AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan) asymptomatic ddC
Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddI
Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;
combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ)
AIDS, ARC (protease inhibitor) Efavirenz DuPont Merck HIV
infection, (DMP 266) AIDS, ARC (-)6-Chloro-4-(S)- (non-nucleoside
RT cyclopropylethynyl- inhibitor) 4(S)-trifluoro-
methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan
Corp, PLC HIV infection (Gainesville, GA) Famciclovir Smith Kline
herpes zoster, herpes simplex FTC Emory University HIV infection,
AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIV
infection, AIDS, ARC (reverse transcriptase inhibitor) HBY097
Hoechst Marion HIV infection, Roussel AIDS, ARC (non-nucleoside
reverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV
infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS,
Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon
alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV
infection, AIDS, ARC, asymptomatic HIV positive, also in
combination with AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV
retinitis KNI-272 Nat'l Cancer Institute HIV-assoc. diseases
Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse
transcriptase inhibitor); also with AZT Lobucavir Bristol-Myers
Squibb CMV infection Nelfinavir Agouron HIV infection,
Pharmaceuticals AIDS, ARC (protease inhibitor) Nevirapine
Boeheringer HIV infection, Ingleheim AIDS, ARC (RT inhibitor)
Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide T
Peninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium
Astra Pharm. CMV retinitis, HIV Phosphonoformate Products, Inc.
infection, other CMV infections PNU-140690 Pharmacia Upjohn HIV
infection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIV
infection, AIDS RBC-CD4 Sheffield Med. HIV infection, Tech
(Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection, AIDS, ARC
(protease inhibitor) Saquinavir Hoffmann- HIV infection, LaRoche
AIDS, ARC (protease inbitor) Stavudine; d4T Bristol-Myers Squibb
HIV infection, AIDS, Didehydrodeoxy- ARC thymidine Valaciclovir
Glaxo Wellcome Genital HSV & CMV infections Virazole
Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive,
LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC Zalcitabine
Hoffmann-LaRoche HIV infection, AIDS, ARC, with AZT Zidovudine; AZT
Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in
combination with other therapies IMMUNOMODULATORS AS-101
Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn Advanced AIDS
Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX) CL246,738
American Cyanamid AIDS, Kaposi's Lederle Labs sarcoma EL10 Elan
Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPharm
Blocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC,
in combination w/TNF (tumor necrosis factor) Granulocyte Genetics
Institute AIDS Macrophage Colony Sandoz Stimulating Factor
Granulocyte Hoechst-Roussel AIDS Macrophage Colony Immunex
Stimulating Factor Granulocyte Schering-Plough AIDS, Macrophage
Colony combination Stimulating Factor w/AZT HIV Core Particle Rorer
Seropositive HIV Immunostimulant IL-2 Cetus AIDS, in combination
Interleukin-2 w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, in
Interleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase
in Interleukin-2 CD4 cell counts (aldeslukin) Immune Globulin
Cutter Biological Pediatric AIDS, in Intravenous (Berkeley, CA)
combination w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New
Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New
Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl Merieux Institute
AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi's sarcoma
Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARC
Enkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma
Muramyl-Tripeptide Granulocyte Amgen AIDS, in combination Colony
Stimulating w/AZT Factor Remune Immune Response Immunotherapeutic
Corp. rCD4 Genentech AIDS, ARC Recombinant Soluble Human CD4
rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS, ARC Soluble
Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa 2a
AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV
infection Soluble T4 Thymopentin Immunobiology HIV infection
Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in
combination Factor; TNF w/gamma Interferon ANTI-INFECTIVES
Clindamycin with Pharmacia Upjohn PCP Primaquine Fluconazole Pfizer
Cryptococcal meningitis, candidiasis Pastille Squibb Corp.
Prevention of Nystatin Pastille oral candidiasis Ornidyl Merrell
Dow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate
(IM & IV) (Rosemont, IL) Trimethoprim Antibacterial
Trimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCP
treatment Pentamidine Fisons Corporation PCP prophylaxis
Isethionate for Inhalation Spiramycin Rhone-Poulene Cryptosporidial
diarrhea Intraconazole- Janssen-Pharm. Histoplasmosis; R51211
cryptococcal meningitis Trimetrexate Wamer-Lambert PCP Daunorubicin
NeXstar, Sequus Kaposi's sarcoma Recombinant Human Ortho Pharm.
Corp. Severe anemia Erythropoietin assoc. with AZT therapy
Recombinant Human Serono AIDS-related Growth Hormone wasting,
cachexia Megestrol Acetate Bristol-Myers Squibb Treatment of
anorexia assoc. W/AIDS Testosterone Alza, Smith Kline AIDS-related
wasting Total Enteral Norwich Eaton Diarrhea and Nutrition
Pharmaceuticals malabsorption related to AIDS
[0204] Additionally, the compounds of the invention herein may be
used in combination with another class of agents for treating AIDS
which are called HIV entry inhibitors. Examples of such HIV entry
inhibitors are discussed in DRUGS OF THE FUTURE 1999, 24(12), pp.
1355-1362; CELL, Vol. 9, pp. 243-246, Oct. 29, 1999; and DRUG
DISCOVERY TODAY, Vol. 5, No. 5, May 2000, pp. 183-194.
[0205] It will be understood that the scope of combinations of the
compounds of this invention with AIDS antivirals, immunomodulators,
anti-infectives, HIV entry inhibitors or vaccines is not limited to
the list in the above Table, but includes in principle any
combination with any pharmaceutical composition useful for the
treatment of AIDS.
[0206] Preferred combinations are simultaneous or alternating
treatments of with a compound of the present invention and an
inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV
reverse transcriptase. An optional fourth component in the
combination is a nucleoside inhibitor of HIV reverse transcriptase,
such as AZT, 3TC, ddC or ddI. A preferred inhibitor of HIV protease
is indinavir, which is the sulfate salt of
N-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-
-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide
ethanolate, and is synthesized according to U.S. Pat. No.
5,413,999. Indinavir is generally administered at a dosage of 800
mg three times a day. Other preferred protease inhibitors are
nelfinavir and ritonavir. Another preferred inhibitor of HIV
protease is saquinavir which is administered in a dosage of 600 or
1200 mg tid. Preferred non-nucleoside inhibitors of HIV reverse
transcriptase include efavirenz. The preparation of ddC, ddI and
AZT are also described in EPO 0,484,071. These combinations may
have unexpected effects on limiting the spread and degree of
infection of HIV. Preferred combinations include those with the
following (1) indinavir with efavirenz, and, optionally, AZT and/or
3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddI
and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC;
(3) stavudine and 3TC and/or zidovudine; (4) zidovudine and
lamivudine and 141W94 and 1592U89; (5) zidovudine and
lamivudine.
[0207] In such combinations the compound of the present invention
and other active agents may be administered separately or in
conjunction. In addition, the administration of one element may be
prior to, concurrent to, or subsequent to the administration of
other agent(s).
Abbreviations
[0208] The following abbreviations, most of which are conventional
abbreviations well known to those skilled in the art, are used
throughout the description of the invention and the examples. Some
of the abbreviations used are as follows:
2 h = hour(s) rt = room temperature mol = mole(s) mmol =
millimole(s) g = gram(s) mg = milligram(s) mL = milliliter(s) TFA =
Trifluoroacetic Acid DCE = 1,2-Dichloroethane CH.sub.2Cl.sub.2 =
Dichloromethane TPAP = tetrapropylammonium perruthenate THF =
Tetrahydofuran DEPBT = 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazi-
n-4(3H)- one DMAP = 4-dimethylaminopyridine P-EDC = Polymer
supported 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide EDC =
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide DMF =
N,N-dimethylformamide Hunig's Base = N,N-Diisopropylethylamine
mCPBA = meta-Chloroperbenzoic Acid azaindole = 1H-Pyrrolo-pyridine
4-azaindole = 1H-pyrrolo[3,2-b]pyridine 5-azaindole =
1H-Pyrrolo[3,2-c]pyridine 6-azaindole = 1H-pyrrolo[2,3-c]pyridine
7-azaindole = 1H-Pyrrolo[2,3-b]pyridine PMB = 4-Methoxybenzyl DDQ =
2,3-Dichloro-5,6-dicyano-1,4-be- nzoquinone OTf =
Trifluoromethanesulfonoxy NMM = 4-Methylmorpholine PIP-COPh =
1-Benzoylpiperazine NaHMDS = Sodium hexamethyldisilazide EDAC =
1-(3-Dimethylaminopropyl)-3-eth- ylcarbodiimide TMS =
Trimethylsilyl DCM = Dichloromethane DCE = Dichloroethane MeOH =
Methanol THF = Tetrahrdrofuran EtOAc = Ethyl Acetate LDA = Lithium
diisopropylamide TMP-Li = 2,2,6,6-tetramethylpiperidinyl lithium
DME = Dimethoxyethane DIBALH = Diisobutylaluminum hydride HOBT =
1-hydroxybenzotriazole CBZ = Benzyloxycarbonyl PCC = Pyridinium
chlorochromate
[0209] Chemistry
[0210] The present invention comprises compounds of Formula I,
their pharmaceutical formulations, and their use in patients
suffering from or susceptible to HIV infection. The compounds of
Formula I include pharmaceutically acceptable salts thereof.
[0211] The synthesis procedures and anti-HIV-1 activities of
indoleoxoacetic pyrrolidine containing analogs are below.
Procedures for making Z are described herein or in many cases
references of Blair, Wang, Wallace, references 93-95
respectively.
[0212] Additional general procedures to construct substituted
azaindole Q and Z of Formula I and intermediates useful for their
synthesis are described in the following Schemes 1-16. 10
[0213] Step A in Scheme 1 depicts the synthesis of an aza indole
intermediate, 2, via the well known Bartoli reaction in which vinyl
magnesium bromide reacts with an aryl or heteroaryl nitro group,
such as in 1, to form a five-membered nitrogen containing ring as
shown. Some references for the above transformation include:
Bartoli et al. a) Tetrahedron Lett. 1989, 30, 2129. b) J. Chem.
Soc. Perkin Trans. 1 1991, 2757. c) J. Chem. Soc. Perkin Trans. II
1991, 657. d) Synthesis (1999), 1594. In the preferred procedure, a
solution of vinyl Magnesium bromide in THF (typically 1.0M but from
0.25 to 3.0M) is added dropwise to a solution of the nitro pyridine
in THF at -78.degree. under an inert atmosphere of either nitrogen
or Argon. After addition is completed, the reaction temperature is
allowed to warm to -20.degree. and then is stirred for
approximately 12 h before quenching with 20% aq ammonium chloride
solution. The reaction is extracted with ethyl acetate and then
worked up in a typical manner using a drying agent such as
anhydrous magnesium sulfate or sodium sulfate. Products are
generally purified using chromatography over Silica gel. Best
results are generally achieved using freshly prepared vinyl
Magnesium bromide. In some cases, vinyl Magnesium chloride may be
substituted for vinyl Magnesium bromide.
[0214] Substituted azaindoles may be prepared by methods described
in the literature or may be available from commercial sources. Thus
there are many methods for carrying out step A in the literature
and the specific examples are too numerous to even list. A review
on the synthesis of 7-azaindoles has been published (Merour et. al.
reference 102). Alternative syntheses of aza indoles and general
methods for carrying out step A include, but are not limited to,
those described in the following references (a-k below): a)
Prokopov, A. A.; Yakhontov, L. N. Khim.-Farm. Zh. 1994, 28(7),
30-51; b) Lablache-Combier, A. Heteroaromatics. Photoinduced
Electron Transfer 1988, Pt. C, 134-312; c) Saify, Zafar Said. Pak.
J. Pharmacol. 1986, 2(2), 43-6; d) Bisagni, E. Jerusalem Symp.
Quantum Chem. Biochem. 1972, 4, 439-45; e) Yakhontov, L. N. Usp.
Khim. 1968, 37(7), 1258-87; f) Willette, R. E. Advan. Heterocycl.
Chem. 1968, 9, 27-105; g) Mahadevan, I.; Rasmussen, M. Tetrahedron
1993, 49(33), 7337-52; h) Mahadevan, I.; Rasmussen, M. J.
Heterocycl. Chem. 1992, 29(2), 359-67; i) Spivey, A. C.; Fekner,
T.; Spey, S. E.; Adams, H. J. Org. Chem. 1999, 64(26), 9430-9443;
j) Spivey, A. C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998,
39(48), 8919-8922; k) Advances in Heterocyclic Chemistry (Academic
press) 1991, Vol. 52, pg 235-236 and references therein.
[0215] Step B. Intermediate 3 can be prepared by reaction of
aza-indole, intermediate 2, with an excess of ClCOCOOMe in the
presence of AlCl.sub.3 (aluminum chloride) (Sycheva et al, Ref. 26,
Sycheva, T. V.; Rubtsov, N. M.; Sheinker, Yu. N.; Yakhontov, L. N.
Some reactions of 5-cyano-6-chloro-7-azaindoles and lactam-lactim
tautomerism in 5-cyano-6-hydroxy-7-azaindolines. Khim. Geterotsikl.
Soedin., 1987, 100-106). Typically an inert solvent such as
CH.sub.2Cl.sub.2 is used but others such as THF, Et.sub.2O, DCE,
dioxane, benzene, or toluene may find applicability either alone or
in mixtures. Other oxalate esters such as ethyl or benzyl mono
esters of oxalic acid could also suffice for either method shown
above. More lipophilic esters ease isolation during aqueous
extractions. Phenolic or substituted phenolic (such as
pentafluorophenol) esters enable direct coupling of the
HW(C.dbd.O)A group, such as a piperazine, in Step D without
activation. Lewis acid catalysts, such as tin tetrachloride,
titanium IV chloride, and aluminum chloride are employed in Step B
with aluminum chloride being most preferred. Alternatively, the
azaindole is treated with a Grignard reagent such as MeMgI (methyl
magnesium iodide), methyl magnesium bromide or ethyl magnesium
bromide and a zinc halide, such as ZnCl.sub.2 (zinc chloride) or
zinc bromide, followed by the addition of an oxalyl chloride mono
ester, such as ClCOCOOMe (methyl chlorooxoacetate) or another ester
as above, to afford the aza-indole glyoxyl ester (Shadrina et al,
Ref. 25). Oxalic acid esters such as methyl oxalate, ethyl oxalate
or as above are used. Aprotic solvents such as CH.sub.2Cl.sub.2,
Et.sub.2O, benzene, toluene, DCE, or the like may be used alone or
in combination for this sequence. In addition to the oxalyl
chloride mono esters, oxalyl chloride itself may be reacted with
the azaindole and then further reacted with an appropriate amine,
such as a piperazine derivative (See Scheme 52, for example).
[0216] Step C. Hydrolysis of the methyl ester, (intermediate 3,
Scheme 1) affords a potassium salt of intermediate 4, which is
coupled with mono-benzoylated piperazine derivatives as shown in
Step D of Scheme 1. Some typical conditions employ methanolic or
ethanolic sodium hydroxide followed by careful acidification with
aqueous hydrochloric acid of varying molarity but 1M HCl is
preferred. The acidification is not utilized in many cases as
described above for the preferred conditions. Lithium hydroxide or
potassium hydroxide could also be employed and varying amounts of
water could be added to the alcohols. Propanols or butanols could
also be used as solvents. Elevated temperatures up to the boiling
points of the solvents may be utilized if ambient temperatures do
not suffice. Alternatively, the hydrolysis may be carried out in a
non polar solvent such as CH.sub.2Cl.sub.2 or THF in the presence
of Triton B. Temperatures of -78.degree. C. to the boiling point of
the solvent may be employed but -10.degree. C. is preferred. Other
conditions for ester hydrolysis are listed in reference 41 and both
this reference and many of the conditions for ester hydrolysis are
well known to chemists of average skill in the art.
[0217] Alternative Procedures for Step B and C:
[0218] Imidazolium Chloroaluminate:
[0219] We found that ionic liquid 1-alkyl-3-alkylimidazolium
chloroaluminate is generally useful in promoting the Friedel-Crafts
type acylation of indoles and azaindoles. The ionic liquid is
generated by mixing 1-alkyl-3-alkylimidazolium chloride with
aluminium chloride at room temperature with vigorous stirring. 1:2
or 1:3 molar ratio of 1-alkyl-3-alkylimidazolium chloride to
aluminium chloride is preferred. One particular useful imidazolium
chloroaluminate for the acylation of azaindole with methyl or ethyl
chlorooxoacetate is the 1-ethyl-3-methylimidazolium
chloroaluminate. The reaction is typically performed at ambient
temperature and the azaindoleglyoxyl ester can be isolated. More
conveniently, we found that the glyoxyl ester can be hydrolyzed in
situ at ambient temperature on prolonged reaction time (typically
overnight) to give the corresponding glyoxyl acid for amide
formation (Scheme 2). 11
[0220] A representative experimental procedure is as follows:
1-ethyl-3-methylimidazolium chloride (2 equiv.; purchased from TCI;
weighted under a stream of nitrogen) was stirred in an oven-dried
round bottom flask at r.t. under a nitrogen atmosphere, and added
aluminium chloride (6 equiv.; anhydrous powder packaged under argon
in ampules purchased from Aldrich preferred; weighted under a
stream of nitrogen). The mixture was vigorously stirred to form a
liquid, which was then added azaindole (1 equiv.) and stirred until
a homogenous mixture resulted. The reaction mixture was added
dropwise ethyl or methyl chlorooxoacetate (2 equiv.) and then
stirred at r.t. for 16 h. After which time, the mixture was cooled
in an ice-water bath and the reaction quenched by carefully adding
excess water. The precipitates were filtered, washed with water and
dried under high vacuum to give the azaindoleglyoxyl acid. For some
examples, 3 equivalents of 1-ethyl-3-methylimidazolium chloride and
chlorooxoacetate may be required.
[0221] Related references: (1) Welton, T. Chem Rev. 1999, 99, 2071;
(2) Surette, J. K. D.; Green, L.; Singer, R. D. Chem. Commun. 1996,
2753; (3) Saleh, R. Y. WO 0015594.
[0222] Step D. The acid intermediate, 4, from step C of Scheme 1 is
coupled with an amine A(C.dbd.O)WH preferably in the presence of
DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) and
N,N-diisopropylethylamine, commonly known as Hunig's base, to
provide azaindole piperazine diamides. DEPBT was prepared according
to the procedure of Ref. 28, Li, H.; Jiang, X.; Ye, Y. -H.; Fan,
C.; Romoff, T.; Goodman, M. Organic Lett., 1999, 1, 91-93.
Typically an inert solvent such as DMF or THF is used but other
aprotic solvents could be used. The group W as referred to herein
is described below.
[0223] The amide bond construction reaction could be carried out
using the preferred conditions described above, the EDC conditions
described below, other coupling conditions described in this
application, or alternatively by applying the conditions or
coupling reagents for amide bond construction described later in
this application for construction of substituents R.sub.1-R.sub.4.
Some specific nonlimiting examples are given in this
application.
[0224] It should be noted that in many cases reactions are depicted
for only one position of an intermediate, such as the R.sup.5
position, for example. It is to be understood that such reactions
could be used at other positions, such as R.sup.2-R.sup.4, of the
various intermediates. Reaction conditions and methods given in the
specific examples are broadly applicable to compounds with other
substitution and other tranformations in this application. Schemes
1 and 2 describe general reaction schemes for taking appropriately
substituted Q (indoles and azaindoles) and converting them to
compounds of Formula I. While these schemes are very general, other
permutations such as carrying a precursor or precursors to
substituents R.sup.2 through R.sup.5 through the reaction scheme
and then converting it to a compound of Formula I in the last step
are also contemplated methods of this invention. Nonlimiting
examples of such strategies follow in subsequent schemes. 12
[0225] The amide coupling with amine H--W--C(O)A is shown in Scheme
3, step a3. The group W as referred to herein is either 13
[0226] One preferred method for carrying out this reaction is the
use of the peptide coupling reagent
3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin- -4(3H)-one (DEPBT)
and an amine H--W--C(O)A in DMF solvent containing a tertiary amine
such as N,N-diisopropylethylamine. Commonly used amide bond
coupling conditions, e.g. EDC with HOBT or DMAP, are also employed
in some examples. Typical stoichiometries are given in the specific
examples but these ratios may be modified.
[0227] The amide bond construction reactions depicted in step a3 or
step a5 of Schemes 3 and 4 respectively could be carried out using
the specialized conditions described herein or alternatively by
applying the conditions or coupling reagents for amide bond
construction described in Wallace, reference 95. Some specific
nonlimiting examples are given in this application.
[0228] Additional procedures for synthesizing, modifying and
attaching groups: WC(O)--A are contained in references 93-95 or
described below except that the piperazine intermediates are
replaced by the pyrrolidines described herein. 14 15
[0229] Scheme 4a provides a more specific example of the
transformations previously described in Scheme 1. Intermediates
6-10 are prepared by the methodologies as described for
intermediates 1a-5a in Scheme 1. Scheme 5 is another embodiment of
the transformations described in Schemes 1 and 4a. Conversion of
the phenol to the chloride (Step S, Scheme 5) may be accomplished
according to the procedures described in Reimann, E.; Wichmann, P.;
Hoefner, G.; Sci. Pharm. 1996, 64(3), 637-646; and Katritzky, A.
R.; Rachwal, S.; Smith, T. P.; Steel, P. J.; J. Heterocycl. Chem.
1995, 32(3), 979-984. Step T of Scheme 5 can be carried out as
described for Step A of Scheme 3. The bromo intermediate can then
be converted into alkoxy, chloro, or fluoro intermediates as shown
in Step U of Scheme 5. Scheme 2A describes the preferred method for
preparing intermediate 6c or other closely related compounds
containing a 4 methoxy group in the 6-azaindole system. When step U
is the conversion of the bromide into alkoxy derivatives, the
conversion may be carried out by reacting the bromide with an
excess of sodium methoxide in methanol with cuprous salts, such as
copper I bromide, copper I iodide, and copper I cyanide. The
temperature may be carried out at temperatures of between ambient
and 175.degree. but most likely will be around 115.degree. C. or
100.degree. C. The reaction may be run in a pressure vessel or
sealed tube to prevent escape of volatiles such as methanol. The
preferred conditions utilize 3 UUq of sodium methoxide in methanol,
CuBr as the reaction catalyst (0.2 to 3 equivalents with the
preferred being 1 eq or less), and a reaction temperature of
115.degree. C. The reaction is carried out in a sealed tube or
sealed reaction vessel. The conversion of the bromide into alkoxy
derivatives may also be carried out according to procedures
described in Palucki, M.; Wolfe, J. P.; Buchwald, S. L.; J. Am.
Chem. Soc. 1997, 119(14), 3395-3396; Yamato, T.; Komine, M.;
Nagano, Y.; Org. Prep. Proc. Int. 1997, 29(3), 300-303; Rychnovsky,
S. D.; Hwang, K.; J. Org. Chem. 1994, 59(18), 5414-5418. Conversion
of the bromide to the fluoro derivative (Step U, Scheme 2A) may be
accomplished according to Antipin, I. S.; Vigalok, A. I.;
Konovalov, A. I.; Zh. Org. Khim. 1991, 27(7), 1577-1577; and
Uchibori, Y.; Umeno, M.; Seto, H.; Qian, Z.; Yoshioka, H.; Synlett.
1992, 4, 345-346. Conversion of the bromide to the chloro
derivative (Step U, Scheme 2A) may be accomplished according to
procedures described in Gilbert, E. J.; Van Vranken, D. L.; J. Am.
Chem. Soc. 1996, 118(23), 5500-5501; Mongin, F.; Mongin, O.;
Trecourt, F.; Godard, A.; Queguiner, G.; Tetrahedron Lett. 1996,
37(37), 6695-6698; and O'Connor, K. J.; Burrows, C. J.; J. Org.
Chem. 1991, 56(3), 1344-1346. Steps V, W and X of Scheme 2A are
carried out according to the procedures previously described for
Steps B, C, and D of Scheme 1, respectively. The steps of Scheme 5
may be carried out in a different order as shown in Scheme 6 and
Scheme 7. 16 17 18 192021
[0230] Scheme 8 shows the synthesis of 4-azaindole derivatives
1b-5b, 5-azaindole derivatives 1c-5c, and 7-azaindole derivatives
1d-5d. The methods used to synthesize 1b-5b, 1c-5c, and 1d-5d are
the same methods described for the synthesis of 1a-5a as described
in Scheme 3. It is understood, for the purposes of Scheme 8, that
1b is used to synthesize 2b-5b, 1c provides 2c-5c and 1d provides
2d-5d.
[0231] The compounds where there is a single carbonyl between the
azaindole and group W can be prepared by the method of Kelarev, V.
I.; Gasanov, S. Sh.; Karakhanov, R. A.; Polivin, Yu. N.;
Kuatbekova, K. P.; Panina, M. E.; Zh. Org. Khim 1992, 28(12),
2561-2568. In this method azaindoles are reacted with
trichloroacetyl chloride in pyridine and then subsequently with KOH
in methanol to provide the 3-carbomethoxy azaindoles shown in
Scheme 4 which can then be hydrolyzed to the acid and carried
through the coupling sequence with HW(C.dbd.O)A to provide the
compounds of Formula I wherein a single carbonyl links the
azaindole moiety and group W. 22
[0232] An alternative method for carrying out the sequence outlined
in steps B-D (shown in Scheme 8) involves treating an azaindole,
such as 11, obtained by procedures described in the literature or
from commercial sources, with MeMgI and ZnCl.sub.2, followed by the
addition of ClCOCOCl (oxalyl chloride) in either THF or Et.sub.2O
to afford a mixture of a glyoxyl chloride azaindole, 12a, and an
acyl chloride azaindole, 12b. The resulting mixture of glyoxyl
chloride azaindole and acyl chloride azaindole is then coupled with
mono-benzoylated piperazine derivatives under basic conditions to
afford the products of step D as a mixture of compounds, 13a and
13b, where either one or two carbonyl groups link the azaindole and
group W. Separation via chromatographic methods which are well
known in the art provides the pure 13a and 13b. This sequence is
summarized in Scheme 10, below. 23 24
[0233] Scheme 11 depicts a general method for modifying the
substituent A. Coupling of H--W--C(O)OtBu using the conditions
described previously for W in Scheme 1, Step D provides Boc
protected intermediate, 15. Intermediate 15 is then deprotected by
treatment with an acid such as TFA, hydrochloric acid or formic
acid using standard solvents or additives such as CH.sub.2Cl.sub.2,
dioxane, or anisole and temperatures between -78.degree. C. and
100.degree. C. Other acids such as aq hydrochloric or perchloric
may also be used for deprotection. Alternatively other nitrogen
protecting groups on W such as Cbz or TROC, may be utilized and
could be removed via hydrogenation or treatment with zinc
respectively. A stable silyl protecting group such as phenyl
dimethylsilyl could also be employed as a nitrogen protecting group
on W and can be removed with fluoride sources such as
tetrabutylammonium fluoride. Finally, the free amine is coupled to
acid A--C(O)OH using standard amine-acid coupling conditions such
as those used to attach group W or as shown below for amide
formation on positions R.sub.1-R.sub.4 to provide compound 16.
[0234] Scheme 12 a preferred method for preparing H--W--C(O)--A.
Specific details are contained in the experimental section.
Additional examples of the preparation of 3-amino and 3-aminomethyl
pyrrolidines are described in Patane et al PCT Patent Application
WO 98/57640. Scheme 13 depicts a specific route to compounds of the
invention Q in which Q is an indole with a dicarbonyl at the 3
position and W is an aminomethyl pyrollidine attached to Q via the
primary amine. A specific procedure where A is phenyl is contained
in the experimental. Q could also be alternative indoles and
azaindoles and A other substituents as needed to prepare compounds
of the invention. Scheme 14 describes a similar sequence except
that the amino methyl pyrrolidine, W is attached to the dicarbonyl
via the secondary ring nitrogen and A is --OtBu. As shown, acidic
removal of the tertbutoxycarbonyl group provides a free primary
amine or amine hydrochloride which may be reacted with acyl
chlorides or chloroformates to give additional compounds of the
invention with various A groups. The example where A is phenyl is
described in detail in the experimental section. Scheme 15
describes similar chemistry but shows how the 7-position of the
indole may be funtionalized by an aldehyde, carboxylic acid, or
methyl carboxamide. This sequence is also described in the
experimental section. A chemist skilled in the art can recognize
how this chemistry could be utilized on other examples where Q, W,
and A are modified. 2526 27 28 2930
[0235] As shown below in Scheme 16, step a13, suitable substituted
indoles, such as the bromoindole intermediate, 10, may undergo
metal mediated couplings with aryl groups, heterocycles, or vinyl
stannanes to provide compounds within Formula I wherein R.sup.5 is
aryl, heteroaryl, or heteroalicyclic for example. The bromoindole
intermediates, 10 (or indole triflates or iodides) may undergo
Stille-type coupling with heteroarylstannanes as shown in Scheme
17, step a14. Conditions for this reaction are well known in the
art and references 72-74 as well as reference 91 provide numerous
conditions in addition to the specific examples provided in Scheme
17 and in the specific embodiments. It can be well recognized that
an indole stannane could also couple to a heterocyclic or aryl
halide or triflate to construct compounds of Formula I. Suzuki
coupling (reference 71) between the bromo intermediate, 10, and a
suitable boronate could also be employed and some specific examples
are contained in this application. Other Suzuki conditions,
partners, and leaving groups have utility. Suzuki couplings between
chloro intermediates are also feasible. If standard conditions fail
new specialized catalysts and conditions can be employed.
Procedures describing catalysts which are useful for coupling
boronates with aryl and heteroaryl chlorides are known in the art
(reference 100 a-g). The boronate could also be formed on the
indole and then subjected to Suzuki coupling conditions. The same
coupling methodologies may be used in the case where Q contains
azaindoles rather than indoles. 31 32
[0236] Chemistry
[0237] All Liquid Chromatography (LC) data were recorded on a
Shimadzu LC-10AS liquid chromatograph using a SPD-10AV UV-Vis
detector with Mass Spectrometry (MS) data determined using a
Micromass Platform for LC in electrospray mode.
[0238] LC/MS Method (i.e., Compound Identification)
[0239] Note: column A is used unless otherwise indicated in the
preparation of intermediates or examples.
3 Column A: YMC ODS-A S7 3.0 .times. 50 mm column Column B:
PHX-LUNA C18 4.6 .times. 30 mm column Column C: XTERRA ms C18 4.6
.times. 30 mm column Column D: YMC ODS-A C18 4.6 .times. 30 mm
column Column E: YMC ODS-A C18 4.6 .times. 33 mm column Column F:
YMC C18 S5 4.6 .times. 50 mm column Column G: XTERRA C18 S7 3.0
.times. 50 mm column Gradient: 100% Solvent A/0% Solvent B to 0%
Solvent A/ 100% Solvent R.sub.t in min. 2 minutes Gradient time:
Hold time 1 minute Flow rate: 5 mL/min Detector Wavelength: 220 nm
Solvent A: 10% MeOH/90% H.sub.2O/0.1% Trifluoroacetic Acid Solvent
B: 10% H.sub.2O/90% MeOH/0.1% Trifluoroacetic Acid
[0240] Compounds purified by preparative HPLC were diluted in MeOH
(1.2 mL) and purified using the following methods on a Shimadzu
LC-10A automated preparative HPLC system or on a Shimadzu LC-8A
automated preparative HPLC system with detector (SPD-10AV UV-VIS)
wavelength and solvent systems (A and B) the same as above.
[0241] Preparative HPLC Method (i.e., Compound Purification)
[0242] Purification Method: Initial gradient (40% B, 60% A) ramp to
final gradient (100% B, 0% A) over 20 minutes, hold for 3 minutes
(100% B, 0% A)
4 Solvent A: 10% MeOH/90% H.sub.2O/0.1% Trifluoroacetic Acid
Solvent B: 10% H.sub.2O/90% MeOH/0.1% Trifluoroacetic Acid Column:
YMC C18 S5 20 .times. 100 mm column Detector Wavelength: 220 nm
[0243] Intermediate 1
[0244] Methanesulfonic acid 1-benzyl-pyrrolidin-3-ylmethyl ester
33
[0245] This tranformation was carried out via the method in J. L.
Marco et.al. reference 96. Methanesulfonyl chloride (0.10 mol, 7.8
mL) was added slowly to a solution of racemic
1-benzyl-pyrolidin-3-ol (0.085 mol, 15 g) in 150 mL of
dichloromethane which was stirring under a nitogen atmosphere at a
temperature of -20.degree. C. The reaction was stirred for an
additional 1.5 h after addition was completed. The reaction was
poured into a separatory funnel containing additional
dichloromethane and washed with five thirty mL portions of
saturated aqueous sodium bicarbonate. The organic layer was washed
with one portion of water and then one portion of saturated aq
NaCl. The organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to provide 22.75 g of crude
mesylate which was used directly following characterization by
proton NMR and LC/MS.
[0246] Intermediate 2
[0247] 1-Benzyl-pyrrolidine-3-carbonitrile 34
[0248] This tranformation was carried out using the method
described in C. Thomas et. al. reference 97. The mesylate of
racemic 1-benzyl-pyrrolidin-3-ol (0.039 mol, 10 g), prepared as
described above, sodium cyanide (0.24 mol, 15 g) and
tetrabutylammonium cyanide (10 g, 0.037 mol) in 75 mL of DMSO was
stirred at 80-85.degree. C. for 16 h. The reaction mixture was
partitioned between diethyl ether and sat. aq sodium bicarbonate.
The aqueous layer was extracted twice with ether and the combined
organic layer was washed successively with sodium bicarbonate,
water, and sat aq. NaCl. The organic layer was dried over anhydrous
magnesium sulfate, concentrated, and purified by flash
chromatography over silica gel using a gradient of 20 to 30% ethyl
acetate in hexane to afford 5.5 g of the desired product.
[0249] Intermediate 3
[0250] C-(1-Benzyl-pyrrolidin-3-yl)-methylamine 35
[0251] This reaction was carried out according to the procedure in
M. R. Pavia et.al. reference 98. The nitrite (0.03 mol, 5.5 g) was
dissolved in THF and cooled to 0.degree. C. Lithium aluminum
hydride (0.03 mol, 1.14 g) was added into the solution in one
portion. After the addition was finished, the colling bath was
removed and the reaction was stirred at ambient temperature for 18
h. The reaction was filtered and the filtrate was aconcentrated in
vacuo to provide the crude product which was used directly in the
next reaction.
[0252] Intermediate 4
[0253] (1-Benzyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl
ester 36
[0254] A mixture of crude amine (0.028 mol, 5.3 g), triethylamine
(0.034 mol, 4.7 mL), and and ditertbutyl dicarbonate (0.034 mol,
7.4 g) in dichloromethane was stirred at ambient temperature for 3
h. The reaction was diluted with dichloromethane, and then washed
with water and then sat aq NaCl. The organic extract was dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
Purification via flash chromatography over silica gel provided 4.2
g of the desired carbamate. 1H NMR (300 MHz, CDCl3):
7.32.about.7.30(m, 5H), 3.59.about.3.58(m, 2H), 3.17.about.3.02(m,
2H), 2.73.about.2.28(m, 5H), 2.04.about.1.90(m, 1H),
1.60.about.1.48(m,1H), 1.45(s,9H).
[0255] Intermediate 5
[0256] Pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester 37
[0257] The benzyl amine (4.2 g) and 2.1 g of 10% Pd/C in methanol
was shaken under 50PSI of hydrogen on a Parr apparatus for 20 h.
The reaction mixture was filtered through celite and concentrated
in vacuo to give a residue which was used directly without further
purification. 1H NMR (300 MHz, CDCl3): 3.15.about.1.82(m, 8H),
1.55.about.1.45(m, 1H), 1.43(s,9H).
[0258] Intermediate 6
[0259] (1-Benzoyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl
ester 38
[0260] The amine (14.65 mmol, 2.93 g) was dissolved in
dichloromethane and treated with DMAP (14.65 mmol, 1.79 g), EDC
(14.65 mmol, 2.80 g), and then benzoic acid (13.18 mmol, 0.9 eq).
The reaction was stirred for 16 h at ambient temperature and then
diluted with dichloromethane. The organic layer was washed with
water and sat aq. NaCl and dried over anhydrous sodium sulfate. The
solution was filtered and concentrated in vacuo to provide a
residue which was purified by by flash chromatography over silica
gel to provide 3.06 g of the desired benzamide. 1H NMR (300 MHz,
CDCl3): 7.55.about.7.34(m, 5H), 3.80.about.3.10(m, 6H),
2.55.about.1.58(m, 3), 1.40(s,9H).
[0261] Intermediate 7
[0262] (3-Aminomethyl-pyrrolidin-1-yl)-phenyl-methanone 39
[0263] The carbamate was stirred in 20 mL of 4N HCl in dioxane for
20 h. The reaction mixture was concentrated on a rotary evaporator
and dried under vacuum to provide the hydrochloride salt which was
used directly without further purification.
EXAMPLE 1
N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-(4-fluoro-1H-indol-3-yl)-2-oxo-aceta-
mide
[0264] 40
[0265] The acid chloride (1 mmol, 225 mg) was added to a solution
of the amine hydrochloride (1 mmol, 240 mg) and diisopropyl ethyl
amine (10 mmol, 1.74 mL) in 5 mL of anhydrous TUF under a nitrogen
atmosphere. The reaction was stirred for 16 h at ambient
temperature and then poured into ethyl acetate. The organic layer
was washed with water and then sat aq NaCl and then dried over
anhydrous magnesium sulfate. Filtration and concentration in vacuo
provided a crude product which was purified by flash chromatography
over silica gel to provide 208 mg of the desired
N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-(4-fluoro-1H-indol-3-yl)-2-oxo-acet-
amide.
[0266] 1H NMR (500 MHz, CD3OD): 8.69 (s), 8.56 (s), 1H.
7.55.about.7.40 (m, 5H), 7.31.about.7.20 (m, 2H), 6.96.about.6.87
(m, 1H), 3.81.about.3.29 (m, 6H), 2.70.about.1.73 (m, 3H).
[0267] LC/MS: (ES+) m/z (M+H)+=394, RT=1.06.
EXAMPLE 2
{1-[2-(4-Fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-carbam-
ic acid tert-butyl ester
[0268] 41
[0269] The acid chloride (2 mmol, 453 mg) was added to a solution
of the amine hydrochloride (2 mmol, 400 mg) and diisopropyl ethyl
amine (4 mmol, 0.7 mL) in 12 mL of anhydrous THF under a nitrogen
atmosphere. The reaction was stirred for 18 h at ambient
temperature and then poured into ethyl acetate. The organic layer
was washed with water and then sat aq NaCl and then dried over
anhydrous magnesium sulfate. Filtration and concentration in vacuo
provided a crude product which was purified by flash chromatography
over silica gel to provide 475 mg of the desired
3-{[2-(4-Fluoro-1H-indol-3-yl)-2-oxo-acetylamino]-methyl}-pyrrolidine-1-c-
arboxylic acid tert-butyl ester.
[0270] 1H NMR (500 MHz, CD3OD): 8.17(s), 8.14(S), 1H.
7.32.about.7.24(m, 2H), 6.97.about.6.93(m, 1H), 3.73.about.3.04(m,
6H), 2.46.about.2.43(m, 1H), 2.09.about.2.01(m, 1H),
1.74.about.1.73(m, 1H), 1.44(s, 9H).
[0271] Intermediate 8 42
[0272] The carbamate was stirred in 15 mL of 4N HCl in dioxane for
20 h. The reaction mixture was concentrated on a rotary evaporator
and dried under vacuum to provide the hydrochloride salt which was
used directly without further purification.
EXAMPLE 3
N-{1-[2-(4-Fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-benz-
amide and Example 4
N-{1-[2-(1-Benzoyl-4-fluoro-1H-indol-3-yl)-2-oxo-acety-
l]-pyrrolidin-3-ylmethyl}-benzamide
[0273] 43
[0274] Benzoyl chloride (0.46 mmol, 54 .mu.L) and then diisopropyl
ethyl amine (0.92 mmol, 0.16 mL) were added to a stirring solution
of amine hydrochloride (0.46 mmol, 150 mg) in 5 mL of THF under an
atmosphere of nitrogen at ambient temperature. The reaction was
stirred for 18 h and then the THF was removed in vacuo. The residue
was dissolved in ethyl acetate and washed with water and then sat
aq NaCl. The organic extract was dried, filtered, concentrated, and
purified via flash chromatography to the desired product of example
3:
[0275] 1H NMR (500 MHz, CD3OD): 8.18 (s), 8.14 (s), 1H.
7.85.about.7.82 (m, 1H), 7.72.about.7.68 (m, 1H), 7.54.about.7.24
(m, 5H), 6.97.about.6.90 (m, 1H), 3.80.about.3.29 (m, 6H),
2.67.about.2.61 (m, 1H), 2.20.about.2.05(m, 1H), 1.87.about.1.81(m,
1H).
[0276] LC/MS: (ES+) m/z (M+H)+=394, RT=1.74. and the bis benzylated
product Example 4 which resulted from a second benzylation of the
indole nitrogen:
[0277] LC/MS: (ES+) m/z (m+H)+=498; RT=1.46
EXAMPLE 5
N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-(4-fluoro-7-formyl-1H-indol-3-yl)-2--
oxo-acetamide
[0278] 44
[0279] DEPBT (2.13 mmol, 514 mg) was added to a stirring solution
of the aldehyde acid (prepared as described in WO 00/76521, 2.13
mmol, 500 mg), amine hydrochloride (2.13 mmol, 514 mg), and
diisopropyl ethylamine (4.26 mmol, 0.74 mL) in 5 mL of DMF at
ambient temperature. The reaction was stirred for 16 h and then the
DMF was removed in vacuo. The residue was dissolved in ethyl
acetate and water was added. After separation the water layer was
reextracted with ethyl acetate. The combined organic extracts were
dried over anhydrous magnesium sulfate, concentrated and
chromatographed over silica gel to provide the desired product.
[0280] 1H NMR (300 MHz, CD3OD): 10.06 (s, 1H); 8.79 (s), 8.72 (s),
1H; 7.89.about.7.84 (m, 1H); 7.53.about.7.40 (m, 5H);
7.15.about.7.06 (m, 1H); 3.81.about.3.29 (m, 6H); 2.68.about.2.51
(m,1H); 2.17.about.2.00 (m, 1H); 1.87.about.1.72 (m, 1H).
[0281] LC/MS: (ES+) m/z (m+H)+=422; RT=1.29.
EXAMPLE 6
N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-oxo-2-(1H-pyrrolo[2,3-b]pyridin-3-yl-
)-acetamide
[0282] 45
[0283] DEPBT (1.32 mmol, 395 mg) was added to a stirring solution
of the potassium salt (prepared as described in WO 01/62255, 1.32
mmol, 300 mg), amine hydrochloride (1.32 mmol, 318 mg), and
diisopropyl ethylamine (2.64 mmol, 0.46 mL) in 3 mL of DMF at
ambient temperature. The reaction was stirred for 16 h and then the
DMF was removed in vacuo. The residue was dissolved in ethyl
acetate and water was added. After separation the water layer was
reextracted with ethyl acetate. The combined organic extracts were
washed with sat aq NaCl, dried over anhydrous magnesium sulfate,
concentrated and chromatographed over silica gel to provide 268 mg
of the desired product.
[0284] 1H NMR (500 MHz, CD3OD): 8.92.about.8.89 (m),
8.81.about.8.79 (m), 1H; 8.68.about.8.60 (m, 1H); 8.34.about.8.8.32
(m, 1H); 7.54.about.7.43 (m, 5H); 7.33.about.7.7.26 (m, 1H);
3.96.about.3.26 (m, 6H); 2.66.about.2.52 (m, 1H); 2.16.about.2.05
(m,1H); 1.85.about.1.74 (m, 1H).
[0285] LC/MS: (ES+) m/z (m+H)+=377; RT=1.18
EXAMPLE 7
3-(1-Benzoyl-pyrrolidin-3-ylmethyl)-aminooxalyl)-4-fluoro-1H-indole-7-carb-
oxylic acid
[0286] 46
[0287] Silver nitrate (AgNO3, 1.48 mmol, 252 mg) was dissolved in 2
mL of water. A solution of NaOH (2.96 mmol, 118 mg) in 2 mL of
methanol and 2 mL of water was added to the silver nitrate solution
and a brown precipitate formed. The aldehyde (0.74 mmol, 313 mg)
was added into the solution/precipitate in one portion. The
reaction was heated to 90.degree. C. and stirred for 15 h. After
coiling to ambient temperature, the reaction was filtered through
celite using ethyl acetate washes. The filtrate was extracted with
ethyl acetate. The aqueous layer was acidified with 2N HCl to about
PH 2. The resulting solid was collected by filtration to give the
desired acid. 1H NMR (500 MHz, CD3OD): 8.79 (s), 8.70 (s), 1H;
8.05.about.7.92 (m, 1H); 7.53.about.7.44 (m, 5H); 7.05.about.6.93
(m, 1H); 3.78.about.3.26 (m, 6H); 2.66.about.2.53 (m, 1H);
2.17.about.2.06 (m, 1H); 1.84.about.1.75 (m, 1H).
[0288] LC/MS: (ES+) m/z (m+H)+=438; RT=1.33.
EXAMPLE 8
3-(1-Benzoyl-pyrrolidin-3-ylmethyl)-aminooxalyl)-4-fluoro-1H-indole-7-carb-
oxylic acid methylamide
[0289] 47
[0290] The acid (19 mg,1 equivalent) was dissolved in 1 mL of DMF
and 1.5 equivalents of 1,1-carbonyl diimidazole was added. The
reaction was stirred at ambient temperature for 15 min and then 4
equivalents (0.1 ml) of 2N methyl amine in THF was added. The
reaction was stirred overnight and then the DMF was removed in
vacuo. The residue was chromatographed to afford 12 mg of the
desired methyl amide.
[0291] LC/MS: (ES+) m/z (m+H)+=451; RT=1.26
EXAMPLE 9
N-{1-[2-(7-Bromo-4-fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmeth-
yl}-benzamide
[0292] 48
[0293] The ketoacid (0.97 mmol, 280 mg), the amine (0.97 mmol, 200
mg) and diisopropyl ethyl amine (0.34 mL) and DEPBT (0.97 mmol, 292
mg) were dissolved in 2 mLof dry DMF under an atmosphere of
nitrogen. The reaction was stirred for 36 h at ambient temperature
and then poured into 10 mL of ethyl acetate. The organic layer was
washed with two 10 mL portions of water and then the aqueous layer
was back extracted with 10 mL of EtOAc. The combined organic
extracts were dried over anhydrous magnesium sulfate. Filtration
and concentration in vacuo provided a crude product which was
purified by flash chromatography over silica gel using gradients of
50 to 100% EtOAc: Hexane then 2 to 5% MeOH/EtOAc to provide 29 mg
of the desired amide as a light brown solid.
[0294] 1H NMR (500 MHz, CD3OD): 8.43 (s), 8.38 (s), 1H;
8.01.about.7.97 (m, 1H); 7.83.about.7.79 (m, 1H); 7.69.about.7.34
(m, 4H); 4.13.about.1.20 (m, 9H).
[0295] LC/MS: (ES+) m/z (m+H)+=475; RT=1.27.
EXAMPLE 10
N-{1-[2-(7-Bromo-4-fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmeth-
yl}-benazmide
[0296] 49
[0297] The ketoacid (0.97 mmol, 280 mg), the amine (0.97 mmol, 200
mg) and diisopropyl ethyl amine (0.34 mL) and DEPBT (0.97 mmol, 292
mg) were dissolved in 2 mLof dry DMF under an atmosphere of
nitrogen. The reaction was stirred for 36 h at ambient temperature
and then poured into 10 mL of ethyl acetate. The organic layer was
washed with two 10 mL portions of water and then the aqueous layer
was back extracted with 10 mL of EtOAc. The combined organic
extracts were dried over anhydrous magnesium sulfate. Filtration
and concentration in vacuo provided a crude product which was
purified by flash chromatography over silica gel using gradients of
50 to 100% EtOAc: Hexane then 2 to 5% MeOH/EtOAc to provide 108 mg
of the desired amide as a yellow solid.
[0298] 1H NMR (500 MHz, CD3OD): 8.43 (s), 8.39 (s), 1H;
8.02.about.7.97 (m, 1H); 7.84.about.7.81 (m, 1H); 7.69.about.7.66
(m, 1H); 7.54.about.7.35 (m, 3H); 4.13.about.1.21 (m, 9H)
[0299] LC/MS: (ES+) m/z (m+H)+=475; RT=1.19, 1.27.
EXAMPLE 11
N-(1-{2-[4-Fluoro-7-(1H-pyrazol-3-yl)-1H-indol-3-yl]-2-oxo-acetyl}-pyrroli-
din-3-ylmethyl)-benz Amide
[0300] 50
[0301] The bromide (0.12 mmol, 59 mg), the pyrazole stannane (0.24
mmol, 86 mg), and palladium tetrakis triphenyl phosphine (0.012
mmol, 14 mg) were dissolved in 0.5 mLof dry dioxane and heated in a
sealed tube at 140 to 145.degree. C. for 17 h. After cooling to
room temperature, the reaction was filtered through filter paper
and the filtrate concentrated by rotary evaporation. The residue
was dissolved in 2 mL of MeOH and purified using preparative thin
layer chromatography to provide 12.6 mg of the desired pyrazole as
a light yellow solid.
[0302] 1H NMR (500 MHz, CD3OD): 8.62.about.8.57 (m, 1H),
8.32.about.8.30 (m, 1H); 7.92.about.7.15 (m, 10H); 4.05.about.1.82
(m, 9H)
[0303] LC/MS: (ES+) m/z (m+H)+=475; RT=1.01, 1.10.
EXAMPLE 12
N-(1-{2-[4-Fluoro-7-(1H-pyrazol-3-yl)-1H-indol-3-yl]-2-oxo-acetyl}-pyrroli-
din-3-ylmethyl)-benz amide
[0304] 51
[0305] The bromide (0.046 mmol, 22 mg), the pyrazole stannane
(0.092 mmol, 33 mg), and palladium tetrakis triphenyl phosphine (10
mg) were dissolved in 0.5 mLof dry dioxane and heated in a sealed
tube at 140 to 145.degree. C. for 17 h. After cooling to room
temperature, the reaction was filtered through filter paper and the
filtrate concentrated by rotary evaporation. The residue was
dissolved in 2 mL of MeOH and purified using preparative thin layer
chromatography to provide 4.8 mg of the desired pyrazole as a light
yellow solid.
[0306] 1H NMR (500 MHz, CD3OD): 8.60.about.8.54 (m, 1H),
8.29.about.8.28 (m, 1H); 7.91.about.7.15 (m, 10H); 4.06.about.1.80
(m, 9H)
[0307] LC/MS: (ES+) m/z (m+H)+=475; RT=1.01, 1.10.
EXAMPLE 13
2-(N-benzoylaminoethyl)-1-[(indol-3-yl)-2-oxoacetyl]-pyrrolidine
[0308] 52
[0309] Preparation of compound C,
2-(N-benzoylaminoethyl)-1-[(indol-3-yl)--
2-oxoacetyl]-pyrrolidine:
[0310] Tri-ethylamine (1 ml) was added into a solution of
indole-3-glyoxylyl chloride, intermediate 9 (50 mg, purchased from
Lancaster) and intermediate 10 2-(N-benzoylaminoethyl)-pyrrolidine
(49 mg, Wang, et al, Tetrahedron Lett. 1999, 40, 6745-6747) in THF
(5 ml). After the reaction was stirred for 10 hours, the solvents
were removed under vaccum to afford a residue which was purified
using Shimadzu automated preparative HPLC System to give
2-(N-benzoylaminoethyl)-1-[(ind- ol-3-yl)-2-oxoacetyl]-pyrrolidine
(20 mg). Start %=0
[0311] Final %=100
[0312] Gradient time=2 minute
[0313] Flow Rate=5 ml/min
[0314] Wavelength=220
[0315] Column: XTERRA ms C18 4.6.times.30 mm
[0316] Rf=1.57 minute
[0317] MS (M+H) for C22H22N3O3
[0318] Cald=376.17
[0319] Obsd=376.23
EXAMPLE 14
1H-Indole-3-carboxylic acid
(1-benzoyl-pyrrolidin-3-yl)-methyl-amide
[0320] 53
[0321] The procedure is the same as the following one, which was
described in Blair et. al. PCT WO 00/76521 54
[0322] Indole 3-carboxylic acid, (2.0 g) was dissolved in 5 ml of
SOCl.sub.2. The mixture was heated to reflux for 30 minutes.
Removal of excess of SOCl.sub.2 under vaccum provided intermediate
9, indole 3-carbonyl chloride, which was carried to the next step
without further purification.
[0323] A mixture of indole 3-carbonyl chloride, intermediate 9 (50
mg), N-Benzoyl-3-methylamino-pyrrolidine, intermediate 10, (57 mg),
pyridine (44 mg) in THF (5 ml) was stirred at room temperature for
10 hours. Solvents were removed under vaccum, and the residue was
purified using a Shimadzu automated preparative HPLC System to give
78 mg of the compound of example 14,
N-Benzoyl-3-[N-(indol-3-yl-carbonyl)-N-methyl]amino-pyrrol-
idine:
[0324] MS m/z: (M+H).sup.+ calcd for
C.sub.21H.sub.19FN.sub.3O.sub.3: 348.17; found 348.22. HPLC
retention time: 1.40 p minutes (column A). 55
[0325] Biology
[0326] ".mu.M" means micromolar;
[0327] "mL" means milliliter;
[0328] ".mu.l" means microliter;
[0329] "mg" means milligram;
[0330] The materials and experimental procedures used to obtain the
results reported in Tables 1-2 are described below.
[0331] Cells:
[0332] Virus production--Human embryonic Kidney cell line, 293,
propagated in Dulbecco's Modified Eagle Medium (Life Technologies,
Gaithersburg, Md.) containing 10% fetal Bovine serum (FBS, Sigma,
St. Louis, Mo.).
[0333] Virus infection-Human epithelial cell line, HeLa, expressing
the HIV-1 receptors CD4 and CCR5 was propagated in Dulbecco's
Modified Eagle Medium (Life Technologies, Gaithersburg, Md.)
containing 10% fetal Bovine serum (FBS, Sigma, St. Louis , Mo.) and
supplemented with 0.2 mg/mL Geneticin (Life Technologies,
Gaithersburg, Md.) and 0.4 mg/mL Zeocin (Invitrogen, Carlsbad,
Calif.).
[0334] Virus--Single-round infectious reporter virus was produced
by co-transfecting human embryonic Kidney 293 cells with an HIV-1
envelope DNA expression vector and a proviral cDNA containing an
envelope deletion mutation and the luciferase reporter gene
inserted in place of HIV-1 nef sequences (Chen et al, Ref. 41).
Transfections were performed using lipofectAMINE PLUS reagent as
described by the manufacturer (Life Technologies, Gaithersburg,
Md.).
[0335] Experiment
[0336] 1. Compound was added to HeLa CD4 CCR5 cells plated in 96
well plates at a cell density of 1.times.10.sup.3 cells per well in
100 .mu.l Dulbecco's Modified Eagle Medium containing 10% fetal
Bovine serum at a concentration of <20 .mu.M.
[0337] 2. 100 .mu.l of single-round infectious reporter virus in
Dulbecco's Modified Eagle Medium was then added to the plated cells
and compound at an approximate multiplicity of infection (MOI) of
0.01, resulting in a final volume of 200 .mu.l per well and a final
compound concentration of <10 .mu.M.
[0338] 3. Samples were harvested 72 h after infection.
[0339] 4. Viral infection was monitored by measuring luciferase
expression from viral DNA in the infected cells using a luciferase
reporter gene assay kit (Roche Molecular Biochemicals,
Indianapolis, Ind.). Infected cell supernatants were removed and 50
.mu.l of Dulbecco's Modified Eagle Medium (without phenol red) and
50 .mu.l of luciferase assay reagent reconstituted as described by
the manufacturer (Roche Molecular Biochemicals, Indianapolis, Ind.)
was added per well. Luciferase activity was then quantified by
measuring luminescence using a Wallac microbeta scintillation
counter.
[0340] 5. The percent inhibition for each compound was calculated
by quantifying the level of luciferase expression in cells infected
in the presence of each compound as a percentage of that observed
for cells infected in the absence of compound and subtracting such
a determined value from 100.
[0341] 6. An EC.sub.50 provides a method for comparing the
antiviral potency of the compounds of this invention. The effective
concentration for fifty percent inhibition (EC.sub.50) was
calculated with the Microsoft Excel Xlfit curve fitting software.
For each compound, curves were generated from percent inhibition
calculated at 10 different concentrations by using a four
paramenter logistic model (model 205). The EC.sub.50 data for the
compounds is shown in Tables 2-4. Table 1 is the key for the data
in Table 2.
[0342] Results
5TABLE 1 Biological Data Key for EC.sub.50s Compounds with EC50
>50 nM but Compounds not yet tested at Compounds Compounds* with
EC.sub.50s >1 higher with with EC.sub.50s >5 .mu.M .mu.M but
<5 .mu.M concentrations EC50 <1 .mu.M Group C Group B Group
A' Group A *Some of these compounds may have been tested at a
concentration lower then their EC.sub.50 but showed some ability to
cause inhibition and thus should be evaluated at a higher
concentration to determine the exact EC.sub.50.
[0343] In Tables 2-5, X.sub.2, X.sub.4 etc. indicates the point of
attachment.
6TABLE 2 56 Examples EC.sub.50 Table Entry Group (Example from
Number.) Z W A Table 1 1 (Example 1) 57 58 59 A 2 (Example 2) 60 61
62 C 3 (Example 3) 63 64 65 A 4 (Example 4) 66 67 68 A 5 (Example
5) 69 70 71 B 6 (Example 6) 72 73 74 C 7 (Example 7) 75 76 77 B 8
(Example 8) 78 79 80 A 9 (Example 9) 81 82 83 A 10 (Example 10) 84
85 86 A 11 (Example 11) 87 88 89 A 12 (Example 12) 90 91 92 A 13
(Example 13) 93 94 95 A 14 (Example 14) 96 97 98 C 15 (Example 15)
99 100 101 C 16 (Example 16) 102 103 104 A'
[0344] The compounds of the present invention may be administered
orally, parenterally (including subcutaneous injections,
intravenous, intramuscular, intrasternal injection or infusion
techniques), by inhalation spray, or rectally, in dosage unit
formulations containing conventional non-toxic pharmaceutically
acceptable carriers, adjuvants and diluents.
[0345] Thus, in accordance with the present invention, there is
further provided a method of treating and a pharmaceutical
composition for treating viral infections such as HIV infection and
AIDS. The treatment involves administering to a patient in need of
such treatment a pharmaceutical composition comprising a
pharmaceutical carrier and a therapeutically effective amount of a
compound of the present invention.
[0346] The pharmaceutical composition may be in the form of orally
administrable suspensions or tablets; nasal sprays, sterile
injectable preparations, for example, as sterile injectable aqueous
or oleagenous suspensions or suppositories.
[0347] When administered orally as a suspension, these compositions
are prepared according to techniques well known in the art of
pharmaceutical formulation and may contain microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweetners/flavoring agents known in the art. As immediate release
tablets, these compositions may contain microcrystalline cellulose,
dicalcium phosphate, starch, magnesium stearate and lactose and/or
other excipients, binders, extenders, disintegrants, diluents, and
lubricants known in the art.
[0348] The injectable solutions or suspensions may be formulated
according to known art, using suitable non-toxic, parenterally
acceptable diluents or solvents, such as mannitol, 1,3-butanediol,
water, Ringer's solution or isotonic sodium chloride solution, or
suitable dispersing or wetting and suspending agents, such as
sterile, bland, fixed oils, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid.
[0349] The compounds of this invention can be administered orally
to humans in a dosage range of 1 to 100 mg/kg body weight in
divided doses. One preferred dosage range is 1 to 10 mg/kg body
weight orally in divided doses. Another preferred dosage range is 1
to 20 mg/kg body weight in divided doses. It will be understood,
however, that the specific dose level and frequency of dosage for
any particular patient may be varied and will depend upon a variety
of factors including the activity of the specific compound
employed, the metabolic stability and length of action of that
compound, the age, body weight, general health, sex, diet, mode and
time of administration, rate of excretion, drug combination, the
severity of the particular condition, and the host undergoing
therapy.
* * * * *