BENZODIAZEPINE HYDRAZIDE DERIVATIVES AS INHIBITORS OF HIV INTEGRASE

DERIVES DE BENZODIAZEPINE HYDRAZIDE UTILISES COMME INHIBITEURS DE L'INTEGRASE DU VIH

English Abstract

Compounds having a benzodiazepine hydrazide core are described. These
compounds are useful in the inhibition of HIV integrase, the prevention or
treatment of infection by HIV and the treatment of AIDS, either as compounds,
pharmaceutically acceptable salts, pharmaceutical composition ingredients,
whether or not in combination with other antivirals, immunomodulators,
antibiotics or vaccines. Methods of treating AIDS and methods of preventing or
treating infection by HIV are also described.

French Abstract

L'invention porte sur des composés possédant un noyau de benzodiazépine hydrazide. Ces composés sont utilisés dans l'inhibition de l'intégrase du VIH, la prévention ou le traitement des infections à VIH et dans le traitement du SIDA, que ce soit des composés, des sels pharmaceutiquement acceptables, des ingrédients de compositions pharmaceutiques, en combinaison ou non avec d'autres agents antiviraux, des immunomodulateurs, des antibiotiques ou des vaccins. Des procédés de traitement du SIDA et des procédés de prévention ou de traitement des infections à VIH sont également décrits.

Claims

-29-

WHAT IS CLAIMED IS:

1. A compound of the formula:
Image
wherein:
X and Y are independently H, C1, Br or F;
R is heterocycle, which is unsubstituted or substituted with amino,
azido, C1-4 alkyl, phenyloxy, C1-4 alkoxy, halo, nitro,
phenyl or halophenyl,
wherein heterocycle is independently selected from: piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,
furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl;
or pharmaceutically acceptable salts thereof.




-30-

2. The compound according to Claim 1, of the
formula;

Image

wherein:
X and Y are independently H, Cl or Br;
R is heterocycle, which is unsubstituted or substituted with C1-4
alkyl, or C1-4 alkoxy;
wherein heterocycle is independently selected from: piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,
furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl;
or pharmaceutically acceptable salts thereof.

3. The compound according to Claim 1, of the
formula:



-31-

Image or Image

wherein:
X and Y are independently H, C1, or Br;
R is
Image, or Image
wherein: R is unsubstituted or substituted with one or
two of:
C1-4 alkyl;
nitro;
C1-4 alkoxy; or
halo-C1-4 alkyl,
n is 3 to 6,
or a pharmaceutically acceptable salt thereof.

4. The compound according to Claim 1, of the
formula:


-32-

Image or Image

wherein:
R is pyrazinyl, pyridyl, pyrimidinyl, quinolinyl, any of which R
substituents are unsubstituted or substituted with C1-4 alkyl,
or pharmaceutically acceptable salts thereof.

5. The compound according to Claim 1 selected
from:
Image and Image
or a pharmaceutically acceptable salt thereof.

6. A method of inhibiting HIV integrase, comprising
administering to a mammal an effective amount of a compound of
the formula:



-33-


Image


wherein:
X and Y are independently H, Cl, Br or F;
R is aryl or heterocycle, either of which is unsubstituted or
substituted with amino, azido, C1-4 alkyl, phenyloxy, C1-4
alkoxy, halo, nitro, phenyl or halophenyl,
wherein heterocycle is independently selected from: piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,
furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl;
or pharmaceutically acceptable salts thereof.

7. The method of inhibiting HIV integrase according
to Claim 6 comprising administering to the mammal an effective
amount of a compound of the formula:



-34-

Image or Image
wherein:
X and Y are independently H, C1 or Br;
R is aryl or heterocycle, either of which is unsubstituted or
substituted with C 1-4 alkyl, or C 1-4 alkoxy,
wherein heterocycle is independently selected from: piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,
furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl;
or pharmaceutically acceptable salts thereof.

8. The method of inhibiting HIV integrase according
to Claim 6 comprising administering to the mammal an effective
amount of a compound of the formula:




-35-


Image


wherein:
X and Y are independently H, Cl, or Br;
R is

Image

wherein:
R is unsubstituted or substituted with one or more of C1-4
alkyl; vitro; C1-4 alkoxy or halo-C1-4 alkyl,
n is 3 to 6,
or a pharmaceutically acceptable salt thereof.
9. The method of inhibiting HIV integrase according
to Claim 6 comprising administering to the mammal an effective
amount of a compound of the formula:




-36-

Image



R is aryl, pyrazinyl, pyridyl, imidazolyl, pyrimidinyl, quinolinyl,
any of which R substituents are unsubstituted or substituted
with C1-4 alkyl,
or a pharmaceutically acceptable salt thereof.
10. The method of inhibiting HIV integrase according
to Claim 6 comprising administering to the mammal an effective
amount of a compound of the formula:

Image

or pharmaceutically acceptable salt thereof.
11. The method of inhibiting HIV integrase according
to Claim 6 comprising administering to the mammal an effective
amount of a compound of the formula:




-37-


Image

or a pharmaceutically acceptable salt thereof.
12. A method of preventing infection of HIV, or of
treating infection by HIV or of treating AIDS or ARC, in a
mammalian subject in need thereof, comprising administering to a
mammal an effective amount of a compound of the formula:

Image

wherein:
X and Y are independently H, Cl, Br or F;
R is aryl or heterocycle, either of which is unsubstituted or
substituted with amino, azido, C1-4 alkyl, phenyloxy, C1-4
alkoxy, halo, nitro, phenyl or halophenyl,
wherein heterocycle is independently selected from: piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,




-38-



isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,
furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl;
or a pharmaceutically acceptable salt thereof.
13. The method according to Claim 12, of preventing
infection of HIV, or of treating infection by HIV or of treating AIDS
or ARC in a mammalian subject in need thereof, comprising
administering to the mammal an effective amount of a compound of
the formula:

Image

wherein:
X and Y are independently H, Cl or Br;
R is aryl or heterocycle, either of which is unsubstituted or
substituted with C1-4 alkyl, or C1-4 alkoxy;
wherein heterocycle is independently selected from: piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,




-39-



isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,
furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl;
or pharmaceutically acceptable salts thereof.
14. The method according to Claim 12, of preventing
infection of HIV, or of treating infection by HIV or of treating AIDS
or ARC in a mammalian subject in need thereof, comprising
administering to the mammal an effective amount of a compound of
the formula:

Image

wherein:
X and Y are independently H, Cl, or Br;
R is

Image

wherein R is unsubstituted or substituted with one or more
of C1-4 alkyl; nitro; C1-4 alkoxy or halo-C1-4 alkyl;
n is 3 to 6;




-40-


or a pharmaceutically acceptable salt thereof.
15. The method according to Claim 12, of preventing
infection of HIV, or of treating infection by HIV or of treating AIDS
or ARC in a mammalian subject in need thereof, comprising
administering to the mammal an effective amount of a compound of
the formula:

Image
wherein:
R is aryl, pyrazinyl, pyridyl, imidazolyl, pyrimidinyl, quinolinyl,
any of which R substituents are unsubstituted or substituted
with C1-4 alkyl,
or a pharmaceutically acceptable salt thereof.
16. The method according to Claim 12, of preventing
infection of HIV, or of treating infection by HIV or of treating AIDS
or ARC in a mammalian subject in need thereof, comprising
administering to the mammal an effective amount of a compound of
the formula:



-41-



Image


or pharmaceutically acceptable salt thereof.




-42-



17. The method according to Claim 12, of preventing
infection of HIV, or of treating infection by HIV or of treating AIDS
or ARC in a mammalian subject in need thereof, comprising
administering to the mammal an effective amount of a compound of
the formula:

Image

or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition useful for
inhibiting HIV integrase, comprising a therapeutically effective
amount of a compound of the formula:

Image

wherein:
X and Y are independently H, Cl, Br or F;
R is heterocycle, which is unsubstituted or substituted with amino,
azido, C1-4 alkyl, phenyloxy, C1-4 alkoxy, halo, nitro,
phenyl or halophenyl,




-43-



wherein heterocycle is independently selected from: piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,
furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl;
or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.
19. A pharmaceutical composition useful for
preventing or treating infection of HIV or for treating AIDS or
ARC, comprising an effective amount of a compound of the formula:

Image

wherein:
X and Y are independently H, Cl, Br or F;
R is heterocycle, which is unsubstituted or substituted with amino,
azido, C1-4 alkyl, phenyloxy, C1-4 alkoxy, halo, nitro,
phenyl or halophenyl;




-44-



wherein heterocycle is independently selected from: piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,
furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl;
or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.
20. A pharmaceutical composition made by combining
a pharmaceutically acceptable carrier and a compound of the
formula:

Image

wherein:
X and Y are independently H, Cl, Br or F;
R is heterocycle, which is unsubstituted or substituted with amino,
azido, C1-4 alkyl, phenyloxy, C1-4 alkoxy, halo, nitro,
phenyl or halophenyl,




-45-

wherein heterocycle is independently selected from: piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,
furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl;
or a pharmaceutically acceptable salt thereof.
21. A process for making a composition comprising:
combining a pharmaceutically acceptable carrier and a compound of
the formula:

Image

wherein:
X and Y are independently H, Cl, Br or F;
R is heterocycle, which is unsubstituted or substituted with amino,
azido, C1-4 alkyl, phenyloxy, C1-4 alkoxy, halo, nitro,
phenyl or halophenyl,



-46-


wherein heterocycle is independently selected from: piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,
furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl;
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a
therapeutically effective amount of a compound of the formula:

Image

wherein:
X and Y are independently H, Cl, Br or F;
R is heterocycle, which is unsubstituted or substituted with amino,
azido, C1-4 alkyl, phenyloxy, C1-4 alkoxy, halo, nitro,
phenyl or halophenyl,
wherein heterocycle is independently selected from: piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,



-47-


2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,
furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl;
or a pharmaceutically acceptable salt thereof;
in combination with a therapeutically effective amount of an AIDS
treatment agent selected from:
(1) an AIDS antiviral agent,
(2) an anti-infective agent, and
(3) an immunomodulator.
23. The composition of Claim 22 wherein the antiviral
agent is an HIV protease inhibitor.
24. The composition of Claim 23 wherein the HIV
protease inhibitor is N-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-
phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-
butylcarboxamido)-piperazinyl))-pentaneamide or a pharmaceutically
acceptable salt thereof.

Description

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TITLE OF THE INVENTION
BENZODIAZEPINE HYDRAZIDE DERIVATIVES AS
INHIBITORS OF HIV INTEGRASE
S BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus
(HN) is the etiological agent of the complex disease that includes
progressive destruction of the immune system (acquired immune
deficiency syndrome; AIDS) and degeneration of the central and
peripheral nervous system. This virus was previously known as
LAV, HTLV-III, or ARV. A common feature of retrovirus
replication is the insertion by virally-encoded integrase of proviral
DNA into the host cell genome, a required step in HIV replication in
human T-lymphoid cells. Integration is believed to occur in three
stages: cleavage of two nucleotides from the 3' termini of the linear
proviral DNA; covalent joining of the recessed 3' OH termini of the
proviral DNA at a staggered cut made at the host target site; repair
synthesis by host enzymes.
Nucleotide sequencing of HIV shows the presence of a
Col gene in one open reading frame [Ratner, L. et al., Nature, 313,
277(1985)]. Amino acid sequence homology provides evidence that
the pol sequence encodes reverse transcriptase, an integrase and an
HIV protease jToh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D.
et al., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351
{1987)].
It is known that some antiviral compounds act as
inhibitors of HIV and are effective agents in the treatment of AIDS
and similar diseases, e.g., azidothymidine or AZT. Applicants
demonstrate that the compounds of this invention are inhibitors of
HIV integrase, probably by inhibiting catalysis rather than
preventing assembly. The particular advantage of the present
invention is highly specific inhibition of HIV integrase. The
compounds of the present do not inhibit a variety of other protein-
nucleic acid interactions, including enzymatic reactions involving

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HIV reverse transcriptase, DNase I, Eco RI endonuclease, or
mammalian polymerase II, as well as other related interactions, e.g.,
involving HIV TAT protein.
Vejdelek et al., "Potential Anxiolytics and Hypnotics: 1-
(Alkanesulfonamidoalkyl)-6-aryl-8-halogeno-s-triazolo[4,3-aJ-1,4-
benzodiazepines and related compounds," Collection Czechoslovak
Chem. Commun. 53:132-144 (1987), describe the following
compounds of structural formula IA:
NHNHCOR2
m_
R1
CI
IA
Compound R 1 R2
N
1 Cl ~ NH
CH3
N1
2 Br ~ NH
CH3
N
3 Cl -~ ~ ~~N
as useful in intermediates in making the psychoactive drugs of
structural formula IIA:
T .. T


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R3~ N
~' ~N
N
R \ -- N
1
R4
BRIEF DESCRIPTION OF THE INVENTION
Compounds of formula I, as herein defined, are
disclosed. These compounds are useful in the inhibition of HIV
integrase, the prevention of infection by HIV, the treatment of
infection by HIV and in the treatment of AIDS and/or ARC, either as
compounds, pharmaceutically acceptable salts or hydrates (when
appropriate), pharmaceutical composition ingredients, whether or
not in combination with other antivirals, anti-infectives,
immunomodulators, antibiotics or vaccines. Methods of treating
AIDS, methods of preventing infection by HIV, and methods of
treating infection by HIV are also disclosed.
DETAILED DESCRIPTION OF THE INVENTION AND
PREFERRED EMBODIMENTS
This invention is concerned with compounds of formula
I, combinations thereof, or pharmaceutically acceptable salts thereof,
in the inhibition of HIV integrase, the prevention or treatment of
infection by HIV and in the treatment of the resulting acquired
immune deficiency syndrome (AIDS). Compounds of formula I are
tautomers defined as follows:

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N-N
N R N N- N I I R
X- fl O X O
~N or 'N
Y V
(I)
wherein X and Y are independently H, Cl, Br or F;
R is aryl or heterocycle, either of which is unsubstituted or
substituted with amino, azido, C 1-4 alkyl, phenyloxy, C I -q. alkoxy,
halo, vitro, phenyl or halophenyl,
provided that:
(a) R is not 4-cinnolinyl, and
(b) when R is 5-methyl-4-imidazolyl, X is H or F;
or pharmaceutically acceptable salts thereof.
In one embodiment of the present invention is directed
to the tautomers of structural formula I,
N-N
N R N N-N II R
O O
''N X ~N
or
Y Y
(I)
wherein X and Y are independently H, Cl or Br;
r r ~ .I __..~. __._


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R is aryl or heterocycle, either of which is unsubstituted or
substituted with C1 _4 alkyl, or C1 _q. alkoxy,
provided that:
when R is 5-methyl-4-imidazolyl, X is H;
or pharmaceutically acceptable salts thereof.
In one class of this embodiment, X and Y are
independently H, Cl, or Br;
R is
N
~C H2)n N
~OoO ,
, oN
wherein R is unsubstituted or substituted with one or more of C1_4
alkyl; vitro; C 1-4 alkoxy or halo-C 1 _4 alkyl,
n is 3 to 6,
or a pharmaceutically acceptable salt thereof.
A particular subclass of this class is directed to
tautomers of structural formula (I) wherein: X and Y are hydrogen;
R is aryl, pyrazinyl, pyridyl, imidazolyl, pyrimidinyl, quinolinyl,
any of which R substituents are unsubstituted or substituted with
C1-4 alkyl, or pharmaceutically acceptable salts thereof.
Particular examples of compounds of the present
invention are:
H O O
N
N, .H N N N.N N
NO H NO
N ~N
and


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and pharmaceutically acceptable salts thereof.
The present invention further relates to a method of
inhibiting HIV integrase comprising administering to a mammal,
most particularly a human, an effective amount of a compound of
formula (I).
The present invention also has as an object the method of
preventing infection of HN, or of treating infection by HIV or of
treating AIDS or ARC in subject in need of such treatment,
comprising administering to the mammal, most particularly a human,
an effective amount of a compound of structural formula (I).
Yet another object of the present invention is to provide
pharmaceutical compositions comprising a compound of formula (I)
and a pharmaceutically acceptable carrier.
The present invention also relates to the use of a
compound of structural formula (I) for the preparation of a
medicament useful for the treating infection by HIV, or of treating
AIDS or ARC in a subject in need of such treatment, and for
prevention infection of HN in an exposed subject.
The compounds of the present invention may have
asymmetric centers and may occur, except when specifically noted,
as racemates, racemic mixtures or as individual diastereomers, or
enantiomers, with all isomeric forms being included in the present
invention.
When any variable (e.g., R, etc.} occurs more than one
time in any constituent or in formula I, its definition at each
occurrence is independent of its definition at every other occurrence.
Also, combinations of substituents and/or variables are permissible
only if such combinations result in stable compounds.
As used herein except where noted, "alkyl" is intended
to include both branched- and straight-chain saturated aliphatic
hydrocarbon groups having the specified number of carbon atoms.
"Halogen" or "halo" as used herein, means fluoro, chloro, bromo and
iodo.
r T T T


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_ 7 _
As used herein, with exceptions as noted, "aryl" is intended
to mean phenyl (Ph) or naphthyl.
The term heterocycle or heterocyclic, as used herein except
where noted, represents a stable 5- to 7-membered mono- or bicyclic or
stable 7- to 10-membered bicyclic heterocyclic ring system, any ring of
which may be saturated or unsaturated, and which consists of carbon
atoms and from one to three heteroatoms selected from the group
consisting of N, O and S, and wherein the nitrogen and sulfur
heteroatoms may optionally be oxidized, and the nitrogen heteroatom
may optionally be quaternized, and including any bicyclic group in
which any of the above-defined heterocyclic rings is fused to a benzene
ring. The heterocyclic ring may be attached at any heteroatom or
carbon atom which results in the creation of a stable structure.
Examples of such heterocyclic elements include piperidinyl, piperazinyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,
azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,
pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl,
isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,
quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,
benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl,
benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl.
The pharmaceutically acceptable salts of the compounds of
this invention include those formed from cations such as sodium,
potassium, aluminum, calcium, lithium, magnesium, zinc, and from
bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine,
arginine, ornithine, choline, N,N'-dibenzylethylenediamine,
chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,
diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and
tetramethylammonium hydroxide. These salts may be prepared by
standard procedures, e.g. by reacting the free acid with a suitable
organic or inorganic base.

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_ g _
The compounds of the present invention can be
synthesized by the following Schemes.
SCHEME I
NH2 N O
glycine ester HCI
CI
O in pyridine CI ~ ~N
A
H N O Lawesson's N S
Pd-C reagent
THF
NaOH -N -N
MeOH
B
RCON2H3
1:1
EtOH:CHCl3
H H
N N_N~R
R is heterocycle or aryl, O
unsubstituted or substituted -N
with amido, azido, C1-4alkyl,
phenyloxy, C1-4alkoxy, halo,
vitro, phenyl, or halophenyl
C
, _ , T


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_9_
In Scheme 1, 2-amino-5-chlorobenzophenone is reacted
with glycine esters to give A. Thiation is carried out by subsequent
reaction with Lawesson's reagent, which upon further reaction with
RCON2H3, affords compounds of formula C of the present invention.
See also Sternbach, L.H., et al., J. Org. Chem. 27, 3788(1962}.
SCHEME II
O O O O
\ OH SO~ \ ~ CI NH2 Y
N~ I / N
I\ /I
O / \
O 98%
D X
n _ /O O
N2H4 \
I I / N N
Y O O
E X
F P4S10
H
H S m_ ~N NH2
m _ i,
N
I I
Y Y
G
X is H, CI, Br or F.
Y is H, CI Br or F.

i i
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- 10-
Scheme II illustrates another way to build benzodiazepine
hydrazides of the present invention. N-Phthaloylglycine D is converted
to its acid chloride, then reacted with 2-amino-5-substituted
benzophenone to give E. See also Vejdelek, Z., et al., Coll. Czech.
Chem. Commun. 45, 3593(1980). Reaction with hydrazine gives the
benzodiazep-2-one F, which is then subjected to thiation. A further step
with hydrazine gives G, another set of compounds of the present
invention.
SCHEME III
O
H H
~N-NH2 ~N-H R
EDC
HOBT
DMF
Y Y
R is aryl or heterocycle, either of which is unsubstituted
or substituted with amino, azido, C 1 _4 alkyl, phenyloxy, C 1-4
alkoxy, halo, nitro, phenyl or halophenyl.
SCHEME IV
O
H H ~R
m ,N-NH2 m_ iN H
THF
I EtsN I
Acid Chloride
Y Y
_ _. .__ _._.~._ _. _. ..w ...
i i 1


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-11-
R is aryl or heterocycle, either of which is unsubstituted or
substituted with amino, azido, C1-4 alkyl, phenyloxy, C1_q. alkoxy, halo,
nitro, phenyl or halophenyl.
Schemes III and IV illustrate how to derivatize the
hydrazide group by either EDC ( 1-(3-dimethylamionopropyl)-3-
ethylcarbodiimide hydrochloride) -mediated coupling to a carboxylic
acid or direct acylation with an acid chloride.
The compounds of the present inventions are useful in
the inhibition of HIV integrase, treatment of infection by human
immunodeficiency virus (HIV) and the treatment of consequent
pathological conditions such as AIDS. Treating AIDS or preventing
or treating infection by HIV is defined as including, but not limited
to, treating a wide range of states of HIV infection: AIDS, ARC
(AIDS related complex), both symptomatic and asymptomatic, and
actual or potential exposure to HIV. For example, the compounds of
this invention are useful in treating infection by HIV after suspected
past exposure to HN by e.g., blood transfusion, exchange of body
fluids, bites, accidental needle stick, or exposure to patient blood
during surgery.
The compounds of this invention are useful in the
preparation and execution of screening assays for antiviral
compounds. For example, the compounds of this invention are
useful for isolating enzyme mutants, which are excellent screening
tools for more powerful antiviral compounds. Furthermore, the
compounds of this invention are useful in establishing or determining
the binding site of other antivirals to HIV integrase, e.g., by
competitive inhibition. Thus the compounds of this invention are
commercial products to be sold for these purposes.
For these purposes, 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


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- 12-
dosage unit formulations containing conventional non-toxic
pharmaceutically-acceptable carriers, adjuvants and vehicles.
The terms "administration of" and or "administering a"
compound should be understood to mean providing a compound of the
invention or a prodrug of a compound of the invention to the individual
in need of treatment.
Thus, in accordance with the present invention there is
further provided a method of treating and a pharmaceutical
composition for treating HIV infection and AIDS. The treatment
involves administering to a patient in need of such treatment a
therapeutically-effective amount of a compound of the present
invention.
As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
1 S specified amounts, as well as any product which results, directly or
indirectly, from combination of the specified ingredients in the
specified amounts.
The present invention also has the objective of providing
suitable systemic, oral, parenteral and topical pharmaceutical
formulations for use in the methods of treatment of the present
invention. The compositions containing the compound of the present
invention for use in the treatment of the above-noted hyperandrogenic
conditions can be administered in a wide variety of therapeutic dosage
forms in conventional vehicles for systemic administration. For
example, the compounds can be administered in such oral dosage forms
as tablets, capsules (each including timed release and sustained release
formulations), pills, powders, granules, elixirs, tinctures, solutions,
suspensions, syrups and emulsions. Likewise, they may also be
administered in intravenous (both bolus and infusion), intraperitoneal,
subcutaneous, topical with or without occlusion, or intramuscular form,
all using forms well known to those of ordinary skill in the
pharmaceutical arts. The compositions may also be administered as a
nasal spray or as a suppository.
T ~.


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-13-
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
sweeteners/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.
When administered by nasal aerosol or inhalation, these
compositions are prepared according to techniques well-known in the
art of pharmaceutical formulation and may be prepared as solutions
in saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other solubilizing or dispersing agents known in the art.
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.
When rectally administered in the form of suppositories,
these compositions may be prepared by mixing the drug with a
suitable non-irritating excipient, such as cocoa butter, synthetic
glyceride esters or polyethylene glycols, which are solid at ordinary
temperatures, but liquidify and/or dissolve in the rectal cavity to
release the drug.
The compounds of this invention can be administered
orally to humans in a dosage range of 1 to 1000 mg/kg body weight
in single or divided doses. One preferred dosage range is 0.1 to 200
mg/kg body weight orally in single or divided doses. Another
preferred dosage range is 1.0 to 100 mg/kg body weight orally in


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-14-
single or divided doses. For oral administration, the compositions
are preferably provided in the form of tablets containing 1.0 to 1000
milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15Ø
20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0,
500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the
active ingredient for the symptomatic adjustment of the dosage to the
patient to be treated. 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.
The present invention is also directed to combinations of
the HIV integrase inhibitor 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. The term
"administration" refers to both concurrent and sequential
administration of the active agents.
TABLE
ANTIVIRALS
Drug Name Manufacturer Indication
AL-721 Ethigen ARC, PGL
(Los Angeles, CA) HIV positive, AIDS
Recombinant Human Triton Biosciences AIDS, Kaposi's
Interferon Beta {Almeda, CA) sarcoma, ARC
t


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-15-
Acemannan Carrington Labs ARC (See also
(Irving, TX) immunomodulators)
Cytovene Syntex sight
Ganciclovir (Palo Alto, CA) threatening CMV
peripheral CMV
retinitis
d4T Bristol-Myers AIDS, ARC
Didehydrodeoxy- (New York, NY)
thymidine
ddI Bristol-Myers AIDS, ARC
Dideoxyinosine (New York, NY)
EL 10 Elan Corp, PLC HIV infection
(Gainesville, GA) (See also immuno-
modulators)

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Dru~Name Manufacturer Indication
Trisodium Astra Pharm. CMV retinitis, HIV
Phosphonoformate Products, Inc. infection, other
{Westborough, MA) CMV infections
Dideoxycytidine; Hoffman-La Roche AIDS, ARC
ddC (Nutley, NJ)
Novapren Novaferon Labs, Inc. HIV inhibitor
(Akron, OH)
Diapren, Inc.
(Roseville, MN,
marketer)
Peptide T Peninsula Labs AIDS
Octapeptide (Belmont, CA)
Sequence
Zidovudine; AZT Burroughs Wellcome AIDS, adv, ARC
(Rsch. Triangle pediatric AIDS,
Park, NC) Kaposi's sarcoma,
asymptomatic HIV
infection, less severe
HIV disease, neuro-
logical involvement,
in combination with
other therapies.
i i ~ T


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-17-
Drug Name Manufacturer Indication
Ansamycin Adria Laboratories ARC
LM 427 (Dublin, OH)
Erbamont
(Stamford, CT)
Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV
Ind. Ltd. positive
(Osaka, 3apan) asymptomatic
Virazole Viratek/ICN asymptomatic HIV
Ribavirin (Costa Mesa, CA) positive, LAS, ARC
Alpha Interferon Burroughs Wellcome Kaposi's sarcoma,
(Rsch. Triangle HIV in combination
Park, NC) w/Retrovir
Acyclovir Burroughs Wellcome AIDS, ARC,
asymptomatic HIV
positive, in
combination with
AZT.
Antibody which Advanced AIDS, ARC
neutralizes pH Biotherapy
labile alpha aber- Concepts (Rockville,
rant Interferon MD)
in an immuno-
adsorption
column

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- 1~ -
Indinavir Merck & Co., Inc. AIDS, ARC,


Rahway, NJ pediatric AIDS


(protease inhibitor)


Lamivudine Glaxo Wellcome AIDS, ARC


(3TC) (Rsch. Triangle (protease inhibitor)


Park, NC)


Nevirapine Boeheringer AIDS, ARC


Ingleheim (protease inhibitor)


Delaviridine Pharmacia-Upjohn AIRS, ARC


(protease inhibitor)


Ritonavir Abbott AIDS, ARC


' (protease inhibitor)


Saquinavir Hoffmann-LaRoche AmS, ARC


(protease inhibitor)


Nelfinavir Agouron AIDS, ARC


Pharmaceuticals (protease inhibitor)


141 W94 Glaxo-Wellcome AIDS, ARC


(protease inhibitor)


DMP-266 DuPont-Merck AIDS, ARC


Pharmaceuticals (non-nucleoside


reverse transcriptase


inhibitor)


i i ~. T w___.

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IMMUNO-MODULATORS
Drug Name Manufacturer Indication
AS-101 Wyeth-Ayerst Labs. AIDS
(Philadelphia, PA)
Bropirimine Upjohn advanced AIDS


(Kalamazoo, MI)


Acemannan Carnngton Labs, Inc. AIDS, ARC


(Irving, TX) (See also anti-virals)


CL246,738 American Cyanamid AIDS, Kaposi's


(Pearl River, NY) sarcoma


Lederle Labs


(Wayne, NJ)


EL 10 Elan Corp, PLC HIV infection


(Gainesville, GA) (See also anti-virals)


Gamma Interferon Genentech ARC, in combina-


(S. San Francisco, tion w/TNF (tumor
CA}


necrosis factor)


Granulocyte Genetics Institute AIDS
Macrophage (Cambridge, MA)
Colony Sandoz (East Hanover,
Stimulating Factor NJ)

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WO 98118473 PCT/US97/19230
-20-
Dru,gLName Manufacturer Indication


Granulocyte Hoeschst-Roussel AIDS


Macrophage Colony (Somerville, NJ)


Stimulating FactorImmunex


(Seattle, WA)


Granulocyte Schering-Plough AIDS


Macrophage Colony (Madison, NJ)


Stimulating Factor AIDS, in combina-


tion w/AZT


HIV Core Particle Rorer seropositive HIV


Immunostimulant (Ft. Washington, PA)


IL-2 Cetus AIDS, in combina-


Interleukin-2 (Emeryville, CA) tion w/AZT


IL-2 Hoffman-La Roche AIDS, ARC, HIV,


Interleukin-2 (Nutley, NJ) in combination


Immunex w/AZT


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


_. _. _...__.__.__..____ _
~ i 1 T

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-21 -
Drug Name Manufacturer Indication


Imuthiol Diethyl Merieux Institute AIDS, ARC


Dithio Carbamate (Miami, FL)


Alpha-2 Schering Plough Kaposi's sarcoma


Interferon (Madison, NJ) w/AZT: AIDS


Methionine- TNI Pharmaceutical AIDS, ARC


Enkephalin (Chicago, IL)


MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma


Muramyl-Tripeptide (Summit, NJ}


Granulocyte Amgen AIDS, in


Colony (Thousand Oaks, combination w/AZT


Stimulating Factor CA)
rCD4 Genentech AIDS, ARC
Recombinant (S. San Francisco,
Soluble Human CD4 CA)
rCD4-IgG AIDS, ARC
hybrids
Recombinant Biogen AIDS, ARC
Soluble Human CD4 (Cambridge, MA)
Interferon Alfa 2a Hoffman-La Roche Kaposi's sarcoma
(Nutley, NJ) AIDS, ARC, in
combination w/AZT

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Drug~Name Manufacturer Indication


SK&F106528 Smith, Kline & French HIV infection


Soluble T4 Laboratories


(Philadelphia, PA)


Thymopentin Immunobiology HIV infection


Research Institute


(Annandale, NJ)


Tumor Necrosis Genentech ARC, in combination


Factor; TNF (S. San Francisco, w/gamma Interferon
CA)


ANTI-INFECTIVES


Drug N~ Manufacturer Indication


Clindamycin withUpjohn PCP


Primaquine (Kalamazoo, MI)


Fluconazole Pfizer cryptococcal


(New York, NY) meningitis,


candidiasis


Pastille Squibb Corp. prevention of
oral


Nystatin Pastille(Princeton, NJ) candidiasis


Ornidyl Merrell Dow PCP


Eflornithine (Cincinnati, OH)


Pentamidine LyphoMed PCP treatment


Isethionate (IM (Rosemont, IL)
&


IV)


~ i ~ r

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Dru Name Manufacturer Indication
Piritrexim Burroughs Wellcome PCP treatment
(Rsch. Triangle Park,
NC)
Pentamidine Fisons Corporation PCP prophylaxis
isethionate for (Bedford, MA)
inhalation
Spiramycin Rhone-Poulenc cryptosporidial diarrhea
Pharmaceuticals
(Princeton, NJ)
Intraconazole- Janssen Pharm. histoplasmosis;
RSI211 (Piscataway, NJ) cryptococcal meningitis
Trimetrexate Warner-Lambert pCp
OTHER
Dru Name Manufacturer Indication
Recombinant Human Ortho Pharm. Corp. severe anemia assoc.
Erythropoietin (Raritan, NJ) with AZT therapy
Megestrol Acetate Bristol-Myers treatment of
(New York, NY) anorexia assoc.
w/AIDS
Total Enteral Norwich Eaton diarrhea and
Nutrition Pharmaceuticals malabsorption
(Norwich, NY) related to AIDS


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-24-
It will be understood that the scope of combinations of
the compounds of this invention with AIDS antivirals, immuno-
modulators, anti-infectives 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.
Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-
(2(R)-hydroxy-1 (S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-
( I -(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-
piperazinyl))-pentaneamide ethanolate. Its synthesis is set forth in
U.S. 5,413,999. Indinavir is generally administered at a dosage of
800 mg three times a day.
EXAMPLE 1
Step I Preparation of Compound III
n _ ~O N O
CI ~ H2> > ~%Pd/C I /
-N
MeOH, NaOH
A Parr-bottle was charged with 0.074 g (I.85 mmol) of
solid NaOH, 20 mL of dry methanol, 0.500 g ( 1.85 mol) of
compound II, and 0.050 g of 10% Pd on carbon. The Parr-bottle
was placed onto the hydrogenation apparatus, charged with hydrogen
at 42 psi, shaken for 2 hrs 20 min., and the contents were filtered
through a plug of CeliteTM diatomaceous earth which was washed
with 50 mLs of EtOAc. The organic layer was collected and then
concentrated on a rotoevaporator to afford an oil which was
triturated with EtOAc/hexane to give solid product III.
T


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-25-
Step II Preparation of Compound IV
N O N S
Lawesson's Reagent
-N ~ -N
2 hr Room Temp
Ill IV
Ref: Tetrahedron 40, 2047-2052, 1984.
A 100 mL round bottom flask was charged with 1.0 g of II,
the product from Step I, 50 mL of dry THF, and 0.820 g of Lawesson's
reagent. The reaction was allowed to stir for 2 hrs at r.t. The reaction
was concentrated to give an oily residue which was chromatographed
with 3:1 EtOAc/hexane. The fractions containing product were
concentrated and the residual solid was recrystailized using
EtOAc/hexane to afford the desired product IV.


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Step III Preparation of Compound VI
O H O
S H2N, N N N-' N ~ N N
i
I / _N N / _N N
/ 16 hrs, 80°C
IV V VI
The quantity 0.056 g (0.22 mmol) of thioamide IV and
0.061 gms (0.44 mmol) of hydrazide V were heated to 80°C in a
mixture of 1.5 mL of CHC13 and 1.5 mL of EtOH for 16 hrs and then
allowed to cool. The residue was concentrated to dryness and
partitioned between CHCl3 and H20. The water layer contained pure
pyrazine hydrazide starting material by TLC and was discarded. The
CHCl3 layer, which contained some undissolved solid, was concentrated
to give a yellow solid. Trituration of this with EtOAc yielded a
colorless solid which was the desired product VI. 1H NMR (400 MHz,
CD30D): 4.50 (br m, 2H), 7.14 (t, 1H), 7.20 (d, 1H), 7.32 (d, 1H),
7.40-7.55 (m, 6H), 8.70 (s, 1 H), 8.79 (d, 1 H), 9.27 (s, 1 H)
T


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-27-
EXAMPLE 2
Preparation of Compound VII
H O
N'' N' N ~ NH
N-=J
Br V ~=N
CI
VII
Compound VII is synthesized according to Vejdelek
et al., Collect. Czech. Chem. Commun. 53, 132 (1988).
EXAMPLE 3
HN Inte~rase Assay Substrate Cleavage
An assay for trimming of 3' end of HIV long terminal
repeat terminus by HIV-1 integrase was conducted according to
LaFemina, E.R. et al., J. Virol. 10, 5624 ( 1991 ), herein incorporated by
reference for these purposes. To assay inhibition of HIV integrase
substrate cleavage, the reaction was conducted with inhibitor having
various concentrations in the range of 0.1 to 100pM. Results follow:
Compound IC50
VI 2 ~.M
VII 5 ~.M.


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-28-
EXAMPLE 4
AssaX for Inhibition of Strand Transfer by HIV Irate rg ase
Inhibition of strand transfer was conducted according to
Hazuda, D. J. et al. Nucleic Acids Res., 22, 1121 (1994), hereby
incorporated by reference for these purposes.
Results of the assay follow:
Compound IC50
VI 2-3 ~.M
VII 5 ~,M
EXAMPLE 5
Assax for Assembl~of HIV-1 Integrase as Catal t~v Active Complex
Inhibition of assembly of HIV-1 Integrase was conducted
according to Wolfe, A.L. et al., J. Virol. 70, 1424 (1996), herein
incorporated by reference for these purposes.
Results of the assay follow
Compound I~0
VI 5 ~.M
VII 10 ~M
EXAMPLE 6
Oral Composition
As a specific embodiment of an oral composition of a
compound of this invention, 50 mg of a compound of the present
invention is formulated with sufficient finely divided lactose to provide
a total amount of 580 to 590 mg to fill a size O hard gelatin capsule.
While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the invention
encompasses all of the usual variations, adaptations, or modifications, as
come within the scope of the following claims and its equivalents.
r... ...... ...,...... ... ~ t t ~. .