Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2002-05-30
2003-11-18
Bernhardt, Emily (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S238000, C544S295000, C544S357000, C544S367000, C544S369000, C562S089000
Reexamination Certificate
active
06649761
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to the synthesis of &ggr;-hydroxy-4-[[2-oxazolyl]alkyl]-&agr;-[(cyclo)alkyl- or aryl- or heteroaryl-substituted methyl]-2-[[(un)substituted alkyl]aminocarbonyl]-1-piperazinepentanamides which are HIV protease inhibitors. The present invention also includes the preparation of intermediates useful in the synthesis of the piperazinepentanamide HIV protease inhibitors.
BACKGROUND OF THE INVENTION
The HIV retrovirus is the causative agent for AIDS. The HIV-1 retrovirus primarily uses the CD4 receptor (a 58 kDa transmembrane protein) to gain entry into cells, through high-affinity interactions between the viral envelope glycoprotein (gp 120) and a specific region of the CD4 molecule found in T-lymphocytes and CD4 (+) T-helper cells (Lasky L. A. et al.,
Cell
1987, 50: 975-985). HIV infection is characterized by an asymptomatic period immediately following infection that is devoid of clinical manifestations in the patient. Progressive HIV-induced destruction of the immune system then leads to increased susceptibility to opportunistic infections, which eventually produces a syndrome called AIDS-related complex (ARC) characterized by symptoms such as persistent generalized lymphadenopathy, fever, and weight loss, followed itself by full blown AIDS.
As in the case of several other retroviruses, HIV encodes the production of a protease which carries out post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions (S. Crawford et al.,
J. Virol
. 1985, 53: 899). These gene products include pol—which encodes the virion RNA-dependent DNA polymerase (reverse transcriptase), an endonuclease, and HIV protease—and gag—which encodes the core-proteins of the virion. (H. Toh et al.,
EMBO J
. 1985, 4: 1267; L. H. Pearl et al.,
Nature
1987, 329-351; M. D. Power et al.,
Science
1986, 231: 1567).
A number of synthetic anti-viral agents targeted to various stages in the replication cycle of HIV have been disclosed. These agents include inhibitors of HIV cellular fusion (Turpin et al.,
Expert Opinion on Therapeutic Patents
2000, 10: 1899-1909), reverse transcriptase inhibitors (e.g., didanosine, zidovudine (AZT), and efavirenz), integrase inhibitors (Neamati,
Expert Opinion on Investigational Drugs
2000, 10: 281-296), and protease inhibitors (e.g., indinavir, ritonavir, and saquinavir). Protease inhibitors inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the action of virus-encoded proteases which are essential for replication (Kohl, N. E. et al.,
Proc. Natl. Acad. Sci. USA
1988, 85: 4686).
A substantial and persistent problem in the treatment of AIDS has been the ability of the HIV virus to develop resistance to the therapeutic agents employed to treat the disease. Resistance to HIV-1 protease inhibitors has been associated with 25 or more amino acid substitutions in both the protease and the cleavage sites. Many of these viral variants are resistant to all of the HIV protease inhibitors currently in clinical use. See Condra et al.,
Drug Resistance Updates
1998, 1: 1-7; Condra et al.,
Nature
1995, 374: 569-571; Condra et al.,
J. Virol
. 1996, 70:8270-8276; Patrick et al.,
Antiviral Ther
. 1996, Suppl. 1: 17-18; and Tisdale et al.,
Antimicrob. Agents Chemother
. 1995, 39: 1704-1710.
Certain &ggr;-hydroxy-4-[[2-oxazolyl]alkyl]-&agr;-[substituted methyl]-2-[[fluoroalkyl)amino]carbonyl]-1-piperazinepentanamides are HIV protease inhibitors which are much more potent against HIV viral mutants than protease inhibitors presently in clinical use. The synthesis of these compounds is a complicated, multi-step process having a relatively low overall yield. The synthesis of these compounds can be represented by Scheme A as follows, wherein A10 represents the desired piperazinepentaneamide HIV protease inhibitor:
A*=absent, CH
2
, or O;
R
1
*=aryl or heteroaryl, wherein aryl is optionally substituted with one or more of halogen, hydroxy, cyano, alkyl, fluoroalkyl, alkoxy, fluoroalkoxy, S-alkyl, amino, or heteroaryl; and heteroaryl is optionally substituted with one or more of halogen, hydroxy, cyano, alkyl, fluoroalkyl, alkoxy, fluoroalkoxy, S-alkyl, amino, aryl, or heteroaryl.
R
2
*, R
3
*=H or alkyl; or
R
2
* and R
3
* together with the carbon to which they are attached form cycloalkyl;
R
6
*=monofluoroalkyl or polyfluoroalkyl;
R
7*
=alkyl, cycloalkyl, aryl or heteroaryl, wherein aryl is optionally substituted with one or more of halogen, OH, alkyl, alkenyl, alkynyl, fluoroalkyl, alkoxy, or heteroaryl; and heteroaryl is optionally substituted with one or more of halogen, OH, alkyl, alkenyl, alkynyl, fluoroalkyl, alkoxy, or aryl;
R
8
*, R
9
*=H, OH, alkyl, fluoroalkyl, or alkoxy; or
R
8
* and R
9
* together with the carbons to which they are attached form a fused benzene ring.
WO 01/38332 presents a specific example of Scheme A in Example 85, which describes the preparation of (&agr;R,&ggr;S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-&ggr;-hydroxy-4-[1-[5-(5-methoxy-3-pyridinyl)-2-oxazolyl]-1-methylethyl]-&agr;-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide (hereinafter alternatively referred to as Compound 26).
The preparation of the ketoamines of formula R
1*
—C(═O)CH
2
NH
2
employed in Scheme A to make Compound A6 can be represented by Scheme B as follows:
WO 01/38332 contains a specific example of Scheme B in Example 85, which describes the preparation of 3-aminomethylcarbonyl-5-methoxypyridine in Steps B and C.
There is a need for improvements in one or more steps of Scheme A and Scheme B in order to prepare this class of piperazinepentaneamide HIV protease inhibitors more efficiently and more conveniently.
SUMMARY OF THE INVENTION
The present invention provides for improvements in the process for preparing &ggr;-hydroxy-4-[[2-oxazolyl]alkyl]-&agr;-[(cyclo)alkyl- or aryl- or heteroaryl-substituted methyl]-2-[[(un)substituted alkyl]aminocarbonyl]-1-piperazinepentanamides. The present invention includes an improved process for making a 4-[[2-oxazolyl]alkyl]-2-[[(un)substituted alkyl]aminocarbonyl]piperazine by treating a ketoamide precursor with fuming sulfuric acid in the presence of polyphosphoric acid. The present invention also includes a process for enhancing the optical purity of 4-[[2-oxazolyl]alkyl]-2-[[(un)substituted alkyl]aminocarbonyl]-piperazines via the formation 2-naphthalenesulfonic acid crystal salts thereof. The present invention further includes a method for purifying 2-naphthalenesulfonic acid.
The foregoing embodiments as well as other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples, and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention includes a process for preparing a piperazine of Formula (II):
which comprises:
(A) treating a ketoamide of Formula (I):
with fuming sulfuric acid in the presence of polyphosphoric acid to obtain the piperazine II; wherein
stereocenter
a
is either in the R configuration or in the S configuration;
G is a nitrogen-protecting group;
R
1
is:
heterocycle, or substituted heterocycle;
wherein each Q is independently hydrogen, cyano, C
1
-C
4
alkyl, or —O—C
1
-C
4
alkyl;
heterocycle in R
1
is:
substituted heterocycle in R
1
is a heterocycle as defined above with one or more substituents (e.g., from 1 to 4 substituents, or from 1 to 3 substituents; or is di-substituted; or is mono-substituted) independently selected from cyano, C
1
-C
4
alkyl, —O—C
1
-C
4
alkyl, S—(C
1
-C
4
alkyl), NR
a
R
b
, thia
Ikemoto Norihiro
Liu Jinchu
Bernhardt Emily
Camara Valerie J.
Merck & Co. , Inc.
Walton Kenneth R.
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