Efficient synthetic routes for the preparation of rhinovirus...

Details Efficient synthetic routes for the preparation of rhinovirus... Efficient synthetic routes for the preparation of rhinovirus...

2001-10-30

2004-08-10

Powers, Fiona T. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C558S369000, C560S169000

Reexamination Certificate

active

06774243

ABSTRACT:

TECHNICAL FIELD AND INDUSTRIAL APPLICABILITY OF INVENTION
The present invention relates to an improved process for the preparation of ethyl-3-{(5′-methylisoxazole-3′-carbonyl)-L-Val&PSgr;(COCH
2
)-L-(4-F-Phe)-L-((S)-Pyrrol-Ala)}-E-propanoate, its analogs and of pharmaceutically acceptable salts thereof. The present invention also includes a novel group of key intermediate compounds to be used in the above process.
BACKGROUND OF THE INVENTION
Picornaviruses are a family of tiny non-enveloped positive-stranded RNA-containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, meningitis viruses, foot and mouth viruses, hepatitis A virus, and others. The human rhinoviruses are a major cause of the common cold.
Proteolytic 3C enzymes are required for the natural maturation of the picornaviruses. Thus, inhibiting the activity of these proteolytic 3C enzymes should represent an important and useful approach for the treatment and cure of viral infections of this nature, including the common cold.
Some small-molecule inhibitors of the enzymatic activity of picornaviral 3C protease (i.e., antipicornaviral compounds) have been recently discovered. See, for example: U.S. patent application Ser. No. 08/850,398, filed May 2, 1997, by Webber et a.; U.S. patent application Ser. No. 08/991,282, filed Dec. 16, 1997, by Dragovich et al.; and U.S. patent application Ser. No. 08/991,739, filed Dec. 16, 1997, by Webber et al. These U.S. patent applications, the disclosures of which are incorporated herein by reference, describe certain antipicornaviral compounds and methods for their synthesis.
More recently, an especially potent group of antipicornaviral agents have been discovered as set forth in U.S. patent application Ser. No. 60/098,354, (the '354 application) filed Aug. 28, 1998, by Dragovich et al., which is herein incorporated by reference. This application discloses, inter alias, a group of antipicornaviral agents of general formula I. A particularly promising compound, ethyl-3-{(5′-methylisoxazole-3′-carbonyl)-L-Val&PSgr;(COCH
2
)-L-(4-F-Phe)-L-((S)-Pyrrol-Ala)}-E-propanoate, falling within the scope of this group, exhibits excellent antiviral properties against a plethora of Rhinoviral serotypes and is currently in human clinical antipicornavirus agents and suitable synthetic methods for their synthesis. See
Structure
-
Based Design, Synthesis, and Biological Evaluation of Irreversable Human Rhinovirus
3
C Proteases Inhibitors
. 3. For example, General Method V therein discloses a general method for synthesizing the compounds of formula I involving subjecting a carboxylic acid of general formula BB to an amide-forming reaction with an amine of general formula P to provide a final product CC, as shown below.
The '354 application further discloses methods for synthesizing the intermediates of general formulae BB and P, and teaches methods for carrying out the amide-forming reaction referred to above. Thus, the '354 application teaches suitable methods for synthesizing the compounds of general formula I from a carboxylic acid BB (within the scope of the compounds of general formula II referred to below) and the compounds of general formula P (the same as the compounds of general formula III referred to below.) Similarly, two recent publications by Dragovich et al. disclose antipicornavirus agents and suitable synthetic methods for their synthesis. See
Structure Activity Studies of Ketomethylene
-
Containing Peptidomimetics
, Dragovich et al., Journal of Medicinal Chemistry, ASAP, 1999; and
Structure
-
Based Design, Synthesis, and Biological Evaluation of Irreversable Human Rhinovirus
3
C Proteases Inhibitors
. 4
. Incorporation of P
1
Lactam Moieties as L
-
Glutamine Replacements
, Dragovich et al., Journal of Medicinal Chemistry, ASAP, 1999. These aforementioned articles are herein incorporated by reference in their entirety.
However, there is still a desire to discover improved, more efficient, processes and novel intermediates for use in the syntheses of the compounds of the group of antipicornaviral agents. In particular, there is a need for improved methods for synthesizing the compounds of general formulae II and III.
SUMMARY OF THE INVENTION
The present invention relates to the discovery of a cost effective and efficient process for the preparation of the antipicornaviral agents of formula I, such as compound ethyl-3-{(5′-methylisoxazole-3′-carbonyl)-L-Val&PSgr;(COCH
2
)-L-(4-F-Phe)-L-((S)-Pyrrol-Ala)}-E-propanoate, as well as intermediates which are useful in that synthesis.
The antipicornaviral agents of formula I comprise:
wherein R
1
is H, F, an alkyl group, OH, SH, or an O-alkyl group;
R
2
and R
3
are each independently H;
 where n is an integer from 0 to 5, A
1
is CH or N, A
2
and each A
3
are independently selected from C(R
41
)(R
41
), N(R
41
), S, S(O), S(O)
2
, and O, and A
4
is NH or N
41
, where each R
41
is independently H or lower alkyl, provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A
1
, A
2
, (A
3
)
n
, A
4
and C═O, and at least one of R
2
and R
3
is
R
5
and R
6
are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
R
7
and R
8
are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —OR
17
, —SR
17
, —NR
17
R
18
, —NR
19
NR
17
R
18
, or —NR
17
OR
18
, where R
17
, R
18
, and R
19
are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group, provided that at least one of R
7
and R
8
is an alkyl group, an aryl group, a heteroaryl group, —OR
17
, —SR
17
, —NR
17
R
18
, —NR
19
NR
17
R
18
, or —NR
17
OR
18
;
R
9
is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S; and
Z and Z
1
are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R
21
, —CO
2
R
21
, CN, —C(O)NR
21
R
22
, —C(O)NR
21
OR
22
, —C(S)R
21
, —C(S)NR
21
R
22
, —NO
2
, —SOR
21
, —SO
2
R
21
, —SO
2
NR
21
R
22
, —SO(NR
21
)(OR
22
), —SONR
21
, —SO
3
R
21
, —PO(OR
21
)
2
, —PO(R
21
)(R
22
), —PO(NR
21
R
22
)(OR
23
), —PO(NR
21
R
22
)(NR
23
R
24
), —C(O)NR
21
NR
22
R
23
, or —C(S)NR
21
NR
22
R
23
, where R
21
, R
22
, R
23
, and R
24
are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any of two of R
21
, R
22
, R
23
, and R
24
, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z
1
are not both H;
or Z
1
and R
1
, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z
1
and R
1
are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group;
or Z and Z
1
, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z
1
are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group.
As discussed below, these antipicornaviral agents of formula I may be synthesized by subjecting a compound of general formula II together with a compound of general formula III to a suitable amide-forming reaction. The process of the present invention, not only reduces the number of steps required to synthesize the compounds of formula III, but more importantly, it also employs less expensive starting materials and reagents.
These objects, advantages and features of the present invention will be more fully understood and appreciated by reference to the written specification.


REFERENCES:
patent: 4326031 (1982-04-01), Wandrey et al.
paten

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