Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
1999-08-31
2001-07-17
Lilling, Herbert J. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S118000, C435S193000
Reexamination Certificate
active
06261810
ABSTRACT:
FIELD OF INVENTION
The present invention concerns an enzymatic oxidative deamination process to prepare an intermediate useful to prepare compounds having endopeptidase and angiotensin converting enzyme inhibition activity.
BACKGROUND OF THE INVENTION
RobI in U.S. Pat. No. 5,508,272 discloses compounds of the formula
wherein A is
as possessing neutral endopeptidase and angiotensin converting enzyme inhibition activity. Among these compounds is [4S-[4&agr;(R*), 7&agr;, 10a&bgr;]]-octahydro-4-[(2-mercapto-1 -oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid which is currently undergoing clinical evaluation. This compound is reported herein as (1)
RobI discloses that the amino lactam portion of (1), i.e., the intermediate
can be prepared by coupling (S)-2-amino-6,6-dimethoxyhexanoic acid methyl ester with the N-protected amino acid
wherein P
1
is an amino protecting group and P
2
is a sulfur protecting group to give the dipeptide of the formula
Removal of the P
2
protecting group, followed by acid catalyzed cyclization, and removal of the P
1
protecting group gives [4S-(4&agr;, 7&agr;, 10a&bgr;)]-octahydro-4-amino-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid, methyl ester.
RobI discloses preparing (S)-2-amino-6,6-dialkoxyhexanoic acid, alkyl ester, such as (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester, by converting N-protected L-&egr;-hydroxynorleucine to its methyl ester, oxidizing to a corresponding aldehyde, such as of the formula
then reacting with trimethyl orthoformate in the presence of a strong acid catalyst, and removing the P
3
protecting group.
SUMMARY OF THE INVENTION
The present invention provides an enzymatic process for the preparation of the above-described intermediate, i.e., the protected amino lactam portion of (1).
More specifically, the present invention is directed to a process for preparing an amino lactam compound of the formula I
comprising contacting a dipeptide monomer of the formula II
wherein P
1
is an amino protecting group, and R
1
is H, alkyl or of the formula
wherein R
2
is alkyl,
with an aminotransferase enzyme in the presence of a-ketoglutarate under conditions suitable for formation of the compound of formula I. The immediately preceding process will be referred to herein as the “oxidative deamination” process.
In an alternate embodiment, the oxidative deamination process is performed in the presence of a glutamate oxidase enzyme which functions to recycle glutamate formed during the process back to alpha-ketoglutarate.
The present invention is also directed to a process for preparing a dipeptide monomer starting compound of the formula III
comprising contacting a dipeptide dimer compound of the formula IV
wherein P
1
is as defined above,
with a reducing agent under conditions suitable for formation of the compound of formula ill. The immediately preceding process for preparing the dipeptide monomer will be referred to herein as the “reduction” process.
The present invention also concerns an engineered host cell containing recombinant nucleic acid capable of expressing an aminotransferase enzyme. In addition, the invention concerns a novel aminotransferase from Spingomonas sp. and nucleic acid encoding same.
The present invention also concerns the novel compounds of formulas II, III and IV.
REFERENCES:
patent: 5508272 (1996-04-01), Robl
patent: 0 036 776 (1988-11-01), None
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Banerjee Amit
Lust David A.
Moniot Jerome L.
Nanduri Venkata B.
Patel Ramesh N.
Bristol--Myers Squibb Company
Davis Stephen B.
Lilling Herbert J.
Sher Audrey F.
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