Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-10-11
2003-04-01
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S125000, C560S170000, C562S451000, C562S507000, C562S567000
Reexamination Certificate
active
06541654
ABSTRACT:
BACKGROUND OF THE INVENTION
Peptides in which the —CONH— linkage has been replaced by the —COCH
2
— isosteric moiety are known as ketomethylene pseudopeptides
1
having known utility. For example, such ketomethylene pseudopeptides may be useful as antibiotics, antibiotic enhancers or enzyme inhibitors. Further, this structural modification has been used to make peptide-like molecules with improved metabolic stability.
2
This structural motif has been employed for the preparation of numerous enzyme inhibitors,
3
and has even been found as a natural product.
4
There have been a number of ingenious methods developed for the preparation of this important class of compounds. By far the most common approach to the synthesis of this class of peptide isosteres is to ignore the issue of absolute stereochemistry. There are reports of possible solutions to the question of the absolute configuration of the N-terninal optically active center.
6
There is a singular report of a successful approach to the preparation of ketomethylene pseudopeptides with absolute stereocontrol at both asymmetric centers.
7
Inhibitor molecules based on the ketomethylene isostere have been found to be potent inhibitors of ACE (angiotensin converting enzyme),
2
Substance P,
3b
carboxypeptidase A,
3c
carboxypeptidase A,
3c
and HIV protease.
8
The preparation of optically active alpha-amino ketones by dehydrogenation of racemic alpha-amino ketones and hydrogenation using an asymmetric hydrogenation catalyst is disclosed for dehydroketomethylene pseudopeptides having an aromatic substituent adjacent the keto group in U.S. Pat. No. 4,277,420; East German Application Nos. 280,527; 280,528; 280,529; 240,372 described in corresponding Derwent Abstract Numbers 90-362220/49, 90-362221/49, 90-362222/49, 87-057083/09, respectively.
Additional references directed to optically pure optically active intermediates include:
U.S. Pat. No. 4,912,221;
EP Application No. 90307750.1;
U.S. Pat. No. 4,906,773;
U.S. Pat. No. 4,916,252;
U.S. Pat. No. 4,316,847;
EP Application No. 89403599.7;
Japanese Number 3002152A described in WPI Acc No. 91-048825;
German Appl. No. 140-036 described in Derwent Abstract No. 34661C/20.
Disclosure for a rhodium di (1R, 2R)- or (1S, 2S)-bis(phenyl-4-methoxyphenylphosphino)ethane (Rh DiPAMP) catalyst and its use as an enantioselective hydrogenation catalyst is exemplified in each of the following:
J. Am. Chem. Soc.
1977(August 31), 99;17 pp. 594652;
J. Am. Chem. Soc.
1977(September 6), 94:18 pp. 6429-33;
Synthesis
1979(May) pp. 350-2; and
Chem. Ber.
1981, 114, pp. 1137-49.
The present process takes advantage of the very practical method for the preparation of optically active succinates
9
as a key component for a modified Dakin-West reaction. This protocol effectively introduces the C-terminal optically active center with the appropriate D- or L-amino acid absolute configuration at C-2. The Dakin-West reaction does not however offer a method for the control of the N-terminal optically active center at C-5. In an effort to control both asymmetric centers of a ketomethylene pseudopeptide, the present invention provides a method for the dehydrogenation/asymmetric hydrogenation of certain ketomethylene pseudopeptides. The invention is a novel synthetic method for the preparation of this class of peptide isostere in which both asymmetric centers are fixed with known absolute configuration. The present method permits the introduction of the C-5 optically active center with very high optical purity. In addition, since the absolute configuration of the C-5 center is induced by the absolute configuration of the asymmetric catalyst ligand, it is possible to make either optical antipode independently by the appropriate choice of ligand absolute configuration.
The flexibility of our synthesis permits the synthesis of very unique analogues of &agr;-amino ketones that have improved biological properties relative to molecules available by more demanding syntheses. The literature is replete with examples of novel amino acid side chains designed to impart improved biological properties to these molecules.
BRIEF SUMMARY OF THE INVENTION
The present invention is a novel compound of the formula (I or I
1
)
wherein
R
1
is hydrogen, alkyl, lower cycloalkyl, or Ar wherein Ar is an aromatic group, preferably CH
2
Ar, including, particularly, unsubstituted or substituted phenylmethyl;
R
2
is CH
2
R
9
wherein N is
(a) hydrogen,
(b) C
1
-C
4
alkyl optionally substituted with one or more hydroxyl, C
1
-C
3
alkoxy, chloro, or fluoro,
(c) phenyl optionally substituted with one to three of C
1
-C
4
alkyl, halogen where halogen is fluoro, chloro, bromo or iodo, hydroxyl, nitro, C
1
-C
3
alkoxy, or —CO—N(R
7
)2 wherein R
7
is, independently, H or C
1
-C
4
alkyl,
(d) a 5-7 member heterocycle such as pyridyl, furyl, indolyl or benzisoxazolyl,
(e) C
3
-C
7
cycloalkyl, or
(f) naphthyl;
R
3
is
wherein one of R
6
and R
8
is hydrogen and the other is
(1) hydrogen;
(2) alkyl of from 1 to 6 carbons optionally substituted by one or two hydroxyl, chloro or fluoro;
(3) cycloalkyl of from 3 to 7 ring carbons;
(4) Ar
4
which is a group such as phenyl, or phenyl substituted by one to three substituent(s) consisting of
(a) alkyl of from one to four carbons,
(b) halogen consisting of fluoro, chloro, bromo, iodo,
(c) alkoxy of from one to three carbons,
(d) nitro,
(e) amido,
(f) mono- or di-alkyl (of from one to four carbons)amido, or
(g) hydroxy;
(5) Ar
5
which is tolyl;
(6) Ar
6
which is tolyl substituted by one to three substituents consisting of
(a) alkyl of from of one to four carbons,
(b) halogen consisting of fluoro, chloro, bromo, iodo,
(c) alkoxy of from one to three carbons,
(d) nitro,
(e) amido,
(f) mono- or di-alkyl (of from one to four carbons) amido, or
(g) hydroxy;
(7) Ar
7
which is a group optionally attached through a CH
2
and is naphthyl or naphthyl substituted by one to three substituents consisting of
(a) alkyl of from one to four carbons,
(b) halogen consisting of fluoro, chloro, bromo, iodo,
(c) alkoxy of from one to three carbons,
(d) nitro,
(e) amido,
(f) mono- or di-alkyl (of from one to four carbons) amido, or
(g) hydroxy;
(8) Ar
8
which is a group such as indol-3-yl, indol-2-yl, or imidazoly-4-yl or indol-3-ylmethyl, indol-2-ylmethyl or imidazol-4-ylmethyl (preferably unsubstituted or substituted phenyl or indol-3-yl);
(9) NHA wherein A is
(a) trityl,
(b) hydrogen,
(c) alkyl of from one to six carbons,
(d) R
10
CO wherein R
10
is (A) hydrogen, (B) alkyl of from one to six carbons optionally substituted with hydroxyl, chloro, or fluoro, (C) phenyl or naphthyl; unsubstituted or substituted with one to three of (i) alkyl of from one to three carbons, (ii) halogen where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one to three carbons, (vi) CON(R
11
)
2
wherein R
11
is independently hydrogen or alkyl of from one to four carbons, or (D) a 5 to 7 member heterocycle such as indolyl, pyridyl, furyl or benzisoxazolyl;
(e) phthaloyl wherein the aromatic ring is optionally substituted by one to three of (A) alkyl of from one to three carbons, (B) halogen where halogen is F, Cl, Br, or I, (C) hydroxy, (D) nitro, (E) alkoxy of from one to three carbons, (F) CON(R
11
)
2
wherein R
11
is independently hydrogen or alkyl of from one to four carbons,
(f) R
12
(R
13
R
14
C)
m
CO wherein m is one to three and R
12
, R
13
, and R
14
are independently (A) hydrogen, (B) chloro or fluoro, (C) alkyl of from one to three carbons optionally substituted by chloro, fluoro, or hydroxy, (D) hydroxy, (E) phenyl or naphthyl optionally substituted by one to three of (i) alkyl of from one to three carbons, (ii) halogen where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one to three carbons, (vi) CON(R
11
)
2
wherein R
11
is independently hydrogen or alkyl of from one to four carbons, (F) alkoxy of from one to three carbons, (G) 5 to 7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl, or (H) R
12
, R
13
and R
14
are independently joined to form a mon
Banner & Witcoff , Ltd.
Killos Paul J.
Monsanto Company
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