Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-12-11
2001-09-18
Gerstl, Robert (Department: 1613)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S200000
Reexamination Certificate
active
06291678
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the preparation of keto heterocycle derivatives of amino acids that have utility in the preparation of biologically active substances. These derivatives may, for example, be incorporated in inhibitors of serine proteases such as thrombin, Factor Xa, and Factor VIIa. As such these inhibitors have utility in the treatment of diseases that result from abnormal coagulation. Typical pathologic conditions include, for example, venous and arterial thrombosis, atrial fibrillation, stroke, restenosis, and recurrent myocardial infarction. These compounds are useful for preventing or treating unstable angina, refractory angina, disseminated intravascular coagulation, and ocular build up of fibrin. Since thrombin has also been demonstrated to activate a number of different cell types, these compounds are useful for the treatment or prophylaxis of septic shock and other inflammatory responses such as acute or chronic atherosclerosis. The compounds also have utility in treating neoplasia/metastasis and neurodegenerative diseases such as Alzheimer's and Parkinson's disease.
Previously peptidyl keto heterocycles have been prepared by conversion of cyano hydrins to imino ethers derivatives and cyclisation with, for example, amino phenols to afford peptidyl-keto-benzoxazoles (Edwards P D, et al.,
J. Am. Chem. Soc.,
114, 1854 (1992)). Alternatively addition of lithiated heterocycles to N,O-dimethyl amides of the amino acid valine has been shown to proceed in good chemical and optical yield (Edwards P D, et al.,
J. Med. Chem.,
38, 76 (1995)). While the N,O-dimethyl amide of BOCNH-Arg(Mtr) has been used to prepare keto amides (Deng J, et al.,
Angew. Chem. Int. Ed. Engl.,
33 (17),1729 (1994)), and in failed attempts to prepare arginals (Guichard G, et al.,
Pept. Res.,
6, 121 (1993)) they have not previously found use in the preparation of keto heterocycle basic amino acid derivatives.
SUMMARY OF THE INVENTION
Accordingly, a first aspect of the present invention is a novel process for the preparation of a compound of Formula I (D(−)) or Formula I (L(+))
wherein R
1
is
wherein X is O,
S, or
NR
5
wherein R
5
is H,
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl, or
arylalkyl,
n is zero or an integer of 1 to 4, and
R
4
is H,
halogen,
NHR
5
wherein R
5
is as defined above,
NR
5
(R
5a
) wherein R
5
and R
5a
are the same or different and are as defined above for R
5
OR
5
wherein R
5
is as defined above,
NO
2
,
CN,
SO
4
R
5
wherein R
5
is as defined above,
C(═O)NR
5
R
5a
) wherein R
5
and R
5a
are the same or different and are as defined above for R
5
,
CO
2
R
5
wherein R
5
is as defined above,
C(═O)R
5
wherein R
5
is as defined above,
aryl, or
heteroaryl,
wherein t is zero or an integer of 1 to 3, and X, n, and R
4
are as defined above,
wherein X, n, and R
4
are as defined above,
wherein n and R
4
are as defined above,
wherein n and R
4
are as defined above,
wherein n and R
4
are as defined above,
wherein n and R
4
are as defined above,
wherein n and R
4
are as defined above;
R
2
is —(CH
2
)
q
—Y wherein Y is
wherein R
5
is as defined above, and R
6
, R
6a
, R
6b
, R
6c
, R
6d
are the same or different and are H,
alkyl,
alkenyl,
alkynyl,
cycloalkyl, or
OR
5
wherein R
5
is as defined above,
wherein R
5
, R
6
, R
6a
, R
6b
, R
6c
, and R
6d
are as defined above,
wherein p is zero or an integer of 1 to 2, and R
5
R
5a
, R
6
, R
6c
, and R
6d
are as defined above, or
wherein p, R
5
, R
5a
, R
6
R
6c
, and R
6d
are as defined above, and q is an integer of 3 to 6,
wherein u is zero or an integer of one, and p and Y are as defined above,
wherein u and Y are as defined above,
wherein Z is
wherein R
5
, R
6
, R
6a
, R
6b
, R
6c
, and R
6d
are as defined above, or
wherein p, R
5
, R
5a
, R
6
, R
6c
, and R
6d
are as defined above, and
wherein u is as defined above,
wherein u, p, and Z are as defined above,
wherein u, R
5a
, and Y are as defined above,
wherein u, R
5a
, and Y are as defined above,
wherein u, R
5a
, and Y are as defined above,
wherein u, R R
5a
, and Y are as defined above,
wherein u, R
5a
, and Y are as defined above, or
wherein u, R
5a
and Y are as defined above; and
R
3
is H,
—CO
2
R
7
wherein R
7
is alkyl,
cycloalkyl,
cycloalkylalkyl,
arylalkyl, or
aryl, or
wherein R
7
is as defined above; or an addition salt thereof;
which comprises:
step (a) treating a compound of Formula IIIa (D(−)) or Formula IIIa (L(+))
wherein R
3a
is CO
2
R
7
, wherein R
7
is as defined above, or
wherein R
7
is as defined above, and R
2
is as defined above;
with an activating reagent in a solvent to afford an activated acyl intermediate which is treated with a compound of formula:
wherein
R
8
and R
8a
may be the same or different and are
alkyl,
cycloalkyl,
cycloalkylalkyl, or
R
8
and R
8a
may be joined to form a ring of from 4 to 8 atoms, to afford a compound of Formula IIa (D(−)) or Formula IIa (L(+))
wherein R
2
, R
3a
, R
8
, and R
8a
are as defined above;
step (b) treating a compound of Formula IIa (D(−)) or Formula IIa (L(+)) with a compound of Formula IV
R
1
—M IV
wherein M is lithium, cerium halide, titanium alkoxide, titanium halide, or magnesium halide and R
1
is as defined above, in a solvent to afford a compound of Formula Ia (D(−)) or Formula Ia (L(+))
wherein R
1
, R
2
, and R
3a
are as defined above;
step (c) treating a compound of Formula Ia (D(−)) or Formula Ia (L(+)) with a deprotecting reagent in a solvent to afford a compound of Formula Ib (D(−)) or Formula Ib (L(+))
wherein R
1
and R
2
are as defined above.
A second aspect of the present invention is a novel compound of Formula I (D(−)) or Formula I (L(+))
wherein R
1
, R
2
, and R
3
are as defined above; or an addition salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
In the compounds of the present invention, the term “alkyl” means a straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and includes, for example, methyl, n-propyl, tert-butyl, and the like.
The term “alkenyl” means a straight or branched unsaturated hydrocarbon radical having from 2 to 6 carbon atoms and includes, for example, 2-butenyl, 3-methyl-3-butenyl, 1-hexenyl, and the like.
The term “alkynyl” means a straight or branched triple bonded unsaturated hydrocarbon radical having from 2 to 6 carbon atoms and includes, for example, 2-butynyl, 3-hexynyl, and the like.
The term “cycloalkyl” means a saturated hydrocarbon radical having from 3 to 12 carbon atoms and includes, for example, cyclopropyl, cyclopentyl, and the like.
The term “cycloalkylalkyl” means a cycloalkyl group attached to an alkyl group wherein “cycloalkyl” and “alkyl” are as defined above and includes, for example, cyclopropylmethyl, cyclopentylethyl, and the like.
The term “alkyloxy” is O-alkyl as defined above for alkyl.
The term “aryl” means an aromatic radical which is a phenyl or naphthyl group, which may be unsubstituted or substituted by 1 to 5 substituents selected from, alkyl, alkyloxy, wherein the alkyl or alkyloxy substituents may be part of a ring occupying two adjacent ring positions and includes, for example, dihydrobenzopyrans, benzo-1,3-dioxole, and the like.
The term “arylalkyl” means an aromatic radical attached to an alkyl radical wherein “aryl” and “alkyl” are as defined above and includes for example benzyl, and naphthylmethyl.
The term “heteroaryl” means a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2-pyrazinyl, 2-, 4-, or 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzothienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazoly
Berryman Kent A.
Doherty Annette M.
Edmunds Jeremy J.
Plummer Janet S.
Gerstl Robert
Merchant & Gould P.C.
Warner-Lambert & Company
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