N-formyl hydroxylamine containing compounds useful as ACE...

Details N-formyl hydroxylamine containing compounds useful as ACE... N-formyl hydroxylamine containing compounds useful as ACE...

1997-04-04

2004-08-17

Berch, Mark L. (Department: 1624)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C540S491000, C540S522000

Reexamination Certificate

active

06777550

ABSTRACT:

SUMMARY OF THE INVENTION
This invention is directed to novel compounds possessing angiotensin converting enzyme (ACE) inhibitory activity and/or neutral endopeptidase (NEP) inhibitory activity and methods of preparing such compounds. This invention is also directed to pharmaceutical compositions containing such ACE and/or NEP inhibiting compounds or pharmaceutically acceptable salts thereof and the method of using such compositions.
The compounds of this invention are those of the formula (I)
including a pharmaceutically acceptable salt thereof where:
x is 0 or 1;
R is H, alkyl, alkenyl, aryl-(CH
2
)
p
—, heteroaryl-(CH
2
)
p
—, cycloheteroalkyl-(CH
2
)
p
—, or
R can be joined together with the carbon to which it is attached to form a 3 to 7 membered ring which may optionally be fused to a benzene ring;
R
1
is H or —COR
2
where R
2
is alkyl, aryl-(CH
2
)
p
—, cycloheteroalkyl-(CH
2
)
p
—, heteroaryl-(CH
2
)
p
—, alkoxy, or cycloalkyl-(CH
2
)
p
—;
p is O or an integer from 1 to 8; and
A is a dipeptide derived from one or two non-proteinogenic amino acid or is a conformationally restricted dipeptide mimic as described below.
A is a dipeptide derivative of the structure
where R
1a
, R
1b
, R
2a
and R
2b
are independently selected from H, alkyl, aryl-(CH
2
)
p
—, cycloalkyl, cycloheteroalkyl-(CH
2
)
p
—, heteroaryl-(CH
2
)
p
—, biphenylmethyl, or
R
1a
and R
1b
or R
2a
and R
2b
may be joined together to the carbon to which they are attached to form a 3 to 7 membered ring, optionally fused to a benzene ring; and
 refers to an optional 5 or 6 membered ring containing a single hetero atom and which may optionally include an R
5
substituent (as shown) which is H, alkyl, aryl-(CH
2
)
p
or cycloalkyl-(CH
2
)
p
, cycloheteroalkyl-(CH
2
)
p
, or cycloheteroaryl-(CH
2
)
p
—;
R
3
is H, alkyl or aryl-(CH
2
)
p
—;
R
4
is OH, Oalkyl, O—(CH
2
)
p
aryl- or NR
1
(R
2
) where R
1
and R
2
are independently H, alkyl, or aryl(CH
2
)
p
or heteroaryl-(CH
2
)
p
—;
with the proviso that in A(1) at least one of
 is other than a natural &agr;-amino acid, and thus must be other than valine, leucine, phenylalanine, tyrosine, serine, cysteine, threonine, methionine, aspartic acid, glutamic acid, arginine, lysine or proline.
In addition, A can be a conformationally restricted dipeptide mimic which has the structure
and is a non-proteinogenic dipeptide.
Thus, the compound of formula I include
The term “conformationally restricted dipeptide mimic” refers to a structural skeleton which has the attributes of a conventional dipeptide
but having enhanced biological properties due to additional bonds which limit the rotational freedom.
Examples of the A(2) dipeptide mimics include any of the conformationally restricted dipeptide mimics set out below.
With respect to A(5), R
11
and R
12
are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH
2
)
m
—, aryl-(CH
2
)
m
—, substituted aryl-(CH
2
)
m
—, and heteroaryl-(CH
2
)
m
—, or R
11
and R
12
taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, or R
11
and R
12
taken together with the carbon to which they are attached complete a keto substituent, i.e.,
with respect to A(13) R
8
, R
9
and R
7
are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH
2
)
m
—, aryl-(CH
2
)
m
—, substituted aryl-(CH
2
)
m
—, and heteroaryl-(CH
2
)
m
—;
R
10
and R
6
are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH
2
)
m
—, aryl-(CH
2
)
m
, substituted aryl-(CH
2
)
m
—, and heteroaryl-(CH
2
)
m
—, or R
6
and R
10
taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, R
6
and R
8
taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, or R
9
and R
10
taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons;
m is zero or an integer from 1 to 6;
R
4
is OH, Oalkyl, O—(CH
2
)
m
-heteroaryl,
 O—(CH
2
)
m
-aryl, or
 or NR
1
(R
2
);
where R
1
and R
2
are independently H, alkyl, aryl(CH
2
)
p
, aryl or heteroaryl;
R
14
is hydrogen, lower alkyl, cycloalkyl, or phenyl;
R
15
is hydrogen, lower alkyl, lower alkoxy or phenyl;
R
16
is alkyl or aryl-(CH
2
)
m
—; and
R
17
is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH
2
)
m
—, aryl-(CH
2
)
m
—, substituted aryl-(CH
2
)
m
—, or heteroaryl-(CH
2
)
m
—.
R
18
is H, alkyl or alkenyl, and R
18
and R
17
may be taken together with the carbon and nitrogen to which they are attached to complete a saturated N-containing ring of 5 or 6 ring members.
R
19
is H or an alkyl, and in A(4), R
19
and x (which is CH
2
) together with the carbons to which they are attached may form an aromatic ring of carbons (as in A(15).
The starting compounds H-A(1) and H-A(2) are described in the literature or are obtained by modifications of known procedures. For example, the starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formulas A(5), A(13), A(16), A(21), where Y (where present) is CH
2
are disclosed by Thorsett et al., J. Med. Chem., 29, p. 251-260 (1988), Harris et al. in U.S. Pat. Nos. 4,587,050, 4,587,238, 4,629,787 and Yanagisawa et al. in U.S. Pat. No. 4,734,410.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formulas A(3) and A(13) where Y is S(O)n are disclosed by Yanagisawa et al., J., Med. Chem., 30, p. 1984-1991 (1987) and 31, p. 422-428 (1988), Karanewsky in U.S. Pat. No. 4,460,579, Cheung et al. in U.S. Pat. No. 4,594,341, and Yanagisawa et al. in U.S. Pat. No. 4,699,905.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(5) are disclosed by Karanewsky in U.S. Pat. Nos. 4,460,579 and 4,711,884.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formulas A(3) (Y is —CH
2
—, and A(21) are disclosed by Watthey et al., J. Med. Chem., 28, p. 1511-1516 (1985) and Watthey in U.S. Pat. Nos. 4,410,520, 4,470,988, 4,473,575, 4,537,885 and 4,575,503 and also by Parsons et al., Biochemical & Biophysical Research Comm., 117, p. 108-113 (1983) and in U.S. Pat. No. 4,873,235.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(3) and Y is S or O are disclosed by Slade et al., J. Med. Chem., 28, p. 1517-1521 (1985) and in U.S. Pat. No. 4,477,464 and Itoh et al., Chem. Pharm. Bull., 34, p. 1128-1147 (1986) and 34, p. 2078-2089 (1986) as well as Sugihara et al. in U.S. Pat. No. 4,548,932 (Y is O) and Katakami et al. in U.S. Pat. No. 4,539,150 (Y is S).
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(16) can be prepared by reduction of the corresponding starting compounds wherein A(1) or A(2) is as defined in formula A(3).
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(22) are disclosed by Flynn et al in U.S. Pat. No. 4,973,585.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(10) and Y is S, —SO, or —SO
2
are disclosed by Harris et al. and Patchett et al. in U.S. Pat. Nos. 4,415,496 and 4,617,301.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(10) and Y is CH
2
, and is as defined in formula A(23) where X
2
is CH
2
is disclosed by Thorsett, Actual. Chim. Ther., 13, p. 257-268 (1986).
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formulas A(11) and A(19) and A(20) are disclosed by Attwood et al., Federation of European Biochemical Studies, 165, p. 201-206 (1984) and in U.S. Pat. No. 4,512,994 and Natoff et al., Drugs Of The Future, 12, p. 475-483 (1987).
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) i

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