Piperidine compounds

Details Piperidine compounds Piperidine compounds

Filed on

1999-08-18

Date issued

2002-04-23

Examiner

Davis, Zinna Northington (Department: 1612)

Patent Class

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

SubClass

Organic compounds

SubSubClass

Heterocyclic carbon compounds containing a hetero ring...

Other Related Categories

C546S192000

Type

Reexamination Certificate

Status

active

Patent number

06376674

Description

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
Neuraminidase (also known as sialidase, acylneuraminyl hydrolase, and EC 3.2.1.18) is an enzyme common among animals and a number of microorganisms. It is a glycohydrolase that cleaves terminal alphaketosidically linked sialic acids from glycoproteins, glycolipids and oligiosaccharides. Many of the microorganisms containing neuraminidase are pathogenic to man and other animals including fowl, horses, swine and seals. Organisms having N-acetylneuraminidases include bacteria such as
Vibrio cholerae, C. perfringens
and Streptococcus sp. and viruses such as influenza virus, and parainfluenza virus.
Influenza neuraminidase has been implicated in the pathogenicity of influenza viruses. It is thought to help the elution of newly synthesized virons from infected cells and assist in the movement of the virus (through its hydrolase activity) through the mucus of the respiratory tract.
2. Brief Description of Related Art
Von Itzstein, L. M. et al., “Nature”, 363(6428):418-423 (1993), discloses the rational design of sialidase-based inhibitors of influenza virus replication.
Colman, P. M. et al. International Patent Publication No. WO 92/06691 (Int. App. No. PCT/AU90/00501, publication date Apr. 30, 1992), von Itzstein, L. M. et al., European Patent Publication No. 0 539 204 A1 (EP App. No. 92309684.6, publication date Apr. 28, 1993), and von Itzstein, L. M. et al. International Publication No. WO 91/16320 (Int. App. No. PCT/AU91/00161, publication date Oct. 31, 1991) disclose compounds that bind neuraminidase and are asserted to exhibited antiviral activity in vivo.
Umezawa, H. et al., “J. Antibiotics” 27:963-969 (1974), discloses the isolation of Siastatin B. Nishimura, Y. et al., “J. Am. Chem. Soc.” 110:7249-7250 (1988), and “Bull. Chem. Soc. Jpn.” 65:978-986 (1992), disclose the total synthesis of Siastatin B. Nishimura, Y. et al. “J. Antibiotics” 45(10):1662-1668 (1992); 46(2): 300-309 (1993); 46(12):1883-1889 (1993); 47(1):101-107 (1994); and “Nat. prod. Lett.” 1(1): 39-44 (1992); as well as Japanese Patent Applications 92-287381 (Oct. 26, 1992); 90-201437 (Jul. 31, 1990); 88-125020 (May 24, 1988) and 50046895 (Apr. 25, 1975) disclose synthetic transformations of Siastatin B including certain dehydrosiastatin B analogs. Zbiral, E. et al., “Liebigs Ann. Chem.” 129-134 (1991), and von Itzstein, L. M. et al., “Carbohydrate Res.” 244:181-185 (1993), disclose synthetic transformation of the hydroxy group at C4 of sialic acid to an amino group.
OBJECTS OF THE INVENTION
Selected embodiments of the invention satisfy one or more of the following objects:
A principal object of the invention is inhibition of bacteria and viruses, in particular influenza viruses. In particular, an object is inhibition of glycolytic enzymes such as neuraminidase, in particular the selective inhibition of viral or bacterial neuraminidases.
An additional object of the invention is to provide neuraminidase inhibitors that have a retarded rate of urinary excretion, that enter into nasal or pulmonary secretions from the systemic circulation, that have sufficient oral bioavailability to be therapeutically effective, that possess elevated potency, that exhibit clinically acceptable toxicity profiles and have other desirable pharmacologic properties.
Another object is to provide improved and less costly methods for synthesis of neuraminidase inhibitors.
A still further object is to provide improved methods for administration of known and novel neuraminidase inhibitors.
An additional object is to provide compositions useful in preparing polymers, surfactants or immunogens and for use in other industrial processes and articles.
These and other objects will be readily apparent to the ordinary artisan from consideration of the invention as a whole.
SUMMARY OF THE INVENTION
Compounds, or compositions having formula (IX) are provided herein:
wherein
E
1
is —(CR
1
R
1
)
m1
W
1
;
G
1
is N3, —CN, —OH, —OR
6a
, —NO
2
, or —(CR
1
R
1
)
m1
W
2
;
T
1
is —NR
1
W
3
, or a heterocycle;
J
1a
are independently R
1
, Br, Cl, F, I, CN, NO
2
or N
3
;
J
2
and J
2a
are independently H or R
1
;
R
1
is independently H or alkyl of 1 to 12 carbon atoms;
R
2
is independently R
3
or R
4
wherein each R
4
is independently substituted with 0 to 3 R
3
groups;
R
3
is independently F, Cl, Br, I, —CN, N
3
, —NO
2
, OR
6a
, —OR
1
, —N(R
1
)
2
, —N(R
1
)(R
6b
), —N(R
6b
)
2
, —SR
1
, —SR
6a
, —S(O)R
1
, —S(O)
2
R
1
, —S(O)OR
1
, —S(O)OR
6a
, —S(O)
2
OR
1
, —S(O)
2
OR
6a
, —C(O)OR
1
, —C(O)R
6c
, —C(O)OR
6a
, —OC(O)R
1
, —N(R
1
)(C(O)R
1
), —N(R
6b
)(C(O)R
1
), —N(R
1
)(C(O)OR
1
), —N(R
6b
)(C(O)OR
1
), —C(O)N(R
1
)
2
, —C(O)N(R
6b
)(R
1
), —C(O)N(R
6b
)
2
, —C(NR
1
)(N(R
1
)
2
), —C(N(R
6b
))(N(R
1
)
2
), —C(N(R
1
))(N(R
1
)(R
6b
)), —C(N(R
6b
))(N(R
1
)(R
6b
)), —C(N(R
1
))(N(R
6b
)
2
), —C(N(R
6b
))(N(R
6b
)
2
), —N(R
1
)C(N(R
1
))(N(R
1
)
2
), —N(R
1
)C(N(R
1
))(N(R
1
)(R
6b
)), —N(R
1
)C(N(R
6b
))(N(R
1
)
2
), —N(R
6b
)C(N(R
1
))(N(R
1
)
2
), —N(R
6b
)C(N(R
6b
))(N(R
1
)
2
), —N(R
6b
)C(N(R
1
))(N(R
1
)(R
6b
)), —N(R
1
)C(N(R
6b
))(N(R
1
)(R
6b
)), —N(R
1
)C(N(R
1
))(N(R
6b
)
2
), —N(R
6b
)C(N(R
6b
))(N(R
1
)(R
6b
)), —N(R
6b
)C(N(R
1
))(N(R
6b
)
2
), —N(R
1
)C(N(R
6b
))(N(R
6b
)
2
), —N(R
6b
)C(N(R
6b
))(N(R
6b
)
2
), ═O, ═S, ═N(R
1
) or ═N(R
6b
);
R
4
is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
R
5
is independently R
4
wherein each R
4
is substituted with 0 to 3 R
3
groups;
R
5a
is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R
3
groups;
R
6a
is independently H or an ether- or ester-forming group;
R
6b
is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
R
6c
is independently H or the residue of an amino-containing compound;
W
1
is a group comprising an acidic hydrogen, a protected acidic group, or an R
6c
amide of the group comprising an acidic hydrogen;
W
2
is a group comprising a basic heteroatom or a protected basic heteroatom, or an R
6b
amide of the basic heteroatom;
W
3
is W
4
or W
5
;
W
4
is R
5
or —C(O)R
5
, —C(O)W
5
, —SO
2
R
5
, or —SO
2
W
5
;
W
5
is carbocycle or heterocycle wherein W
5
is independently substituted with 0 to 3 R
2
groups;
W
6
is —R
5
, —W
5
, —R
5a
W
5
, —C(O)OR
6a
, —C(O)R
6c
, —C(O)N(R
6b
)
2
, —C(NR
6b
)(N(R
6b
)
2
), —C(NR
6b
)(N(H)(R
6b
)), —C(N(H)(N(R
6b
)
2
), —C(S)N(R
6b
)
2
, or —C(O)R
2
; and
each m
1
is independently an integer from 0 to 2; provided, however, that compounds are excluded wherein J
1a
is H, each J
2
is H, J
2a
is H and T
1
is —N(H)(Ac) and:
E
1
is —CO
2
H or —CO
2
CH
3
,
G
1
is —OBoc, and
W
6
is Boc;
E
1
is —CO
2
H or —CO
2
CH
3
,
G
1
is —OH, and
W
6
is H;
E
1
is —CO
2
H, —CO
2
CH
3
or —CO
2
Bn
G
1
is —OH, and
W
6
is Boc;
E
1
is —CONH
2
,
G
1
is —OH, and
W
6
is Boc or H;
E
1
is —CO
2
H or —CO
2
CH
3
,
G
1
is OH, and
W
6
is Bn; or
E
1
is —CO
2
H or —CO
2
CH
3
,
G
1
is —OH, and
W
6
is —CH
2
CH(OH)CH
2
(OH);
wherein Bn is benzyl and Boc is —CO
2
C(CH
3
)
3
; and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
In another embodiment, compounds, or compositions having formula (X) are provided herein:
wherein
one Z
1
is W
6
and the other Z
1
is G
1
;
Z
2
is H or W
6
;
E
1
is —(CR
1
R
1
)
m1
W
1
;
G
1
is —OH, —OR
6a
, or —(CR
1
R
1
)
m1
W
2
;
T
1
is —NR
1
W
3
or a heterocycle;
J
1
and J
1a
are independently R
1
, Br, Cl, F, I, CN, NO
2
or N
3
;
J
2
is H or R
1
;
R
1
is independently H or alkyl of 1 to 12 carbon atoms;
R
2
is independently R
3
or R
4
wherein each R
4
is independently substituted with 0 to 3 R
3
groups;
R
3
is independently F, Cl, Br, I, —CN, N
3
, —NO
2
, —OR
6a
, —OR
1
, —N(R
1
)
2
, —N(R
1
)(R
6b
), —N(R
6b
)
2
, —SR
1
, SR
6a
, —S(O)R
1
, —S(O)
2
R
1
, —S(O)OR
1
, —S(O)OR
6a
, —S(O)
2
OR
1
, —S(O)
2
OR
6a
, —C(O)OR
1
, —C(O)R
6c
, —C(O)OR

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