Compounds and methods for synthesis and therapy

Details Compounds and methods for synthesis and therapy Compounds and methods for synthesis and therapy

1999-04-08

2001-05-01

Lambkin, Deborah C. (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S424000

Reexamination Certificate

active

06225341

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 alpha-ketosidically 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. These pathogenic organisms include influenza virus.
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
Itzstein, M. von 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), Itzstein, L. M. von et al.; European Patent Publication No. 0 539 204 A1 (EP App. No. 92309684.6, publication date Apr. 28, 1993), and Itzstein, L. M. von 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.
OBJECTS OF THE INVENTION
A principal object of the invention is inhibition of 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 (I) or (II) are provided herein:
wherein
A
1
is —C(J
1
)═, or —N═;
A
2
is —C(J
1
)
2
—, —N(J
1
)—, —N(O)(J
1
)—, —N(O)═, —S—, —S(O)—, —S(O)
2
— or —O—;
E
1
is —(CR
1
R
1
)
m1
W
1
;
G
1
is N
3
, —CN, —OH, —R
6a
, —NO
2
, or —(CR
1
R
1
)
m1
W
2
;
T
1
is —NR
1
W
3
, a heterocycle, or is taken together with U
1
or G
1
to form a group having the structure
U
1
is H or —X
1
W
6
;
J
1
and 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
;
X1 is a bond, —O—, —N(H)—, —N(W
6
)—, —N(OH)—, —N(OW
6
)—, —N(NH
2
)—, —N(N(H)(W
6
))—, —N(N(W
6
)
2
)—, —N(H)N(W
6
)—, —S—, —SO—, or —SO
2
—, and
each m
1
is independently an integer from 0 to 2; provided, however, that compounds are excluded wherein:
(a) A
1
is —CH═ or —N═ and A
2
is —CH
2
—;
(b) E
1
is COOH, P(O)(OH)
2
, SOOH, SO
3
H, or tetrazol;
(c) G
1
is CN, N(H)R
20
, N
3
, SR
20
, OR
20
, guanidino, —N(H)CN
(d) T
1
is —NHR
20
;
(e) R
20
is H; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; an allyl group or an unsubstituted aryl group or an aryl substituted by a halogen, an OH group, an NO
2
group, an NH
2
group or a COOH group;
(f) J
1
is H and J
1a
is H, F Cl, Br or CN;
(g) J
2
is H and J
2a
is H, CN or N
3
;
(h) U
1
is CH
2
YR
20a
, CHYR
20a
CH
2
YR
20a
or CHYR
20a
CHYR
20a
CH
2
YR
20a
;
(i) R
20a
is H or acyl having 1 to 4 carbon atoms;
(j) Y is O, S, H or NH;
(k) 0 to 2 YR
20a
are H, and
(l) successive Y moieties in a U
1
group are the same or different, and when Y is H then R
20a
is a covalent bond,
and provided that if G
1
is N
3
then U
1
is not —CH
2
OCH
2
Ph.
and the pharmaceutically acceptable salts and solvates thereof;
and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
Another embodiment of the invention is directed to compounds of the formula:
wherein
E
1
is —(CR
1
R
1
)
m1
W
1
;
G
1
is N
3
, —CN, —OH, —OR
6a
, —NO
2
, or —(CR
1
R
1
)
m1
W
2
;
T
1
is —NR
1
W
3
, a heterocycle, or is taken together with U
1
or G
1
to form a group having the structure
U
1
is H or —X
1
W
6
and, if —X
1
W
6
, then U
1
is a branched chain;
J
1
and 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(

Affiliated with

Also associated with

Rating

Compounds and methods for synthesis and therapy does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Compounds and methods for synthesis and therapy, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compounds and methods for synthesis and therapy will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2555126