Heterocyclic sulfamides

Details Heterocyclic sulfamides Heterocyclic sulfamides

2000-01-13

2001-06-05

Shah, Mukund J. (Department: 1609)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

active

06242601

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field
The present invention relates to heterocyclic sulfonamides and their use as medicaments.
2. Description
The publications EP 0 713 875 and EP 0 799 209 disclose sulfonamide compounds as endothelin receptor inhibitors. However, there is an art felt need for compounds having high antagonistic potency and high plasma levels following oral administration that lead to enhanced efficacy after oral administration.
SUMMARY OF THE INVENTION
The subject invention provides compounds of formula:
wherein
R
1
is pyridyl, pyridyl substituted with halogen, lower alkyl, hydroxy-lower alkyl or lower alkenyl, pyrrolyl, pyrrolyl substituted with halogen, lower alkyl, hydroxy-lower alkyl or lower alkenyl, imidazolyl, imidazolyl substituted with halogen, lower alkyl, hydroxy-lower alkyl or lower alkenyl, thiazolyl, thiazolyl substituted with halogen, lower alkyl, hydroxy-lower alkyl or lower alkenyl, thiazolinyl, thiazolinyl substituted with halogen, lower alkyl, hydroxy-lower alkyl or lower alkenyl, oxazolyl, or oxazolyl substituted with halogen, lower alkyl, hydroxy-lower alkyl or lower alkenyl;
R
2
is R
21
, —Y—R
22
, heterocyclyl, or heterocyclyl that is mono-, di- or tri-substituted, independently, with hydroxy, lower alkenyl, amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkyl or hydroxy-lower alkyl;
R
21
is cyano, hydroxy-lower alkyl, carboxy, —C(O)NR
a
R
b
, —(CH
2
)
1-4
NHR
c
, —(CH
2
)
1-4
NHC(O)NH(CH
2
)
0-3
CH
3
, amidino, hydroxyamidino, lower alkoxycarbonyl or hydroxy-lower alkoxycarbonyl;
R
22
is hydrogen, lower alkanoyl, carboxy-lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, di-lower alkylcarbamoyl-lower alkyl, allyl, lower alkyl or hydroxy-lower alkyl;
R
a
is hydrogen, lower alkyl, or lower alkyl substituted with hydroxy or lower alkoxy;
R
b
is hydrogen or lower alkyl;
R
c
is hydrogen, acetyl or lower alkylsulfonyl;
X is —CH— or —N—; and
Y is —O—, —NH—;
and pharmaceutically acceptable salts and esters thereof.
While all combinations of the above-mentioned substituents are envisioned, certain substituents are favored. For example, where R
1
is pyridyl, pyridyl substituted with halogen, lower alkyl, hydroxy-lower alkyl or lower alkenyl, thiazolyl, or thiazolyl substituted with halogen, lower alkyl, hydroxy-lower alkyl or lower alkenyl. More preferred is where R
1
is pyridyl, pyridyl substituted with lower alkyl or lower alkenyl, thiazolyl, or thiazolyl substituted with lower alkyl or lower alkenyl.
When R
2
is R
21
, preferred compounds are where R
21
is cyano, hydroxy-lower alkyl, carboxy, lower alkoxycarbonyl, —C(O)NR
a
R
b
, —CH
2
NHR
c
, amidino, hydroxyamidino or —CH
2
NHC(O)NHCH
2
CH
3
, and R
a
, R
b
and R
c
are as defined above. More preferred compounds are where R
21
is cyano, carboxy, carbamoyl, lower alkoxycarbonyl, hydroxy-lower alkyl, acetylaminomethyl or methylsulfonylaminomethyl.
Another favored group of compounds are those where R
2
is R
21
, —Y—R
22
or heterocyclyl selected from the group consisting of 2-pyrimidinyl, 2-imidazolyl, [1,2,4]oxadiazol-3-yl, 2-oxazolyl or 2-thiazolyl, 2-pyrimidinyl mono-, di- or tri-substituted, independently, with lower alkyl, hydroxy-lower alkyl, lower alkenyl, lower alkoxycarbonylamino, lower alkanoylamino, hydroxy or amino, 2-imidazolyl mono-, di- or tri-substituted, independently, with lower alkyl, hydroxy-lower alkyl, lower alkenyl, lower alkoxycarbonylamino, lower alkanoylamino, hydroxy or amino, [1,2,4]oxadiazol-3-yl mono-, di- or tri-substituted, independently, with lower alkyl, hydroxy-lower alkyl, lower alkenyl, lower alkoxycarbonylamino, lower alkanoylamino, hydroxy or amino, 2-oxazolyl mono-, di- or tri-substituted, independently, with lower alkyl, hydroxy-lower alkyl, lower alkenyl, lower alkoxycarbonylamino, lower alkanoylamino, hydroxy or amino, and 2-thiazolyl mono-, di- or tri-substituted, independently, with lower alkyl, hydroxy-lower alkyl, lower alkenyl, lower alkoxycarbonylamino, lower alkanoylamino, hydroxy or amino. More preferred compounds include those where R
2
is R
21
, —Y—R
22
or heterocyclyl selected from the group consisting of 2-pyrimidinyl, 2-imidazolyl, [1,2,4]oxadiazol-3-yl, 2-pyrimidinyl substituted with lower alkyl, isopropenyl, t-butoxycarbonylamino, formylamino, acetylamino, hydroxy, amino or hydroxymethyl, 2-imidazolyl substituted with lower alkyl, isopropenyl, t-butoxycarbonylamino, formylamino, acetylamino, hydroxy, amino or hydroxymethyl, and [1,2,4]oxadiazol-3-yl substituted with lower alkyl, isopropenyl, t-butoxycarbonylamino, formylamino, acetylamino, hydroxy, amino or hydroxymethyl.
Yet another group of favored compounds are those where R
2
is R
22
and R
22
is hydrogen, lower alkyl, carboxymethyl, lower alkoxycarbonyl-lower alkyl, carbamoylmethyl, dimethylcarbamoylmethyl, hydroxy-lower alkyl or acetyl. Preferred are where R
22
is hydrogen, lower alkyl, lower alkoxycarbonyl-lower alkyl or hydroxy-lower alkyl.
A special category of compounds are those of the formula:
wherein
R
1
is pyridyl or pyridyl substituted with lower alkyl;
R
2
is hydroxy, carboxy or methoxycarbonyl; and
X is —CH— or —N—;
and pharmaceutically acceptable salts and esters thereof.
R
1
is favorably pyridyl substituted with lower alkyl, preferably methylpyridyl and specifically R
1
is 5-methyl-pyridine-2-yl.
R
2
may favorably be hydroxy, especially where X is —CH—.
X can also be —N—. In such cases, it is favored when R
2
is carboxy or methoxycarbonyl.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting the invention.
The present invention relates to compounds of the formula (I)
wherein
R
1
is pyridyl, pyrrolyl, imidazolyl, thiazolyl, thiazolinyl or oxazolyl, optionally substituted with halogen, lower alkyl, hydroxy-lower alkyl or lower alkenyl;
R
2
is R
21
, —Y—R
22
or heterocyclyl, wherein heterocyclyl may optionally be mono-, di- or tri-substituted, independently, with hydroxy, lower alkenyl, amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkyl or hydroxy-lower alkyl;
R
21
is cyano, hydroxy-lower alkyl, carboxy, —C(O)NR
a
R
b
, —(CH
2
)
1-4
NHR
c
, —(CH
2
)
1-4
NHC(O)NH(CH
2
)
0-3
CH
3
, amidino, hydroxyamidino, lower alkoxycarbonyl or hydroxy-lower alkoxycarbonyl;
R
22
is hydrogen, lower alkanoyl, carboxy-lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, di-lower alkylcarbamoyl-lower alkyl, allyl, lower alkyl or hydroxy-lower alkyl;
R
a
is hydrogen or lower alkyl, optionally substituted with hydroxy or lower alkoxy;
R
b
is hydrogen or lower alkyl;
R
c
is hydrogen, acetyl or lower alkylsulfonyl;
X is —CH— or —N—; and
Y is —O—, —NH—;
and pharmaceutically acceptable salts and esters thereof.
The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant.
Furthermore, the present invention relates to the use of such compounds for the preparation of medicaments for the treatment and/or prophylaxis of disorders that are associated with abnormal vascular tone and endothelial dysfunction.
The present invention also relates to processes for the preparation of the compounds of formula (I).
In addition, the present invention relates to a method for the prophylactic and/or therapeutic treatment of disorders which are associated with abnormal vascular tone and endothelial dysfunction, which method comprises administering a compound of formula (I) to a human or an animal.
The sulfonamides of the present invention are inhibitors of endothelin receptors. They can accordingly be used for the treatment of disorders which are associated with abnormal vascular tone and endothelial dysfunction.
EP 0 713 875 and EP 0 799 209 disclose sulfonamide compounds as endothelin receptor inhibitors. However, the compounds of the present inven

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