Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-17
2004-07-27
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S269000, C544S321000, C544S330000
Reexamination Certificate
active
06767909
ABSTRACT:
The present invention relates to the use of selective alpha-2B-adrenoceptor antagonists for the manufacture of a pharmaceutical preparation useful for the treatment or prevention of diseases mediated by the alpha-2B-adrenoceptor in mammals.
BACKGROUND OF THE INVENTION
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
It is known that alpha-2B-adrenoceptors mediate vascular contractions. Therefore, alpha-2B-antagonists are useful in the treatment or prevention of diseases involving vascular contraction. It has also been found that certain individuals have a genetic polymorphism in the alpha-2B-adrenoceptor gene. It has been observed that the alpha-2B-adrenoceptor protein in some subjects has a deletion of 3 glutamates from the glutamic acid repeat element of 12 glutamates (amino acids 297-309), in an acid stretch of 17 amino acids, located in the third intracellular loop of the receptor polypeptide (WO 01/29082; Heinonen et al., 1999).
OBJECTS AND SUMMARY OF THE INVENTION
An object of this invention is to provide compounds useful for the treatment or prevention of a disease mediated by the alpha-2B-adrenoceptor in a mammal.
Thus this invention concerns a novel compound of formula (I)
or a pharmaceutically acceptable salt thereof.
R
1
, R
2
, R
3
, R
4
and R
5
are independently of each other H, a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
X is H, a straight or branched alkyl chain having 1 to 4 carbon atoms, phenyl or —OH;
Z is H, acetyl, —CH
2
—Ph—O—CF
3
or —CH
2
—Ph—CF
3
, where Ph is phenyl;
Y is a ring structure optionally linked to formula (I) with an alkyl chain having one or two carbon atoms, wherein the ring structure is
a) phenyl optionally mono- or disubstituted, wherein each substituent is independently selected from the group consisting of a halogen, a straight or branched alkyl or alkoxy chain with 1 to 4 carbon atoms, a halogen substituted methyl or methoxy group, a nitrile group, an amide group, amino group, or a nitro group;
b) 2-benzimidazolyl, 2-imidazolyl, or 2- or 3-indolyl, wherein one N optionally has a substituent that is a straight or branched alkyl or alkoxy chain with 1 to 4 carbon atoms, or benzyl; and wherein the 2-benzimidazolyl, 2-imidazolyl, or 2- or 3-indolyl is optionally mono- or disubstituted, wherein each substituent is independently a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
(c) pyridinyl optionally mono- or disubstituted, wherein each substituent is independently a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen; or
(d) naphthyl optionally mono- or disubstituted, wherein each substituent is independently a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
provided that
if R
1
is methyl; and R
2
, R
4
, R
5
, Z and X is H;
then Y cannot be an unsubstituted 2-benzimidazolyl if R
3
is methyl or H,
nor can Y be a monosubstituted 2-benzimidazolyl wherein one N has a methyl or ethyl substitution if R
3
is methyl.
The following previously known compounds are thus excluded: 4-[(1H-benzimidazol-2-ylmethyl)-amino]-N-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide (Kumar & Reddy, 1985), N-(4,6-dimethylpyrimidin-2-yl)-4-[(1-methyl-1H-benzimidazol-2-ylmethyl)-amino]-benzenesulfonamide (No 653716, ChemBridge Corporation, 16981 Via Tazon, Suite G, San Diego, Calif. 92127) and N-(4,6-dimethylpyrimidin-2-yl)-4-[(1-ethyl-1H-benzimidazol-2-ylmethyl)-amino]-benzenesulfonamide (No AE-848/34956037, SPECS and BioSPECS B. V., Fleminglaan 16, 2289 C P Rijswijk, The Netherlands) and N-(4-methyl-2-pyrimidinyl)-4-[(1H-benzimidazol-2-ylmethyl)-amino]-benzenesulfonamide (Farag & El-Mouafi & Khalifa, 1991).
This invention further concerns a method for the treatment or prevention of a disease mediated by the alpha-2B-adrenoceptor in a mammal, comprising administering an alpha-2B-adrenoceptor antagonist to a mammal in need of said treatment, said antagonist comprising a compound of formula (I)
or a pharmaceutically acceptable salt thereof wherein
R
1
, R
2
, R
3
, R
4
and R
5
are independently of each other H, a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
X is H, a straight or branched alkyl chain having 1 to 4 carbon atoms, phenyl, —-OH or ═O;
Z is H, acetyl, —CH
2
—Ph—O—CF
3
or —CH
2
—Ph—CF
3
, where Ph is phenyl;
Y is a ring structure optionally linked to formula (I) with an alkyl chain having one or two carbon atoms, wherein the ring structure is
a) phenyl optionally mono- or disubstitued, wherein each substituent is independently selected from the group consisting of a halogen, a straight or branched alkyl or alkoxy chain with 1 to 4 carbon atoms, a halogen substituted methyl or methoxy group, an acetyl group, a nitrile group, an amide group, an amino group, or a nitro group;
b) 2-benzimidazolyl, 2-imidazolyl, or 2- or 3-indolyl, wherein one N optionally has a substituent that is a straight or branched alkyl or alkoxy chain with 1 to 4 carbon atoms, or benzyl; and wherein the 2-benzimidazolyl, 2-imidazolyl, or 2- or 3-indolyl is optionally mono- or disubstituted, wherein each substituent can independently be a straight or branched alkyl or alkoxy group having 1 to 4 carbon atoms, or a halogen;
(c) pyridinyl optionally mono- or disubstituted, wherein each substituent is independently a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen; or
(d) naphthyl optionally mono- or disubstituted, wherein each substituent is independently a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
provided that
if R
1
and R
3
is methyl; and R
2
, R
4
, R
5
, Z and X is H;
then Y cannot be a monosubstituted 2-benzimidazolyl wherein one N has a methyl or ethyl substitution; or
if R
1
and R
3
is methyl; R
2
, R
4
, R
5
and Z is H and X is ═O;
then Y cannot be a monosubstituted phenyl with an ethoxy group in the 4-position.
The following compounds previously known to be selective alpha-2B-adrenoceptor antagonists are thus excluded: N-(4,6-dimethylpyrimidin-2-yl)-4-[(1-methyl-1H-benzimidazol-2-ylmethyl)-amino]-benzenesulfonamide (No 653716, ChemBridge Corporation, 16981 Via Tazon, Suite G, San Diego, Calif. 92127), N-(4,6-dimethylpyrimidin-2-yl)-4-[(1-ethyl-1H-benzimidazol-2-ylmethyl)-amino]-benzenesulfonamide (No AE-848/34956037, SPECS and BioSPECS B. V., Fleminglaan 16, 2289 C P Rijswijk, The Netherlands) and N-[4-(4,6-dimethylpyrimidin-2-ylsulfamoyl)-phenyl]-4-ethoxy-benzamide (No AF-399/36012031, SPECS and BioSPECS B. V., Fleminglaan 16, 2289 C P Rijswijk, The Netherlands).
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds of the invention are compounds of formula (I)
as defined in the preceding summary or pharmaceutically acceptable salts thereof wherein R
1
and R
3
are methyl and R
2
, R
4
and R
5
are H.
In some preferable compounds X is H, Y is a phenyl optionally mono- or disubstituted with a straight or branched alkoxy group and Z is H. Compounds fulfilling all of the aforementioned characteristics and wherein said phenyl is substituted and said alkoxy substituent is methoxy are 4-(2,4-dimethoxybenzylamino)-N-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, N-(4,6-dimethylpyrimidin-2-yl)-4-(3-methoxybenzylamino)-benzenesulfonamide, 4-(3,5-dimethoxybenzylamino)-N-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, 4-(2,5-dimethoxybenzylamino)-N-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide and N-(4,6-dimethylpyrimidin-2-yl)-4-(2-methoxybenzylamino)-benzenesulfonamide.
In other preferred compounds X is H, Y is a phenyl optionally mono- or disubstituted with a straight or branched alkyl and/or a halogen and Z is H. These comprise compounds such as 4-benzylamino-N-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, N-(4,6-dimethylpyrimidin-2-yl)-4-(2-methylbenzylamino)-benzenesulfona
Hoffrén Anna-Maria
Joutsamo Topi
Salo Harri
Tauber Andrei Yurievitch
Wurster Siegfreid
Balasubramanian Venkataraman
Lydon James C.
Oy Juvantia Pharma Ltd.
Shah Mukund J.
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