Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-20
2003-12-09
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S198000, C546S199000, C546S271700, C546S273400, C514S322000, C514S338000
Reexamination Certificate
active
06660751
ABSTRACT:
This invention relates to novel sulfonamide compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.
WO 97/29097, WO 98/48681 and WO 97/49695 all disclose a series of sulfonamide derivatives that are 5-HT
7
receptor antagonists and are useful in the treatment of various CNS diseases. Malleron et al (J. Med. Chem., 1993, 36, 1194-1202) discloses a series of indole derivatives that are claimed to act as potent and selective serotonin uptake inhibitors.
A structurally novel class of compounds has now been found which also possess 5-HT
7
receptor antagonist activity. The present invention therefore provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
Q is phenyl or thienyl;
R
1
is halogen, hydroxy, C
1-6
alkyl, CF
3
, OCF
3
or C
1-6
alkoxy;
m is 0, 1, 2 or 3;
R
2
is C
1-4
alkyl;
X is nitrogen, carbon or CH,
is a single bond when X is nitrogen or CH or
is a double bond when X is carbon;
D is a single bond, C═O, O or CH
2
subject to the proviso that when X is nitrogen then D is not oxygen;
P is phenyl, naphthyl, a 5 or 6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a benzofused heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur;
R
3
is C
1-6
alkyl optionally substituted by NR
4
R
5
, aryl, arylC
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, cyano, hydroxy, nitro, halogen, CF
3
, C
2
F
5
, NR
4
R
5
, CONR
4
R
5
, NR
4
COR
5
, S(O)
p
NR
4
R
5
, CHO, OCF
3
, SCF
3
, CH
2
OR
6
, CO
2
R
6
or COR
6
where p is 0, 1 or 2 and R
4
, R
5
and R
6
are independently hydrogen, C
1-6
alkyl, aryl or arylC
1-6
akyl;
n is 0, 1, 2 or 3.
Alkyl groups whether alone or as part of another group may be straight chain or branched. The term ‘halogen’ is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine. The term ‘aryl’ is used herein to describe, unless otherwise stated, a group such as phenyl or naphthyl optionally substituted by one or more C
1-6
alkyl or halogen. The term ‘naphthyl’ is used herein to denote, unless otherwise stated, both naphthalen-1-yl and naphthalen-2-yl groups.
When Q is thienyl a preferred group is thien-2-yl. Preferably Q is phenyl.
When m is 1, R
1
is preferably halogen (particularly fluorine or chlorine), a C
1-6
alkyl group (particularly methyl, ethyl, isopropyl or t-butyl), CF
3
or C
1-6
alkoxy group (particularly methoxy or ethoxy). When m is 2 or 3 the groups R
1
may be the same or different.
When Q=phenyl and m=1 preferred examples include moieties in which R
1
is either a fluoro group with a para relationship with respect to the sulfonamide group or is a methyl group with a meta relationship with respect to the sulfonamide linkage. When Q=phenyl and m=2 preferred examples include those in which the R
1
groups are independently halogen or C
1-6
alkyl substituted at the 2, 3 or 2, 4 positions with respect to the sulfonamide linkage. When Q=phenyl and m=3 preferred examples include those in which the R
1
groups are independently halogen (particularly chloro), C
1-6
alkyl (particularly methyl) or CF
3
substituted at the 2, 4 and 5 positions with respect to the sulfonamide linkage.
Suitable examples of R
2
groups include methyl, ethyl, isopropyl or n-butyl. Preferably R
2
is methyl or isopropyl, most preferably isopropyl.
Preferably X is nitrogen or CH such that
is a single bond. Most preferably X is CH.
Preferably D is a single bond.
When P is a 5 or 6 membered heteroaryl ring suitable examples include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyl and pyrazinyl. When P is a benzofused heteroaryl ring suitable examples include indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl and isoquinolinyl. The heterocyclic groups listed above can be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom. It will be appreciated however, that when D is O then the heteroaryl ring must be linked to the rest of the molecule via a carbon atom. Preferably P is phenyl, naphthyl, pyrirnidin-2-yl or is a benzofused heteroaryl ring selected from the group consisting of quinolin-4yl, 2-oxo-2,3-dihydrobenzimidazol-1-yl, 2-oxo-2,3-dihydrobenzaxazol-1-yl, indol-3-yl, indol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl and particularly benzimidazol-2-yl.
When n is 1, R
3
is preferably halogen (particularly fluorine or chlorine), a C
1-6
alkyl optionally substituted by NR
4
R
5
(particularly methyl), hydroxy, CF
3
, C
1-6
alkoxy (particularly methoxy) or groups COR
6
or CO
2
R
6
in which R
6
is methyl. When n is 2 or 3 the groups R
3
may be the same or different. Preferably n is 0 or 1.
Particularly preferred compounds of the invention include:
N-(2-(4-(1H-Benzimidazol-2-yl)-piperidin-1-yl)-ethyl)-3,N-dimethyl benzene sulfonamide,
3,4 Dichloro-N-(2-(4(1H-indol-3-yl)-piperidin-1-yl)-ethyl)-N-methyl-benzene sulfonamide,
2,4,5-Trichloro-N-ethyl-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl)-benzene sulfonamide,
2,4,5-Trichloro-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl)-N-isopropyl benzene sulfonamide,
4-Chloro-2,5-dimethyl-N-(2-(4-(5-fluoro-1 H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl)-N-isopropyl benzene sulfonamide,
N-(2-(4-(1H-Benzimidazol-2-yl)-piperazin-1-yl)-ethyl)-2,4,5-trichloro-N-isopropyl-benzene-sulfonamide,
3,N-Dimethyl-N-(2-(4-(2-methyl-1H-indol-3-yl)-3,6dihydro-2H-pyridin-1-yl)-ethyl)-benzene sulfonamide,
4-Fluoro-(N-(2-(4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)3,6-dihydro-2H-pyridin-1-yl)ethyl)-benzene sulfonamide,
2,3,4-Trichloro-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl-N-methyl-benzene-sulfonamide,
2,5-Dibromo-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl-N-methyl-benzene-sulfonamide,
2,4-Dichloro-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl-5,N-dimethyl-benzene-sulfonamide,
4,5-Dichloro-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)piperidin-1-yl)-ethyl)-N-methyl-2-trifluoromethyl-benzenesulfonamide,
2-Chloro-4-fluoro-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl-N-methyl-benzene-sulfonamide,
N-(2-(4-(1H-Benzimidazol-2-yl)-piperazin-1-yl)-ethyl)-3,N-dimethyl benzene sulfonamide,
N-2-(4-(1H-Benzimidazol-2-yl)-piperazin-1-yl)-ethyl)-2,4,5-trichloro-N-methyl-benzenesulfonamide,
2,4,5-Trichloro-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)piperazin-1-yl)-ethyl)-N-methyl benzene sulfonamide,
4-Fluoro-N-(2-(4-(2-methoxyphenyl)-piperazin-1-yl)-ethyl)-N-methyl benzene sulfonamide
N-{2-[4-(1H-Benzimidazol-2-yl)-piperazin-1-yl]-ethyl}-2,4-dichloro-5,N-dimethyl-benzenesulfonamide
or a pharmaceutically acceptable salt thereof
Other preferred compounds of this invention include those shown in Tables 1-5 below.
The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, futmaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
Compounds of formula (I) may also form solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term ‘compound of formula (I)’ also includes these forms.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms including diastereomers and enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.
The present invention also provides a process for the preparation of a compound of
Berch Mark L.
Habte Kahsay
Kinzig Charles M.
McCarthy Mary E.
Simon Soma G.
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