Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-08
2003-02-18
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S300000, C514S339000, C514S406000, C514S415000, C514S416000, C546S113000, C546S016000, C546S227000, C548S364700, C548S482000
Reexamination Certificate
active
06521638
ABSTRACT:
The present invention relates to novel 2,3-dihydro-1H-isoindole derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, as modulators of dopamine D
3
receptors, in particular as antipsychotic agents.
U.S. Pat. No. 5,294,621 describes tetrahydropyridine derivatives of the formula:
wherein
is an optionally substituted thienyl or optionally substituted phenyl ring; R
1
, R
2
and R3are each inter alia hydrogen; X is inter alia (CH
2
)mNR
7
CO; m is 2-4; and Ar
1
is an optionally substituted heterocyclic ring or an optionally substituted phenyl ring. The compounds are said to be useful as antiarrhythmic agents.
EPA 431,580 describes compounds of formula
wherein R is OR
3
, NR
4
R
5
, or N(OR
4
)R
5
, R
4
and R
5
are inter alia hydrogen, lower alkyl, aroyl or heteroaroyl; m is zero, 1 or 2; R
1
is hydrogen, aryl or various heteroaryl groups; n is zero or 1-4; and R
2
is:
The compounds are said to be dopaminergic agents useful as antipsychotics, antihypertensives and also of use in the treatment of hyperprolactinaemia-related conditions and several central nervous system disorders.
WO 95/10513 describes benzothiophene derivatives and related compounds as estrogen agonists.
WO 97/43262 and WO 98/06699 describe tetrahydroisoquinoline derivatives as having affinity for the dopamine D
3
receptor.
We have now found a class of 2,3-dihydro-1H-isoindole derivatives which have affinity for dopamine receptors, in particular the D
3
receptor, and thus potential in the treatment of conditions wherein modulation of the D
3
receptor is beneficial, eg as antipsychotic agents.
In a first aspect the present invention provides compounds of formula (I):
wherein:
R
1
represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C
1-4
alkyl, C
1-4
alkoxy, arylC
1-4
alkoxy, C
1-4
alkylthio, C
1-4
alkoxyC
1-4
alkyl, C
3-6
cycloalkylC
1-4
alkoxy, C
1-4
alkanoyl, C
1-4
alkoxycarbonyl, C
1-4
alkylsulfonyl, C
1-4
alkylsulfonyloxy, C
1-4
alkylsulfonylC
1-4
alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC
1-4
alkyl, C
1-4
alkylsulfonamido, C
1-4
alkylamido, C
1-4
alkylsulfonamidoC
1-4
alkyl, C
1-4
alkylamidoC
1-4
alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC
1-4
alkyl, arylcarboxamidoC
1-4
alkyl, aroyl, aroylC
1-4
alkyl, or arylC
1-4
alkanoyl group; a group R
3
OCO(CH
2
)
p
, R
3
CON(R
4
)(CH
2
)
p
, R
3
R
4
NCO(CH
2
)
p
or R
3
R
4
NSO
2
(CH
2
)
p
where each of R
3
and R
4
independently represents a hydrogen atom or a C
1-4
alkyl group or R
3
R
4
forms part of a C
3-6
azacyloalkane or C
3-6
(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar
3
—Z, wherein Ar3 represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring and Z represents a bond, O, S, or CH
2
;
R
2
represents a hydrogen atom or a C
1-4
alkyl group;
q is 1 or 2;
A represents a group of the formula (a), (b), (c) or (d):
Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring; or an optionally substituted bicyclic ring system;
Ar
1
and Ar
2
each independently represent an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring; and
Y represents a bond, —NHCO—, —CONH—, —CH
2
—, or —(CH2)
m
Y
1
(CH2)
n
—, wherein Y
1
represents O, S, SO
2
, or CO and m and n each represent zero or 1 such that the sum of m+n is zero or 1; providing that when A represents a group of formula (a), any substituent present in Ar ortho to the carboxamide moiety is necessarily a hydrogen or a methoxy group;
r and s independently represent an integer from zero to 3 such that the sum of r and s is equal to an integer from 1 to 4;
V represents a bond, O or S;
and salts thereof.
In the compounds of formula (I) above an alkyl group or moiety may be straight or branched. Alkyl groups which may be employed include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and any branched isomers thereof such as isopropyl, t-butyl, sec-butyl, and the like.
When R
1
represents an arylC
1-4
alkoxy, arylsulfonyl, arylsulfonyloxy, arylsulfonylC
1-4
alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC
1-4
alkyl, arylcarboxamidoC
1-4
alkyl, aroyl, aroylC
1-4
alkyl, or arylC
1-4
alkanoyl group, the aryl moiety may be selected from an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heterocyclic ring. In the group R
1
an aryl moiety may be optionally substituted by one or more substituents selected from hydrogen, halogen, amino, cyano, C
1-4
alkyl, C
1-4
alkylamino, C
1-4
dialkylamino, C
1-4
alkylamido, C
1-4
alkanoyl, or R
5
R
6
NCO where each of R
5
and R
6
independently represents a hydrogen atom or C
1-4
alkyl group.
A halogen atom present in the compounds of formula (I) may be fluorine, chlorine, bromine or iodine.
When q is 2, the substituents R
1
may be the same or different.
An optionally substituted 5- or 6-membered heterocyclic aromatic ring, as defined for any of the groups Ar, Ar
1
, Ar
2
or Ar
3
may contain from 1 to 4 heteroatoms selected from O, N or S. When the ring contains 2-4 heteroatoms, one is preferably selected from O, N and S and the remaining heteroatoms are preferably N. Examples of 5 and 6-membered heterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl and pyrazolyl.
Examples of bicyclic, for example bicyclic aromatic or heteroaromatic, ring systems for Ar include naphthyl, indazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, quinoxolinyl, quinazolinyl, cinnolinyl, isoquinolinyl, pyrazolo[1,5-a]pyrimidyl, pyrrolo[3,2-b]pyridyl, pyrrolo[3,2-c]pyridyl, thieno[3,2-b]thiophenyl, 1,2-dihydro-2-oxo-quinolinyl, 3,4-dihydro-2-oxo-4H-benzoxazinyl, 1,2-dihydro-2-oxo-3H-indolyl.
The rings Ar, Ar
1
, or Ar
2
may each independently be optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, or a hydroxy, oxo, cyano, nitro, trifluoromethyl, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylenedioxy, C
1-4
alkanoyl, C
1-4
alkylsulfonyl, C
1-4
alkylsulfinyl, C
1-4
alkylthio, R
7
SO
2
N(R
8
)—, R
7
R
8
NSO
2
—, R
7
R
8
N—, R
7
R
8
NCO—, or R
7
CON(R
8
)— group wherein each of R
7
and R
8
independently represents a hydrogen atom or a C
1-4
alkyl group, or R
7
R
8
together form a C
3-6
alkylene chain.
Alternatively, Ar and Ar
2
may be optionally substituted by one or more 5- or 6-membered heterocyclic rings, as defined above, optionally substituted by a C
1-2
alkyl or R
7
R
8
N— group; wherein R
7
and R
8
are as defined above.
In the rings Ar and Ar
2
substituents positioned ortho to one another may be linked to form a 5- or 6-membered ring.
It will be appreciated that for use in medicine the salts of formula (I) should be physiologically acceptable. Suitable physiologically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids eg. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other non-physiologically acceptable salts eg. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. Also included within the scope of the invention are solvates and hydrates of compounds of formula (I).
Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
Johnson Christopher Norbert
Stemp Geoffrey
Huang Evelyn Mei
Kinzig Charles M.
SmithKline Beecham p.l.c.
Stein-Fernandez Nora
Venetianer Stephen A.
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