Tetraisoquinoline derivatives as modulators of dopamine D3...

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S307000

Reexamination Certificate

active

06414154

ABSTRACT:

This is a 371 of PCT/EP99/03371 filed May 14, 1999, which claims benefit from the following Provisional Application No. GB 98 10876.4, filed May 20, 1998.
The present invention relates to novel tetrahydroisoquinoline 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 R
3
are each inter alia hydrogen; X is inter alia (CH
2
)
m
NR
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.
We have now found a class of tetrahydroisoquinoline 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
1
—Z, wherein Ar
1
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 formula
—(CH
2
)
r
—V—(CH
2
)
s
—Ar
 wherein
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;
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;
or a salt 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, arylsulfonyC
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 either of the groups Ar or Ar
1
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, isoxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl 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, 2,3-dihydro-3-oxo-4H-benzoxazinyl, 1,2-dihydro-2-oxo-3H-indolyl.
The group Ar or Ar
1
may be independently optionally substituted by one or more substituents selected from: a halogen atom, or a hydroxy, oxo, cyano, nitro, 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 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.
The group Ar may be optionally substituted by one or more substituents selected from: a halogen atom, cyano, methoxy, methylenedioxy, acetyl, acetylamino, methylsulfonyl, methylsulfonyloxy, methylaminosulfonyl, methylsulfonylamino, or methylaminocarbonyl group.
In the group Ar 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.
The compounds of formula (I) can exist in the form of cis- and trans-isomers with respect to the configuration at the cyclohexyl ring. Preferably the compounds of the invention are in the trans configuration with respect to the cyclohexyl ring.
In compounds of formula (I), it is preferred that R

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