Sulfonylpyrazole and sulfonylpyrazoline carboxamidine derivatives as 5-HT
This invention concerns compounds of the general formula (1): and derivatives thereof, which are antagonists of 5-HT 6 receptors, wherein the symbols have the meanings given in the description. The invention also concerns methods for the preparation of these compounds, to novel intermediates useful for their synthesis, and to uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in treating at least on disease or condition chosen from Parkinson's disease, Huntington's chorea, schizophrenia, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder, Irritable Bowel Syndrome, obesity and type-2 diabetes.
1. A compound of formula (1 X ):
or a stereoisomer, N-oxide thereof, or pharmacologically acceptable salt of any of the foregoing, wherein:
X is chosen from halogen and S-alkyl(C 1-4 );
R 1 is chosen from hydrogen, an unsubstituted alkyl(C 1-4 ) group, and an alkyl(C 1-4 ) group substituted with one or more halogen atoms;
R 2 and R 3 independently are chosen from hydrogen, an unsubstituted alkyl(C 1-4 ) group, an alkyl-(C 1-4 ) group substituted with one or more halogen atoms, and a phenyl-alkoxy(C 1-4 )-alkyl(C 1-4 ) group optionally substituted with one or more halogen atoms, or,
R 1 and R 2 , together with the carbon atoms marked ‘a’ and ‘b’ form a C 5-8 -cycloalkyl ring, or
R 2 and R 3 , together with the carbon atom marked ‘b’ form a C 3-8 -cycloalkyl ring, or,
R 2 and R 3 , together with the carbon atom marked ‘b’ form an C 5-8 -heterocycloalkyl ring optionally substituted with one or more substituents Y, wherein Y is chosen from (C 1-3 )alkyl, tri-fluoromethyl, fluoro, chloro, bromo, hydroxyl, (C 1-3 )alkyloxy, trifluoromethoxy, and amino;
R 4 and R 5 independently are chosen from hydrogen, an unsubstituted alkyl(C 1-4 ) group, an alkyl-(C 1-4 ) group substituted with one or more halogen atoms, a monocyclic or a fused-bicyclic aromatic or hetero-aromatic group, optionally substituted with one or more substituents Y, as defined above, or,
R 3 and R 4 , together with the carbon atoms marked ‘b’ and ‘c’ form a C 3-8 -cycloalkyl ring, or,
R 3 and R 4 , together with the carbon atoms marked ‘b’ and ‘c’ form a C 5-8 -heterocycloalkyl ring, optionally substituted with one or more substituents Y, as defined above; and
R 8 is a monocyclic or a fused-bicyclic aromatic or hetero-aromatic group, optionally substituted with one or more substituents Y, as defined above, or,
R 8 is a —CR 9 ═CR 10 -aryl group wherein R 9 and R 10 independently are chosen from hydrogen and an alkyl-(C 1-3 ) group, and wherein aryl is chosen from a monocyclic, a fused bicyclic aromatic, and a hetero-aromatic group, or,
R 8 is chosen from a —C≡C-aryl group, wherein aryl is chosen from a monocyclic, a fused bicyclic aromatic, and a hetero-aromatic group, a piperidinyl group optionally substituted with one or more substituents Y, as defined above, and a —NR 11 R 12 group, wherein R 11 and R 12 independently are chosen from hydrogen, an unsubstituted alkyl-(C 1-3 ) group, and a phenyl or benzyl group, wherein the phenyl or benzyl group is optionally substituted with one or more substituents Y, as defined above.
2. A compound of formula (1 Z ):
or a stereoisomer, N-oxide thereof, or pharmacologically acceptable salt of any of the foregoing, wherein:
R 1 is chosen from hydrogen, an unsubstituted alkyl(C 1-4 ) group, and an alkyl(C 1-4 ) group substituted with one or more halogen atoms;
R 2 and R 3 independently are chosen from hydrogen, an unsubstituted alkyl(C 1-4 ) group, an alkyl-(C 1-4 ) group substituted with one or more halogen atoms, and a phenyl-alkoxy(C 1-4 )-alkyl(C 1-4 ) group optionally substituted with one or more halogen atoms, or,
R 1 and R 2 , together with the carbon atoms marked ‘a’ and ‘b’ form a C 5-8 -cycloalkyl ring, or
R 2 and R 3 , together with the carbon atom marked ‘b’ form a C 3-8 -cycloalkyl ring, or,
R 2 and R 3 , together with the carbon atom marked ‘b’ form an C 5-8 -heterocycloalkyl ring optionally substituted with one or more substituents Y, wherein Y is chosen from (C 1-3 )alkyl, tri-fluoromethyl, fluoro, chloro, bromo, hydroxyl, (C 1-3 )alkyloxy, trifluoromethoxy, and amino;
R 4 and R 5 independently are chosen from hydrogen, an unsubstituted alkyl(C 1-4 ) group, an alkyl-(C 1-4 ) group substituted with one or more halogen atoms, a monocyclic or a fused-bicyclic aromatic or hetero-aromatic group, optionally substituted with one or more substituents Y, as defined above, or,
R 3 and R 4 , together with the carbon atoms marked ‘b’ and ‘c’ form a C 3-8 -cycloalkyl ring, or,
R 3 and R 4 , together with the carbon atoms marked ‘b’ and ‘c’ form a C 5-8 -heterocycloalkyl ring, optionally substituted with one or more substituents Y, as defined above; and
R 6 and R 7 independently are chosen from a hydrogen atom, an alkyl(C 1-4 ) group, an alkyl(C 1-4 ) group substituted with one or more halogen atoms, a (C 1-3 )alkoxy group, a dialkyl(C 1-3 )-amino-alkyl(C 1-3 ) group, a monocyclic or fused bicyclic aromatic or hetero-aromatic group, optionally substituted with one or more substitutents Y, as defined above, a C 5-8 -cycloalkyl or a C 5-8 -heterocycloalkyl group, optionally substituted with one or more substituents Y, as defined above, and a benzyl group, or
R 6 and R 7 , together with the nitrogen atom to which they are attached, form a C 5-8 -hetero-cycloalkyl group, optionally substituted with one or more substituents Y, as defined above,
with the proviso that when R 2 , R 3 , R 6 , and R 7 are hydrogen, and R 4 or R 5 is phenyl optionally substituted with one or more substituents Y, as defined above, R 1 is not methyl, and with the proviso that R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , are not simultaneously all hydrogen atoms.
3. A process for preparing a compound of formula (1′), comprising:
(i) reacting a compound of formula (X), obtained by reacting a compound of formula (IX) with an alkyl halide, with a pyrazoline of formula
in the presence of a base, to yield a compound of formula (1 Z ), and
(ii) reacting a compound of formula (1 Z ) with a sulfonyl halide of formula R 8 —SO 2 —X, wherein X is Br, CI or F, in an aprotic solvent, in the presence of a base,
wherein:
R 1 is chosen from hydrogen, an unsubstituted alkyl(C 1-4 ) group, and an alkyl(C 1-4 ) group substituted with one or more halogen atoms;
R 2 and R 3 independently are chosen from hydrogen, an unsubstituted alkyl(C 1-4 ) group, an alkyl-(C 1-4 ) group substituted with one or more halogen atoms, and a phenyl-alkoxy(C 1-4 -alkyl(C 1-4 ) group optionally substituted with one or more halogen atoms, or,
R 1 and R 2 , together with the carbon atoms marked ‘a’ and ‘b’ form a C 5-8 -cycloalkyl ring, or
R 2 and R 3 , together with the carbon atom marked ‘b’ form a C 3-8 -cycloalkyl ring, or,
R 2 and R 3 , together with the carbon atom marked ‘b’ form an C 5-8 -heterocycloalkyl ring optionally substituted with one or more substituents Y, wherein Y is chosen from (C 1-3 )alkyl, tri-fluoromethyl, fluoro, chloro, bromo, hydroxyl, (C 1-3 )alkyloxy, trifluoromethoxy, and amino;
R 4 and R 5 independently are chosen from hydrogen, an unsubstituted alkyl(C 1-4 ) group, an alkyl-(C 1-4 ) group substituted with one or more halogen atoms, a monocyclic or a fused-bicyclic aromatic or hetero-aromatic group, optionally substituted with one or more substituents Y, as defined above, or,
R 3 and R 4 , together with the carbon atoms marked ‘b’ and ‘c’ form a C 3-8 -cycloalkyl ring, or,
R 3 and R 4 , together with the carbon atoms marked ‘b’ and ‘c’ form a C 5-8 -heterocycloalkyl ring, optionally substituted with one or more substituents Y, as defined above;
R 6 independently is chosen from a hydrogen atom, an alkyl(C 1-4 ) group, an alkyl(C 1-4 ) group substituted with one or more halogen atoms, a (C 1-3 )alkoxy group, a dialkyl(C 1-3 )-amino-alkyl(C 1-3 ) group, a monocyclic or fused bicyclic aromatic or hetero-aromatic group, optionally substituted with one or more substitutents Y, as defined above, a C 5-8 -cycloalkyl or a C 5-8 -heterocycloalkyl group, optionally substituted with one or more substituents Y, as defined above, and a benzyl group; and
R 8 is a monocyclic or a fused-bicyclic aromatic or hetero-aromatic group, optionally substituted with one or more substituents Y, as defined above, or,
R 8 is a —CR 9 ═CR 10 -aryl group wherein R 9 and R 10 independently are chosen from hydrogen and an alkyl-(C 1-3 ) group, and wherein aryl is chosen from a monocyclic, a fused bicyclic aromatic, and a hetero-aromatic group, or,
R 8 is chosen from a —C≡C-aryl group, wherein aryl is chosen from a monocyclic, a fused bicyclic aromatic, and a hetero-aromatic group, a piperidinyl group optionally substituted with one or more substituents Y, as defined above, and a —NR 11 R 12 group, wherein R 11 and R 12 independently are chosen from hydrogen, an unsubstituted alkyl-(C 1-3 ) group, and a phenyl or benzyl group, wherein the phenyl or benzyl group is optionally substituted with one or more substituents Y, as defined above.