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US 5,965,579 AGranted
Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them
AssigneeSanofi
InventorsBernard Labeeuw, Danielle Gully, Francis Jeanjean, Jean-Charles Molimard, Robert Boigegrain
Life of this patent
Estimating the term…
Abstract
The invention relates to compounds of the formula: ##STR1## Compounds of the above formula have a great affinity for the neurotensin receptors.
Claims16
Compound of formula:
- ##STR123## in which:
- R.sub.1 represents a group chosen from:
- --T--CN;
- --C(NH.sub.2).dbd.NOH;
- --C(.dbd.NOH)NH(CH.sub.2).sub.r NR.sub.5 R.sub.6 ;
- --T--C(NR.sub.12 R.sub.13).dbd.NR.sub.14 ;
- --C(NH.sub.2).dbd.NO(CH.sub.2).sub.r NR.sub.5 R.sub.6 ;
- --T--CONR.sub.a R.sub.b ;
- --T--CONR.sub.7 R.sub.c ;
- --Y--CO.sub.2 R.sub.7 ;
- --OR.sub.d ;
- --T--NR.sub.5 R.sub.6, on condition that R.sub.5 and R.sub.6 do not simultaneously represent hydrogen when T represents a direct bond;
- --T--N(R.sub.7 )COR.sub.e ;
- --SO.sub.2 NR.sub.a R.sub.b ;
- --T--N(R.sub.7)SO.sub.2 R'.sub.7 ;
- --T--NR.sub.27 R.sub.28 ;
- --NR.sub.a R.sub.b represents a group chosen from:
- ##STR124## --NR.sub.7 (CH.sub.2).sub.q CN;
- --NR.sub.7 (CH.sub.2).sub.q C(NR.sub.12 R.sub.13).dbd.NR.sub.14 ;
- --NR.sub.7 (CH).sub.q CONH.sub.2 ;
- --NR.sub.7 (CH.sub.2).sub.q CO.sub.2 R.sub.7 ;
- NR.sub.21 (CH.sub.2).sub.s CR.sub.7 R.sub.8 (CH.sub.2).sub.t NR.sub.25 R.sub.26 ;
- R.sub.c represents a group chosen from:
- --X--OR.sub.7 ;
- --CHR.sub.20 --CO.sub.2 R.sub.7 ;
- --(CH.sub.2).sub.4 CH(NH.sub.2)CO.sub.2 R.sub.7 ;
- R.sub.d represents a group chosen from:
- --X--NR.sub.5 R.sub.6 ;
- --Y--CONR.sub.5 R.sub.6 ;
- --Y--CO.sub.2 R.sub.7 ;
- --Y--SO.sub.2 NR.sub.5 R.sub.6 ;
- ##STR125## R.sub.e represents a group chosen from:
- R.sub.16 ;
- --Y--NR.sub.5 R.sub.6 ;
- --Y--NHCOR.sub.16 ;
- --CH(R.sub.17)NR.sub.5 R.sub.6 ;
- ##STR126## --(CH.sub.2).sub.q CN;
- --(CH.sub.2).sub.q C(NR.sub.12 R.sub.13).dbd.NR.sub.14 ;
- --NR.sub.18 R.sub.19 ;
- R.sub.2 and R.sub.3 each independently represent hydrogen, a (C.sub.1 -C.sub.6)alkyl, a (C.sub.3 -C.sub.8)cycloalkylmethyl, a (C.sub.3 -C.sub.8)-cycloalkyl, a halogen, a nitro, a trifluoromethyl, a group --OR.sub.4, a group --NR.sub.5 R.sub.6, a 1-purrolyl, a cyano, a carbamoyl;
- or R.sub.2 and R.sub.3 together constitute a trimethylene, tetramethylene or pentamethylene group;
- R.sub.4 represents hydrogen;
- a (C.sub.1 -C.sub.6)alkyl;
- a (C.sub.3 -C.sub.4)-alkenyl;
- a (C.sub.3 -C.sub.8)cycloalkyl;
- a (C.sub.3 -C.sub.8)cycloalkylmethyl;
- a (C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkylene;
- a benzyl;
- R.sub.5 and R.sub.6 each independently represent a hydrogen, a (C.sub.1 -C.sub.6)alkyl;
- a (C.sub.3 -C.sub.8)alkenyl;
- a (C.sub.3 -C.sub.8)cycloalkylmethyl;
- a benzyl;
- or R.sub.5 and R.sub.6, together with the nitrogen atom to which they are attached, represent a piperidine;
- R'.sub.5 and R'.sub.6 each independently represent a hydrogen or a (C.sub.1 -C.sub.6)alkyl;
- or alternatively, R'.sub.5 and R'.sub.6, together with the nitrogen atom to which they are attached, represent a piperidine;
- R'.sub.7 represents a (C.sub.1 -C.sub.4)alkyl;
- a phenyl which is unsubstituted or substituted one or more times with a (C.sub.1 -C.sub.4)alkyl;
- a group --X--NR.sub.5 R.sub.6 ;
- R.sub.7 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl or a benzyl;
- R.sub.8 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a hydroxyl, or R.sub.7 and R.sub.8, together with the carbon atom to which they are attached, constitute a (C.sub.3 -C.sub.5)cycloalkane;
- R.sub.9 represents hydrogen, a (C.sub.1 -C.sub.4)alkyl, a benzyl, a group --X--OH or a group --X--NR'.sub.5 R'.sub.6, a (C.sub.3 -C.sub.8)alkenyl;
- R.sub.10 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a benzyl, a carbamoyl, a cyano;
- R.sub.11 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a group --X--OH, a group --X--NR'.sub.5 R'.sub.6 ;
- R.sub.12 and R.sub.13 each independently represent a hydrogen or a (C.sub.1 -C.sub.4)alkyl;
- R.sub.14 represents hydrogen, R.sub.14 can, in addition, represent a (C.sub.1 -C.sub.4)alkyl when R.sub.12 represents hydrogen and R.sub.13 represents a (C.sub.1 -C.sub.4)alkyl;
- or R.sub.13 and R.sub.14 together represent a group Z;
- R.sub.15 represents hydrogen, a (C.sub.1 -C.sub.4)alkyl, a group --(CH.sub.2).sub.s NR.sub.5 R.sub.6 ;
- R.sub.16 represents hydrogen, a (C.sub.1 -C.sub.8)alkyl, a (C.sub.3 -C.sub.8)-cycloalkyl, a phenyl, a 2-piperidyl, a 3-piperidyl, a 4-piperidyl;
- R.sub.17 represents a (C.sub.1 -C.sub.6)alkyl, a phenyl, a benzyl, a hydroxy(C.sub.1 -C.sub.4)alkyl, an amino(C.sub.1 -C.sub.4)alkyl;
- R.sub.18 and R.sub.19 each independently represent a hydrogen, a (C.sub.1 -C.sub.4)alkyl;
- R.sub.18 may, in addition, represent a group --(CH.sub.2).sub.q --NR.sub.5 R.sub.6 ;
- or R.sub.18 and R.sub.19, together with the nitrogen atom to which they are attached, represent a piperidine;
- R.sub.20 represents hydrogen, a (C.sub.1 -C.sub.4)alkyl, a benzyl, a hydroxyphenylmethyl, a hydroxy(C.sub.1 -C.sub.4)alkyl, a mercapto(C.sub.1 -C.sub.4)alkyl;
- a --(CH.sub.2).sub.3 --NH--C(.dbd.NH)NH.sub.2 group, a --(CH.sub.2).sub.4 NH.sub.2 group;
- R.sub.21 represents a (C.sub.1 -C.sub.4)alkyl, an allyl or a benzyl;
- R.sub.22 and R.sub.23 each independently represent a (C.sub.1 -C.sub.6)-alkyl;
- or alternatively R.sub.22 and R.sub.23, together with the nitrogen atom to which they are attached, represent a piperidine;
- R.sub.24 represents a (C.sub.1 -C.sub.4)alkyl, a benzyl, an allyl, a hydroxy(C.sub.1 -C.sub.4)alkyl, a (C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkyl;
- o.crclbar. represents an anion;
- R.sub.25 represents hydrogen or a (C.sub.1 -C.sub.6)alkyl;
- R.sub.26 represents a (C.sub.1 -C.sub.4)alkoxycarbonyl, a benzyloxycarbonyl;
- a (C.sub.1 -C.sub.4)alkylcarbonyl;
- R.sub.27 represents a hydrogen;
- a (C.sub.1 -C.sub.4)alkyl, a (C.sub.1 -C.sub.4)-alkylcarbonyl;
- a group --CO--(CH.sub.2).sub.r --OH;
- a group SO.sub.2 R'.sub.7 ;
- R.sub.28 represents a group --X--NR.sub.5 R.sub.6 ;
- s=0 to 3;
- t=0 to 3, on the condition that (s+t), in a same group, is greater than or equal to 1;
- r=2 to 5;
- q=1 to 5;
- T represents a direct bond or (C.sub.1 -C.sub.7)alkylene;
- X represents a (C.sub.2 -C.sub.7)alkylene;
- Y represents a (C.sub.1 -C.sub.7)alkylene;
- Z represents a (C.sub.2 -C.sub.6)alkylene;
- the bivalent radicals A and E, together with the carbon atom and the nitrogen atom to which they are attached, constitute a saturated 6-membered heterocycle which can, in addition, be substituted with one or more (C.sub.1 -C.sub.4)alkyls;
- the group --NH--AA(OH) represents the residue of an amino acid:
- ##STR127## where x.sub.a is hydrogen and x'.sub.a is hydrogen, a (C.sub.1 -C.sub.5)-alkyl or a non-aromatic C.sub.3 -C.sub.15 carbocyclic radical;
- or alternatively, x.sub.a and x'.sub.a, together with the carbon atom to which they are attached, form a non-aromatic C.sub.3 -C.sub.15 carbocycle;
- its salts and its quaternary ammonium salts formed with acyclic or cyclic tertiary amines and its solvates;
- with the proviso that at least one of the substituents R.sub.1, R.sub.2, or R.sub.3 comprises a pyridine or piperidine group.
98 more elements
Compound of formula:
- ##STR143## in which:
- R.sub.1x is at position 4 or 5 and represents a group chosen from --T--CONR.sub.a R.sub.b, --SO.sub.2 NR.sub.a .sub.b, --T--NR.sub.5 R.sub.6, --N(R.sub.7)COR.sub.e, --OR.sub.d, --N(R.sub.7)SO.sub.2 R'.sub.7, --TNR.sub.27 R.sub.28, wherein --T-- represents a direct bond or (C.sub.1 -C.sub.7) alkylene;
- N represent a group chosen from:
- ##STR144## --NR.sub.7 (CH.sub.2).sub.q CN;
- --NR.sub.7 (CH.sub.2).sub.q C(NR.sub.12 R.sub.13).dbd.NR.sub.44 ;
- --NR.sub.7 (CH.sub.2).sub.q CONH.sub.2 ;
- --NR.sub.7 (CH.sub.2).sub.q CO.sub.2 R.sub.7 ;
- --NR.sub.21 (CH.sub.2).sub.5 CR.sub.7 R.sub.8 (CH.sub.2).sub.t NR.sub.25 R.sub.26 ;
- R.sub.d represents a group chosen from:
- --X--NR.sub.5 R.sub.6 ;
- --Y--CONR.sub.5 R.sub.6 ;
- --Y--CO.sub.2 R.sub.7 ;
- --Y--SO.sub.2 NR.sub.5 R.sub.6 ;
- ##STR145## R.sub.e represents a group chosen from:
- --R.sub.16 ;
- --Y--NR.sub.5 R.sub.6 ;
- --Y--NHCOR.sub.16 ;
- --CH(R.sub.17)NR.sub.5 R.sub.6 ;
- ##STR146## --(CH.sub.2).sub.q CN;
- --(CH.sub.2).sub.q C(NR.sub.12 R.sub.13).dbd.NR.sub.14 ;
- --NR.sub.18 R.sub.19 ;
- R.sub.5 and R.sub.6 each independently represent a hydrogen, a (C.sub.1 -C.sub.6)alkyl;
- a (C.sub.3 -C.sub.8) alkenyl;
- a (C.sub.3 -C.sub.8) cycloalkyl-methyl;
- a benzyl;
- or R.sub.5 and R.sub.6, together with the nitrogen to which they are attached, represent a piperidine;
- R'.sub.5 and R'.sub.6 each independently represent a hydrogen, a (C.sub.1 -C.sub.6)alkyl, or together with the nitrogen to which they are attached, represent a piperidine;
- R.sub.7 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl or a benzyl;
- R'.sub.7 represents a (C.sub.1 -C.sub.4)alkyl;
- a phenyl which is unsubstituted or substituted one or more times with a (C.sub.1 -C.sub.4)alkyl or a group (C.sub.2 -C.sub.7)alkylene--NR,R.sub.6 ;
- R.sub.8 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a hydroxyl, or R.sub.7 and R.sub.8 together with the carbon to which they are attached, constitute a (C.sub.3 -C.sub.5)cycloalkane;
- R.sub.11 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a (C.sub.2 -C.sub.7)alkylene-OH, or a group (C.sub.2 -C.sub.7)alkylene--NR'.sub.5 R'.sub.6 ;
- R.sub.12 and R.sub.13 each independently represent a hydrogen or a (C.sub.1 -C.sub.4)alkyl;
- R.sub.16 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a (C.sub.3 -C.sub.8)cycloalkyl, a phenyl, a 2-piperidyl, a 3-piperidyl, or a 4-piperidyl;
- R.sub.17 represents a (C.sub.1 -C.sub.6)alkyl, a phenyl, a benzyl, a hydroxy (C.sub.1 -C.sub.4)alkyl, an amino (C.sub.1 -C.sub.4)alkyl;
- R.sub.18 and R.sub.19 each independently represent a hydrogen, a (C.sub.1 -C.sub.4)alkyl or, together with the nitrogen atom to which they are attached, represent a piperidine;
- R.sub.18 may represent a group --(CH.sub.2).sub.q --NR.sub.5 R.sub.6 ;
- R.sub.21 represents a (C.sub.1 -C.sub.4)alkyl, an allyl or a benzyl;
- R.sub.22 and R.sub.23 each independently represent (C.sub.1 -C.sub.6)alkyl or together with the nitrogen atom to which they are attached, represent piperidine;
- R.sub.24 represents a (C.sub.1 -C.sub.4)alkyl, a benzyl, an allyl, a hydroxy (C.sub.1 -C.sub.4)alkyl, or a (C.sub.1 -C.sub.4)alkoxy (C.sub.1 -C.sub.4)alkyl;
- R.sub.25 represents a hydrogen or a (C.sub.1 -C.sub.6)alkyl;
- R.sub.26 represents a (C.sub.1 -C.sub.4)alkoxycarbonyl, a benzyloxycarbonyl or a (C.sub.1 -C.sub.4)alkylcarbonyl;
- R.sub.27 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a (C.sub.1 -C.sub.4)-alkylcarbonyl, a group --CO(CH.sub.2).sub.2-5 --OH or a group SO.sub.2 R'.sub.7 ;
- R.sub.28 represents a group (C.sub.2 -C.sub.7)alkylene-NR.sub.5 R.sub.6 ;
- and q is 1-5;
- R.sub.2x and R.sub.3x each independently represent hydrogen, a (C.sub.1 -C.sub.6)alkyl, a (C.sub.2 -C.sub.8)cycloalkyl, or a (C.sub.3 -C.sub.8) cycloalkylmethyl, or R.sub.2x and R.sub.3x together constitute a tetramethylene group, on the condition that R.sub.2x and R.sub.3x do not simultaneously represent hydrogen;
- its salts and its quaternary ammonium salts formed with acyclic or cyclic tertiary amines and its solvates.
44 more elements
Dependencies are inferred from the claim text.