Benzamide derivatives as vasopressin antagonists

A process for preparing a compound of the formula (I):

• wherein
• R1 is aryl or haloaryl, each of which is substituted with lower alkoxy substituted with N-(lower alkyl)-piperazinylcarbonyl, esterified carboxy or carboxy;
• or pyridyl, or thienyl, each of which are optionally substituted with esterified carboxy;
• R2 is lower alkyl optionally substituted with hydroxy, aryl or acyl;
• or cyclo(lower)alkyl;
• R3 is hydrogen, halogen, lower alkyl, lower alkoxy, nitro or amino;
• R4 is lower alkyl;
• or optionally substituted aryl;
• X is CH;
• and
• Y is CH;
• or a pharmaceutically acceptable salt thereof, which comprises,
• 1) reacting a compound of the formula (II):
• or a salt thereof with a compound of the formula (III):
• or a reactive compound thereof at the carboxy group or a salt thereof to provide a compound of the formula (I):
• or a salt thereof, or
• 2) reacting a compound of the formula (IV):
• or a salt thereof with a compound of the formula (IV):
• or a reactive compound thereof at the carboxy group or a salt thereof to provide a compound of the formula (I):
• or a salt thereof, or
• 3) subjecting a compound of the formula (Ia):
• or a salt thereof to a deesterification reaction to provide a compound of the formula (Ib):
• or a salt thereof, and wherein in the above formulas,
• Ra1 and Rb1 are each independently as defined above for R1;
• and further
• wherein Ra1 contains ester groups, and Rb1 has said ester groups removed by said deesterification reaction;
• or
• 4) subjecting a compound of the formula (Ic):
• or salt thereof to deacylation reaction to provide a compound of the formula (Id):
• or a salt, thereof, and wherein in the above formulas,
• Rc1 and Rd1 are each independently as defined above for R1,
• wherein Rc1 contains an ester group, and Rd1 has said ester group removed by said deacylation reaction;
• 5) subjecting a compound of the formula (Ie):
• or a salt thereof to an elimination reaction of the N-protective group to provide a compound of the formula (If):
• or a salt thereof, and wherein in the above formulas,
• Re1 and Rf1 are each independently as defined above for R1, and further wherein
• Re1 contains a protected amino group, and Rf1 has said protecting group removed by said elimination reaction;
• 6) reacting a compound of the formula (Ib):
• or a reactive compound thereof at the carboxy group or a salt thereof with an amine or its salt to provide a compound of the formula (Ig):
• or a salt thereof, and wherein in the above formulas,
• Rb1 and Rg1 are each independently as defined for R1, further wherein
• Rb1 contains a carboxy group, and Rg1 contains a carbamoyl group corresponding to said carboxy group of Rb1;
• or
• 7) reacting a compound of the formula (Ih):
• or a reactive compound thereof at the carboxy group or a salt thereof with an azide compound and then reacting the resultant product with an acid to provide a compound of the formula (Ii):
• or a salt thereof, and wherein in the above formulas,
• Rh1 and Ri1 are each independently as defined above for R1, further wherein
• Rh1 contains a carboxy group, and and Ri1 contains an amino group corresponding to said carboxy group of Rh1;
• or
• 8) subjecting a compound of the formula (Ij):
• or a salt thereof to reduction to provide a compound of the formula:
• or a salt thereof, and wherein in the above formulas,
• Rj1 and Rk1 are each independently as defined above for R1, and further wherein
• Rj1 contains unsaturated aliphatic groups, and Rk1 contains saturated aliphatic groups corresponding thereto;
• or
• 9) reacting a compound of the formula (Il):
• or a salt thereof with a reducing agent to provide a compound of the formula (Im):
• or a salt thereof, and wherein in the above formulas,
• Rl1 and Rm1 are each independently as defined above for R1, and further wherein
• Rl1 contains esterified carboxy, and Rm1 contains hydroxymethyl corresponding thereto;
• or
• 10) reacting a compound of the formula:
• or a salt thereof with an acylating agent to provide a compound of the formula (Ic):
• or a salt thereof, and wherein in the above formulas,
• Rc1 and Rd1 are each independently as defined above;
• or
• 11) subjecting a compound of the formula:
• or a salt thereof to oxidation reaction to provide a compound of the formula (In):
• or a salt thereof, and wherein in the above formulas,
• Rm1 and Rn1 are each independently as defined above for R1, wherein
• Rm1 is as define above, and Rn1 is substituted with alkanoyl or formyl groups;
• or
• 12) reacting a compound of the formula (In):
• or a salt thereof with mono or di(lower)alkylamine, N-acyl(lower)alkyl-N-lower alkylamine, or a salt thereof in the presence of a reducing agent to provide a compound of the formula (Io):
• or a salt thereof, in the above formulas,
• Rn1 and Ro1 are each independently as defined above for R1, and further wherein
• Ro1 further contains substituent groups comprising (lower alkyl)amino (lower)alkyl, N-acyl (lower)alkylamino;
• or
• 13) reacting a compound of the formula (Ip):
• or a salt thereof with lower alkanal to provide a compound of the formula (Iq):
• or a salt thereof, and wherein in the above formulas,
• Rp1 and Rq1 are each independently as defined above for R1, and further wherein
• Rp1 contains an amino group, and Rq1 contains a corresponding alkylated amino group;
• or
• 14) subjecting a compound of the formula:
• or a salt thereof to catalytic reduction to provide a compound of the formula (Is):
• or a salt thereof, in the above formulas,
• Rr1 and Rs1 are each independently as defined above for R1, and further wherein
• Rr1 contains a methoxy group, and Rs1 contains a corresponding hydroxy group;
• 15) reacting a compound of the formula (Is):
• or a salt thereof with a compound of the formula (VI):
• Z1−R5 (VI)
• or a salt thereof to provide a compound of the formula (It):
• or a salt thereof, and wherein in the above formulas,
• Rs1 is as defined above;
• Z1 is an acid residue;
• and
• Rt1 is as defined for Rs1, except that hydroxy groups of Rt1 are converted to alkoxy groups, which are optionally substituted;
• or
• 16) reacting a compound of the formula:
• or a salt thereof with a compound of the formula:
• Z2−R6 (VIII)
• to provide a compound of the formula (Iw):
• or a salt thereof, and wherein in the above formulas,
• R6 is lower alkyl substituted with acyl;
• Z2 is an acid residue;
• and
• Ru1 contains alkoxy substituted with acyl, and
• Rv1 contains alkoxy substituted with acyl(lower)alkyloxyimino;
• or
• 17) reacting a compound of the formula:
• or a salt thereof with an amine or potassium phthalimide to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• Rw1 and Rx1 are as defined above for R1, wherein Rw1 contains alkoxy substituted with halogen, and Rx1 contains alkoxy substituted with amino, lower alkylamino or, phthalimido at a corresponding position.
• 18) reacting a compound of the formula:
• or a salt thereof with an acylating agent to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• Ry1 and Rz1 are as defined above for R1, wherein Ry1 contains an amino group, and Rz1 contains an acylated amino at a corresponding position;
• or
• 19) reacting a compound of the formula:
• or a salt thereof with or lower alkylhydrazine to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• Raa1 and Rab1 are as defined above for R1, and further wherein Raa1 contains an aryloxycarbonylamino substituent, and Rab1 contains an alkylhydrazinocarbonylamino substituent in a corresponding position;
• or
• 20) reacting a compound of the formula:
• or a salt thereof with heterocyclic compound substituted with hydroxy to provide a compound of the formula:
• or a salt thereof, and wherein in the above formulas,
• Raa1 is as defined above, and Rac1 contains a lower alkyl substituent substituted with heterocyclicoxycarbonylamino, or alkoxy substitued with heterocyclicoxycarbonylamino;
• or
• 21) reacting a compound of the formula:
• or a salt thereof with an N-containing heterocyclic compound or lower alkylamino(lower)alkylamine to provide a compound of the formula:
• or a salt thereof, and wherein in the above formulas,
• Rad1 and Rae1 are as defined above for R1, and further wherein Rad1 contains an aryloxycarbonyloxy substituent, and Rae1 contains heterocyclic carbonyloxy at a corresponding position;
• 22) subjecting a compound of the formula:
• or a salt thereof to reduction to provide a compound of the formula:
• or a salt thereof, and wherein in the above formulas,
• Ra4 is aryl substituted with nitro;
• and
• Rb4 is aryl substituted with amino;
• or
• 23) subjecting a compound of the formula:
• or a salt thereof to reduction to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• Ra3 is nitro;
• and
• Rb3 is amino;
• or
• 24) reacting a compound of the formula:
• or a salt thereof with a compound of the formula:
• B—CH2—R7 (VIII)
• or a reactive compound thereof to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• Rf1 is lower alkyl, aryl, haloaryl, cyclo(lower)alkyl or a heterocyclic group, each of which is substituted with fornyl;
• lower alkyl substituted with formyl;
• or lower alkoxy substituted with formyl;
• B is carboxy, esterified carboxy, di-esterified phosphono or triphenylphosphonium salt;
• R7 is lower alkyl optionally substituted with acyl;
• and
• Rg1 is lower alkyl, aryl, haloaryl, cyclo(lower)alkyl or a heterocyclic group, each of which is substituted with lower alkenyl optionally substituted with acyl;
• lower alkenyloxy optionally substituted with acyl;
• or
• 25) reacting a compound of the formula:
• or a salt thereof with a reducing agent to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• Ra2 is lower alkyl substituted with carboxy or esterified carboxy;
• and
• Rb2 is lower alkyl substituted with hydroxy;
• or
• 26) reacting a compound of the formula:
• or a salt thereof with a reducing agent to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas;
• Ra1 and Rb1 are as defined above for R1, and further wherein Ra1 contains a lower alkyl or alkoxy group substituted with esterified carboxy;
• and Rb1 contains a corresponding lower alkyl or alkoxy group substituted with formyl;
• 27) reacting a compound of the formula:
• or a salt thereof with hydroxylamine or its salt to provide a compound of the formula:
• or a salt thereof, in the above formulas,
• Raj1 and Rak1 are as defined above for R1, and further wherein Raj1 contains an alkoxy group substituted with formyl, and Rak1 contains a corresponding alkoxy group substituted with hydroxyimino;
• 28) reacting a compound of the formula:
• or a salt thereof with lower alkanal to provide a compound of the formula:
• or a salt thereof, in the above formulas,
• Rc4 is aryl substituted with lower alkylamino;
• or
• 29) reacting a compound of the formula:
• or a salt thereof with an azide compound to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• Ral1 and Ram1 are as defined above for R1, and further wherein Ral1 contains a cyano substituent, and Ram1 contains a tetrazolyl substituent at a corresponding position;
• or
• 30) subjecting a compound of the formula:
• or a salt thereof with an oxidizing agent to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• Ran1 and Rao1 are as defined above for R1, and further wherein Ran1 contains a lower alkythio substituted with acyl, and Rao1 contains a lower alkylsulfinyl or lowr alkylsulfonyl substituted with acyl at a corresponding position;
• or,
• 31) subjecting a compound of the formula:
• or a salt thereof to introduction reaction of N-protective group to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• Rap1 and Raq1 are as defined above for R1, and further wherein Rap1 contains alkoxy substituted with acyl(lower) alkylamino, and Raq1 contains alkoxy substituted with N-protected-acyl(lower) alkylamino at a corresponding position;
• or
• 32) reacting a compound of the formula:
• or a salt thereof with a halogenating agent to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• Rar1 and Ras1 are as defined above for R1, and further wherein Rar1 contains alkyl or alkoxy substituted with hydroxy, and Ras1 contains lower alkyl or alkoxy substituted with halogen, or
• 33) reacting a compound of the formula:
• or a salt thereof with an acylating agent to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• Rat1 and Rau1 are as defined above for R1, and further wherein Rat1 contains alkoxy substituted with piperazinylcarbonyl, and Rau1 contains alkoxy substituted with acylpiperazinylcarbonyl;
• or
• 34) subjecting a compound of the formula:
• or a salt thereof to deesterification reaction to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• R2 is lower alkyl substituted with esterified carboxy;
• and
• R2 is lower alkyl substituted with carboxy;
• or
• 35) reacting a compound of the formula:
• or its reactive compound thereof at the carboxy group or a salt thereof with an amine or a salt thereof to provide a compound of the formula:
• or a salt thereof, wherein in the above formulas,
• Rd2 is lower alkyl substituted with carboxy;
• Re2 is lower alkyl substituted with substituted or unsubstituted N-containing heterocycliccarbonyl;
• carbamoyl;
• or substituted or unsubstituted lower alkylcarbamoyl.