Patent Application
20090054440
The present invention relates to substituted quinoline-4-carboxylic acid hydrazides defined herein, pharmaceutical compositions comprising them and their use in treating diseases mediated by neurokinin-2 and/or neurokinin-3 (NK-3) receptors. These compounds can thus be used in methods of treatment to suppress and treat such disorders.
Background information on NK-3 receptor antagonists can be found in literature reviews such as Giardina and Raveglia, Exp. Opin. Ther. Patents (1997) 2(4): 307-323 and Giardina et al., Exp. Opin. Ther. Patents (2000) 10(6): 939-960. These references also contain pertinent information on preclinical validation of therapies that can be treated with NK-3 antagonists.
Published International application WO2005/000247 (SmithKline Beecham Corporation) discloses the compounds of formula (A):
where R1, R2, R3, R4, R5 and R6 are defined therein, as NK2 and NK3 receptor antagonists useful in the treatment of respiratory diseases.
Published International application WO2004/072045 (Merck Sharp & Dohme Ltd) discloses the compounds of formula (B):
where R1, R2, R3, R4, R5, X and Y are defined therein, as NK2 and NK3 receptor antagonists useful in the treatment of schizophrenia, COPD, asthma and irritable bowel syndrome.
The present invention thus provides a compound of Formula (I):
wherein:
R1 is an aryl or heteroaryl ring, wherein aryl is phenyl or naphthyl and heteroaryl is a 5-membered unsaturated ring containing 1, 2, 3 or 4 nitrogen atoms and/or, an oxygen or sulfur atom provided no more than two nitrogen atoms are present, or a 6-membered unsaturated ring containing 1, 2 or 3 nitrogen atoms, said ring being optionally substituted by one, two or three groups independently chosen from hydroxy, halogen, nitro, cyano, amino, CF3, C1-4alkyl, C2-4alkenyl and C2-4alkynyl;
or R1 is ORa, C(O)Ra, COORa, S(O)2Ra, NRaRb, CONRaRb, SO2NRaRb or a non-aromatic ring of 3 to 8 ring atoms where said ring optionally contains a double bond, and where said ring optionally contains 1, 2 or 3 heteroatoms selected from N, O or S or a group C(O), S(O), S(O)2, NH or NC1-4alkyl, and where said ring is also optionally fused to aryl, and where said ring is further optionally bridged by (CH2)1-4, and where said ring is also optionally substituted by 1, 2 or 3 groups independently chosen from hydroxy, halogen, NO2, CN, NH2, CF3, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, ORa and CO2Ra, where Ra and Rb are independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl and (CH2)0-3aryl, optionally substituted by hydroxy or halogen;
or, when R1 is CONRaRb or SO2NRaRb, Ra, Rb and the nitrogen atom to which they are attached form a piperidine, piperazine, pyrrolidine, morpholine, aziridine, azetidine or azepine ring, optionally substituted by 1, 2 or 3 groups independently chosen from hydroxy, C1-4alkyl or C1-4alkoxy;
R2 is hydrogen, hydroxy, halogen, CN or CO2H;
or R2 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C1-6alkoxy, C(O)OC1-6alkyl, Het, heteroaryl or aryl, optionally substituted by C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, (CH2)0-3aryl, (CH2)0-3heteroaryl, (CH2)0-3Het, OHet, C(O)C1-6alkyl, C(O)OC1-6alkyl, S(O)2C1-6alkyl, hydroxy or one to eight halogen atoms, where OHet is optionally substituted by C1-4alkyl;
or R2 is NRdRe,
where Rd and Re are independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, (CH2)0-3aryl, (CH2)0-3heteroaryl, (CH2)0-3Het, C(O)C1-6alkyl, C(O)OC1-6alkyl and S(O)2C1-6alkyl, optionally substituted by NRfRg halogen, C1-6alkyl, hydroxy, C1-6alkoxy, CN or CO2H, where Rf and Rg are independently selected from hydrogen and C1-6alkyl,
or Rd and Re, together with the nitrogen atom to which they are attached, form a nitrogen-containing 3- to 7-membered heterocycle optionally containing a further nitrogen, oxygen or sulfur atom or a S(O) or S(O)2 group;
which heterocycle is optionally substituted by 1, 2 or 3 groups independently chosen from C1-6alkyl, oxo, halogen and (CH2)0-6Rh, where Rh is hydroxy, C1-6alkoxy, C3-8cycloalkyl, bicyclo[3.3.1]non-9-yl, C(O)Ri, C(O)ORi, NRiRj, CONRiRj, Het, heteroaryl, aryl, SO2Het, SO2heteroaryl, SO2(CH2)0-3aryl or SO2C1-6alkyl, where C1-6alkyl and C3-8cycloalkyl, either as separate moieties or as part of a moiety, and heteroaryl, Het and aryl are optionally substituted by 1 to 8 halogen atoms, hydroxy, methoxy, oxo, C1-4alkyl, CF3 or CH2CF3, and C3-8cycloalkyl is optionally fused or spiro-fused to Het, heteroaryl or aryl, where Het and aryl, either as separate moieties or as part of a moiety, are optionally substituted by C1-6alkyl, hydroxy or halogen, and optionally fused to Het, heteroaryl, aryl or C3-8cycloalkyl, and where Ri and Rj are independently selected from hydrogen, C1-6alkyl, (CH2)0-3aryl, (CH2)0-3heteroaryl, (CH2)0-3Het and C(O)C1-6 alkyl;
which heterocycle is further optionally fused or spiro-fused to Het, heteroaryl, aryl or C3-8cycloalkyl, optionally substituted by C1-6alkyl, C3-8cycloalkyl, hydroxy, C1-6alkoxy, halogen, oxo, C(O)OC1-6alkyl, Het, CF3, CHF2 or CH2CF3;
which heterocycle is further optionally bridged by —(CH2)1-2—;
R3 is hydrogen, hydroxy, halogen, NO2, CN, NH2, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy or C(O)OC1-6alkyl, optionally substituted by 1 to 8 halogen atoms;
R4 is hydrogen, C1-6alkyl, C(O)C1-6alkyl, C(O)OC1-6alkyl, (CH2)0-3phenyl or heteroaryl, optionally substituted by 1 to 3 halogen atoms;
R5 is hydrogen, C1-6alkyl, hydroxy or C1-6alkoxy;
X and Y are independently chosen from hydrogen, hydroxy, nitro, cyano, CF3, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C1-6alkoxy, C(O)NRkRm, CO2Rk and (CH2)0-4NRnRp, SO2Rk, SO2NRkRm, optionally substituted by 1 to 8 halogen atoms;
Rk and Rm are independently chosen from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl and (CH2)0-4aryl;
Rn and Rp are independently chosen from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, aryl, C(O)Rq, COORq and S(O)2Rq;
Rq is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or (CH2)0-4aryl;
Z is a bond, O, S, SO, SO2, CO, NRcSO2 or SO2NRc, NRc, NRcCO or CONRc, where Rc is hydrogen or C1-6alkyl, optionally substituted by one to four halogen atoms;
or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, there is provided a compound of Formula (Io):
wherein:
R1 is an aryl or heteroaryl ring, wherein aryl is phenyl or naphthyl and heteroaryl is a 5-membered unsaturated ring containing 1, 2, 3 or 4 nitrogen atoms and/or, an oxygen or sulfur atom provided no more than two nitrogen atoms are present, or a 6-membered unsaturated ring containing 1, 2 or 3 nitrogen atoms, said ring being optionally substituted by one, two or three groups independently chosen from hydroxy, halogen, nitro, cyano, amino, CF3, C1-4alkyl, C2-4alkenyl and C2-4alkynyl;
or R1 is ORa, C(O)Ra, COORa, S(O)2Ra, NRaRb, CONRaRb, SO2NRaRb or a non-aromatic ring of 3 to 8 ring atoms where said ring optionally contains a double bond, and where said ring optionally contains 1, 2 or 3 heteroatoms selected from N, O or S or a group C(O), S(O), S(O)2, NH or NC1-4alkyl, and where said ring is also optionally fused to aryl, and where said ring is further optionally bridged by (CH2)1-4, and where said ring is also optionally substituted by 1, 2 or 3 groups independently chosen from hydroxy, halogen, NO2, CN, NH2, CF3, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, ORa and CO2Ra, where Ra and Rb are independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl and (CH2)0-3aryl, optionally substituted by hydroxy or halogen;
or, when R1 is CONRaRb or SO2NRaRb, Ra, Rb and the nitrogen atom to which they are attached form a piperidine, piperazine, pyrrolidine, morpholine, aziridine, azetidine or azepine ring, optionally substituted by 1, 2 or 3 groups independently chosen from hydroxy, C1-4alkyl or C1-4alkoxy;
R2 is hydrogen, hydroxy, halogen, CN or CO2H;
or R2 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C1-6alkoxy, C(O)OC1-6alkyl, Het, heteroaryl or aryl, optionally substituted by C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, (CH2)0-3aryl, (CH2)0-3heteroaryl, (CH2)0-3Het, C(O)C1-6alkyl, C(O)OC1-6alkyl, S(O)2C1-6alkyl or one to eight halogen atoms;
or R2 is NRdRe,
where Rd and Re are independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, (CH2)0-3aryl, (CH2)0-3heteroaryl, (CH2)0-3Het, C(O)C1-6alkyl, C(O)OC1-6alkyl and S(O)2C1-6alkyl, optionally substituted by NRfRg, halogen, C1-6alkyl, hydroxy, C1-6alkoxy, CN or CO2H, where Rf and Rg are independently selected from hydrogen and C1-6alkyl, or Rd and Re, together with the nitrogen atom to which they are attached, form a saturated nitrogen-containing 3- to 7-membered heterocycle optionally containing a further nitrogen, oxygen or sulfur atom or a S(O) or S(O)2 group;
which heterocycle is optionally substituted by 1, 2 or 3 groups independently chosen from C1-6alkyl, oxo, halogen and (CH2)0-6Rh, where Rh is hydroxy, C1-6alkoxy, C3-8cycloalkyl, C(O)Ri, C(O)ORi, NRiRj, CONRiRj, Het, heteroaryl, aryl, SO2Het, SO2heteroaryl, SO2(CH2)0-3aryl or SO2C1-6alkyl, where C1-6alkyl and C3-8cycloalkyl, either as separate moieties or as part of a moiety, are optionally substituted by 1 to 8 halogen atoms or C1-4alkyl, and C3-8cycloalkyl is optionally fused or spiro-fused to Het, heteroaryl or aryl, where Het and aryl, either as separate moieties or as part of a moiety, are optionally substituted by C1-6alkyl, hydroxy or halogen, and optionally fused to Het, heteroaryl, aryl or C3-8cycloalkyl, and where Ri and Rj are independently selected from hydrogen, C1-6alkyl, (CH2)0-3aryl, (CH2)0-3heteroaryl, (CH2)0-3Het and C(O)C1-6 alkyl;
which heterocycle is further optionally fused or spiro-fused to Het, heteroaryl, aryl or C3-8cycloalkyl, optionally substituted by C1-6alkyl, C3-8cycloalkyl, hydroxy, C1-6alkoxy, halogen, oxo, CF3, CHF2 or CH2CF3;
which heterocycle is further optionally bridged by —(CH2)1-2—;
R3 is hydrogen, hydroxy, halogen, NO2, CN, NH2, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy or C(O)OC1-6alkyl, optionally substituted by 1 to 8 halogen atoms;
R4 is hydrogen, C1-6alkyl, C(O)C1-6alkyl, C(O)OC1-6alkyl or (CH2)0-3phenyl;
R5 is hydrogen, C1-6alkyl, hydroxy or C1-6alkoxy;
X and Y are independently chosen from hydrogen, hydroxy, nitro, cyano, CF3, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C1-6alkoxy, C(O)NRkRm, CO2Rk and (CH2)0-4NRnRp, SO2Rk, SO2NRkRm, optionally substituted by 1 to 8 halogen atoms;
Rk and Rm are independently chosen from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl and (CH2)0-4aryl;
Rn and Rp are independently chosen from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, aryl, C(O)Rq, COORq and S(O)2Rq;
Rq is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or (CH2)0-4aryl;
Z is a bond, O, S, SO, SO2, CO, NRcSO2 or SO2NRc, NRc, NRcCO or CONRc, where Rc is hydrogen or C1-6alkyl, optionally substituted by one to four halogen atoms;
or a pharmaceutically acceptable salt thereof.
In one embodiment of the invention, R1 is aryl or heteroaryl, optionally substituted by 1, 2 or 3 groups independently chosen from hydroxy, halogen, nitro, cyano, amino, CF3, C1-4alkyl, C2-4alkenyl or C2-4alkynyl. Preferably, R1 is aryl, optionally substituted by hydroxy, halogen or CF3. More preferably, R1 is phenyl, optionally substituted by hydroxy, halogen or CF3. Most preferably, R1 is phenyl.
In another embodiment of the invention, R2 is CN, CO2H, C(O)OC1-6alkyl, Het, heteroaryl, aryl or NRdRe, where Het, heteroaryl and aryl are optionally substituted by C1-6alkyl C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, (CH2)0-3aryl, (CH2)0-3heteroaryl, (CH2)0-3Het, C(O)C1-6alkyl, C(O)OC1-6alkyl, S(O)2C1-6alkyl or one to eight halogen atoms, and where NRdRe is as hereinbefore defined.
Preferably, R2 is CN, CO2H, C(O)OCH3, piperidinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl or NRdRe, where piperidinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl are optionally substituted by C1-6alkyl, and where NRdRe is as hereinbefore defined.
More preferably, R2 is CN, CO2H, C(O)OCH3, phenyl, imidazolyl, triazolyl or NRdRe, where imidazolyl and triazolyl are optionally substituted by methyl or ethyl, and where NRdRe is as hereinbefore defined.
Most preferably, R2 is CN, CO2H, C(O)OCH3, phenyl, 1-methyl-1H-imidazol-2-yl, 1-methyl-1H-1,2,4,-triazol-3-yl, 1-methyl-1H-1,2,4-triazol-5-yl or NRdRe, where NRdRe is as hereinbefore defined.
When R2 is NRdRe, preferably Rd and Re are independently selected from C1-6alkyl, (CH2)0-3aryl, (CH2)0-3heteroaryl and (CH2)0-3Het, optionally substituted by N(C1-6alkyl)2, C1-6alkyl, hydroxy, CN or CO2H,
or Rd and Re, together with the nitrogen atom to which they are attached, form a saturated nitrogen-containing 5- or 6-membered heterocycle optionally containing a further nitrogen, oxygen or sulfur atom, which heterocycle is optionally substituted by C1-4alkyl, oxo, halogen or (CH2)0-6Rh,
where Rh is as hereinbefore defined,
which heterocycle is further optionally fused or spiro-fused to Het, heteroaryl or aryl, optionally substituted by hydroxy, halogen, oxo or CF3,
which heterocycle is further optionally bridged by —(CH2)1-2—.
More preferably, Rd and Re are independently selected from C1-4alkyl, (CH2)0-2aryl, (CH2)0-2heteroaryl and Het, optionally substituted by N(C1-4alkyl)2, C1-4alkyl, hydroxy, CN or CO2H, or Rd and Re, together with the nitrogen atom to which they are attached, form a saturated nitrogen-containing 5- or 6-membered heterocycle optionally containing a further nitrogen or sulfur atom, which heterocycle is optionally substituted by methyl, ethyl, propyl, oxo, chlorine, fluorine or (CH2)0-6Rh, where Rh is as hereinbefore defined, which heterocycle is further optionally fused or spiro-fused to pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, imidazolyl, triazolyl or phenyl, optionally substituted by halogen, oxo or CF3.
Most preferably, Rd and Re are independently selected from methyl, ethyl, propyl, butyl, (CH2)1-2phenyl, (CH2)thienyl, (CH2)1-2pyridyl and piperidine, optionally substituted by N(CH3)2, methyl, hydroxy, CN or CO2H,
or Rd and Re, together with the nitrogen atom to which they are attached, form a piperidinyl, piperazinyl, thiazolidinyl or thiomorpholinyl ring,
optionally substituted by methyl, ethyl, isopropyl, oxo, fluorine or (CH2)0-6Rh, where Rh is as hereinbefore defined, which heterocycle is further optionally fused or spiro-fused to pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, imidazolyl, triazolyl or phenyl, optionally substituted by oxo or CF3.
Especially, Rd is methyl, ethyl, propyl or butyl, and Re is methyl, ethyl, propyl, (CH2)phenyl, (CH2)2phenyl, (CH2)thienyl, (CH2)pyridyl, (CH2)2pyridyl and piperidinyl, optionally substituted by N(CH3)2, methyl, hydroxy, CN or CO2H,
or Rd and Re, together with the nitrogen atom to which they are attached, form a piperidin-1-yl, piperazin-1-yl, 1,3-thiazolidin-3-yl or thiomorpholin-4-yl ring,
optionally substituted by methyl, ethyl, isopropyl, oxo, fluorine or (CH2)0-6Rh, where Rh is as hereinbefore defined,
which heterocycle is further optionally fused to pyrrolidinyl, 4-trifluoromethylimidazolyl, 1,2,4-triazolyl, 3-trifluoromethyl-1,2,4-triazolyl or phenyl,
or further optionally spiro-fused to 2-oxotetrahydrofuranyl or 2-oxoimidazolidinyl.
More especially, Rd is methyl, ethyl, n-propyl or n-butyl and Re is (CH2)2OH, (CH2)CN, (CH2)2CN, (CH2)CH(OH)CH2OH, (CH2)phenyl, CH(CO2H)phenyl, CH2CH(OH)phenyl, (CH2)2N(CH3)2, (CH2)3N(CH3)2, (CH2)thienyl, (CH2)pyridyl, (CH2)2pyridyl or 1-methylpiperidin-4-yl,
or Rd and Re, together with the nitrogen atom to which they are attached, form a piperidin-1-yl, piperazin-1-yl, 1,3-thiazolidin-3-yl or thiomorpholin-4-yl, 3-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl), 2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, 3-(5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl), 3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, 2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, or 3,4-dihydroisoquinolin-2-(1H)-yl ring, where the piperidin-1-yl and piperazin-1-yl rings are optionally substituted by methyl, ethyl, isopropyl, oxo, fluorine or (CH2)0-6Rh, where Rh is as hereinbefore defined, which heterocycle is further optionally spiro-fused to 2-oxotetrahydrofuranyl or 2-oxoimidazolidinyl.
When Rd and Re, together with the nitrogen atom to which they are attached, form a heterocycle as hereinbefore defined, and that heterocycle is substituted by (CH2)0-6Rh, preferably Rh is hydroxy, C1-4alkoxy, C3-6cycloalkyl, C(O)Ri, C(O)ORi, NRiRj, CONRiRj, Het, heteroaryl, aryl, SO2Het, SO2heteroaryl, SO2(CH2)0-1aryl or SO2C1-4alkyl, where C1-4 alkyl, either as a separate moiety or as part of a moiety, is optionally substituted by 1 to 4 halogen atoms, where Het and aryl, either as separate moieties or as part of a moiety, are optionally substituted by C1-4alkyl, hydroxy or halogen, and optionally fused to Het, and where Ri and Rj are as hereinbefore defined.
In another embodiment of the invention, R3 is hydrogen, hydroxy, halogen, C1-4alkyl, C2-4alkenyl or C2-4alkynyl, optionally substituted by 1 to 8 halogen atoms. Preferably, R3 is hydrogen, halogen, C1-4alkyl, C2-4alkenyl or C2-4alkynyl. More preferably, R3 is hydrogen, halogen or C1-4 alkyl. Most preferably, R3 is hydrogen.
In another embodiment of the invention, R4 is C(O)C1-6alkyl, C(O)OC1-6alkyl, phenyl or benzyl. Preferably, R4 is C(O)CH2CH3, C(O)OCH3, C(O)OCH2CH3, phenyl or benzyl. More preferably, R4 is C(O)OCH3.
In another embodiment of the invention, R5 is hydrogen, C1-4alkyl or hydroxy. More preferably, R5 is hydrogen or hydroxy. Most preferably, R5 is hydrogen.
In another embodiment of the invention, X is hydrogen, hydroxy, nitro, cyano, CF3, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or C1-6alkoxy. Preferably, X is hydrogen, halogen, C1-6alkyl or C2-6alkenyl. More preferably, X is hydrogen or halogen. Most preferably, X is hydrogen.
In another embodiment of the invention, Y is hydrogen, hydroxy, nitro, cyano, CF3, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or C1-6alkoxy. Preferably, Y is hydrogen or halogen, C1-6alkyl or C2-6alkenyl. More preferably, Y is hydrogen or halogen. Most preferably, Y is hydrogen.
In another embodiment of the invention, Z is a bond, O or S. More preferably, Z is a bond or O.
In one embodiment of the present invention, there is provided the compound of formula (Ia):
or a pharmaceutically acceptable salt thereof,
wherein Rh is as defined in relation to formula (I),
or wherein (CH2)0-3Rh is C1-6alkyl.
Preferably, Rh is t-butyl, hydroxy, trifluoromethyl, C3-6cycloalkyl, C(O)Ri, C(O)ORi, CONRiRj, Het, heteroaryl, aryl, SO2heteroaryl, SO2(CH2)0-3aryl or SO2C1-4alkyl,
where C3-6cycloalkyl is optionally substituted by C1-4alkyl and optionally spiro-fused to Het,
where SO2C1-4alkyl is optionally substituted by 1 to 6 halogen atoms,
where Het and aryl, either as separate moieties or as part of a moiety, are optionally substituted by C1-4alkyl hydroxy or methoxy,
and where Ri and Rj are independently selected from C1-4alkyl, (CH2)0-1aryl, heteroaryl and Het, or (CH2)0-3Rh is methyl, ethyl or isopropyl.
Examples of suitable Rh groups are t-butyl, hydroxy, cyclopropyl, cyclopentyl, cyclohexyl, methylcyclohexyl, 1,4-dioxaspiro[4.5]dec-8-yl, pyridyl, pyrimidyl, tetrahydropyranyl, phenyl, hydroxyphenyl, C(O)CH3, C(O)CH2CH3, C(O)CH(CH3)2, C(O)C(CH3)3, C(O)phenyl, C(O)CH2phenyl, C(O)N(CH3)2, C(O)morpholinyl, C(O)furanyl, C(O)OCH3, C(O)OC(CH3)3, C(O)OCH2CH(CH3)2, C(O)CH2phenyl, SO2CH3, SO2CH2CH3, SO2CH2CH2CH3, SO2phenyl, SO2CH2phenyl, SO2CF3, SO2pyridyl, SO2thienyl, SO2(methylpyrazolyl), trifluoromethyl, dimethylcyclopentyl, methyltetrahydrofuranyl, methyltetrahydropyranyl, thiane, thianedioxide, methylthiazole, methylfurazan and methoxypyrimidine.
In another embodiment of the present invention, there is provided the compound of formula (Ib):
or a pharmaceutically acceptable salt thereof,
where Rd and Re are as defined in relation to formula (I).
Preferably, Rd and Re, together with the nitrogen atom to which they are attached, form a saturated nitrogen-containing 5- or 6-membered heterocycle optionally containing a further nitrogen, oxygen or sulfur atom, which heterocycle is optionally substituted by C1-4alkyl, oxo, halogen, or (CH2)0-6Rh where Rh is as defined in relation to formula (I), which heterocycle is optionally fused or spiro-fused to Het, heteroaryl or aryl, optionally substituted by hydroxy, oxo, halogen or CF3.
More preferably, Rd and Re, together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, substituted piperazinyl, thiazolidinyl or thiomorpholinyl heterocycle, which heterocycle is optionally substituted by methyl, oxo, fluorine or (CH2)0-6Rh, where Rh is hydroxy, methoxy, C(O)Ri, C(O)ORi, NRiRj, CONRiRj, Het, heteroaryl or aryl, where Ri and Rj are as defined in relation to formula (I), which heterocycle is optionally fused to Het, heteroaryl or aryl, optionally substituted by CF3, which heterocycle is further optionally spiro-fused to Het, optionally substituted by hydroxy or oxo.
Examples of suitable groups where Rd and Re, together with the nitrogen atom to which they are attached, form a heterocycle as hereinbefore described are thiazolidin-3-yl, thiomorpholin-4-yl, 3-hydroxypyrrolidin-1-yl, 2-(hydroxymethyl)pyrrolidin-1-yl, 2-(methoxymethyl)pyrrolidin-1-yl, 2-carboxypyrrolidin-1-yl, 2-(aminocarbonyl)pyrrolidin-1-yl, 2-[(dimethylamino)carbonyl]pyrrolidin-1-yl, 2-pyridin-3-ylpyrrolidin-1-yl, 3-[acetyl(methyl)amino]pyrrolidin-1-yl, 4,4-difluoropiperidin-1-yl, 3-hydroxypiperidin-1-yl, 4-hydroxypiperidin-1-yl, 2-(hydroxymethyl)piperidin-1-yl, 3-carboxypiperidin-1-yl, 4-carboxypiperidin-1-yl, 3-(aminocarbonyl)piperidin-1-yl, 4-(aminocarbonyl)piperidin-1-yl, 4-(ethoxycarbonyl)piperidin-1-yl, 4-pyrrolidin-1-ylpiperidin-1-yl, 1,4′-bipiperidin-1′-yl, 3-(piperidin-1-ylmethyl)piperidin-1-yl, 3-(3-ethyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl, 3-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl, 4-(2H-tetrazol-2-yl)piperidin-1-yl, 4-(2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-yl)piperidin-1-yl, 3,4-dihydroisoquinolin-2(1H)-yl, 2-oxo-1,3,8-triazaspiro[4.5]dec-8-yl, 1-oxo-2-oxa-8-azaspiro[4.5]dec-8-yl, 2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl, 2-oxo-4-tertbutyloxycarbonylpiperazin-1-yl, 3-oxo-4-methylpiperazin-1-yl, 3-oxo-4-pyridin-4-ylpiperazin-1-yl, 4-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-3-oxopiperazin-1-yl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, 3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, 2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, and 2-(trifluoromethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl.
Further examples of suitable groups where Rd and Re, together with the nitrogen atom to which they are attached, form a heterocycle as herinbefore described are:
Also, preferably, Rd and Re are independently selected from C1-6alkyl, (CH2)0-3aryl, (CH2)0-3heteroaryl and (CH2)0-3Het, optionally substituted by N(C1-6alkyl)2, halogen, C1-6alkyl, hydroxy, CN or CO2H.
More preferably, Rd and Re are independently selected from C1-4alkyl, (CH2)1-2aryl, (CH2)1-2 heteroaryl and Het, optionally substituted by N(C1-4alkyl)2, C1-4alkyl, hydroxy, CN or CO2H.
Most preferably, Rd is methyl, ethyl, propyl, butyl or cyanoethyl and Re is C1-3alkyl, (CH2)1-2phenyl, CH2thienyl, (CH2)1-2pyridyl or piperidinyl, optionally substituted by N(CH3)2, methyl, hydroxy, CN or CO2H.
Examples of suitable Rd groups are methyl, ethyl, n-butyl and cyanoethyl.
Examples of suitable Re groups are cyanomethyl, hydroxyethyl, cyanoethyl, dimethylaminoethyl, dimethylaminopropyl, 2,3-dihydroxypropyl, phenylmethyl, carboxy(phenyl)methyl, 2-hydroxy-2-phenylethyl, 2-thienylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl and 1-methylpiperidin-4-yl.
In another embodiment of the present invention, there is provided the compound of formula (Ic):
or a pharmaceutically acceptable salt thereof,
wherein R2 is as defined in relation to formula (I).
Preferably, R2 is C1-6alkyl, CN, CO2H, C(O)OC1-6alkyl, aryl, heteroaryl or OHet, optionally substituted by C1-4alkyl, hydroxy or halogen. More preferably, R2 is (CH2)1-4OH, (CH2)1-4Br, CN, CO2H, C(O)OCH3, phenyl, imidazolyl, triazolyl or O-piperidinyl, optionally substituted by methyl, ethyl or tbutyl. Most preferably, R2 is CN, CO2H, C(O)OCH3, phenyl, 1-methyl-1H-imidazol-2-yl, 1-methyl-1H-1,2,4-triazol-5-yl, 1-methyl-1H-1,2,4-triazol-3-yl, 1-hydroxyethyl. 1-bromoethyl or
In another embodiment of the present invention, there is provided the compound of formula (Id):
or a pharmaceutically acceptable salt thereof,
wherein X is selected from NO2, CN, CF3 and halogen,
and Rd and Re are defined in relation to formula (I).
Preferably, X is CN or halogen. More preferably, X is CN, fluorine or bromine.
Preferably, X is at the 5-, 7- or 8-position of the quinoline system.
Preferably, Rd and Re, together with the nitrogen atom to which they are attached, form a saturated nitrogen-containing 6-membered heterocycle optionally containing a further nitrogen atom, which heterocycle is optionally substituted by C1-4alkyl, C3-8cycloalkyl, bicyclo[3.3.1]non-9-yl or Het, which optional substituent is optionally substituted by 1 to 8 halogen atoms or C1-4alkyl;
which heterocycle is further optionally fused to Het or heteroaryl, optionally substituted by hydroxy or oxo;
which heterocycle is further optionally bridged by —CH2—.
More preferably, Rd and Re, together with the nitrogen atom to which they are attached, form a piperazinyl ring, optionally substituted by C3-4alkyl, C4-6cycloalkyl, bicyclo[3.3.1]non-9-yl or tetrahydropyranyl, which optional substituent is optionally substituted by 1 to 3 halogen atoms or C1-2alkyl;
which heterocycle is further optionally fused to morpholinyl, pyrrolidinyl or triazolyl, optionally substituted by hydroxy or oxo;
which heterocycle is further optionally bridged by —CH2—.
Most preferably, Rd and Re, together with the nitrogen atom to which they are attached, form a piperazinyl ring, optionally substituted by ipropyl, tbutyl, cyclohexyl, bicyclo[3.3.1]non-9-yl or 4-tetrahydropyranyl, which optional substituent is optionally substituted by 1 to 3 fluorine atoms or methyl;
which heterocycle is further optionally fused to morpholinyl, pyrrolidinyl or 1,2,4-triazolyl, optionally substituted by hydroxy or oxo;
which heterocycle is further optionally bridged by —CH2—.
In another embodiment of the present invention, there is provided the compound of formula (Ie):
or a pharmaceutically acceptable salt thereof,
wherein Rr is hydrogen, C1-6alkyl or (CH2)0-6Rh,
where Rh is as defined in relation to formula (I), and where C1-6alkyl, C3-8cycloalkyl and heteroaryl are optionally substituted by 1 to 8 halogen atoms or C1-4alkyl.
Preferably, Rr is hydrogen, C1-4alkyl or (CH2)0-1Rh, where Rh is C4-6cycloalkyl, C(O)Ri, Het or heteroaryl, where C1-4alkyl and heteroaryl are optionally substituted by 1 to 8 fluorine atoms or C1-4alkyl, and where Ri is as defined in relation to formula (I). More preferably, Rr is hydrogen, C1-3alkyl, C4-6cycloalkyl, C(O)C1-4alkyl, Het or CH2heteroaryl, where C1-3alkyl and CH2heteroaryl are optionally substituted by 1 to 3 fluorine atoms, methyl or butyl. Most preferably, Rr is hydrogen, methyl, ipropyl, CH2CH2CF3, cyclohexyl, C(O)C(CH3)3, 4-tetrahydropyranyl,
In another embodiment of the present invention, there is provided the compound of formula (If):
or a pharmaceutically acceptable salt thereof,
wherein R3 and R4 are as defined in relation to formula (I).
Preferably, R3 is hydrogen, hydroxy or halogen. More preferably, R3 is hydrogen or fluorine.
Preferably, R4 is C1-6alkyl, C(O)OC1-4alkyl, phenyl or heteroaryl, optionally substituted by 1 to 3 halogen atoms. More preferably, R4 is C1-4alkyl, C(O)OC1-4alkyl, phenyl, pyridyl or thiazolyl, optionally substituted by 1 to 3 fluorine atoms. Most preferably, R4 is ethyl, C(O)OCH3, phenyl, 3-fluorophenyl, 3-pyridyl or 2-thiazolyl.
In another embodiment of the present invention, there is provided the compound of formula (Ig):
or a pharmaceutically acceptable salt thereof,
wherein Z and R2 are as defined in relation to formula (I).
Preferably Z is O, S, SO or SO2.
Preferably, R2 is C1-6alkyl, Het or heteroaryl, optionally substituted by C1-6alkyl or Het. More preferably, R2 is C1-4alkyl, pyrrolidinyl, piperidinyl or triazolyl, optionally substituted by C1-4alkyl or tetrahydropyranyl. Most preferably, R2 is methyl, 3-pyrrolidinyl, 4-piperidinyl or 5-triazolyl, optionally substituted by ethyl or 4-tetrahydropyranyl.
In another embodiment of the present invention, there is provided the compound of formula (Ih):
or a pharmaceutically acceptable salt thereof,
wherein R2 and R4 are as defined in relation to formula (I).
Preferably, R2 is C-linked Het, optionally substituted by C1-6alkyl, C(O)OC1-6alkyl or (CH2)0-3Het. More preferably, R2 is C-linked piperidinyl, optionally substituted by C1-4alkyl, C(O)OC1-4alkyl or Het. Most preferably, R2 is 3- or 4-piperidinyl, optionally substituted by butyl, C(O)Obutyl or tetrahydropyranyl. Especially, R2 is 4-piperidinyl, optionally substituted by tbutyl, C(O)Otbutyl or 4-tetrahydropyranyl.
Preferably, R4 is hydrogen or C(O)OC1-6alkyl. More preferably, R4 is hydrogen or C(O)OC1-4alkyl. Most preferably, R4 is hydrogen or C(O)OCH3.
Particularly preferred compounds of the present invention include those named in the Examples and Tables hereinbelow.
The present invention includes within its scope solvates of the compounds of formula (I), for example hydrates, and salts thereof.
The present invention also includes within its scope any enantiomers, diastereomers, geometric isomers and tautomers of the compounds of formula (I). It is to be understood that all such insomers and mixtures thereof are encompassed within the scope of the invention.
The independent syntheses of any optical isomers or their chromatographic separations may be achieved as known in the art. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
As used herein, the term “C1-6alkyl” means linear or branched chain alkyl groups having from 1 to 6 carbon atoms and includes all of the hexyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. “C1-4alkyl” and “C1-2alkyl” shall be understood in an analogous manner, as shall “C1-6alkoxy” and “C1-4 alkoxy”.
The term “C2-6alkenyl” means linear or branched chain alkenyl groups having from 2 to 6 carbon atoms and includes all of the hexenyl and pentenyl isomers as well as 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl).
The term “C2-6alkynyl” means linear or branched chain alkynyl groups having from 2 to 6 carbon atoms and includes all of the hexynyl and pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, 2-propynyl, and ethynyl (or acetylenyl).
The term “C3-8cycloalkyl” means a cyclic alkane ring having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The term “C4-7cycloalkyl” refers to a cyclic ring selected from cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term “halogen” refers to fluorine, chlorine, bromine and iodine.
The term “aryl” means phenyl or naphthyl.
The term “heteroaryl” means a 5-membered unsaturated ring containing 1, 2, 3 or 4 nitrogen atoms and/or an oxygen or sulfur atom provided no more than two nitrogen atoms are present, or a 6-membered unsaturated ring containing 1, 2 or 3 nitrogen atoms, and includes the following groups: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and pyrrolidinyl.
The term “Het” means a heteroaliphatic ring of 3 to 7 ring atoms, which ring contains 1, 2 or 3 heteroatoms selected from N, O or S or a group S(O), S(O)2, NH or NC1-4alkyl. Examples of Het include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, dioxolanyl, pyran, dioxanyl, morpholine, oxathiolanyl, dithianyl, oxathianyl, thiomorpholinyl, trioxanyl, trithianyl.
The terms “thiophenyl” and “thienyl” have the same meaning herein and are used interchangeably. Similarly, the following pair of terms has the same meaning: “pyridinyl” and “pyridyl”.
Exemplary compounds of the present invention include those listed in the Examples section and their pharmaceutically acceptable salts.
These compounds and those defined by the immediately preceding definitions are useful in therapy, especially as NK-2 and/or NK-3 antagonists, particularly as NK-3 antagonists.
The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention to the individual in need of treatment.
The term “subject,” (alternatively referred to herein as “patient”) as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, palmoate, and the like, can be used as the dosage form.
Also, in the case of an alcohol group being present, pharmaceutically acceptable esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.)
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
In the treatment or prevention of conditions which require NK-3 receptor modulation an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The present invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Thus, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.
Likewise, there is provided the use of a compound of formula (I) for the manufacture of a medicament for treating a neurokinin-2 and/or neurokinin-3 mediated disease.
There is also disclosed a method of treatment of a subject suffering from a neurokinin-2 and/or neurokinin-3 mediated disease, which comprises administering to that patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Examples of diseases mediated by neurokinin-2 and/or neurokinin 3 include CNS disorders such as depression (which term includes bipolar (manic) depression (including type I and type II), unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features (e.g. lethargy, over-eating/obesity, hypersomnia) or postpartum onset, seasonal affective disorder and dysthymia, depression-related anxiety, psychotic depression, and depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion); anxiety disorders (including generalised anxiety disorder (GAD), social anxiety disorder (SAD), agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder, and obsessive compulsive disorder); phobias (including agoraphobia and social phobia); psychosis and psychotic disorders (including schizophrenia, schizo-affective disorder, schizophreniform-diseases, -acute psychosis, alcohol psychosis, autism, delirium, mania (including acute mania), manic depressive psychosis, hallucination, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases such as Alzheimer's disease); post-traumatic stress disorder; attention deficit hyperactive disorder (ADHD); cognitive impairment (e.g. the treatment of impairment of cognitive functions including attention, orientation, memory (memory disorders, amnesia, amnesic disorders and age-associated memory impairment) and language function, and including cognitive impairment as a result of stroke, Alzheimer's disease, Aids-related dementia or other dementia states, as well as other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states)); convulsive disorders such as epilepsy (which includes simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures); psychosexual dysfunction (including inhibited sexual desire (low libido), inhibited sexual arousal or excitement, orgasm dysfunction, inhibited female orgasm and inhibited male orgasm, hypoactive sexual desire disorder (HSDD), female sexual desire disorder (FSDD), and sexual dysfunction side-effects induced by treatment with antidepressants of the SSRI-class); sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy); disorders of eating behaviours (including anorexia nervosa and bulimia nervosa); neurodegenerative diseases (such as Alzheimer's disease, ALS, motor neuron disease and other motor disorders such as Parkinson's disease (including relief from locomotor deficits and/or motor disability, including slowly increasing disability in purposeful movement, tremors, bradykinesia, hyperkinesia (moderate and severe), akinesia, rigidity, disturbance of balance and co-ordination, and a disturbance of posture), dementia in Parkinson's disease, dementia in Huntington's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like, and demyelinating diseases such as multiple sclerosis and amyotrophiclateral sclerosis); withdrawal from abuse of drugs including smoking cessation or reduction in level or frequency of such activities (such as abuse of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like compounds, opiates such as cannabis, heroin, morphine, sedative, hypnotic, amphetamine or amphetamine-related drugs such as dextroamphetamine, methylamphetamine or a combination thereof); pain (which includes neuropathic pain (including diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; pain associated with fibromyalgia or cancer; AIDS-related and HIV-related neuropathy; chemotherapy-induced neuropathy; neuralgia, such as post-herpetic neuralgia and trigeminal neuralgia; sympathetically maintained pain and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions such as rheumatoid arthritis and osteoarthritis; reflex sympathetic dystrophy such as shoulder/hand syndrome), acute pain (e.g. musculoskeletal pain, post operative pain and surgical pain), inflammatory pain and chronic pain, pain associated with normally non-painful sensations such as “pins and needles” (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased, sensitivity, to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia), pain associated with migraine, and non-cardiac chest pain); certain CNS-mediated disorders such as emesis, irritable bowel syndrome, and non-ulcer dyspepsia; COPD, asthma, cough, gastro-oesophageal reflex induced cough, and exacerbated asthma; urinary incontinence; hypertension; and conditions associated with platelet hyperaggregability such as tissue ulceration, nephrotic syndrome, diabetes, migraine, coronary artery disease, pre-eclampsia and stroke. Preferably, the compounds of the invention are useful for the treatment of depression; anxiety disorders; phobias; psychosis and psychotic disorders; post-traumatic stress disorder; attention deficit hyperactive disorder (ADHD); withdrawal from abuse of drugs including smoking cessation or reduction in level or frequency of such activities; and irritable bowel syndrome. More preferably, the compounds of the invention are useful for the treatment of depression; anxiety disorders; phobias; and psychosis and psychotic disorders (especially schizophrenia, schizo-affective disorder, and schizophreniform diseases. Most preferably, the compounds of the invention are useful for the treatment of schizophrenia.
The compounds for use in the present invention are generally active in the following tests. They normally have an IC50 of less than 1 μM and preferably less than 100 nM.
Details of the NK-2 receptor and its heterologous expression can be found in Gerard et al., J. Biol. Chem., 265: 20455-20462, 1990 and Huang et al., Biochem., 33: 3007-3013, 1994. The latter paper also contains details of mutant scanning.
Details of the NK-3 receptor and its heterologous expression can be found in Huang et al, BBRC, 1992, 184: 966-972 and Sadowski et al., Neuropeptides, 1993, 24: 317-319.
A membrane preparation is prepared as follows. A 10-layer cell factory is seeded with CHO cells stably expressing NK-3 receptors. The CHO cells are prepared in a triple T175 flask in 11 growth medium which contains Iscore's modified Dulbecco's medium containing 10 ml/1200 mM L-Glutamine, 10 ml/l penicillin-streptomycin, one vial of hypoxanthine-thymidine 500×/l, 1 mg/ml geneticin and 10% fetal bovine serum (inactivated). The cells are grown for 3 days in an incubator. The medium is washed off and the factory is rinsed twice with 400 ml PBS (Ca, Mg-free). 400 ml enzyme free dissoc. solution (EFDS) is added and the factory is maintained for 10 min at room temperature. The cells are dislodged and the suspension poured into 500 ml centrifuge bottles. The process is repeated with 200 ml EFDS and the mixtures pooled giving 6 bottles in all, which are spun in a centrifuge for 10 min at 2200 rpm.
The supernatants are aspirated and the residual cell pellets are frozen at −80° for 30 min to improve cell lysis and then resuspended in 40 ml Tris with inhibitors per cell factory. The cells are homogenized in 40 ml aliquots with 8 strokes of a glass-teflon grinder at setting 40. The homogenate is transferred to 50 ml centrifuge tubes and placed on a rocker for 15 min at r.t. The homogenate is rehomogenised and held on ice if necessary before being centrifuged again as above.
The supernatant is transferred to Sorvall tubes for an SS-34 roter and held on ice.
40 ml cold Tris with inhibitors is used to resuspend and combine the pellets which are again spun as above. The supernatants are again transferred to Sorvall tubes which, with those above, are spun at 18000 rpm for 20 min.
The supernatants are discarded and the pellets resuspended in a Storage Buffer consisting of 2.50 ml 1M Tris pH7.4, 50 μl 1000× protease inhibitors (4 mg/ml leupeptin (Sigmo), 40 mg/ml Bacitracin (Sigma) and 10 mM phosphoranidon (Peninsula) all dissolved in water) plus 0.5 ml 0.5M MnCl2 made up to 50 ml with H2Odd. A 10 ml syringe is used with 20-, 23- and 25-gauge needles sequentially.
A Bradford protein assay in conducted on 2-10 μl aliquots with BSA as standard before 500-1000 μl aliquots are snap-frozen in liquid nitrogen for storage at −80° C.
The membrane binding assay is carried out as follows. The amount of membranes needed to specifically bind ≦10% of 125I-NeurokinB is predetermined. The frozen stocks are then diluted to allow addition in 50 μl.
The test compounds are dissolved in DMSO. An automated apparatus (Tecan) is programmed to add 5 μl of compound or DMSO, approximately 100,000 cpm of isotope in 20 μl buffer which is prepared from 50 μMTris, pH7.5, 150 ↑M NaCl, bovine serum albumin to 0.02%, and protease inhibitors as in the storage buffer, made up as 0.5M stock, and 175 μl assay buffer (as the storage buffer but containing 5 μM MnCl2 and without NaCl) into deep well Marsh boxes (Marsh Biomedical Products) in a 96-well format. Excess unlabelled competing peptide is added by hand for non-specific binding as indicated below. The binding reaction is initiated by adding 50 μl of cell membranes. The tubes are incubated with shaking for 1 h at r.t. and filtered on a Tomtec 96 well cell harvester using Mach III filtermats (Tomtec) or using either a Packard 96-well harvester or Tomtec 9600 using Unifilter GF/C (Packard), presoaked in 0.25% polyethyleneimine and washed five times with 1× wash buffer (0.1M·Tris, pH7.4 and 1M NaCl, 1×=100 ml of 10× stock per litre of cold distilled water). If using Unifilter plates, 60 μl Microscint 20 (Packard) is added to each well and the plate is then heat-sealed before counting in a Packard Topcount. Alternatively the filters from the filtermat are placed in 75×100 mm plastic tubes and counted on a Cobra gamma counter.
For the assay, typically 10 μg of membrane is used at 25,000 cpm which is filtered over a Unifilter GF/C presoaked in 0.5% BSA.
Assays for binding at the neurokinin-2 receptor can be carried out in an analogous manner.
Compounds of formula (I) of the type:
can be made by reacting a compound of formula (II) with a compound of formula (III):
where R1, R3, R4, X and Y are as defined above, hal is a halogen atom (such as chlorine or bromine), Rt is hydrogen or oxo, and P1 is a suitable protecting group, such as tert-butyloxycarbonyl. The reaction may optionally be carried out in the presence of a deprotonating agent, such as LHMDS, in a suitable solvent, such as TUF. The product of the reaction may then be deprotected under suitable conditions and further functionalised by reacting with the compound of formula (IV):
L1-CH2)0-3Rh (IV)
where Rh is as defined above and L1 is a suitable leaving group. Examples of the compound of formula (IV) include alkyl anhydrides such as acetic anhydride, arylsulfonyl chlorides, such as benzensulfonyl chloride, and dialkylhaloacetamides such as 2-chloro-N,N-dimethylacetamide. Alternatively, the deprotected product of the reaction of compounds (1I) and (III), may be alkylated by treatment with an aldehyde or a ketone, such as tetrahydropyran-4-one, in the presence of a reducing agent, such as sodium triacetoxyborohydride.
Compounds of formula (I) of the type:
where R1, R3, R4, X, Y, Rd and Re are as defined above can be made by reacting a compound of formula (II) with a compound of formula (V):
HNRdRe (V)
where Rd and Re are as defined above. The reaction may be carried out at raised temperature or under microwave irradiation in a suitable solvent, such as TUF.
Compounds of formula (I) of the type:
where R1, R2, R3, R4, X and Y are as defined above can be prepared by reacting a compound of formula (VI) with a compound of formula (VII):
where R1, R2, R3, R4, X and Y are as defined above and P2 is a suitable protecting group. The reaction may be carried out by pre-reacting the compound of formula (VI) with oxalyl chloride and DMF and then adding the compound of formula (VII). The reaction may be carried out in a suitable solvent, such as dichloromethane.
Alternatively, the compounds of formula (I) of the same type can be prepared by reacting a compound of formula (VIII) with a compound of formula (IX):
where R1, R2, R3, R4, X and Y are as defined above and hal is a halogen atom such as chlorine. The reaction may be carried out in the presence of a base, such as potassium carbonate or sodium iodide, in a suitable solvent, such as TUF.
Compounds of formula (I) can be converted into other compounds of formula (I) using techniques known in the art.
For instance, a compound of formula (I) where R2 is C(O)OC1-6alkyl may be converted into a compound of formula (I) where R2 is COOH by alkaline or acid hydrolysis under conditions readily apparent to the skilled person.
The compounds of formulae (II) to (IX) are known in the art or can be made by known methods from known compounds.
Where they are not commercially available, the compounds of formulae (II) to (IX) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
During any of the above synthetic sequences, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd ed., 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
1H nmr spectra were recorded on Bruker AM series spectrometers operating at (reported) frequencies between 300 and 600 MHz. Chemical shifts (6) for signals corresponding to non-exchangeable protons (and exchangeable protons where visible) are recorded in parts per million (ppm) relative to tetramethylsilane and are measured using the residual solvent peak as reference. Signals are reported in the order: number of protons; multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; and combinations thereof); coupling constant(s) in hertz. Mass spectral (MS) data were obtained on a Waters Micromass ZQ or a Waters Micromass ZMD operating in negative (ES−) or positive (ES+) ionisation mode and results are reported as the ratio of mass over charge (m/z) for the parent ion only. Preparative scale HPLC separations were carried out using mass triggered HPLC on a preparative Agilent 100 separation module. Compounds were either eluted with linear gradients of acetonitrile/0.1% TFA and water/0.1% TFA or with acetonitrile and water (containing ammonium carbonate to give a pH of 10). In all cases flow rates between 15 and 25 mL/min were used.
Abbreviations used herein, particularly the Schemes and Examples, including the following: —
Ac2O, acetic anhydride; DCE, 1,1-dichloroethene; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; EtOAc, ethyl acetate; Et2O, diethyl ether; ES+ electrospray; h, hour(s); HPLC, high performance liquid chromatography; LHMDS, lithium hexamethyldisilazide; MeCN, acetonitrile; MeOH, methanol; min, minute(s); NBS, N-bromosuccinimide; PhMe, toluene; RT, room temperature; TFA, trifluoroacetic acid; TUF, tetrahydrofuran.
The following Examples illustrate the present invention:
To a slurry of isatin (20 g, 0.136 mol) in acetic acid (370 mL) was added propiophenone (18 mL, 0.136 mol) and the mixture was heated in an oil bath at 75° C. for 5 min before adding HCl concentrated (124 mL). Heating was continued at 105° C. for 16 h and the mixture was cooled to RT followed by addition of H2O (800 mL). The solid which formed was collected by filtration, washed with Et2O and dried in vacuo at 60° C. to leave 15.6 g (43%) of the title compound as a brown solid. m/z (ES+) 264 [M+H+].
To a suspension of 3-methyl-2-phenylquinoline-4-carboxylic acid (Description 1, 5.0 g, 0.019 mol) in CH2Cl2 (60 mL) was added oxalyl chloride (3.32 mL, 0.038 mol) followed by DMF (2 drops). The mixture was stirred at RT for 1 h and the solvent was then evaporated in vacuo. To a solution of the residue in CH2Cl2 (30 mL) was added Et3N (5.30 mL, 0.038 mol) followed by a solution of phenylhydrazine (2.80 mL, 0.028 mol) in CH2Cl2 (30 mL). The mixture was stirred at RT for 5 h, diluted with H2O/brine and the product extracted with CH2Cl2 (×5). The combined organic layers were dried (MgSO4), evaporated in vacuo and the residue was purified by flash chromatography on silica gel eluting with 30% EtOAc/isohexane to leave 4.0 g of the title compound (59%). m/z (ES+) 354 [M+H+]
To a suspension of 3-methyl-N′,2-diphenylquinoline-4-carbohydrazide (Description 2, 4.0 g, 0.011 mol) in PhMe (120 mL) was added methyl chloroformate (1.75 mL, 0.022 mol) and the mixture was refluxed at 110° C. for 16 h. The mixture was diluted with H2O and the product extracted with EtOAc (×3). The combined organic phases were dried (MgSO4) and evaporated in vacuo to give 4.26 g of the title compound (95%). m/z (ES+) 412 [M+H+]
A solution of methyl 2-[(3-methyl-2-phenylquinolin-4-yl)carbonyl]-1-phenylhydrazinecarboxylate (Description 3, 4.26 g. 0.010 mol) in THF (100 ml) was cooled at −78° C. and LHMDS 1M in THF (15.6 mL, 0.015 mol) was added followed by methyl chloroformate (1.6 mL, 0.020 mol). The cooling bath was removed and the reaction allowed to warm to +15° C. and then partitioned between H2O and EtOAc and extracted further with EtOAc. The combined organic layers were dried (MgSO4) and evaporated to dryness. The residue obtained was dissolved in CCl4 (100 mL), NBS (3.70 g, 0.020 mol) was added and the mixture was exposed to the light of a quartz lamp for 90 min. The reaction mixture was then left cooling to RT, the solid was filtered off washing with CCl4 and the filtrate evaporated to dryness. This was dissolved in EtOAc, washed with H2O, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 20% EtOAc/isohexane to leave 4.12 g of the title compound as a white solid (76%). m/z (ES+) 548/550 [M+H+].
A suspension of 3-methyl-2-phenylquinoline-4-carboxylic acid (Description 1, 0.200 g, 0.76 mmol) and NBS (0.270 g, 1.52 mmol) in DCE (20 mL) was exposed to the light of a quartz lamp for 5 h. The cooled (RT) reaction mixture was evaporated in vacuo and the residue was dissolved in EtOAc and water and the product was extracted with EtOAc (×2). The organic layers were combined, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/isohexane/AcOH (70:30:1) to give the title compound as a mixture with succinimide and the 3-(chloromethyl)-2-phenylquinoline-4-carboxylic acid analogue. m/z (ES+) 342/344 [M+H+]
To a suspension of 3-(bromomethyl)-2-phenylquinoline-4-carboxylic acid (Description 5, 0.100 g, 0.29 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (0.051 mL, 0.58 mmol) followed by DMF (1 drop) and the mixture stirred at RT for 1 h. The solvent was then evaporated in vacuo and the residue dissolved in CH2Cl2 (2 mL), Et3N (0.081 mL, 0.58 mmol) was added followed by methyl 1-phenylhydraziniumcarboxylate hydrochloride (Description 10, 0.060 g, 0.29 mmol) and the mixture stirred at RT overnight. The reaction mixture was partitioned between water and CH2Cl2, extracted with CH2Cl2 (×2) and the organic layers were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with isohexane/EtOAc (70:30) to give 0.043 g of the title compound (33%). m/z (ES+) 446/448 [M+H+]
A suspension of methyl 2-[(3-methyl-2-phenylquinolin-4-yl)carbonyl]-1-phenylhydrazinecarboxylate (Description 3, 0.15 g, 0.365 mmol) and NBS (0.129 g, 0.725 mmol) in CCl4 (20 ml) was illuminated by the light of a quartz lamp for 1.5 h allowing the temperature to increase to approx. 75° C. The solvent was removed in vacuo and a solution of the residue dissolved in CH2Cl2 was purified on silica gel eluting with 10% to 20% EtOAc in isohexane to give the title compound after evaporation and crystallisation from Et2O:isohexane (1:1). m/z (ES+) 490/492(M+H).
To a stirred cooled (5° C.) solution of phenyl hydrazine (20 g, 0.185 mol) in EtOAc and saturated NaHCO3 (200 mL) was added K2CO3 (10 g, 0.72 mol) followed by the slow addition (over 0.5 h) of a solution of benzyl chloroformate (34.8 g, 0.204 mol) in EtOAc (100 mL). The mixture was stirred at 0° C. to 5° C. for 0.5 h and the organic phase was dried (MgSO4). The solvent was removed in vacuo and the residue was washed with isohexane (100 mL twice) and dried to give 43.9 g of the title compound. 1H NMR (CDCl3, 500 Mz) δ 7.42-7.05 (11H, m), 5.23 (2H, m), 3.79 (3H, m) as a mixture of rotamers.
To a solution of the product of Description 8 was suspended in PhMe (500 mL) was added methyl chloroformate (17.5 mL, 0.226 mol). The mixture was heated at 100° C. for 1.5 h and the resulting clear solution was cooled to RT and evaporated to dryness to give the title compound as a foam (58 g).
A mixture of the product of Description 9 (58 g) and 10% Pd on C (4 g) in MeOH (400 mL) was hydrogenated for 1 h at 30-40 psi of H2. The mixture was filtered and 1 M HCl in MeOH (200 mL) was added to the filtrate. The solution was evaporated to dryness and the solid residue was washed with Et2O to give 31.9 g of the title compound. 1H NMR (CDCl3, 500 Mz) δ 9.2 (3H, broad s), 7.55 (2H, d, J 7.5), 7.45 (2H, t, J 6.7), 7.35 (1H, t, J 7.5), 3.73 (3H, s) as a mixture of rotamers.
To a suspension of 3-hydroxy-2-phenylquinoline-4-carboxylic acid (2.65 g, 0.01 mol, as described in Giardina et al., J. Med. Chem. 1999, 42, 1053-1065) and K2CO3 (5.53 g, 0.04 mol) in THF (50 mL) was added benzyl bromide (2.99 mL, 0.025 mol) and NaI (0.01 g) and the mixture was heated under reflux for 14 h. After this time, the reaction mixture was reduced in volume to ˜20 mL and a further portion of benzyl bromide (1 mL. 0.008 mol) was added and heating was continued under reflux for a further 24 h. The reaction mixture was then filtered, concentrated in vacuo, dissolved in methanol (100 mL) and treated with 2N NaOH solution (25 mL) under reflux temperature for 4 h. The solvents were removed under vacuum and the residue was partitioned between H2O (100 mL) and Et2O (2×100 mL). The aqueous layer was acidified with concentrated HCl and the solid produced was collected by filtration and washed first with H2O then Et2O in the sinter funnel and then dried in vacuo at 80° C. to leave 2.45 g of the title compound as a white solid. m/z (ES+) 356 [M+H+]
To a solution of methyl 2-{[3-(benzyloxy)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Example 95, 2.4 g, 0.048 mmol) in MeOH (80 mL) under an atmosphere of N2 was added 10% Pd on C catalyst (0.2 g) then the reaction mixture was shaken on a Parr apparatus under 50 psi of H2 for 18 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was recrystallised from isopropanol to give 0.73 g of the title compound as a white solid. m/z (ES+) 414 [M+H+].
To a cooled (0° C.) solution of 4-mercaptopyridine (250 mg, 2.25 mmol) in conc. HCl (2 mL) was added 35% H2O2 solution (0.25 mL, 2.57 mmol) with stirring. After 30 min, chlorine gas was passed through the solution for 1.5 h then ice was added and the volume adjusted by addition of water to 10 mL. A portion of this crude mixture was used immediately for the preparation of Example 12.
To a solution of dimethyl 1-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-2-phenylhydrazine-1,2-dicarboxylate (Description 4, 1.5 g, 2.74 mmol) in Et2O (20 mL) was added a solution of N-butoxycarbonylpiperazine (1.02 g, 5.48 mmol) in Et2O (10 mL). The suspension was stirred at RT for 16 h when CH2Cl2 (30 mL) was added followed by pyrrolidine (2.5 mL, 41.3 mmol). The clear solution was stirred at RT for 11 h then the solvent was removed in vacuo. The residue was partioned between CH2Cl2 and saturated NaHCO3 and the organic phase was dried (MgSO4) and evaporated to a small volume. The solution was applied to a column containing silica gel and the product eluted with increasing concentrations (10% to 50%) EtOAc in isohexane to give the title compound as a foam (1.54 g) after evaporation. m/z (ES+) 596 [M+H+].
tert-Butyl-4-[(4-{[2-(methoxycarbonyl)-2-phenylhydrazino]carbonyl}-2-phenylquinolin-3-yl)methyl]piperazine-1-carboxylate (Example 1, 0.842 g, 1.41 mmol) was dissolved in anhydrous TFA (20 mL). After 1 h, the solution was evaporated to dryness and the residue dissolved in EtOAc (50 mL) and aqueous K2CO3 (50 mL). The organic phase was washed with saturated brine, dried (MgSO4) and evaporated to dryness. Upon addition of Et2O, a colourless solid formed. The suspension was evaporated to dryness to give the title compound. 1H NMR (500 MHz, DMSO d6) δ 11.5 (1H, s), 8.3 (2H, broad s), 8.07 (1H, d, J 3.4), 7.84 (1H, t), 7.7 (1H, broad s), 7.54-7.46 (9H, m), 7.34 (1H, t), 3.82 (3H, s), 3.7-3.5 (2H, v. broad m), 2.6 (4H, broad s), 2.1 (4H, broad s). m/z (ES+) 496 [M+H+].
Methyl 1-phenyl-2-{[2-phenyl-3-(piperazin-1-ylmethyl)quinolin-4-yl]carbonyl}hydrazinecarboxylate (Example 2, 15 mg, 0.030 mmol) was dissolved in CH2Cl2 (0.5 mL) and to this was added Et3N (0.011 mL, 0.079 mmol) and benzenesulfonyl chloride (16 mg, 0.091 mmol). The solution was stirred at RT for 20 min, evaporated to dryness and a solution of the residue in DMSO (0.5 ml) was purified by preparative HPLC. The fractions from the column which contained product were applied to a Bond Elut™ cartridge (SCX, 0.5 g), washed with MeOH and the product eluted with 2 M NH3 in MeOH (5 mL). The solution was evaporated to dryness to give 5.2 mg of the title compound. m/z (ES+) 637 (M+H).
Methyl 1-phenyl-2-{[2-phenyl-3-(piperazin-1-ylmethyl)quinolin-4-yl]carbonyl}hydrazinecarboxylate (Example 2, 16.4 mg, 0.033 mmol) was dissolved in CH2Cl2 (0.5 mL) and to this was added Ac2O (0.014 mL, 0.148 mmol). The solution was stirred at RT for 1 h and then evaporated to dryness. The residue dissolved in MeOH was applied to a Bond Elut™ cartridge (SCX, 0.5 g), washed with MeOH and the product eluted with 2 M NH3 in MeOH (5 mL). The solution was evaporated to dryness to give 14.7 mg of the title compound. m/z (ES+) 538 (M+H).
The following compounds were prepared by a method analogous to that described in Example 3 (Method A) or that described in Example 4 (Method B).
To a solution of tetrahydropyran-4-one (0.1 mL, 1.08 mmol) and methyl 1-phenyl-2-{[2-phenyl-3-(piperazin-1-ylmethyl)quinolin-4-yl]carbonyl}hydrazinecarboxylate (Example 2, 134 mg, 0.27 mmol) in CH2Cl2 (0.5 mL) was added acetic acid (0.016 mL) and sodium triacetoxyborohydride (115 mg, 0.54 mmol). The solution was stirred at RT for 3 h when 1 M aqueous HCl (0.5 mL) was added followed 15 minutes later by EtOAc (30 mL), H2O (30 mL) and sufficient NaHCO3 to adjust the pH to >6. The organic phase was dried (MgSO4) and evaporated to dryness. The residue was dissolved in the minimum CH2Cl2 and this solution was applied to a column containing silica gel and the product eluted by increasing concentrations of MeOH (0-5%) in EtOAc. The fractions containing product were evaporated to dryness and the residue was dissolved in 1:1 CH2Cl2: Et2O to which was subsequently added 1 M HCl in Et2O (0.24 mL). The suspension was evaporated to give the title compound as a fine colourless solid. 1H NMR (360 MHz, DMSO d6, 329° K) δ 11.4 (1H, s), 10.43 (1H, broad s), 8.07 (1H, d J 6.4), 8.0 (1H, broad s), 7.83 (1H, apparent t, J 6.2), 7.76 (1H, apparent t, J 6.2), 7.56-7.45 (8H, m), 7.33 (1H, apparent t, J 5.5), 5.7-4.7 (very broad signal), 3.9 (2H, dd, J 9, 3.5), 3.84 (3H, s), 3.69 (2H, broad s), 3.26 (2H, t, J 8.7), 3.18 (2H, broad s), 2.44-2.29 (6H, m), 1.85 (2H, dm, J 7.6), 1.60 (2H, m). m/z (ES+) 580 (M+H).
The following compounds were prepared in an analogous manner and were isolated by a combination of either flash chromatography on silica gel or preparative hplc and Bond Elut™ LR (SCX)
A solution of methyl 1-phenyl-2-{[2-phenyl-3-(piperazin-1-ylmethyl)quinolin-4-yl]carbonyl}hydrazinecarboxylate (Example 2, 138 mg, 0.28 mmol) and Et3N (0.1 mL) in CH2Cl2 (5 mL) was added 2-chloro-N,N-dimethylacetamide (0.086 mL, 0.84 mmol) and the solution was heated for a total of 8 h. The mixture was diluted with CH2Cl2 and washed with NaHCO3 solution, dried (MgSO4) and evaporated to dryness. A concentrated solution of the residue in CH2Cl2 was purified by flash chromatography on silica gel eluting with increasing concentrations of EtOAc in isohexane (20% to 100%). Fractions containing the product were evaporated to a small volume and 2 M HCl in Et2O (0.1 mL). The product was precipitated by addition of further Et2O (10 mL) and the suspension evaporated to give the title compound as a solid. 1H NMR (360 MHz, DMSO d6 at 329° C.) δ 11.49 (1H, s), 9.46 (1H, broad s), 8.05 (1H, d, J 8.4), 8.00 (1H, broad s), 7.88 (1H, t, J 7.4), 7.66 (1H, t, J 7.7), 7.6-7.45 (8H, m), 7.33 (1H, t, J 7.4), 4.08 (2H, s), 3.83 (3H, s), 3.66 (2H, broad s), 3.14 (2H, broad s), 2.90 (3H, s), 2.86 (3H, s), 2.61 (2H, broad s), 2.4-2.16 (4H, broad m). m/z (ES+) 581 (M+H).
The Examples in the following table were prepared using the product of Example 2 as starting material and the appropriate alkylating agent by a method analogous to Method D using either heating in an oil bath or in a microwave reactor and the product was isolated by chromatography on silica gel or by preparative HPLC.
To a solution of methyl 2-{[3-(chloromethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Description 6) in THF was added the amine (2 eq) and the reaction was refluxed at 65° C. overnight (Et3N was added where the salt of the amine was used). Alternatively the reaction was carried out under microwave irradiation at 120-140° C. for 15-50 min. The solvent was evaporated in vacuo and the residue was purified either by LC-MS or by flash chromatography.
To a solution of 4-tert-butoxycarbonylpiperazin-2-one (125 mg, 0.80 mmol) in THF (4 mL) at −78° C. was added 1 M LHMDS in hexane (0.65 mL, 0.65 mmol). To the resultant clear solution was added a solution of dimethyl 1-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-2-phenylhydrazine-1,2-dicarboxylate (Description 4, 336 mg, 0.61 mmol) in THF (4 mL). The solution was allowed to warm to RT overnight. A solution of 4-tert-butoxycarbonylpiperazin-2-one (125 mg, 0.80 mmol) in THF (4 mL) at −78° C. was added 1 M LHMDS in hexane (0.65 mL, 0.65 mmol) and this solution was added to the reaction mixture at RT and the solution was stirred at RT for an additional 16 h. Acetic acid (0.1 mL) was added and the product was partitioned between EtOAc and saturate brine. The organic phase was dried (MgSO4), evaporated to dryness and the residue was purified by chromatography initially on silica gel (eluting with increasing concentrations of EtOAc in isohexane (0-100%) and subsequently by RP preparative HPLC to give the title compound as a foam (57 mg). 1H NMR (500 MHz, DMSO d6) δ 11.7 (1H, s), 8.11 (1H, d, J 8.4), 7.88 (1H, t, J 7.5), 7.72 (1H, broad s), 7.53-7.43 (10H, m), 7.34 (1H, t, J 7.1), 4.93 (2H, broad s), 3.80 (3H, s), 3.41 (2H, s), 3.21 (2H, broad m), 2.79 (1H, m), 2.7 (1H, m). m/z (EI+) 610 (M+H).
tert-Butyl-4-[(4-{[2-(methoxycarbonyl)-2-phenylhydrazino]carbonyl}-2-phenylquinolin-3-yl)methyl]-2-oxopiperazin-1-carboxylate (Example 94, 47 mg, 0.077 mmol) was dissolved in TFA (5 mL) and the solution stirred for 0.3 h. The solvent was removed by evaporation and the residue was dissolved in MeOH (5 mL). The solution was applied to a Bond Elut™ SCX (0.5 g) washed with MeOH (5 mL) and the product eluted with 2M NH3 in MeOH (5 mL). The solution was evaporated to give the title compound. 1H NMR (500 MHz, CDCl3) δ 11.7 (1H, s), 8.1 (1H, d, J 8.6), 7.86 (1H, t, J 7.5), 7.71 (1H, broad s), 7.56-7.42 (10H, m), 7.32 (1H, t, J 7.0), 4.95 (1H, broad s), 4.5 (1H, broad s), 3.8 (3H, s), 2.75 (3H, m), 2.6 (1H, m). m/z (EI+) 510 (M+H).
To a solution of 3-benzyloxy-2-phenylquinoline-4-carboxylic acid (Description 11, 2.12 g, 6 mmol) in CH2Cl2 (60 mL) was added oxalyl chloride (0.782 mL, 9 mmol) and 1 drop of DMF. The solution was stirred at RT for 1 h then concentrated in vacuo and azeotroped with two further 50 mL portions of CH2Cl2. The residue was redissolved in CH2Cl2 (50 mL) and added to a solution containing methyl 1-phenylhydraziniumcarboxylate chloride (Description 9, 1.8 g, 9 mmol) and Et3N (3.3 mL, 24 mmol) in CH2Cl2 (90 mL). The clear solution was stirred at RT for 14 h and then was partitioned between CH2Cl2 and saturated NaHCO3 and the organic phase was dried (Na2SO4) and evaporated to a small volume. The solution was applied to a column containing silica gel and the product eluted with increasing concentrations (0% to 30%) EtOAc in isohexane to give the title compound as a foam (2.45 g) after evaporation. 1H NMR (500 MHz, CDCl3): δ 8.26 (2H, s), 8.17 (1H, d, J 8.3), 7.99 (2H, s), 7.72 (1H, t, J 7.1), 7.63 (1H, t, J 7.2), 7.49 (5H, s), 7.19 (2H, t, J 7.3), 6.92 (2H, d, J 7.2), 4.66 (2H, s), 3.88 (3H, s). m/z (ES+) 504 [M+H+].
To a solution of methyl 1-phenyl-2-{[2-phenyl-3-(hydroxy)quinolin-4-yl]carbonyl}hydrazinecarboxylate (Description 12, 0.2 g, 0.48 mmol) in THF (5 mL) was added K2CO3 (0.2 g, 1.44 mmol) and 2-chloromethyl-1-methyl-triazole hydrochloride (0.088 g, 0.6 mmol) and NaI (5 mg). The solution was heated at 60° C. for 14 h then filtered through a sinter funnel and the filtrate was concentrated in vacuo. The residue was applied to a column containing silica gel and the product was eluted with increasing concentrations (0% to 50%) EtOAc in isohexane to give the title compound as a white solid (70 mg) after evaporation. 1H NMR (500 MHz, CDCl3): δ 10.60 (1H, br s), 8.07 (2H, t, J 9.3), 7.88 (2H, d, J 6.5), 7.68 (1H, t, J 7.4), 7.59 (4H, d, J 8.5), 7.52 (3H, d, J 7.2), 7.40 (2H, t, J 6.9), 7.30 (1H, d, J 6.9), 5.00 (2H, s), 3.89 (3H, s), 3.25 (3H, s). m/z (ES+) 509 [M+H+].
This compound was prepared according to the procedure outlined in Example 97 replacing 2-chloromethyl-1-methyl-triazole hydrochloride with bromoacetonitrile. 1H NMR (500 MHz, CDCl3): 8.35 (1H, s), 8.19 (1H, d, J 8.4), 8.15 (H, br s), 7.99 (2H, d, J 6.3), 7.77 (1H, t, J 7.7), 7.65 (1H, t, J 7.6), 7.60 (2H, d, J 7.3), 7.55 (3H, q, J 6.9), 7.47 (2H, t, J 7.9), 7.35 (1H, t, J 7.4), 4.45 (2H, s), 3.93 (3H, s). m/z (ES+) 453 [M+H+].
This compound was prepared according to the procedure outlined in Example 97 replacing 2-chloromethyl-1-methyl-triazole hydrochloride with methylbromoacetate. 1H NMR (500 MHz, CDCl3): 9.39 (1H, s), 8.13 (2H, d, J 8.1), 7.97 (2H, d, J 6.8), 7.69 (1H, d, J 7.7), 7.59 (2H, s), 7.50 (3H, d, J 7.5), 7.40 (2H, t, J 7.4), 7.29 (2H, s), 4.30 (2H, s), 3.88 (3H, s), 3.58 (3H, s). m/z (ES+) 486 [M+H+].
To a solution of methyl-2-{[3-(2-methoxy-2-oxoethoxy)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Example 99, 0.248 g, 0.00051 mol) in methanol (10 mL) was added 2 N NaOH solution (2 mL) and the mixture was stirred at RT for 16 h. Water (20 mL) was added and the aqueous solution was washed with Et2O (2×20 mL) then acidified with conc. HCl to pH 1 and extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (Na2SO4) and evaporated to give the title compound as a white solid (200 mg). 1H NMR (500 MHz, CDCl3): δ 9.10 (1H, br s), 8.13 (1H, d, J 8.1), 8.06 (1H, t, J 9.9), 7.91 (2H, s), 7.69 (1H, d, J 7.7), 7.59-7.26 (9H, m), 4.26 (2H, s), 3.86 (3H, s). m/z (ES+) 472 [M+H+].
This compound was prepared according to the procedure outlined in Example 97 replacing 2-chloromethyl-1-methyl-triazole hydrochloride with 2-chloromethyl-1-methyl-imidazole hydrochloride. 1H NMR (500 MHz, DMSO d6): δ 11.68 (1H, s), 8.10 (1H, d, J 8.3), 7.81 (3H, t, J 6.9), 7.73 (1H, t, J 7.5), 7.53-7.51 (6H, m), 7.42 (1H, s), 7.36 (2H, t, J 7.7), 7.28 (1H, t, J 7.4), 6.43 (1H, s), 4.68 (2H, s), 3.84 (3H, s), 3.01 (3H, s). m/z (ES+) 508 [M+H+].
This compound was prepared according to the procedure outlined in Example 97 replacing 2-chloromethyl-1-methyl-triazole hydrochloride with 2-chloromethyl-5-methyl-imidazole hydrochloride. 1H NMR (500 MHz, CDCl3): δ 11.06 (1H, s), 8.25 (1H, d, J 8.3), 8.13 (1H, d, J 8.2), 7.89 (1H, s), 7.82 (2H, t, J 7.2), 7.71 (1H, t, J 7.7), 7.59-7.51 (6H, m), 7.40 (2H, t, J 7.7), 7.30 (1H, d, J 7.3), 4.86 (2H, s), 3.90 (3H, s), 3.71 (3H, s). m/z (ES+) 509 [M+H+].
NaH (60% in mineral oil, 0.2 g, 5 mmol) was added to a solution of methyl 2-[(3-methyl-2-phenylquinolin-4-yl)carbonyl]-1-phenylhydrazinecarboxylate (Description 3, 3.3 g, 8 mmol) in THF (66 mL) and the mixture was stirred at RT until the effervescence had subsided. Di-t-butylpyrocarbonate (1.77 g, 8.12 mmol) was added and the mixture was stirred at 60° C. for 1.25 h. The mixture was cooled and acetic acid (0.7 mL), EtOAc and water were added. The layers were separated and the organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a foam.
2-(1,1-Dimethylethyl) 1-methyl 2-[(3-methyl-2-phenylquinolin-4-yl)carbonyl]-1-phenylhydrazinedicarboxylate (Description 14, 8 mmol) and NBS (2.2 g, 12.4 mmol)) were suspended in CCl4 (40 mL) and purged thoroughly with nitrogen. The mixture was irradiated with the light from a quartz lamp until the conversion to the product was complete as determined by hplc (3 h.). The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 and filtered through a plug of silica gel, eluting with CH2Cl2. The eluent fractions containing product was evaporated under reduced pressure, triturated with ether and cooled to 0° C. The solid was collected and dried in vacuo to give the title compound as a colorless solid (3.7 g, 78%). 1H NMR (500 MHz, CDCl3) mixture of rotamers δ 8.44 (0.5H, d, J 8.3), 8.17 (1H, broad s), 7.80 (0.8H, t, J 7.4), 7.75-7.28 (11.2H, m), 5.0-4.6 (0.5H, m), 4.3 (1.3H, s), 4.04 (0.5H, s), 3.92 (2.9H, s), 3.87 (0.8H, s), 0.99-0.90 (9H, m).
2-(1,1-Dimethylethyl) 1-methyl 2-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinedicarboxylate (Description 15, 0.45 g) was dissolved in TFA (5 mL) and stirred at RT for 1 h. The solvent was evaporated under reduced pressure and the residue was partitioned between aqueous NaHCO3 (saturated) and EtOAc. The organic layer was dried (MgSO4) and solvent was evaporated under reduced pressure. The residue was triturated with ether-hexane (1:1) and the solid was collected and dried in vacuo to give the title compound as a colorless solid (0.27 g, 73%). m/z (ES+) 492, 490 [M+H+].
KOH (88 g, 1560 mmol) in water (400 mL) was added over 30 min. to a suspension of 7-fluoroisatin (64.4 g, 390 mmol) in ethanol (200 mL). Propiophenone (51.9 mL, 390 mmol) was added and the mixture was heated under reflux for 24 h. The mixture was cooled, and hydrochloric acid (conc., 128 mL, 1404 mmol) then acetic acid (11.16 mL, 195 mmol) were added. The mixture was stirred at RT for 16 h. and the solid was collected, washing with water (600 mL), ethanol (200 mL) and hexane/Et2O (1:1, 400 mL). The solid was flushed with toluene (3×500 mL) and dried in vacuo to give the title compound as an off-white solid (91.44 g, 325 mmol, 83%). 1H NMR (500 MHz, DMSO-d6) δ 14.4 (1H, br s), 7.70-7.45 (8H, m), 2.40 (3H, s)
Oxalyl chloride (12.47 mLl, 142 mmol) was added dropwise to a suspension of 8-fluoro-3-methyl-2-phenylquinoline-4-carboxylic acid (Description 17, 26.71 g, 95 mmol) in CH2Cl2 (320 mL) and DMF (0.5 mL) and the mixture was stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue was flushed with toluene (250 mL). The residue was dissolved in CH2Cl2 (150 mL) and added dropwise over 30 min. to a stirred mixture of phenylhydrazine (9.81 mL, 100 mmol), potassium carbonate (26.2 g, 190 mmol), water (250 mL) and CH2Cl2 (150 mL). The mixture was stirred at RT for 6 h., the layers were separated and the aqueous layer was washed with brine (saturated, 500 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (400 mL), washed with hydrochloric acid (1M, 2×400 mL), aqueous NaOH (1M, 2×400 mL) and brine (400 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. 2-Propanol (300 mL) was added and the mixture was heated under reflux for 15 min. The mixture was cooled and the solid was collected and dried in vacuo to give the title compound as a cream solid (31.53 g, 89%). m/z (ES+) 372 [M+H+].
Prepared from 8-fluoro-3-methyl-N′,2-diphenylquinoline-4-carbohydrazide (Description 18) according to the method of Description 3. m/z (ES+) 430 [M+H+].
Prepared from methyl 2-[(8-fluoro-3-methyl-2-phenylquinolin-4-yl)carbonyl]-1-phenylhydrazinecarboxylate (Description 19) according to the method of Description 14. m/z (ES+) 530 [M+H+].
Prepared from 2-(1,1-dimethylethyl) 1-methyl 2-[(8-fluoro-3-methyl-2-phenylquinolin-4-yl)carbonyl]-1-phenylhydrazinedicarboxylate (Description 20) according to the method of Description 15. m/z (ES+) 608, 610 [M+H+].
Prepared from 2-(1,1-dimethylethyl) 1-Methyl 2-{[8-fluoro-3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinedicarboxylate (Description 21) according to the method of Description 16. m/z (ES+) 508, 510 [M+H+].
Prepared from 4-fluorisatin and propiophenone according to the method of Description 17. m/z (ES+) 282 [M+H+].
Prepared from 5-fluoro-3-methyl-2-phenylquinoline-4-carboxylic acid (Description 23) according to the method of Description 18. m/z (ES+) 372 [M+H+].
Prepared from 5-fluoro-3-methyl-N′,2-diphenylquinoline-4-carbohydrazide (Description 24) according to the method of Description 3. m/z (ES+) 430 [M+H+].
Prepared from methyl 2-[(5-fluoro-3-methyl-2-phenylquinolin-4-yl)carbonyl]-1-phenylhydrazinecarboxylate (Description 25) according to the method of Description 14. m/z (ES+) 530 [M+H+].
Prepared from 2-(1,1-dimethylethyl) 1-methyl 2-[(5-fluoro-3-methyl-2-phenylquinolin-4-yl)carbonyl]-1-phenylhydrazinedicarboxylate (Description 26) according to the method of Description 15. m/z (ES+) 608/610 [M+H+].
Prepared from 2-(1,1-dimethylethyl) 1-methyl 2-{[5-fluoro-3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinedicarboxylate (Description 27) according to the method of Description 16. m/z (ES+) 508/510 [M+H+].
Prepared from 7-bromoisatin and propiophenone according to the method of Description 17. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (1H, d, J 1.8), 7.82 (1H, dd, J 1.9, 8.9), 7.76 (1H, d, J 8.9), 7.61 (2H, dd, J 2.0, 7.9), 7.56-7.50 (3H, m), 2.37 (3H, s).
Prepared from 7-bromo-3-methyl-2-phenylquinoline-4-carboxylic acid (Description 29) according to the method of Description 18. 1H NMR (400 MHz, CDCl3) δ 8.34-8.31 (1H, m), 7.94 (1H, br s), 7.70-7.62 (2H, m), 7.50-7.42 (5H, m), 7.31 and 7.18 (2H, two t, J 7.9), 7.02-6.88 (3H, m), 6.69 and 6.55 (1H, two m), 2.43 and 2.32 (3H, two s).
Prepared from 7-bromo-3-methyl-N′,2-diphenylquinoline-4-carbohydrazide (Description 30) according to the method of Description 3. m/z (ES+) 490/492 [M+H+].
Prepared from methyl 2-[(7-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]-1-phenylhydrazinecarboxylate (Description 31) according to the method of Description 14. m/z (ES+) 490/492 [M-Boc+2H+].
Prepared from 2-(1,1-dimethylethyl) 1-methyl 2-[(7-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]-1-phenylhydrazinedicarboxylate (Description 32) according to the method of Description 15. m/z (ES+) 668/670/672 [M+H+].
Prepared from 2-(1,1-dimethylethyl) 1-methyl 2-{[7-bromo-3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinedicarboxylate (Description 33) according to the method of Description 16. m/z (ES+) 568/570/572 [M+H+].
A mixture of 3-(bromomethyl)-2-phenylquinoline-4-carboxylic acid (Description 5, 3.4 g, 10.3 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (1.24 g, 9.1 mmol) and triethylamine (1.39 mL, 1.01 g, 10 mmol) in DMF (50 mL) was heated at 60° C. for 40 h. The mixture was cooled and the solvent was evaporated under reduced pressure. EtOAc (500 mL) was added and the mixture was heated to reflux, filtered and cooled. The solvent was evaporated under reduced pressure to a volume of 100 mL and the solid was collected and dried in vacuo to give the title compound as a solid (1.0 g, 28%). m/z (ES+) 386 [M+H+].
Prepared from isatin and 1-phenyl-4-penten-1-one according to the method of Description 17.
Prepared from 2-phenyl-3-(2-propenyl)quinoline-4-carboxylic acid (Description 36) according to the method of Description 18.
Prepared from N′,2-diphenyl-3-(2-propenyl)quinoline-4-carbohydrazide (Description 37) according to the method of Description 3.
Prepared from methyl 2-{[2-phenyl-3-(2-propenyl)quinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Description 38) according to the method of Description 14.
Ozone was bubbled through a stirred, cooled (−78° C.) solution of 2-(1,1-dimethylethyl) 1-methyl 2-{[2-phenyl-3-(2-propenyl)quinolin-4-yl]carbonyl}-1-phenylhydrazinedicarboxylate (Description 39, 200 mg, 0.46 mmol) in CH2Cl2/methanol (9:1, 50 mL) until a blue color persisted. The mixture was flushed with oxygen, then nitrogen and dimethylsulfide (0.5 mL) was added. The mixture was allowed to warm to RT, washed with aqueous NaHCO3 (saturated) and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 20% EtOAc in isohexanes, to give the title compound (100 mg). m/z (ES+) 540 [M+H+].
Prepared from 2-(1,1-dimethylethyl) 1-methyl 2-{[3-(2-oxoethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinedicarboxylate (Description 40, 100 mg, 0.185 mmol) and 4-piperidinol according to the method of Description 61.
Sulfuric acid (conc., 6.0 mL) was added to a suspension of 3-hydroxy-2-phenylquinoline-4-carboxylic acid (15.0 g, 56.5 mmol) in methanol (100 mL) and the mixture was heated under reflux for 96 h. The mixture was cooled and the solvent was evaporated under reduced pressure. Water (200 mL) and CH2Cl2 (200 mL) were added, the aqueous layer was basified with solid sodium carbonate and the layers were separated. The aqueous layer was extracted with CH2Cl2 (4×) and the combined organic fractions dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow solid. m/z (ES+) 280 [M+H+]
Di-t-butyl azodicarboxylate (11.05 g, 48.0 mmol) and triphenylphosphine (12.58 g, 48.0 mmol) were added to a stirred solution of methyl 3-hydroxy-2-phenylquinoline-4-carboxylate (Description 42, 6.7 g, 24.0 mmol) and 1-(1,1-dimethylethyl)-4-piperidinol (4.53 g, 28.8 mmol) in THF (60 mL) and the mixture was stirred at RT for 72 h. Water (100 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic fractions were washed with water (2×100 mL), brine (2×100 mL), dried (Na2SO4), and the solvent was evaporated under reduced pressure to give the title compound as an orange oil (4.2 g, 42%). m/z (ES+) 419 [M+H+]
KOH (2.68 g, 47.8 mmol) was added to a solution of methyl 3-[1-(1,1-dimethylethyl)piperidin-4-yloxy]-2-phenylquinoline-4-carboxylate (Description 43, 4.0 g, 9.56 mmol) in methanol (60 mL) and the mixture was heated under reflux for 72 h. The mixture was cooled and the solvent was evaporated under reduced pressure. Water (50 mL) and EtOAc (50 mL) were added and the aqueous phase was adjusted to pH 5 with acetic acid. The layers were separated and the aqueous layer was extracted with EtOAc (4×50 mL). The combined organic fractions were dried (Na2SO4), and the solvent was evaporated under reduced pressure to give the title compound as a pale brown solid (3.8 g, 98%). m/z (ES+) 405 [M+H+]
Prepared from 1,1-dimethylethyl 4-hydroxypiperidinecarboxylate and methyl 3-hydroxy-2-phenylquinoline-4-carboxylate according to the method of Description 43. m/z (ES+) 463 [M+H+]
Prepared from methyl 3-[1-(1,1-dimethylethyloxycarbonyl)piperidin-4-yloxy]-2-phenylquinoline-4-carboxylate (Description 45) according to the method of Description 44. m/z (ES+) 449 [M+H+]
To a solution of 4-piperidinemethanol (11.5 g, 0.1 mol) in CH2Cl2 (200 mL) was added di-t-butyldicarbonate (23.98 g, 0.11 mol) and the mixture was stirred at RT for 16 h. The solvent was removed by evaporation and the resultant solid was dried under vacuum for 3 h.
To a cooled (−60° C.) solution of DMSO (17.2 mL) in CH2Cl2 (55 mL) was slowly added a solution of oxalyl chloride (10.2 mL) in CH2Cl2 (140 mL). After stirring the cloudy solution at −60° C. for 20 min, a solution of 1-(1,1-dimethylethyl)carbonyl-4-piperidinemethanol (prepared above) in dichloromethane (55 mL) was added over 20 min. and then the mixture was stirred at −60° C. for an additional 20 min. Triethylamine (70 mL) was added and the solution was allowed to warm to RT. Water (100 mL) was added and the organic phase was washed with aqueous citric acid (1M, 2×100 mL), water and saturated brine, dried (MgSO4). Removal of the solvent by evaporation gave 1-(1,1-dimethylethyl)carbonyl-4-piperidinecarboxaldehyde as an oil (23.9 g).
To a cooled (−78° C.) solution of LHMDS (1M in THF, 87 mL, 87 mmol) in THF (100 mL) was added a solution of acetophenone (10.44 g, 87 mmol) in THF (30 mL). After stirring the solution at −78° C. for 1 h., a solution of 1-(1,1-dimethylethyl)carbonyl-4-piperidinecarboxaldehyde (18.6 g, 87 mmol) in THF (50 mL) was added and the mixture was stirred at −78° C. for 30 min. then allowed to warm to −30° C. Aqueous citric acid (1M, 200 mL) was added and the mixture was warmed to RT. EtOAc (400 mL) was added and organic phase was washed with water and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 (200 mL), cooled in an ice bath and triethylamine (24.2 mL, 174 mmol) was added. Methanesulfonyl chloride (8 mL) was slowly added and the mixture was stirred at 0° C. for 60 min. and then heated under reflux for 30 min. To the cooled solution was added CH2Cl2 (200 mL) and saturated aqueous NaHCO3 solution and the solution was stirred at RT for 30 min. The layers were separated and the organic phase was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with increasing amounts of EtOAc in isohexane (10-30%) to give the title compound as an oil (21.6 g, 78%). 1H NMR (500 MHz, CDCl3): δ 7.92 (2H, t, J 7.1), 7.58-7.46 (3H, m), 6.99 (1H, dd, J 6.5, 15.6), 6.87 (1H, dd, J 1.0, 15.5), 4.14-4.10 (2H, m), 2.80 (2H, m), 2.44-2.38 (1H, m), 1.80 (2H, d, J 12.3), 1.46 (9H, s), 1.46-1.40 (2H, m).
A mixture of 1,1-dimethylethyl 4-[(1E)-3-oxo-3-phenyl-1-propenyl]-1-Piperidinecarboxylate (Description 47, 21.1 g, 67 mmol) and 10% palladium on carbon (1.9 g) in EtOAc (300 mL) was shaken under hydrogen (30 psi) for 6 h. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound as an oil (20.9 g). 1H NMR (500 MHz, CDCl3): δ 7.97-7.91 (2H, d, J 7.8), 7.58-7.52 (1H, t), 7.46 (2H, t, J 7.6), 4.12 (2H, m), 3.00 (2H, t, J 7.5), 2.68 (3H, m), 1.70 (4H, m), 1.42 (10H, m), 1.26 (2H, t, J 7.1).
1,1-Dimethylethyl 4-(3-oxo-3-phenyl-1-propyl-1-piperidinecarboxylate (Description 48, 20.9 g, 65.9 mmol) was added to a solution of isatin (9.69 g, 65.9 mmol) in ethanol (68 mL) and KOH (14.76 g, 264 mmol) dissolved in water (68 mL). The solution was heated at 100° C. for 5 days, cooled to RT and diluted with water (300 mL). The mixture was washed with Et2O (2×100 mL), neutralized by addition of acetic acid (16 mL) and extracted with EtOAc (5×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with Et2O (20 mL) and the solid was collected and dried in vacuo to give the title compound (5.6 g). m/z 447 (M+H).
3-({1-[(1,1-Dimethylethoxy)carbonyl]piperidin-4-yl}methyl-2-phenylquinoline-4-carboxylic Acid (Description 49, 1.2 g) was dissolved in TFA (5 mL) and stirred at RT for 30 min. The solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2 (10 mL) and aqueous potassium carbonate (10%, 10 mL) and benzyl chloroformate (0.52 mL) were added. The mixture was stirred at RT for 1 h, then the CH2Cl2 was evaporated under reduced pressure. The mixture was extracted EtOAc (3×30 mL). and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as an oil (1.1 g).
Oxalyl chloride (0.038 mL) was added slowly to a solution of DMF (0.5 mL) in CH2Cl2 (5 mL) and the mixture was stirred at RT for 20 min. 3-({1-[(1,1-Dimethylethoxy)carbonyl]piperidin-4-yl}methyl-2-phenylquinoline-4-carboxylic acid (Description 49, 100 mg, 0.224 mmol) in CH2Cl2 (5 mL) was added and the mixture was stirred at RT for 1.5 h. The CH2Cl2 was evaporated under reduced pressure and the residue was quickly partitioned between EtOAc and aqueous NaHCO3 (saturated). The organic layer was washed with water (3×) and brine, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was dissolved in CH2Cl2 (5 mL) and phenylhydrazine (48 mg) was added. The mixture was stirred at RT for 16 h, then the solvent evaporated under reduced pressure. The residue was partitioned between EtOAc and aqueous citric acid (10%). The organic fraction was dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 10%-40% EtOAc in hexane, to give the title compound (42 mg). m/z (ES+) 537 [M+H+].
Prepared from 3-({1-[(1,1-dimethylethoxy)carbonyl]piperidin-4-yl}methyl)-N′,2-diphenylquinoline-4-carbohydrazide (Description 51) according to the method of Description 3. m/z (ES+) 595 [M+H+].
Prepared from 3-({1-[(phenylmethoxy)carbonyl]piperidin-4-yl}methyl)-2-phenylquinoline-4-carboxylic acid (Description 50) according to the method of Description 18. m/z (ES+) 571 [M+H+].
Prepared from 3-({1-[(phenylmethoxy)carbonyl]piperidin-4-yl}methyl)-N′,2-diphenylquinoline-4-carbohydrazide (Description 53) according to the method of Description 3. m/z (ES+) 629 [M+H+].
Palladium on carbon (10%, 60 mg) was added to a solution of methyl 2-{[3-({1-[(phenylmethethoxy)carbonyl]piperidin-4-yl}methyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Description 54, 130 mg) and acetic acid (6 mL) in EtOAc (20 mL) and the mixture was stirred under hydrogen (1 atm.) for 72 h. The mixture was filtered, the solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to give the title compound. m/z (ES+) 495 [M+H+].
Sodium azide (0.1593 g, 2.45 mol) was added to a solution of methyl 2-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Description 16) (1.20 g, 2.45 mmol) in anhydrous DMF (50 mL) and the mixture was stirred at RT for 5 h. The mixture was partitioned between water (200 mL) and EtOAc (200 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and evaporated to give the title compound.
A slurry solution of 1-bromo-3-fluorobenzene (0.32 mL, 2.86 mmol), phenyl hydrazine (0.33 mL, 3.43 mmol) and sodium t-butoxide (0.38 g, 4.01 mmol) in diisopropylamine (12 mL) was degassed by bubbling nitrogen through for 15 min. Palladium acetate (0.032 g, 0.143 mmol) and (1,1′-binaphthalene)-2,2′-diylbis(diphenylphosphine) (0.089 g, 0.143 mmol) were added and the mixture was heated at 80° C. for 4 h. The mixture was cooled, diluted with Et2O, filtered through Celite and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with isohexane/CH2Cl2 (50:50) to give the title compound (0.41 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.34 (2H, dd, J 8.4, 15.8), 7.27 (2H, d, J 1.2), 7.19-7.07 (2H, m), 6.93-6.87 (2H, m), 6.59-6.55 (1H, m), 4.15 (2H, br s).
Prepared from 3-fluorophenylhydrazine hydrochloride according to the method of Description 57. m/z (ES+) 221 [M+H+].
Prepared from 3-bromopyridine and phenylhydrazine according to the method of Description 57. m/z (ES+) 186 [M+H+].
NaH (60% dispersion in mineral oil, 0.92 g, 23.1 mmol) was added to a solution of phenylhydrazine (0.50 g, 4.62 mmol) in 1,4-dioxane (8.0 mL) and the mixture was stirred at RT for 20 min. 2-Bromo-1,3-thiazole (0.41 mL, 4.62 mmol) was added and the mixture was heated under reflux for 12 h. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with isohexane/EtOAc (70:30) to give the title compound (0.19 g, 21%). m/z (ES+) 192 [M+H+].
Acetic acid (0.5 mL) and sodium triacetoxyborohydride (4.2 g, 20.0 mmol) were added to a solution of 1-(phenylmethyl)-4-piperidinamine (1.9 g, 10.0 mmol) and tetrahydro-4H-pyran-4-one (1.0 g, 10.0 mmol) in CH2Cl2 (50 mL) and the mixture was stirred at RT for 18 h. Water (50 mL) was added, the layers were separated and the aqueous layer was extracted with chloroform/1-propyl alcohol (90/10, 4×50 mL). The combined organic fractions were dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (30 mL), palladium on carbon (10%, 300 mg) was added and the mixture was shaken under hydrogen (45 psi) for 48 h. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound (1.14 g, 95%) as a colorless solid. m/z (ES+) 185 [M+H+].
Methyl magnesium bromide (1.4M in toluene/THF 75:25, 31.8 mL, 44.5 mmol) was added slowly to a stirred, cooled (−78° C.) solution of 3-ethyl 1-(1,1-dimethylethyl) 1,3-piperidinedicarboxylate (5.2 g, 20.2 mmol) in THF (30 mL) and the mixture was allowed to warm to RT and stirred for 1 h. Aqueous ammonium chloride (saturated, 10 mL) was added and the mixture was partitioned between aqueous ammonium chloride (saturated, 50 mL) and EtOAc (2×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (4.67 g, 95%).
Methanolic hydrogen chloride (1M, 8 mL) was added to 1,1-dimethylethyl 3-(1-hydroxy-1-methylethyl)-1-piperidinecarboxylate (Description 62, 1.0 g, 4.1 mmol) in methanol (8 mL) and the mixture was stirred at RT overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol and applied to a Bond Elut™ cartridge (SCX, 10 g). The cartridge was washed with MeOH and then eluted with methanolic ammonia (2M, 50 mL). The solvent was under reduced pressure to give the title compound (350 mg, 60%); m/z (ES+) 144 [M+H+].
Carbonyldiimidazole (39.4 g, 243 mmol) was added in portions to a stirred solution of 1-(1,1-dimethylethyl) 4-piperidinedicarboxylate (42.5 g, 187 mmol) in CH2Cl2 (550 mL) and the mixture was stirred at 4° C. overnight. The mixture was poured into Et2O (2 L) and ice water (2 L), the layers were separated and the organic layer was washed with cold aqueous NaHCO3 (saturated, 500 mL) and brine (500 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (52 g).
Acetone (41 mL) in THF (300 mL) was added dropwise to a stirred suspension of KH (30% in mineral oil, 75 g, 561 mmol) in THF (1.4 L) at RT. The mixture was cooled to −78° C. and treated with 1-(1,1-dimethylethyl) 4-piperidinedicarboxylate anhydride with 1H-imidazole-1-carboxylic acid (Description 64, 52 g) in THF (500 mL). The mixture was allowed to warm to RT and stirred overnight, then ethanol (50 mL) was added dropwise over 5 min. The mixture was poured into hydrochloric acid (1N, 2 L) and extracted with Et2O (2×1 L). The combined organic fractions were washed with aqueous NaHCO3 (saturated, 500 mL) and brine (500 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. Isohexane (1 L) and MeCN (500 mL) were added, the layers were separated and the isohexane layer was extracted with MeCN (500 mL). The MeCN layers were combined and the solvent was evaporated under reduced pressure. The residue was filtered through a silica pad, eluting with 0-20% EtOAc in hexanes, to give the title compound as a colorless solid (36 g, 72%). 1H NMR (CDCl3) δ 5.50 (1H, s), 4.18-4.11 (2H, m), 2.79-2.62 (2H, m), 2.34-2.27 (1H, m), 2.07 (3H, s), 1.80 (2H, brd, J 14.3), 1.60-1.51 (2H, m), 1.46 (9H, s).
(1,1-Dimethylethyl)hydrazine hydrochloride (14.8 g, 118 mmol) then triethylamine (17 mL, 120 mmol) were added to a solution of 1,1-dimethylethyl 4-(1,3-dioxobutyl)piperidinecarboxylate (Description 65, 8 g, 29.7 mmol) in ethanol (200 mL) and the mixture was stirred at RT overnight. The solvent was evaporated under reduced pressure and the residue was suspended in EtOAc (1 L), washed with aqueous NaOH (1N, 500 mL), water (500 mL) and brine (500 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (9.5 g). 1H NMR (CDCl3) δ 5.87 (1H, s), 4.27-4.18 (2H, m), 3.09-2.99 (1H, m), 2.79-2.68 (2H, m), 2.20 (3H, s), 1.85 (2H, brd, J 13.3), 1.63 (9H, s), 1.61-1.52 (2H, m), 1.48 (9H, s).
Methanolic hydrogen chloride (1N, 100 mL) was added to a solution of 1,1-dimethylethyl 4-[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]piperidinecarboxylate (Description 66, 9.5 g, 29 mmol) in methanol (100 mL) and the mixture was stirred at RT for 4 h. The solvent was evaporated under reduced pressure and the residue was triturated with EtOAc. The solid was collected, suspended in aqueous NaOH (4N, 20 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (6.4 g). 1H NMR (CDCl3) δ 5.91 (1H, s), 3.17 (2H, brd, J 13.0), 3.03 (1H, tt, J 13.0 and 4.3), 2.69 (2H, dt, J 12.8 and 3.5), 2.21 (3H, s), 1.86 (2H, brd, J 13.4), 1.67 (9H, s), 1.68-1.56 (2H, m).
Prepared from 1,1-dimethylethyl 4-(1,3-dioxobutyl)piperidinecarboxylate (Description 65) according to the methods of Description 66 and Description 67, substituting trifluoroethylhydrazine oxalate for (1,1-dimethylethyl)hydrazine hydrochloride. 1H NMR (CDCl3) δ 5.91 (1H, s), 4.58 (2H, dd, J 16.4 and 8.6), 3.17 (2H, brd, J 13.2), 2.70 (2H, dt, J 12.5 and 2.4), 2.60 (1H, tt, J 12.1 and 4.1), 2.23 (3H, s), 1.82 (2H, brd, J 14.4), 1.58 (2H, qd, J 12.5 and 3.8).
The following compounds were prepared from 1,1-dimethylethyl 1-piperazinecarboxylate and suitable ketones according to the methods of Description 61 and Description 67.
Prepared from 1,1-dimethylethyl 1-piperazinecarboxylate and tetrahydro-4H-thiopyran-4-one according to the method of Description 61.
4-Methylmorpholine-N-oxide (3.0 g, 25.6 mmol) and osmium tetroxide (2% in t-butanol, 1 mL) were added to a solution of 1,1-dimethylethyl 4-[tetrahydro-2H-thiopyran-4-yl]-1-piperazinecarboxylate (Description 74, 7.8 g, 27 mmol) in THF (30 mL) and the mixture was stirred at RT for 72 h. The mixture was poured into water (30 mL), extracted with EtOAc (3×30 mL) and the combined organic fractions were dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was dissolved in methanolic hydrogen chloride (1M, 100 mL) and the mixture was stirred for at RT for 20 h. The solvent was evaporated under reduced pressure and the residue was triturated with cold iso-hexane. The solid was collected and dried in vacuo to give the title compound as a colorless solid (2.56 g, 43%). m/z (ES+) 219 [M+H+]
A mixture of tetrahydro-4H-pyran-4-one (25.0 g, 250 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (51.2 g, 275 mmol) and 1,2,3-triazole (20.7 g, 300 mmol) in toluene (200 mL) was heated under reflux with azeotropic removal of water overnight. The mixture was allowed to cool to RT and was then added over 40 min. via cannula to a solution of methyl magnesium chloride (3M in THF, 333 mL, 1 mol), keeping the internal temperature below 24° C., and the mixture was stirred at RT for 3 h. The mixture was poured slowly onto aqueous ammonium chloride solution (20%, 500 mL), keeping the temperature below 30° C. The layers was separated and the aqueous layer was extracted with EtOAc. The combined organic fractions were washed with aqueous NaOH (2M, 400 mL) and water (400 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give an orange oil (70 g). A sample (5 g) was purified by column chromatography on silica gel, eluting with CH2Cl2 (containing 1% ammonia) containing a gradient of methanol (0-3%), to give the title compound as a pale yellow oil (2.3 g, 81%); m/z (ES+) 285 [M+H+].
Prepared from 1,1-dimethylethyl 4-(4-methyltetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (Description 76) according to the method of Description 67. m/z (ES+) 185 [M+H+].
Prepared from cyclohexanone and 1,1-dimethylethyl 1-piperazinecarboxylate according to the methods of Description 76 and Description 67. m/z (ES+) 183 [M+H+].
A solution of 2-bromo-2-methylpropionic acid (21.47 g, 128.6 mmol) in toluene (50 mL) was added dropwise in the dark over 30 min. to a mixture of phenylmethyl 1-piperazinecarboxylate (28 g, 127.3 mmol), triethylamine (71 mL, 509.2 mmol), Hyflo™ (30 g) and silver (I) oxide (29.5 g, 127.3 mmol) in toluene (100 mL) and the mixture was stirred at RT overnight. The mixture was filtered through a pad of Hyflo™, washing with toluene. The solvent was evaporated under reduced pressure to give the title compound. m/z (ES+) 307 [M+H+].
Isobutyl chloroformate (1 mL, 8 mmol) was added to a mixture of α,α-dimethyl-4-[(phenylmethoxy)carbonyl]-1-piperazineacetic acid (Description 79, 2 g, 7.35 mmol) and triethylamine (2 mL, 14.7 mmol) in THF (50 mL) and the mixture was stirred at RT for 90 min. The mixture was filtered through Hyflo™ and sodium borohydride (1.4 g) in water (50 mL) was added. The mixture was washed with NaHCO3 solution (saturated) and the organic layer was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3 (Aq.) (99:1:0.1) to give the title compound as a colorless oil (1 g).
Phenylmethyl 4-(2-hydroxy-1,1-dimethylethyl)-1-piperazinecarboxylate (Description 80, 800 mg, 2.74 mmol) in CH2Cl2 (25 mL) was added to a stirred, cooled (−78° C.) solution of (N-ethylethanaminato)trifluorosulfur (0.542 mL, 4.10 mmol) in CH2Cl2 (25 mL) and the mixture was stirred at −78° C. for 30 min. The mixture was allowed to warm to RT, diluted with CH2Cl2 (25 mL), washed with water (50 mL) and NaOH (4M), dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3 (Aq.) (99:1:0.1) to give the title compound as a yellow oil (492 mg, 61%).
Palladium on carbon (5%, 500 mg, 4.70 mmol) and formic acid (1 mL, 26.1 mmol) were added to a solution of phenylmethyl 4-(2-fluoro-1,1-dimethylethyl)-1-piperazinecarboxylate (Description 81, 492 mg, 1.671 mmol) in methanol (25 mL) and the mixture was stirred at RT for 30 min. The mixture was filtered through celite, washing with methanol (25 mL). Ethereal HCl (1M, 3 mL) was added and the solvent was evaporated under reduced pressure to give the title compound (320 mg, 97%). m/z (ES+) 161 [M+H+].
4-(Chloromethyl)-2-methylthiazole hydrochloride (92 g, 0.5 mol) in methanol (400 mL) was added slowly to a stirred solution of piperazine (500 g, 5.81 mol) in methanol (800 mL) and the mixture was heated under reflux for 3 h. The mixture was cooled and methanolic KOH (1 mol in 400 mL) was added. The mixture was stirred at RT overnight, filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in iso-propanol, filtered and purified by flash column chromatography on silica gel, eluting with iso-propanol-triethylamine (5:1) and the residue was vacuum distilled. A fraction with b.p. 123-127° C./˜1 torr was collected to give the title compound as a light-yellow dense oil which formed hygroscopic low melting (30° C.) crystals on standing (57.1 g, 58%). 1H NMR (D6-DMSO) δ 7.20 (1H, s), 3.45 (2H, s), 3.15 (1H, br s), 2.60 (4H, t), 2.50 (3H, s), 2.30 (4H, m).
Bromoacetyl bromide (23.5 mL, 0.27 mol) was added slowly to a stirred, cooled mixture of 3-fluoroaniline (25 g, 0.225 mol) in EtOAc (250 mL) and aqueous KHCO3 solution (20%, 250 mL). The mixture was allowed to warm to RT and the layers were separated. The organic layer was diluted with EtOAc, washed with aqueous citric acid (10%) and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (51.72 g, 92%), 1H NMR (360 MHz, CD3OD) δ 7.54 (1H, dt, J 11, 2), 7.34-7.24 (2H, m), 6.84 (1H, t, J 7), 3.96 (2H, s).
Ethanolamine (4.5 mL, 75 mmol) was added to stirred 2-bromo-N-(3-fluorophenyl)acetamide (Description 84, 5.0 g, 21 mmol) in EtOAc (25 mL) and the mixture was stirred at 60° C. for 2 h. The mixture was cooled, EtOAc and water were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was suspended in EtOAc (135 mL) and tributylphosphine (5.3 mL, 21 mmol) was added. The mixture was cooled to 0° C. and di-tert-butylazodicarboxylate (4.8 g, 21 mmol) was added dropwise over 1 h. The mixture was stirred at 0° C. for 0.5 h., then at 40° C. for 1.5 h. The mixture was cooled and ethanolic HCl (4M, 4.7 mL) was added. The mixture was stored at 0° C. for 0.5 h., and the solid was collected, washing with cold EtOAc, and dried in vacuo to give the title compound. 1H NMR (400 MHz, CD3OD) δ 3.68-3.71 (2H, m), 3.97-4.00 (2H, m), 4.02 (2H, s), 7.12 (1H, m), 7.18-7.22 (2H, m), 7.48 (1H, m).
Lithium aluminium hydride (1M in THF, 50.0 mL, 50.0 mmol) was added dropwise to a stirred, cooled (0° C.) solution of (RS)-ethyl 1,4-bis(phenylmethyl)-2-piperazinecarboxylate (8.65 g, 25.5 mmol) in THF (100 mL) and the mixture was stirred at RT for 17 h. The mixture was cooled to 0° C. and water (2 mL), then aqueous NaOH (4M, 8 mL) and water (2 mL) were added slowly. The mixture was stirred at RT for 1 h., filtered through Celite®, washing with THF (100 mL), and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (6.8 g, 90%). m/z (ES+) 296 [M+H+]
1,1-Dimethylethyl bromoacetate (20 mL, 140 mmol) was added to a rapidly stirred mixture of (RS)-1,4-bis(phenylmethyl)-2-piperazinemethanol (Description 86, 4.1 g, 13.98 mmol) and tetrabutylammonium sulfate (1.0 g, 2.96 mmol) in toluene (30 mL) and aqueous NaOH (50%, 30 mL). The mixture was stirred at RT for 4 h., then the layers were separated and the aqueous layer was extracted with toluene (2×20 mL). The combined organic fractions were dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with EtOAc/isohexane (5% to 20%), to give the title compound as a yellow oil (5.3 g, 93%). m/z (ES+) 410 [M+H+]
Palladium on carbon (10%, 200 mg) was added to a solution of (RS)-1,1-dimethylethyl[1,4-bis(phenylmethyl)-2-piperazinemethoxy]acetate (Description 87, 1.3 g, 3.17 mmol) in ethanol (20 mL) and the mixture was shaken under hydrogen (45 psi) for 36 h. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (20 mL), sodium ethoxide (200 mg) was added and the mixture was stirred at 85° C. for 72 h. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol and applied to a Bond Elut™ cartridge (SCX, 5 g). The cartridge was washed with MeOH and then eluted with methanolic ammonia (2M, 25 mL). The solvent was under reduced pressure to give the title compound as a colorless solid (380 mg, 77%). m/z (ES+) 157 (M+H).
Borane-THF complex (1M in tetrahydrofuran, 30 mL, 30 mmol) was added to a stirred, cooled (0° C.) solution of (RS)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (Description 88, 1.6 g, 10.2 mmol) in THF (30 mL) and the mixture was stirred at 60° C. for 24 h. The mixture was cooled to 0° C., methanol was added slowly and the mixture was stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol and applied to a Bond Elut™ cartridge (SCX, 10 g). The cartridge was washed with MeOH and then eluted with methanolic ammonia (2M, 50 mL). The solvent was under reduced pressure to give the title compound as a colorless solid (1.0 g, 67%). m/z (ES+) 143 (M+H).
Pivaloyl chloride (6.46 mL, 53 mmol) was added dropwise to a stirred, cooled (0° C.) mixture of pyrazinamine (5.0 g, 53 mmol) and triethylamine (8.06 mL, 58 mmol) in CH2Cl2 (80 mL) and the red mixture was stirred at 0° C. for 1 h., then at RT for 2 h. The mixture was filtered, washing with CH2Cl2 and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with CH2Cl2/methanol 95:5 to give the title compound (8.16 g, 87%). m/z (ES+) 180 [M+H+].
Phosphorous pentachloride (12.45 g, 59 mmol) was added to a solution of 2,2-dimethyl-N-pyrazin-2-ylpropanamide (Description 90, 8.16 g, 46 mmol) in 1,2-dichloroethane (200 mL) and the mixture was heated under reflux for 11 h. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was suspended in THF (150 mL) and aqueous hydroxylamine (50%, 18 mL) was added dropwise. The mixture was stirred at RT overnight then aqueous NaHCO3 was added and the mixture was extracted with EtOAc (3×). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (8.76, 98%). m/z (ES+) 195 [M+H+].
A mixture of N′-hydroxy-2,2-dimethyl-N-pyrazin-2-ylpropanimidamide (Description 91, 8.76 g, 46 mmol) and polyphosphoric acid (90 mL) was stirred at 130° C. overnight, cooled and added to ice. The mixture was neutralized with aqueous ammonium hydroxide and extracted with EtOAc (3×). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with isohexane/EtOAc (70:30) to give the title compound (1.04 g, 13%). m/z (ES+) 177 [M+H+].
Palladium on carbon (10%) was added to a solution of 2-(1,1-dimethylethyl)-[1,2,4]triazolo[1,5-a]pyrazine (Description 92, 0.50 g, 2.83 mmol) in ethanol (15 mL) and the mixture was stirred under hydrogen (1 atmosphere) overnight. The mixture was filtered, washing with ethanol, and the solvent was evaporated under reduced pressure to give the title compound (0.47 g, 92%). m/z (ES+) 181 [M+H+].
Prepared from pyrazineamine and acetic anhydride according to the method of Description 90. m/z (ES+) 138 [M+H+].
Prepared from N-pyrazin-2-ylacetamide (Description 94) according to the method of Description 91.
Prepared from N′-hydroxy-N-pyrazin-2-ylethanimidamide (Description 95) according to the method of Description 92. m/z (ES+) 135 [M+H+].
Prepared from 2-methyl[1,2,4]triazolo[1,5-a]pyrazine (Description 96) according to the method of Description 93. m/z (ES+) 139 [M+H+].
Palladium on carbon (10%, 0.05 g) 1 was added to a solution of 1,2,4-triazolo[4,3-a]pyrazin-3(2H)-one (0.12 g) in absolute ethanol (50 mL) and the mixture was shaken under hydrogen (50 psi) for 16 h. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.112 g). 1H NMR (500 MHz, DMSO-d6): δ 11.42 (1H, br s), 3.72 (2H, s), 3.48 (2H, s), 3.03 (2H, s).
A mixture of methyl 2-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Description 16, 0.21 g, 0.43 mmol), 2,3,5,6,7,8-hexahydro-1,2,4-triazolo[4,3-a]pyrazine-3-one (Description 98, 50 mg, 0.36 mmol) and triethylamine (0.06 mL, 44 mg, 0.43 mmol) in THF (2 mL) was heated under reflux for 16 h. The mixture was cooled and EtOAc (30 mL), water (30 mL) and aqueous NaHCO3 (saturated, 20 mL) were added. The layers were separated and the organic layer was washed with aqueous NaHCO3 (saturated, 20 mL) and brine (20 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel, eluting with EtOAc, to give the title compound as a colorless solid (87 mg, 44%). m/z (ES+) 550 [M+H+].
The following compounds were prepared according to the method of Example 103, substituting a suitable 3-(bromomethyl)-2-phenylquinoline for methyl 2-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate and a suitable amine for 1,2,4-triazolo[4,3-a]pyrazin-3(2H)-one.
A mixture of methyl 2-[(7-bromo-3-{[4-(1,1-dimethylethyl)piperazin-1-yl]methyl}-2-phenylquinolin-4-yl)carbonyl]-1-phenylhydrazinecarboxylate (Example 191, 104.4 mg, 0.166 mmol), zinc cyanide (11.7 mg, 0.100 mmol, zinc powder (1.7 mg, 0.026 mmol), tris(dibenzylideneacetal)palladium(0) (3.7 mg, 0.0040 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (4.3 mg, 0.0078 mmol) was flushed with nitrogen, then anhydrous N,N-dimethylacetamide (2 mL) was added. The mixture was degassed with bubbling nitrogen for 10 min, then stirred vigorously at 120° C. for 75 min. The mixture was cooled, diluted with EtOAc (25 mL) and washed with aqueous ammonia (2N, 25 mL) and brine (25 mL). The organic layer was dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH (95:5) to give the title compound as a colorless solid (92.4 mg, 97%): 1H NMR (500 MHz, DMSO-d6) δ 11.60 (1H, s), 8.65 (1H, s), 8.06 (1H, br s), 7.54-7.44 (10H, m), 7.33 (1H, t, J 7.0), 3.82 (3H, s), 3.53 (2H, br s), 2.03 (4H, br s), 1.91 (4H, br s), 0.85 (9H, s). m/z (ES+) 577 [M+H+].
The following compounds were prepared as mixtures of diastereoisomers from methyl 1-phenyl-2-{[2-phenyl-3-(piperazin-1-ylmethyl)quinolin-4-yl]carbonyl}hydrazinecarboxylate (Example 2) and appropriately substituted cyclopentanones according to the method of Description 61.
The following compounds were prepared from methyl 1-phenyl-2-{[2-phenyl-3-(2-oxo-piperazin-1-ylmethyl)quinolin-4-yl]carbonyl}hydrazinecarboxylate (Example 95) and appropriate ketones according to the method of Description 61.
To a solution of 1,2,4-triazole (0.031 g, 0.45 mmol) in THF (3 mL) was added NaH (60% dispersion in mineral oil, 0.027 g, 0.9 mmol). After stirring the mixture for 5 min., methyl 2-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Description 16, 0.1 g, 0.24 mmol) was added. The mixture was stirred at RT for 1 h., then the solvent was evaporated under reduced pressure. The residue was partitioned between water (5 mL) and CH2Cl2 (2×10 mL) and the organic layer was dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel preparative plate chromatography eluting with 40% EtOAc in isohexane to give the title compound as a colorless solid (11 mg). 1H NMR (500 MHz, CDCl3): δ 11.11 (1H, br s), 8.14 (1H, d, J 8.2), 8.00 (1H, d, J 8.4), 7.80 (2H, m), 7.64-7.18 (11H, m), 6.96 (1H, s), 6.00 (1H, br s), 5.60 (1H, br s), 3.79 (3H, s). m/z (ES+) 479 [M+H+].
Prepared from benzimidazole and methyl 2-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Description 16) according to the method of Example 203. 1H NMR (500 MHz, CDCl3): 8.5 (1H, br s), 8.24 (1H, d, J 8.4), 7.92 (1H, m), 7.82 (1H, m), 7.31-6.54 (16H, m), 5.49 (1H, br s), 5.28 (1H, br s), 3.63 (3H, br s). m/z (ES+) 528 [M+H+].
Prepared from tetrazole and methyl 2-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Description 16) according to the method of Example 203, separating with preparative plate chromatography, eluting with 50% EtOAc/isohexane as eluent. The less polar isomer was methyl 2-([2-phenyl-3-(1H-tetrazol-1-ylmethyl)quinolin-4-yl]carbonyl)-1-phenylhydrazinecarboxylate, 1H NMR (500 MHz, CDCl3): δ 9.54 (1H, br s), 8.15 (1H, d, J 8.3), 7.95 (1H, d, J 8.2), 7.83 (1H, m), 7.66 (1H, m), 7.57-7.18 (11H, m), 6.30 (1H, br s), 5.79 (1H, br s), 3.77 (3H, s). m/z (ES+) 480 [M+H+]. The more polar isomer was methyl 2-([2-phenyl-3-(2H-tetrazol-2-ylmethyl)quinolin-4-yl]carbonyl)-1-phenylhydrazinecarboxylate, 1H NMR (500 MHz, CDCl3): δ 9.36 (1H, br s), 8.31 (1H, s) 8.11 (1H, d, J 8.4), 8.00 (1H, m), 7.77 (1H, m), 7.59 (1H, m), 7.42-7.18 (8H, m), 6.95 (2H, d, J 7.8), 6.00 (2H, br s), 3.65 (3H, br s). m/z (ES+) 480 [M+H+].
Prepared from 3-methoxycarbonyl-1,2,4-triazole and methyl 2-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Description 16) according to the method of Example 203. 1H NMR (500 MHz, CDCl3): 10.91 (1H, br s), 8.14 (1H, d, J 8.3), 7.98 (1H, d, J 8.4), 7.81 (1H, t, J 7.5), 7.61 (3H, dd, J 8.0, 8.6), 7.55-7.49 (3H, m), 7.47-7.41 (2H, m), 7.35 (1H, d, J 7.1), 7.20 (2H, d, J 6.3), 7.00 (1H, s), 5.63 (1H, d, J 13.9), 5.30 (1H, s), 3.90 (3H, s), 3.78 (3H, s). m/z (ES+) 537 [M+H+].
A solution of methyl 2-{[3-(azidomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate in DMSO (Description 56, 0.245M, 0.417 mL, 0.102 mmol) was added to 2-ethynylpyridine (10.3 μL, 0.102 mmol), followed by water (0.104 mL), aqueous copper (II) sulfate (1M, 10.2 μL, 0.0102 mmol) and aqueous sodium ascorbate (1M, 20.4 μL, 0.0204 mmol). The mixture was stirred at RT for 17 h, additional DMSO (0.521 mL) was added and the mixture was stirred at RT for 24 h. The mixture was purified by preparative HPLC (Xterra column, eluting with 15-100% MeCN/NH4CO3(aq)) to give the title compound (17.8 mg, 51%). 1H NMR (400 MHz, DMSO) δ 3.82 (3H, s), 7.30-7.42 (10H, m), 7.53 2H, m), 7.78 (1H, br s), 7.84 (1H, t, 7.7), 7.91-7.96 (2H, m), 8.09 (1H, br s), 8.13 (1H, d, J 8.3), 8.51 (1H, d, J 4.5), 11.91 (1H, s).
The following compounds were prepared according to the method of Example 207, substituting a suitable alkyne for 2-ethynylpyridine.
Prepared from 2-(1,1-dimethylethyl) 1-methyl 2-[{3-[2-(4-hydroxy)piperidinoethyl]-2-phenylquinolin-4-yl}carbonyl]-1-phenylhydrazinedicarboxylate (Description 41) according to the method of Description 16. m/z (ES+) 525 [M+H+].
Lithium borohydride (2M in THF, 0.4 mL) was added to a solution of methyl 2-{[3-(2-methoxy-2-oxoethoxy)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Example 99, 0.38 g, 0.8 mmol) in THF (8 mL) and the mixture was stirred at RT for 1 h. Saturated aqueous ammonium chloride (4 mL) was added and the mixture was stirred at RT for 5 min. Et2O (20 mL) was added and the layers were separated. The organic layer was dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 50% EtOAc in isohexane to give the title compound as a colorless solid (240 mg). 1H NMR (500 MHz, CDCl3): 8.89 (1H, s), 8.11 (1H, d, J 8.3), 7.98 (1H, d, J 8.3), 7.93 (2H, t, J 3.8), 7.65 (1H, t, J 7.6), 7.58-7.43 (8H, m), 7.39-7.33 (1H, m), 3.87 (3H, s), 3.73 (2H, m), 3.58 (2H, t, J 12.0), 1.60 (1H, br s). m/z (ES+) 458 [M+H+].
Carbon tetrabromide (0.080 g) and triphenylphosphine (0.064 g) were added to a solution of methyl 2-{[3-(2-hydroxyethoxy)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Example 213, 0.1 g, 0.22 mmol) in CH2Cl2 (5 mL) and the mixture was stirred at RT for 14 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography eluting with 0-60% EtOAc in isohexane to give the title compound as a colorless solid (32 mg). 1H NMR (500 MHz, CDCl3): 8.37 (1H, s), 8.16 (2H, d, J 8.2), 8.00 (2H, d, J 6.5), 7.72 (1H, t, J 7.7), 7.62 (3H, t, J 9.7), 7.52-7.44 (5H, m), 7.34 (1H, t, J 7.4), 3.94-3.92 (5H, m), 3.19 (2H, t, J 6.3). m/z (ES+) 522 and 520 [M+H+].
Prepared from 3-[1-(1,1-dimethylethyl)piperidin-4-yloxy]-2-phenylquinoline-4-carboxylic acid (Description 44) according to the method of Description 18. m/z (ES+) 495 [M+H+]
Prepared from 3-[1-(1,1-Dimethylethyl)piperidin-4-yloxy]-N′,2-diphenylquinoline-4-carbohydrazide (Example 215) according to the method of Description 3. m/z (ES+) 553 [M+H+].
Prepared from methyl 3-[1-(1,1-dimethylethyloxycarbonyl)piperidin-4-yloxy]-2-phenylquinoline-4-carboxylic acid (Description 46) according to the method of Description 18. m/z (ES+) 539 [M+H+]
Prepared from 3-[1-(1,1-dimethylethyloxycarbonyl)piperidin-4-yloxy]-N′,2-diphenylquinoline-4-carbohydrazide (Example 217) according to the method of Description 3. m/z (ES+) 597 [M+H+].
Prepared from methyl 2-({3-[1-(1,1-dimethylethyloxycarbonyl)piperidin-4-yloxy]-2-phenylquinolin-4-yl}carbonyl)-1-phenylhydrazinecarboxylate (Example 218) according to the method of Description 16. m/z (ES+) 497 [M+H+]
Prepared from methyl 2-({2-phenyl-3-(piperidin-4-yloxy)quinolin-4-yl}carbonyl)-1-phenylhydrazinecarboxylate (Example 219) according to the method of Description 61. m/z (ES+) 581 [M+H+]
Prepared from 2-(1,1-dimethylethyl) 1-methyl 2-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinedicarboxylate (Description 15) and 1,1-dimethylethyl 3-hydroxy-1-azetidinecarboxylate according to the methods of Example 203, followed by treatment with TFA according to the method of Description 16 and reductive amination with tetrahydro-4H-pyran-4-one according to the method of Description 61. m/z (ES+) 567 [M+H+].
Prepared from 2-(1,1-dimethylethyl) 1-methyl 2-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinedicarboxylate (Description 15) and 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate according to the method of Example 203 followed by treatment with TFA according to the method of Description 16. m/z (ES+) 511 [M+H+].
Prepared from methyl 1-phenyl-2-({2-phenyl-3-[(4-piperidinyloxy)methyl]quinolin-4-yl}carbonyl)hydrazinecarboxylate (Example 222) and tetrahydro-4H-pyran-4-one according to the method of Description 61. m/z (ES+) 595 [M+H+].
Prepared from (2-ethyl-2H-[1,2,4]triazol-3-yl)-methanol and methyl 2-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Description 16) according to the method of Example 203. 1H NMR (500 MHz, CDCl3): δ 10.06 (1H, s), 8.12 (1H, d, J 8.4), 7.99 (1H, d, J 8.3), 7.75 (1H, t, J 7.7), 7.65 (1H, s), 7.61-7.55 (5H, m), 7.47-7.43 (5H, m), 7.34 (1H, t, J 7.3), 4.90 (2H, br s), 4.58 (2H, br s), 4.05 (2H, q, J 7.1), 3.85 (3H, s), 1.38 (3H, t, J 7.3). m/z (ES+) 537 [M+H+].
Methyl 2-{[3-(bromomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Description 16, 417 mg, 0.71 mmol) in DMSO (10 mL) was heated to 110° C. for 3 h. The mixture was cooled, water and EtOAc were added and the layers were separated. The organic layer was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane (10:90) to give the title compound (62 mg). m/z (ES+) 458 [M+H+].
3-Chlorobenzenecarboperoxoic acid (77%, 22 mg) was added to a solution of methyl 2-{[3-(methylthiomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Example 225, mg, 0.055 mmol) in CH2Cl2 (1 mL) and the mixture was stirred at RT overnight. The mixture was washed with aqueous sodium metabisulfite, aqueous NaHCO3 (saturated) and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (14 mg). m/z (ES+) 490 [M+H+].
Oxone™ (38 mg) was added to methyl 2-{[3-(methylthiomethyl)-2-phenylquinolin-4-yl]carbonyl}-1-phenylhydrazinecarboxylate (Example 225, 28 mg, 0.06 mmol) and wet alumina (0.6 g) in CH2Cl2 (5 mL) and the mixture was heated under reflux overnight. The mixture was cooled, filtered and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (2 mg). m/z (ES+) 474 [M+H+].
Prepared from methyl 2-({3-[(piperidin-4-yl)methyl]-2-phenylquinolin-4-yl}carbonyl)-1-phenylhydrazinecarboxylate (Description 55) and tetrahydro-4H-pyran-4-one according to the method of Description 61. m/z (ES+) 579 [M+H+].
The following compounds were prepared from 3-(5,6-dihydro[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-ylmethyl)-2-phenylquinoline-4-carboxylic acid (Description 35) and a suitable hydrazine according to the method of Description 18.
Prepared from 3-({1-[(1,1-dimethylethoxy)carbonyl]piperidin-4-yl}methyl-2-phenylquinoline-4-carboxylic Acid (Description 49) and N,N-diphenylhydrazine according to the method of Description 51. m/z (ES+) 613 [M+H+].
| Number | Date | Country | Kind |
|---|---|---|---|
| 0509405.7 | May 2005 | GB | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB2006/050092 | 5/5/2006 | WO | 00 | 11/7/2007 |
