US 5,204,354 AGranted

Substituted quinazolinones as neurotensin antagonists useful in the treatment of CNS disorders

AssigneeMerck & Co., Inc.

InventorsPrasun K. Chakravarty, E. M. Naylor, Richard W. Ransom

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Abstract

Substituted quinazolinones of the formula are useful as neurotensin antagonists. ##STR1##

Claims14

Dependent claims

A method of treating central nervous system disorders which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of structural formula:

##STR16## or a pharmaceutically acceptable salt thereof, wherein:
L is connected with J or K to form an aromatic ring as defined below;
J is --C(.dbd.M)-- or J and L are connected together to form a 6 carbon aromatic ring substituted with R.sup.7a, R.sup.7b, R.sup.8a and R.sup.8b ;
K is --C(.dbd.M)-- or K and L are connected together to form a 6 carbon aromatic ring substituted with R.sup.7a, R.sup.7b, R.sup.8a and R.sup.8b, provided that only one of J and K is --C(.dbd.M)--;
M is O or NR.sup.22 ;
R.sup.1 is
(a) --NHSO.sub.2 R.sup.23,
(b) --NHSO.sub.2 NHCOR.sup.23,
(c) --NHCONHSO.sub.2 R.sup.23,
(d) --SO.sub.2 NHR.sup.23,
(e) --SO.sub.2 NHCOR.sup.23,
(f) --SO.sub.2 NHCONR.sup.4 R.sup.23,
(g) --SO.sub.2 NHCOOR.sup.23,
(h) --SO.sub.2 NHOR.sup.23,
(i) --CH.sub.2 SO.sub.2 NHCOR.sup.23,
(j) --CH.sub.2 SO.sub.2 NHCONHR.sup.23,
(k) --CO.sub.2 H, or
(l) --1H-tetrazol-5-yl;
R.sup.2a and R.sup.2b are each independently
(a) H,
(b) Cl, Br, I, F,
(c) CF.sub.3,
(d) C.sub.1 -C.sub.6 -alkyl,
(e) C.sub.1 -C.sub.6 -alkoxy,
(f) C.sub.1 -C.sub.6 -alkyl-S--,
(g) C.sub.2 -C.sub.6 -alkenyl,
(h) C.sub.2 -C.sub.6 -alkynyl,
(i) C.sub.3 -C.sub.7 -cycloalkyl,
(j) aryl, or
(k) aryl-C.sub.1 -C.sub.6 -alkyl;
R.sup.3a is
(a) H,
(b) Cl, Br, I, F,
(c) C.sub.1 -C.sub.6 -alkyl,
(d) C.sub.1 -C.sub.6 -alkoxy, or
(e) C.sub.1 -C.sub.6 -alkoxyalkyl;
R.sup.3b is
(a) H,
(b) Cl, Br, I, F,
(c) C.sub.1 -C.sub.6 -alkyl,
(d) C.sub.3 -C.sub.7 -cycloalkyl,
(e) C.sub.1 -C.sub.6 -alkoxy,
(f) CF.sub.3,
(g) C.sub.2 -C.sub.6 -alkenyl, or
(h) C.sub.2 -C.sub.6 -alkynyl;
R.sup.4 is
(a) H,
(b) C.sub.1 -C.sub.6 -alkyl,
(c) aryl, wherein aryl is phenyl or naphthyl, either unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, N(R.sup.4).sub.2, CO.sub.2 R.sup.4, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, NO.sub.2, CF.sub.3, C.sub.1 -C.sub.4 -alkylthio, and OH;
(d) aryl-C.sub.1 -C.sub.6 alkyl, or
(e) heteroaryl, wherein heteroaryl is an unsubstituted, monosubstituted or disubstituted five or six membered aromatic ring selected from thiazole, imidazole, pyrazole, oxazole, pyridine, thiazine, pyrazine, pyrimidine wherein the substituents are members selected from the group consisting of --OH, --SH, --C.sub.1 -C.sub.4 -alkyl, --C.sub.1 -C.sub.4 -alkoxy, --CF.sub.3, Cl, Br, F, I, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 --(C.sub.1 -C.sub.4 -alkyl), --NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl) and --N(C.sub.1 -C.sub.4 -alkyl).sub.2 ;
E is a single bond, --NR.sup.13 (CH.sub.2).sub.s --, --S(O).sub.x (CH.sub.2).sub.s --where x is 0 to 2 and s is 0 to 5, --CH(OH)--, --O--, or --CO--;
R.sup.6 is
(a) H,
(b) aryl,
(c) C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.5 -alkenyl or C.sub.2 -C.sub.5 -alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of aryl, Cl, Br, I, F, C.sub.3 -C.sub.7 -cycloalkyl, --NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl), --OR.sup.4, --N(C.sub.1 -C.sub.4 -alkyl).sub.2, --NH--SO.sub.2 R.sup.4, --COOR.sup.4, and --SO.sub.2 NHR.sup.9 ;
or
(d) heteroaryl, or
(e) C.sub.3 -C.sub.7 -cycloalkyl;
R.sup.7a and R.sup.7b are independently
(a) H,
(b) C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl or C.sub.2 -C.sub.6 -alkynyl,
(c) Cl, Br, I, F,
(d) CF.sub.3,
(e) when R.sup.7a and R.sup.7b are bonded to adjacent carbon atoms, they joined to form a phenyl ring, or
(f) aryl;
R.sup.8a and R.sup.8b are independently
(a) H,
(b) C.sub.1 -C.sub.6 -alkyl, unsubstituted or substituted with a substituent selected from the group consisting of --OH, -guanidino, C.sub.1 -C.sub.4 -alkoxy, --N(R.sup.4).sub.2, COOR.sup.4, --CON(R.sup.4).sub.2, --O--COR.sup.4, -aryl, -heteroaryl, --S(O).sub.x --R.sup.23, -tetrazol-5-yl, --CONHSO.sub.2 R.sup.23, --SO.sub.2 NH-heteroaryl, --SO.sub.2 NHCOR.sup.23, --PO(OR.sup.4).sub.2, --PO(OR.sup.4)R.sup.9, --SO.sub.2 NH-CN, --NR.sup.10 COOR.sup.23, morpholino, N--(C.sub.1 -C.sub.6 -alkyl)piperazine, and --COR.sup.4,
(c) --CO-aryl,
(d) --C.sub.3 -C.sub.7 -cycloalkyl,
(e) Cl, Br, I, F,
(f) --OH,
(g) --OR.sup.23,
(h) --C.sub.1 -C.sub.4 -perfluoroalkyl,
(i) --S(O).sub.x --R.sup.23,
(j) --COOR.sup.4,
(k) --SO.sub.3 H,
(l) --NR.sup.4 R.sup.23,
(m) --NR.sup.4 COR.sup.23,
(n) --NR.sup.4 COOR.sup.23,
(o) --SO.sub.2 NR.sup.9 R.sup.10,
(p) --NO.sub.2,
(q) --NR.sup.4 SO.sub.2 R.sup.23,
(r) --NR.sup.4 CONR.sup.4 R.sup.23, ##STR17## (t) -aryl or -heteroaryl as defined above, (u) --NHSO.sub.2 CF.sub.3,
(v) --SO.sub.2 NH-heteroaryl,
(w) --SO.sub.2 NHCOR.sup.23,
(x) --CONHSO.sub.2 R.sup.23,
(y) --PO(OR.sup.4).sub.2,
(z) --PO(OR.sup.4)R.sup.9,
(aa) -tetrazol-5-yl,
(bb) --CONH(tetrazol-5-yl),
(cc) --COR.sup.4,
(dd) --SO.sub.2 NHCN, ##STR18## (ff) --CO-heteroaryl, (gg) --NR.sup.4 SO.sub.2 NR.sup.23 R.sup.9,
(hh) --N[CH.sub.2 CH.sub.2 ].sub.2 NR.sup.24, wherein R.sup.24 is C.sub.1 -C.sub.6 -alkyl, --C.sub.3 -C.sub.7 -cycloalkyl, --CONR.sup.9 R.sup.10, -heteroaryl, -phenyl, --CO--C.sub.3 -C.sub.7 -cycloalkyl, --CO--C.sub.1 -C.sub.6 -alkyl, --SO.sub.2 --C.sub.1 -C.sub.6 -alkyl, or --SO.sub.2 --C.sub.3 -C.sub.7 -cycloalkyl, or
(ii) --N[CH.sub.2 CH.sub.2 ].sub.2 O;
R.sup.9 is H, C.sub.1 -C.sub.5 -alkyl, aryl or arylmethyl;
R.sup.10 is H, C.sub.1 -C.sub.4 -alkyl;
R.sup.11 is H, C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.4 -alkenyl, C.sub.1 -C.sub.4 -alkoxy alkyl, or ##STR19## R.sup.12 is --CN, --NO.sub.2, --CF.sub.3 or --CO.sub.2 R.sup.4 ;
R.sup.13 is H, (C.sub.1 -C.sub.4 -alkyl)CO--, C.sub.1 -C.sub.6 -alkyl, allyl, C.sub.3 -C.sub.6 -cycloalkyl, aryl or arylmethyl;
R.sup.14 is H, C.sub.1 -C.sub.8 -alkyl, C.sub.1 -C.sub.8 -perfluoroalkyl, C.sub.3 -C.sub.6 -cycloalkyl, aryl or arylmethyl;
R.sup.15 is H, C.sub.1 -C.sub.6 -alkyl;
R.sup.16 is H, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, aryl or arylmethyl;
R.sup.17 is --NR.sup.9 R.sup.10, --OR.sup.10, --NHCONH.sub.2, --NHCSNH.sub.2, ##STR20## R.sup.18 and R.sup.19 are independently C.sub.1 -C.sub.4 -alkyl or taken together are --(CH.sub.2).sub.q --where q is 2 or 3;
R.sup.20 is H, --NO.sub.2, --NH.sub.2, --OH or --OCH.sub.3;
R.sup.21 is H, aryl, or C.sub.1 -C.sub.4 -alkyl optionally substituted with aryl, --NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl), --N(C.sub.1 -C.sub.4 -alkyl).sub.2, --CO.sub.2 R.sup.4, --OH, --SO.sub.3 H, or --SO.sub.2 NH.sub.2 ;
R.sup.22 is
(a) aryl,
(b) heteroaryl,
(c) C.sub.1 -C.sub.6 -alkyl unsubstituted or substituted with a substituent selected from the group consisting of aryl, heteroaryl, --OH, --NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl), --N(C.sub.1 -C.sub.4 -alkyl).sub.2, --CO.sub.2 R.sup.4, Cl, Br, F, I, and --CF.sub.3, or
(d) perfluoro-C.sub.1 -C.sub.4 -alkyl;
R.sup.23 is
(a) aryl,
(b) heteroaryl,
(c) C.sub.3 -C.sub.7 -cycloalkyl,
(d) C.sub.1 -C.sub.8 -alkyl wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of aryl, heteroaryl, --OH, --SH, C.sub.1 -C.sub.4 -alkyl, --O(C.sub.1 -C.sub.4 -alkyl), --S(C.sub.1 -C.sub.4 -alkyl), --CF.sub.3, Cl, Br, F, I, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 --C.sub.1 -C.sub.4 -alkyl, --NH.sub.2, --NR.sup.4 CO.sub.2 R.sup.22, --NH(C.sub.1 -C.sub.4 -alkyl), --N(C.sub.1 -C.sub.4 -alkyl).sub.2, --PO.sub.3 H.sub.2, --PO(OH)(O--C.sub.1 -C.sub.4 -alkyl), --PO(OR.sup.4)R.sup.9, --NR.sup.4 COR.sup.22, --CONR.sup.4 R.sup.22, --OCONR.sup.4 R.sup.22, --SO.sub.2 NR.sup.4 R.sup.22, or --NR.sup.4 SO.sub.2 R.sub.22, or
(e) perfluoro-C.sub.1 -C.sub.4 -alkyl;
X is
(a) a carbon-carbon single bond,
(b) --CO--,
(c) --O--,
(d) --S--, ##STR21## (h) --OCH.sub.2 --, (i) --CH.sub.2 O--
(j) --SCH.sub.2 --,
(k) --CH.sub.2 S--,
(l) --NHC(R.sup.9)(R.sup.10),
(m) --NR.sup.9 SO.sub.2 --,
(n) --SO.sub.2 NR.sup.9 --,
(o) --C(R.sup.9)(R.sup.10)NH--,
(p) --CH.dbd.CH--,
(q) --CF.dbd.CF--,
(r) --CH.dbd.CF--,
(s) --CF.dbd.CH--,
(t) --CH.sub.2 CH.sub.2 --,
(u) --CF.sub.2 CF.sub.2 --, ##STR22## r is 1 or 2.

131 more elements

Dependencies are inferred from the claim text.

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