US 5,502,187 AGranted

Pharmaceutically active bicyclic-heterocyclic amines

AssigneeThe Upjohn Company

InventorsDonald E. Ayer, Gordon L. Bundy, Eric J. Jacobsen

Life of this patent

Estimating the term…

Abstract

The pharmaceutically active bicyclic heterocyclic amines (XXX) ##STR1## where W.sub.1 is --N.dbd. or --CH.dbd.; W.sub.3 is --N.dbd. or --CH.dbd.; W.sub.5 is --N.dbd. or --CR.sub.5 -- with the proviso that W.sub.5 is --CR.sub.5 -- when both W.sub.1 and W.sub.3 are --N.dbd. which are useful as pharmaceuticals in treating mild and/or moderate to severe head injury, subarachnoid hemorrhage and subsequent ischemic stroke, asthma and reduction of mucous formation/secretion in the lung and other diseases and injuries.

Claims25

Dependent claims

A bicyclic heterocyclic amines of the formula (XXX)

where
W.sub.1 is --N.dbd. or --CH.dbd.;
W.sub.3 is --N.dbd. or --CH.dbd.;
W.sub.5 is --N.dbd. or --CR.sub.5 -- with the proviso that W.sub.5 is --CR.sub.5 -- when both W.sub.1 and W.sub.3 are --N.dbd.;
where
R.sub.5 is
(C.sub.5 -1)
(A) --H,
(C.sub.5 -2)
(B) C.sub.1 -C.sub.8 alkyl optionally substituted with 1 thru 4 R.sub.5-1 where R.sub.5-1 is
(1) --F, --Cl, --Br,
(2) C.sub.1 -C.sub.4 alkyl,
(3) --CF.sub.3,
(4) -.phi.,
(5) --OR.sub.5-2 where R.sub.5-2 is
(a) --H,
(b) C.sub.1 -C.sub.4 alkyl,
(c) phosphate,
(d) sulfate,
(e) --CO--R.sub.5-8 where R.sub.5-8 is C.sub.1 -C.sub.4 alkyl or C.sub.6 -C.sub.9 aralkyl,
(f) --CO--NR.sub.5-10 R.sub.5-11 where R.sub.5-10 and R.sub.5-11 are the same or different and are --H or C.sub.1 -C.sub.3 alkyl,
(g) sulfamate,
(h) glucosyl,
(i) galactosyl,
(j) glucuronic acid,
(k) maltosyl,
(l) arabinosyl,
(m) xylosyl,
(n) --CO--CH(NH.sub.2)--H,
(o) --CO--CH(NH.sub.2)--CH.sub.3,
(p) --CO--CH(NH.sub.2)--CH(CH.sub.3).sub.2,
(q) --CO--CH(NH.sub.2)--CH.sub.2 --CH(CH.sub.3).sub.2,
(r) --CO--CH(NH.sub.2)--CH(CH.sub.3)--CH.sub.2 --CH.sub.3,
(s) --CO--CH(NH.sub.2)--CH.sub.2 --OH
(t) --CO--CH(NH.sub.2)--CH(OH)--CH.sub.3,
(u) --CO--CH(NH.sub.2)--CH.sub.2 -.phi.,
(v) --CO--CH(NH.sub.2)--CH.sub.2 - p-phenyl!--OH,
(w) --CO--CH(NH.sub.2)--CH.sub.2 - 2-indolyl!
(x) --CO--CH(NH.sub.2)--CH.sub.2 --SH,
(y) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --S--CH.sub.3,
(z) --CO--C*H--NH--CH.sub.2 --CH.sub.2 --C*H.sub.2 where the carbon atoms marked with an "*" are bonded together to form a heterocyclic ring,
(aa) --CO--C*H--NH--CH.sub.2 --CH(OH)--C*H.sub.2 where the carbon atoms marked with an "*" are bonded together to form a heterocyclic ring,
(bb) --CO--CH(NH.sub.2)--CH.sub.2 --COOH,
(cc) --CO--CH(NH.sub.2)--CH.sub.2 --CONH.sub.2,
(dd) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --COOH,
(ee) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CONH.sub.2,
(ff) --CO--CH(NH.sub.2)--CH.sub.2 --C*--NH--CH.dbd.N--C*H.dbd. where the carbon atoms marked with an "*" are bonded together to form a heterocyclic ring,
(gg) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH--C(.dbd.NH)--NH.sub.2,
(hh) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --NH.sub.2,
(ii) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH(OH)--CH.sub.2 --NH.sub.2,
(jj) --CO--CH.sub.2 --CH.sub.2 --NH.sub.2,
(kk) --CO--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH.sub.2,
(ll) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH.sub.2,
(mm) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH--CO--NH.sub.2,
(nn) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --OH,
(6) --SR.sub.5-2 where R.sub.5-2 is defined above,
(7) --NHR.sub.5-3 where R.sub.5-3 is --H or C.sub.1 -C.sub.4 alkyl,
(8) --NR.sub.5-4 R.sub.5-5 where R.sub.5-4 and R.sub.5-5 are the same or different and are C.sub.1 -C.sub.4 alkyl or may taken together with the attached nitrogen atom to form the heterocyclic ring --N*--(CH.sub.2).sub.n1 --R.sub.5-6 --(CH.sub.2).sub.n2 * where the atoms marked with an asterisk (*) are bonded together resulting in the formation of a ring, where n.sub.1 is 1 thru 5, n.sub.2 is 0 thru 3 and R.sub.5-6 is
(a) --CH.sub.2 --,
(b) --O--,
(c) --S--,
(d) --NR.sub.5-9 where R.sub.5-9 is
(i) C.sub.1 -C.sub.6 alkyl optionally substituted with 1 thru 3--OH or --OCH.sub.3,
(ii) C.sub.1 -C.sub.6 alkylcarbonyl,
(iii) C.sub.1 -C.sub.6 alkoxycarbonyl,
(iv) C.sub.6 -C.sub.12 arylalkyl,
(v) -.phi.,
(vi)--SO.sub.2 --C.sub.1 -C.sub.8 alkyl,
(vii) CH.sub.3 --C*--O--CO--O--C*--CH.sub.2 -- where the carbon atoms designated by * are attached by a double bond to form a five member ring,
(9) --(CH.sub.2).sub.n3 CO.sub.2 R.sub.5-2, where n.sub.3 is 0 thru 6 and R.sub.5-2 is as defined above,
(10) --(CH.sub.2).sub.n3 CON(R.sub.5-3).sub.2 where n.sub.3 is as defined as above and where R.sub.5-3 may be the same or different and is defined above,
(11) --(CH.sub.2).sub.n3 CONR.sub.5-4 R.sub.5-5 where n.sub.3, R.sub.5-4, R.sub.5-5 are as defined above,
(12) --(CH.sub.2).sub.n1 OR.sub.5-2 where R.sub.5-2 and n.sub.1 are as defined above,
(13) --(CH.sub.2).sub.n1 OCOR.sub.5-3 where R.sub.5-3 and n.sub.1 are as defined above,
(14) --(CH.sub.2).sub.n1 SR.sub.5-2 where R.sub.5-2 and n.sub.1 are as defined above,
(15) --(CH.sub.2).sub.n1 NHR.sub.5-3 where R.sub.5-3 and n.sub.1 are as defined above,
(16) --(CH.sub.2).sub.n1 NR.sub.5-4 R.sub.5-5 where R.sub.5-4, R.sub.5-5, and n.sub.1 are as defined above,
(C.sub.5 -3)
(C) --(CH.sub.2).sub.n3 -.phi. optionally substituted with 1 thru 4 R.sub.5-1 where R.sub.5-1 and n.sub.3 are as defined as above,
(D) --(CH.sub.2).sub.n3 -pyridin-2-, 3- or 4-yl optionally substituted with 1 thru 4 R.sub.5-1 where n.sub.3 and R.sub.5-1 are as defined above,
(E) --(CH.sub.2).sub.n3 -naphthalin-1-, 2-yl optionally substituted with 1 thru 4 R.sub.5-1 where n.sub.3 and R.sub.5-1 are as defined above,
(C.sub.5 -5)
(F) --(CH.sub.2).sub.n3 CO.sub.2 R.sub.5-2 where n.sub.3 and R.sub.5-2 are as defined above,
(C.sub.5 -6)
(G) --(CH.sub.2).sub.n3 CON(R.sub.5-3).sub.2 where n.sub.3 is as defined as above and where R.sub.5-3 may be the same or different and is as defined above,
(C.sub.5 -7)
(H) --(CH.sub.2).sub.n3 CONR.sub.5-4 R.sub.5-5 where n.sub.3, R.sub.5-4, R.sub.5-5 are as defined above,
(C.sub.5 -8)
(I) --(CH.sub.2).sub.n3 SO.sub.3 R.sub.5-2 where n.sub.3 and R.sub.5-2 are as defined above,
(C.sub.5 -9)
(J) --C.sub.3 -C.sub.7 cycloalkyl;
where
R.sub.2-1 is
(A) --H,
(B) C.sub.1 -C.sub.8 alkyl optionally substituted with 1 thru 4
(1) --F,
(2) --Cl,
(3) --OR.sub.5-2 where R.sub.5-2 is as defined above,
(4) --N(R.sub.5-9).sub.2 where R.sub.5-9 may be the same or different and is as defined above;
where
R.sub.2-2 is
(A) --H,
(B) C.sub.1 -C.sub.8 alkyl optionally substituted with 1 thru 4
(1) --F,
(2) --Cl,
(3) --OR.sub.5-2 where R.sub.5-2 is as defined above,
(4) --N(R.sub.5-9).sub.2 where R.sub.5-9 may be the same or different and is as defined above, or R.sub.2-1 and R.sub.2-2 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of
(A) 1-pyrrolidinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is selected from the group of
(1) C.sub.1 -C.sub.6 alkyl optionally substituted with 1 thru 3 --OH or --OCH.sub.3,
(2) C.sub.1 -C.sub.6 alkenyl optionally substituted with 1 thru 3 --OH or --OCH.sub.3,
(3) C.sub.1 -C.sub.6 alkylcarbonyl,
(4) C.sub.1 -C.sub.6 alkoxycarbonyl,
(5) C.sub.6 -C.sub.12 arylalkyl,
(6) .dbd.O,
(7) --OH,
(8) --C.tbd.N,
(9) --CO.sub.2 R.sub.2-4 where R.sub.2-4 is
(a) --H,
(b) C.sub.1 -C.sub.4 alkyl,
(c) C.sub.6 -C.sub.12 aryl,
(d) C.sub.6 -C.sub.12 aralkyl,
(10) --NH.sub.2,
(11) --Cl,
(12) --F,
(13) --Br,
(14) -.phi. optionally substituted with 1 thru 3 --F, --Cl, --Br, --OH, --OCH.sub.3, --OCH.sub.2 -.phi., --NO.sub.2, C.sub.1 -C.sub.3 alkyl, --NH.sub.2, --NHCH.sub.3, N(CH.sub.3).sub.2, --CO.sub.2 R.sub.2-4 where R.sub.2-4 is as defined above,
(15) --(CH.sub.2).sub.n4 NR.sub.2-6 R.sub.2-7 where R.sub.2-6 and R.sub.2-7 are the same or different and are C.sub.1 -C.sub.4 alkyl or may taken together with the attached nitrogen atom to form the heterocyclic ring --N*--(CH.sub.2).sub.n5 --R.sub.2-8 --(CH.sub.2).sub.n6 * where the atoms marked with an asterisk (*) are bonded together resulting in the formation of a ring, where n.sub.4 is 0 thru 3, n.sub.5 is 1 thru 5, n.sub.6 is 0 thru 3 and R.sub.2-8 is
(a) --CH.sub.2 --,
(b) --O--,
(c) --S--,
(d) --NR.sub.2-4 where R.sub.2-4 is as defined above,
(B) 1-piperdinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(C) 1-morpholinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(D) 1-piperazinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above and optionally substituted in the 4-position with R.sub.2-5 where R.sub.2-5 is
(1) C.sub.1 -C.sub.6 alkyl optionally substituted with 1 thru 3 --OH or --OCH.sub.3,
(2) C.sub.1 -C.sub.6 alkylcarbonyl,
(3) C.sub.1 -C.sub.6 alkoxycarbonyl,
(4) C.sub.6 -C.sub.12 arylalkyl,
(5) -.phi.,
(6)--SO.sub.2 -C.sub.1 -C.sub.8 alkyl,
(7) CH.sub.3 --C*--O--CO--O--C*--CH.sub.2 -- where the carbon atoms designated by * are attached by a double bond to form a five member ring,
(E) 1-aziridinyl optionally substituted on carbon with 1 thru 2 R.sub.2-3 where R.sub.2-3 is as defined above,
(F) 1-azetidinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(G) 1-hexamethyleneimino optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(H) 1-pyrrolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(I) 1-imidazolyl optionally substituted on carbon with 1 thru 3 R.sub.2, .sub.3 where R.sub.2-3 is as defined above,
(J) 1-pyrazoyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(K) 1-pyrazolidinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(L) 1,2,3-triazolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(M) 1,2,4-triazolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(N) 1-tetrazolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(O) 1-thiomorpholinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(P) 1-thiazolidinyl, optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above, ##STR7## where R.sub.2-3 and R.sub.2-5 are as defined above,
where
R.sub.2-9 is
(A) --(CH.sub.2).sub.n4 where n.sub.4 is 1 thru 3,
(B) --CH.sub.2 OCH.sub.2,
(C) --CH.sub.2 SCH.sub.2,
(D) --CH.sub.2 SO.sub.2 CH.sub.2,
(E) --CH.sub.2 S,
(F) --CH.sub.2 SO.sub.2,
(G) --CH.sub.2 N(R.sub.2-5)CH.sub.2 where R.sub.2-5 is as defined above, with the proviso that R.sub.2-1 and R.sub.2-2 can not both be --H;
where R.sub.4-1 is defined the same as R.sub.2-1, but may be the same or different than R.sub.2-1,
where R.sub.4-2 is defined the same as R.sub.2-2, but may be the same or different than R.sub.2-2, with the proviso that R.sub.4-1 and R.sub.4-2 can not both be --H;
where (R.sub.6 -1) R.sub.6 is defined the same as R.sub.5, but may be the same or different than R.sub.5, with the proviso that;
(I) one of R.sub.5, R.sub.6 or R.sub.7 must be selected from the group consisting of
(C.sub.5 -3)
(C) --(CH.sub.2).sub.n3 -.phi. optionally substituted with 1 thru 4 R.sub.5-1 where R.sub.5-1 and n.sub.3 as defined as above,
(D) --(CH.sub.2).sub.n3 -pyridin-2-, 3- or 4-yl optionally substituted with 1 thru 4 R.sub.5-1 where n.sub.3 and R.sub.5-1 are as defined above,
(E) --(CH.sub.2).sub.n3 -naphthalin-1-, 2-yl optionally substituted with 1 thru 4 R.sub.5-1 where n.sub.3 and R.sub.5-1 are as defined above, and
(II) for at least one of these three aromatic substituents, n.sub.3 must be 0;
where R.sub.7 is defined the same as R.sub.5, but may be the same or different than R.sub.5 ;
with the proviso that W.sub.1 and W.sub.3 can not both be --CH.dbd., and pharmaceutically acceptable salts thereof.

170 more elements

A bicyclic heterocyclic amines of the formula (XXX) ##STR8## where W.sub.1 is --N.dbd.;

W.sub.3 is --N.dbd.;
W.sub.5 is --CR.sub.5 --;
(R.sub.6 -2)
where R.sub.5 and R.sub.6 are taken together with the attached carbon atoms to form a ring selected from the group consisting of
(R.sub.6 -2A)
--C*--(CH.sub.2).sub.n7 --C*-- where the carbon atoms marked by an asterick (*) are the carbon atoms in the 5-member nitrogen containing ring which are bonded together by the double bond (C.dbd.C), where n.sub.7 is 3-5, and
(R.sub.6 -2B)
--C*--CR.sub.56-1 .dbd.CR.sub.56-2 --CR.sub.56-3 .dbd.CR.sub.56-4 --C*-- where the carbon atoms marked by an asterick (*) are the carbon atoms in the 5-member nitrogen containing ring which are bonded together by the double bond (C.dbd.C), where R.sub.56-1, R.sub.56-2, R.sub.56-3 and R.sub.56-4 are --H, --F, --Cl, --Br, --OH, --NO.sub.2, C.sub.1 -C.sub.3 alkyl, --NH.sub.2, --NHCH.sub.3, N(CH.sub.3).sub.2, --CO.sub.2 R.sub.56-5 where R.sub.56-5 is:
--H,
C.sub.1 -C.sub.4 alkyl,
C.sub.6 -C.sub.12 aryl,
C.sub.6 -C.sub.12 aralkyl;
where
R.sub.2-1 is
(A) --H,
(B) C.sub.1 -C.sub.8 alkyl optionally substituted with 1 thru 4
(1) --F,
(2) --Cl,
(3) --OR.sub.2-10 where R.sub.2-10 is
(a) --H,
(b) C.sub.1 -C.sub.4 alkyl,
(c) phosphate,
(d) sulfate,
(e) --CO--R.sub.2-11 where R.sub.2-11 is C.sub.1 -C.sub.4 alkyl or C.sub.6 -C.sub.9 aralkyl,
(f) --CO--NR.sub.2-12 R.sub.2-13 where R.sub.2-12 and R.sub.2-13 are the same or different and are --H or C.sub.1 -C.sub.3 alkyl,
(g) sulfamate,
(h) glucosyl,
(i) galactosyl,
(j) glucuronic acid,
(k) maltosyl,
(l) arabinosyl,
(m) xylosyl,
(n) --CO--CH(NH.sub.2)--H,
(o) --CO--CH(NH.sub.2)--CH.sub.3,
(p) --CO--CH(NH.sub.2)--CH(CH.sub.3).sub.2,
(q) --CO--CH(NH.sub.2)--CH.sub.2 --CH(CH.sub.3).sub.2,
(r) --CO--CH(NH.sub.2)--CH(CH.sub.3)--CH.sub.2 --CH.sub.3,
(s) --CO--CH(NH.sub.2)--CH.sub.2 --OH
(t) --CO--CH(NH.sub.2)--CH(OH)--CH.sub.3,
(u) --CO--CH(NH.sub.2)--CH.sub.2 -.phi.,
(v) --CO--CH(NH.sub.2)--CH.sub.2 - p-phenyl!--OH,
(w) --CO--CH(NH.sub.2)--CH.sub.2 - 2-indolyl!
(x) --CO--CH(NH.sub.2)--CH.sub.2 --SH,
(y) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --S--CH.sub.3,
(z) --CO--C*H--NH--CH.sub.2 --CH.sub.2 --C*H.sub.2 where the carbon atoms marked with an "*" are bonded together to form a heterocyclic ring,
(aa) --CO--C*H--NH--CH.sub.2 --CH(OH)--C*H.sub.2 where the carbon atoms marked with an "*" are bonded together to form a heterocyclic ring,
(bb) --CO--CH(NH.sub.2)--CH.sub.2 --COOH,
(cc) --CO--CH(NH.sub.2)--CH.sub.2 --CONH.sub.2,
(dd) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --COOH,
(ee) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CONH.sub.2,
(ff) --CO--CH(NH.sub.2)--CH.sub.2 --C*--NH--CH.dbd.N--C*H.dbd. where the carbon atoms marked with an "*" are bonded together to form a heterocyclic ring,
(gg) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH--C(.dbd.NH)--NH.sub.2,
(hh) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --NH.sub.2,
(ii) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH(OH)--CH.sub.2 --NH.sub.2,
(jj) --CO--CH.sub.2 --CH.sub.2 --NH.sub.2,
(kk) --CO--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH.sub.2,
(ll) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH.sub.2,
(mm) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH--CO--NH.sub.2,
(nn) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --OH,
(4) --N(R.sub.2-14).sub.2 where R.sub.2-14 may be the same or different and is
(a) C.sub.1 -C.sub.6 alkyl optionally substituted with 1 thru 3 --OH or --OCH.sub.3,
(b) C.sub.1 -C.sub.6 alkylcarbonyl,
(c) C.sub.1 -C.sub.6 alkoxycarbonyl,
(d) C.sub.6 -C.sub.12 arylalkyl,
(e) -.phi.,
(f) --SO.sub.2 -C.sub.1 -C.sub.8 alkyl,
(g) CH.sub.3 --C*--O--CO--O--C*--CH.sub.2 -- where the carbon atoms marked by an asterick (*) are attached by a double bond to form a five member ring,
where
R.sub.2-2 is
(A) --H,
(B) C.sub.1 -C.sub.8 alkyl optionally substituted with 1 thru 4
(1) --F,
(2) --Cl,
(3) --OR.sub.2-10 where R.sub.2-10 is as defined above,
(4) --N(R.sub.2-14).sub.2 where R.sub.2-14 may be the same or different and is as defined above, or R.sub.2-1 and R.sub.2-2 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of
(A) 1-pyrrolidinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is selected from the group of
(1) C.sub.1 -C.sub.6 alkyl optionally substituted with 1 thru 3 --OH or --OCH.sub.3,
(2) C.sub.1 -C.sub.6 alkenyl optionally substituted with 1 thru 3 --OH or--OCH.sub.3,
(3) C.sub.1 -C.sub.6 alkylcarbonyl,
(4) C.sub.1 -C.sub.6 alkoxycarbonyl,
(5) C.sub.6 -C.sub.12 arylalkyl,
(6) .dbd.O,
(7) --OH,
(8) --C.tbd.N,
(9) --CO.sub.2 R.sub.2-4 where R.sub.2-4 is
(a) --H,
(b) C.sub.1 -C.sub.4 alkyl,
(c) C.sub.6 -C.sub.12 aryl,
(d) C.sub.6 -C.sub.12 aralkyl,
(10) --NH.sub.2,
(11) --Cl,
(12) --F,
(13) --Br,
(14) -.phi. optionally substituted with 1 thru 3 --F, --Cl, --Br, --OH, --OCH.sub.3, --OCH.sub.2 -.phi., --NO.sub.2, C.sub.1 C.sub.3 alkyl, --NH.sub.2, --NHCH.sub.3, N(CH.sub.3).sub.2, --CO.sub.2 R.sub.2-4 where R.sub.2-4 is as defined above,
(15) --(CH.sub.2).sub.n4 NR.sub.2-6 R.sub.2-7 where R.sub.2-6 and R.sub.2-7 are the same or different and are C.sub.1 -C.sub.4 alkyl or may taken together with the attached nitrogen atom to form the heterocyclic ring --N*--(CH.sub.2).sub.n5 --R.sub.2-8 --(CH.sub.2).sub.n6 * where the atoms marked with an asterisk (*) are bonded together resulting in the formation of a ring, where n.sub.4 is 0 thru 3, n.sub.5 is 1 thru 5, n.sub.6 is 0 thru 3 and R.sub.2-8 is
(a)--CH.sub.2 --,
(b) --O--,
(c) --S--,
(d) --NR.sub.2-4 where R.sub.2-4 is as defined above,
(B) 1-piperdinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(C) 1-morpholinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(D) 1-piperazinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above and optionally substituted in the 4-position with R.sub.2-5 where R.sub.2-5 is
(1) C.sub.1 -C.sub.6 alkyl optionally substituted with 1 thru 3 --OH or --OCH.sub.3,
(2) C.sub.1 -C.sub.6 alkylcarbonyl,
(3) C.sub.1 -C.sub.6 alkoxycarbonyl,
(4) C.sub.6 -C.sub.12 arylalkyl,
(5) -.phi.,
(6)--SO.sub.2 -C.sub.1 -C.sub.8 alkyl,
(7) CH.sub.3 --C*--O--CO--O--C*--CH.sub.2 -- where the carbon atoms marked by an asterick (*) are attached by a double bond to form a five member ring,
(E) 1-aziridinyl optionally substituted on carbon with 1 thru 2 R.sub.2-3 where R.sub.2-3 is as defined above,
(F) 1-azetidinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(G) 1-hexamethyleneimino optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(H) 1-pyrrolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(I) 1-imidazolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(J) 1-pyrazoyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(K) 1-pyrazolidinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(L) 1,2,3-triazolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(M) 1,2,4-triazolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(N) 1-tetrazolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(O) 1-thiomorpholinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(P) 1-thiazolidinyl, optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above, ##STR9## where R.sub.2-3 and R.sub.2-5 are as defined above,
where
R.sub.2-9 is
(A) --(CH.sub.2).sub.n4 where n.sub.4 is 1 thru 3,
(B) --CH.sub.2 OCH.sub.2,
(C) --CH.sub.2 SCH.sub.2,
(D) --CH.sub.2 SO.sub.2 CH.sub.2,
(E) --CH.sub.2 S,
(F) --CH.sub.2 SO.sub.2,
(G) --CH.sub.2 N(R.sub.2-5)CH.sub.2 where R.sub.2-5 is as defined above, where R.sub.4-1 is defined the same as R.sub.2-1, but may be the same or different than R.sub.2-1, where R.sub.4-2 is defined the same as R.sub.2-2, but may be the same or different than R.sub.2-2 ;
where R.sub.7 is
(C.sub.7 -1)
(A) --H,
(C.sub.7 -2)
(B) C.sub.1 -C.sub.8 alkyl optionally substituted with 1 thru 4 R.sub.7-1 where R.sub.7-1 is
(1) --F, --Cl, --Br,
(2) C.sub.1 -C.sub.4 alkyl,
(3) --CF.sub.3,
(4) -.phi.,
(5) --OR.sub.7-2 where R.sub.7-2 is
(a) --H,
(b) C.sub.1 -C.sub.4 alkyl,
(c) phosphate,
(d) sulfate,
(e) --CO--R.sub.7-8 where R.sub.7-8 is C.sub.1 -C.sub.4 alkyl or C.sub.6 -C.sub.9 aralkyl,
(f) --CO--NR.sub.7-10 R.sub.7-11 where R.sub.7-10 and R.sub.7-11 are the same or different and are --H or C.sub.1 -C.sub.3 alkyl,
(g) sulfamate,
(h) glucosyl,
(i) galactosyl,
(j) glucuronic acid,
(k) maltosyl,
(l) arabinosyl,
(m) xylosyl,
(n) --CO--CH(NH.sub.2)--H,
(o) --CO--CH(NH.sub.2)--CH.sub.3,
(p) --CO--CH(NH.sub.2)--CH(CH.sub.3).sub.2,
(q) --CO--CH(NH.sub.2)--CH.sub.2 --CH(CH.sub.3).sub.2,
(r) --CO--CH(NH.sub.2)--CH(CH.sub.3)--CH.sub.2 --CH.sub.3,
(s) --CO--CH(NH.sub.2)--CH.sub.2 --OH
(t) --CO--CH(NH.sub.2)--CH(OH)--CH.sub.3,
(u) --CO--CH(NH.sub.2)--CH.sub.2 -.phi.,
(v) --CO--CH(NH.sub.2)--CH.sub.2 - p-phenyl!--OH,
(w) --CO--CH(NH.sub.2)--CH.sub.2 - 2-indolyl!
(x) --CO--CH(NH.sub.2)--CH.sub.2 --SH,
(y) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --S--CH.sub.3,
(z) --CO--C*H--NH--CH.sub.2 --CH.sub.2 --C*H.sub.2 where the carbon atoms marked with an asterick (*) are bonded together to form a heterocyclic ring,
(aa) --CO--C*H--NH--CH.sub.2 --CH(OH)--C*H.sub.2 where the carbon atoms marked with an asterick (*) are bonded together to form a heterocyclic ring,
(bb) --CO--CH(NH.sub.2)--CH.sub.2 --COOH,
(cc) --CO--CH(NH.sub.2)--CH.sub.2 --CONH.sub.2,
(dd) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --COOH,
(ee) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CONH.sub.2,
(ff) --CO--CH(NH.sub.2)--CH.sub.2 --C*--NH--CH.dbd.N--C*H.dbd. where the carbon atoms marked with an asterick (*) are bonded together to form a heterocyclic ring,
(gg) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH--C(.dbd.NH)--NH.sub.2,
(hh) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --NH.sub.2,
(ii) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH(OH)--CH.sub.2 --NH.sub.2,
(jj) --CO--CH.sub.2 --CH.sub.2 --NH.sub.2,
(kk) --CO--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH.sub.2,
(ll) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH.sub.2,
(mm) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH--CO--NH.sub.2,
(nn) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --OH,
(6) --SR.sub.7-2 where R.sub.7-2 is defined above,
(7) --NHR.sub.7-3 where R.sub.7-3 is --H or C.sub.1 -C.sub.4 alkyl,
(8) --NR.sub.7-4 R.sub.7-5 where R.sub.7-4 and R.sub.7-5 are the same or different and are C.sub.1 -C.sub.4 alkyl or may taken together with the attached nitrogen atom to form the heterocyclic ring --N*--(CH.sub.2).sub.n1 --R.sub.5-6 --(CH.sub.2).sub.n2 * where the atoms marked with an asterisk (*) are bonded together resulting in the formation of a ring, where n.sub.1 is 1 thru 5, n.sub.2 is 0 thru 3 and R.sub.5-6 is
(a) --CH.sub.2 --,
(b) --O--,
(c) --S--,
(d) --NR.sub.7-9 where R.sub.7-9 is
(i) C.sub.1 -C.sub.6 alkyl optionally substituted with 1 thru 3 --OH or --OCH.sub.3,
(ii) C.sub.1 -C.sub.6 alkylcarbonyl,
(iii) C.sub.1 -C.sub.6 alkoxycarbonyl,
(iv) C.sub.6 -C.sub.12 arylalkyl,
(v) -.phi.,
(vi) --SO.sub.2 -C.sub.1 -C.sub.8 alkyl,
(vii) CH.sub.3 --C*--O--CO--O--C*--CH.sub.2 -- where the carbon atoms designated by * are attached by a double bond to form a five member ring,
(9) --(CH.sub.2).sub.n3 CO.sub.2 R.sub.7-2, where n.sub.3 is 0 thru 6 and R.sub.7-2 is as defined above,
(10) --(CH.sub.2).sub.n3 CON(R.sub.7-3).sub.2 where n.sub.3 is as defined as above and where R.sub.7-3 may be the same or different and is defined above,
(11) --(CH.sub.2).sub.n3 CONR.sub.7-4 R.sub.7-5 where n.sub.3, R.sub.7-4, R.sub.7-5 are as defined above,
(12) --(CH.sub.2).sub.n1 OR.sub.7-2 where R.sub.7-2 and n.sub.1 are as defined above,
(13) --(CH.sub.2).sub.n1 OCOR.sub.7-3 where R.sub.7-3 and n.sub.1 are as defined above,
(14) --(CH.sub.2).sub.n1 SR.sub.7-2 where R.sub.7-2 and n.sub.1 are as defined above,
(15) --(CH.sub.2).sub.n1 NHR.sub.7-3 where R.sub.7-3 and n.sub.1 are as defined above,
(16) --(CH.sub.2).sub.n1 NR.sub.7-4 R.sub.7-5 where R.sub.7-4, R.sub.7-5, and n.sub.1 are as defined above,
(C.sub.5 -3)
(C) --(CH.sub.2).sub.n3 -.phi. optionally substituted with 1 thru 4 R.sub.7-1 where R.sub.7-1 and n.sub.3 are as defined as above,
(D) --(CH.sub.2).sub.n3 -pyridin-2-, 3- or 4-yl optionally substituted with 1 thru 4 R.sub.7-1 where n.sub.3 and R.sub.7-1 are as defined above,
(E) --(CH.sub.2).sub.n3 -naphthalin-1-, 2-yl optionally substituted with 1 thru 4 R.sub.7-1 where n.sub.3 and R.sub.7-1 are as defined above,
(C.sub.5 -5)
(F) --(CH.sub.2).sub.n3 CO.sub.2 R.sub.7-2 where n.sub.3 and R.sub.7-2 are as defined above,
(C.sub.5 -6)
(G) --(CH.sub.2).sub.n3 CON(R.sub.7-3).sub.2 where n.sub.3 is as defined as above and where R.sub.7-3 may be the same or different and is as defined above,
(C.sub.5 -7)
(H) --(CH.sub.2).sub.n3 CONR.sub.7-4 R.sub.7-5 where n.sub.3, R.sub.7-4, R.sub.7-5 are as defined above,
(C.sub.5 -8)
(I) --(CH.sub.2).sub.n3 SO.sub.3 R.sub.7-2 where n.sub.3 and R.sub.7-2 are as defined above,
(C.sub.5 -9)
(J) --C.sub.3 -C.sub.7 cycloalkyl;
with the provisos:
(1) that when R.sub.7 is --H, R.sub.56-1, R.sub.56-3 and R.sub.56-4 can not be --OH;
(2) that when R.sub.2-1 and R.sub.2-2 is taken together with the attached nitrogen atom to form 1-pyrrolidinyl, and R.sub.4-1 and R.sub.4-2 is taken together with the attached nitrogen atom to form 1-pyrrolidinyl, R.sub.7 is not --CH.sub.2 --CH.sub.2 -morphinyl;
and pharmaceutically acceptable salts thereof.

217 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/317,934Filed 3 Oct 1994 · continuation in part
Priority: 3 Apr 1992
Granted: 26 Mar 1996
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
C07H 15/26
Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals: acyclic or…
C07D
Heterocyclic compounds

Family

Serial863,646Parent of this continuation-in-part · filed 3 Apr 1992
Serial128,957Parent of this continuation · filed 29 Sep 1993
Serial222,995Parent of this continuation · filed 5 Apr 1994
US 5,502,187 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A bicyclic heterocyclic amines of the formula (XXX)

where
W.sub.1 is --N.dbd. or --CH.dbd.;
W.sub.3 is --N.dbd. or --CH.dbd.;
W.sub.5 is --N.dbd. or --CR.sub.5 -- with the proviso that W.sub.5 is --CR.sub.5 -- when both W.sub.1 and W.sub.3 are --N.dbd.;
where
R.sub.5 is
(C.sub.5 -1)
(A) --H,
(C.sub.5 -2)
(B) C.sub.1 -C.sub.8 alkyl optionally substituted with 1 thru 4 R.sub.5-1 where R.sub.5-1 is
(1) --F, --Cl, --Br,
(2) C.sub.1 -C.sub.4 alkyl,
(3) --CF.sub.3,
(4) -.phi.,
(5) --OR.sub.5-2 where R.sub.5-2 is
(a) --H,
(b) C.sub.1 -C.sub.4 alkyl,
(c) phosphate,
(d) sulfate,
(e) --CO--R.sub.5-8 where R.sub.5-8 is C.sub.1 -C.sub.4 alkyl or C.sub.6 -C.sub.9 aralkyl,
(f) --CO--NR.sub.5-10 R.sub.5-11 where R.sub.5-10 and R.sub.5-11 are the same or different and are --H or C.sub.1 -C.sub.3 alkyl,
(g) sulfamate,
(h) glucosyl,
(i) galactosyl,
(j) glucuronic acid,
(k) maltosyl,
(l) arabinosyl,
(m) xylosyl,
(n) --CO--CH(NH.sub.2)--H,
(o) --CO--CH(NH.sub.2)--CH.sub.3,
(p) --CO--CH(NH.sub.2)--CH(CH.sub.3).sub.2,
(q) --CO--CH(NH.sub.2)--CH.sub.2 --CH(CH.sub.3).sub.2,
(r) --CO--CH(NH.sub.2)--CH(CH.sub.3)--CH.sub.2 --CH.sub.3,
(s) --CO--CH(NH.sub.2)--CH.sub.2 --OH
(t) --CO--CH(NH.sub.2)--CH(OH)--CH.sub.3,
(u) --CO--CH(NH.sub.2)--CH.sub.2 -.phi.,
(v) --CO--CH(NH.sub.2)--CH.sub.2 - p-phenyl!--OH,
(w) --CO--CH(NH.sub.2)--CH.sub.2 - 2-indolyl!
(x) --CO--CH(NH.sub.2)--CH.sub.2 --SH,
(y) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --S--CH.sub.3,
(z) --CO--C*H--NH--CH.sub.2 --CH.sub.2 --C*H.sub.2 where the carbon atoms marked with an "*" are bonded together to form a heterocyclic ring,
(aa) --CO--C*H--NH--CH.sub.2 --CH(OH)--C*H.sub.2 where the carbon atoms marked with an "*" are bonded together to form a heterocyclic ring,
(bb) --CO--CH(NH.sub.2)--CH.sub.2 --COOH,
(cc) --CO--CH(NH.sub.2)--CH.sub.2 --CONH.sub.2,
(dd) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --COOH,
(ee) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CONH.sub.2,
(ff) --CO--CH(NH.sub.2)--CH.sub.2 --C*--NH--CH.dbd.N--C*H.dbd. where the carbon atoms marked with an "*" are bonded together to form a heterocyclic ring,
(gg) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH--C(.dbd.NH)--NH.sub.2,
(hh) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --NH.sub.2,
(ii) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH(OH)--CH.sub.2 --NH.sub.2,
(jj) --CO--CH.sub.2 --CH.sub.2 --NH.sub.2,
(kk) --CO--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH.sub.2,
(ll) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH.sub.2,
(mm) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --CH.sub.2 --NH--CO--NH.sub.2,
(nn) --CO--CH(NH.sub.2)--CH.sub.2 --CH.sub.2 --OH,
(6) --SR.sub.5-2 where R.sub.5-2 is defined above,
(7) --NHR.sub.5-3 where R.sub.5-3 is --H or C.sub.1 -C.sub.4 alkyl,
(8) --NR.sub.5-4 R.sub.5-5 where R.sub.5-4 and R.sub.5-5 are the same or different and are C.sub.1 -C.sub.4 alkyl or may taken together with the attached nitrogen atom to form the heterocyclic ring --N*--(CH.sub.2).sub.n1 --R.sub.5-6 --(CH.sub.2).sub.n2 * where the atoms marked with an asterisk (*) are bonded together resulting in the formation of a ring, where n.sub.1 is 1 thru 5, n.sub.2 is 0 thru 3 and R.sub.5-6 is
(a) --CH.sub.2 --,
(b) --O--,
(c) --S--,
(d) --NR.sub.5-9 where R.sub.5-9 is
(i) C.sub.1 -C.sub.6 alkyl optionally substituted with 1 thru 3--OH or --OCH.sub.3,
(ii) C.sub.1 -C.sub.6 alkylcarbonyl,
(iii) C.sub.1 -C.sub.6 alkoxycarbonyl,
(iv) C.sub.6 -C.sub.12 arylalkyl,
(v) -.phi.,
(vi)--SO.sub.2 --C.sub.1 -C.sub.8 alkyl,
(vii) CH.sub.3 --C*--O--CO--O--C*--CH.sub.2 -- where the carbon atoms designated by * are attached by a double bond to form a five member ring,
(9) --(CH.sub.2).sub.n3 CO.sub.2 R.sub.5-2, where n.sub.3 is 0 thru 6 and R.sub.5-2 is as defined above,
(10) --(CH.sub.2).sub.n3 CON(R.sub.5-3).sub.2 where n.sub.3 is as defined as above and where R.sub.5-3 may be the same or different and is defined above,
(11) --(CH.sub.2).sub.n3 CONR.sub.5-4 R.sub.5-5 where n.sub.3, R.sub.5-4, R.sub.5-5 are as defined above,
(12) --(CH.sub.2).sub.n1 OR.sub.5-2 where R.sub.5-2 and n.sub.1 are as defined above,
(13) --(CH.sub.2).sub.n1 OCOR.sub.5-3 where R.sub.5-3 and n.sub.1 are as defined above,
(14) --(CH.sub.2).sub.n1 SR.sub.5-2 where R.sub.5-2 and n.sub.1 are as defined above,
(15) --(CH.sub.2).sub.n1 NHR.sub.5-3 where R.sub.5-3 and n.sub.1 are as defined above,
(16) --(CH.sub.2).sub.n1 NR.sub.5-4 R.sub.5-5 where R.sub.5-4, R.sub.5-5, and n.sub.1 are as defined above,
(C.sub.5 -3)
(C) --(CH.sub.2).sub.n3 -.phi. optionally substituted with 1 thru 4 R.sub.5-1 where R.sub.5-1 and n.sub.3 are as defined as above,
(D) --(CH.sub.2).sub.n3 -pyridin-2-, 3- or 4-yl optionally substituted with 1 thru 4 R.sub.5-1 where n.sub.3 and R.sub.5-1 are as defined above,
(E) --(CH.sub.2).sub.n3 -naphthalin-1-, 2-yl optionally substituted with 1 thru 4 R.sub.5-1 where n.sub.3 and R.sub.5-1 are as defined above,
(C.sub.5 -5)
(F) --(CH.sub.2).sub.n3 CO.sub.2 R.sub.5-2 where n.sub.3 and R.sub.5-2 are as defined above,
(C.sub.5 -6)
(G) --(CH.sub.2).sub.n3 CON(R.sub.5-3).sub.2 where n.sub.3 is as defined as above and where R.sub.5-3 may be the same or different and is as defined above,
(C.sub.5 -7)
(H) --(CH.sub.2).sub.n3 CONR.sub.5-4 R.sub.5-5 where n.sub.3, R.sub.5-4, R.sub.5-5 are as defined above,
(C.sub.5 -8)
(I) --(CH.sub.2).sub.n3 SO.sub.3 R.sub.5-2 where n.sub.3 and R.sub.5-2 are as defined above,
(C.sub.5 -9)
(J) --C.sub.3 -C.sub.7 cycloalkyl;
where
R.sub.2-1 is
(A) --H,
(B) C.sub.1 -C.sub.8 alkyl optionally substituted with 1 thru 4
(1) --F,
(2) --Cl,
(3) --OR.sub.5-2 where R.sub.5-2 is as defined above,
(4) --N(R.sub.5-9).sub.2 where R.sub.5-9 may be the same or different and is as defined above;
where
R.sub.2-2 is
(A) --H,
(B) C.sub.1 -C.sub.8 alkyl optionally substituted with 1 thru 4
(1) --F,
(2) --Cl,
(3) --OR.sub.5-2 where R.sub.5-2 is as defined above,
(4) --N(R.sub.5-9).sub.2 where R.sub.5-9 may be the same or different and is as defined above, or R.sub.2-1 and R.sub.2-2 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of
(A) 1-pyrrolidinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is selected from the group of
(1) C.sub.1 -C.sub.6 alkyl optionally substituted with 1 thru 3 --OH or --OCH.sub.3,
(2) C.sub.1 -C.sub.6 alkenyl optionally substituted with 1 thru 3 --OH or --OCH.sub.3,
(3) C.sub.1 -C.sub.6 alkylcarbonyl,
(4) C.sub.1 -C.sub.6 alkoxycarbonyl,
(5) C.sub.6 -C.sub.12 arylalkyl,
(6) .dbd.O,
(7) --OH,
(8) --C.tbd.N,
(9) --CO.sub.2 R.sub.2-4 where R.sub.2-4 is
(a) --H,
(b) C.sub.1 -C.sub.4 alkyl,
(c) C.sub.6 -C.sub.12 aryl,
(d) C.sub.6 -C.sub.12 aralkyl,
(10) --NH.sub.2,
(11) --Cl,
(12) --F,
(13) --Br,
(14) -.phi. optionally substituted with 1 thru 3 --F, --Cl, --Br, --OH, --OCH.sub.3, --OCH.sub.2 -.phi., --NO.sub.2, C.sub.1 -C.sub.3 alkyl, --NH.sub.2, --NHCH.sub.3, N(CH.sub.3).sub.2, --CO.sub.2 R.sub.2-4 where R.sub.2-4 is as defined above,
(15) --(CH.sub.2).sub.n4 NR.sub.2-6 R.sub.2-7 where R.sub.2-6 and R.sub.2-7 are the same or different and are C.sub.1 -C.sub.4 alkyl or may taken together with the attached nitrogen atom to form the heterocyclic ring --N*--(CH.sub.2).sub.n5 --R.sub.2-8 --(CH.sub.2).sub.n6 * where the atoms marked with an asterisk (*) are bonded together resulting in the formation of a ring, where n.sub.4 is 0 thru 3, n.sub.5 is 1 thru 5, n.sub.6 is 0 thru 3 and R.sub.2-8 is
(a) --CH.sub.2 --,
(b) --O--,
(c) --S--,
(d) --NR.sub.2-4 where R.sub.2-4 is as defined above,
(B) 1-piperdinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(C) 1-morpholinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(D) 1-piperazinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above and optionally substituted in the 4-position with R.sub.2-5 where R.sub.2-5 is
(1) C.sub.1 -C.sub.6 alkyl optionally substituted with 1 thru 3 --OH or --OCH.sub.3,
(2) C.sub.1 -C.sub.6 alkylcarbonyl,
(3) C.sub.1 -C.sub.6 alkoxycarbonyl,
(4) C.sub.6 -C.sub.12 arylalkyl,
(5) -.phi.,
(6)--SO.sub.2 -C.sub.1 -C.sub.8 alkyl,
(7) CH.sub.3 --C*--O--CO--O--C*--CH.sub.2 -- where the carbon atoms designated by * are attached by a double bond to form a five member ring,
(E) 1-aziridinyl optionally substituted on carbon with 1 thru 2 R.sub.2-3 where R.sub.2-3 is as defined above,
(F) 1-azetidinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(G) 1-hexamethyleneimino optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(H) 1-pyrrolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(I) 1-imidazolyl optionally substituted on carbon with 1 thru 3 R.sub.2, .sub.3 where R.sub.2-3 is as defined above,
(J) 1-pyrazoyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(K) 1-pyrazolidinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(L) 1,2,3-triazolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(M) 1,2,4-triazolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(N) 1-tetrazolyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(O) 1-thiomorpholinyl optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above,
(P) 1-thiazolidinyl, optionally substituted on carbon with 1 thru 3 R.sub.2-3 where R.sub.2-3 is as defined above, ##STR7## where R.sub.2-3 and R.sub.2-5 are as defined above,
where
R.sub.2-9 is
(A) --(CH.sub.2).sub.n4 where n.sub.4 is 1 thru 3,
(B) --CH.sub.2 OCH.sub.2,
(C) --CH.sub.2 SCH.sub.2,
(D) --CH.sub.2 SO.sub.2 CH.sub.2,
(E) --CH.sub.2 S,
(F) --CH.sub.2 SO.sub.2,
(G) --CH.sub.2 N(R.sub.2-5)CH.sub.2 where R.sub.2-5 is as defined above, with the proviso that R.sub.2-1 and R.sub.2-2 can not both be --H;
where R.sub.4-1 is defined the same as R.sub.2-1, but may be the same or different than R.sub.2-1,
where R.sub.4-2 is defined the same as R.sub.2-2, but may be the same or different than R.sub.2-2, with the proviso that R.sub.4-1 and R.sub.4-2 can not both be --H;
where (R.sub.6 -1) R.sub.6 is defined the same as R.sub.5, but may be the same or different than R.sub.5, with the proviso that;
(I) one of R.sub.5, R.sub.6 or R.sub.7 must be selected from the group consisting of
(C.sub.5 -3)
(C) --(CH.sub.2).sub.n3 -.phi. optionally substituted with 1 thru 4 R.sub.5-1 where R.sub.5-1 and n.sub.3 as defined as above,
(D) --(CH.sub.2).sub.n3 -pyridin-2-, 3- or 4-yl optionally substituted with 1 thru 4 R.sub.5-1 where n.sub.3 and R.sub.5-1 are as defined above,
(E) --(CH.sub.2).sub.n3 -naphthalin-1-, 2-yl optionally substituted with 1 thru 4 R.sub.5-1 where n.sub.3 and R.sub.5-1 are as defined above, and
(II) for at least one of these three aromatic substituents, n.sub.3 must be 0;
where R.sub.7 is defined the same as R.sub.5, but may be the same or different than R.sub.5 ;
with the proviso that W.sub.1 and W.sub.3 can not both be --CH.dbd., and pharmaceutically acceptable salts thereof.

170 more elements

Facts

Application

08/317,934Filed 3 Oct 1994 · continuation in part

Priority

3 Apr 1992

Granted

26 Mar 1996

Term ends

Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
C07H 15/26
Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals: acyclic or…
C07D
Heterocyclic compounds