Fused tricyclic derivatives of naphthyridinone and pyridone and the corresponding thiones

Claim 2

A compound having the structural formula I wherein: A is B is independently oxygen or sulfur; R 1 -R 8 may be the same or different and are hydrogen or alkyl having from 1 to 6 carbon atoms or two adjacent R 1 -R 8 substituents may be combined to form an additional carbon to carbon bond; 1 and m may be the same or different and are 0 or 1; the rinc labeled, Q, may optionally contain up to two additional double bonds; n is 0, 1 or 2; W and X may be the same or different and are hydrogen, hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, nitro, alkoxy having from 1 to 6 carbon atoms, tri-fluoromethyl, cyano, cycloalkyl having from 3 to 7 carbon atoms, alkenyloxy having from 3 to 6 carbon atoms, alkynyloxy having from 3 to 6 carbon atoms, S(O) p -R a [wherein p is 0, 1 or 2 and R a is alkyl having from 1 to 6 carbon atoms], NHSO 2 R a [wherein R a is defined herein], NHSO 2 CF 3 , NHCOCF 3 , SO 2 NH 2 , COR b [wherein R b is OH, NH 2 or OR a (wherein R a is defined herein)], O-D-COR b [wherein D is alkylene having from 1 to 4 carbon atoms and R b is defined herein], or NHCOR c [wherein R C is hydrogen, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, COR d (wherein R d is hydroxy or alkoxy having from 1 to 6 carbon atoms) or NHR e (wherein R e is hydrogen or alkyl having from 1 to 6 carbon atoms)], or phenoxy [wherein the benzene ring may be substituted with any of the other substituents W and X]; Y and Z may be the same or different and are CH or N; V is phenyl, naphthyl, indenyl, indanyl, pyridyl, pyrimidinyl, thienyl, furyl or thiazolyl, any of which may be substituted with W and X as defined herein; and R 9 and R 10 are independently hydrogen or alkyl having from 1 to 6 carbon atoms,

Claim 3

The compounds defined in claim 1 wherein n is 0.

Claim 4

The compounds defined in claim 2 wherein Y is CH.

Claim 5

The compounds defined in claim 3 having the structural formula:

Claim 6

The compounds defined in claim 4 wherein Z is N.

Claim 7

The compounds defined in claim 5 wherein 1 and m are 0.

Claim 8

The compounds defined in claim 5 wherein 1 and m are 1.

Claim 9

The compounds defined in claim 6 or 7 wherein B is oxygen.

Claim 10

The compounds defined in claim 8 wherein V is

Claim 11

The compounds defined in claim 9 having the structural formula:

Claim 12

The compounds defined in claim 9 having the structural formula:

Claim 13

The compounds defined in claim 10 or 11 wherein R 1 -R 8 are hydrogen or methyl.

Claim 14

The compounds defined in claim 12 wherein zero or one of R 1 -R 8 is methyl and the rest are hydrogen.

Claim 15

The compounds defined in claim 6 having the structural formula:

Claim 16

The compounds defined in claim 6 having the structural formula:

Claim 17

The compounds defined in claim 13 or 15 wherein W is 3-chloro and X is hydrogen, chlorine or fluorine.

Claim 18

1 7. The compounds defined in claim 13 or 15 wherein W is 3-methoxy and X is hydrogen or fluorine.

Claim 19

18 . The compounds defined in claim 13 or 15 wherein W and X are both hydrogen.

Claim 20

The compounds defined in claim 1 having the names: 3,5-dihydro-5-phenyl-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 6-phenyl-2,3,4,6-tetrahydro-pyrano[3,2-c][1,8]-naphthyridin-5-one; 2-methyl-3,5-dihydro-5-phenyl-furo[3,2-c] [1,8]-naphthyridin-4[2H]-one; 3,9-dihydro-9-phenyl-furo[2,3-b][1,8]naphthyridin-4[2H]-one; - 3,9-dihydro-9-(p-methylphenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-2-methyl-9-phenyl-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(p-methylphenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(p-fluorophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(m-methoxyphenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(m-methylthiophenyl)-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,9-dihydro-9-(p-fluorophenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(m-methoxyphenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(m-methylthiophenyl)-furo[3,2-c] [1,8]-naphthyridin-4[2H]-one;3,5-dihydro-5-(3,4-dichlorophenyl)-furo[3,2-c] [1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3,4-dichlorophenyl)-2-methyl-furo [3,2-c] [1 ,8]-naphthyridin-4 [2H]-one; 3,5-dihydro-5-(4-chlorophenyl)-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3-chlorophenyl)-fur-o[3,2-c] [1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3-chlorophenyl)-2-methyl-furo[3,2-c] [1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(4-fluorophenyl)-2-methy-furo[3,2-c] [1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3-methoxyphenyl)-2-methyl-furo [3,2-c] [1,8]-naphthyridin-4[2H]-one; 3,5,dihydro-5-(3,5-dichlorophenyl)-furo[3,2-c] [1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3,5-dichlorophenyl)-2-methyl-furo [3,2-c] [1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-phenyl-2,2-dimethyl-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5 - dihydro-5-(3-methysulfonylaminophenyl)-2-methyl- f uro [3,2-c3 [1 ,8]-naphthyridin-4 [2H]-one; 3,5-dihydro-5-(3-methylsulfonylaminophenyl)-furo [3,2-c] [1,8]-naphthyridin-4[2H]-one; 3,9-Dihydro-9-(3,4-dichlorophenyl)-furo[2,3-b] [1,8]-naphthyridin-4[2H]-one; 3,9-Dihydro-9-(4-chlorophenyl)-furo[2,3-b] [1,8]-naphthyridin-4[2H]-one; 3,9-Dihydro-9-(3-chlorophenyl)-furo[2,3-b][1,8]-naphthyridin-4[2H]-one; 3,9-Dihydro-9-(3-chlorophenyl)-2-methyl-furo[2,3-b] [1,8]-naphthyridin-4[2H]-one; 3,9-Dihydro-9-(4-fluorophenyl)-2-methyl-furo[2,3-b] [1,8]-naphthyridin-4[2H]-one; 3,9-Dihydro-9-(3-methoxyphenyl)-2-methyl-furo [2,3-b] [1,8]-naphthyridin-4[2H]-one; 3,9-Dihydro-9-(3,5-dichlorophenyl)-furo[2,3-b] [1,8]-naphthyridin-4[2H]-one; 3 9-Dihydro-9-(3,5-dichlorophenyl)-2-methyl-furo [2,3-b][1,8]-naphthyridin-4[2H]-one; 3,9-Dihydro-9-(3-methylsulfonylaminophenyl)-2-methyl- furo[2,3-b][1,8]-naphthyridin-4[2H]-one; 6-(4-Chlorophenyl)-2,3,4,6-tetrahydro-5H-pyrano[3,2-c]-[1,8]naphthyridin-5-one; 6-(3,4-Dichlorophenyl)-2,3,4,6-tetrahydro-5H-pyrano [3,2-c][1,8]naphthyridin-5-one; 6-(4-Methoxyphenyl)-2,3,4,6-tetrahydro-5H-pyrano [3,2-c] [1,8]naphthyridin-5-one; 6-(4-Methylphenyl)-2,3,4,6-tetrahydro-5H-pyrano [3,2-c] [1,8] naphthyridin-5-one; 10-(3,4-Dichlorophenyl)-2,3,4,10-tetrahydro-5H-pyrano-[2,3-b] [1,8] naphthyridin-5-one; 10-(4-Methoxyphenyl)-2,3,4,10-tetrahydro-5H-pyrano-[2,3-b][1,8]naphthyridin-5-one; 10-(4-Chlorophenyl)-2,3,4,10-tetrahydro-5H-pyrano-(2,3-b][1,8]naphthyridin-5-one; 10-(4-Methylphenyl)-2,3,4,10-tetrahydro-5H-pyrano-[2,3-b] [1,8] naphthyridin-5-one; 10-Phenyl-2,3,4,10-tetrahydro-5H-pyrano-[2,3-b][1,8]-naphthyridin-5-one; 7-Phenyl-3,4,5,7-tetrahydro-oxepino[3,2-c] [1,8]-naphthyridin-6[2H]-one; 7-(4-Chlorophenyl)-3,4,5,7-tetrahydro-oxepino-[3,2-c] [1,8]-naphthyridin-6[2H]-one; 7-(3-Chlorophenyl)-3,4,5,7-tetrahydro-oxepino-[3,2-c] [1,8]-naphthyridin-6[2H]-one; 7-(3-Methoxyphenyl)-3,4,5,7-tetrahydro-oxepino-[3,2-c][1,8]-naphthyridin-6[2H]-one; and 7-(3-Hydroxyphenyl)-3,4,5,7-tetrahydro-oxepino-[3,2-c] [1,8]-naphthyridin-6[2H]-one.

Claim 21

2 0 . A pharmaceutical composition which comprises a compound having structural formula I as defined in claim 1, in combination with a pharmaceutically acceptable carrier.

Claim 22

A process for the preparation of a compound of formula I as defined in claim I which is characterized by: a) treating a compound of the general formula in which l,m,n, V,W, X ,Y,Z, and R 1 -R 10 are as defined with respect to formula I, with a dehydrating agent under anhydrous conditions to produce a compound of formula I in which A represents the grouping A" and both Bs are oxygen; b) treating a compound having the general formula in which l,n, V,W,X,Y,Z,R I- R 6 , R 9 and R 10 are as defined above, with a strong aqueous acid solution to produce a compound of formula I in which A represents the grouping A ' wherein m is zero and both Bs are oxygen; c) cyclising a compound of the general formula in which Lg is a leaving group, l,m,n, V,W,X,Y,Z and R 1 -R 10 are as defined with respect to formula I, to produce a compound of formula I, in which the grouping A is A' and both Bs are oxygen. d) treating.a compound of general formula II as defined in process a) above, under cyclising and thiating conditions so as to produce a compound of formula I or mixture thereof in which one or both Bs are sulfur and, if desired, separating a compound of formula I from a mixture so produced; e) treating a compound having the general formula in which l , n , V , W , X , Y , Z , R I- R 6 , R 9 and R 10 are as defined above with respect to formula I under thiating conditions so as to produce a compound of formula I in which the grouping A is A'wherein m is zero, B atom in ring Q is oxygen and the other B atom is sulphur. f) subjecting a compound having the general formula in which l,n, V,W,X,Y,Z, R 1 -R 6 , R 9 and R 10 are as defined above with respect to formula I, to intramolecular rearrangement, so as to produce a compound of formula I as defined above in which the grouping A is A', m is zero and both Bs are oxygen, g) subjecting a compound of the general formula I in which one of the B atoms is oxygen and.the other is sulphur, to intramolecular rearrangement whereby the grouping A' or A" is converted respectively to the grouping A" or A' such that a cyclic oxygen atom or sulphur atom becomes a doubly bonded oxygen atom or sulphur atom and the doubly bonded oxygen atom or sulphur atom becomes the ring oxygen atom or sulphur atom; and thereafter, if desired, transforming a compound of formula I so obtained by a process a), b), c), d), e), f) or g) into another compound of formula I.

Claim 23

The use of a compound of formula I as defined in claim I in the treatment in mammals of allergic reactions,or inflammation, or peptic ulcers.