PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF HYPERPROLIFERATE SKIN DISEASE

Abstract: The use of azanaphthalenes of formulae (Ia), (Ib) and (Ic) for the preparation of compositions useful in the treatment of hyperproliferate skin disease: (Ia), (Ib), (Ic), wherein Ac is Ac' or Ac''.

Description: PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF HYPERPROLIFERATE SKIN DISEASE This invention relates to the use of certain azanaphthalenesof the formulae la, lb and Ic defined below in the preparation for pharmaceutical compositions useful in treating hyperproliferative skin disease in mammals. The compounds of the formulae la, lb and Ic are known compounds: Compounds la and methods for their preparation are disclosed in the published European patent application No. 84114974.3; publication No. 0144996. Compounds lb and methods for their preparation are disclosed in PCT application No. U.S. 86/01518; Publication No. WO 87/ 00752. Compounds Ic and methods for their preparation are disclosed in the published European patent application No. 84105923.1; publication No. 0127135. All compounds are k nown to have anti-allergic, anti-inflammatorv and/or cytopro ec ive effect. It has now surprisingly been found that the compounds also are useful in treatment of hyperproliferative skin d iseases. As used herein, this term means any condition the symptoms of which include accelerated skin cell production manifested as scaling, plagues or papular lesions. Examples of hyperproliferative skin diseases include psoriasis, eczema, dandruff, etc. The compounds useful in the present invention are azanaphtalene compounds of formulae la, lb or Ic or solvates thereof: wherein Ϊ two of the ring groups a , b, c and d may be CH or N and the rema ining two groups represent CH; Y a and 2 a independently represent O or S ; a represents 0, S (0 ) na , N-R 8 a or C( R a ) 2 ; each R a independently represents hydrogen , alkyl having from 1 to 6 carbon atoms, CH,0H, COR 7 , ( wherein R' a represents hydrogen or alkyl having from 1 to 6 carbon atoms) or hydroxy, with the proviso that only one hydroxy group can be attached to one carbon atom; each R' a independently is as defined for R a above, except that when V a represents 0, S(0) na or N-R 8 a , ' a may not be hydroxy; Q R a is hydrogen, alkyl having from 1 to 6 carbon atoms, carboxylic acyl having from 2 to 7 carbon atoms, alkylsulfonyl having from 1 to 6 carbon atoms, carboalkoxy having from 2 to 7 carbon atoms, C0NH 2 , phenyl or pyridyl of which the last two may be substituted with up to three substituents Q a , whereby each Q a independently is hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, nitro, alkoxy having from 1 to 6 carbon atoms, trifluorometh l, 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(0) na -R a {wherein na is as defined above and R 9 a is alkyl having from 1 to 6 carbon atoms}, NHS0 2 R a {wherein R 9 a is as defined above}, NHS0 2 CF 3 , S0 2 NH 2 , COR 10 a {wherein. R 10 a is OH, NH 2 or 0R 9 a (wherein R 9 a is as defined above)}, 0-B a -COR 10 a {wherein B a is alk lene having from 1 to 4 carbon atoms and R a is as defined above}, or NHCOR-'-^ {wherein R is hydrogen, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, COR^ a (wherein R a is hydroxy or alkoxy having from 1 to 6 carbon atoms) or NHR iJ a (wherein R a is hydrogen or alkyl having 1 to 6 carbon atoms)}; R and R a may be the same or different and are hydrogen, alkyl having from 1 to 6 carbon atoms, halogen, nitro, alkoxy having from 1 to 6 carbon atoms, trifluoromethyl, alkylthio having 1 to 6 carbon atoms or cyano ; na is 0, 1 or 2, ra is 0, 1 or 2; qa is an integer of from 1 to 5; and A a is phenyl, naphthyl, indenyl, indanyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidyl, 2- or 3- pyrazinyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5- i idazolyl, 2-, 4- or 5-thiazolyl or 2-, 4- or 5- oxazolyl, any of which may be substituted with up to three substituents Q a as defined herein above; or pharmaceutic l acceptable salts, solvates, or esters thereof, in a combination with a pharmaceutically acceptable carrier, wherein: W and X may be the same or different and each independently represents -CH= or -N= ; Z-i and Z 2 are the same or different and each independently represents 0 or S ; R , R , R , R ~ and R are the same or different and each may be independently selected from the group consisting of H, alkyl having from 1 to 12 carbon atoms, alkenyl having from 3 to 8 carbon atoms, alkynyl having from 3 to 8 carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms in the alkoxy portion and from 2 to 6 atoms in the alkyl portion thereof, hydroxyalkyl having from 2 to 8 carbon atoms, cycloalkyl having from 3 to 8 carbon atoms, acyloxyalkyl having from 1 to 6 carbon atoms in the acyloxy portion and from 2 to 8 carbon atoms in the alkyl portion thereof, and -R 6 -C0 2 R° wherein R 6 represents an alkylene group having from 1 to 6 carbon atoms and R° represents hydrogen or an alkyl group having from 1 to 6 carbon atoms, with the provisos that in R , R 2 , or R 3 the OH of the hydroxyalkyl group and the acyloxy of the acyloxyalkyl group are not joined to a carbon atom that is attached to the nitrogen atom to which R 1 , R 2 , and R 3 are attached and that, when R , R and/or R 3 are alkenyl or alkynyl, there is at least one carbon-carbon single bond between the nitrogen atom to which R 1 , R 2 , and R 3 are attached and the carbon-carbon double or triple bond; in addition, one of R 1 , R 2 or R 3 can be an aryl group or an aromatic heterocyclic group, either of which can be substituted with one to three substituents Y as defined below; in further addition, two of R 1 , R and R T can be joined together to represent a ring which can contain from 2 to 8 carbon atoms, said ring optionally containing - a -0-, -S- and/or -NR 4 - heteroatomic group (wherein R 4 is as defined above) and/or optionally containing a carbon- carbon double bond, and said ring optionally being substituted with one to three additional substituents R which substituents may be the sa e or different and are each independently selected from OH with the proviso that OH is not on a carbon already joined to a hetero atom, acyloxy having from 1 to 6 carbon atoms, hydroxyalkyl having from 1 to 8 carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms in each of the alkoxy and alkyl portions thereof, alkyl having from 1 to 6 carbon atoms, alkenyl having from 3 to 8 carbon atoms, alkynyl having from 3 to 8 carbon atoms, or any two R 7 substituent groups may represent a hydrocarbon ring having from 4 to 8 total carbon atoms; and in still further addition, all three of R1, R2 and R 3 together with the nitrogen atom to which they are attached can be joined together to represent a polycyclic ring, which polycyclic ring can optionally be substituted by one to three substituent groups R as defined above; m is an integer of from 0 to 3; n is an integer of from 0 to 2; Q represents an aryl or an aromatic heterocyclic group which can optionally be substituted with 1 to 3 substituents Y as defined below; and each Y substituent" is independently selected from the group consisting of hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, N0 2 , alkoxy having from 1 to 6 carbon atoms, trifluoromethyl, 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, hydroxyalkyl having from 1 to 6 carbon atoms, -S(0) n -R Q (wherein R ° represents alkyl having from 1 to 6 carbon atoms and n is as defined above), -S0 2 NH 2 , -CO-R 9 (wherein R 9 represents OH, -NH-R 8 or -O-R 8 , where R 8 is as defined above), -O-B-COR 9 (wherein B represents an alkylene group havinq from 1 to 4 carbon atoms and R 9 is as defined above), -NH 2 , -NHCHO, -NH-CO-R 9 (wherein R 9 is as defined above, with the proviso that it is not hydroxy), -NH-COCF3, -NH-S0 2 R 8 (wherein R 8 is as defined above), and -NHS0 2 CF 3 ; wherein : A " A C A C B is independently oxygen or sulfur; R C -R c may be the same or different and are hydrogen or alkyl having from 1 to 6 carbon atoms or two adjacent R 1 C ~R 8 c substituents may be combined to form an additional carbon to carbon bond; re and mc may be the same or different and are 0 or one; the ring labeled Q c may optionally contain up to two additional double bonds; nc is 0, 1 or 2; c and X c 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-f luoromethyl, 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, SCOJp^R 1 ^ {wherein pc is 0, 1 or 2 and R 11 c is alkyl having from 1 to 6 carbon atoms}. NHS0 2 R 11 c {wherein R 11 c is as defined above}, NHS0 2 CF 3 , NHCOCF3, S0 2 NH 2 , COR 12 c {wherein R 12 c is OH, NH 2 or 0R 11 C (wherein R 11 c is as defined above)}, 0-D c -COR 12 c {wherein D c is alkylene having from 1 to 4 carbon atoms and R c is as defined above}, or NHC0R 13 c {wherein R 13 c is hydrogen, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, COR 14 c (wherein R- c is hydroxy or alkoxy having from 1 to 6 carbon atoms) or NHR 15 G (wherein R c is hydrogen or alkyl having from 1 to 6 carbon atoms)}, or phenoxy {wherein th.e benzene ring may be substituted ' with any of the other substituents W c and X c }; Y c and Z c may be the same or different and are CH or N? V ~ c is phenyl, naphthyl, indenyl, indanyl, 2-, 3- or 4-pyridyl, 2-, 3- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl or 2-, or 4- or 5-thiazolyl, any of which may be substituted with W and X_ as defined above; and R 9 a_nd., n R10 c are independently hydrogen or alkyl having from 1 to 6 carbon atoms. The compounds of formulae la, lb and Ic can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention. Certain compounds of the invention may exist in isomeric forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. A preferred subgenus of compounds of formula I. is that wherein a and Z a are both oxygen. Preferably, a, b and c represent CH and d is either CH or N. A further preferred feature is that ra is zero, i.e. the group A a is directly attached to the ring-nitrogen atom, qa is preferably 2, 3 or 4, V a most preferably is CH 2 or 0 and R a and R a are both hydrogen, Particularly preferred are compounds of the structural formula II a : wherein d is CH or N, qa is 2, 3 or 4 and A a , V a , R a and R' a are as defined above. When utilized herein and in the appended claims the below listed terms, unless specified otherwise, are defined as follows: halogen - comprises fluorine, chlorine, bromine and iodine; alkyl and alkoxy - comprises straight and branched carbon chains containing from 1 to 6 carbon atoms; a lkenyloxy - compr ises stra ight and bra nched carbon cha ins conta ining from 3 to 6 carbon atoms and compr ising a carbon to carbon double bond ; and alkynyloxy - comprises stra ight and branched carbon cha ins conta in ing from 3 to 6 carbon atoms and comprising a carbon to carbon tr iple bond . The compounds include a and a -( ,C)θ_μ, - substituent wherein the Ra 3 R a R a groups may vary independently. Thus, for example, when ra or qa equals 2 the following patterns of substitution (wherein hydrogen and CH 3 are used to represent any substituents R a ) are contemplated: -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -, -CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 -, -(C(CH 3 )H) 2 - and the like. In addition when ra or qa equals 2, substituents such as -C(CH 3 ) 2 CH(C 2 H 5 )-, -CH(CH 3 )CH(C 2 H 5 ) are also contemplated. It is obvious to one of ordinary skill in the art that due to problems of stability there are limitations involving the R g and R' a groups. -One limitation is that neither R a can be a hydroxy group attached to the carbon alpha to the ring nitrogen atom. Another limitation is that the R^ and R' a groups cannot both be hydroxy groups attached to the same carbon atoms. Certain compounds may exist in isomeric forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. In the structural formulas I a and II a herein, when a represents a hetero atom in the spiro ring, V " a is attached directly to the spiro carbon atom, i.e., the carbon atom identified as number 3 in structural formula I a . The preferred compounds of formula I a summerized as follows: compounds of formula I a wherein a and Z a are both oxygen and/or ra is zero and/or R a and R a are both hydrogen and/or qa is 2, 3 or 4 and/or R a and R' a independently are hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl or iso-butyl and/or A a is phenyl or phenyl substituted with one or two substituents Q a and/or V_ is 0, S(0) ' n na_ or N-R preferably O; wherein all of a, b, c, and 4 d are CH or d is N and a, b and c are CH. Representative compounds of formula I a are exemplified below in Table I: TABLE I No. _d_ a_ ^ *a , & ^(R' a ) 2 (C a R ^ ) ^_ m.p. (°C ) 1 N CH phenyl 0 0 CH 2 trimethylene 174-178 2 N CH 3-hydroxy 0 0 CH 2 trimethylene 218-220 phenyl . 3 N CH 3-methoxy 0 0 CH 2 trimethylene 159-160.5 phenyl 4 CH CH phenyl 0 0 CH 2 trimethylene 168-168 5 N CH 3, 4-chloro 0 0 CH 2 trimethylene 143-145.5 phenyl 6 N CH 4-chloro 0 0 CH 2 trimethylene 168.5-172 phenyl 7 N CH 4-methγl 0 0 CH 2 trimethylene 177-178.5 phenyl e 8 N CH 3-chloro 0 0 CH 2 trimethylene 165-167 phenyl 9 ' N CH 3-chloro s 0 CH 2 trimethylene 168-170 phenyl 10 N CH phenyl s 0 CH 2 trimethylene 188-189.5 11 N CH 3-ethyloxa lyl- ■ 0 0 CH 2 trimethylene 158-160 amino phenyl 12 N CH 3-fomylamino- 0 0 CH 2 trimethylene 222-224 phenyl 13 N CH 3-aminophenyl 0 0 CH 2 trimethylene 200-202 14 N CH 3-{ethyloxy- 0 0 CH 2 trimethylene 103-105 carbonyl- methoxy )phenγl 15 N CH phenyl 0 0 0 trimethylene 241.5-243 (1/3 hydr 16 N CH phenyl 0 0 0 ethylene 233-235.5 18 N CH phenyl 0. 0 S trimethylene 19 N CH 3, 4-dichloro 0 0 0 tetra ethylene phenyl 20 N CH 3-chloro- 0 0 0 tetramethylene 158.5-160 phenyl 21 N CH 4-chloro- 0 0 0 tetramethylene 229-231.5 phenyl (he ihydr 22 N CH 3-msthoxy- 0 0 0 tetramethylene 181-183 phenyl 23 N CH 4-methoxy 0 0 0 tetramethylene phenyl A preferred subqenus of compounds lb is represented by those compounds in which at least one of W and X is N. More preferably, W is CH and X is N. Moreover, at least one of Z^ and Z 2 is preferably 0 and m and n are preferably 0. An additional preferred subqenus of compounds is represented by the structural formula lib. (lib) wherein R , R , R , Q, 1 and are as defined above. Preferably, at least one of Z- j _ and Z 2 is 0. In addition, Q is preferably an aryl group, which may be optionally .substituted with one to three Y groups, more preferably, one or two Y groups. The compounds, when in their zwitterionic form, have good solubility in ph siological fluids, such as blood, plasma, saliva, etc., and in general in polar solvents, such as water and ethanol, which can be used in compositions for delivering the compounds to patients. This characteristic is advantageous in that the compounds are expected to be more easily absorbed gastrointestinally and therefore provide good activity when administered orally. Of course compounds in other forms, such as esters, also have therapeutic activity. propynyloxy, hydroxyethyl, methylthio, me hylsulfonyl , carboxv, acetoxy, N-methylaminocarbonyl, ace o yme ho , acetamido, methylsulfonamido and the like. Exemplary compounds within the scope of formula lib are: The compounds are zwitterionic or inner salts, i.e., they are both positively and negatively charged. However, pharmaceutically acceptable salts of such compounds are also included, i.e., pharmaceutically acceptable acid addition or basic salts. Examples of suitable acid addition salts include the chloride (from hydrochloric acid), methyl sulfate (from methyl sulfuric acid) sulfate (from sulfuric acid) and bromide. Basic salts can be formed when at least one of R , R and R is H. Examples of suitable basic salts include sodium, potassium or calcium salts (from their corresponding hydroxides). In addition, esters of the zwitterionic compounds are within the scope of this invention. Such esters may be formed, e.g., by reacting the zwitterionic compounds with an acyl halide in solvent, such as methylene chloride and base, such as t iethylamine. The compounds of formula lb can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., a hemihydrate. Hydrates and other solvates are formed by contacting the unsolvated form with the solvent. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention. Certain compounds may exist in isomeric and tautomeric forms. The invention includes all such isomers and tauto ers - the isomers both in pure form and in admixture, including racemic mixtures. Subgenera of compounds of formula l c are compounds wherein B c is oxygen; compounds wherein B c is oxygen and A c is A' c ; compounds wherein nc is zero and/or Y c is CH; typical subgeneric groups of compounds of formula l wherein W"c_, V * c_, " Xc, " Zc, * R ' >1 x p --RR 8a , re and mc are as defined herein; compounds of formula 2 wherein c , X c , R 1 c , R C , R 3 C , and R 4 c are as defined above, wherein preferably R c / R c , R c and R 4 are Hydrogen or methyl; in particular compounds of formula 1 wherein W c , X c , Z c , V„, x ,, to R 0 ,,, re and mc are as defined above wherein preferably Z c is N and/or re and mc are both zero or one or the sum of re and mc is one and/or B c is oxygen and/or * c is of formula 7; compounds of formula 3 wherein W_, X_ and R 1 A -R8° are as defined above, wherei.n preferably R 1 C ~R8 c are hydrogen or methyl, especially hyrogen, or one of R 1 C -R 8 c is methyl and the rest are hydrogen and/or c is 3-chloro and X c is hydrogen, chlorine or fluorine or W c is 3-methoxy and X c is hydrogen or fluorine or c and X c are both hydrogen; compounds of formula 5 wherein W c , X c , V c , R l c , R 2 C , R 3 C and R 4 C are as defined above? compounds of formula 6 wherein W c , X c , R^, R 2 C , R 3 C and R C are as defined above, wherein preferably c is 3-chloro and X c is hydrogen, chlorine or fluorine or c is 3-methoxy and c is hydrogen or fluorine or W c and X c are both hydrogen. Representative compounds of formula I c are exemplified by the following compounds: 3,5-dihydro-5-phenyl-furo [3,2-c] [1,8] naphthyridin-4 [2_HJ - one; 3,5-dihydro-5-phenγl-thieno [3,2-c] [l,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]- naphthyr idin-4 [2_H]-one; 3 , 9-dihydro-9-phenyl-furo [2 , 3-b] [1,8] naphthyr idin-4 [2_H] - one; 3 , 9-dihy dro-9- ( p-methylphenyl ) -furo [2 , 3-b] [ 1 , 8] naphthy - ridin-4 [2H_]-one; 3 , 9-dihy dro-2-me th 1-9-phenyl-furo [2 , 3-b] [1,8] naphthy - idin-4[2H_]-one; 3 r 5-dihydro-5- (p-methylphenyl ) -furo [3 , 2-c] [1,8] naphthy - ridin-4[2_H]-one; 3 , 5-dih dro-5 - ( -f luorophen 1 ) -furo [3,2-c] [1,8] naphthy - ridin-4[2H_]-one; 3,5-dihydro-5-(m-methoxyphenγl)-furo [3,2-c] [1,8] naphthy- 3,5-dihydro-5-(m-methylthiophenyl)-furo[3,2-c] [1,8]- naphthyridin-4 [2H_]-one; 3 , 9-dihy dro-9- ( p-f luoropheny 1 ) -furo [2 , 3-b] [1,8] naphthy - ridin-4[2_H_]-one; 3 , 9-dihydro-9- (m-methoxy phenyl ) -furo [2 , 3-b] [ 1 , 8] naphthy - ridin-4 [2J3] -one ; 3 , 9-dih dro-9*-(m-methylthiophenyl) -furo [3,2-c] [1,8]- naphthyridin-4 [2_H]-one; 3 , 5-dih dro-5- ( 3 , 4-dichlorophehy 1 ) -furo [3 , 2-c] [1,8]- naphthyridin-4[2ji]-one; 3,5-dih dro-5-(3,4-dichlorophenyl)-2-methyl-furo [3,2-c] [1 ,8] -naphthyr idin-4[2_H] -one ; 3 , 5-dihy ro-5-(4-chlorophenyl) -furo [3,2-c] [1,8] - naphthyr idin-4 [2jϊ]-one; 3,5-dihydro-5-(3-chlorophenyl)-furo [3,2-c] [1,8] - naphthyr idin-4 [2_H] -one ; 3, 5-dihy dro-5-(3-chlorophenyl)-2-methyl-furo [3,2-c] [1,8]- naphthyridin-4[2H -one; 3 , 5-dihy dro-5-( 4-f luoropheny l)-2-methyl-furo [3,2-c] [1,8] - naphthyr i din -4 [2H_]-one; 3 , 5-dihy dro-5- ( 3-methoxypheny 1 ) -2-methyl-furo [3,2-c] [1,8] -naphthyridin-4 [2_H]-one; 3 , 5-dihydro-5-( 3 , 5-dichloropheny 1 ) -furo [3 , 2-c ] [1,8]- naphthyridin-4 [2_H_]-one; 3,5-dihydro-5-(3,5-dichlorophenyl)-2-methyl-furo [3 , 2-c ] [ 1 , 8] -naphthyr idin-4 [2H_] -one ; 3 , 5-dihydro-5-phenyl-2 , 2-dimethy 1-furo [3 , 2-c] [1,8]- naphthyr idin-4 [2_H_] -one ; 3,5-dihydro-5-( 3-methylsulfonylaminophenyl) -2-methy 1- furo [3,2-c] [1, 8] -naphthyr idin-4[2H_] -one; 3 , 5-dih dro-5-(3-me thy lsulfonylaminophenyl) -furo [3,2-c] [1, 8] -naphthyr idin-4 [2H_]-one; 3 , 9-dih dro-9- ( 3 , 4-dichloropheny 1 ) -furo [2 , 3-b] [1,8]- naphthyr idin-4 [2H] -one ; 3 , 9-dihydro-9- ( 4-chlorophenyl ) -furo [2 , 3-b] [ 1 , 8] - naphthyr idin-4 [2HJ -one ; 3, 9-dih dro-9-( 3-chlorophenyl ) -furo [2 , 3-b] [1,8]- naphthyridin-4 [2H_]-one; 3 , 9-dihy dro-9- ( 3-chloroρheny 1 ) -2-methy 1 -furo [2 , 3-b] [1,8]- naphthyr idin-4 [2HJ -one; 3 , 9-dihydro-9- ( 4-f luorophenyl ) -2-methy 1-furo [2 , 3-b] [1,8]- naphthyr idin-4 [2J3] -one ; 3 , 9-dihy dro-9- ( 3-methoxyphenyl ) -2-meth 1-furo [2, 3-b] [1, 8] -naphthyr idin-4[2_H] -one; 3,9-dihydro-9-(3,5-dichlorophenyl)-furo [2, 3-b] [1,8]- naphthyridin-4 [2H_]-one; 3 , 9-dihy dro-9- ( 3 , 5-dichloropheny 1 ) -2-meth 1-furo [2, 3-b] [1 ,8] -naphthyr idin-4[2Hj -one; 3 , 9-dihy dro-9- ( 3-methy lsulfonylaminophenyl ) -2-methy 1- furo[2,3-b] [1, 8] -naphthyr idin-4[2H_] -one; 6- ( 4-chlorophenyl ) -2 , 3, 4 , 6-tetrahydro-5_H_-pyrano [3 , 2-c] - [1, 8] naphthyr idin-5-one; β-(3,4-dichlorophenyl)-2,3,4,6-tetrahydro-5_H_-pyrano [3,2-c] [1,8] naphthyr idin-5-one; 6-(4-methoxyphenyl)-2,3,4,6-tetrahydro-5j3_-pyrano [3,2-c] [1,8] naphthyr idin-5-one; 6-( 4-methylphenyl ) -2 , 3 , 4, 6-tetrahydro-5H_-pyrano [3,2-c] [1, 8] naphthy idin-5-one; 10-( 3 , 4-dichlorophenyl ) -2 , 3 , 4 , 10-tetrahydro-5_H_-pyrano- [2,3-b] [1, 8] naphthyr idin-5-one; 10-(4-methoxyphenyl)-2,3,4,10-tetrahydro-5_H_-pyrano- [2,3-b] [l,8Jnaphthyridin-5-one; 10-( 4-chloropheny1)-2,3,4,10-tetrahydro-5H_-pyrano- (2,3-b] [1,8]naphthyridin-5-one; 10-( 4-methylphenγl) -2,3,4, 10-tetrahydro-5jl_-pyrano- (2, 3-b] [l,8Inaphthyridin-5-one; 10-phenyl-2 , 3 , 4, 10-tetrahydro-5H_-pyrano- [2 , 3-b] [1,8]- naphthyr idin-5-on ; 7-phenyl-3 ,4,5, 7-tetrahydro-oxepino [3 , 2-c] [1,8]- naphthy idin-6 [2H_]-one; 7- ( 4-chlorophenγl ) -3 , 4,5 , 7-tetrahydro-oxepino- [3 , 2-c] [1,8] -naphthyr idin-6 [2_H] -one ; 7-( 3-chloropheny 1 ) -3 , 4 ,5 , 7-tetrahydro-oxepino- [3,2-c] [l,8]-naphthyridin-6[2Hj-one; 7- ( 3-methoxyphenyl ) -3 , 4,5 , 7-tetrahydro-oxepino- [3,2-cl [l,8]-naphthyridin-6[2jJ_]-one; and 7- ( 3-hy droxypheny 1 ) -3 , 4 , 5 , 7-tetrahy dr o-oxepino- [ 3 , 2-c] [1,8] -naphthyr idin-6 [2_HJ -one . Eff ectiveness of the compounds fo r t h e t rea t ment of hyperproliferative skin disease in mamma l s is d emonstrated by the Arachidonic Acid Mouse Ear T est d escri b e d below. The Arachidonic Acid Mouse Ear T est is a recognized model for assessing the effectiveness of compounds for the treatment of h yperproliferative skin disease. Arachidonic Acid Mouse Ear Test, Materials and Methods Charles River, female, CD, (SD) BR mice, 6 weeks old, are caged 8/group and allowed to acclimate 1-3 weeks prior to use. Arachidonic acid (AA) is dissolved in reagent grade acetone (2 q/.Ol ml) and stored at -20°C for a maximum of 1 week prior to use. Inflammatory reactions are induced by applying 10 μl of AA to both surfaces of one ear (4 mg total) . Test drugs are dissolved in either reagent grade acetone or aqueous ethanol (only if insoluble in acetone) at the same doses selected by Opas et al. , Fed. Proc. 43, Abstract 2983, p. 1927 (1984) and Young et al. , J. Invest. Dermatol. 82, pp. 367-371 (1984). These doses are employed to ensure maximum responses and to overcome any difference in topical absorption which could occur with any drug applied in an aqueous ethanol vehicle. The test drug is applied 30 minutes prior to challenge with AA. The severity of the inflammation is measured as a function of increased ear weight. A 6 mm punch biopsy is removed 1 hour after AA challenge and weighed to the nearest 0.1 mg. Mean ± standard error and all possible comparisons are made via Duncan's Multiple Range Statistic. The results of the above test for a representative selection of compounds of formula la, lb and Ic are given in Table II; Compound Dose (mg/ear) Tissue Wt ι (g ) % Inhibition 1 1.0 1.33* 0.40 82 1 0.1 2.01* 0.69 72 2 1.0 0.6 * 0.4 90 2 0.5 1.0 ± 0.5 76 3 1.0 " 0.83* 0.34 90 3 0.1 1.40* 0.18 83 4 0.5 3.01± 0.47 61 4 0.1 4.35* 0.01 43 Effectiveness of the compounds used herein is furt demonstrated using, for example, the compound 3,9- dihy d ro-9-(3-chlorophenyl)-2-methyl-furo[2,3-b] [1,8] - naphthyridin-4[2H_]-one which exhibits activity at an effective dose (ED 5Q ) of 0.13 mg which gives 50% inhibition. Based upon the above, the compounds used herein are effective for the treatment of hyperpro¬ liferative skin disease. Based upon the test results, the compounds used herein can be administered by any conventional route, e.g., orally, topically, paren- terally, etc. in a dosage range of about 0.05 mg/kg to about 50 mg/kg to treat hyperproliferative skin disease. The dosage to be administered and the route of administration depends upon the particular compound used, the age and general health of the patient and the severity of the inflammatory condition. Thus, the dose ultimately decided upon must be left to the judgment of a trained health-care practitioner. When administered parenterally, e.g. intravenously, the compounds are administered at a dosage range of about 0.01-10 mg/kg of body weight in single or multiple daily doses. The compounds can be administered in unit dosage forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, suppositories, mechanical delivery devices, e.g. transdermal, and the like. For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets dispersible granules, capsules, cachets and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compound. In the tablet the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferalby contain from 5 or 10 to about 70 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyleellulose, a low melting wax, cocoa butter and the like. The terra "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. For the treatment of hyper¬ prolif rative skin disease, the preferred route of administration is topical. In this preferred φethoc}, a pharmaceutical formulation comprising the active ingredient together with a non-toxic pharmaceutically acceptable topical carrier, usually in concentrations ranging from about 0.001 percent to about 10 percent, preferably from about 0.1 to about 5 percent, is applied several times daily to the affected skin until the condition has improved. Topical applications may then be continued at less frequent intervals (e.g., once a day) to control the condition. The compounds may be conveniently applied in a liquid solvent, preferably in a water- miscible liquid carrier made up of hydrophilic liquids having a high solvating action, e.g., a solution which comprises, for example, propylene glycol and polyethylene glycol. Alternatively, the compound may be applied in dry form, such as a powder * Other forms in which the compound may be used topically include creams, lotions, aerosols, dusts and ointments which are prepared by combining the compound with conventional pharmaceutical diluents and carriers commonly used in topical dry, liquid, cream and aerosol formulations. The ointments and creams may, for example, be formulated with an aqueous oily base with the addition of suitable thickening and/or gelling agents. Such bases may thus, for example, include water and/or oil such as liquid paraffin or vegatable oil, such as peanut oil or castor oil. Thickening agents which may be used according to the nature of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycols, woolfat, hydrogenated lanolin, beeswax, etc. Lotions may be formulated with an aqueous or oily base and will, in general, also include one or more of the following, namely, stabilizing agents, emulsifying agents, dispensing agents, suspending agents, thickening agents, coloring agents, perfumes and the like. For preparing suppositories, a low melting wax such as a mixture of fatty acid glyce ides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylσellulose, sodium carboxymethylcellulose and other well-known suspending agents. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. These particular solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit. Alternatively, sufficient solid may be provides so that after conversion to liquid form, multiple individual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as_with a syringe, teaspoon or other volumetric container. When multiple liquid doses are so prepared, it is preferred to maintain the unused portion of said liquid doses at low temperature (i.e., under refrigeration) in order to retard possible decomposition. The solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavo ants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like. The solvent utilized for preparing the liquid form preparation may be water, isotonic water, ethanol, glycerine, propylene glycol and the like as well as mixtures thereof. Naturally, the solvent utilized will be chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use. Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet or tablet itself or it can be the appropriate number of any of these in packaged form. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to about 500 mg according to the particular application and the potency of the active ingredient. The compositions can, if desired, also contain other therapeutic agents. The dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated and the particular compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. The following formulations exemplify some of the dosage forms. In each, the active ingredient is a compound represented by structural formulae la, lb or Ic, such as 9-(3-chlorophenyl)-3,9-dihydro-2-methyl-furo j^,3-bj [l,8I naphthyridine-4 (2H)-one, and is referred to as "active compound". However, any other compound falling within the scope of formulae la, lb or Ic could be substituted therefore. FORMULATIONS Formulation I: Ointment Formula mg/g Active Compound 1.0-20.0 Benzyl Alcohol, NF 10.0 Mineral Oil, USP 50.0 White Petrolatum, USP to make 1.0 g Procedure Mix and heat to 65°C, a weighted quantity of white petrolatum, mineral oil, benzyl alcohol, and cool to 50°-55°C. with stirring. Disperse active compound in a portion of the mineral oil and then add to the above mixture with stirring. Cool to room temperature. Formulation II: Cream Formula mg, '9 Active Compound i .o-: 20 . , 0 Stearic Acid, USP 60 .0 Glyceryl Monostearate 100 .0 Propylene Glycol, USP 50 .0 Polyethylene Sorbitan Monopalmitate 50 .0 Sorbitol Solution, USP 30 .0. Benzyl Alcohol, NF 10 .0 Purified Water, USP to make 1 .0 g Procedure Heat the stearic acid, glyceryl monostearate and polyethylene sorbitan monopalmitate to 70°C. In a separate vessel, dissolve sorbital solution, benzyl alcohol, water, and half quantity of propylene glycol and heat to 70°C. Add the aqueous phase to oil phase with high speed lightning stirring. Dissolve the active compound in remaining quantity of propylene glycol and add to the above emulsion when the temperature of emulsion is 37°-40°C. Mix uniformly with stirring and cool to room temperature. Formulation III: Gel Formula mg./g Active Compound 1.0-20.0 Propylene Glycol, USP 300.0 Butylated Hydroxytoluene 5.0 Carbomer 940 5.0 Sodium Hydroxide (added as a 1% w/w solution in proplyene glycol) 0.7 Polyethylene Glycol 400, USP 669.3-688. Procedure Prepare a 1% solution of the sodium hydroxide in propylene glycol and hold. Add approximately one-half the remaining propylene glycol, and the polyethylene glycol 400 to a suitable vessel and mix. Dissolve the butylated hydroxytoluene in this mixture. Disperse the carbomer 940 in the above mixture with vigorous agitation. Add the solution of sodium hydroxide with high speed agitation to bring pH up to 7 and recirculation until a thick gel forms. Dissolve the active compound in the remaining propylene glycol and add to the gel slowly as the gel is continuously recirculated. Formulation IV: Lotion Formula mg/g Active Compound 1.0-20.0 Carbomer 940 3.0 Sodium hydroxide (charged as 4% w/w 0.05 aqueous solution) Isopropyl Alcohol 40.00 Purified Water, USP to make 1.0 g Procedure Prepare a 4% solution of sodium hydroxide in water. Heat the purified water to 60°C. Add carbomer 940 and mix at high speed until dispersed. Cool the above mixture to room temperature and slowly charge sodium hydroxide until uniform. Add 80% of isopropyl alcohol to the above with mixing. Dissolve the active compound in remaining isopropanol. Add this to the mixture with stirring. Adjust pH to 5.0 to 5.5 with sodium hydroxide, if necessary. Formulation V: Topical Aerosol Formula mg/g Active Compound 1.0-20.0 Caprylic/Capric Triglyceride 50.00 Mineral Oil 20.00 Specially Denatured Alcohol 150.00 Hydrocarbon Aerosol Propellant q.s. ad. l.Og Procedure Add and mix the caprylic/capric triglyceride mineral oil and specially denatured alcohol in a suitable compounding tank. Add the active compound drug and continue mixing until the active compound is dissolved or dispersed unifor ily. Fill the concentrate into cans and then fill the required amount of hydrocarbon aerosol propellant. Formulation VI: Tablets No. Ingredient mmgg//ttaabblleett mmgg//ttaabi let 1. Active compound 1 10000 5 50000 2. Lactose USP 1 12222 1 11133 3. Corn Starch, Food Grade, 3 300 4 400 as a 10% paste in Purified Water 4. Corn Starch, Food Grade 45 40 5. Magnesium Stearate 3 7 Total 300 700 Method of Manufacture Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4") if needed. Dry the damp granules. Screen the dried granules if needed and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weight on " a suitable tablet machine. Formulation VII: Capsules No. Ingredient mg/capsule mg/capsule 1. Active compound 100 500 2. Lactose USP 106 123 3. Corn Starch, Food Grade 40 70 4. Magnesium Stearate NF 4 7 Total 250 700 Method of Manufacture Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine. Formulation VIII: Parenteral Ingredient mg/vial mg/vial Active Compound Sterile Powder 100 ' 500 Add sterile water for injection or bacteriostatic water for injection, for reconstitution. Formulation VIX: Injectable Ingredient mg/vial Active Compound 100 Methyl p-hydroxybenzoate 1 , .8 Propyl p-hydroxybenzoate 0 , .2 Sodium Bisulfite 3 , .2 Disodium Edetate 0 , . 1 Sodium Sulfate 2 .6 Water for Injection q.s. ad 1 , .0 ml Method of Manufacture 1. Dissolve parabens in a portion (85% of the final volume) of the water for injection at 65-70°C. 2. Cool to 25-35°C Charge and dissolve the sodium bisulfite, disodium edetate and sodium sulfate. 3. Charge and dissolve drug. 4. Bring the solution to final volume by added water for injection. 5. Filter the solution through 0.22 membrane and fill into appropriate containers. 6. Terminally sterilize the units by autoclaving. The quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency of the active ingredient. The compositions can, if desired, also contain other therapeutic agents. The amount of active compound applied to the involved lesions may be varied depending upon the requirements of the patient, the severity of the condition being treated and the particular compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

Claims: CLAIMS: 1. Use of an azanaphthalene for preparing a medicament for treating hyperproliferative skin disease, said azanaphthalene having the structural formula la, lb or Ic: wherein: two of the ring groups a, b, c and d may be CH or N and the remaining two groups represent CH; Y_ and Z_ independently represent 0 or S; V a represents 0, S (0 ) na , N-R 8 a or C; each R a independently represents hydrogen , a lkyl having from 1 to 6 carbon atoms , CH 2 OH, COR a (wherein R 7 a represents hydrogen or alkyl having from 1 to 6 carbon atoms) or hydroxy, with the proviso that only one hydroxy group can be attached to one carbon atom; each R' a independently is as defined for R a above, except that when V a represents 0, S(0) na or N-R° a , R may not be hydroxy; g R a is hydrogen, alkyl having from 1 to 6 carbon atoms, carboxylic acyl having from 2 to 7 carbon atoms, alkylsulfonyl having from 1 to 6 carbon atoms, carboalkoxy having from 2 to 7 carbon atoms, C0NH 2 , phenyl or pyridyl of which the last two may be substituted with up to three substituents Q , whereby each Q a independently is hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, nitro, alkoxy having from 1 to 6 carbon atoms, trifluoromethyl, 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(0)„ -R 9 .wherein na is as defined herein and R 9 is alkyl having from 1 to 6 carbon atoms}, NHS0 R a {wherein R 9 a is as defined above}, NHS0 2 CF 3 , S0 2 NH 2 , COR 10 a {wherein R 10 a is OH, NH 2 or 0R 9 a (wherein R 9 a is as defined above)}, O-B a -COR 10 a {wherein B & is alkylene having from 1 to 4 carbon atoms and R a is as defined above}, or NHC0R lx a {wherein R lx a is hydrogen, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, C0R i2 (wherein R- a is hydroxy or alkoxy having from 1 to 6 carbon atoms) or NHR 13 a (wherein R 13 a is hydrogen or alkyl having 1 to 6 carbon atoms)}; R a and R a may be the same or different and are hydrogen, alkyl having from 1 to 6 carbon atoms, halogen, nitro, alkoxy having from 1 to 6 carbon atoms, trifluoromethyl, alkylthio having 1 to 6 carbon atoms or cyano; na is 0, 1 or 2; ra is 0, 1 or 2; qa is an integer of from 1 to 5 ; and A a is phenyl , naphth 1 , indenyl , indanyl , 2- , 3- or 4-py idyl , 2-, 4-, 5- or 6-pyrimidyl , 2- or 3- pyrazinyl , 2- or 3-furyl , 2- or 3-thienyl , 2- , 4- or 5- imidazolyl , 2-, 4- or 5-thiazolyl or 2-, 4- or 5- oxazσlyl , any of which may be substituted with up to three substituents Q a as defined herein above , or a solvate of such a compound of formula la; or pharmaceutical acceptable salts, solvates, or esters thereof, in a combination with a pharmaceutically acceptable carrier, wherein: W and X may be the same or different and each independently represents -CH= or -N= ; Z j _ and are the same or different and each independently represents 0 or S ; R , R , R , R and R are the same or different and each may be independently selected from the group consisting of H, alkyl having from 1 to 12 carbon atoms, alkenyl having from 3 to 8 carbon atoms, alkynyl having from 3 to 8 carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms in the alkoxy portion and from 2 to 6 atoms in the alkyl portion thereof, hydroxyalkyl having from 2 to 8 carbon atoms, cycloalkyl having from 3 to 8 carbon atoms, acyloxyalk l having from 1 to 6 carbon atoms in the acyloxy portion and from 2 to 8 carbon atoms in the alkyl portion thereof, and -R°-C0 2 R wherein represents an alkylene group having from 1 to 6 carbon atoms and R° represents hydrogen or an alkyl group having from 1 to 6 carbon atoms, with the provisos that in R , R 2 , or R 3 the OH of the hydroxyalkyl group and the acyloxy of the acyloxyalkyl group are not joined to a carbon atom that is attached to the nitrogen atom to which R 1 , R 2 , and R 3 are attached and that, when R , R and/or R 3 are alkenyl or alkynyl, there is at least one carbon-carbon single bond between the nitrogen atom to which R 1 , R 2 , and R 3 are attached and the carbon-carbon double or triple bond; in addition, one of R 1 , R 2 or R 3 can be an aryl group or an aromatic heterocyclic group, either of which can be substituted with one to three substituents Y as defined below; in further addition, two of R 1 , and 3 can be joined together to represent a ring which can contain from 2 to 8 carbon atoms, said ring optionally containing a -0-, -S- and/or -NR 4 - heteroato ic group (wherein R is as defined above) and/or optionally containing a carbon- carbon double bond, and said ring optionally being substituted with one to three additional substituents R 7 which substituents may be the same or different and are each independently selected from OH with the proviso that OH is not on a carbon already joined to a hetero atom, acyloxy having from 1 to 6 carbon atoms, hydroxyalkyl having from 1 to 8 carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms in each of the alkoxy and alkyl portions thereof, alkyl having from 1 to 6 carbon atoms, alkenyl having from 3 to 8 carbon atoms, alkynyl having from 3 to 8 carbon atoms, or any two R 7 substituent groups may represent a hydrocarbon ring having from 4 to 8 total carbon atoms; and in still further addition, all three of R 1 , 2 and R 3 together with the nitrogen atom to which they are attached can be joined together to represent a polycyclic ring, which, polycyclic ring can optionally be substituted by one to three substituent groups R as defined above? m is an integer of from 0 to 3; n is an integer of from 0 to 2; Q represents an aryl or an aromatic heterocyclic group which can optionally be substituted with 1 to 3 substituents Y as defined below? and each Y substituent is independently selected from the group consisting of hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, N0 2 , alkoxy having from 1 to 6 carbon atoms, tri luorome h l, cyano, cycloalkyl having from 3 to 7 carbon atoms, alkenyloxy having from 3 to 6 carbon atoms, alkynyloxy having from 3. o 6 carbon atoms, g hydroxyalkyl having from 1 to 6 carbon atoms, -S(0) n -R g (wherein R represents alkyl having from 1 to 6 carbon atoms and n is as defined above), -S0 2 NH 2 , -CO-R 9 (wherein R 9 represents OH, -NH-R 8 or -O-R 8 , where R 8 is as defined above), -O-B-COR 9 (wherein B represents an alkylene group havinα from 1 to 4 carbon atoms and R 9 is as defined above), -NH 2 , -NHCHO, -NH-CO-R 9 (wherein R 9 is as defined above, with the proviso that it is not hydroxy), -NH-COCF3, -NH-S0 2 R 8 (wherein R 8 is as defined above), and -NHS0 2 CF 3 ♦ wherein: A n A c B is independently oxygen or sulfur; R T x -R a _ may be the same or different and are hydrogen or alkyl having from 1 to 6 carbon atoms or two adjacent R 1 -1 -R 8° c substituents may be combined to form an additional carbon to carbon bond; rc and mc may be the same or different and are 0 or one; the ring labeled Q c may optionally contain up to two additional double bonds; nc is 0, 1 or 2; and X c 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-f luoromethyl, 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(0) DC -R A1 C {wherein pc is 0, 1 or 2 and R 11 c is alkyl having from 1 to 6 carbon atoms}, NHS0 2 R 11 c {wherein R 1 ^ is as defined above}, NHS0 2 CF 3 , NHCOCF3, S0 2 NH 2 , C0R 12 c {wherein R 12 c is OH, NH 2 or OR 1] - c (wherein R ll c is as defined above)}, 0-D c -COR 12 c {wherein D c is alkylene having from 1 to 4 carbon atoms and R c is as defined above}, or NHCOR 13 c {wherein R 13 c is hydrogen, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, C0R x4 c (wherein c is hydroxy or alkoxy having from 1 to 6 carbon atoms) or NHR 15 G (wherein R c 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 c and X c }? Y c and Z_ may be the same or different and are CH or N; c is phenyl, naphthy 1, indenyl, indanyl, 2-, 3- or 4-pyridyl, 2-, 3- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl or 2-, or 4- or 5-thiazolyl, any of which may be substituted with W_ and X_ as defined above; and R 9 G and R ^ G_ are independently hydrogen or alkyl having from 1 to 6 carbon atoms and solvates of such compounds. 2. The use according to claim 1 wherein in formula I α,, / . Y «_ and Z C,t are both oxygen and/or ra is zero and/or R a and R a are both hydrogen and/or qa is 2, 3 or 4 and/or R c„ and R' Cl independently are hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl or iso-butyl and/or A_ is phenyl or phenyl substituted with one or two substituents Q a and/or V 3,. is 0, S(0)„πα_ or N-R 8 ci preferably 0. 3. The use according to claim 1 or 2 wherein in formula I C_l all of a, b, c, and d are CH or a and d are both N and b and c are bot CH or d is N and a, b and c are CH. „ 4. The use according to claim 1 wherein the compound of formula I a is 1 '-phenyl -spiro [cyclopentane-1 ,3 '-( 1-8 ) naphthyr idine] 2' ,4'-<l'_HJ-dione; 1 '-phenyl -spiro [cyclopentane-1 ,3 '-quinoline]-2 ' , 4' - (l'H_)-dione; 1 '-( 4-methylphenyl) spiro [cyclopentane-1 ,3 ' - ( l,8)naphthyridine]-2' ,4'-( 1 '_H_)-dione; l'-( 4-chlorophenyl) spiro [cyclopentane-1 ,3'- (l,8)naphthyridine]-2' , 4 '-( 1 *H)-dione ; 1 ' -( 3 , 4-dichlorophenyl) spiro [cyclopentane-1 ,3 l - (1,8) naphthyr idine ] -2 ' , 4 * -( 1 ' _H_) -dione ; !'-( 3-chlorophenyl ) spiro [cvclopentane-1,3 ' - (1,8) naphthyr idine ] -2 ' , 4 • - ( 1 « jl_) -diόne ; 1 ' - ( 3-methoxyphenyl ) spiro [cyclopentane-1 , 3 ' - (1,8) naphthyr idine ] -2 • , 4 • - ( 1 *H) -dione ; l*-( 3-hydroxyphenyl) spiro [cyclopentane-1,3'- (1,8) naphthyr idine ] -2 , • 4 • - ( 1 l ) -dione ; 1* -phenyl spiro [cyclopentane-1,3 ' -σ inoline] -2 * ,4'-( l'_H)- dione; l-phenyl-3 ' ,4, ' ,5 ' ,6'-tetrahydrospiro [1,8-naphthyr idine- 3 , 2 ' - ( 2H_) pyran ] -2 , 4-dione ; l-(3-methoxyphenyl)-3 ' ,4' ,5* ,6 '-tetrahydrospiro [1,8- naphthyr idine-3 , 2 * -( 2H) pyran ] -2 , 4-dione ; 4 , 5-dihydro-l ' -pheny 1-spiro [f uran-2 ( 3H_) , 3 ' ( 2 '_H (1,8) naphthyr idine] -2' ,4' { l'_H_) -dione; 1-phenyl-spiro [l,8-naphthyridine-3,2 '-oxetane] -2,4-dione; or l-(3-chlorphenyl)-3',4' ,5' , 6' -tetrahydrospiro [1,8- naphthyr idine-3 , 2 * - ( 2R) pyran ] -2 , 4-dione or solvate thereof. 5. The use according to claim 1 wherein the compound is of the formula and pharmaceutically acceptable salts, esters, and solvates thereof, wherein: W and X may be the same or different and each independently represents CH or N ; Zi and Z 2 are the same or different and each independently represents O or S ; R 1 , R 2 , R 3 , R 4 and R 5 are the same or different and each may be independently selected from the group consisting of H, alkyl having from 1 to 12 carbon atoms, alkenyl having from 3 to 8 carbon atoms, alkynyl having from 3 to 8 carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms in the alkoxy portion and from 2 to 6 atoms in the alkyl portion thereof, hydroxyalkyl having from 2 to 8 carbon atoms, cycloalkyl having from 3 to 8 carbon atoms, acyloxyalkyl having from 1 to 6 carbon atoms in the acyloxy portion and from 2 to 8 carbon atoms in the alkyl portion thereof, and -R -C0 R u wherein R represents an alkylene group having from 1 to 6 carbon atoms and R represents hydrogen or an alkyl group having from 1 to 6 carbon atoms, with the provisos that in R 1 , R2 , and R 3 the OH of the hydroxyalkyl group and the acyloxy of the acyloxyalkyl group are not joined to a carbon atom that is attached to the nitrogen atom to which R 1 , R2 , and R 3 J are attached and that, when R 1 , R and/or R 3 are alkenyl or alkynyl, there is at least one carbon-carbon single bond between the nitrogen atom to which R 1 , R , and R 3 are attached and the carbon-carbon double or triple bond; in addition, one of R 1 , R2 or R 3 can be an aryl group or an aromatic heterocyclic group , either of which can be substituted with one to three substituents Y as defined below; in further addition , two of R 1 , R and R 3 can be joined together to represent a r ing which can conta in from 2 to 8 carbon atoms , sa id ring optionally containing a -O-, -S- and/or -NR - heteroatomic group (wherein R * is as defined above ) and/or optiona lly containing a carbon- carbon double bond, and said ring optionally being substi¬ tuted with one to three additional substituents R which substituents may be the same or different and are each independently selected from OH with the proviso that OH is not on a carbon already joined to a hetero atom, acyloxy having from 1 to 6 carbon atoms, hydroxyalkyl having from 1 to 8 carbon atoms , alkoxyalkyl having from 1 to 6 carbon atoms in each of the alkoxy and alkyl portions thereof , alkyl having from 1 to 6 carbon atoms , alkenyl having from 3 to 8 carbon toms, alkynyl having from 3 to 8 carbon atoms, or any two R substituent groups may represent a hydrocarbon ring having from 4 to 8 total carbon atoms ; in still further addition , all three of R 1 , R 2 and R together with the nitrogen atom to which they are attached can be joined together to represent a polycyclic ring, which polycyclic ring can optionally be substituted by one to three substituents groups R as defined above ; m is an integer of from 0 to 3 ; n is an integer of from 0 to 2 ; Q represents an aryl or an aromatic - heterocyclic group which can optionally be substituted with 1 to 3 substituents Y as defined below; each Y substituent is independently selected from the group consisting of hydroxy, alkyl having from 1 to 6 carbon atoms , halogen , N0 2 , alkoxy having from 1 to 6 carbon atoms, trifluoromethyl, 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, g hydroxyalkyl having from 1 to 6 carbon atoms, -S(O) -R° (wherein R represents alkyl having from 1 to 6 carbon q atoms and n is as defined above), -S0 2 H 2 , -C0-R J (wherein R represents OH, -NH-R 8 or -O-R , where R is g as defined above), -0-B-COR^ (wherein B represents an alkylene group having from 1 to 4 carbon atoms and R is as defined above), -NH 2 , -NHCHO, -NH-CO-R 9 (wherein R 9 is as defined above, with the proviso that it is not hydroxy), -NH-COCF3, _NH - S0 2 R8 (wherein R 8 is as defined above), and -NHS0 2 CF 3 ; and 3-dimeth lamino-4-hydroxy-l-phenyl-2-σ inolone and l-benzyl-3-dimeth lamino-4-hydroxy-l-phen l-2- quinolone are excluded. 6. The use according to claim 5, wherein in the formula at least one of W and X is -N=. 7. The use according to claim 6, wherein in the formula X is -N=, W is -CH= and Z^ and Z 2 are both 0. 8. The use according to any one of claims 5 to 7 wherein in the formula n and are 0. 9. The use according to claim 5 whereby the compound is selected from: l-( 1, 2-dihy ro-4-hydroxy-l -phenyl -2 -oxo-1 , 8-naph hyr idin- 3-yl )-l-methyl-pyrrolidinium hydroxide, inner salt; l-( 1, 2-dih dro-4-hydro y-1-phen 1-2-oxo -1,8-naphthy idin - 3-yl)-pyrrolidinium hydroxide, inner salt; l-( 1, 2- d ih d ro-4-hydro y-1 -phen l -2-oxo -1,8-naph thy r idin - 3-yl )-4-hydroxy-ρiperidinium hydroxide, inner salt; l-( 1, 2- d ih ro-4-hy d roxy-l-pheny 1-2-oxo-l, 8-naphthyridin- 3-yl )-quinuclidinium hydroxide, inner salt; l-( 1, 2-dihy dro-4-hydroxy-l-phenyl-2-oxo-l , 8-naphthyr idin- 3-yI) -I-methyl-morpholinium hydroxide, inner salt; 1-(1, 2-dih dro-4-hydroxy-l-phenyl-2-oxo-l, 8-na h h idin - 3-yl)-piperidinium hydroxide, inner salt; or l-( l,2-dihydro-4-hydroxy-l-phenyl-2-oxo-l,8-naphthyridin- 3-yl)-2-hydroxymethyl-piperidinium hydroxide, inner salt; or pharmaceutic lly acceptable salts, esters, and solvates thereof. 10 . The u se acc ording to claim 9 wherein the compound is 1- ( 1 d i h y d ro-4- h y d roxy-l-phenyl-2-oxo-l,8-naphthyridin-3-yl)- 1-methyl-pyrrolidinium hydroxide, inner salt, and pharmaceutically acceptable salts, esters, or solvates thereof. 11. The use according to claim 1 wherein in formula I nc is zero and/or Y c is CH. 12. The use accordinq to claim 1 wherein the compound of formula I c has the structural formula wherein W c , X c , Z c , c , R i c to R 8 C , rc and mc are as defined in claim 1 wherein preferably Z is N and/or rc and mc are both zero or one or the sum of rc and mc is one and/or B G is oxyqen and/or 13. The use according to claim 1 wherein the compound of formula I has the structural formula B= 4 wherein c , ?c , e as defined in claim 1, prefera are hydrogen Qr methyl. 14. The use according to claim 1 wherein sai d com p ound of formula Ic has the structural formula: wherein c , X c and R 1 C -R 8 C are as defined in claim 1, preferably R^- -R 8 c are hydrogen or methyl, especially hydrogen. or one of R^ C -R 8 C is methyl and the rest are hydrogen and/or is 3-chloro and X is hydrogen, chlorine or fluorine or W is 3-methoxy and X is hydrogen or fluorine or and X c are both hydrogen. 15. The use according to claim 1 wherein said compound of formula I G_ has the structural formula: wherein c , X c , V , R c , R c , R c and R 4 are as defined in claim 1. 16. The use according to claim 1 wherein said compound has the structural formula: wherein W c , X c , R .1 i c , R^ c , R J C and R 4 C are as defined in claim 1, preferably c is 3-chloro and X c is hydrogen, chlorine or fluorine or c is 3-methoxy and X c is hydrogen or fluorine or c and c are both hydrogen. 17. The use according to claim 1 wherein the compound of formula I c is 3 , 5-dih dro-5 -phenyl -furo [3,2-c] [1 ,8] naphthyr idin- 4[2H_]-one; 3,5-dihydro-5-phenyl-thieno [3,2-c] [1,8]- naphthyr idin -4 [2H_] -one ; 6-phenyl-2 ,3,4,6-tetrahydro-pyrano [3 ,2-c] [1,8]- naphthγridin-5-one; 2-methvl-3,5-dihydro-5-phenyl-furo [3,2-c] [1,8] - naphthyr idin-4 [2Hj-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-f luorophen l) -furo [3,2-c] [1,8]- naphthyr idin-4 [2HJ -one ? 3,5-dihydro-5-(m-methoxγphenyl)-furo [3,2-c] [1,8]- naphthyr idin-4 [2H_]-one; 3 ,5-dihydro-5-(m-methylthiophenyl)-furo [3 ,2-c] [1,81- naphthyr idin-4 [2H_] -one ; 3,9-dihydro-9-(p-fluorophenyl)-furo [2,3-b] [1,8]- naphthyridin-4 [2H]-one; 3 , -dihydro-9-(m-methoxyphenyl )-furo [2 , 3- b] [ 1,8] naphthyr idin-4[2_HJ -one; 3,9-dihydro-9-(m-methylthioρhenyl)-furo [3,2-c] [1,8] naphthyr id in -4 [2H_]-one ;3, 5-dihy dro-5-( 3,4- dichlorophenyl)-furo [3,2-c] [1,8] -naphthyr id in -4 [2_H]-one ; 3 , 5-dihy dro-5-( 3 , 4-dichlorophenyl ) -2-methy 1- uro [3,2-c] [1 ,8] -naphthyr idin -4 [2 J -one; 3 , 5-dihy dro-5-( 4-chlorophenyl ) -f uro [ 3 , 2-c ] [1,8]- naphthyr idin-4 [2_H] -one ? 3,5-dihydro-5-(3-chlorophenyl)-furo [3,2-c] [1,8]- naphthyridin-4 [2H -one; 3 ,5-dihydro-5-( 3-chlorophenyl )-2-methyl-furo [3 ,2-c] ■ [l,8]-naphthyridin-4 [2Hj-one; 3 , 5-dihy dro-5-( 4-f luorophenyl) -2-methy 1-f uro [3 ,2-c] - [l,8]-naphthyridin-4 [2Hj-one? 3, 5-dihy dro-5-( 3-me thoxypheny 1 ) -2-methy 1-furo- [3,2-c] [l,8]-naphthyridin-4 [2 ]-one;. 3,5-dihydro-5-(3,5-dichlorophenyl)-furo [3,2-c] [1,8]- naphthyridin-4 [2jϊ]-one; 3 ,5-dihydro-5-( 3,5-dichlorophenyl)-2-methyl-furo [3,2-c] [l,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-methysulfonγlaminophenyl)-2-methyl- furo [3,2-c] [l,8]-naphthyridin-4[2jϊJ-one; 3 ,5-dihydro-5-( 3-methylsulfonylaminophenyl )-furo [3,2-c] [l,8]-naphthγridin-4 [2H_]-one; 3 , 9-dihydro-9-( 3 , 4-dichlorophenyl )-furo [2 , 3-b] [1,8]- naphthyr idin-4 [2H_] -one ; 3 , 9-dihy dro-9- ( 4-chlorophen 1 ) -furo [2 , 3-b] [1,8]- naphthyr idin-4 [2H_]-one; 3 , 9-dihydro-9-( 3-chloropheny 1 )-furo [2 , 3-b] [ 1 , 8] - naphthyr idin-4 [2H_]-one; 3 , 9-dih dro-9-( 3-chlorophenyl ) -2 -meth l -furo [2 , 3- b] [l,8]-naphthyridin-4[2H]-one; 3 ,9-dihydro-9-( 4-f luorophen l)-2-me th 1-furo [2,3- b] [ 1, 81 -naphthyr idin -4 [2H_] -one; 3 ,9-dihydro-9-( 3-methoxyρhenyl )-2-meth l-furo [2,3-b] [l,8]-naphthyridin-4 [2HJ-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] -naphthyr idin-4[2Hj -one; 3,9-dihydro-9-( 3-methylsulfonylaminophenγl)-2- methyl-furo [2,3-b] [1 ,8] -naphthyr idin-4 [2H_]-one; 6-( 4-chlorophenyl )-2 , 3 , 4, 6-tetrahydro-5_H-pyrano [3,2- c]-[l, 8] naphthyr idin-5-one? 6-( 3 , 4-dichloropheny 1 ) -2 , 3 , 4, δ-tetrahydro-5_Hj-pyrano [3,2-cl [l,8]naphthyridin-5-one; 6- ( 4 -me thoxypheny 1 ) -2 , 3 , 4 , 6-te trahydro-5_H_-pyrano [3,2-c] [1,8] naphthyr idin-5-one; 6-(4-methylphenyl)-2,3,4,6-tetrahydro-5_H-pyrano [3,2-c] [1, 8] naphthyr idin-5-one; 10- ( 3 , 4-dichloropheny 1 )-2 ,3 , 4 , 10-te trahy dro-5_H_- pyrano- [2 , 3-b] [1,8] naphthy idin-5-one ; 10-(4-methoxyphenyl)-2 ,3,4, 10-te trahy dro-5_H_-pyrano- [2,3-b] [1, 8] naphthyr idin-5-one; 10- ( 4-chloropheny 1 ) -2 , 3 , 4 , 10-te trahy dro -5H_-pyrano- (2,3rb] [1, 8] naphthyr idin-5-one? 10-(4-methylphenyl)-2,3,4,10-tetrahydro-5_H_-pyrano- (2, 3-b] [1, 8] naphthyr idin-5-one? 10-phenyl-2 ,3 , 4, 10-te trahydro-5_H_-pyrano- [2 , 3- bj [l,8]-naphthyridin-5-one; 7-phenyl-3 ,4,5, 7-te rahydro-oxepino [3 , 2-c] [1,8]- naphthy idin-6 [2Jϊ]-one; 7-( 4-chloropheny 1 )-3 ,4,5, 7-tetrahydro-oxepino- [ 3 , 2-c ] [1,8] -naphthyr idin-6 [2j3_] -one ; 7- ( 3-chlorophenyl )-3 ,4,5, 7-te trah dro-oxepino- [3,2-c] [1, 8] -naphthyr idin-6 [2_H_]-one; 7- ( 3-me hoxyphenyl ) -3,4,5,7-tetrahydro-oxepino- [3,2-c] [1 ,8] -naphthy idin-6 [2_H_] -one; or 7- ( 3-hydroxyphenyl )-3 , 4,5 , 7-tetrahydro-oxepino- [3 , 2-c] [1,8] -naphthyr idin-6 [2HJ -one .

Inventors: BLYTHIN DAVID J, BLYTHIN, DAVID, J.
Applicants: SCHERING CORP, SCHERING CORPORATION
Application year: 1987
Main classification: A61K31
IPC codes: A61K31, A61P17, A61P43, C07D221, C07D451, C07D453, C07D471, C07D491, C07D495, C07D519