Hydroxamate derivatives of selected nonsteroidal anti-inflammatory acyl residues having cyclooxygenase and 5-lipoxygenase inhibition

Claim 2

A process for the preparation of a compound of the formula and pharmaceutically acceptable acid addition or base salts thereof wherein i) RCO is an acyl residue of selected NSAIDS; ii) R, is hydrogen, lower alkyl or acyl; iii) R 2 is H, lower alkyl, cycloalkyl of from three to twelve carbon atoms of which from three to seven carbons are ring carbons, aryl, arylalkyl or heteroaryl with the overall proviso that when the acyl residue is of the formula wherein R 4 is hydrogen or lower alkyl, then R 3 is hydrogen, phenylmethyl, allyl, vinyl, isopropenyl, benzoyl, chlorobenzoyl, methoxybenzoyl, and thiomethylbenzoyl; and when the acyl residue is of the formula wherein R s , R s , R 7 and R 8 are independently H, chlorine, fluorine, or bromine, lower alkyl, lower alkoxy, or trifluoromethyl but when R4. is hydrogen then are not all hydrogen; and R 4 is otherwise independently as defined above; then R 1 and R 2 cannot both be hydrogen, comprising a compound of the formula RCOOH wherein RCO is as defined above in step (1) treated with a compound selected from the group consisting of (i) bromo or chloro producing agent in the presence of a base; or (ii) a coupling agent; and then the product of step (1) is further treated with a compound of the formula wherein R 1 are as defined above or an acid addition salt thereof, to obtain the compound of the formula I.

Claim 3

A process according to claim 1 for the preparation of a compound of formula I wherein RCO is selected from the groups consisting of in which R ia is selected from the group consisting of benzene, naphthalene, biphenyl and substituted benzene, naphthalene and biphenyl radicals in which said substituent is selected from the group consisting of halogen, lower alkyl, lower alkylthio, lower alkoxy, trifluoromethyl, phenoxy, lower alkyl phenoxy, lower alkoxy phenoxy, halogenophenoxy, trifluoroacetyl, difluoroacetyl, monofluoroacetyl, di-lower alkyl sulfamyl, lower alkanoyl, di-lower alkyl carboxamido, cyano, carb-lower alkoxy, trifluoromethylthio, lower alkyl sulfinyl, lower alkylsulfonyl, benzylthio, lower alkylbenzylthio, lower alkoxybenzylthio, halogenobenzylthio, mercapto, nitro, amino, di-(lower alkyl)amino, lower alkylamino, lower alkanoylamino, hydroxy, lower alkanoyloxy, trifluoroacetoxy, difluoroacetoxy, monofluoroacetoxy, benzyloxy, lower alkylbenzyloxy, lower alkoxylben- zyloxy, and halogenobenzyloxy; R 2a is selected from the group consisting of hydrogen, lower alkenyl and lower alkyl; R 3a is selected from the group consisting of hydrogen and lower alkyl; R 4a is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, fluorine and trifluoromethyl; R 5a is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino, di(lower alkyl) amino, lower alkanoylamino, lower alkanoyl, lower alkylamino, bis(hydroxy lower alkyl)amino, 1-pyrrolidino, 4-methyl-1-piperizinyl, 4-morpholinyl, cyano, amino lower alkyl, di-lower alkyl amino, lower alkyl, trifluoromethyl, halogen, di(lower alkyl)sulfamyl, benzylthio, lower alkylbenzylthio, lower alkoxybenzylthio, halogenobenzylthio, benzyloxy, lower alkylbenzyloxy, lower alkoxybenzyloxy, halogenobenzyloxy, lower alkenyl, lower alkenyloxy, 1-azacyclopropyl, cyclopropyl(lower alkoxy) methoxy, and cyclobutyl(lower alkoxy) methoxy; wherein R tb is hydrogen, lower alkyl or halogenated lower alkyl; R 2b is hydrogen or alkyl; R 3b , R 4b ,R 5b and R 6b each are hydrogen, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino, lower dialkylamino, lower dialkylamino lower alkyl, sulfamyl, lower alkylthio, mercapto, hydroxy, hydroxy lower alkyl, lower alkylsulfonyl, halogen, carboxyl, carbo-lower alkoxy, carbamido, halogenoalkyl, cycloalkyl, or cycloalkoxy; R 7b is lower alkylthio, alkylsulfinyl or alkylsulfonyl; R 8b is hydrogen, halogen, hydroxy, alkoxy or haloalkyl; and wherein: A rc represents a member selected from the group consisting of phenyl, thienyl, 5-methylthienyl, monosubstituted phenyl, disubstituted phenyl and trisubstituted phenyl, each substituent of said substituted phenyls being a member selected from the group consisting of halo, lower alkyl, trifluoromethyl, lower alkoxy, nitro, amino, methylthio and cyano; Ar 1c represents a member selected from the group consisting of phenyl, monosubstituted phenyl, disubstituted phenyl and trisubstituted phenyl, each substituent of said substituted phenyls being a member selected from the group consisting of halo, lower alkyl and lower alkoxy; R c represents a member selected from the group consisting of hydrogen and lower alkyl; R 1c represents a member selected from the group consisting of hydrogen, lower alkyl and benzyl; R 2c represents a member selected form the group consisting of R 3c represents a member selected from the group consisting of CO; R 4c represents lower alkyl; R 5c represents lower alkyl; and R 6c represents a member selected from the group consisting of hydrogen and lower alkyl; (d) wherein R d represents a group selected from: wherein R 1e and R 2e are each radicals of the group consisting of thienyl, furyl, naphthyl, phenyl, and phenyl bearing from one to two substituents of the group consisting of (lower)alkyl, (lower)alkoxy, chloro, bromo, fluoro, di-(lower alkyl)amino, nitro, amino and trifluoromethyl, and wherein R 3e is a radical from the group consisting of -CH 2 -CO, -CH 2 -CH 2 -CO, and -CH(CH 3 )-CO; wherein Y is hydrogen, chloro, bromo, fluoro, hydroxy, (lower)alkyl, (lower)alkoxy, mercapto, cyano, nitro, amino or (lower)alkylthio; wherein Rg represents hydrogen or a lower alkyl group having from one to four carbon atoms and R 1g represents hydrogen, a lower alkyl group having from one to 4 carbon atoms, a lower alkoxy group having from one to four carbon atoms, chloro, fluoro or bromo, the R 1g substitution being at the ortho, meta or para positions of the aroyl group; wherein R 1h represents a hydrogen or halogen atom or a trihalomethyl or lower alkoxy group; R 2h represents a hydrogen atom or a lower alkyl group; wherein R 1i is a member selected from the group consisting of cycloalkyl with five to seven carbon atoms and lower alkyl substituted cycloalkyl; R 21 is a member selected from the group consisting of halogen, nitro, cyano, trifluoromethyl and lower alkylsulfonyl; R 3 , is hydrogen; X i is halogen; wherein R 1ji and R 2ji are selected from the group consisting of phenyl, halophenyl, lower alkylphenyl, dimethylphenyl, lower alkoxyphenyl, dimethoxyphenyl, lower alkylmercaptophenyl, trifluoromethylphenyl, furyl, thienyl, and naphthyl with the proviso that at least one of R 1ji and R 2ji is phenyl or substituted phenyl; wherein R 1jii is hydrogen, lower alkyl, phenyl, phenyl monosubstituted with lower alkyl, lower alkoxy or halogen, naphthyl, benzyl or benzyl wherein the phenyl ring thereof is monosubstituted with lower alkoxy or halogen; wherein R 1jiii is phenyl; R 2jiii is phenyl, p-halogenophenyl, p-methylphenyl or furyl; R 3jiii is hydrogen, phenyl, or furyl; wherein R 1jiv is phenyl, R 2jiv is phenyl, p-halogenophenyl, p-methylphenyl, R 3jiv is hydrogen or phenyl; wherein R k represents hydrogen or methyl, R 1k represents hydrogen, methyl or ethyl, and Y k represents hydrogen, halogen, or alkyl or alkoxy of 1 through 4 carbon atoms; wherein R 11 is a lower alkyl or lower alkyl substituted by cycloalkyl of from three to 12 carbons having from three to seven ring carbons, lower alkenylenyl, lower alkynylenyl, aryl, benzoyl, benzoyl substituted by halogen, lower alkyl, lower alkoxy or heterocycle, such as morpholinyl piperidinyl, furanyl, and thiophenyl; R 2e and R 3e are the same or different and are lower alkyl, aryl and R 4e is hydrogen or lower alkyl; [in which A m represents a lower straight chain or branched alkylene group; R m represents a cyclohexyl or aromatic radical; R m represents a halogen atom, trifluoromethyl radical, an alkoxy or alkyl radical containing 1 to 4 carbon atoms or a N,N-dialkylamino radical wherein each of the alkyl groups contain 1 to 4 carbon atoms] as well as alkyl esters thereof (in which the alkyl group in the alcoholic moiety contains 1 to 4 carbon atoms); in which R 1n is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, phenyl, benzyl and 2-thienyl, R 2n , R 3n , R 4n and R 5n are the same or different and are each selected from the group consisting of hydrogen and lower alkyl, R 6an , R 6bn , R 6cn , and R 6dn are the same or different and selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro, halo, mercapto, lower alkylthio, trifluoromethyl, amino and sulfamoyl, R 7n is selected from the group consisting of hydrogen, lower alkyl and lower alkenyl, X is selected from the group consisting of oxy and thio, Y is selected from the group consisting of carbonyl, in which each of R 8n , R 9n , R 10n , R 11n , R 12n and R 13n is hydrogen or lower alkyl; wherein R o is hydrogen or lower alkyl; in which R 1 p is hydrogen or lower alkyl; R 2 p is hydrogen, alkyl, alkenyl three or four ring-membered cycloalkyl, cycloalkenyl or cycloalkyl-methyl cycloalkenyl-methyl; Ph is (i) 1,3- or 1,4-phenylene, (ii) (lower alkyl)-1,3- or 1,4-phenylene, (iii) (lower alkoxy)-1,3- or 1,4-phenylene, (iv) mono- or di-(halogeno)-1,3- or 1,4-phenylene, (v) (trifluoromethyl)-1,3- or 1,4-phenylene, (vi) (nitro)-1,3- or 1,4-phenylene, (vii) (amino-1,3- or 1,4-phenylene, (viii) di-lower alkylamino)-1,3- or 1,4-phenylene; and ApN- is monocyclic five to seven ring-membered lower alkyleneamino, piperazino, morpholino, thiamorpholino or N-(lower alkyl, hydroxy lower alkyl, HPh-lower alkyl or HPh) piperazino; wherein Rq is hydrogen, halogen, hydroxy, cyano, lower alkyl, hydroxy-lower alkyl, lower alkoxy, acetyl, benzyloxy, lower alkylthio, trifluoromethyl, carboxy, carbo-lower alkoxy, nitro, amino, mono-lower alkylamino, di-lower alkylamino, sulfamoyl, di-lower alkylsulfamoyl or difluoromethylsulfonyl; R 1q is halogen, cyano, hydroxy-lower alkyl, lower alkoxy, acetyl, acetamido, benzyloxy, lower alkylthio, trifluoromethyl, hydroxy, carboxy, carbo-lower alkoxy, nitro, amino, mono-lower alkylamino, di-lower alkylamino, sulfamoyl, di-lower alkylsulfamoyl or difluoromethylsulfonyl; or Rq taken together with an adjacent R 1q is also lower al- kylenedioxy; R 2q is wherein Yq and Xq, independently, are hydrogen or lower alkyl, and nq is one to seven and R 3 q is hydrogen, lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, lower alkanoyl, halo-substituted lower alkanoyl, benzyl, halo-benzyl, benzoyl or halo-benzoyl; and when Xq and Yq are different, their enantiomers; wherein each of the substituents R 2r and R 3r is a member of the group consisting of unsubstituted phenyl, naphthyl, thienyl and furyl radicals and phenyl radicals substituted by a substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro and trifluoromethyl radicals; and wherein R 1n is selected from the group consisting of carboxyalkyl- and carboxyalkenyl radicals each containing from two to five carbons; wherein each of X 1s and X 2s is a hydrogen atom, a halogen atom, an alkyl group having one to four carbon atoms or an alkoxy group having one to four carbon atoms; each of R 1s and R 2s is a hydrogen atom or an alkyl group having one to four carbon atoms; AS is carbonyl, methylene or alkylidene having two to four carbon atoms; Y s is -0-; and ring P s represents a pyridine or pyridine N-oxide ring; wherein: Ar t CO is an aroyl substituent the Art function of which is a member selected from the group consisting of 2-thienyl, 5-lower alkyl-2-thienyl, 5-halo-2-thienyl, 2-naphthyl and 3-pyridyl, said Ar t CO being in the meta- or para-position relative to the acetyl function; either of R t and R lt is hydrogen, the other being a member selected from the group consisting of hydrogen, halo and lower alkyl, provided that, when said R t is halo or lower alkyl, then said Ar t CO is in the aforementioned para-position, and when said R 1t is halo or lower alkyl, then said Ar t CO is in the aforementioned meta-position, and further provided that when said R t or R 1t is halo, then said Art is a member selected from the group consisting of 2-thienyl, 5-lower alkyl-2-thienyl and 5-halo-2- thienyl; either of R 2t and R 3t is a member selected from the group consisting of hydrogen, allyl and lower alkyl, the other being a member selected from the group consisting of hydrogen and lower alkyl, provided that, when either of said R 2t and R 3t is allyl, the other is hydrogen, and when either of said R 2t and R 3t is lower alkyl, the other is a member selected from the group consisting of hydrogen and lower alkyl; R 2t and R 3t taken together, is an alkylene bridge attached to the a-carbon of the acetic acid function: wherein n t is an integer from two to five; and wherein lower alkyl as above employed is a radical having from one to five carbon atoms; wherein Ar ti CO is an aroyl substituent the Ar ti function of which is a member selected from the group consisting of 2-thienyl, 5-methyl-2-thienyl, 5-chloro-2- thienyl, 2-naphthyl and 3-pyridyl, said Ar ti CO being in the meta- or para-position relative to the acetic acid function; either of R ti and R 1ti is hydrogen, the other being a member selected form the group consisting of hydrogen, chloro and methyl, provided that, when said R ti is chloro or methyl, then said Ar ti CO is in the aforementioned para-position, and when said R 1ti is. chloro or methyl, then said Ar ti CO is in the aforementioned meta-position, and further. provided that, when said R ti and R 1ti is chloro, then said Ar ti is a member selected from the group consisting of 2-thienyl, 5-methyl-2-thienyl and 5-chloro-2- thienyl; either of R 2ti and R 3ti is a member selected from the group consisting of hydrogen, allyl and lower alkyl, the other being a member selected from the group consisting of hydrogen and lower alkyl, provided that, when either of said R 2ti and R 3ti is allyl, the other is hydrogen, and when either of said R 2ti and R 311 is lower alkyl, the other is a member selected from the group consisting of hydrogen and lower alkyl; R 2ti and R 3ti , taken together, is an alkylene bridge attached to the a-carbon of the acetic acid function: wherein n ti is an integer from two to five; and wherein lower alkyl as above employed is a radical having from one to five carbons; wherein: Ar tii CO is an aroyl substituent the Ar tii function of which is a member selected from the group consisting of 2-thienyl, 5-lower alkyl-2-thienyl and 5-halo-2-thienyl, said Ar tii CO being in the meta- or para-position relative to the acetic acid function; either of R tii and R 1tii is hydrogen, the other being a member selected from the group consisting of hydrogen, halo and lower alkyl, provided that, when said R tii is halo or lower alkyl, then said Ar tii CO is in the aforementioned para-position, and when said R 1tii is halo or lower alkyl, then said Ar tii CO is in the aforementioned meta-position; either of R 2tii and R 3tii is a member selected from the group consisting of hydrogen, allyl and lower alkyl, the other being a member selected from the group consisting of hydrogen and lower alkyl, provided that, when either of said R 2tii and R 3tii is allyl, the other is hydrogen, and when said R 2tii and R 3tii is lower alkyl, the other is a member selected from the group consisting of hydrogen and lower alkyl; R 2tii and R 3til together is also an alkylene bridge with a-carbon of the acetic acid function: wherein n tii is an integer from two to five; and wherein lower alkyl as above employed is a radical having from one to five carbon atoms; or wherein: Ar tiii CO is an aroyl substituent the Ar tiii function of which is a member selected from the group consisting of 2-thienyl, 5-methyl-2-thienyl and 5-chloro-2- thienyl, said Ar tiii CO being in the meta- or para-position relative to the acetic acid function; either of Run and R 1tiii is hydrogen, the other being a member selected from the group consisting of hydrogen, chloro and methyl, provided that, when said Run is chloro or methyl, then said Ar tiii CO is in the aforementioned para-position, and when said R 1tiii is chloro or methyl, then said Ar tiii CO is in the aforementioned meta-position; either of R 2tiii and R 3tiii is a member selected from the group consisting of hydrogen, allyl and lower alkyl, the other being a member selected from the group consisting of hydrogen and lower alkyl, provided that, when either of said R 2tiii and R 3tiii is allyl, the other is hydrogen, and when either of said R 2tii and R 3tiii is lower alkyl, the other is a member selected from the group consisting of hydrogen and lower alkyl; R Ztiii and R 3tiii together is also an alkylene bridge with a-carbon of the acetic acid function: wherein n tiii is an integer from two to five; and wherein lower alkyl as above employed is a radical having from one to five carbon atoms; wherein each of R 1u and R 2u is a hydrogen atom or an alkyl group having one to four carbon atoms; each of X 1u and X 2u is a hydrogen atom, a halogen atoms, an alkyl group having one to four carbon atoms or an alkoxy group having one to four carbon atoms; and Y u is CO; wherein: R 2v and R 3v each are phenyl or phenyl mono- or di-substituted by at least one member selected from the group consisting of alkyl, alkoxy, alkylmercapto, monoalkylamino, dialkylamino or alkanoylamino wherein the alkyl, alkoxy and alkanoyl each are of up to four carbon atoms, F, Cl, Br, I, CF 3 , OH, methylenedioxy, NH 2 and N0 2 ; A v is C na H 2na wherein na is an integer from one to ten inclusive or and Z v is 0 or S; where R 1w , R 2w , R 3W and R 4w are independently hydrogen, chlorine, fluorine, bromine, lower alkyl, lower alkoxy and R 2 may additionally be trifluoromethyl, and R 5W is H or lower alkyl with exclusion of Ri, R 2 and R 3 as hydrogen simultaneously; (x) the acyl residue of (±)-a-methyl-3-phenyl-7-benzofuranepropionic acid; where Xv is Ray and Rβy are hydrogen or lower alkyl and Ry is halo.

Claim 4

A process according to claim 1 for the preparation of a compound of formula I which is selected from the group consisting of (Z)-6-fluoro-N-hydroxy-N,2-dimethyl-3-[[4-(methylsulfinyl)phenyl]methylene]-3H-indene-1-acetamide; (Z)-6-fluoro-N-methoxy-2-methyl-3-[[4-(methyl sulfinyl)phenyl]methylene]-3H-indene-1-acetamide; (Z)-6-fluoro-N-hydroxy-2-methyl-3-[[4-(methylsulfinyl)phenyl]methylene]-3H-indene-1-acetamide; (Z)-6-fluoro-N-hydroxy-N-(1-methylethyl)-2-methyl-3-[[4-(methylsulfinyl)phenyl]methylene]-3H-indene-1-acetamide; 1-(4-chlorobenzoyl-N-hydroxy-5-methoxy-N,2-dimethyl-1H-indole-3-acetamide; 1-4-chlorobenzoyl-N,5-dimethoxy-2-methyl-1 H-indole-3-acetamide; 1-(4-chlorobenzoyl-N-hydroxy-5-methoxy-2-methyl-N-(1-methylethyl)-1H-indole-3-acetamide; 1-(4-chlorobenzoyl-N-cyclohexyl-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-acetamide; 1-(4-chlorobenzoyl)-N,5-dimethoxy-N,2-dimethyl-1 H-indole-3-acetamide; a1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-phenyl-1H-indole-3-acetamide: 1-(4-chlorobenzoyl)-N-benzyl-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-acetamide; N-methoxy-2-[(2,6-dichlorophenyl)amino]benzeneacetamide or N-hydroxy-N-methyl-2-[(2,6-dichlorophenyl)-amino] benzeneacetamide.

Claim 5

A process for the preparation of a compound of formula I according to claim 2 wherein I c is 5-(4-methylbenzoyl)-1-methylpyrrolo-2-acetyl; or wherein RCO is l e wherein R 1e is phenyl, R 3e is -CH 2 CO-and R 2e is p-chlorophenyl; or wherein RCO is If wherein Y is chloro; or wherein RCO is I 9 wherein Rg and R 19 are hydrogen; or wherein RCO is I h werhein R ih and R 2h are hydrogen; or wherein RCO is wherein R 1i is cyclohexyl, R 31 is H and R 2i and X i are chloro; or wherein RCO is I ji wherein R 1ji is phenyl, and R 2ji is para-chlorophenyl; or wherein RCO is l k wherein Y k and R 1k are hydrogen and R k is methyl; or wherein RCO is I 1 wherein R 21 and R 31 are CH 3 , R 41 is hydrogen and R 11 is p-chlorophenyl; or wherein RCO is I m wherein R m is methoxy, A m is -CH 2 -, and R m is p-chlorophenyl; or wherein RCO is I n wherein R 1n and R 6dn are ethyl, Y is acetyl, and R 2n , R 3n , R 4 n , R sn , R 6an , R 6bn , R 6 c n and R 7n are hydrogen; or wherein RCO is I o wherein R o is CH 3 ; or wherein RCO is Ip wherein one of R 1p is hydrogen and one of R 2 p is methyl, Ph is -1,4-(3-chlorophenylene) and ApN- is or wherein RCO is Iq wherein R 2 q is 2-acetyl, Rq is 6-chloro, and R 1q and R 3 q are hydrogen; or wherein RCO is I r wherein R 1r is 3-propionyl and R 2r and R 3r are phenyl; or wherein RCO is 2-(5H-[1]benzopyrano[2,36]pyridin-7-yl) propionyl; or wherein RCO is It wherein Art is 2-thienyl, R t , R 1t and R 2t are hydrogen and R 3t is methyl; or wherein RCO is I u wherein X 1u , X 2u and R 1u are hydrogen and y 2U is methyl; or wherein RCO is I v wherein Z v is oxygen, A v is and R zv and R 3v are each p-chlorphenyl; or wherein RCO is ly wherein Ry is m-chloro and Ray and Rβy are hydrogen.

Claim 6

A method of use of a compound of formula I according to claim 1 for the manufacturing of pharmaceuticals for treating a condition advantageously affected by inhibition of 5-lipoxygenase, cycloox- yoenase, or both.

Claim 7

A process according to claim 1 for the preparation of a compound of the formula I wherein a compound of the formula RCOOH wherein RCO is as defined above is (1) treated with a coupling agent and then (2) reacted with a compound of the forumula wherein R 1 and R 2 are as defined above to obtain the compound of the formula I.

Claim 8

A process of the Claim 1 wherein RCO is I b wherein R 7b is alkylsulfinyl or wherein RCO is I w .

Claim 9

A process of the Claim 1 wherein RCO is I b wherein R 7b is alkylsulfinyl.

Claim 10

A process of the Claim 1 wherein RCO is I w .