Leukotriene antagonists

Claim 2

A compound of the formula or a pharmaceutically acceptable salt thereof, wherein: R 1 is or halo; R 2 is halo or hydroxy; R 3 is C 1 -C 12 alkyl, hydroxy-substituted C 1 -C 12 alkyl, or C 2 -C 6 alkenyl; Y is -O-, or -CR 6 R 7 -; Z is -O-, or -CR 8 R 9 -, or when taken together, -Y-Z is -CH=CH-; n is 1-10; D is CN, SCN or QR 4 ; Q is -O-, -NR-, or a bond; R 4 is -COR 10 , hydroxy, -NR 11 R 12 , SO(=NH)NH 2 , or where R is hydrogen or C 1 -C 3 alkyl; R 5 is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or phenyl optionally substituted with halo, C 1 -C 4 alkyl, or C 1 -C 4 akoxy; each of R 6 , R 7 , R 8 , and R 9 is independently hydrogen, C 1 -C 10 alkyl, phenyl, or benzyl; R 10 is hydroxy, C 1 -C 4 alkoxy, -NHOH, or -NR 11 R 12 ; each of R 11 and R 12 is independently hydrogen, C 1 -C 3 alkyl, or when taken together with the nitrogen atom form a morpholine or N-methyl piperazine ring; and p is 0, 1, or 2; with the provisions that: a) when R 1 is may not be hydroxy; b) when one of Y and Z is -O- or the other of Y and Z may not be -O- or and c) when R 4 is COR 10 , hydroxy, -NR 11 R 12 , or -SC(=NH)NH 2 , Q may only be a bond.

Claim 3

A compound of formula (I) wherein D is Q R 4 .

Claim 4

A compound of formula (I) wherein D is Q R 4 .

Claim 5

A compound of claim 1 which is 5-(2-propyl-3,4-dichlorophenoxy)pentanoic acid or a pharmaceutically acceptable salt thereof, or 4-(2-propyl-3,4-dichlorobenzyloxy)butanoic acid or a pharmaceutically acceptable salt thereof, or 6-(2-propyl-3,4-dichlorophenyl)hexanoic acid or a pharmaceutically acceptable salt thereof, or 5-[4-(2-propyl-3,4-dichlorophenoxy)butyl]-tetrazole or a pharmaceutically acceptable salt thereof, or 5-[3-(2-propyl-3,4-dichlorobenzyloxy)propyl]-tetrazole or a pharmaceutically acceptable salt thereof, or 5-[5-(2-propyl-3,4-dichlorophenyl)pentyl]-tetrazole or a pharmaceutically acceptable salt thereof, or 5-[3-(2-propyl-3,4-dichlorophenoxy)propyl- thio]-tetrazole or a pharmaceutically acceptable salt thereof, or 5-[2-(2-propyl-3,4-dichlorobenzyloxy)ethyl- thio]-tetrazole or a pharmaceutically acceptable salt thereof, or 5-[4-(2-propyl-3,4-dichlorophenyl)butylthio]-tetrazole or a pharmaceutically acceptable salt thereof. 4. A pharmaceutical formulation comprising a compound of formula (I) as defined in any one of claims 1-3, provided D is QR 4 , in association with one or more pharmaceutically acceptable carriers or diluents therefore.

Claim 6

A process for preparing a compound of formula (I) which comprises (a) reacting a compound of formula (II) wherein R 1 , R 2 , and R 3 are as defined in formula (I), and Y is S or O, with a compound of formula (III) wherein R 8 , R 9 , and n are as defined in formula (I), X is a leaving group, and D is CN, SCN, or QR 4 as defined in formula (I) to provide a compound of formula (I) wherein Y is S or O; or (b) reacting a compound of the formula wherein R 1 , R 2 , R 3 , R 6 , and R 7 are as defined in formula (I) with a compound of the formula wherein n is as defined in formula (I), D is CN, SCN, or QR 4 as defined in formula (I), and one of V and W is a leaving group and the other is -ZH, where Z is O or S to provide a compound of formula (I) wherein Z is O or S; or (c) reacting a compound of formula (XIII) wherein R 1 , R 2 , and R 3 are as defined in formula (I) and X' is halo, with a compound of formula (XIV) wherein n is as defined in formula (I) and D is CN, SCN, or QR 4 as defined in formula (I), to provide a compound of formula (I) wherein Y-Z is -CH=CH-; or (d) reacting a compound of formula (XVI) wherein R 1 , R 2 , and R 3 are as defined in formula (I), with a compound of the formula (XVII) wherein n is as defined in formula (I), X' is halo, and D is CN, SCN, or QR 4 as defined in formula (I) to provide a compound of formula (I) wherein Y-Z is -CH=CH-; or (e) reacting a compound of formula (I) wherein D is CN with an alkali metal azide and ammonium chloride, or with tetramethylquanidinium azide to provide a compound of formula (I) wherein D is 5-tetrazolyl; or (f) reacting a compound of formula IV wherein R 1 , R 2 , R 3 , R 9 , R 8 , and n are as defined in formula (I) Y is O or S, and D' is halo, with an alkali metal cyanide or an alkali metal thiocyanate to provide a compound of formula (I) wherein D is CN or SCN; or (g) reacting a compound of formula IV wherein D' is halo with 5-mercaptotetrazole to provide a compound of formula (I) wherein D is thiotetrazole; or (h) oxidizing a compound of formula (I) wherein Y or Z is S or SO to provide the corresponding compound of formula (I) wherein Y or Z is SO or SO 2 ; and (i) optionally salifying the resulting compound of formula (I).

Claim 7

A process for preparing a compound of formula (I) which comprises (a) reacting a compound of formula (II) wherein R 1 , R 2 , and R 3 are as defined in formula (I), and Y is S or O, with a compound of formula (III) wherein R 8 , R 9 , and n are as defined in formula (I), X is a leaving group, and D is CN, SCN, or QR 4 as defined in formula (I) to provide a compound of formula (I) wherein Y is S or O; or (b) reacting a compound of the formula wherein R 1 , R 2 , R 3 , R 6 , and R 7 are as defined in formula (I) with a compound of the formula wherein n is as defined in formula (I), D is CN, SCN, or QR 4 as defined in formula (I), and one of V and W is a leaving group and the other is -ZH, where Z is O or S to provide a compound of formula (I) wherein Z is O or S; or (c) reacting a compound of formula (XIII) wherein R 1 , R 2 , and R 3 are as defined in formula (I) and X' is halo, with a compound of formula (XIV) wherein n is as defined in formula (I) and D is CN, SCN, or QR 4 as defined in formula (I), to provide a compound of formula (I) wherein Y-Z is -CH=CH-; or (d) reacting a compound of formula (XVI) wherein R 1 , R 2 , and R 3 are as defined in formula (I), with a compound of the formula (XVII) wherein n is as defined in formula (I), X' is halo, and D is CN, SCN, or QR 4 as defined in formula (I) to provide a compound of formula (I) wherein Y-Z is -CH=CH-; or (e) reacting a compound of formula (I) wherein D is CN with an alkali metal azide and ammonium chloride, or with tetramethylquanidinium azide to provide a compound of formula (I) wherein D is 5-tetrazolyl; or (f) reacting a compound of formula IV wherein R 1 , R 2 , R 3 , R 9 , R 8 , and n are as defined in formula (I) Y is O or S, and D' is halo, with an alkali metal cyanide or an alkali metal thiocyanate to provide a compound of formula (I) wherein D is CN or SCN; or (g) reacting a compound of formula IV wherein D' is halo with 5-mercaptotetrazole to provide a compound of formula (I) wherein D is thiotetrazole; or (h) oxidizing a compound of formula (I) wherein Y or Z is S or SO to provide the corresponding compound of formula (I) wherein Y or Z is SO or SO 2 ; and (i) optionally salifying the resulting compound of formula (I).

Claim 8

Use of a compound of formula (I) as claimed in any one of claims 1-3, provided D is QR4, for treatment or prevention of any condition characterized by excessive release of leukotrienes.

Claim 9

Use of a compound of formula (I) is claimed in any one of claims 1-3, provided D is QR 4 , for treatment or prevention of immediate hypersensitivity reaction.

Claim 10

A compound of formula (I) as claimed in any one of claims 1-3, provided D is QR 4 for use in treating or preventing any condition characterized by excessive release of leukotrienes, or for treating or preventing immediate hypersensitivity reaction.

Claim 11

A process for preparing a compound of the formula or a pharmaceutically acceptable salt thereof, wherein: R 1 is or halo; R 2 is halo or hydroxy; R 3 is C 1 -C 12 alkyl, hydroxy-substituted C 1 -C 12 alkyl, or C 2 -C 6 alkenyl; Y is -O-, or -CR 6 R 7 -; Z is -O-, or -C R 8 R 9 - , or when taken together, -Y-Z is -CH=CH-; n is 1-10; D is CN, SCN or QR 4 ; Q is -O-, -NR-, or a bond; R 4 is -COR 10 , hydroxy, -NR 11 R 12 , SC(=NH)NH 2 , or where R is hydrogen or C 1 -C 3 alkyl; R 5 is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or phenyl optionally substituted with halo, C 1 -C 4 alkyl, or C 1 -C 4 akoxy; each of R 6 , R 7 , R 8 , and R 9 is independently hydrogen, C 1 -C 10 alkyl, phenyl, or benzyl; R 10 is hydroxy, C 1 -C 4 alkoxy, -NHOH, or -NR 11 R 12 ; each of R 11 and R 12 is independently hydrogen, C 1 -C 3 alkyl, or when taken together with the nitrogen atom form a morpholine or N-methyl piperazine ring; and p is 0, 1, or 2; with the provisions that: a) when R 1 is may not be hydroxy; b) when one of Y and Z is -O- or the other of Y and Z may not be -O- or and c) when R 4 .is COR 10 , hydroxy, -NR 11 R 12 , or -SC( = NH)NH 2 , Q may only be a bond, which comprises (a) reacting a compound of formula (II) wherein R 1 , R 2 , and R 3 are as defined in formula (I), and Y is S or O, with a compound of formula (III) wherein R 8 , R 9 , and n are as defined in formula (I), X is a leaving group, and D is CN, SCN, or QR 4 as defined in formula (I) to provide a compound of formula (I) wherein Y is S or O; or (b) reacting a compound of the formula wherein R 1 , R 2 , R 3 , R 6 , and R 7 are as defined in formula (I) with a compound of the formula wherein n is as defined in formula (I), D is CN, SCN, or QR 4 as defined in formula (I), and one of V and W is a leaving group and the other is -ZH, where Z is O or S to provide a compound of formula (I) wherein Z is O or S; or (c) reacting a compound of formula (XIII) wherein R 1 , R 2 , and R 3 are as defined in formula (I) and X' is halo, with a compound of formula (XIV) wherein n is as defined in formula (I) and D is CN, SCN, or QR 4 as defined in formula (I), to provide a compound of formula (I) wherein Y-Z is -CH=CH-; or (d) reacting a compound of formula (XVI) wherein R 1 , R 2' and R 3 are as defined in formula (I), with a compound of the formula (XVII) wherein n is as defined in formula (I), X' is halo, and D is CN, SCN, or QR 4 as defined in formula (I) to provide a compound of formula (I) wherein Y-Z is -CH=CH-; or (e) reacting a compound of formula (I) wherein D is CN with an alkali metal azide and ammonium chloride, or with tetramethylquanidinium azide to provide a compound of formula (I) wherein D is 5-tetrazolyl; or (f) reacting a compound of formula IV wherein R 1 , R 2 , R 3 , R 9 , R 8 , and n are as defined in formula (I) Y is O or S, and D' is halo, with an alkali metal cyanide or an alkali metal thiocyanate to provide a compound of formula (I) wherein D is CN or SCN; or (g) reacting a compound of formula IV wherein D' is halo with 5-mercaptotetrazole to provide a compound of formula (I) wherein D is thiotetrazole; or (h) oxidizing a compound of formula (I) wherein Y or Z is S or SO to provide the corresponding compound of formula (I) wherein Y or Z is SO or S0 2 ; and (i) optionally salifying the resulting compound of formula (I).

Claim 12

A process for preparing a compound of the formula or a pharmaceutically acceptable salt thereof, wherein: R 1 is or halo; R 2 is halo or hydroxy; R 3 is C 1 -C 12 alkyl, hydroxy-substituted C 1 -C 12 alkyl, or C 2 -C 6 alkenyl; Y is -O-, or -CR 6 R 7 -; Z is -O-, or -C R 8 R 9 - , or when taken together, -Y-Z is -CH=CH-; n is 1-10; D is CN, SCN or QR 4 ; Q is -O-, -NR-, or a bond; R 4 is -COR 10 , hydroxy, -NR 11 R 12 , SC(=NH)NH 2 , or where R is hydrogen or C 1 -C 3 alkyl; R 5 is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or phenyl optionally substituted with halo, C 1 -C 4 alkyl, or C 1 -C 4 akoxy; each of R 6 , R 7 , R 8 , and R 9 is independently hydrogen, C 1 -C 10 alkyl, phenyl, or benzyl; R 10 is hydroxy, C 1 -C 4 alkoxy, -NHOH, or -NR 11 R 12 ; each of R 11 and R 12 is independently hydrogen, C 1 -C 3 alkyl, or when taken together with the nitrogen atom form a morpholine or N-methyl piperazine ring; and p is 0, 1, or 2; with the provisions that: a) when R 1 is may not be hydroxy; b) when one of Y and Z is -O- or the other of Y and Z may not be -O- or and c) when R 4 .is COR 10 , hydroxy, -NR 11 R 12 , or -SC( = NH)NH 2 , Q may only be a bond, which comprises (a) reacting a compound of formula (II) wherein R 1 , R 2 , and R 3 are as defined in formula (I), and Y is S or O, with a compound of formula (III) wherein R 8 , R 9 , and n are as defined in formula (I), X is a leaving group, and D is CN, SCN, or QR 4 as defined in formula (I) to provide a compound of formula (I) wherein Y is S or O; or (b) reacting a compound of the formula wherein R 1 , R 2 , R 3 , R 6 , and R 7 are as defined in formula (I) with a compound of the formula wherein n is as defined in formula (I), D is CN, SCN, or QR 4 as defined in formula (I), and one of V and W is a leaving group and the other is -ZH, where Z is O or S to provide a compound of formula (I) wherein Z is O or S; or (c) reacting a compound of formula (XIII) wherein R 1 , R 2 , and R 3 are as defined in formula (I) and X' is halo, with a compound of formula (XIV) wherein n is as defined in formula (I) and D is CN, SCN, or QR 4 as defined in formula (I), to provide a compound of formula (I) wherein Y-Z is -CH=CH-; or (d) reacting a compound of formula (XVI) wherein R 1 , R 2' and R 3 are as defined in formula (I), with a compound of the formula (XVII) wherein n is as defined in formula (I), X' is halo, and D is CN, SCN, or QR 4 as defined in formula (I) to provide a compound of formula (I) wherein Y-Z is -CH=CH-; or (e) reacting a compound of formula (I) wherein D is CN with an alkali metal azide and ammonium chloride, or with tetramethylquanidinium azide to provide a compound of formula (I) wherein D is 5-tetrazolyl; or (f) reacting a compound of formula IV wherein R 1 , R 2 , R 3 , R 9 , R 8 , and n are as defined in formula (I) Y is O or S, and D' is halo, with an alkali metal cyanide or an alkali metal thiocyanate to provide a compound of formula (I) wherein D is CN or SCN; or (g) reacting a compound of formula IV wherein D' is halo with 5-mercaptotetrazole to provide a compound of formula (I) wherein D is thiotetrazole; or (h) oxidizing a compound of formula (I) wherein Y or Z is S or SO to provide the corresponding compound of formula (I) wherein Y or Z is SO or S0 2 ; and (i) optionally salifying the resulting compound of formula (I).

Claim 13

The process of claim 1 when used to prepare a compound of formula (I) wherein D is QR 4 .

Claim 14

The process of claim 1 when used to prepare 5-(2-propyl-3,4-dichlorophenoxy)pentanoic acid or a pharmaceutically acceptable salt thereof, or 4-(2-propyl-3,4-dichlorobenzyloxy)butanoic acid or a pharmaceutically acceptable salt thereof, or 6-(2-propyl-3,4-dichlorophenyl)hexanoic acid or a pharmaceutically acceptable salt thereof, or 5-[4-(2-propyl-3,4-dichlorophenoxy)butyl]-tetrazole or a pharmaceutically acceptable salt thereof, or 5-[3-(2-propyl-3,4-dichlorobenzyloxy)propyl]-tetrazole or a pharmaceutically acceptable salt thereof, or 5-[5-(2-propyl-3,4-dichlorophenyl)pentyl]-tetrazole or a pharmaceutically acceptable salt thereof, or 5-[3-(2-propyl-3,4-dichlorophenoxy)propyl- thio]-tetrazole or a pharmaceutically acceptable salt thereof, or 5-[2-(2-propyl-3,4-dichlorobenzyloxy)ethyl- thio]-tetrazole or a pharmaceutically acceptable salt thereof, or . 5-[4-(2-propyl-3,4-dichlorophenyl)butylthio]-tetrazole or a pharmaceutically acceptable salt thereof. 4. A compound of formula (I) whenever prepared by the process of claim 1.