Interphenylene 9-thia-11-oxo-12-aza-prostanoic acids

Claim 2

A compound of the formula: ##STR47## wherein R is carboxy, a carboxy salt, a carboxy ester of the formula COOR 5 wherein R 5 is C 1-10 alkyl, or CONHR 6 wherein R 6 is amino or methylsulfonyl; A is a p-phenylene or a m-phenylene or substituted phenylene derivative in which one or two of the phenylene hydrogens is replaced by a methyl or a halo substituent, or 2,5-thienylene or 2,5-furylene; n is 3 or 4; m is 0, 1, or 2; R 1 is hydrogen, deuterium, or methyl; Z is alkylene or unsaturated alkylene having from 2-3 carbon atoms; R 2 is hydrogen or lower alkanoyl; R 3 is hydrogen or straight chain C 1-3 alkyl; and R 4 is lower straight chain or branched alkyl having from 3-7 carbon atoms, an unsaturated alkyl having from 3-7 carbon atoms, or a substituted lower alkyl selected from polyfluoro alkyl of from 3-7 carbon atoms and lower alkoxy methylene; or R 3 and R 4 taken together with the carbon atom connecting R 3 and R 4 is a cyclic substituent selected from a bridged or unbridged alicyclic ring of from 5-9 carbon atoms or a heterocyclic ring containing sulfur or oxygen and from 5-7 ring-forming carbon atoms.

Claim 3

The compound of claim 1 wherein R is carboxy or carboxy salt having the formula --COO - M + wherein M + is a pharmaceutically acceptable cation derived from a metal or an amine.

Claim 4

The compound of claim 2 having the formula: ##STR48## wherein X is chlorine or methyl; r is 0, 1, or 2; n is 3 or 4; R 1 is hydrogen, deuterium, or methyl; Z is ethylene, trimethylene, cis or trans-propenylene, or propynylene; R 3 is hydrogen or lower alkyl of 1-3 carbon atoms; and R 4 is 4-pentenyl, 5,5,5-trifluoropentyl, or lower straight or branched chain alkyl of 3-7 carbon atoms.

Claim 5

The compound of claim 3 wherein r is 0, n is 3, and R 1 is hydrogen.

Claim 6

The compound of claim 4 wherein Z is ethylene.

Claim 7

4-{3-[3-(3-Hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 5 wherein R 3 is hydrogen and R 4 is pentyl.

Claim 8

4-{3-[3-(3-Hydroxydecyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 5 where R 3 is hydrogen and R 4 is heptyl.

Claim 9

4-{3-[3-(3-Hydroxy-4,4-dimethyloctyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 5 where R 3 is hydrogen and R 4 is 1,1-dimethylpentyl.

Claim 10

4-{3-[3-(3-Hydroxy-7-octenyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 5 where R 3 is hydrogen and R 4 is 4-pentenyl.

Claim 11

4-{3-[3-(3-Hydroxy-8,8,8-trifluorooctyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 5 where R 3 is hydrogen and R 4 is 5,5,5-trifluoropentyl.

Claim 12

4-{3-[3-(3-Hydroxy-3-methyloctyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 5 where R 3 is methyl and R 4 is pentyl.

Claim 13

The compound of claim 2 having the formula: ##STR49## wherein X is chlorine or methyl; r is 0, 1, or 2; n is 3 or 4; R 1 is hydrogen, deuterium, or methyl; Z is ethylene, trimethylene, cis or trans-propenylene, or propynylene; and R 4 is CH 2 OR 7 wherein R 7 is lower straight or branched chain alkyl of 2-5 carbon atoms.

Claim 14

The compound of claim 12 wherein r is 0, n is 3, and R 1 is hydrogen.

Claim 15

The compound of claim 13 wherein Z is ethylene.

Claim 16

4-{3-[3-(3-Hydroxy-4-propoxybutyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 14 where R 7 is propyl.

Claim 17

The compound of claim 2 having the formula: ##STR50## wherein X is chlorine or methyl; r is 0, 1, or 2; n is 3 or 4; m is 0, 1, or 2; R 1 is hydrogen, deuterium, or methyl; Z is ethylene, trimethylene, propenylene, or propynylene; y is 0, 2, or 3; and W is polymethylene of 2-6 carbon atoms.

Claim 18

The compound of claim 16 where r is 0, m is 0, and R 1 is hydrogen.

Claim 19

The compound of claim 17 where Z is ethylene.

Claim 20

4-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 18 where n is 3, y is 0, and W is trimethylene.

Claim 21

4-{3-[3-[2-(1-Hydroxycyclopentyl)ethyl]-4-oxo-2-triazolidinyl]propyl}benzoic acid, the compound of claim 18 where n is 3, y is 0, and W is ethylene.

Claim 22

4-{3-[3-[2-(1-Hydroxycycloheptyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 18 where n is 3, y is 0, and W is tetramethylene.

Claim 23

4-{3-[3-[2-(1-Hydroxy-4,4-dimethylcyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 18 where n is 3, y is 0, and W is 2,2-dimethyltrimethylene.

Claim 24

4-{3-[3-[2-(9-Hydroxy-9-bicyclo[3.3.1]nonyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 18 where n is 3, y is 3, and W is trimethylene.

Claim 25

4-{4-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]butyl}benzoic acid, the compound of claim 18 where n is 4, y is 0, and W is trimethylene.

Claim 26

The compound of claim 17 where Z is trimethylene.

Claim 27

4-{3-[3-[3-(1-Hydroxycyclohexyl)propyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 25 where n is 3, y is 0, and W is trimethylene.

Claim 28

The compound of claim 17 where Z is cis-propenylene.

Claim 29

4-{3-[3-[3-(1-Hydroxycyclohexyl)-(Z)-2-propenyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 27 where n is 3, y is 0, and W is trimethylene.

Claim 30

The compound of claim 17 where Z is trans-propenylene.

Claim 31

4-{3-[3-[3-(1-Hydroxycyclohexyl)-(E)-2-propenyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 29 where n is 3, y is 0, and W is trimethylene.

Claim 32

The compound of claim 17 where Z is propynylene.

Claim 33

4-{3-[3-[3-(1-Hydroxycyclohexyl)-2-propynyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 31 where n is 3, y is 0, and W is trimethylene.

Claim 34

The compound of claim 16 where X is chlorine, r is 1, m is 0, R 1 is hydrogen, and Z is ethylene.

Claim 35

4-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-3-chlorobenzoic acid, the compound of claim 33 where n is 3, y is 0, W is trimethylene, with chlorine in the 3-position of the phenylene group.

Claim 36

4-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-2-chlorobenzoic acid, the compound of claim 33 where n is 3, y is 0, W is trimethylene with chlorine in the 2-position of the phenylene group.

Claim 37

The compound of claim 16 where X is methyl, r is 1, m is 0, R 1 is hydrogen, and Z is ethylene.

Claim 38

4-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-3-methylbenzoic acid, the compound of claim 36 where n is 3, y is 0, W is trimethylene with methyl in the 3-position of the phenylene group.

Claim 39

The compound of claim 16 where m is 1, r is 0, R 1 is hydrogen, and Z is ethylene.

Claim 40

4-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-1,4-dioxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 38 where n is 3, y is 0, and W is trimethylene.

Claim 41

The compound of claim 16 where m is 2, r is 0, R 1 is hydrogen, and Z is ethylene.

Claim 42

4-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-1,1,4-trioxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 40 where n is 3, y is 0, and W is trimethylene.

Claim 43

The compound of claim 16 where m is 0, r is 0, R 1 is methyl, and Z is ethylene.

Claim 44

4-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-5,5-dimethyl-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 42 where n is 3, y is 0, and W is trimethylene.

Claim 45

The compound of claim 16 where m is 0, r is 0, R 1 is deuterium, and Z is ethylene.

Claim 46

4-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-5,5-dideuterio-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 44 where n is 3, y is 0, and W is trimethylene.

Claim 47

The compound of claim 2 having the formula: ##STR51## wherein X is chlorine or methyl; r is 0, 1, or 2; n is 3 or 4; m is 0, 1, or 2; R 1 is hydrogen or methyl; Z is ethylene, trimethylene, propenylene, or propynylene; and y is 4 to 8.

Claim 48

The compound of claim 46 where r is 0, m is 0, R 1 is hydrogen, and Z is ethylene.

Claim 49

3-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 47 where n is 3, and y is 5.

Claim 50

The compound of claim 2 having the formula: ##STR52## wherein n is 3 or 4; R 1 is hydrogen or methyl; Z is ethylene, trimethylene, propenylene, or propynylene; and y is 4 to 8.

Claim 51

5-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}thiophene-2-carboxylic acid, the compound of claim 49 where n is 3, R 1 is hydrogen, Z is ethylene, and y is 5.

Claim 52

The compound of claim 2 having the formula: ##STR53## wherein n is 3 or 4; R 1 is hydrogen or methyl; Z is ethylene, trimethylene, propenylene, or propynylene; and y is 4 to 8.

Claim 53

5-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}furan-2-carboxylic acid, the compound of claim 51 where n is 3, R 1 is hydrogen, Z is ethylene, and y is 5.

Claim 54

The compound of claim 2 having the formula: ##STR54## wherein n is 3 or 4; R 1 is hydrogen or methyl; Z is ethylene, trimethylene, propenylene, or propynylene; w and y are each 1 to 5 with the sum of w and y being from 4 to 6; and A is oxygen or sulfur.

Claim 55

4-{3-[3-[2-(4-Hydroxytetrahydro-4-pyranyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 53 where n is 3, R 1 is hydrogen, Z is ethylene, w and y are each 2, and A is oxygen.

Claim 56

44-{3-[3-[2-(4-Hydroxytetrahydro-4-thiopyranyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 53 where n is 3, R 1 is hydrogen, Z is ethylene, w and y are each 2, and A is sulfur.

Claim 57

The compound of claim 1 wherein R is COOR 5 where R 5 is C 1-10 alkyl.

Claim 58

Methyl 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoate, the compound of claim 56 where A is unsubstituted p-phenylene (r=0), n is 3, m is 0, R 1 is hydrogen, R 2 is hydrogen, R 3 and R 4 are lower alkyl, joined to form a cyclohexane ring together with the carbon atom joining R 3 and R 4 .

Claim 59

The compound of claim 1 wherein R is CONHR 6 where R 6 is amino and R 2 is hydrogen.

Claim 60

4-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid hydrazide, the compound of claim 58 where A is unsubstituted p-phenylene (r=0), n is 3, m is 0, R 1 is hydrogen, and R 3 and R 4 are lower alkyl joined to form a cyclohexane ring together with the carbon atom joining R 3 and R 4 .

Claim 61

The compound of claim 1 wherein R is CONHR 6 where R 6 is methylsulfonyl.

Claim 62

N-Methylsulfonyl-4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzamide, the compound of claim 60 where A is unsubstituted p-phenylene (r=0), n is 3, m is 0, R 1 and R 2 are hydrogen, and R 3 and R 4 are lower alkyl joined to form a cyclohexane ring together with the carbon atom joining R 3 and R 4 .

Claim 63

The compound of claim 1 wherein R is carboxy, carboxy salt, or COOR 5 where R 5 is C 1-10 alkyl; and R 2 is acetyl.

Claim 64

4-{3-[3-[2-(1-Acetoxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 62 where R is carboxy, A is unsubstituted p-phenylene (r=0), n is 3, m is 0, R 1 is hydrogen, and R 3 and R 4 are lower alkyl joined to form a cyclohexane ring together with the carbon atom joining R 3 and R 4 .

Claim 65

A pharmaceutical composition for improving renal function in patients with renal impairment comprising an aqueous, oily, or enteric-coated pharmaceutical carrier and an effective renal vasodilator amount of a compound of the formula: ##STR55## wherein R is carboxy, a carboxy salt, a carboxy ester of the formula COOR 5 wherein R 5 is C 1-10 alkyl, or CONHR 6 wherein R 6 is amino or methylsulfonyl; A is a p-phenylene or a m-phenylene or substituted phenylene derivative in which one or two of the phenylene hydrogens is replaced by a methyl or a halo substituent, or 2,5-thienyl or 2,5-furylene; n is 3 or 4; m is 0, 1, or 2; R 1 is hydrogen, deuterium, or methyl; Z is alkylene or unsaturated alkylene having from 2-3 carbon atoms; R 2 is hydrogen or lower alkanoyl; R 3 is hydrogen or straight chain C 1-3 alkyl; and R 4 is a lower straight chain or branched alkyl having from 3-7 carbon atoms, an unsaturated alkyl having from 3-7 carbon atoms, or a substituted lower alkyl selected from polyfluoro alkyl of from 3-7 carbon atoms and lower alkoxy methylene; or R 3 and R 4 taken together with the carbon atom connecting R 3 and R 4 is a cyclic substituent selected from a bridged or unbridged alicyclic ring of from 5-9 carbon atoms or a heterocyclic ring containing sulfur or oxygen and from 5-7 ring-forming carbon atoms.

Claim 66

A pharmaceutical composition for improving renal function in patients with renal impairment comprising an aqueous, oily, or enteric-coated pharmaceutical carrier and an effective renal vasodilator amount of a compound of the formula: ##STR55## wherein R is carboxy, a carboxy salt, a carboxy ester of the formula COOR 5 wherein R 5 is C 1-10 alkyl, or CONHR 6 wherein R 6 is amino or methylsulfonyl; A is a p-phenylene or a m-phenylene or substituted phenylene derivative in which one or two of the phenylene hydrogens is replaced by a methyl or a halo substituent, or 2,5-thienyl or 2,5-furylene; n is 3 or 4; m is 0, 1, or 2; R 1 is hydrogen, deuterium, or methyl; Z is alkylene or unsaturated alkylene having from 2-3 carbon atoms; R 2 is hydrogen or lower alkanoyl; R 3 is hydrogen or straight chain C 1-3 alkyl; and R 4 is a lower straight chain or branched alkyl having from 3-7 carbon atoms, an unsaturated alkyl having from 3-7 carbon atoms, or a substituted lower alkyl selected from polyfluoro alkyl of from 3-7 carbon atoms and lower alkoxy methylene; or R 3 and R 4 taken together with the carbon atom connecting R 3 and R 4 is a cyclic substituent selected from a bridged or unbridged alicyclic ring of from 5-9 carbon atoms or a heterocyclic ring containing sulfur or oxygen and from 5-7 ring-forming carbon atoms.

Claim 67

A composition of claim 64 wherein R is carboxy, A is phenyl, n is 3, m is 0, R 1 is hydrogen, Z is ethylene, R 2 is hydrogen, and R 3 and R 4 taken together with the carbon atom connecting R 3 and R 4 is cyclohexyl.