Bicyclic carboxylic acids and their derivatives as nep and aca inhibitors

Claim 2

A compound of Claim 1 having the formula wherein: A is R₂ is hydrogen, or R₁₁-S-; R₃ is hydrogen or lower alkyl of 1 to 4 carbons; r is zero or one; R₁₁ is lower alkyl or 1 to 4 carbons; R₁ is aryl-CH₂-, substituted aryl-CH₂-, heteroaryl-CH₂-, cycloalkyl-CH₂- wherein cycloalkyl is of 3 to 7 carbons, or straight or branched chain alkyl of 1 to 7 carbons and R₁₂ is hydrogen; or R₁ and R₁₂ taken together with the carbon to which they are attached complete a cycloalkyl ring of 5 to 7 carbons; R₆ is lower alkyl of 1 to 4 carbons or phenyl; n is one or two; m is zero or one; X is O or S; and Y is CH₂, O, or S provided that Y is O or S only when m is one.

Claim 3

A compound of Claim 2 wherein: R₂ is hydrogen or R₃ is hydrogen; r is zero or one; R₁ is benzyl, cyclopropylmethyl, or straight or branched chain alkyl of 3 to 5 carbons; R₁₂ is hydrogen; n is one or two; m is zero or one; X is O or S; and Y is CH₂, O, or S provided that Y is O or S only when m is one.

Claim 4

A compound of Claim 3 wherein: X is S; Y is CH₂; n is two; m is one; r is zero or one; R₂ is hydrogen; R₁ is benzyl or isobutyl; and R₁₂ is hydrogen; or X is S; Y is CH₂; n is one; m is one; r is zero; R₂ is hydrogen; R₁ is benzyl; and R₁₂ is hydrogen; or X is S; Y is CH₂; n is two; m is zero; r is zero; R₂ is hydrogen; R₁ is benzyl, cyclopropylmethyl, n-butyl, isobutyl, n-propyl, or -CH₂C(CH₃)₃; and R₁₂ is hydrogen; or X is O; Y is CH₂; n is two; m is one; r is zero; R₂ is hydrogen; R₁ is benzyl; and R₁₂ is hydrogen; X is O; Y is CH₂; n is two; m is zero; r is zero; R₂ is hydrogen; R₁ is benzyl; and R₁₂ is hydrogen; X is O; Y is O; n is two; m is one; r is zero; R₂ is hydrogen; R₁ is benzyl; and R₁₂ is hydrogen; X is S; Y is O; n is two; m is one; r is zero; R₂ is hydrogen; R₁ is benzyl; and R₁₂ is hydrogen.

Claim 5

The compound of Claim 4: [4S-[4α(R*),7α,10aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid; [4S-[4α(R*),7α,10aβ]]-octahydro-4-[ (2-mercapto-1-oxo-3-phenylpropyl]amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid,1,1-dimethylethylamine salt; [4S-[4α(S*),7α,10aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl]amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid; [4S-[4α(R*),7α,10aβ]]-octahydro-4-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid; [4S-[4α(R*),7α,10aβ]]-octahydro-4-methyl-1-oxopentyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid; [3R-[3α(s*),6α,9aβ]]-hexahydro-3-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-4-oxo-2H,6H-pyrido[2,1-b][1,3]thiazine-6-carboxylic acid; [4S-[4α(R*),7α,9aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxopyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid; [4S-[4α(R*),7α,9aβ]]-octahydro-4-[(3-cyclopropyl-2-mercapto-1-oxopropyl)amino]-5-oxopyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid; [4S-[4α(R*),7α,9aβ]]-octahydro-4-[(2-mercapto-1-oxohexyl)amino]-5-oxopyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid; [4S-[4α(R*),7α,9aβ]]-octahydro-4-[(2-mercapto-1-oxo-4-methylpentyl)amino]-5-oxopyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid; [4S-[4α(R*),7α,9aβ]]-octahydro-4-[(2-mercapto-1-oxopentyl)amino]-5-oxopyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid; [4S-[4α(R*),7α,9aβ]]-octahydro-4-[(2-mercapto-4,4-dimethyl-1-oxopentyl)amino]-5-oxopyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid; [4S-[4α(R*),7α,10aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]oxazepine-7-carboxylic acid; [4S-[4α(R*),7α,9aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxopyrrolo[2,1-b][1,3]oxazepine-7-carboxylic acid; [4S-[4α(R*),7α,10aβ]]-octahydro,4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo[1,4]oxazino[3,4-b][1,3]oxazepine-7-carboxylic acid; or [4S-[4α(R*),7α,10aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo[1,4]oxazino[3,4-b][1,3]thiazepine-7-carboxylic acid.

Claim 6

The compound of the formula or such a compound in pharmaceutically acceptable salt form.

Claim 7

A pharmaceutical composition for use in the treatment of cardiovascular disease such as hypertension and congestive heart failure comprising a pharmaceutically acceptable carrier and one or more compounds of the formula or such a compound in pharmaceutically acceptable salt form, wherein A, X, Y, n, m and R₃ are as defined in Claim 1.

Claim 8

A compound of the formula or such a compound in salt form wherein: X is O or S; n is one or two; m is zero or one; Y is CH₂, O, or S provided that Y is O or S only when m is one; R₃ is hydrogen, lower alkyl, or aryl-(CH₂) p -; and p is zero or an integer from 1 to 6.

Claim 9

A process for preparing the compounds of the formula which comprises: a) when A is and R₃ is hydrogen, coupling the acylmercapto sidechain of the formula or an activated form thereof with the amine of the formula in the presence of a coupling reagent wherein X, Y, m, n, R₆, r, R₁,and R₁₂ are as defined in Claim 1 and R₃ is hydrogen or an acid protecting group followed by removal of the acyl group and the R₃ acid protecting group; b) when A is coupling the carboxylic acid of the formula or an activated form thereof with the amine of the formula in the presence of a coupling reagent wherein X, Y, m, n, R₁ and R₁₂ are as defined in Claim 1, and R₃ and R₇ are acid protecting groups; c) when A is and R₃ is hydrogen, reacting the keto acid or ester of the formula under reducing conditions or the triflate of the formula with the amine of the formula wherein X, Y, m, n, R₇ and R₁ are as defined in Claim 1 and R₃ is an acid protecting group followed by removal of the R₃ acid protecting group; and d) when A is and R₃ is hydrogen, coupling a phosphonochloridate of the formula with the amine of the formula wherein X, Y, m, n, and R₄ are as defined in Claim 1 and R₃ and R₅ are acid protecting groups followed by removal of the R₃ and R₅ acid protecting groups.

Claim 10

A process for preparing the compounds of the formula wherein: X is O or S; n is one or two; m is zero or one; Y is CH₂, O or S provided that Y is O or S only when m is one; and R₃ is an acid protecting group; which comprises: a) coupling an amino acid of the formula with the amino acid ester of the formula to give the dipeptide wherein: P₁ is an amino protecting group or a group which together with the N-atom forms a protecting group; and P₂ is a hydroxy or mercapto protecting group; b) selectively removing the P₂ protecting group from the product of part (a); c) cyclizing the product of part (b) to give and d) removing the P₁ protecting group of the product of part (c) to give the desired product.

Claim 11

A process of Claim 10 wherein: X is S; n is one or two; Y is CH₂; m is zero or one; which comprises: a) coupling an amino acid of the formula with the amino acid ester of the formula to give the dipeptide of the formula wherein: P₁ is an amino protecting group or a group which together with the N-atom forms a protecting group; and P₂ is a hydroxy protecting group; b) selectively removing the P₂ protecting group from the product of part (a) to give the corresponding hydroxy compound; c) converting the hydroxy product from part (b) to the mercaptan of the formula d) cyclizing the mercaptan product of part (c) to give and e) removing the P₁ protecting group from the product of part (d) to give the desired product.

Claim 12

A process of Claim 10 wherein: X is S; n is two; Y is S or O; and m is one; which comprises; a) coupling an amino acid of the formula with the amino acid ester of the formula to give the dipeptide of the formula wherein: P₁ is an amino protecting group or a group which together with the N-atom forms a protecting group; and P₂ is a hydroxy protecting group; b) selectively removing the P₂ protecting group from the product of part (a) to give the corresponding hydroxy compound; c) converting the hydroxy product from part (b) to the mercaptan of the formula d) cyclizing the mercaptan product of part (c) to give and e) removing the P₁ protecting group from the product of part (d) to give the desired product.

Claim 13

A process for preparing the compounds of the formula wherein: X is O or S; n is one or two; m is zero or one; and R₃ is an acid protecting group; which comprises: a) coupling an amino acid of the formula with the hydroxy amino acid ester of the formula to give the dipeptide of the formula wherein: P₁ is an amino protecting group or a group which together with the N-atom forms a protecting group; and P₂ is a hydroxy or mercapto protecting group; b) oxidizing the hydroxy product of part (a) to the aldehyde of the formula c) selectively removing the P₂ protecting group from the aldehyde product of part (b); d) cyclizing the product of part (c) to give and e) removing the P₁ protecting group of the product of part (d) to give the desired product.

Claim 14

A process for preparing the compound of the formula wherein P₁ is a nitrogen protecting group and R₆ is as defined in Claim 1 which comprises a) reacting L-methionine to introduce the P₁ protecting group; b) esterifying the product from part (a) for example, by treatment with an alcohol, alkyl-OH, in the presence of an acid catalyst to give c) reacting the ester product of part (b) with an oxidixing agent such as N-chlorosuccinimide in an aqueous solvent to give d) treating the sulfoxide product of part (c) with an acid anhydride of the formula to give and e) treating the product of part (d) with an alkali metal hydroxide followed by removal of formaldehyde, and treatment with an acid anhydride or acid halide to give the desired product.

Claim 15

A process for preparing the compound of the formula wherein m is zero or one and R₃ is zero or one and R₃ is an easily removable ester protecting group which comprises: a) reacting a solution of diethylacetamido malonate with a base such as sodium hydride followed by reaction with a haloalkylacetate of the formula wherein halo is Br, I, or Cl to give b) treating the product of part (a) with sodium hydroxide and heat and then acid and heat to give c) treating the product of part (b) with a hydrolyzing enzyme such as porcine kidney acylase to give and d) treating the product of part (c) to introduce the R₃ group and give the desired product.

Claim 16

A process for preparing the compound of the formula wherein m is zero or one and R₃ is an acid protecting group which comprises: a) reacting the aldehyde of the formula wherein P₃ is an N-protecting group or a group which together with N-atom forms a protecting group with the orthoformate of the formula HC (̵O-alkyl)₃ in the presence of an acid catalyst and the alcohol of the formula alkyl-OH to give and b) selective removal of the P₃ protecting group from the product of part (a) to give the desired final product.

Claim 17

A compound of any one of claims 1-6 for use as an active pharmaceutical substance.

Claim 18

Use of a compound of any one of claims 1-6 for the manufacture of a medicament for treatment of cardiovascular disease.