TETRAHYDROPYRROLOPYRIMIDINEDIONES AND THEIR USE AS HUMAN NEUTROPHIL ELASTASE INHIBITORS

摘要

Compounds of formula (I) and multimers therof are inhibitors of human neutrophil elastase activity, and of utility in the treatment of, e.g., COPD:(I) wherein A is aryl or heteroaryl; D is oxygen or sulphur; R<SUP>1</SUP>, R<SUP>2</SUP> and R<SUP>3</SUP> are independently each hydrogen, halogen, nitro, cyano, C<SUB>1</SUB>-C<SUB>6</SUB>-alkyl, C<SUB>2</SUB>-C<SUB>6</SUB>-alkenyl, C<SUB>2</SUB>-C<SUB>6</SUB>-alkynyl, hydroxy or Cr<SUB>1</SUB>-C<SUB>6</SUB>-alkoxy or C<SUB>2</SUB>-C<SUB>6</SUB>-alkenyloxy, wherein C<SUB>1</SUB>-C<SUB>6</SUB>-alkyl and C<SUB>1</SUB>-C<SUB>6</SUB>-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and Cr<SUB>1</SUB>C<SUB>4</SUB>-alkoxy; R and R<SUP>4</SUP> each independently represent a radical of formula -[X]<SUB>m</SUB>-[Alk<SUP>1</SUP>]p-[Q]<SUB>n</SUB>-[Alk<SUP>2</SUP>]q-[X<SUP>1</SUP>]<SUB>k</SUB>-Z wherein k, m, n, p and q are independently 0 or 1; AIk<SUP>1</SUP> and AIk<SUP>2</SUP> each independently represent an optionally substituted C<SUB>1</SUB>-C<SUB>6</SUB> alkylene, or C<SUB>2</SUB>-C<SUB>6</SUB> alkenylene radical which may optionally contain an ether (-O-), thioether (-S-) or amino (-NR<SUP>A</SUP>-) link wherein R<SUP>A</SUP> is hydrogen or C<SUB>1</SUB>-C<SUB>3</SUB> alkyl; Q represents (i) -O-, -S-, -S(O)-, -S(O)<SUB>2-</SUB>, -S<SUP>+</SUP>(R<SUP>A</SUP>)-, -N(R<SUP>A</SUP>)-, -N<SUP>+</SUP>(R<SUP>A</SUP>)(R<SUP>B</SUP>)-, -C(O)-, -C(O)O-, -OC(O)-, -C(=O)NR<SUP>A</SUP> -, -NR<SUP>A</SUP>C(=O)-, -S(O<SUB>2</SUB>)NR<SUP>A</SUP>-, -NR<SUP>A</SUP>S(O<SUB>2</SUB>)-, -NR<SUP>A</SUP>C(=O)NR<SUP>B</SUP>-, -NR<SUP>A</SUP>C(=NR<SUP>A</SUP>)NR<SUP>B</SUP>-, -C(=NR<SUP>D</SUP>)NR<SUP>E</SUP>-, -NR<SUP>E</SUP>C(=NR<SUP>D</SUP>)-, wherein R<SUP>A</SUP>, R<SUP>B</SUP>, R<SUP>D</SUP> and R<SUP>E </SUP>are independently hydrogen, d-C6 alkyl, or C<SUB>3</SUB>-C<SUB>6</SUB> cycloalkyl, or R<SUP>A</SUP> and R<SUP>B</SUP> or R<SUP>D</SUP> and R<SUP>E</SUP> taken together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which my contain a further heteroatom selected from N, O and S, or (ii) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 3-6 ring members; X represents -(C=O)-, -S(O<SUB>2</SUB>)-, -C(O)O-, -(C=O)NR<SUP>A</SUP>-, or -S(O2)NR<SUP>A</SUP>-, wherein R<SUP>A</SUP> is hydrogen, C<SUB>1</SUB>-C<SUB>6</SUB> alkyl, or C3-C6 cycloalkyl; X<SUP>1</SUP> represents -O-, -S-, or -NH; and Z is hydrogen or an optionally substituted mono- or bicyclic carbocyclic or heterocyclic radical having 3-6 ring members.