Acylguanidines for treating osteoarthritis

Abstract

The present invention relates to compounds of the formula (I) and in particular to medicaments comprising at least one compound of the formula I for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions in the triggering of which cathepsin D is involved, in particular for use in the treatment and/or prophylaxis of osteoarthritis, traumatic cartilage injuries, arthritis, pain, allodynia or hyperalgesia.

Claims

1. A compound of formula I, ##STR00377## in which R.sup.1 denotes a C.sub.1-10-straight-chain or branched alkyl group, C.sub.3-20-mono-, bi- or tricyclic cycloalkyl group, C.sub.4-20-mono- or bicyclic cycloalkylalkyl group, C.sub.3-20-mono- or bicyclic aryl group, C.sub.4-20-mono- or bicyclic arylalkyl group, mono- or bicyclic heteroaryl group having 1-14 carbons and 1-7 heteroatoms from O, S or N, mono- or bicyclic heteroarylalkyl group having 2-20 C atoms and 1-7 heteroatoms selected independently of one another from O, S or N, which is unsubstituted or mono-, di- or trisubstituted by (CH.sub.2).sub.nOR.sup.7, N, Hal, OCF.sub.3, CF.sub.3, O, A, (CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.7SO.sub.2R.sup.7, (CH.sub.2).sub.nSO.sub.2NR.sup.7R.sup.8, R.sup.2 denotes C.sub.1-10-a straight-chain or branched alkyl, cyclohexylethyl, benzyl or phenylethyl, each of which is unsubstituted or mono-, di- or trisubstituted by (CH.sub.2).sub.nOR.sup.7 or Cl, R.sup.3 denotes a C.sub.1-10-straight-chain or branched alkyl group, C.sub.3-20-mono-, bi- or tricyclic cycloalkyl group, C.sub.4-20-mono- or bicyclic cycloalkylalkyl group, mono- or bicyclic heterocycloalkyl group having 1-14 atoms and 1-7 heteroatoms selected independently of one another from O, S or N, mono- or bicyclic heterocycloalkylalkyl group having 2-20 C atoms and 1-7 heteroatoms selected independently of one another from O, S or NC.sub.3-20-mono- or bicyclic aryl group, C.sub.4-20-mono- or bicyclic arylalkyl group, mono- or bicyclic heteroaryl group having 1-14 C atoms and 1-7 heteroatoms independently of one another selected from O, S or N, or mono- or bicyclic heteroarylalkyl group having 2-20 C atoms and 1-7 heteroatoms selected independently of one another from O, S or N, which is unsubstituted or mono-, di- or trisubstituted by (CH.sub.2).sub.nOR.sup.7, N, Hal, OCF.sub.3, CF.sub.3, (CH.sub.2).sub.n COOR.sup.7, O, A, (CH.sub.2)CN, (CH.sub.2).sub.nNR.sup.7SO.sub.2R.sup.7, (CH.sub.2).sub.nSO.sub.2NR.sup.7R.sup.8, (CH.sub.2)N(C[Hal].sub.3).sub.2, (CH.sub.2).sub.nCHOH(CH.sub.2).sub.nOR.sup.7 or (CH.sub.2).sub.nO(CH.sub.2).sub.mOR.sup.7 R.sup.7, R.sup.8 are, independently of one another, H or A and, in NR.sup.7R.sup.8, R.sup.7 and R.sup.8, together with the N atom to which they are bonded, may form a 5-, 6- or 7-membered heterocycle, which may optionally contain one or two further heteroatoms selected from the group consisting of N, O and S, A is selected from the group consisting of alkyl, alkenyl, alkynyl and cycloalkyl, n, m are, independently of one another, 0, 1, 2, 3, 4, or 5, and Hal is, independently of one another, F, Cl, Br or I, or physiologically acceptable salts, solvates, prodrugs or stereoisomers thereof, including mixtures thereof in all ratios.

2. A compound selected from the group consisting of: TABLE-US-00005 1. (R)-3-(2,4-dichlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide, 2. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-methoxybenzyl)- 3-phenylpropionamide, 3. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1- ethylpropyl)propionamide trifluoroacetate, 4. (R)-3-(2,4-dichlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propionamide, 5. (S)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3-dioxo-1,3- dihydroisoindol-2-yl)ethyl]-3-(4-methoxyphenyl)propionamide, 6. (S)-3-(4-chlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- [2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propionamide, 7. (S)-3-(2,4-dichlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propionamide, 8. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(3,4-dimethoxy- phenyl)ethyl]-3-phenylpropionamide, 9. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3-dioxo-1,3- dihydroisoindol-2-yl)ethyl]propionamide, 10. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-phenethyl-3- phenylpropionamide, 11. (R)-N-[2-(4-chlorophenyl)ethyl]-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 12. (R)-N-[2-(2,4-dichlorophenyl)ethyl]-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 13. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3-dioxo-1,3- dihydroisoindol-2-yl)ethyl]-3-phenylpropionamide, 14. (S)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3-dioxo-1,3- dihydroisoindol-2-yl)ethyl]-3-phenylpropionamide, 15. (R)-N-[2-(2-bromo-4,5-dimethoxyphenyl)ethyl]-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 16. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(4- sulfamoylbenzyl)propionamide, 17. (R)-N-(4-cyano-3-fluorobenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 18. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-(4-methoxyphenyl)propionamide, 19. (R)-N-cyclohexylmethyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- 3-phenylpropionamide trifluoroacetate, 20. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluorobenzyl)-3- phenylpropionamide, 21. (R)-N-(3,4-difluorobenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 22. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 23. (R)-N-(2-bromo-4,5-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 24. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((1S,2R)-2- hydroxyindan-1-yl)-3-phenylpropionamide, 25. (R)-3-cyclohexyl-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 26. (R)-N-benzyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-methyl-3- phenylpropionamide, 27. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-methyl-3-phenylpropionamide, 28. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenylpropion- amide, 29. (R)-N-(3,4-dichlorobenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 30. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-pyridin-4- ylmethylpropionamide, 31. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-pyridin-2- ylmethylpropionamide, 32. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-[3-(1H- tetrazol-5-yl)benzyl]propionamide, 33. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-isobutyl-3-phenyl- propionamide, 34. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2,2-dimethyl- propyl)-3-phenylpropionamide, 35. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methylbutyl)-3- phenylpropionamide, 36. (R)-N-(4-tert-butylcyclohexyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 37. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-methoxy- ethoxy)benzyl]-3-phenylpropionamide, 38. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-hydroxy- ethoxy)benzyl]-3-phenylpropionamide, 39. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1-ethylpropyl)-3- phenylpropionamide, 40. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-isopropyl-3-phenyl- propionamide, 41. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2-ethylbutyl)-3- phenylpropionamide, 42. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((S)-2-methyl- butyl)-3-phenylpropionamide, 43. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((S)- 2-methylbutyl)propionamide, 44. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-fluoro-3-methoxybenzyl amide, 45. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid isobutyl amide, 46. (2R,3R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-methyl- pentanecarboxylic acid 4-fluoro-3-methoxybenzyl amide, 47. (R)-N-(2-benzo-1,3-dioxol-5-ylethyl)-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 48. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(2- pyridin-4-ylethyl)propionamide, 49. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-hydroxypropionamide, 50. (R)-3-tert-butoxy-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 51. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3,4-dimethoxybenzyl amide, 52. (R)-N-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3- phenylpropionamide, 53. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide, 54. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methoxybenzyl)- 3-phenylpropionamide, 55. (R)-3-(2-chlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- [2-(3,4-dimethoxyphenyl)ethyl]propionamide, 56. (R)-3-(4-chlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- [2-(3,4-dimethoxyphenyl)ethyl]propionamide, 57. 5-((R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionylamino)furan-2-carboxylic acid methyl ester, 58. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-thiophen- 2-ylmethylpropionamide, 59. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-ethoxypyridin-2- ylmethyl)-3-phenylpropionamide, 60. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide, 61. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-4-phenylbutyramide, 62. (1S,3S,4S)-4-((R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3- phenylpropionylamino)-3-hydroxycyclohexanecarboxylic acid methyl ester, 63. (R)-N-(3,5-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 64. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((R)-1-hydroxy- methyl-3-methylbutyl)-3-phenylpropionamide, 65. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((S)-1-hydroxy- methyl-3-methylbutyl)-3-phenylpropionamide, 66. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-methyl- cyclohexyl)-3-phenylpropionamide, 67. (2R,3R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-methyl- pentanoic acid isobutyl amide, 68. R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid ((S)-2-methylbutyl) amide, 69. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[1-(4- fluoro-3-methoxyphenyl)cyclopropyl]propionamide, 70. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid [1-(4-fluoro-3-methoxyphenyl)cyclopropyl] amide, 71. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[1-(4-fluoro-3- methoxyphenyl)cyclopropyl]-3-phenylpropionamide, 72. (R)-3,N-dicyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- propionamide, 73. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid cyclohexyl amide, 74. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(tetra- hydropyran-4-yl)propionamide, 75. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid (tetrahydropyran-4-yl) amide, 76. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1-methylpiperidin- 4-yl)-3-phenylpropionamide, 77. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid (1-methylpiperidin-4-yl) amide, 78. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,5-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 79. (R)-2-{N-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 80. (R)-3-cyclohexyl-2-{N-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide, 81. (R)-3-cyclohexyl-2-{N-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide, 82. (R)-N-cyclopropylmethyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- 3-phenylpropionamide, 83. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(S)-1-(3-methoxy- phenyl)ethyl]-3-phenylpropionamide, 84. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(R)-1-(3-methoxy- phenyl)ethyl]-3-phenylpropionamide, 85. (S)-3-cyclohexyl-N-cyclopropylmethyl-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 86. (S)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(S)- 1-(3-methoxyphenyl)ethyl]propionamide, 87. (S)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(R)- 1-(3-methoxyphenyl)ethyl]propionamide, 88. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(tetra- hydropyran-4-ylmethyl)propionamide, 89. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methoxypropyl)- 3-phenylpropionamide, 90. (S)-3-cyclohexyl-N-cyclohexylmethyl-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 91. (S)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- (tetrahydropyran-4-ylmethyl)propionamide, 92. (S)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- methoxypropyl)propionamide, 93. (R)-3-cyclohexyl-2-{N-[3-(3,4-dimethoxyphenyl)propionyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 94. (R)-2-[N-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-3-cyclohexyl-N-(4- fluoro-3-methoxybenzyl)propionamide, 95. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(4-methylpentanoyl)- guanidino]propionamide, 96. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(indane-2-carbonyl)- guanidino]propionamide, 97. (R)-2-{N-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3,4-dimethoxybenzyl amide, 98. (R)-3-cyclohexyl-2-[N-(2-cyclohexylacetyl)guanidino]-N-(4-fluoro-3- methoxybenzyl)propionamide, 99. (R)-2-{N-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 100. (R)-3-cyclohexyl-N-((S)-2-methylbutyl)-2-[N-(3-phenylpropionyl)- guanidino]propionamide, 101. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(3-phenylpropionyl)- guanidino]propionamide, 102. (R)-3-cyclohexyl-N-((S)-2-methylbutyl)-2-(N-phenylacetylguanidino)- propionamide, 103. (R)-2-[N-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-3-cyclohexyl-N- isobutylpropionamide, 104. (R)-2-[N-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-N-(3,4-dimethoxy- benzyl)-3-phenylpropionamide, 105. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-[N-(3-phenylpropionyl)guanidino]- propionamide, 106. (R)-3-cyclohexyl-2-[N-(indane-2-carbonyl)guanidino]-N-isobutylpropion- amide, 107. (R)-N-(3,4-dimethoxybenzyl)-2-[N-(indane-2-carbonyl)guanidino]-3-phenyl- propionamide, 108. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[3-(3,4-dimethoxyphenyl)propionyl]- guanidino}-3-phenylpropionamide, 109. (R)-2-{N-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-isobutylpropionamide, 110. (R)-2-{N-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-N-(3,4- dimethoxybenzyl)-3-phenylpropionamide, 111. (R)-2-{N-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid isobutyl amide, 112. (R)-2-{N-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-fluoro-3-methoxybenzyl amide, 113. (R)-3-cyclohexyl-2-{N-[2-(3-methoxyphenyl)acetyl]guanidino}-N-((S)-2- methylbutyl)propionamide, 114. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(3-methoxy- phenyl)acetyl]guanidino}propionamide, 115. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-(N-phenylacetylguanidino)- propionamide, 116. (R)-3-cyclohexyl-N-isobutyl-2-[N-(4-methylpentanoyl)guanidino]propion- amide, 117. (R)-3-cyclohexyl-N-isobutyl-2-{N-[2-(3-methoxyphenyl)acetyl]guanidino}- propionamide, 118. (R)-3-cyclohexyl-2-[N-(2-cyclohexylacetyl)guanidino]-N-isobutylpropion- amide, 119. (R)-N-(3,4-dimethoxybenzyl)-2-[N-(4-methylpentanoyl)guanidino]-3- phenylpropionamide, 120. (R)-2-[N-(2-cyclohexylacetyl)guanidino]-N-(3,4-dimethoxybenzyl)-3- phenylpropionamide, 121. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3-methoxyphenyl)acetyl]guanidino}- 3-phenylpropionamide, 122. (R)-N-(3-methoxybenzyl)-2-{N-[2-(3-methoxyphenyl)acetyl]guanidino}-3- phenylpropionamide, 123. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(3-methoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 124. (R)-2-[N-(2-cyclohexylacetyl)guanidino]-N-(4-fluoro-3-methoxybenzyl)-3- phenylpropionamide, 125. (R)-N-isobutyl-2-{N-[2-(4-methoxyphenyl)acetyl]guanidino}-3-phenyl- propionamide, 126. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(4-methoxyphenyl)acetyl]guanidino}- 3-phenylpropionamide, 127. (R)-N-isobutyl-2-[N-(2-phenoxyacetyl)guanidino]-3-phenylpropionamide, 128. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N-[2-(4-trifluoromethylphenyl)- acetyl]guanidino}propionamide, 129. (R)-3-phenyl-N-(4-sulfamoylbenzyl)-2-{N-[2-(4-trifluoromethoxyphenyl)- acetyl]guanidino}propionamide, 130. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N-[2-(4-trifluoromethoxyphenyl)- acetyl]guanidino}propionamide, 131. (R)-N-isobutyl-2-[N-(3-methylbutyryl)guanidino]-3-phenylpropionamide, 132. (R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-[N-(3-methylbutyryl)guanidino]-3- phenylpropionamide, 133. (R)-2-[N-(3-methylbutyryl)guanidino]-3-phenyl-N-(4-sulfamoylbenzyl)- propionamide, 134. (R)-N-(3,4-dimethoxybenzyl)-2-[N-(3-methylbutyryl)guanidino]-3-phenyl- propionamide, 135. (R)-4-methyl-2-[N-(3-methylbutyryl)guanidino]-pentanoic acid 3,4- dimethoxybenzyl amide, 136. (R)-N-isobutyl-2-(N-isobutyrylguanidino)-3-phenylpropionamide, 137. (R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N-isobutyrylguanidino)-3-phenyl- propionamide, 138. (R)-2-(N-isobutyrylguanidino)-3-phenyl-N-(4-sulfamoylbenzyl)propion- amide, 139. (R)-N-(3,4-dimethoxybenzyl)-2-(N-isobutyrylguanidino)-3-phenylpropion- amide, 140. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2-methyl- sulfamoylbenzyl)-3-phenylpropionamide, 141. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 142. (R)-N-benzo-1,3-dioxol-5-ylmethyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 143. (R)-N-(2,3-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 144. (R)-N-(3-bromobenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3- phenylpropionamide, 145. (R)-N-(3-chlorobenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3- phenylpropionamide, 146. (R)-N-benzyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionamide, 147. (R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-N-[2-(3,4-dimethoxy- phenyl)ethyl]-3-phenylpropionamide, 148. (S)-3-(2,4-dichlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]- 2-{N-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 149. (S)-3-(4-chlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-2- {N-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 150. (R)-3-(2,4-dichlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]- 2-{N-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 151. (S)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-(4-methoxyphenyl)-2- {N-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 152. (R)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-2-{N-[2-(3-phenoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 153. (S)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-2-{N-[2-(3-phenoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 154. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(2,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 155. (R)-2-{N-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 156. (R)-3-cyclohexyl-2-{N-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide, 157. (R)-3-cyclohexyl-2-{N-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide, 158. (R)-2-[N-(2-adamantan-1-ylacetyl)guanidino]-N-(3,4-dimethoxybenzyl)-3- phenylpropionamide, 159. 2-[N-(2-adamantan-1-ylacetyl)guanidino]-3-cyclohexyl-N-isobutylpropion- amide, 160. 2-[N-(2-adamantan-1-ylacetyl)guanidino]-3-cyclohexyl-N-(4-fluoro-3- methoxybenzyl)propionamide, 161. 2-[N-(2-adamantan-1-ylacetyl)guanidino]-N-(4-fluoro-3-methoxybenzyl)-3- phenylpropionamide, 162. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- sulfamoylbenzyl)propionamide, 163. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid cyclopropylmethyl amide, 164. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-sulfamoylbenzyl amide, 165. (R)-3-cyclohexyl-N-cyclopropylmethyl-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 166. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(S)- 1-(3-methoxyphenyl)ethyl]propionamide, 167. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(R)- 1-(3-methoxyphenyl)ethyl]propionamide, 168. (R)-3-cyclohexyl-N-cyclohexylmethyl-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 169. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- (tetrahydropyran-4-ylmethyl)propionamide, 170. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- methoxypropyl)propionamide, 171. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- (tetrahydrothiopyran-4-yl)propionamide, 172. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(tetra- hydrothiopyran-4-yl)propionamide, 173. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid (tetrahydrothiopyran-4-yl) amide, 174. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- (tetrahydropyran-4-yl)propionamide, 175. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1- methylpiperidin-4-yl)propionamide, 176. (R)-N-(5-chlorothiophen-2-ylmethyl)-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 177. (R)-N-(5-chlorothiophen-2-ylmethyl)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 178. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-fluoro-4-meth- oxybenzyl)-3-phenylpropionamide, 179. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- fluoro-4-methoxybenzyl)propionamide, 180. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3-fluoro-4-methoxybenzyl amide, 181. (R)-3-cyclohexyl-N-(3,4-difluorobenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 182. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3,4-difluorobenzyl amide, 183. (R)-N-(6-chloropyridin-3-ylmethyl)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 184. (R)-N-((S)-sec-butyl)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide, 185. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- (trans-4-hydroxycyclohexyl)propionamide, 186. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid (6-chloropyridin-3-ylmethyl) amide, 187. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluorobenzyl)propionamide, 188. (R)-3-cyclohexyl-N-cyclopropyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide, 189. (R)-3-cyclohexyl-N-cyclopentyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide, 190. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid 4-fluorobenzyl amide, 191. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid cyclopentyl amide, 192. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid ((S)-sec-butyl) amide, 193. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid ((R)-sec-butyl) amide, 194. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid (trans-4-hydroxycyclohexyl) amide, 195. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid (cis-4-hydroxycyclohexyl) amide, 196. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid (S)-indan-1-yl amide amide, 197. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid (R)-indan-1-ylamide amide, 198. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid (4-methoxyindan-2-yl) amide, 199. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid (5-methoxyindan-2-yl) amide, 200. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid 3-(1H-tetrazol-5-yl)benzyl amide, 201. (R)-3-cyclohexyl-2-{N-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide, 202. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(cis- 4-hydroxycyclohexyl)propionamide, 203. (R)-N-((R)-sec-butyl)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide, 204. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(2,5-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 205. (R)-2-{N-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 206. (R)-3-cyclohexyl-2-{N-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide, 207. (R)-3-cyclohexyl-2-{N-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide, 208. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(S)- indan-1-ylpropionamide)propionamide, 209. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(R)- indan-1-ylpropionamide, 210. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- methoxyindan-2-yl)propionamide, 211. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(5- methoxyindan-2-yl)propionamide, 212. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- (1H-tetrazol-5-yl)benzyl]propionamide, 213. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(4-fluoro-3-methoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 214. (R)-3-cyclohexyl-2-{N-[2-(4-fluoro-3-methoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide, 215. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(4-fluoro-3- methoxyphenyl)acetyl]guanidino}propionamide, 216. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(3-fluoro-4-methoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 217. (R)-3-cyclohexyl-2-{N-[2-(3-fluoro-4-methoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide, 218. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(3-fluoro-4- methoxyphenyl)acetyl]guanidino}propionamide, 219. (R)-N-(4-fluoro-3-methoxybenzyl)-3-phenyl-2-[N-(2-tetrahydropyran-4-yl- acetyl)guanidino]propionamide, 220. (R)-3-cyclohexyl-N-isobutyl-2-[N-(2-tetrahydropyran-4-ylacetyl)guanidino]- propionamide, 221. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(2-tetrahydropyran-4- ylacetyl)guanidino]propionamide, 222. (R)-3-cyclohexyl-2-{N-[2-(2,6-difluoro-4-methoxyphenyl)acetyl]- guanidino}-N-(4-fluoro-3-methoxybenzyl)propionamide, 223. (R)-3-cyclohexyl-2-{N-[2-(2,6-difluoro-4-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 224. (R)-3-cyclohexyl-2-[N-(3, 3-dimethylbutyryl)guanidino]-N-(4-fluoro-3- methoxybenzyl)propionamide, 225. (R)-3-cyclohexyl-2-[N-(3,3-dimethylbutyryl)guanidino]-N-isobutylpropion- amide. 226. (R)-3-cyclohexyl-2-{N-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide, 227. (R)-2-{N-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3-methoxy- benzyl)-3-phenylpropionamide, 228. (R)-2-{N-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, (R)-2-{N-[2-(2-bromo-4-methoxy- phenyl)acetyl]guanidino}-3-cyclohexyl-N-isobutylpropionamide, 229. (R)-2-{N-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclohexyl-N- isobutylpropionamide, 230. (R)-2-{N-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclohexyl-N- (4-fluoro-3-methoxybenzyl)propionamide, 231. (S)-2-benzyl-4-{N-[(R)-1-(4-fluoro-3-methoxybenzylcarbamoyl)-2- phenylethyl]guanidino}-4-oxobutyric acid methyl ester, 232. (S)-2-benzyl-4-[N-((R)-2-cyclohexyl-1-isobutylcarbamoylethyl)- guanidino]-4-oxobutyric acid methyl ester, 233. (S)-2-benzyl-4-{N-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzyl- carbamoyl)ethyl]guanidino}-4-oxobutyric acid methyl ester, 234. (R)-2-{N-[2-(2-bromophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4-fluoro- 3-methoxybenzyl)propionamide, 235. (R)-2-{N-[2-(2-bromophenyl)acetyl]guanidino}-3-cyclohexyl-N-isobutyl- propionamide, 236. (R)-2-{N-[2-(2-bromophenyl)acetyl]guanidino}-N-(4-fluoro-3-methoxy- benzyl)-3-phenylpropionamide, 237. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-((S)-5-oxo- pyrrolidin-2-yl)acetyl]guanidino}propionamide, 238. (R)-3-cyclohexyl-N-isobutyl-2-{N-[2-((S)-5-oxopyrrolidin-2-yl)acetyl]- guanidino}propionamide, 239. (S)-2-benzyl-4-{N-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzyl- carbamoyl)ethyl]guanidino}-4-oxobutyric acid, 240. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N-[2-(2,3,4-trimethoxyphenyl)- acetyl]guanidino}propionamide, 241. (R)-N-(4-fluoro-3-methoxybenzyl)-3-phenyl-2-{N-[2-(2,3,4-trimethoxy- phenyl)acetyl]guanidino}propionamide, 242. (R)-3-cyclohexyl-N-isobutyl-2-{N-[2-(2,3,4-trimethoxyphenyl)acetyl]- guanidino}propionamide, 243. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(2,3,4- trimethoxyphenyl)acetyl]guanidino}propionamide, 244. (R)-2-{N-[2-(3,4-difluorophenyl)acetyl]guanidino}-N-(3,4-dimethoxy- benzyl)-3-phenylpropionamide, 245. (R)-2-{N-[2-(3,4-difluorophenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 246. (R)-3-cyclohexyl-2-{N-[2-(3,4-difluorophenyl)acetyl]guanidino}-N- isobutylpropionamide, 247. (R)-3-cyclohexyl-2-{N-[2-(3,4-difluorophenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide, 248. (R)-N-cyclobutyl-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide, 249. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid cyclobutyl amide, 250. (R)-2-{N-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 251. (R)-3-cyclohexyl-2-{N-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N- isobutylpropionamide, 252. (R)-3-cyclohexyl-2-{N-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide, 253. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- trifluoromethylbenzyl)propionamide, 254. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-trifluoromethylbenzyl amide, 255. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-trifluoromethylbenzyl)propionamide, 256. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-fluoro-3-trifluoromethylbenzyl amide, 257. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- trifluoromethoxybenzyl)propionamide, 258. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3-trifluoromethoxybenzyl amide, 259. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethoxybenzyl)-2-{N-[2-(4- fluoro-3-trifluoromethylphenyl)acetyl]guanidino}propionamide, 260. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethylbenzyl)-2-{N-[2-(4-fluoro- 3-trifluoromethylphenyl)acetyl]guanidino}propionamide, 261. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(2,4,6-trifluoro- phenyl)acetyl]guanidino}propionamide, 262. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethoxybenzyl)-2-{N-[2-(2,4,6- trifluorophenyl)acetyl]guanidino}propionamide, 263. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethylbenzyl)-2-{N-[2-(2,4,6- trifluorophenyl)acetyl]guanidino}propionamide, 264. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(4-fluoro-3- trifluoromethylphenyl)acetyl]guanidino}propionamide, 265. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-trifluoromethoxybenzyl)propionamide, 266. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-fluoro-3-trifluoromethoxybenzyl amide, 267. (R)-N-[(S)-1-(3-chlorophenyl)-2-oxopyrrolidin-3-yl]-3-cyclohexyl-2-{N- [2-(3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 268. (R)-N-[(R)-1-(3-chlorophenyl)-2-oxopyrrolidin-3-yl]-3-cyclohexyl-2-{N- [2-(3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 269. (R)-2-{N-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-(1H-tetrazol-5-yl)benzyl amide, 270. (R)-2-{N-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-[3-(1H-tetrazol-5-yl)benzyl]propionamide, 271. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(3-fluoro-4- trifluoromethoxyphenyl)acetyl]guanidino}propionamide, 272. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4- (1H-tetrazol-5-yl)benzyl]propionamide, 273. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 4-(1H-tetrazol-5-yl)benzyl amide, 274. (R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-isobutyl- propionamide, 275. (R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4-fluoro- 3-methoxybenzyl)propionamide, 276. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- fluoro-4-(1H-tetrazol-5-yl)benzyl]propionamide, 277. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-fluoro-4-(1H-tetrazol-5-yl)benzyl amide, 278. (R)-2-{N-[2-(2-bromo-4-trifluoromethylphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 279. (R)-2-[N-((2S,4R)-1-acetyl-4-methoxypyrrolidine-2-carbonyl)guanidino]- 3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 280. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(2-piperidin-1-yl- acetyl)guanidino]propionamide, 281. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- sulfamoylbenzyl)propionamide, 282. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(2-morpholin-4-yl- acetyl)guanidino]propionamide, 283. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(4-sulfamoyl- phenyl)acetyl]guanidino}propionamide, 284. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(2-fluoro-4- methoxyphenyl)acetyl]guanidino}propionamide, 285. (R)-3-cyclohexyl-2-{N-[2-(2-fluoro-4-methoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 286. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N-{2-[4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl]acetyl}guanidino)propionamide, 287. (R)-2-{N-[2-(3-cyanophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4-fluoro- 3-methoxybenzyl)propionamide, 288. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(3-methane- sulfonylaminophenyl)acetyl]guanidino}propionamide, 289. 4-[((R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- propionylamino)methyl]benzoic acid methyl ester, 290. 4-[((R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoylamino)methyl]benzoic acid methyl ester, 291. 4-[((R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionylamino)methyl]benzoic acid methyl ester, 292. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- (5-methyl-1,2,4-oxadiazol-3-yl)benzyl]propionamide, 293. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl amide, 294. 4-(2-{N-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzylcarbamoyl)ethyl]- guanidino}-2-oxoethyl)-2-ethoxybenzoic acid ethyl ester, 295. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(2-pyridin-2-yl- acetyl)guanidino]propionamide, 296. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(2-isobutoxy- acetyl)guanidino]propionamide, 297. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 4-(1,2,3-thiadiazol-4-yl)benzyl amide, 298. (R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-(3- sulfamoylbenzyl)propionamide, 299. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(4- (1,2,3-thiadiazol-4-yl)benzyl)propionamide, 300. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzyl]-3-phenylpropionamide, 301. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(4-tetrazol-1-yl- phenyl)acetyl]guanidino}propionamide, 302. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-methyl- imidazol-1-yl)benzyl]-3-phenylpropionamide, 303. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- (2-methylimidazol-1-yl)benzyl]propionamide, 304. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3-(2-methylimidazol-1-yl)benzyl amide, 305. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(3- (1,2,4-triazol-1-yl)benzyl)propionamide, 306. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- 1,2,4-triazol-1-ylbenzyl)propionamide, 307. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-(1,2,4-triazol-1-yl)benzyl amide, 308. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide, 309. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-(5-hydroxy- 1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide, 310. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4- (5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide, 311. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- (5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide, 312. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide, 313. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(5-hydroxy- 1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide, 314. (R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-[4-(1H- tetrazol-5-yl)benzyl]propionamide, 315. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- 1,2,3-thiadiazol-4-ylbenzyl)propionamide, 316. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- (2-methyl-2H-pyrazol-3-yl)benzyl]propionamide, 317. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-(2-methyl-2H-pyrazol-3-yl)benzyl amide, 318. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-methyl-2H- pyrazol-3-yl)benzyl]-3-phenylpropionamide, 319. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- (1-methyl-1H-pyrazol-3-yl)benzyl]propionamide, 320. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-(1-methyl-1H-pyrazol-3-yl)benzyl amide, 321. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(1-methyl-1H- pyrazol-3-yl)benzyl]-3-phenylpropionamide, 322. (R)-2-{N-[2-(4-chloro-2-fluorophenyl)acetyl]guanidino}-3-cyclohexyl-N- (4-fluoro-3-methoxybenzyl)propionamide, 323. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- thiazol-2-ylbenzyl)propionamide, 324. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-thiazol-2-ylbenzyl amide, 325. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(3- thiazol-2-ylbenzyl)propionamide, 326. (R)-2-[N-((1S,4R)-2-bicyclo[2.2.1]hept-2-ylacetyl)guanidino]-3-cyclo- hexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 327. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide, 328. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4- fluoro-3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide, 329. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 4-fluoro-3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide, 330. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-fluoro-3-(5- hydroxy-1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide, 331. (R)-2-[N-((1S,4R)-2-bicyclo[2.2.1]hept-2-ylacetyl)guanidino]-3-cyclo- hexyl-N-[3-(1H-tetrazol-5-yl)benzyl]propionamide, 332. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N-[3- (1H-tetrazol-5-yl)benzyl]propionamide, 333. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N-{2-[4-(2H-tetrazol- 5-yl)phenyl]acetyl}guanidino)propionamide, 334. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(4-propylcyclo- hexyl)acetyl]guanidino}propionamide, 335. (R)-3-cyclohexyl-2-{N-[2-(4-propylcyclohexyl)acetyl]guanidino}-N-[3- (1H-tetrazol-5-yl)benzyl]propionamide, 336. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-fluoro-3-(2H- tetrazol-5-yl)benzyl]-3-phenylpropionamide, 337. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4- fluoro-3-(2H-tetrazol-5-yl)benzyl]propionamide, 338. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 4-fluoro-3-(2H-tetrazol-5-yl)benzyl amide, 339. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- {(S)-1-[3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide, 340. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N-{(S)- l-[3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide, 341. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- {(S)-1-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide, 342. (R)-N-[4-(bistrifluoromethylamino)benzyl]-3-cyclohexyl-2-{N-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide, 343. 4-[((R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- propionylamino)methyl]benzoic acid, 344. 3-[((R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl- propionylamino)methyl]benzoic acid methyl ester, 345. 3-[((R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-4-methyl- pentanoylamino)methyl]benzoic acid methyl ester, 346. (R)-N-[3-(bistrifluoromethylamino)benzyl]-3-cyclohexyl-2-{N-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide, 347. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N-{2-[3-(2H-tetrazol- 5-yl)phenyl]acetyl}guanidino)propionamide, 348. (R)-N-{1-[4-(bistrifluoromethylamino)phenyl]cyclopropyl}-3-cyclohexyl- 2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 349. (R)-3-cyclohexyl-N-((R)-2,3-dihydroxypropyl)-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 350. (R)-3-cyclohexyl-N-((S)-2,3-dihydroxypropyl)-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, or physiologically acceptable salts, solvates, prodrugs or stereoisomers thereof, including mixtures thereof in all ratios.

3. A process for the preparation of the compounds of the formula I according to claim 1, a) obtaining a compound of the formula VII, ##STR00378## in which R.sup.1 is as defined in claim 1, by acylation of a pyrazole-1-carboxamidine of the formula XI ##STR00379## using an acid of the formula X or an acid derivative of the formula Xa, ##STR00380## in which R.sup.1 has the meanings indicated above and X denotes a halogen, alkyl- or aryloxycarbonyloxy, and obtaining a compound of the formula VIII ##STR00381## in which R.sup.1 has the meanings indicated above and R.sup.11 denotes a protecting group for amines or imines, by reacting a guanidine of the formula IX, ##STR00382## in which R.sup.11 has the meanings indicated above, with an acid of the formula X or an activated acid derivative of the formula Xa, ##STR00383## in which R.sup.1 and X have the meanings indicated above, and preparing a compound of the formula III, ##STR00384## in which R.sup.1 and R.sup.11 have the meanings indicated above and L a leaving group selected from a 1-pyrrazolyl group and a trifluoromethylsulfonylamino group, by either in the case where L denotes a 1-pyrazolyl group, introducing a protecting group R.sup.11 into a compound of the formula VII, or, in the case where L denotes a trifluoromethylsulfonylamino group, preparing a compound of the formula III by reaction of a compound of the formula VIII with trifluoromethanesulfonic anhydride, and preparing a compound of the formula II, ##STR00385## in which R.sup.2 and R.sup.3 are as defined in claim 1, by preparing a compound of the formula IV, ##STR00386## in which R.sup.2, R.sup.3 and R.sup.11 have the meanings indicated above, by coupling an amino acid of the formula V, ##STR00387## in which R.sup.3 and R.sup.11 have the meanings indicated above, to an amine of the formula VI,
H.sub.2NR.sup.3VI in which R.sup.3 has the meanings indicated above, and preparing a compound of the formula II by removing R.sup.11 from a compound of the formula IV, and then obtaining a compound of the formula Ia ##STR00388## in which R.sup.1, R.sup.2, R.sup.3 and R.sup.11 have the meanings indicated above, by reaction of an amine of the formula II with an acylguanidine of the formula III, and a compound of the formula I is obtained by removing R.sup.11 from a compound of the formula Ia, or b) reacting a compound of the formula VII with an amine of the formula II, or c) converting the base of a compound of the formula I into one of its salts by treatment with an acid, or d) converting an acid of a compound of the formula I into one of its salts by treatment with a base.

4. A method for inhibiting cathepsin D, comprising administering to a subject in need thereof an effective amount of a Compound according to claim 1 or physiologically acceptable salts, solvates, prodrugs or stereoisomers thereof, including mixtures thereof in all ratios.

5. A pharmaceutical composition comprising at least one compound according to claim 1 and/or physiologically acceptable salts, solvates, prodrugs or stereoisomers thereof, including mixtures thereof in all ratios, and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition according to claim 5, comprising further excipients and/or adjuvants.

7. A pharmaceutical composition comprising at least one compound according to claim 1 and/or physiologically acceptable salts, solvates, prodrugs or stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active compound.

8. A process for the preparation of a pharmaceutical composition comprising bringing a compound according to claim 1 and/or one of its physiologically acceptable salts, solvates, prodrugs or stereoisomers, including mixtures thereof in all ratios, into a suitable dosage form together with a solid, liquid or semi-liquid excipient or adjuvant.

9. A method for the treatment of physiological and/or pathophysiological states, selected from the group consisting of arthrosis, traumatic cartilage injuries, arthritis, pain, allodynia and hyperalgesia, comprising administering to a subject in need thereof an effective amount of a compound of claim 1.

10. A method for the treatment of physiological and/or pathophysiological states selected from the group consisting of Alzheimer's disease, Huntington's disease, mucolipidosis, breast cancer, contact dermatitis, late-onset hypersensitivity reaction, inflammation, endometriosis, scarring, benign prostate hyperplasia, osteosarcoma, rickets, skin diseases, such as, for example, psoriasis, immunological diseases, autoimmune diseases and immunodeficiency diseases, comprising administering to a subject in need thereof an effective amount of a compound of claim 1.

11. A method according to claim 9, wherein the administration is intra-articular administration.

12. A set (kit) consisting of separate packs of a) an effective amount of a compound according to claim 1 and/or physiologically acceptable salts, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and b) an effective amount of a further medicament active compound.

Description

EXAMPLE 1

Illustrative Compounds of the Formula I

(1) TABLE-US-00003 TABLE 2 Compound CathD LC/MS No. Structure IC.sub.50 nM (M + H) 1 300 617 2 190 505 3 140 461 4 110 626 5 0 3400 588 6 2600 592 7 3300 626 8 82 549 9 482 10 580 489 11 950 523 12 950 557 13 180 558 14 558 15 0 120 628 16 82 554 17 730 518 18 160 565 19 400 481 20 270 493 21 370 511 22 50 523 23 260 614 24 517 25 0 120 541 26 1400 489 27 1300 549 28 385 29 1000 543. 30 1900 476 31 476 32 110 543 33 170 441 34 660 455 35 0 280 455 36 230 523 37 130 549 38 100 535 39 170 455 40 290 427 41 469 42 230 455 43 31 461 44 24 489 45 0 240 407 46 26 489 47 760 533 48 490 49 1500 475 50 330 531 51 67 501 52 140 467 53 72 447 54 78 505 55 0 400 583 56 310 583 57 1900 509 58 890 481 59 520 60 17 529 61 74 537 62 1900 541 63 260 535 64 1800 485 65 0 1100 485 66 210 481 67 150 407 68 330 421 69 15 555 70 86 515 71 130 549 72 97 473 73 210 433 74 680 469 75 0 440 435 76 482 77 448 78 700 535 79 470 523 80 98 529 81 180 447 82 900 439 83 130 519 84 420 519 85 00 530 445 86 01 320 525 87 02 525 88 03 2400 483 89 04 1100 457 90 05 1300 487 91 06 1700 489 92 07 1800 463 93 08 57 543 94 09 270 513 95 0 940 449 96 490 495 97 2000 471 98 140 475 99 8.6 607 100 570 415 101 230 483 102 250 515 103 59 431 104 440 519 105 0 1300 489 106 140 413 107 440 501 108 110 549 109 55 526 110 90 614 111 380 377 112 160 459 113 240 431 114 110 499 115 0 2300 475 116 590 367 117 310 417 118 560 393 119 455 120 1300 481 121 1800 505 122 1900 475 123 980 493 124 2000 469 125 0 2700 411 126 1500 505 127 397 128 1700 543 129 578 130 2200 559 131 347 132 445 133 460 134 441 135 0 1900 407 136 333 137 441 138 446 139 427 140 210 568 141 58 535 142 200 519 143 280 535 144 130 554 145 0 130 510 146 120 475 147 360 524 148 659 149 2000 625 150 480 559 151 620 152 1600 590 153 590 154 390 535 155 0 240 523 156 48 447 157 46 529 158 533 159 960 445 160 620 527 161 2100 521 162 49 560 163 400 405 164 270 520 165 0 445 166 525 167 525 168 487 169 489 170 463 171 491 172 485 173 451 174 475 175 0 488 176 516 177 522 178 523 179 529 180 489 181 517 182 477 183 517 184 447 185 00 489 186 01 476 187 02 499 188 03 431 189 04 459 190 05 459 191 06 419 192 07 260 407 193 08 420 407 194 09 650 449 195 0 450 449 196 11 467 197 450 467 198 260 497 199 280 497 200 370 509 201 72 557 202 220 489 203 110 447 204 1200 535 205 0 610 523 206 447 207 110 529 208 11 507 209 320 507 210 210 537 211 260 537 212 92 549 213 230 511 214 170 435 215 0 63 517 216 360 511 217 230 435 218 120 516 219 760 471 220 1100 395 221 190 477 222 41 535 223 91 453 224 449 225 0 367 226 140 475 227 370 551 228 250 572 229 43 496 230 42 578 231 1600 549 232 770 473 233 450 555 234 250 548 235 0 230 466 236 970 541 237 476 238 > 394 239 541 240 1300 565 241 430 553 242 120 477 243 66 559 244 1500 511 245 0 900 499 246 340 423 247 200 505 248 120 445 249 410 405 250 498 251 422 252 504 253 220 549 254 460 509 255 0 280 567 256 440 527 257 280 565 258 530 525 259 240 609 260 320 593 261 57 523 262 310 577 263 230 561 264 84 555 265 0 530 583 266 620 543 267 290 585 268 200 585 269 240 588 270 140 628 271 380 571 272 44 549 273 510 509 274 110 421 275 0 51 504 276 81 567 277 690 527 278 74 616 279 520 280 476 281 13 560 282 1400 478 283 110 548 284 35 517 285 00 80 435 286 01 61 551 287 02 56 494 288 03 20 562 289 04 90 539 290 05 470 499 291 06 350 533 292 07 120 563 293 08 390 523 294 09 24 585 295 0 230 470 296 100 465 297 240 525 298 48 535 299 230 559 300 780 557 301 52 537 302 2000 555 303 490 561 304 2400 521 305 0 830 542 306 93 548 307 440 508 308 525 309 700 559 310 47 565 311 89 565 312 380 525 313 530 559 314 200 524 315 0 45 565 316 100 561 317 320 521 318 400 555 319 41 561 320 230 521 321 240 555 322 49 522 323 67 564 324 220 524 325 0 290 558 326 110 487 327 47 497 328 170 583 329 550 543 330 630 577 331 550 507 332 100 517 333 42 537 334 130 517 335 0 470 537 336 550 561 337 88 567 338 280 527 339 45 563 340 49 531 341 13 581 342 340 632 343 525 344 514 345 0 473 346 632 347 537 348 658 349 465 350 465

(2) TABLE-US-00004 TABLE 3 The following compounds are also in accordance with the invention, where the numbering of the respective compound corresponds to the corresponding structure having the same numbering from Table 2, 1. (R)-3-(2,4-dichlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide, 2. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-methoxy- benzyl)-3-phenylpropionamide, 3. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(1-ethylpropyl)propionamide trifluoroacetate, 4. (R)-3-(2,4-dichlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propion- amide, 5. (S)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3- dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-(4-methoxyphenyl)propion- amide, 6. (S)-3-(4-chlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propion- amide, 7. (S)-3-(2,4-dichlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propion- amide, 8. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(3,4- dimethoxyphenyl)ethyl]-3-phenylpropionamide, 9. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3- dioxo-1,3-dihydroisoindol-2-yl)ethyl]propionamide, 10. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-phenethyl-3- phenylpropionamide, 11. (R)-N-[2-(4-chlorophenyl)ethyl]-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 12. (R)-N-[2-(2,4-dichlorophenyl)ethyl]-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 13. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3- dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-phenylpropionamide, 14. (S)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3- dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-phenylpropionamide, 15. (R)-N-[2-(2-bromo-4,5-dimethoxyphenyl)ethyl]-2-{N-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}-3-phenylpropionamide, 16. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(4- sulfamoylbenzyl)propionamide, 17. (R)-N-(4-cyano-3-fluorobenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 18. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-(4-methoxyphenyl)propionamide, 19. (R)-N-cyclohexylmethyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide trifluoroacetate, 20. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro- benzyl)-3-phenylpropionamide, 21. (R)-N-(3,4-difluorobenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 22. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 23. (R)-N-(2-bromo-4,5-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 24. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((1S,2R)-2- hydroxyindan-1-yl)-3-phenylpropionamide, 25. (R)-3-cyclohexyl-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 26. (R)-N-benzyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- methyl-3-phenylpropionamide, 27. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-methyl-3-phenylpropionamide, 28. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionamide, 29. (R)-N-(3,4-dichlorobenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 30. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- pyridin-4-ylmethylpropionamide, 31. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- pyridin-2-ylmethylpropionamide, 32. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-[3- (1H-tetrazol-5-yl)benzyl]propionamide, 33. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-isobutyl-3- phenylpropionamide, 34. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2,2- dimethylpropyl)-3-phenylpropionamide, 35. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methyl- butyl)-3-phenylpropionamide, 36. (R)-N-(4-tert-butylcyclohexyl)-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 37. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2- methoxyethoxy)benzyl]-3-phenylpropionamide, 38. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2- hydroxyethoxy)benzyl]-3-phenylpropionamide, 39. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1-ethyl- propyl)-3-phenylpropionamide, 40. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-isopropyl-3- phenylpropionamide, 41. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2-ethyl- butyl)-3-phenylpropionamide, 42. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((S)-2- methylbutyl)-3-phenylpropionamide, 43. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-((S)-2-methylbutyl)propionamide, 44. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-fluoro-3-methoxybenzyl amide, 45. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid isobutyl amide, 46. (2R,3R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-methyl- pentanecarboxylic acid 4-fluoro-3-methoxybenzyl amide, 47. (R)-N-(2-benzo-1,3-dioxol-5-ylethyl)-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 48. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(2- pyridin-4-ylethyl)propionamide, 49. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-hydroxypropionamide, 50. (R)-3-tert-butoxy-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 51. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3,4-dimethoxybenzyl amide, 52. (R)-N-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- 3-phenylpropionamide, 53. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 54. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methoxy- benzyl)-3-phenylpropionamide, 55. (R)-3-(2-chlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide, 56. (R)-3-(4-chlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide, 57. 5-((R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionylamino)furan-2-carboxylic acid methyl ester, 58. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- thiophen-2-ylmethylpropionamide, 59. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-ethoxy- pyridin-2-ylmethyl)-3-phenylpropionamide, 60. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-methoxybenzyl)propionamide, 61. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-4-phenylbutyramide, 62. (1S,3S,4S)-4-((R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- 3-phenylpropionylamino)-3-hydroxycyclohexanecarboxylic acid methyl ester, 63. (R)-N-(3,5-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 64. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((R)-1- hydroxymethyl-3-methylbutyl)-3-phenylpropionamide, 65. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((S)-1- hydroxymethyl-3-methylbutyl)-3-phenylpropionamide, 66. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-methyl- cyclohexyl)-3-phenylpropionamide, 67. (2R,3R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-methyl- pentanoic acid isobutyl amide, 68. R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid ((S)-2-methylbutyl) amide, 69. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[1-(4-fluoro-3-methoxyphenyl)cyclopropyl]propionamide, 70. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid [1-(4-fluoro-3-methoxyphenyl)cyclopropyl] amide, 71. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[1-(4-fluoro- 3-methoxyphenyl)cyclopropyl]-3-phenylpropionamide, 72. (R)-3,N-dicyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide, 73. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid cyclohexyl amide, 74. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- (tetrahydropyran-4-yl)propionamide, 75. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (tetrahydropyran-4-yl) amide, 76. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1-methyl- piperidin-4-yl)-3-phenylpropionamide, 77. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (1-methylpiperidin-4-yl) amide, 78. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,5-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 79. (R)-2-{N-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 80. (R)-3-cyclohexyl-2-{N-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-methoxybenzyl)propionamide, 81. (R)-3-cyclohexyl-2-{N-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 82. (R)-N-cyclopropylmethyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 83. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(S)-1-(3- methoxyphenyl)ethyl]-3-phenylpropionamide, 84. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(R)-1-(3- methoxyphenyl)ethyl]-3-phenylpropionamide, 85. (S)-3-cyclohexyl-N-cyclopropylmethyl-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 86. (S)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[(S)-1-(3-methoxyphenyl)ethyl]propionamide, 87. (S)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[(R)-1-(3-methoxyphenyl)ethyl]propionamide, 88. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- (tetrahydropyran-4-ylmethyl)propionamide, 89. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methoxy- propyl)-3-phenylpropionamide, 90. (S)-3-cyclohexyl-N-cyclohexylmethyl-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 91. (S)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(tetrahydropyran-4-ylmethyl)propionamide, 92. (S)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-methoxypropyl)propionamide, 93. (R)-3-cyclohexyl-2-{N-[3-(3,4-dimethoxyphenyl)propionyl]- guanidino}-N-(4-fluoro-3-methoxybenzyl)propionamide, 94. (R)-2-[N-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-3-cyclohexyl-N- (4-fluoro-3-methoxybenzyl)propionamide, 95. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(4-methyl- pentanoyl)guanidino]propionamide, 96. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(indane-2- carbonyl)guanidino]propionamide, 97. (R)-2-{N-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3,4-dimethoxybenzyl amide, 98. (R)-3-cyclohexyl-2-[N-(2-cyclohexylacetyl)guanidino]-N-(4-fluoro-3- methoxybenzyl)propionamide, 99. (R)-2-{N-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3- cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 100. (R)-3-cyclohexyl-N-((S)-2-methylbutyl)-2-[N-(3-phenylpropionyl)- guanidino]propionamide, 101. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(3-phenyl- propionyl)guanidino]propionamide, 102. (R)-3-cyclohexyl-N-((S)-2-methylbutyl)-2-(N-phenylacetyl- guanidino)propionamide, 103. (R)-2-[N-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-3-cyclohexyl-N- isobutylpropionamide, 104. (R)-2-[N-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-N-(3,4- dimethoxybenzyl)-3-phenylpropionamide, 105. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-[N-(3-phenylpropionyl)- guanidino]propionamide, 106. (R)-3-cyclohexyl-2-[N-(indane-2-carbonyl)guanidino]-N-isobutyl- propionamide, 107. (R)-N-(3,4-dimethoxybenzyl)-2-[N-(indane-2-carbonyl)guanidino]-3- phenylpropionamide, 108. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[3-(3,4-dimethoxyphenyl)- propionyl]guanidino}-3-phenylpropionamide, 109. (R)-2-{N-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3- cyclohexyl-N-isobutylpropionamide, 110. (R)-2-{N-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-N- (3,4-dimethoxybenzyl)-3-phenylpropionamide, 111. (R)-2-{N-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid isobutyl amide, 112. (R)-2-{N-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-fluoro-3-methoxybenzyl amide, 113. (R)-3-cyclohexyl-2-{N-[2-(3-methoxyphenyl)acetyl]guanidino}-N- ((S)-2-methylbutyl)propionamide, 114. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(3-methoxy- phenyl)acetyl]guanidino}propionamide, 115. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-(N-phenylacetyl- guanidino)propionamide, 116. (R)-3-cyclohexyl-N-isobutyl-2-[N-(4-methylpentanoyl)guanidino]- propionamide, 117. (R)-3-cyclohexyl-N-isobutyl-2-{N-[2-(3-methoxyphenyl)acetyl]- guanidino}propionamide, 118. (R)-3-cyclohexyl-2-[N-(2-cyclohexylacetyl)guanidino]-N-isobutyl- propionamide, 119. (R)-N-(3,4-dimethoxybenzyl)-2-[N-(4-methylpentanoyl)guanidino]- 3-phenylpropionamide, 120. (R)-2-[N-(2-cyclohexylacetyl)guanidino]-N-(3,4-dimethoxybenzyl)- 3-phenylpropionamide, 121. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3-methoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 122. (R)-N-(3-methoxybenzyl)-2-{N-[2-(3-methoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 123. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(3-methoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 124. (R)-2-[N-(2-cyclohexylacetyl)guanidino]-N-(4-fluoro-3-methoxy- benzyl)-3-phenylpropionamide, 125. (R)-N-isobutyl-2-{N-[2-(4-methoxyphenyl)acetyl]guanidino}-3- phenylpropionamide, 126. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(4-methoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 127. (R)-N-isobutyl-2-[N-(2-phenoxyacetyl)guanidino]-3-phenylpropion- amide, 128. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N-[2-(4-trifluoromethyl- phenyl)acetyl]guanidino}propionamide, 129. (R)-3-phenyl-N-(4-sulfamoylbenzyl)-2-{N-[2-(4-trifluoromethoxy- phenyl)acetyl]guanidino}propionamide, 130. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N-[2-(4-trifluoromethoxy- phenyl)acetyl]guanidino}propionamide, 131. (R)-N-isobutyl-2-[N-(3-methylbutyryl)guanidino]-3-phenylpropion- amide, 132. (R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-[N-(3-methylbutyryl)- guanidino]-3-phenylpropionamide, 133. (R)-2-[N-(3-methylbutyryl)guanidino]-3-phenyl-N-(4-sulfamoyl- benzyl)propionamide, 134. (R)-N-(3,4-dimethoxybenzyl)-2-[N-(3-methylbutyryl)guanidino]-3- phenylpropionamide, 135. (R)-4-methyl-2-[N-(3-methylbutyryl)guanidino]-pentanoic acid 3,4- dimethoxybenzyl amide, 136. (R)-N-isobutyl-2-(N-isobutyrylguanidino)-3-phenylpropionamide, 137. (R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N-isobutyrylguanidino)-3- phenylpropionamide, 138. (R)-2-(N-isobutyrylguanidino)-3-phenyl-N-(4-sulfamoylbenzyl)- propionamide, 139. (R)-N-(3,4-dimethoxybenzyl)-2-(N-isobutyrylguanidino)-3-phenyl- propionamide, 140. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2-methyl- sulfamoylbenzyl)-3-phenylpropionamide, 141. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 142. (R)-N-benzo-1,3-dioxol-5-ylmethyl-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 143. (R)-N-(2,3-dimethoxybenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 144. (R)-N-(3-bromobenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 145. (R)-N-(3-chlorobenzyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 146. (R)-N-benzyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3- phenylpropionamide, 147. (R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-N-[2-(3,4-dimethoxy- phenyl)ethyl]-3-phenylpropionamide, 148. (S)-3-(2,4-dichlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)- ethyl]-2-{N-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 149. (S)-3-(4-chlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)- ethyl]-2-{N-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 150. (R)-3-(2,4-dichlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)- ethyl]-2-{N-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 151. (S)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-(4-methoxy- phenyl)-2-{N-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 152. (R)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-2-{N-[2-(3- phenoxyphenyl)acetyl]guanidino}-3-phenylpropionamide, 153. (S)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-2-{N-[2-(3- phenoxyphenyl)acetyl]guanidino}-3-phenylpropionamide, 154. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(2,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 155. (R)-2-{N-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 156. (R)-3-cyclohexyl-2-{N-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 157. (R)-3-cyclohexyl-2-{N-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-methoxybenzyl)propionamide, 158. (R)-2-[N-(2-adamantan-1-ylacetyl)guanidino]-N-(3,4-dimethoxy- benzyl)-3-phenylpropionamide, 159. 2-[N-(2-adamantan-1-ylacetyl)guanidino]-3-cyclohexyl-N-isobutyl- propionamide, 160. 2-[N-(2-adamantan-1-ylacetyl)guanidino]-3-cyclohexyl-N-(4-fluoro- 3-methoxybenzyl)propionamide, 161. 2-[N-(2-adamantan-1-ylacetyl)guanidino]-N-(4-fluoro-3-methoxy- benzyl)-3-phenylpropionamide, 162. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-sulfamoylbenzyl)propionamide, 163. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid cyclopropylmethyl amide, 164. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-sulfamoylbenzyl amide, 165. (R)-3-cyclohexyl-N-cyclopropylmethyl-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 166. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[(S)-1-(3-methoxyphenyl)ethyl]propionamide, 167. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[(R)-1-(3-methoxyphenyl)ethyl]propionamide, 168. (R)-3-cyclohexyl-N-cyclohexylmethyl-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 169. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(tetrahydropyran-4-ylmethyl)propionamide, 170. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-methoxypropyl)propionamide, 171. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(tetrahydrothiopyran-4-yl)propionamide, 172. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- (tetrahydrothiopyran-4-yl)propionamide, 173. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (tetrahydrothiopyran-4-yl) amide, 174. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(tetrahydropyran-4-yl)propionamide, 175. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(1-methylpiperidin-4-yl)propionamide, 176. (R)-N-(5-chlorothiophen-2-ylmethyl)-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 177. (R)-N-(5-chlorothiophen-2-ylmethyl)-3-cyclohexyl-2-{N-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide, 178. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-fluoro-4- methoxybenzyl)-3-phenylpropionamide, 179. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-fluoro-4-methoxybenzyl)propionamide, 180. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-fluoro-4-methoxybenzyl amide, 181. (R)-3-cyclohexyl-N-(3,4-difluorobenzyl)-2-{N-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 182. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3,4-difluorobenzyl amide, 183. (R)-N-(6-chloropyridin-3-ylmethyl)-3-cyclohexyl-2-{N-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide, 184. (R)-N-((S)-sec-butyl)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 185. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(trans-4-hydroxycyclohexyl)propionamide, 186. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (6-chloropyridin-3-ylmethyl) amide, 187. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluorobenzyl)propionamide, 188. (R)-3-cyclohexyl-N-cyclopropyl-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 189. (R)-3-cyclohexyl-N-cyclopentyl-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 190. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-fluorobenzyl amide, 191. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid cyclopentyl amide, 192. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid ((S)-sec-butyl) amide, 193. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid ((R)-sec-butyl) amide, 194. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (trans-4-hydroxycyclohexyl) amide, 195. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (cis-4-hydroxycyclohexyl) amide, 196. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (S)-indan-1-yl amide amide, 197. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (R)-indan-1-ylamide amide, 198. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (4-methoxyindan-2-yl) amide, 199. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (5-methoxyindan-2-yl) amide, 200. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-(1H-tetrazol-5-yl)benzyl amide, 201. (R)-3-cyclohexyl-2-{N-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 202. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(cis-4-hydroxycyclohexyl)propionamide, 203. (R)-N-((R)-sec-butyl)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 204. (R)-N-(3,4-dimethoxybenzyl)-2-{N-[2-(2,5-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 205. (R)-2-{N-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 206. (R)-3-cyclohexyl-2-{N-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 207. (R)-3-cyclohexyl-2-{N-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-methoxybenzyl)propionamide, 208. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(S)-indan-1-ylpropionamide)propionamide, 209. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(R)-indan-1-ylpropionamide, 210. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-methoxyindan-2-yl)propionamide, 211. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(5-methoxyindan-2-yl)propionamide, 212. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(1H-tetrazol-5-yl)benzyl]propionamide, 213. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(4-fluoro-3-methoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 214. (R)-3-cyclohexyl-2-{N-[2-(4-fluoro-3-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 215. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(4-fluoro-3- methoxyphenyl)acetyl]guanidino}propionamide, 216. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(3-fluoro-4-methoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 217. (R)-3-cyclohexyl-2-{N-[2-(3-fluoro-4-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 218. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(3-fluoro-4- methoxyphenyl)acetyl]guanidino}propionamide, 219. (R)-N-(4-fluoro-3-methoxybenzyl)-3-phenyl-2-[N-(2-tetrahydro- pyran-4-ylacetyl)guanidino]propionamide, 220. (R)-3-cyclohexyl-N-isobutyl-2-[N-(2-tetrahydropyran-4-ylacetyl)- guanidino]propionamide, 221. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(2-tetrahydro- pyran-4-ylacetyl)guanidino]propionamide, 222. (R)-3-cyclohexyl-2-{N-[2-(2,6-difluoro-4-methoxyphenyl)acetyl]- guanidino}-N-(4-fluoro-3-methoxybenzyl)propionamide, 223. (R)-3-cyclohexyl-2-{N-[2-(2,6-difluoro-4-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 224. (R)-3-cyclohexyl-2-[N-(3,3-dimethylbutyryl)guanidino]-N-(4-fluoro- 3-methoxybenzyl)propionamide, 225. (R)-3-cyclohexyl-2-[N-(3,3-dimethylbutyryl)guanidino]-N-isobutyl- propionamide. 226. (R)-3-cyclohexyl-2-{N-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide, 227. (R)-2-{N-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 228. (R)-2-{N-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)-3-phenylpropionamide, (R)-2-{N-[2-(2- bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclohexyl-N-isobutyl- propionamide, 229. (R)-2-{N-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-isobutylpropionamide, 230. (R)-2-{N-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 231. (S)-2-benzyl-4-{N-[(R)-1-(4-fluoro-3-methoxybenzylcarbamoyl)-2- phenylethyl]guanidino}-4-oxobutyric acid methyl ester, 232. (S)-2-benzyl-4-[N-((R)-2-cyclohexyl-1-isobutylcarbamoylethyl)- guanidino]-4-oxobutyric acid methyl ester, 233. (S)-2-benzyl-4-{N-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzyl- carbamoyl)ethyl]guanidino}-4-oxobutyric acid methyl ester, 234. (R)-2-{N-[2-(2-bromophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4- fluoro-3-methoxybenzyl)propionamide, 235. (R)-2-{N-[2-(2-bromophenyl)acetyl]guanidino}-3-cyclohexyl-N- isobutylpropionamide, 236. (R)-2-{N-[2-(2-bromophenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 237. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-((S)-5-oxo- pyrrolidin-2-yl)acetyl]guanidino}propionamide, 238. (R)-3-cyclohexyl-N-isobutyl-2-{N-[2-((S)-5-oxopyrrolidin-2-yl)- acetyl]guanidino}propionamide, 239. (S)-2-benzyl-4-{N-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzyl- carbamoyl)ethyl]guanidino}-4-oxobutyric acid, 240. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N-[2-(2,3,4-trimethoxy- phenyl)acetyl]guanidino}propionamide, 241. (R)-N-(4-fluoro-3-methoxybenzyl)-3-phenyl-2-{N-[2-(2,3,4- trimethoxyphenyl)acetyl]guanidino}propionamide, 242. (R)-3-cyclohexyl-N-isobutyl-2-{N-[2-(2,3,4-trimethoxyphenyl)- acetyl]guanidino}propionamide, 243. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(2,3,4- trimethoxyphenyl)acetyl]guanidino}propionamide, 244. (R)-2-{N-[2-(3,4-difluorophenyl)acetyl]guanidino}-N-(3,4-dimethoxy- benzyl)-3-phenylpropionamide, 245. (R)-2-{N-[2-(3,4-difluorophenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 246. (R)-3-cyclohexyl-2-{N-[2-(3,4-difluorophenyl)acetyl]guanidino}-N- isobutylpropionamide, 247. (R)-3-cyclohexyl-2-{N-[2-(3,4-difluorophenyl)acetyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 248. (R)-N-cyclobutyl-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 249. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid cyclobutyl amide, 250. (R)-2-{N-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 251. (R)-3-cyclohexyl-2-{N-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N- isobutylpropionamide, 252. (R)-3-cyclohexyl-2-{N-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 253. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-trifluoromethylbenzyl)propionamide, 254. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-trifluoromethylbenzyl amide, 255. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-trifluoromethylbenzyl)propionamide, 256. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-fluoro-3-trifluoromethylbenzyl amide, 257. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-trifluoromethoxybenzyl)propionamide, 258. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-trifluoromethoxybenzyl amide, 259. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethoxybenzyl)-2-{N-[2-(4- fluoro-3-trifluoromethylphenyl)acetyl]guanidino}propionamide, 260. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethylbenzyl)-2-{N-[2-(4- fluoro-3-trifluoromethylphenyl)acetyl]guanidino}propionamide, 261. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(2,4,6- trifluorophenyl)acetyl]guanidino}propionamide, 262. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethoxybenzyl)-2-{N-[2- (2,4,6-trifluorophenyl)acetyl]guanidino}propionamide, 263. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethylbenzyl)-2-{N-[2- (2,4,6-trifluorophenyl)acetyl]guanidino}propionamide, 264. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(4-fluoro-3- trifluoromethylphenyl)acetyl]guanidino}propionamide, 265. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-trifluoromethoxybenzyl)propionamide, 266. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-fluoro-3-trifluoromethoxybenzyl amide, 267. (R)-N-[(S)-1-(3-chlorophenyl)-2-oxopyrrolidin-3-yl]-3-cyclohexyl-2- {N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 268. (R)-N-[(R)-1-(3-chlorophenyl)-2-oxopyrrolidin-3-yl]-3-cyclohexyl-2- {N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 269. (R)-2-{N-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-4- methylpentanecarboxylic acid 3-(1H-tetrazol-5-yl)benzyl amide, 270. (R)-2-{N-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3- cyclohexyl-N-[3-(1H-tetrazol-5-yl)benzyl]propionamide, 271. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(3-fluoro-4- trifluoromethoxyphenyl)acetyl]guanidino}propionamide, 272. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[4-(1H-tetrazol-5-yl)benzyl]propionamide, 273. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 4-(1H-tetrazol-5-yl)benzyl amide, 274. (R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N- isobutylpropionamide, 275. (R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4- fluoro-3-methoxybenzyl)propionamide, 276. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-fluoro-4-(1H-tetrazol-5-yl)benzyl]propionamide, 277. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-fluoro-4-(1H-tetrazol-5-yl)benzyl amide, 278. (R)-2-{N-[2-(2-bromo-4-trifluoromethylphenyl)acetyl]guanidino}-3- cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 279. (R)-2-[N-((2S,4R)-1-acetyl-4-methoxypyrrolidine-2-carbonyl)- guanidino]-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propion- amide, 280. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(2-piperidin-1- ylacetyl)guanidino]propionamide, 281. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-sulfamoylbenzyl)propionamide, 282. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(2-morpholin- 4-ylacetyl)guanidino]propionamide, 283. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(4- sulfamoylphenyl)acetyl]guanidino}propionamide, 284. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(2-fluoro-4- methoxyphenyl)acetyl]guanidino}propionamide, 285. (R)-3-cyclohexyl-2-{N-[2-(2-fluoro-4-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 286. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N-{2-[4-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl]acetyl}guanidino)propionamide, 287. (R)-2-{N-[2-(3-cyanophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4- fluoro-3-methoxybenzyl)propionamide, 288. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(3- methanesulfonylaminophenyl)acetyl]guanidino}propionamide, 289. 4-[((R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionylamino)methyl]benzoic acid methyl ester, 290. 4-[((R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoylamino)methyl]benzoic acid methyl ester, 291. 4-[((R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionylamino)methyl]benzoic acid methyl ester, 292. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]propionamide, 293. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl amide, 294. 4-(2-{N-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzylcarbamoyl)- ethyl]guanidino}-2-oxoethyl)-2-ethoxybenzoic acid ethyl ester, 295. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(2-pyridin-2-yl- acetyl)guanidino]propionamide, 296. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N-(2-isobutoxy- acetyl)guanidino]propionamide, 297. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 4-(1,2,3-thiadiazol-4-yl)benzyl amide, 298. (R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-(3- sulfamoylbenzyl)propionamide, 299. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(4- (1,2,3-thiadiazol-4-yl)benzyl)propionamide, 300. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzyl]-3-phenylpropionamide, 301. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(4-tetrazol- 1-ylphenyl)acetyl]guanidino}propionamide, 302. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-methyl- imidazol-1-yl)benzyl]-3-phenylpropionamide, 303. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(2-methylimidazol-1-yl)benzyl]propionamide, 304. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-(2-methylimidazol-1-yl)benzyl amide, 305. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(3- (1,2,4-triazol-1-yl)benzyl)propionamide, 306. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-1,2,4-triazol-1-ylbenzyl)propionamide, 307. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(1,2,4-triazol-1-yl)benzyl amide, 308. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide, 309. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-(5- hydroxy-1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide, 310. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[4-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide, 311. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide, 312. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide, 313. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(5- hydroxy-1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide, 314. (R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-[4- (1H-tetrazol-5-yl)benzyl]propionamide, 315. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-1,2,3-thiadiazol-4-ylbenzyl)propionamide, 316. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(2-methyl-2H-pyrazol-3-yl)benzyl]propionamide, 317. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(2-methyl-2H-pyrazol-3-yl)benzyl amide, 318. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-methyl- 2H-pyrazol-3-yl)benzyl]-3-phenylpropionamide, 319. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(1-methyl-1H-pyrazol-3-yl)benzyl]propionamide, 320. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(1-methyl-1H-pyrazol-3-yl)benzyl amide, 321. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(1-methyl- 1H-pyrazol-3-yl)benzyl]-3-phenylpropionamide, 322. (R)-2-{N-[2-(4-chloro-2-fluorophenyl)acetyl]guanidino}-3- cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 323. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-thiazol-2-ylbenzyl)propionamide, 324. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-thiazol-2-ylbenzyl amide, 325. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(3- thiazol-2-ylbenzyl)propionamide, 326. (R)-2-[N-((1S,4R)-2-bicyclo[2.2.1]hept-2-ylacetyl)guanidino]-3- cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 327. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 328. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[4-fluoro-3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide, 329. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 4-fluoro-3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide, 330. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-fluoro-3- (5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide, 331. (R)-2-[N-((1S,4R)-2-bicyclo[2.2.1]hept-2-ylacetyl)guanidino]-3- cyclohexyl-N-[3-(1H-tetrazol-5-yl)benzyl]propionamide, 332. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N- [3-(1H-tetrazol-5-yl)benzyl]propionamide, 333. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N-{2-[4-(2H- tetrazol-5-yl)phenyl]acetyl}guanidino)propionamide, 334. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N-[2-(4-propyl- cyclohexyl)acetyl]guanidino}propionamide, 335. (R)-3-cyclohexyl-2-{N-[2-(4-propylcyclohexyl)acetyl]guanidino}-N- [3-(1H-tetrazol-5-yl)benzyl]propionamide, 336. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-fluoro-3- (2H-tetrazol-5-yl)benzyl]-3-phenylpropionamide, 337. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[4-fluoro-3-(2H-tetrazol-5-yl)benzyl]propionamide, 338. (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 4-fluoro-3-(2H-tetrazol-5-yl)benzyl amide, 339. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-{(S)-1-[3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide, 340. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N- {(S)-1-[3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide, 341. (R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-{(S)-1-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide, 342. (R)-N-[4-(bistrifluoromethylamino)benzyl]-3-cyclohexyl-2-{N-[2- (3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 343. 4-[((R)-3-cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionylamino)methyl]benzoic acid, 344. 3-[((R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl- propionylamino)methyl]benzoic acid methyl ester, 345. 3-[((R)-2-{N-[2-(4-chlorophenyl)acetyl]guanidino}-4-methyl- pentanoylamino)methyl]benzoic acid methyl ester, 346. (R)-N-[3-(bistrifluoromethylamino)benzyl]-3-cyclohexyl-2-{N-[2- (3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 347. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N-{2-[3-(2H- tetrazol-5-yl)phenyl]acetyl}guanidino)propionamide, 348. (R)-N-{1-[4-(bistrifluoromethylamino)phenyl]cyclopropyl}-3- cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}propion- amide, 349. (R)-3-cyclohexyl-N-((R)-2,3-dihydroxypropyl)-2-{N-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide, 350. (R)-3-cyclohexyl-N-((S)-2,3-dihydroxypropyl)-2-{N-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide,
and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

(3) For the avoidance of any doubt, the compound according to the invention is unambiguously defined by the depiction of the chemical structure in all cases where the chemical name of the compound and the depiction of the chemical structure of the compound for a compound according to the invention incorrectly do not agree.

(4) The mass signals were determined on an Agilent 1200 instrument: Chromolith Speed Rod RP 18e 50-4.6 mm LCMS; polar. m, 2.4 ml/min, 220 nm, buffer A 0.05% of HCOOH/H2O, buffer B 0.04% of HCOOH/ACN, 0.0-2.8 min 4%-100% of buffer B; 2.8-3.3 min 100% of buffer B 3.3-3.4 min 100%-4% of buffer B

(5) The retention times were determined on a Merck-Hitachi LaChrom instrument:

(6) Chromolith Speed Rod RP18e-100-4.6 HPLC; 5 min 4 ml 215 nm; 4 ml/min, 215 nm, buffer A 0.05% of TFA/H2O, buffer B 0.04% of TFA/ACN, 0.0-0.2 min 5% of buffer B; 0.2-5.0 min 5%-100% of buffer B; 5.0-5.5 min 99%-5% of buffer B

EXAMPLE 2

Preparation of (R)-3-(2,4-dichlorophenyl)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide trifluoroacetate (compound No. 1)

(7) ##STR00366##

(8) 197.4 l of 4-methylmorpholine were added to the solution of 500 mg (1.5 mmol) of (R)-2-tert-butoxycarbonylamino-3-(2,4-dichlorophenyl)propionic acid in 10 ml of tetrahydrofuran under nitrogen, and the mixture was cooled to 50 C. After addition of 194.6 l (1.5 mmol) of isobutyl chloroformate, the reaction solution was stirred at 50 C. for 15 min, 248.7 (1.5 mmol) of 2-(3,4-dimethoxyphenyl)ethylamine were then added, the mixture was subsequently stirred at 40 C. for a further 30 min and at room temperature for two hours. The reaction mixture was then evaporated in vacuo, the residue was taken up in 10 ml of 5% sodium hydrogencarbonate solution, and the aqueous mixture was extracted three times with 10 ml of ethyl acetate each time. Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent gave 655 mg (88% yield) of tert-buty {(R)-2-(2,4-dichlorophenyl)-1-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]ethyl}carbamate as colourless crystals. LC/MS (M+Na):520.

(9) ##STR00367##

(10) 655 mg (1.32 mmol) of tert-butyl {(R)-2-(2,4-dichlorophenyl)-1-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]ethyl}carbamate (1a)) were dissolved in 15 ml of dioxane, and 15 ml of 4N HCl/dioxane solution were added. Reaction mixture was subsequently stirred overnight at room temperature, then evaporated to dryness, and the residue was dried in vacuo at 60 C. for five hours, giving 571 mg (100%) of (R)-2-amino-3-(2,4-dichlorophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide hydrochloride as pale-yellow solid. LC/MS (M+H) 397. .sup.1H NMR (500 MHz, DMSO-d.sup.6) 8.53 (broad s, 4H; NH), 7.61 (d, J=2.0, 1H), 7.39 (dd, J=8.3, 2.0, 1 H), 7.34 (d, J=8.3, 1 H), 6.83 (d, J=8.2, 1 H), 6.78 (d, J=1.8, 1H), 6.63 (dd, J=8.1, 1.7, 1H), 3.94 (broad s, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 3.32-3.26 (m, 1H), 3.18 (dq, J=12.5, 6.4, 2H), 3.09 (dd, J=13.8, 8.4, 1 H), 2.61-2.51 (m, 2H).

c) 2-(3,4-Dimethoxyphenyl)-N-(iminopyrazol-1-ylmethyl)acetamide

(11) ##STR00368##

(12) 1.067 ml (1.2 mmol)) of ethyl chloroformate were added to the solution of 2 g (10.2 mmol) of 3,4-dimethoxyphenylacetic acid and 2.24 ml of 4-methylmorpholine in 50 ml of dichloromethane with ice-cooling and under an N.sub.2 atmosphere, The reaction mixture was subsequently stirred with ice-cooling for one hour, 1.64 g (11.2 mmol) of pyrazole-1-carboxamidine hydrochloride were then added, and stirring was continued at room temperature for fifteen hours. The reaction solution was then washed with 10 ml of 5% sodium hydrogencarbonate solution and 10 ml of water and dried over sodium sulfate. After the desiccant had been filtered off and the solvent had been stripped off, the product was purified by column chromatography. Yield 1.85 g (62.1%) LC/MS (M+H) 289. .sup.1H NMR (400 MHz, DMSO-d.sup.6) 9.30 (broad s, 2H), 8.46 (d, J=2.6, 1 H), 7.91 (d, J=1.6, 1H), 6.93 (d, J=1.7, 1H), 6.87 (d, J=8.2, 1H), 6.81 (dd, J=8.2, 1.7, 1H), 6.58 (dd, J=2.6, 1.6, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.62 (s, 2H).

(13) ##STR00369##

(14) 100 mg (0.35 mmol) of 2-(3,4-dimethoxyphenyl)-N-(iminopyrazol-1-yl-methyl)acetamide (1c)) and 150.45 mg (0.35 mmol) of (R)-2-amino-3-(2,4-dichlorophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide hydrochloride (1 b)) are suspended in 2 ml of tetrahydrofuran. After addition of 58 l of triethylamine, the suspension is heated at 90 C. for 2 hours and then cooled to room temperature. The reaction mixture is subsequently evaporated to dryness, and the residue is purified by column chromatography (RP-HPLC select B; 0.1% solution of trifluoroacetic acid in acetonitrile/water), giving 44 mg (16.5%) of the title compound in the form of the trifluoroacetate salt as white amorphous solid. LC/MS (M+H) 617. .sup.1H NMR (500 MHz, DMSO-d.sup.6) 11.32 (s, 1H), 8.99 (d, J=8.3, 1H), 8.88 (broad s, 2H), 8.32 (t, J=5.2, 1H), 7.54 (s, 1H), 7.29 (dd, J=8.3, 2.0, 1H), 7.14 (d, J=8.3, 1H), 6.93 (d, J=8.2, 1 H), 6.89 (d, J=1.5, 1 H), 6.84 (d, J=8.2, 1 H), 6.79 (dd, J=8.0, 1.6, 2H), 6.67 (dd, J=8.1, 1.6, 1H), 4.62 (dd, J=13.0, 5.5, 1H), 3.75 (s, 6H), 3.73 (s, 3H), 3.70 (s, 3H), 3.67 (s, 2H), 3.40-3.27 (m, 3H), 3.04 (dd, J=14.3, 6.4, 1 H), 2.76-2.56 (m, 2H).

(15) Compounds Nos. 4-14 were prepared analogously to the process from Example 2.

EXAMPLE 3

Preparation of (R)-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]-guanidino}-N-(4-methoxybenzyl)-3-phenylpropionamide trifluoroacetate

a) tert-Butyl[1-[2-(3,4-dimethoxyphenyl)acetylamino]-1-pyrazol-1-ylmeth-(Z)-ylidene]carbamate

(16) ##STR00370##

(17) 1.17 g (29.38 mmol; 60% suspension in paraffin oil) of sodium hydride are added to the solution of 2.42 g (8.4 mmol) of 2-(3,4-dimethoxyphenyl)-N-(iminopyrazol-1-ylmethyl)acetamide (1c)) in 50 ml of tetrahydrofuran and 2 ml of dimethylformamide with ice-cooling and under a nitrogen atmosphere, and the mixture is stirred for 20 min. After addition of 11 g (50.36 mmol) of di-tert-butyl dicarbonate, the reaction mixture is stirred at room temperature for 48 hours, then evaporated to dryness, the residue is taken up in 10 ml of 5% sodium hydrogencarbonate solution, and the aqueous mixture is extracted three times with 10 ml of ethyl acetate each time. After the combined organic extracts have been dried over sodium sulfate and the solvent has been stripped off, the product is purified by column chromatography on silica gel (ethyl acetate/n-heptane), giving 1.86 g (52.5%) of tert-butyl[1-[2-(3,4-dimethoxyphenyl)acetylamino]-1-pyrazol-1-ylmeth-(Z)-ylidene]-carbamate as pale-yellow oil which gradually crystallises. LC/MS: 411 (M+Na). .sup.1H NMR (400 MHz, DMSO-d.sup.6) 11.24 (s, 1H), 8.40 (s, 1H), 7.92 (s, 1H), 6.95 (s, 1H), 6.90 (d, J=8.2, 1 H), 6.84 (d, J=8.2, 1 H), 6.63 (s, 1H), 3.76 (s, 3H), 3.75 (s, 2H), 3.74 (s, 3H), 1.38 (s, 9H).

(18) ##STR00371##

(19) 50 mg of N-ethyldiisopropylamine and 54.5 mg (0.17 mmol) of (R)-2-amino-N-(4-methoxybenzyl)-3-phenylpropionamide hydrochloride (prepared analogously to 1 b)) are added to the solution of 60 mg (0.15 mmol) of tert-butyl[1-[2-(3,4-dimethoxyphenyl)acetylamino]-1-pyrazol-1-ylmeth-(Z)-ylidene]carbamate (2a)) in 3 ml of tetrahydrofuran, the reaction mixture obtained in this way is stirred at room temperature for 18 hours and then evaporated to dryness. The residue is then dissolved in 3 ml of dichloromethane, 0.5 ml of trifluoroacetic acid is added to the solution, the reaction solution is stirred at room temperature for 15 hours and then evaporated in vacuo. After trituration of the residue with methanol, the product is filtered off with suction and dried at 60 C. in a vacuum drying cabinet for three hours, giving 42 mg (53.8%) the title compound as white powder. LC/MS (M+H) 505. .sup.1H NMR (500 MHz, DMSO-d.sup.6) 11.31 (s, 1H), 8.94 (d, J=8.0, 1H), 8.84 (s, 2H), 8.69 (t, J=4.9, 1H), 7.28-7.19 (m, 3H), 7.17-7.11 (m, 2H), 7.10 (d, J=8.4, 2H), 6.92 (d, J=8.2, 1H), 6.89 (s, 1H), 6.86 (d, J=8.6, 2H), 6.79 (d, J=8.1, 1H), 4.65 (dd, J=12.8, 6.4, 1H), 4.22 (qd, J=14.7, 5.7, 2H), 3.74 (s, 6H), 3.73 (s, 3H), 3.68 (s, 2H), 3.16 (dd, J=13.9, 5.3, 1H), 3.03 (dd, J=13.9, 6.8, 1H).

(20) Compounds Nos. 15-67 were prepared analogously to the process from Example 3.

EXAMPLE 4

(R)-3-Cyclohexyl-2-{N-[2-(3,4-dimethoxyphenyl)acetyl]-guanidino}-N-(1-ethylpropyl)propionamide

a) BOC-guanidine

(21) ##STR00372##

(22) BOC-guanidine was synthesised in accordance with Ando et al., Tetrahedron (2010), 66(32), 6224-6237: 22.93 g (0.24 mol) of guanidinium chloride are added to the solution of 19.2 g (0.48 mol) of sodium hydroxide pellets in 50 ml of water at 0 C. The solution is left to stir for 10 min., a solution of 13.1 g (60 mmol) of di-tert-butyl dicarbonate in 150 ml of acetone is then added in one portion at 0 C., and the reaction mixture is then left to stir at room temperature for 15 hours. The acetone is subsequently stripped off in vacuo, and the aqueous mixture is extracted twice with 50 ml of ethyl acetate. The combined organic phases are washed with 50 ml of saturated sodium chloride solution and dried over sodium sulfate. After the solvent has been stripped off, the residue is recrystallised from ethyl acetate/n-heptane, giving 8.7 g (91%) of BOC-guanidine as white crystals. EIMS (M+): 159.

b) (3,4-Dimethoxyphenyl)acetyl chloride

(23) ##STR00373##

(24) 5 l of dimethylformamide and then, dropwise, 10.93 ml (127.42 mmol) of oxalyl chloride are added to the solution of 5.00 g (25.48 mmol) of 3,4-dimethoxyphenylacetic acid in 100 ml of dichloromethane with ice-cooling and stirring, and, after removal of the cooling, the mixture is stirred at room temperature for two hours. The reaction mixture is subsequently evaporated to dryness in vacuo, the residue is taken up in 10 ml of toluene, the toluene is stripped off again, the residue is taken up again in 10 ml of toluene, and the toluene is stripped off again. The residue was finally taken up twice in 10 ml of diethyl ether each time, and the diethyl ether was stripped off again, giving 5.5 g (96%) of (3,4-dimethoxyphenyl)acetyl chloride, which is reacted further without additional purification.

c) N-[2-(3,4-Dimethoxyphenyl)acetyl]-N-(tert-butyloxycarbonyl)guanidine

(25) ##STR00374##

(26) 8.72 ml of N-ethyldiisopropylamine are added to the solution of 4.08 g (25.62 mmol) of BOC-guanidine (3a)) in 400 ml of dichloromethane, a solution of 5.50 g (25.62 mmol) of (3,4-dimethoxyphenyl)acetyl chloride (3b)) in 70 ml of dichloromethane is then slowly added dropwise under nitrogen at 10 C., the mixture is then left to stir with ice-cooling for one hour, and finally warmed to room temperature over the course of two hours. The reaction solution is then washed with 20 ml each of 5% sodium hydrogencarbonate solution and saturated sodium chloride solution and then dried over sodium sulfate. After the desiccant has been filtered off and the solvent has been stripped off, the product is purified by column chromatography on silica gel (ethyl acetate/n-heptane), giving 7.1 g (82.5%) of N-[2-(3,4-dimethoxyphenyl)acetyl]-N-(tert-butyloxycarbonyl)-guanidine as yellow oil. LC/MS (M+HBOC) 238.

d) tert-Butyl {[2-(3,4-dimethoxyphenyl)acetylamino]-[(Z)-trifluoromethanesulfonylimino]methyl}carbamate

(27) ##STR00375##

(28) (2010), 66(32), 6224-6237

(29) Analogously to the literature (Feichtinger et al., J. Org. Chem., (1998), 63, 8432-8439), 5.1 g (15.12 mmol) of N-[2-(3,4-dimethoxyphenyl)acetyl]-N-(tert-butyloxycarbonyl)guanidine (3c)); were dissolved in 50 ml of dichloromethane under an N.sub.2 atmosphere. 5.24 ml of triethylamine were added to this solution, and the mixture was cooled to 78 C. 5.5 ml (33.26 mmol) of trifluoromethanesulfonic anhydride dissolved in 10 ml of dichloromethane were added dropwise to this solution at such a rate that the temperature did not rise above 65 C. The reaction mixture was then left to stir at 70 C. for a further 30 min. and then allowed to come to room temperature overnight. Reaction solution was then washed with 10 ml each of 1N sodium hydrogensulfate solution and water, dried over sodium sulfate, filtered and evaporated. The product was purified by column chromatography on silica gel (ethyl acetate/n-heptane), giving 4.4 g (58.1%) of tert-butyl {[2-(3,4-dimethoxyphenyl)acetylamino]-[(Z)-trifluoromethanesulfonylimino]methyl}carbamate LC/MS (M+HBOC) 370.

(30) ##STR00376##

(31) 35.43 l of triethylamine were added to the solution of 60 mg (0.13 mmol) of tert-butyl {[2-(3,4-dimethoxyphenyl)acetylamino]-[(Z)-trifluoromethanesulfonylimino]methyl}carbamate (3d)) and 35.4 mg (0.13 mmol) of (R)-2-amino-3-cyclohexyl-N-(1-ethylpropyl)propionamide hydrochloride (prepared from (R)-2-tert-butoxycarbonylamino-3-cyclohexylpropionic acid and 1-ethyl-propylamine analogously to Example 1 b)) in 2 ml of dichloromethane, and the reaction mixture was stirred at room temperature for 18 hours. 1 ml of trifluoroacetic acid was subsequently added to the reaction mixture, the mixture was stirred at room temperature for a further two hours, then evaporated to dryness in vacuo, and the product was purified by column chromatography (RP-HPLC select B; 0.1% solution of trifluoroacetic acid in acetonitrile/water), giving 21 mg (28.4%) of the title compound as amorphous white powder. LC/MS (M+H) 461. .sup.1H NMR (500 MHz, DMSO-d.sup.6) 11.08 (s, 1H), 8.89 (d, J=7.9, 1 H), 8.80 (broad s, 2H), 6.92 (d, J=8.2, 1 H), 6.90 (d, J=1.6, 1 H), 6.81 (dd, J=8.2, 1.5, 1 H), 1.74-1.53 (m, 6H), 1.53-1.41 (m, 2H), 1.34 (dt, J=13.5, 7.5, 2H), 1.25 (m, 2H), 1.20-1.06 (m, 3H), 1.00-0.84 (m, 2H), 0.81 (td, J=7.4, 4.0, 6H).

(32) Compounds Nos. 68-350 were prepared analogously to the process from Example 4.

Abbreviations

(33) DCM=dichloromethane

(34) DMA=dimethylacetamide

(35) DMF=dimethylformamide

(36) EA=ethyl acetate

(37) MTBE=methyl tert-butyl ether

(38) PE=petroleum ether

(39) RT=room temperature

(40) TFA=trifluoroacetic acid

EXAMPLE 5

In-Vitro Fluorescence Assay for the Identification of Cathepsin D Inhibitors

(41) In order to identify modulators of cathepsin D activity, a continuous enzymatic test was carried out with a synthetic peptide which carries a fluorescent group (MCA=(7-methoxycoumarin-4-yl)acetyl) which is quenched by energy transfer from a Dpn (2,4 dinitrophenyl) group on the same molecule, in Greiner 384-well nb microtitre plates. Cleavage of the peptidic substrate by cathepsin D causes an increase in the fluorescence intensity. In order to determine the efficacy of substances, the time-dependent increase in the fluorescence intensity in the presence of the substance was compared with the time-dependent increase in fluorescence in the absence of substances. The reference substance used was pepstatin A (Sigma-Aldrich). The substrate used was MCA-GKPILFFRLK(Dnp)d-RNH.sub.2 (Enzo Life Sciences, Lrrach). The enzyme employed was cathepsin D isolated from the human liver (Sigma-Aldrich) in a final concentration of 1.4 nM. The test was carried out in 100 mM sodium acetate buffer, 1.25% (v/v) of DMSO, 0.25% (w/v) of Chaps, pH 5.5. 2 l of each substance solution with serially diluted substance concentration were added to in each case 4 l of cathepsin D solution and incubated at room temperature for 10 min. The reaction was started by addition of 2 l of substrate solution (final concentration 5 M). After carrying out a starting-point fluorescence measurement (excitation wavelength 340 nm/emission wavelength 450 nm) using an Envision multilabel reader (Perkin Elmer), the reaction was incubated at room temperature for 60 min. The amount of peptide fragment cleaved off during the reaction time was subsequently measured by determination of the increase in the fluorescence intensity at 450 nm (excitation wavelength 340 nm).

(42) The IC.sub.50 values of the compounds according to the invention are shown in Table 2 from Example 1.

EXAMPLE 6

Cartilage Explant Assay

(43) In order to investigate the effect of potential cathepsin D inhibitors on cartilage degradation, a pH-induced model based on bovine explants is used. The pH of the medium in which the explants are cultivated is matched here to the pathophysiological pH of an arthrotic knee. This pH is pH 5.5. In this ex vivo model, potential cathepsin D inhibitors are subsequently investigated for their action with respect to stopping of the cartilage degradation process. If the cartilage is destroyed, glycosaminoglycans (GAGs) are released into the cell culture supernatant. The amount of GAGs liberated can be determined quantitatively with the aid of DMMB (dimethylmethylene blue hydrochloride). If sulfated GAGs are detected using dimethylmethylene blue hydrochloride, the decrease in the absorption at 633 nm is utilised. Since work can also be carried out at very low GAG concentrations, a dye/GAG complex does not precipitate out even after extended incubation of DMMB with GAG, which sometimes happens after only a short time in other measurement methods. In order to determine the concentration, a calibration line is also recorded using chondroitin sulfate. The GAG values can be used to calculate an IC.sub.50 value, i.e. a concentration at which a substance exhibits 50% of its action.

(44) Solutions:

(45) Incubation Medium, pH 7.4:

(46) DMEM without FBS, addition of 1% of Pen/Strep and 30 g/ml of ascorbic acid, the medium is not stored.

(47) Incubation Medium, pH 5.5:

(48) DMEM without FBS, the pH is adjusted by addition of MES and monitored using a pH meter, addition of 1% of Pen/Strep and 30 g/ml of ascorbic acid.

(49) Solutions for the GAG Measurement:

(50) DMMB colouring solution (V=500 ml):

(51) Dissolve 8 mg of DMMB (dimethylmethylene blue) in 2.5 ml of ethanol+1 g of sodium formate+1 ml of formic acid, make up to 500 ml with bidistilled water.

(52) Incubation Medium: FBS (Medium without FBS)

(53) Chondroitin Sulfate Solutions (Standard Curve)

(54) Preparation of standard solutions with the following concentrations: 50 g/ml; 25 g/ml; 12.5 g/ml; 6.25 g/ml; 3.125 g/ml; 1.56 g/ml; 0.78 g/ml and a blank control of the medium. The preparation of the standard solution is carried out in the medium with which the experiment was also carried out.

(55) 1.) Procedure: pH-Induced Cartilage Degradation of Bovine Explants

(56) The bovine explants are firstly prepared. The induction of the cartilage degradation is carried out in 96-multiwell plates. One explant is cultivated per well. In each case, 200 l of DMEM (incubation medium pH 5.5) without FBS+30 g/ml of ascorbic acid are added. Thus negative control, explants (n=4) are incubated at pH 7.4 (without FBS). This control is not included in the calculation of the data, but instead ensures that the pH change has the desired effect on the liberation of GAG. At this point, the substances to be tested are added. No pre-incubation of the explants is carried out. The explants are cultivated with the corresponding substances for 3 days in the incubator at 37 C. and 7.5% CO.sub.2.

(57) 2.) Incubation Procedure

(58) In order to investigate the effect of cathepsin D inhibitors on the liberation of GAG (glycosaminoglycan), the substances are employed in the desired concentration and cultivated for 3 days. The compounds to be tested are tested in a first experiment in a concentration of 1 M and 1% of DMSO. Substances which have an effect of >50% on the liberation of GAG (this corresponds to <50% of the control in the Assay Explorer) are tested in the next experiment at 100 nM and 1% of DMSO. Substances which have an effect of >50% on the liberation of GAG under these conditions (this corresponds to <50% of the control in the Assay Explorer) are tested in a concentration/effect relationship. The compounds here are investigated in the following concentrations: 30 M, 10 M, 3 M, 1 M, 0.3 M, 0.1 M, 0.03 M, 0.01 M.

(59) The positive control used is pepstatin A with a concentration of 0.01 M.

(60) The assay window is defined by the control (pH 5.5), defined as 0% effect, and the control pH 5.5+0.01 M pepstatin A, defined as 100% effect. After incubation for 3 days, the cell culture supernatants are collected and stored at 20 C. or measured directly. The amount of liberated GAG is measured photometrically.

(61) The effect (1 value) of the respective substance in % based on the positive control (pH 5.5+0.01 M pepstatin A) and the negative control (pH 5.5) is reported for concentrations of 1 M and 100 nM. The value represents the average of 4 replicants. In the determination of a concentration/effect relationship, an IC.sub.50 value is reported to the database (Assay Explorer).

(62) 4.) Measurement

(63) The cell culture supernatants (200 l) are either measured directly or stored at 20 C. In order to ensure an accurate determination of the concentration (g/ml of GAG in the supernatant) of GAG, the measurement values must be located in the linear region of the standard curve. In order to ensure this, various dilutions are routinely introduced (1/5, 1/10, 1/20, 1/40). The dilutions are prepared with medium and introduced automatically (Hamilton) into a 384-well plate (15 l). 60 l of DMMB solution are likewise added automatically (or using a multichannel pipette). A rapid colour reaction occurs, which is subsequently measured at 633 nm using a plate reader (for example Envision).

(64) Depending on the amount of sample present, at least one double determination is carried out.

(65) The data are provided by the MTP reader as csv or xls files and stored as raw data based on this format (xls) or used for the calculation of the percentage effect of the particular compound.

(66) 5.) Quality Controls

(67) As control for the induction of the pH-induced cartilage degradation, 4 explants are incubated at pH 7.4. This corresponds to the physiological pH of the cartilage, and no effect on the liberation of GAG is thus expected here. These GAG values (g/ml of supernatant) are thus always significantly lower than the GAG values for incucation at pH 5.5.

(68) A further control, which both serves for checking of the experiment, but is also important for the definition of the assay window, is the pepstatin control (pH 5.5+0.01 M pepstatin A). This substance non-specifically blocks the activity of most proteases and thus determines the maximum possible effect of a compound.

(69) 6.) Results

(70) All compounds measured exhibited an IC.sub.50 value of 10.sup.8 to 10.sup.10 M in the GAG assay.

(71) (1) Klompmakers, A. & Hendriks, T. (1986) Anal. Biochem. 153, 80-84, Spectrophotometric Determination of Sulfated Glycosaminoglycans.

(72) (2) Groves, P. J. et al. (1997) Anal. Biochem. 245, 247-248 Polyvinyl alcohol-stabilised binding of sulfated GAGs to dimethylmethylene blue.

EXAMPLE 7

Investigation of Anti-Hyperalgesic Effect in Animals

(73) In order to induce an inflammation reaction, a carrageenan solution (CAR, 1%, 50 l) was injected intra-articularly on one side into a rat knee joint. The uninjected side was used for control purposes. Six animals per group were used. The threshold was determined by means of a micrometer screw (medial-lateral on the knee joint), and the thermal hyperalgesia was determined by means of a directed infrared light source by the Hargreaves method (Hargreaves et al., 1988) on the sole of the foot. Since the site of inflammation (knee joint) is different from the site of measurement (paw sole), use is made here of the term secondary thermal hyperalgesia, the mechanism of which is of importance for the discovery of effective analgesics.

(74) Experimental description of thermal hyperalgesia (Hargreaves test): the experimental animal is placed in a plastic chamber on a quartz sheet. Before testing, the experimental animal is firstly given about 5-15 minutes time to familiarise itself with the environment. As soon as the experimental animal no longer moves so frequently after the familiarisation phase (end of the exploration phase), the infrared light source, whose focus is in the plane of the glass bottom, is positioned directly beneath the rear paw to be stimulated. An experiment run is then started by pressing the button: infrared light results in an increase in the skin temperature of the rear paw. The experiment is terminated either by the experimental animal raising the rear paw (as an expression of the pain threshold being reached) or by automatic switching-off of the infrared light source when a prespecified maximum temperature has been reached. Light reflected by the paw is recorded as long as the experimental animal sits still. Withdrawal of the paw interrupts this reflection, after which the infrared light source is switched off and the time from switching on to switching off is recorded. The instrument is calibrated in such a way that the infrared light source increases the skin temperature to about 45 degrees Celsius in 10 s (Hargreaves et al. 1988). An instrument produced by Ugo Basile for this purpose is used for the testing.

(75) CAR was purchased from Sigma-Aldrich. The specific cathepsin D inhibitors according to the invention were administered out intra-articularly 30 minutes before the CAR. Triamcinolone (TAC) in an amount of 10 g/joint was used as positive control, and the solvent (vehicle) was used as negative control. The hyperalgesia is quoted as the difference in the withdrawal times between the inflamed and non-inflamed paw.

(76) Result: TAC was capable of reducing the CAR-induced swelling, but the specific cathepsin D inhibitors according to the invention were not. In contrast, the specific cathepsin D inhibitors according to the invention were able to reduce the extent of thermal hyperalgesia as a function of the dose.

(77) Assessment: it has been shown that the compounds of the present invention exert an anti-hyperalgesic action. This can be postulated, since the compounds exhibited no influence on inflammatory swelling and thus on the hyperalgesia trigger. It can thus be assumed that the compounds develop a pain-reducing action in humans.

EXAMPLE 8

Stability of the Compounds According to the Invention in Bovine Synovial Fluid

(78) 1.) Extraction of Bovine Synovial Fluid

(79) In the preparation of bovine explants (for the diffusion chamber or other assays), either cow hoof (metacarpal joints) or cow knee is used. The synovial fluid can be obtained from both joints. To this end, the synovial fluid is carefully removed from the open joint using a 10 ml syringe and a cannula and transferred into prepared 2 ml Eppendorf vessels. The Eppendorf vessels are labelled depending on the animal (cow passport is available). It must be ensured here that blood does not enter the joint gap during preparation of the joints. If this is the case, the synovial fluid will become a reddish colour and must consequently be discarded. The synovial fluid is basically highly viscous and clear to yellowish in colour. The removal together with a macroscopic analysis of the synovial fluid is documented.

(80) 2.) Batch for Stability Testing of Substances in SF

(81) In order to check the stability of individual compounds, a pool of four different bovine synovial fluids is mixed. To this end, about 1 ml per SF is used. The mixture is prepared directly in a 5 ml glass vessel. The SFs are mixed thoroughly, but carefully. No air bubbles or foam should form. To this end, a vortex unit is used at the lowest speed. The compounds to be tested are tested in an initial concentration (unless required otherwise) of 1 M. After addition of the substance, the batch is again mixed thoroughly and carefully. For visual monitoring, all SF batches are photographed, and the pictures are filed in the eLabBio file for the corresponding experiment. FIG. 1 shows photo documentation of this type by way of example. The batches are incubated in the incubator for 48 h at 37 C. and 7.5% CO.sub.2.

(82) 3.) Sampling

(83) The sampling is carried out after the pre-agreed times (unless required otherwise, see below). 200 l of the SF are removed from the mixture per time and transferred directly into a 0.5 ml low-binding Eppendorf vessel. Low-binding Eppendorf vessels are used in order to minimise interaction of the substances with the plastic of the vessels. 200 l of acetonitrile have already been introduced into the Eppendorf vessel, so that a 1+1 mixture of the SF forms thereafter. This simplifies the subsequent analysis, but precipitation of protein may occur immediately after addition of the SF. This should be noted on the protocol. The 0 h sample is taken immediately after addition of the substance. This corresponds to the 100% value in the stability calculation. Ideally, the concentration employed should be retrieved here. The samples can be frozen at 20 C. 0 h 6 h 24 h 48 h

(84) The negative control used is SF without substance. The positive control used is SF with 1 M of substance. This corresponds to the 0 h value and thus 100% stability.

(85) The samples are stored in low-binding Eppendorf vessels at 20 C. The samples are subsequently measured quantitatively.

(86) 4.) Data Processing

(87) The concentrations measured (ng/ml) are plotted against the time in a graph (GraphPad Prism). The percentage stability of the substance is determined here. The 100% value used is the initial value in the SF at time 0 h. The data are stored in eLabBio under the respective experiment number and reported in the MSR database (as percent stability after the corresponding incubation times).

(88) 5.) Results

(89) All compounds measured remained stable.

EXAMPLE 9

In-Vitro Fluorescence Assay for Identification of Renin-Inhibitory Activity

(90) In order to identify modulators of renin activity, a continuous enzymatic test was carried out with a synthetic peptide which carries a fluorescent group Edans (=(5-(aminoethyl)aminonaphthalenesulfonate) which is quenched by energy transfer from a Dabcyl (4-dimethylaminoazobenzene-4-carboxylate) group on the same molecule, in Greiner 384-well microtitre plates. Cleavage of the peptidic substrate by renin causes an increase in the fluorescence intensity. In order to determine the efficacy of substances, the time-dependent increase in the fluorescence intensity in the presence of the substance was compared with the time-dependent increase in fluorescence in the absence of substances. The reference substance used was renin inhibitor 2 (Z-Arg-Arg-Pro-Phe-His-Sta-Ile-His N-Boc-Lys methyl ester Z) (Sigma-Aldrich). The substrate used was renin FRET substrate I (DABCYL-g-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS) (Anaspec, Fremont Calif.). The enzyme employed was recombinant human renin (Proteos, Kalamazoo, Mich.) in a final concentration of 10 nM. The test was carried out in 50 mM Mops buffer, 1.5% (v/v) of DMSO, 0.1% (w/v) of Igepal, pH 7.2, 0.5% (w/v) of BSA. 2 l of each substance solution with serially diluted substance concentration were added to in each case 4 l of renin solution and incubated at room temperature for 15 min. The reaction was started by addition of 4 l of substrate solution (final concentration 5 M). After carrying out a starting-point fluorescence measurement (excitation wavelength 340 nm/emission wavelength 495 nm) using an Envision multilabel reader (Perkin Elmer), the reaction was incubated at 37 C. for 60 min. The amount of peptide fragment cleaved off during the reaction time was subsequently measured by determination of the increase in the fluorescence intensity at 495 nm (excitation wavelength 340 nm).

(91) Result: all compounds measured have an IC.sub.50 of the renin selectivity of >30 M.

EXAMPLE 10

Injection Vials

(92) A solution of 100 g of a compound of the formula I and 5 g of disodium hydrogenphosphate in 3 I of bidistilled water is adjusted to pH 6.5 using 2N hydrochloric acid, filtered under sterile conditions, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of a compound of the formula I.

EXAMPLE 11

Solution

(93) A solution is prepared from 1 g of a compound of the formula I, 9.38 g of NaH.sub.2PO.sub.4 2H.sub.2O, 28.48 g of Na.sub.2HPO.sub.4. 12 H.sub.2O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 I and sterilised by irradiation. This solution can be used in the form of eye drops.

EXAMPLE 12

Ointment

(94) 500 mg of a compound of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

EXAMPLE 13

Ampoules

(95) A solution of 1 kg of a compound of the formula I in 60 I of bidistilled water is filtered under sterile conditions, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of a compound of the formula I.