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AU3659200A - Prodrugs of thrombin inhibitors - Google Patents

Prodrugs of thrombin inhibitors Download PDF

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Publication number
AU3659200A
AU3659200A AU36592/00A AU3659200A AU3659200A AU 3659200 A AU3659200 A AU 3659200A AU 36592/00 A AU36592/00 A AU 36592/00A AU 3659200 A AU3659200 A AU 3659200A AU 3659200 A AU3659200 A AU 3659200A
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AU
Australia
Prior art keywords
alkyl
pico
pyr
cycloalkyl
cha
Prior art date
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Abandoned
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AU36592/00A
Inventor
Gisela Backfisch
Dorit Baucke
Jurgen Delzer
Wilfried Hornberger
Helmut Mack
Werner Seitz
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BASF SE
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BASF SE
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Application filed by BASF SE filed Critical BASF SE
Publication of AU3659200A publication Critical patent/AU3659200A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)

Description

Prodrugs of thrombin inhibitors The present invention relates to prodrugs of pharmacologically 5 active heterocyclic amidines, from which in vivo compounds result which are competitive inhibitors of trypsin-like serine proteases, particularly thrombin, their preparation and their use as medicaments. The invention also relates to pharmaceutical compositions which contain the prodrugs of the active compounds 10 as constituents, and to the use of the compounds as thrombin inhibitors, anticoagulants and as antiinflammatory agents. Thrombin belongs to the serine proteases group and plays a central role as a terminal enzyme in the blood-clotting cascade. 15 Both the intrinsic and the extrinsic clotting cascades lead, via a number of amplification stages, to the formation of thrombin from prothrombin. The thrombin-catalyzed cleavage of fibrinogin to fibrin then initiates blood clotting and the aggregation of the platelets, which for their parts increase the formation of 20 thrombin by means of the binding of platelet factor 3 and clotting factor XIII and also a whole series of highly active mediators. Thrombin formation and action are central events in the genesis 25 both of white, arterial thrombi and of red, venous thrombi and are therefore potentially effective points of attack for pharmaceuticals. In contrast to heparin, thrombin inhibitors are able, independently of cofactors, simultaneously to completely inhibit the actions of free thrombin and thrombin bound to 30 platelets. In the acute phase, they can prevent thromboembolic events after percutaneous transluminal coronary angioplasty (PTCA) and lysis and can be used as anticoagulants in the extracorporeal circulation (heart-lung machine, hemodialysis). They can also be generally used. for thrombosis prophylaxis, for 35 example after surgical interventions. It is known that synthetic arginine derivatives influence the enzyme activity of the thrombin by interacting with the active serine residue of the protease thrombin. Peptides based on 40 Phe-Pro-Arg, in which the N-terminal amino acid is present in the D form, have proven particularly favorable. D-Phe-Pro-Arg isopropyl ester is described as a competitively acting thrombin inhibitor (C. Mattson et. al. Folia Haematol, 10.9, 43 to 51, 1983). 45 -2 WO 94/29336, EP 0601459, WO 95/23609, EP 0672658, WO 97/23499, WO 98/06740 and WO 95/35309 represent a further development in which the agmatine residue is replaced by an arylamidine residue. Although these compounds have significant antithrombotic action, it is advantageous to improve their pharmacokinetic properties after oral or ?arenteral administration. [nter alia, the influencing of the following pharmacokinetic properties .s desirable: . The improvement of the absorption from the gastrointestinal tract with the aim of a high bioavailability. I. The minimization of the inter- and intraindividual variability of the bioavailability by means of constant absorption II. The achievement of therapeutically relevant activity levels, which are as constant as possible, over the time course. With respect to the therapeutic breadth, plasma concentrations which are as constant as possible over the time course are indispensable, as variations which are too great can lead to undesired side effects. If the plasma concentration of the active compound is too high, bleeding can be expected; if the concentration is too low the risk of thrombus formation increases. 7. The prolongation of the duration of action of the active compound: Active compound is understood as meaning the pharmacologically active substance (drug) in comparison to the substance (prodrug), which first has to be converted into the active compound metabolically. Reduction of trypsin inhibition: since the prodrugs affect the digestive enzyme trypsin markedly less, fewer side effects are to be.expected with the prodrugs. further advantage of the prodrugs compared with the drugs lies in the at that high local concentrations of the drugs do not occur outside a target site. Moreover, with less selective drugs side effects are iimized, as, for example, in the gastrointestinal tract no further cine proteases are inhibited if the drug is essentially formed by :abolism of the prodrug only after or during gastrointestinal passage.
3 The aim of this invention is the improvement of the pharmacokinetic properties of the thrombin inhibitors mentioned in particular in WO 95/35309 and WO 96/25426 by means of suitable prodrugs. 5 The invention relates to compounds of the formula I N N-G l0 A-B-D-N-CK/ /( 2 H-K in which A, B, D, G and K have the following meanings: 15 A is: RIOOC-CH 2 -, RIOOC-CH 2 -CH2-, R 1 0OC-CH(CH 3 )-, HO-CH 2
-CH
2 -,
R
2
R
3
N(O)C-CH
2 -, R 2
R
3 N-O-CO-CH2-,
R
2
N(OH)-CO-CH
2 -, where R 2 and
R
3 independently of one another are H, Ci-C-alkyl,
C
3 -Ce-cycloalkyl, C3-Cs-cycloalkyl-Ci-C3-alkyl, or benzyl, or
R
2 and R 3 together form a C 4
-C
6 -alkylene chain, 20 in which
R
1 is: H-, Ci-C 1 6 -alkyl-, H 3 C-[O-CH2-CH2]q (q = 1-4),
C
1 0 -tricycloalkyl-, Clo-tricycloalkyl-CH2-,
C
3 -Ce-cycloalkyl-, 25 C 3 -Cs-cycloalkyl-Ci-C3-alkyl-, where a phenyl ring can be fused to the cycloalkyl ring, pyranyl-, piperidinyl-, aryl or phenyl-Ci-C3-alkyl-, where except for H all radicals mentioned can optionally carry up to 4 identical or different radicals selected from Ci-C 4 -alkyl, CF 3 , F, Cl, NO 2 , HO or 30 Ci-C 4 -alkoxy radicals, or
R
1 is (2-oxo-1,3-dioxolen-4-yl)methyl-, which can be substituted in the 5-position by Ci-C 16 -alkyl or aryl, or 35
R
1 is: R4-C(O)O-C(R 5 )2-, R 4
-C(O)NR
2
-C(R
5 )2-, where R 4 can be Ci-C-alkyl-,
C
3 -CS-cycloalkyl-Ci-C3-alkyl-,
C
3 -CS-ycloalkyl-,
CI-C
4 -alkyloxy-,
C
3- C 8-cycloalkyl-Ci-C3-alkyloxy-,
C
3- CS-cycloalkyloxy-, aryl- or phenyl-Ci-C 6 -alkyl-, the two 40 radicals R 5 independently of one another are H, CH 3 or C 2
A
5 , and R 2 has the meaning indicated above,
R
6 00C-Ci-C 6 -alkyl, R6R 7
N(O)C-C
1 -C6-alkyl-, R 6
R
7
N-C
2
-C
6 -alkyl-, and in which R 6 and R 7 independently of one another are H or
C
1
-C
6 -alkyl, or 45 4 if R 1 is R6R7N(O)C-Ci-C6-alkyl-,
R
6 and R 7 together form a
C
4
-C
6 -alkylene chain, or A is: Ci-C 4 -alkyl-SO2-(CH 2 )2-6- , HO 3 S-(CH2)4-6-, 5-tetrazolyl-(CH 2 )1-6-,
C
1
-C
4 -alkyl-O-(CH 2 )2-6-,
R
2
R
3 N-(CH2)2-6-,
R
2 S-(CH 2 )2-6 R2R3NSO2-(CH2)2-6-, HO-(CH2)2-6-, 10 B is /
(CH
2 )p -N-
-CO
15 1 8 R p isO,1, 2 20 RB is H-, R 1 0 00C- where
R
10 = C 1
-
1 6 -alkyl-, phenyl-,
C
3
-C
8 -cycloalkyl-, phenyl-Cl-C4-alkyl-,
R
1 1 C(O)-O-CH2-, R11C(O)-O-CH(CH3)-, where
R
1 1 can be Cl-C 4 -alkyl-, phenyl-, benzyl-,
C
3
-C
8 -cycloalkyl- or cyclohexyl-CH2 25 R 9 is C3-8-cycloalkyl-, which can carry up to four identical or different
C
1
-
4 -alkyl radicals, D is: 30 N N ( I0 0 35 G is: -H, -OH, -OR 1 2 , in which 40 R 12 is: -Ci-8-alkyl, -C3-C8-cycloalkyl, -Ci-C 3 -alkyl-C3 -Cs-cycloalkyl, -aryl or -Ci-C 6 -alkylphenyl, which can optionally carry up to three Ci-C 4 -alkyl,
CF
3 , F, Cl, or Ci-C 4 -alkoxy radicals, K is: H, 45 or G and K together form a -C(0)O-group, 5 their configurational isomers, tautomers and their salts with physiologically tolerable acids, where the following applies: 5 (i) if D = (II) or (III) and G = -H, -OH, -OR 12 , in which
R
12 is: -Cl-C 8 -alkyl, -Ci-C 3 -alkyl-C 3
-C
8 -cycloalkyl, -aryl or 10 -Ci-C 6 -alkylphenyl, which can optionally carry up to three Ci-C 4 -alkyl, CF 3 , F, Cl, or Ci-C 4 -alkoxy radicals K is: H, or G and K together form a -C(0)O-group, then A and B have the 15 following meanings: A: R 1 0OC-CH2-, R 1 0OC-CH 2
-CH
2 -, R 1 0OC-CH(CH 3 )-, HO-CH 2
-CH
2 -,
R
2 aR 3 aN(0)C-CH 2 -, R 2
R
3 N-0-CO-CH 2 -, R 2
N(OH)-CO-CH
2 -, where R 2 and R 3 independently of one another ,are H, Ci-C-alkyl,
C
3 -C-cycloalkyl or benzyl or R 2 and R 3 together form a 20 C 4
-C
6 -alkylene chain, R 2 a is equal to H and R 3 a is C 5 -C-alkyl,
C
3 -CB-cycloalkyl or benzyl; in which 25 R 1 is: C 5
-C
16 -alkyl-, H 3 C-[O-CH2-CH2]q (q = 1-4),
C
1 0 -tricycloalkyl-, Cio-tricycloalkyl-CH 2 -, C 3
-C
8 -cycloalkyl-,
C
3-
C
8 -cycloalkyl-Cl-C3-alkyl-, where the phenyl ring can be fused to the cycloalkyl ring, pyranyl-, piperidinyl-, or aryl-, where except for H all radicals mentioned can 30 optionally carry up to four identical or different radicals selected from Ci-C 4 -alkyl, CF 3 , F, Cl, NO 2 , HO or Ci-C 4 -alkoxy radicals, or
R
1 is 2-oxo-1,3-dioxolen-4-yl)methyl- which can be substituted in the 5-position by Ci-C 16 -alkyl or aryl, 35 or
R
1 is: R 4
-C(O)O-C(R
5
)
2 -, R 4
-C(O)NR
2
-C(R
5
)
2 -, where R 4 can be Ci-C 4 -alkyl-, C 3
-C
8 -cycloalkyl-Ci-C 3 -alkyl-, C 3 -C-cycloalkyl-, 4.0 Cl-C 4 -alkyloxy-, C 3 -Cs-cycloalkyl-Ci-C 3 -alkyloxy-,
C
3 -C-cycloalkyloxy-, aryl- or phenyl-Ci-C 6 -alkyl-, the two radicals R 5 independently of one another are H, CH 3 or C 2
H
5 , and R 2 has the meaning indicated above,
R
6 00C-Ci-C 6 -alkyl-, R 6
R
7 N(0).C-C-C 6 -alkyl-, R 6
R
7
N-C
2
-C
6 -alkyl-, 45 and in which R 6 and R 7 independently of one another are H or Ci-C6-alkyl, or 6 if R 1 is R 6
R
7 N(0)C1.C-C 6 -alkyl-,
R
6 and R 7 together form a C4-C6-alkylene chain, or A is: 5 Ci-C 4 -alkyl-SO 2
-(CH
2 )2-6- , HO 3 S-(CH2)4-6-, 5-tetrazolyl-(CH 2 )1-6-, Ci-C 4 -alkyl-0-(CH 2
)
2
-
6 -, R 2
R
3
N-(CH
2
)
2
-
6 -, R 2
S-(CH
2
)
2
-
6 -,
R
2
R
3
NSO
2
-(CH
2
)
2
-
6 -, HO-(CH 2
)
2
-
6 -, 10 B is /R 2CHp i5 1 8 H R p isO,1,2 .0 R 8 is H-, R 1 0 00C- where R 1 0 = C1-1 6 -alkyl-, phenyl-, C3-C8-cycloalkyl-, phenyl-Ci-C4-alkyl-,
R
1 1 C(0)-0-CH 2 -, R11C(O)-O-CH(CH 3 ) -, where R 1 1 can be Ci-C 4 -alkyl-, phenyl-, benzyl-, C3-C8-cycloalkyl- or cyclohexyl-CH 2 -, 5 R 9 is C3--cycloalkyl-, which can carry up to four identical or different
C
1
-
4 -alkyl radicals, ia) 0 Preferred compounds of the formula I in i) are those in which A, B, D, G and K have the following meanings: A is: R 1 00C-CH 2 -, R1OOC-CH 2
-CH
2 -, ROOC-CH(CH 3 )-, 5 in which
R
1 is: C5-C1 6 -alkyl-, H3C-[0-CH2-CH2]q (q = 1-4), Cio-tricycloalkyl-, Clo-tricycloalkyl-CH2-, C3-Cq-cicloalkyl-, C3-Cg-cycloalkyl-Ci-C 3 -alkyl-, where a phenyl ring can be fused to the cycloalkyl ring, pyranyl- piperidinyl-, where except for H all radicals mentioned can optionally carry up to four identical or different radicals selected from CH 3 ,
CF
3 , F, Cl, HO or methoxy radicals, or
R
1 is ( 2 -oxo-1,3-dioxolen-4-yl)methyl-, which can be substituted in the 5-position by Ci-C 3 -alkyl or aryl, or 7
R
1 is: R 4 -C(O)O-C(Rs) 2 -, where R 4 Ci-C 4 -alkyl-, C3-Cs-cycloalkyl-, Ci-C 4 -alkyloxy-, C3-Cs-cycloalkyl-Cl-C 3 -alkyloxy-, C3-C8-cycloalkyloxy-, or aryl- the two radicals R 5 independently of one another are H, CH 3 or C 2
H
5 , 5 R 6 00C-Ci-C 6 -alkyl-, R 6
R
7 N(O)C-Ci-C 6 -alkyl-, R 6
R
7
N-C
2
-C
6 -alkyl-, and in which R 6 and R 7 independently of one another are H or Ci-C 6 -alkyl or, if R 1 is R 6
R
7 N(O)C-Ci-C 6 -alkyl-, R 6 and R 7 together form a
C
4
-C
6 -alkylene chain, 10 B is 9 15
-N--C-CO
1 8 H R p is 0,1
R
8 is H-, R 10 00C- and R 10 = Ci--alkyl-, phenyl-, C3-Ce-cycloalkyl-, phenyl-Ci-C 4 -alkyl-,
R
9 is C3-8-cycloalkyl-, which can carry up to four identical or different C 1 -4-alkyl radicals, 5 D = (II) and G = -H, -OH, -O-Ci-C 8 -alkyl, K is: H O or G and K together form a -C(0)O-group. (ii) if D = (II) or (III) and G = -OR 12 , 5 in which R12 is: -CS-C8-alkyl, -C3-C-cycloalkyl, -Ci-C 3 -alkyl-C 3 -C8-cycloalkyl, -aryl or -C 1 -C6-alkylphenyl, which can optionally carry up to three Ci-C 4 -alkyl, CF 3 , F, Cl, or Ci-C4-alkoxy radicals, K is: H, or G and K together form a -C(O)O-group, then A and B have the following meanings: 8 A: R 1
OOC-CH
2 -, RIOOC-CH 2 -CH2-, R 1 0OC-CH(CH 3 )-, R 2 aR 3 aN(0)C-CH 2 -, where R 2 a and R 3 a independently of one another are H, CI-C 6 -alkyl,
C
3 -CS-cycloalkyl or benzyl or R 2 a and R 3 a together form a
C
4
-C
6 -alkylene chain, 5 in which
R
1 is: H-, Ci-C 4 -alkyl- or phenyl-Ci-C 4 -alkyl-, where except for H all radicals mentioned can optionally carry up to four 10 identical or different radicals selected from Ci-C 4 -alkyl,
CF
3 , F, Cl, N02, HO or Ci-C 4 -alkoxy radicals, B, p and R8, R 9 , R 10 and R 11 have the meaning indicated in i). 15 iia) Preferred compounds of the formula I in ii) are those in which A, B, D, G and K have the following meanings: 20 A is: R 1 0OC-CH 2 -, RIOOC-CH 2
-CH
2 -, RIOOC-CH(CH 3 )-, R 2 aR 3 aN(O)C-CH 2 -, where R 2 a and R 3 a independently of one another are H, Ci-C 6 -alkyl, C 3 -C8-cycloalkyl or benzyl, or R 2 a and R 3 a together form a C 4
-C
6 -alkylene chain, 25 in which
R
1 is: H-, Ci-C 4 -alkyl- or phenyl-Ci-C 4 -alkyl-, where except for H all radicals mentioned can optionally carry up to four identical or different radicals selected from CH 3 , CF 3 , F, Cl, 30 HO or methoxy radicals, B is R 35
(CH
2 )p
-N---CO
1 8 H R 40 p is0,1
R
8 is H-, R 10 00C- and R 10 = Ci- 16 -alkyl-, phenyl-, C 3
-C
8 -cycloalkyl-, benzyl-, 45 and R 9 has the meaning indicated in i) D = (II) G = -OR 1 2
,
9 in which
R
12 is: -C 5
-C
8 -alkyl, -C 3 -C8-cycloalkyl, -Ci-C 3 -alkyl-C 3 -Ce-cycloalkyl, -aryl or -Ci-C 6 -alkylphenyl, which can optionally carry up to three CH 3 -, CF 3 -, F-, Cl-, or 5 methoxy radicals, K is: H, or G and K together form a -C(0)O-group. Particularly preferred prodrugs of the formula I are those where 10 A, B, D, G and K have the following meanings: A is: R10OC-CH2-, R10OC-CH 2
-CH
2 -, R 1 00C-CH(CH 3 )-, in which 15
R
1 is: C 5 -Cio-alkyl-, C 4
-C
7 -cycloalkyl-, C 4
-C
7 ... cycloalkyl-CH 2 -, where all radicals mentioned can optionally carry up to four identical or different radicals selected from CH 3 - and methoxy-, 20 B is /F
(CH
2 )P 25
-N-C-CO
1 8 H R p is 0,1, 30
R
8 is H-,
R
9 is C 4
-
7 -cycloalkyl-, which can carry up to four identical or different methyl or ethyl radicals 35 D is: No 40 0 G is: -OH, K is.: H. 45 10 e aforementioned compounds belong to three groups of substances: The first group comprises prodrugs of thrombin inhibitors (e.g. G equals -OH, -OR 12 ) which is a substance to only a negligible antithromotic effect, which, however, are converted in the organism into the active substance (G equals H). These compounds are included in all claims. The advantage of the prodrugs lies in their improved pharmacokinetic and pharmacodynamic behaviour in the organism. Compounds wherein G equals -OH, -OR 1 2 , and simultaneously A equals
R'OOC-CH
2 -, R 1
OOC-CH
2
-CH
2 -, R 1 0OC-CH(CH 3 )- etc. are double prodrugs which are converted in the organism into the respective drug (G equals -H, A equals HOOC-CH 2 - etc.) by converting both prodrug groups. The second group comprises prodrugs of thrombin inhibitors which show already as a prodrug a thrombin-inhibiting effect (e.g. A equals R'OOC-CH 2 -, R'OOC-CH 2
-CH
2 -, R 1 0OC-CH(CH 3 )- etc. in combination with G equals -H) . The effective substance formed in the organism (drug; A equals HOOC-CH 2 -, HOOC-CH 2
-CH
2 -, HOOC-CH(CH 3 )- etc., G equals -H) shows also a thrombin-inhibiting effect. These are in part compounds of claims 1 (i), 2 and 5. The advantage of these prodrugs lies also in their improved pharmacokinetic and pharmacodynamic behaviour in the organism. The third group comprises thromin inhibitors which per se show the antithrombotic effect (e.g. A equals C 1
-
4 -alkyl-SO 2
-(CH
2
)
2
-
6 -, H0 3
-S
(CH
2 )2-6-, 5-tetrazolyl-(CH 2 )1-6-, C 1
-
4 -alkyl-O-(CH 2 )2-6-, R2 R 3N- (CH 2 ) 2-6, R 2S-(CH 2 )2- 6 -, R2 R 3NS 2
-(CH
2
)
2
-
6 -, in combination with G equals -H). Such compounds are included in claim 1 (i).
11 The following compounds, their configurational isomers, tautomers, and salts with physiologically tolerable acids are furthermore the subject of this invention: 5 HOOC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico
H
3 CO-OC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(OH) ]-pico EtO-OC-CH 2 -( D) -Cha-Pyr-NH-3-[ 6-am-(OH) ]-pico nPrO-OC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico iPrO-OC-CH 2 -(D) -Cha-Pyr-NH-3-[ 6-am-(OH) ]-pico 10 nBuO-OC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico iBuO-OC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico tBuO-OC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico BnO-OC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico
HOOC-CH
2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 15 H 3
CO-OC-CH
2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico EtO-OC-CH 2 -(D)-Chg-Pyr-NH-3-[-6-am-(OH)]-pico nPrO-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico iPrO-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico nBuO-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 20 iBuO-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico tBuO-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico
H
3
CO-OC-CH
2 -(D)-Cha-Pyr-NH-3-[6-am-(H)]-pico EtO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(H)]-pico nPrO-OC-CH 2 -(D) -Cha-Pyr-NH-3-[ 6-am-( H) ] -pico 25 iPrO-OC-CH 2 -( D) -Cha-Pyr-NH-3-[6-am-(H)]-pico nBuO-OC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(H)]-pico iBuO-OC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(H)]-pico tBuO-OC-CH2-( D) -Cha-Pyr-NH-3-[ 6-am- (H) ]-pico
H
3 CO-OC-CH2-( D) -Chg-Pyr-NH-3-[ 6-am-(H)]-pico 30 EtO-OC-CH 2 -( D) -Chg-Pyr-NH-3-[ 6-am-(H)] -pico nPrO-OC-CH 2 -( D) -Chg-Pyr-NH-3-[6-am-(H)]-pico nBuO-OC-CH2-( D) -Chg-Pyr-NH-3-[6-am-(H)]-pico iBuO-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(H)]-pico tBuO-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(H)]-pico 35 HOOC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(O-Allyl)]-pico
H
3
CO-OC-CH
2 -( D) -Chg-Pyr-NH-3-[ 6-am-(OCH 3 ) ]-pico iPrO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OCH 3 )]-pico 40 45 12 The following substances are particularly preferred: 1. CH 3 - (CH 2
)
1 5 0-OC-CH 2 -(D) -Cha-Pyr-NH-3-[ 6-am-(OH) ]-pico 2. CH 3
-(CH
2
)
1 o0-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico 5 3. Piperidin-1-yl-O-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico 4. Piperidin-4-yl-O-OC-CH 2 -( D) -Cha-Pyr-NH-3-[6-am-(OH) ] -pico 5. Decalinyl-O-OC-CH 2 -(D) -Cha-Pyr-NH-3-[ 6-am-(OH) ] -pico 6. tBu-cHexyl-O-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico 7. Ada-CH 2 -0-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico 10 8. 4-tBu-cHexyl-CH2 -0-OC-CH 2 -(D)-Cha-Pyr-NH-3-[ 6-am-(OH) ]-pico 9. CHept-0-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico 10. 3,3,5,5-TetraMe-cHex-O-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico 11. 4-Pyranyl-O-OC-CH 2 -(D) -Cha-Pyr-NH-3-[ 6-am- (OH) ] -pico 12. 2, 4-DiMe-3-Pentyl-O-OC-CH 2 -(D) -Cha-Pyr-NH-3-[ 6-am-(OH) ]-pico 13. 1-Me-cPentyl-O-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico 15 14. a,a-Di-cHex-CH2-O-OC-CH 2 -( D) -Cha-Pyr-NH-3-[ 6-am-(OH) ]-pico 15. - tBu-N-OC-CH 2 -(D) -Cha-Pyr-NH-3-[ 6-am-(OH) ]-pico 16. nHex-N-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico 17. HO-NH-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH.)]-pico 18. cPent-CH 2 -0-OC-CH 2 -(D) -Cha-Pyr-NH-3-[ 6-am- (OH) ] -pico 20 19. cHex-CH 2 -0-OC-CH 2 -(D) -Cha-Pyr-NH-3-[ 6-am-(OH) ]-pico 20. cHex-N(OH)-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico 21. iPr-N(OH)-OC-CH 2 -( D) -Cha-Pyr-NH-3-[ 6-am-(OH )]-pico 22. CH3-N(OH)-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico 23. H2N-0-OC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(OH)i-pico 24. C(CH2) 5N-0-OC-CH 2 -(D) -Cha-Pyr-NH-3- [ 6-am-(OH) ]-pico 25 25. N-Me-4-Pip--OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico 26. (CH 3 ) 3C-CO2-CH 2 -0-OC-CH 2 -(D) -Cha-Pyr-NH-3-[ 6-am-(OH) ]-pico 27. (CH3) 3C-CO2-CH2-0-OC-CH2- (D) -Cha-Pyr-NH-3-[(6-am- (OH) ]-pico 28. (CH3) 3C-CO2-CH2-0-OC-CH2- (D) -Cha-Pyr-NH-3- [6-am- (OH)])-pico 29. (CH 3 ) 3C-CO2-C-C-OCCH 2 -(D)-Cha-Pyr-NH-3-[ 6-am-(OH) ]-pico 30 30 . -Cyclopropylmethyl--OC-CH 2 -(D) -Cha-Pyr-NH-3-[ 6-am-(OH) J pico 31. 1, 3-Dioxol-2-on-4-enyl-O-OC-CH 2 -( D) -Cha-Pyr-NH-3-[6-am (OH)]-pico 32. Cyclopropylmethyl--OC-CH 2 -(D)-Chg-Pyr NH-3-[6-am-(OH) ]-pico 35 33. 1, 3-Dioxol-2-on-4-enyl-O-OC-CH 2 -( D) -Chg-Pyr-NH-3-[ 6-am (OH)]-pico 34. Cyclopropylmethyl-O-OC-CH2 -(D)-Cha-Dep-NH-3-[6-am (OH)]-pico 35. 1,3-Dioxol-2-on-4-enyl-O-OC-CH2 -(D)-Cha-Dep-NH-3-[6-am (OH)]-pico :0 36. Cyclopropylmethyl-O-OC-CH 2 -(D)-Chg-Dep-NH-3-[6-am (OH)]-pico 37. 1, 3-Dioxol-2-on-4-enyl-O-OC-CH 2 -(D) -Chg-Dep-NH-3-[ 6-am (OH)]-pico 38. CH3- (CH2)150-OC-CH2- (D) -Chg-Pyr-NH-3- [6-am- (OH)])-pico 39. CH3(CH2) 100-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 5 40. Piperidin-1-yl-O-OC-CH2-(D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico 42. -Piperidin-4-yl-O-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH )]-pico 4.Decalinyl-O-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 13 43. tBu-cHexyl--OC-CH2-(D )-Chg-Pyr-NH-3-[6-am-(OH)]-pico 44. Ada-CH 2 -0-OC-CH 2 - (D) -Chg-Pyr-NH-3-[ 6-am-(OH) I -pico 45. 4-tBu-cHexyl-CH 2 -0-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(OH) ]-pico 46. cHept-O-OC-CH 2 -( D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico 5 47. 3,3,5,5-TetraMe-Hex-O-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am (OH)]-pico 48. 4-Pyranyl-O-OC-CH 2 -(D) -Chg-Pyr-NH-3-[ 6-am-(OH) 3-pico 4.2, 4-Dime-3-entyOOC-.CH 2 ..(D) -Chg-Pyr-NH-3-[ 6-am-(OH) 3 Pico 50. 1-Me-cPentyl-O-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 10 51. a, a-Di-cHex-CH 2 -0-OC-CH 2 -( D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pica 52. tBu-N-OC-CH 2 -(D) -Chg-Pyr-NH-3-[6-am-(OH) ]-pico 53. nHex-N-OC-CH 2 -( D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico 54. HO-NH-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 55. cPent-CH 2 -0-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 15 56. cHex-CH 2
-O-OC-CH
2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 57. cHex-N( OH) -OC-CH 2 -(D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico 58. iPr-N(OH)-OC-CH2-(D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico 59. CH3-N(OH)-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 60. H2N-0-OC-CH 2 - (D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico 61. c(CH 2 )5N-0-C-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 20 62. N-Me-4-Pip--OC-CH 2 (D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 63. (CH 3 ) 3C-CO2-CH 2 -0-OC-CH 2 - (D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico 64. (CH 3 ) 3C-CO2-CH 2 -0-C-CH 2 - (D) -Chg-Pyr-NH-3- [ 6-am- (OH)] -pico 65. (CH 3 ) 3C-CO2-CH2-O-C-CH 2 -(D) -Chg-Pyr-NH-3-[ 6-am- (OH) ]-pico 66. (CH 3 )3C-CO2-CH 2 -0-OC-CH 2 -(D) -Chg-Pyr-NH-3-f6-am-(OH)]-pico 25 67. nOctO-OC-CH 2 -(D) -Chg-Pyr-NH-3-[ 6-am-(OH) -pico 68. ciex-O-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 69. neoPentO-OC-CH 2 -(D) -Chg-Pyr-NH-3-[ 6-am-( OH) ]-pico 70. CH 3 -0 (CH 2 ) 20-OC-CH 2 -( D) -Chg-Pyr-NH-3-[ 6-am- (OH) ]-pico 71. CH3-[O(CH 2 )2]20-OC
-
CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 72. cHex-CH2-0-OC-CH2-(D)-Chg-Pyr-NH-3-[6-a-m-(OH)]-pico 30 73 . cOctO-OC-CH2-( D )-Chg-Pyr-NH-3-[ 6-am-(OH )]-pico -- 74. 4-Me-cHexyl--OC-CH 2 -( D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico 75. nHexO-OC-CH 2 -(D)-Chg-Pyr-NH-3- [6-am-(OH)]-pico 76. cPentO-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 77. 4-MeO-cHexyl--OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 78. -- 0-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 79. 2-Me-1,3-Dioxane-5-0-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]pico 80. 2,4-DiMe-3-Pent--OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 81. 2-Indan-O-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)] -pico 82. 2,6-DiMe-4-Hept-O-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico O 83. Pyrr-N-CO-(CH 2 ) 3-0-OC-CH 2 - (D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico 84. cHex-N-CO-CH 2 -0-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 85. CH-3-(CH2)p1-OC-CH2-(D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 86. C 3-(CH2)100-OC-CH2-(D)-Chg-Dep-NH-3-[6-am-(OH)I-pico 87. Piperidin-1-yl--OC-CH 2 -(D)-Chg-Dep-NH-3-[6-am-(OH)i-pico 88. Piperidin-4-yl-0-OC-CH 2 -(D) -Chg-Dep-NH-3-[ 6-am-(OH) ]-pico 89. Decalinyl-0-OC-C
H
2-(D)-Chg-Dep-NH-3-[6-am-(OH)]-ico 90. tBu-cHexyl-O-OC-CH 2 -(D)-Chg-Dep-NH-3-[6-am-(OH) ]-pico 91. A 3a-CH2-0-OC-CH2-(D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 14 92. 4-tBu-cHexyl-CH 2 -0-OC-CH2-(D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 93. cHept-O-OC-CH2-(D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 94 3,3,5,5-TetraMe-cHex-O-OC-CH 2 -(D)-Chg-Dep-NH-3-[6-am-(OH)] pico 5 95. 4-Pyranyl-O-OC-CH2- (D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 2,4-DiMe-3-Pentyl-O-OC-CH 2 -(D)-Chg-Dep-NH-3-[6-am-(OH)] 96. .ic ___pico. 97. 1-Me-cPentyl-O-OC-CH 2 -( D) -Chg-Dep-NH-3-( 6-am-(OH) )-pico 98. a, a-Di-cHex-CH 2 -0-OC-CH2-(D) -Chg-Dep-NH-3-[ 6-am-(OH) ] -pico 99. tBu-N-OC-CH2- (D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 10 100. Hex-N-OC-CH 2 -(D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 101. HO-NH-OC-CH 2 -(D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 102. cPent-CH 2 -0-OC-CH2- (D) -Chg-Dep-NH-3- (6-am- (OH) ] -pico 103. cHex-CH 2 -O-OC-CH2- (D) -Chg-Dep-NH-3- [ 6-am-(OH) ) -pico 104. cHex-N(OH)-OC-CH2-(D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 105. iPr-N(OH)-OC-CH 2 -(D)-Chg-Dep-NH-3-[6-am-(.OH) ]-pico 106. CH 3
-N(OH)-OC-CH
2 -(D)-Chg-Dep-NH-3-[6-am-(OH) ]-pico 107. H 2 N-0-OC-CH 2 -(D)-Chg-Dep-NH-3-[6-am-(OH))-pico 108. c(CH 2
)
5 N-0-OC-CH 2 -(D)-Chg-Dep-NH-3-(6-am-(OH) ]-pico 109. N-Me-4-Pip-O-OC-CH2- (D) -Chg-Dep-NH-3- [6-am- (OH) ]-pico 110. (CH 3
)
3
C-CO
2
-CH
2
-O-OC-CH
2 -(D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 20 111. (CH 3
)
3
C-CO
2
-CH
2
-O-OC-CH
2 -(D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 112. (CH 3
)
3
C-CO
2
-CH
2 -0-OC-CH 2 -(D)-Chg-Dep-NH-3-(6-am-(OH)]-pico 113. (CH 3
)
3
C-CO
2
-CH
2 -0-OC-CH2-(D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 114. CH 3
-(CH
2 )150-OC-CH 2 -(D) -Cha-Dep-NH-3- (6-am-(OH) ]-pico 115. CH 3
-(CH
2
)
10 0-OC-CH 2 -(D)-Cha-Dep-NH-3-[6-am-(OH) )-pico 25 116. Piperidin-1-yl-O-OC-CH2-(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 117. Piperidin-4-yl-O-OC-CH2-(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 118. Decalinyl-O-OC-CH 2 - (D) -Cha-Dep-NH-3-[ 6-am-(OH) ]-pico 119. tBu-cHexyl-O-OC-CH 2 -(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 120. Ada-CH 2 -0-OC-CH 2 -(D) -Cha-Dep-NH-3-( 6-am- (OH) ]-pico 121. 4-tBu-cHexyl-CH2--OC-CH2- (D) -Cha-Dep-NH-3- [ 6-am-(OH) ]-pico 30 122. cHept-O-OC-CH2-(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 123. , 3,5,5-TetraMe-cHex-O-OC-CH2-(D) -Cha-Dep-NH-3-[ 6-am-(OH)] pico 124. 4-Pyranyl-O-OC-CH2- (D) -Cha-Dep-NH-3- (6-am- (OH) ]-pico 2,4-DiMe-3-Pentyl-O-OC-CH2-(D)-Cha-Dep-NH-3-[6-am-(OH)] 35 125. .ic pica 126. 1-Me-cPentyl-O-OC-CH2-(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 127. a,a-Di-cHex-CH 2
-O-OC-CH
2 -(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 128. tBu-N-OC-CH 2 -(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 129. nHex-N-OC-CH 2 -(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 130. HO-NH-OC-CH 2 -(D)-Cha-Dep--NH-3-[6-am-(OH)]-pico 40 131. cPent-CH 2 -0-OC-CH2-(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 132. cHex-CH 2 -0-OC-CH 2 -(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 133. cHex-N(OH)-OC-CH 2 -(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 134. iPr-N(OH)-OC-CH 2 -(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 135. CH 3
-N(OH)-OC-CH
2 -(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 136 . H 2 N-0-OC-CH 2 -(D)-Cha-Dep-NH-3-[6-am-(OH) ]-pico 137. c(CH 2
)
5 N-0-OC-CH 2 -(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 138. N-Me-4-Pip-O-OC-CH 2 -(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 139. (CH 3
)
3
C-CO
2
-CH
2 -0-OC-CH 2 -(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 15 140. (CH 3 ) 3C-CO2-CH2-0-OC-CH2- (D)-Cha-Dep-NH-3-6-am-(OH) ] -pico 141. (CH 3 ) 3C-CO2-CH2-0-OC-CH2- (D)-Cha-Dep-NH-3-[6-am-(OH) ] -pico 142. (CH 3 ) 3
C-CO
2
-CH
2 -0-OC-CH 2 -(D) -Cha-Dep-NH-3-[ 6-am-(OH) ] -pico 143. cHN 4
C-CH
2 -(D)-Cha-Pyr-NH-3-[6-am-(OH) )-pico 14 4. cHN 4
C-CH
2 -(D) -Chg-Pyr-NH-3-[ 6-am-(OH) ] -pico 145. NH 2
-CH
2
-CH
2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico 146. NH2-CH2-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 147. NH 2
-CH
2 -CH2-(D)-Chg-Dep-NH-3-[6-am-(OH)]-pico 148. (CH 3
)
2
N-CH
2
-CH
2 -(D)-Cha-Pyr-NH-3-[6-am-(OH) ]-pico 149. (CH3) 2N-CH2-CH2-(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 10 150. (CH3 2N-CH2-CH2-(D)-Cha-Dep-NH-3-[6-am-(OH)]-pico 151. CH 3
-NH-SO
2
-CH
2
-CH
2 -(D)-Cha-Pyr-NH-3-[ 6-am-(OH) ]-pico 152. CH3-NH-SO2-CH2-CH2- (D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 153. CH3-NH-SO2-CH2-CH2- (D)-Cha-Dep-NH-3-6-am-(OH.)]-pico 154. H 2
N-SO
2 CH2-CH 2 -(D)-Cha-Pyr-NH-3-[ 6-am-(OH) ] -pico 15 155. H 2
N-SO
2
-CH
2
-CH
2 -(D)-Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico 156m, H 2
N-SO
2
-CH
2
-CH
2 -(D) -Cha-Dep-NH-3-[ 6-am- (OH) ]-pico 157. HO-OC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(-COO-)]-pico 158. MeO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(-COO-)]-pico 159. HO-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(-COO-) ]-pico 160. MeO-OC-CH2-(D)-Chg-Pyr-NH-3-[6-am-(-COO-)]-pico 20 161. EtO-OC-CH 2 - ( D) -Cha-Pyr-NH-3-[ 6-am-( -COO-) ]-pico 162. cHexO-OC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(-COO-)] -pico List of abbreviations: 25 Adaala: Adamantylalanine Adagly: Adamantylglycine AIBN: Azobisisobutyronitrile Ac: Acetyl 30 Ala: Alanine am: Amidino Asp: Aspartic acid Aze: Azetidinecarboxylic acid Bn: Benzyl 35 Boc: tert-Butyloxycarbonyl Bu: Butyl Cbz: Benzyloxycarbonyl Cha: Cyclohexylalanine Chea: Cycloheptylalanine 40 Cheg: Cycloheptylglycine Chg: Cyclohexylglycine Cog: Cyclooctylglycine Cpa: Cyclopentylalanine Cpg: Cyclopentylglycine 45 DC: Thin-layer chromatography DCC: Dicyclohexylcarbodiimide Dch: Dicyclohexylalanine 16 Dcha: Dicyclohexylamine DCM: Dichlormethane Dep: 4,5-Dehydropipecolic acid DMF: Dimethylformamide 5 DIPEAt Diisopropylethylamine Et: Ethyl Eq: Equivalent Gly: Glycine ham: Hydroxyamidino 10 HOSucc: Hydroxysuccinimide HPLC: High-performance liquid chromatography iPr: Isopropyl Lsg: Solution Me: Methyl 15 bb-Me 2 Cha: 2-Amino-3-cyclohexyl-3-methylbutyric acid or bb-Dimethylcyclohexylalanine 4-MeCha: (4-Methylcyclohex-1-yl)alanine g-MeCha: (1-Methylcyclohex-1-yl)alanine 20 3,3-Me 2 Cha: (3,3-Dimethylcyclohex-1-yl)alanine 4-MeChg: (4-Methylcyclohex-1-yl)glycine 3, 3-Me 2 Chg: (3, 3-Dimethylcyclohex-1-yl) glycine MPLC: Medium-pressure liquid chromatography MTBE: Methyl-tert-butyl ether 25 NBS: N-Bromsuccinimide Nog: Norbornylglycine Oxaz: Oxazole Ph: Phenyl phe: Phenylalanine 30 Pic: Pipecolic acid pico: Picolyl PPA: Propylphosphonic anhydride pro: Proline Py: Pyridine 35 Pyr: 3, 4-Dehydroproline pyraz: Pyrazole pyrr: Pyrrole RT: Room temperature RP-18 Reversed phase C-18 40 t: Tertiary tBu: tertiary-Butyl tert: Tertiary TBAB: Tetrabutylammonium bromide TEA:. Triethylamine 45 TFA: Trifluoroacetic acid TFAA: Trifluoroacetic anhydride thiaz: Thiazole 17 thioph: Thiophene TOTU: O-( Cyanoethoxycarboflylmethylene )amino-] N, N, N' ,N 'tetramethylurofl1u1 tetrafluoroborate 5 Z: tenzyloxycarbonyl nPent: n-Pentyl neoPent: neo-Pentyl (2, 2-dimethyl-1-propyl) n~ex: n-Hexyl cHex: Cyclohexyl 10 c-Pent Cyclopentyl cHN4C- Tetrazolyl- (3-tetrazolyl- or 5-tetrazolyl) c (CE 2 ) N- N-Piperidilyl nOct: n-Octyl 15 O-p-Me-Bl: p-MethylbefzlZ~oxy N-Me-4-Pip-OH N-Methyl-4-piperidilyl alcohol MeO-tetraethoxy: Tetraethylele glycolyl monomethyl ether
CH
3 -(CH2)15O: Hexadecyloxy
CE
3 - (CE 2 ) 100: Undecyloxy 20 4-Pip-O: 4-Piperidiflyloxy 1-Pip-O: 1-Piperidinyloxy tBu-cHexyl-0: 4-tert-Butyl-cyclohexyloxy Ada-CH2-0: 1-Adamfafthylmethyloxy 4...tBuc~exylCH2-O: 4-tert-ButyJlcyclohexylmethyloxy 25 cHept-O: Cycloheptyloxy 3,3,5, 5-tetraMe-cHex-O: 3,3,5, 5-Tetramethylcyclohexalyloxy 4-Pyranyl-O: 4-Pyraflyloxy nPrO: n-Propyloxy nBu-O: n-Butyloxy 30 iBu-O: t-Biityloxy 2, 4-dil~e-3-Peftyl-O: 1-Isopropyl-2-methylpropyloxy 1-Me-cPentyl-O: 1-Methyl-cyclope11tyloxy a, a-di- cHex-CH2-0: Dicyclohexylmethoxy tBu-N: tert-Butylamilo 35 nHex-N: n-Hexylamilo
H
2 N-3-[6-am- (-COO-) ]-pico: 3-[5- (aminomethyl) -2-pyridinyl]-l, 2, 4-oxadiazol-5 one
H
2 N-3-[6-am- (OH) ]-pico: 5- (axinomethyl) -N '-hydroxy-2-pyridin carboximidamide 18 In the description and the claims, the following definitions apply to the individual substituents: The term "cycloalkyl" per se or as part of another substituent 5 includes saturated, cyclic hydrocarbon groups which contain the number of carbon atoms indicated and in which up to two CH2 groups can be replaced by oxygen, sulfur or nitrogen atoms.
C
3
-
8 -cycloalkyl relates to saturated alicyclic rings having 3 to 8 C atoms such as, for example, cyclopropyl, cyclobutyl, 10 cyclopentyl, cyclohexyl, 4-methylcyclohexyl, cyclohexylmethylene, cycloheptyl or cyclooctyl, pyrrolidine, piperidine, morpholine. Pure carbocycles are preferred. The term "alkyl" per se or as part of another substituent denotes 15 a linear or branched alkyl chain radical of the length indicated in each case, which can be saturated or unsaturated and in which up to 5 CH 2 groups can be replaced by oxygen, sulfur or nitrogen atoms. In this case, the heteroatoms are separated from one another by at least two carbon atoms. Thus C 1
.
4 -alkyl is, for 20 example, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 1-but-2-enyl, 2-butyl, CI- 6 -alkyl, for example, C 1
.
4 -alkyl, pentyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl or 3,3-dimethylbutyl. CI--alkyl is additionally the radicals 25 indicated for Ci_ 4 -alkyl, e.g. CI- 6 -alkyl, heptyl, 2-(2-methoxyethoxy)ethyl or octyl. The saturated alkyl chains without heteroatoms are preferred. The term "alkoxy" per se or as part of another substituent 30 denotes a linear or branched alkyl chain radical of the length indicated in each case, which can be saturated or unsaturated and is bonded to the respective parent compound via an oxygen atom. Thus C 1
.
4 -alkoxy is, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy, 2-methyl-2-propoxy, 2-methyl-l-propoxy, 1-butoxy, 35 2-butoxy. The term "aryl" per se or as part of another substituent includes mono-, bi- or tricyclic aromatic hydrocarbons, such as phenyl. naphthyl, tetralinyl, indenyl; fluorenyl, indanyl, anthracenyl, 40 phenanthrenyl. The compounds of the formula I can be present as such or in the form of their salts with physiological tolerable acids. Examples of acids of this type are: hydrochloric acid, citric acid, 45 tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric aid, succinic acid, hydroxysuccinic acid, sulfuric acid, glutaric 19 acid, aspartic acid, pyruvic acid, benzoic .acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine. The novel compounds of the formula I can be employed in the 5 following indications: - disorders whose pathological mechanism is based directly or indirectly on the proteolytic -action of thrombin, 10 - disorders whose pathological mechanism is based on the thrombin-dependent activation of receptors and signal transduction, - disorders which are accompanied by stimulation [e.g. by 15 PAI-1, PDGF (platelet-derived growth factor, P-Selectin, ICAM-1, Tissue factor] or inhibition (e.g. NO synthesis in smooth muscle cells) of gene expression in body cells, - disorders which are based on the mitogenic action of 20 thrombin, - disorders which are based on a thrombin-dependent contractility and permeability change in epithelial cells (e.g. vascular endothelial cells), 25 - thrombin-dependent, thromboembolic events such as deep vein thrombosis, pulmonary embolism, myocardial or cerebral infarct, atrial fibrillation, bypass occlusion, 30 - disseminated intravasal coagulation (DIC), - reocclusion and for the reduction of the reperfusion time in the case of comedication with thrombolytics such as streptokinase, urokinase, prourokinase, T-PA, APSAC, 35 plasminogen activators from the salivary glands of animals, and the recombinant and mutated forms of all these substances, - the occurrence of earlier-reocclusion and later restenosis 40 after PTCA, - the thrombin-dependent proliferation of smooth muscle cells, - the accumulation of active .thrombin in the CNS (e.g. in 45 Alzheimer's disease), 20 - tumor growth and against the adhesion and metastasis of tumor cells. In particular, the novel compounds can be employed for the 5 therapy and prophylaxis of thrombin-dependent thromboembolic events such as deep vein thromboses, pulmonary embolisms, myocardial or cerebral infarcts and unstable angina, and furthermore for the therapy of disseminated intravasal coagulation (DIC). They are furthermore suitable for combination 10 therapy with thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC and other plasminogen activators for reduction of the reperfusion time and prolongation of the reocclusion time. 15 Further preferred application areas are the prevention of thrombin-dependent early reocclusion and late restenosis after percutaneous transluminal coronary angioplasty, the prevention of thrombin-induced proliferation of smooth muscle cells, the prevention of the accumulation of active thrombin in the CNS 20 (e.g. in Alzheimer's disease), tumor control and the prevention of mechanisms which lead to adhesion and metastasis of tumor cells. The novel compounds can further be employed in disorders whose 25 pathological mechanism is based directly or indirectly on the proteolytic action of kininogenases, in particular kallikrein, e.g. in inflammatory conditions such as asthma, pancreatitis, rhinitis, arthritis, urticaria and other internal inflammatory conditions. 30 The compounds according to the invention can be orally administered in the customary manner. Administration can also be carried out through the nasopharyngeal space using vapors or sprays. 35 The dose depends on the age, condition and weight of the patient and on the manner of administration. As a rule, the daily dose of active compound per person is between approximately 10 and 2000 mg in the case of oral administration. This dose can be 40 given in 2 to 4 individual doses or once daily as a slow-release form. The novel compounds can be administered in solid or liquid form in the customary pharmaceutical. administration forms, e.g. as 45 tablets, film-coated tablets, capsules, powders, granules, coated tablets, solutions or sprays. These are prepared in the customary manner. The active compounds can in this case be processed with 21 the customary pharmaceutical exc-ipients such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-delaying agents, antioxidants and/or propellants (cf. H. 5 Sucker et al.: Pharmazeutische Technologie [Pharmaceutical Technology], Thieme-Verlag, Stuttgart, 1978). The administration forms thus obtained normally contain the active compound in an amount from 0.1 to 99% by weight. 10 Experimental section Pharmacological tests The absorption rate of orally administered medicaments from the 15 gastrointestinal tract (GIT) is an important factor with respect to the bioavailability of the medicament. A prerequisite for a high bioavailability is a good absorption rate. A number of in vitro models are available for the study of 20 intestinal absorption. Thus, the human colon adenocarcinoma cell lines THE-29, Caco-2 and.T84 are routinely employed in order to investigate various intestinal transport processes (Madara et al., Am. J. Physiol. 1988, 254: G416-G423; K. L. Audus et al, Pharm. Res. 1990, 7, 435-451). The IEC-18 cell line also proved 25 to be a suitable model for the investigation of the permeability of hydrophibic substances through the intestinal membrane (Ma et al., J. Lab. Clin. Med. 1992; Duizer et al., J. Contr. Rel. 1997). 30 For the transport experiments (Materials, Methods: see R.T. Borchardt, P.L. Smith, G. Wilson, Models for Assessing Drug Absorption and Metabolism, 1st Edition, Plenum Press New York and London, 1996, Chapter 2), the cells are cultured for 17-24 days on Transwell polycarbonate membranes. The experimental chamber is 35 arranged such that the membrane separates the apical compartment from the basolateral compartment. The transport of the test substances from the apical side through the cell layer to the basolateral side can be measured as a function of the pH gradient, e.g. apical (pH 6.0J basolateral (pH 8.0). 40 After incubation of the cells with the test substance, samples are removed from the apical and basolateral sides after a defined time interval (e.g. 24 h). The content of test substance employed and possible metabolites in each of the two compartments is 45 determined by HPLC (comparison of retention times) and HPLC-MS 22 (elucidation of metabolites) analysis. The transport rate is - calculated. With the aid of the values which these tests produce, it is 5 possible to divide the test substances into the following categories: +++ : very good transport ++ : good transport 10 + : moderate transport o : poor transport In the table below, the division into the categories mentioned has been carried out for selected examples: 15 Ex. No. Transport 01 ++ 03 ++ 20 05 +++ 07 + 14 +++ 15 +++ 25 31 o 32 + 30 Pharmacokinetics and clotting parameters in rats The test substances are dissolved in isotonic saline solution immediately before administration to conscious Sprague Dawley rats. The administration volumes are 1 ml/kg for intravenous 35 bolus injection into the tail vein and 10 ml/kg for oral administration, which is carried out by stomach tube. If not mentioned otherwise, taking of blood is carried out 1 h after oral administration of 21.5 mg-kg- 1 or intravenous administration of 1.0 mg-kg- 1 of the test substance or of the corresponding 40 vehicle (control). Five minutes before taking blood, the animals are anesthetized by i.p. administration of 25% strength urethane solution (dose 1 g-kg- 1 i.p.) in physiological saline solution. The carotid artery is dissected and catheterized and blood samples (2 ml) are taken in citrate tubes (1.5 parts of citrate 45 plus 8.5 parts of blood). Directly after taking samples, the ecarin clotting time (ECT) in whole blood is determined. After the preparation of the plasma by centrifugation, the plasma 23 thrombin time and the activated partial thromboplastin time (APTT) are determined with the aid of a coagulometer. Clotting parameters: 5 Ecarin clotting time (ECT): 100 p1 of citrated blood are incubated for 2 min at 37*C in a coagulometer (CL 8, ball type, Bender & Hobein, Munich, FRG). After the addition of 100 pl of prewarmed (37*C) ecarin reagent (Pentapharm), the time until 10 formation of a fibrin clot is determined. Activated thromboplastin time (APTT): 50 p.l of citrate plasma and 50 l of the PTT reagent (Pathrombin, Behring) are mixed and incubated for 2 min at 37 0 C in a coagulometer (CL 8, ball type, 15 Bender & Hobein, Munich, FRG). After the addition of 50 pl of prewarmed (37*C) calcium chloride, the time until formation of a fibrin clot is determined. Thrombin time (TT): 100 pl of citrate-treated plasma are 20 incubated for 2 min at 37*C in a coagulometer (CL-8, ball type, Bender & Hobein, Munich, FRG). After the addition of 100 pl of prewarmed (37 0 C) thrombin reagent (Boehringer Mannheim), the time until the formation of a fibrin clot is determined. 25 Pharmacokinetics and clotting parameters in dogs The test substances are dissolved in isotonic saline solution immediately before administration to conscious mongrel dogs. The administration volumes are 0.1 ml/kg for intravenous bolus 30 injection and 1 ml/kg for oral administration, which is carried out by stomach tube. Before and 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min (if required after 420, 480 min and 24 h) after intravenous administration of 1.0 mg/kg or before and 10, 20, 30, 60, 120, 180, 240, 300, 360, 480 min and 24 h after 35 oral administration of 4.64 mg/kg, samples of venous blood (2 ml) are taken in citrate tubes. Directly after taking the samples, the ecarin clotting time (ECT) in the whole blood is determined. After the preparation of the plasma by centrifugation, the plasma thrombin time and the activated partial thromboplastin time 40 (APTT) are determined with the aid of a coagulometer. The anti-F IIa activity (ATU/ml) and the concentration of the substance are additionally determined by its anti-F-IIa activity in the plasma by means of chromogenic (S-2238) thrombin assay, calibration curves with r-hirudin and the test substance being 45 employed.
24 The plasma concentration of the test substance is the basis for the calculation of the pharmacokinetic parameters: time of maximum plasma concentration (T max), maximum plasma concentration; plasma half-life, to.
5 ; area under the curve (AUC); 5 absorbed part of the test substance (F). Clotting parameter: Ecarin clotting time (ECT): 100 il of citrate-treated blood are incubated for 2 min at 37*C in a coagulometer (CL 8, ball-type, 10 Bender & Hobein, Munich, FRG). After the addition of 100 pl of prewarmed (37*C) ecarin reagent (Pentapharm), the time until the formation of a fibrin clot is determined. Activated thromboplastin time (APTT): 50 pl of citrate-treated 15 plasma and 0 Al of the PTT reagent (Pathrombin, Behring) are mixed and incubated for 2 min at 37"C in a coagulometer (CL 8, ball type, Bender & Hobein, Munich, FRG). After the addition of 50 gl of prewarmed (37*C) calcium chloride, the time until the formation of a fibrin clot is determined. 20 Thrombin time (TT): 100 p1 of citrate-treated plasma are incubated for 2 min at 37 0 C in a coagulometer ((CL 8, ball type, Bender & Hobein, Munich, FRG). After the addition of 100 gl of prewarmed (37"C) thrombin reagent (Boehringer Mannheim), the time 25 until the formation of a fibrin clot is determined. As the prodrugs in some cases are very poor thrombin inhibitors, the proportion of active compound (drug) formed is determined directly by means of the determination of the clotting 30 parameters. The kinetics therefore include the absorption of the prodrug, its metabolization and excretion, and the conversion into the active compound and its metabolization and excretion. The compounds of the formula I can be prepared according to 35 Schemes I-III. The units A, B and D are preferably synthesized separately and employed in suitably protected form (see schemes I-III, use in each case of orthogonal protective groups (P or P*) compatible 0 with the synthesis method used. 5 25 Scheme I A B E D 5 L P OH H L PL 10 p -- OH H- L P L (P) (U)H L 15 (P) L _ N-G H NHK 20 (P = protective group, (P) = protective group or H) Scheme I describes the linear synthesis of the molecule I by protective group removal from P-D-L (L is equal to CONH 2 , CSNH 2 , 25 CN)-, coupling of the amine H-D-L with the N-protected amino acid P-E-OH to give P-E-D-L, removal of the N-terminal protective groups to give H-E-D-L, coupling with the N-protected amino acid P-B-OH to give P-B-E-D-L, removal of the protective group P to give H-B-E-D-L, subsequent coupling or alkylation with the 30 optionally protected (P)-A-U unit (U = leaving group) or reductive alkylation with (P)-A'-U (U = aldehyde, ketone) or Michael addition with a suitable P-A"-C=C- derivative to give (P)-A-B-E-D-L. If L is an amide function, this can be converted into the corresponding nitrile function at the in each case 35 protected stages by dehydration using trifluoroacetic anhydride. Amidine syntheses of compounds of the structural type I starting from the corresponding carboximides, nitriles, thiocarboxamides and hydroxyamidines are described in a number of patent applications (see, for example WO 95/35309, WO 96/17860, 40 WO 96/24609, WO 96/25426, WO 98/09950). Protective groups which may still be present are then removed. 45 26 Scheme II A B E D 5 (P*) (U) H P (P*) p (P*) OH H p 10 (P*) p (P*) OH H L* 15 (P) -______ (P*) N-G NH-K (P**) NG 20 NH-K Scheme II describes the linear synthesis of the molecule I by coupling, alkylation, reductive amination or Michael addition of 25 H-B-P to correspondingly suitable optionally protected (P*)-A units [(P*)-A-U (U = leaving group) or (P*)-A'-U (U = aldehyde, ketone), or (P*)-A"-C=C-derivative] to give (P*)-A-B-P. After removal of the C-terminal protective group to give (P*)-A-B-OH, coupling with H-E-P to give (P*)-A-B-E-P, removal of the . 30 C-terminal protective group again to give (P*)-A-B-E-OH and coupling with H-D-L* (L* is equal to CONH 2 , CSNH 2 , CN, C(=NH)NH-R*; R* is equal to a hydrogen atom or protective group) to give (P*)-A-B-E-D-L*, the reaction of this intermediate to give the final product is carried out analogously to Scheme I. 35 The synthesis of the hydroxyl-, alkoxy- or aryloxyamidines (G = OH, OR) is carried out by reaction of the corresponding nitriles or iminothioester salts with hydroxylamine hydrochloride or 0-substituted hydroxylamine derivatives. (P**) is then introduced by transesterification or starting from the free acid. For the 40 synthesis of the oxadiazolones (G and K together form a COO-group), in particular of the three-substituted 1,2,4-oxadiazol-5-ones, the corresponding amidoximes are reacted, with addition of bases (e.g. NaOH, pyridine, tertiary amines), with carbonic acid derivatives such as, for example, phosgene, 45 di- and triphosgene, carbonyldiimidazole or chloroformic acid 27 esters (R.E. Bolton et al., Tetrahedron Lett. 1995, 36, 4471; K. Rehse, F. Brehme, Arch. Pharm. Med. Chem. 1998, 331, 375). Scheme III 5 A B E D (P*) OH H- L* 10 (P*) L*
NH
2 (P*) NH-G 15 NH-K Scheme III describes a very efficient route for the preparation of the compounds I by a convergent synthesis. The appropriately 20 protected units (P*)-A-B-OH and H-E-D-L* are coupled to one another and the resulting intermediates (P*)-A-B-E-D-L* are reacted to give the final product analogously to scheme I and scheme II. 25 N-terminal protective groups employed are Boc, Cbz or Fmoc; C-terminal protective groups are methyl, tert-butyl and benzyl esters. Amidine protective groups are preferably Boc and Cbz. If the intermediates contain olefinic double bonds, protective groups which are removed hydrogenolytically are unsuitable. 30 The required coupling reactions and the customary reactions of protective group introduction and removal are carried out according to standard conditions of peptide chemistry (see M. Bodanszky, A. Bodanszky "The Practice of Peptide Synthesis", 35 2nd Edition, Springer Verlag Heidelberg, 1994). Boc protective groups are removed by means of dioxane/HCl, diethyl ether/HCl, dichloromethane/HCl or TFA/DCM, Cbz protective groups hydrogenolytically or using HF, and Fmoc protective groups 10 using piperidine. Ester functions are hydrolyzed using LiOH in an alcoholic solvent or in dioxane/water. t-Butyl esters are cleaved using TFA or dioxane/HCl. 5 28 The reactions were checked by means of TLC, the following eluents customarily being used: A. DCM/MeOH 95:5 5 B. DCM/MeOH 9:1 C. DCM/MeOH 8:2 D. DCM/MeOH/50% strength HOAc 40:10:5 E. DCM/MeOH/50% strength HOAc 35:15:5 F. cyclohexane/EA 1:1 10 If column-chromatographic separations- are mentioned, these separations were carried out on silica gel, for which the abovementioned eluents were used. 15 Reversed phase HPLC separations were carried out using acetonitrile/water and HOAc buffer. The starting compounds can be prepared according to the following methods: 20 Units A prepared for alkylation are, for example, tert-butyl a-bromoacetate, adamantyl a-bromoacetate, tert-butyl p-bromopropionate, tert-butyl a-bromopropionate, tert-butyl a-bromobutyrate, 2, 3-dimethyl-2-butyl a-bromoacetate, 25 THP-protected bromoethanol, N-tert-butyl-a-bromoacetamide and N,N,-diethyl-a-bromoacetamide. The tert-butyl esters mentioned, if they cannot be purchased commercially, are prepared analogously to G. Uray, W. Lindner, Tetrahedron 1988, A, 4357-4362. The bromoacetic acid esters, if they are not 30 obtainable commercially, were prepared by reaction of bromoacetyl bromide with the appropriate alcohols with addition of pyridine as a base. B units: 35 A variety of possibilities are available in the literature for the general and specific synthesis of amino acids. Volume E16d/Part 1 - H Houben-Weyl, pp. 406 et seq., inter alia, gives a general overview of this. 40 Frequently employed starting materials were ethyl benzophenoneiminoacetate, diethyl acetamidomalonate and ethyl isonitriloacetate. 45 29 The preparation of various glycine and alanine derivatives was carried out, for example, starting from ethyl isonitroloacetate and an appropriate ketone or aldehyde (see (H.J. Pr~torius, J. Flossdorf, M. R. Kula Chem. Ber. 1975, .Q1, 3079). 5 The syntheses of cyclooctylglycine, 4-isopropylcyclohex-1-yl alanine, 4-methylcyclohex-1-ylalanine and 4-methylcyclohex-1-ylglycine were carried out via the corresponding ethyl 2-formylaminoacrylate (U. Schllkopf and R. 10 Meyer, Liebigs Ann. Chem. 1977, 1174) starting from ethyl isocyanoacetate using the respective carbonyl compounds cyclooctanone, 2-norbornanone, 1-formyladamantane, 1-formyl-1-methylcyclohexane, 1-formyl-4-isopropylcyclohexane, 1-formyl-4-methylcyclohexane and 4-methylcyclohexanone according 15 to the following general procedures: General working procedure for the synthesis of ethyl 2-formylaminoacrylates. 20 The solution of 100 mmol of ethyl isocyanoacetate in 50 ml of THF was added dropwise at 0 to -100C to 100 mmol of potassium tert-butoxide in 150 ml of THF. After 15 min, 100 mmol of the appropriate carbonyl compound in 50 ml of THF were added, the reaction mixture was slowly allowed to rise to RT and the solvent 25 was stripped off on a rotary evaporator. The residue was mixed with 50 ml of water, 100 ml of acetic acid and 100 ml of DCM and the product was extracted with DCM. The DCM phase was dried over Na 2
SO
4 and the solvent was stripped off on a rotary evaporator. If necessary, the products obtained in almost pure form were further 30 purified by column chromatography on silica gel (eluent: mixtures of ether/petroleum ether). General procedure for the synthesis of the amino acid hydrochlorides starting from the ethyl 2-formylaminoacrylates 35 100 mmol of the ethyl 2-formylaminoacrylate were hydrogenated until reaction was complete using Pd/C (10%)/hydrogen in 200 ml of glacial acetic acid. The catalyst was then filtered off, the acetic acid was removed as extensively as possible on the rotary 40 evaporator and the residue was heated to reflux for 5 h in 200 ml of semiconcentrated hydrochloric acid. The hydrochloric acid was stripped off on the rotary evaporator, and the product was dried at 500C in vacuo and washed several times with ether. The hydrochlorides were obtained as slightly colored crystals. 45 30 Starting from 18.9 g (150 mmol) of cyclooctanone, 25.0 g of cyclooctylglycine hydrochloride were obtained. Starting from 16.5 g (150 mmol) of 2-norbornanone, 26.6 g of 2-norbornylglycine hydrochloride were obtained. Starting from 19.7 g (120 mmol) of 5 1-formyladamantane, 26.0 g of adamantylalanine hydrochloride were obtained. Starting from 12.6 g (100 mmol) of 1-formyl-1-methyl cyclohexane, 16.6 g of y-methylcyclohexylalanine hydrochloride were obtained. Starting from 16.8 g (150 mmol) of 4-methylcyclohexanone, 25.9 g of 4-methylcyclohexylglycine 10 hydrochloride were obtained. Starting from 15 g of trans-1-formyl-4-methylcyclohexane, 18 g of trans-4-methylcyclo hex-1-yl-alanine hydrochloride were obtained. Starting from 9 g of 3,3-dimethyl-1-formylcyclohexane, 10 g of 3,3-dimethylcyclo hex-1-ylalanine hydrochloride were obtained. 15 The aldehyde needed for the synthesis, 1-formyl-3,3-dimethyl cyclohexane, was prepared following Moskal and Lensen (Rec. Trav. Chim. Pays-Bas 1987, lIj, 137-141): 20 A solution of n-butyllithium in n-hexane was added dropwise in the course of 10 min at -60 0 C to a stirred solution of diethyl isocyanomethyl phosphonate (17 ml, 105 mmol) in 280 ml of anhydrous diethyl ether. The resulting suspension was stirred at -600C for 15 min. and treated in the course of 10 min with a 25 solution of 3,3-dimethylcyclohexanone (13 g, 105 mmol) in 100 ml of anhydrous diethyl ether, the temperature being kept below -450C. The reaction mixture was allowed to come to 00C and was stirred at this teperature for 90 min., and 150-200 ml of 38% strength aqueous hydrochloric acid were cautiously added. To 30 complete the hydrolysis, the mixure was vigorously stirred at room temperature for 15 h. The organic phase was separated off and washed with 200 ml each of water, saturated sodium hydrogencarbonate solution and saturated sodium chloride solution. It was dried over magnesium sulfate, filtered and 35 concentrated on a rotary evaporator to remove the solvents. The resulting residue was employed without further purification as a starting material for the synthesis of the amino acid. Preparation of cycloheptylglycine, cyclopentylglycine, 40 4-isopropylcyclohexylglycine and 3,3-dimethylcyclohexylglycine These amino acids were prepared by reaction of cycloheptanone, cyclopentanone, 4-isopropylcyclohexanone or 3,3-dimethylcyclo hexanone with ethyl isonitriloacetate according to a procedure of 45 H.J. Pritorius (H.J. Pritorius, J. Flossdorf, M. Kula, Chem. Ber. 1985, 108, 3079).
31 Preparation of H-D,L-Chea-OH 4.0 g of cycloheptylmethyl methanesulfonate (19.39 mmol), prepared from cycloheptylmethanol and methanesulfonyl chloride, 5 were heated to reflux in an inert gas atmosphere for 10 h with 4.9 of benzophenone imine glycine ethyl ester (18.47 mmol), 8.9 g of dry finely powdered potassium carbonate (64.65 mmol) and 1 g of tetrabutylammonium bromide (3 mmol) in 50 ml of dry acetonitrile. The potassium carbonate was then filtered off, the 10 filtrate was evaporated to dryness and the crude product was hydrolyzed directly at RT with stirring for 1.5 h using 20 ml of 2N hydrochloric acid in 40 ml of ethanol. After dilution of the reaction solution, benzophenone was extracted with ethyl acetate in the acidic range, then H-D,L-Chea-OEt was extracted with DCM 15 in the alkaline range (pH = 9), and the solution was dried over magnesium sulfate and concentrated in a rotary evaporator. Yield 3.7 g Q 95% of theory. The amino acids mentioned were converted into the in each case 20 Boc-protected form according to generally known processes using di-tert-butyl dicarbonate in water/dioxane and then recrystallized from ethyl acetate/hexane mixtures or purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether mixtures). 25 The Boc-protected amino acids were employed as B units according to Scheme I. As B units,. the amino acids mentioned were in some cases also 30 converted into the corresponding benzyl esters and linked to the appropriately protected A units. In the case of compounds having a still free NH function, this was then protected by a Boc group, the benzyl ester group was removed by hydrogenation and the unit A-B-OH was purified by crystallization, salt precipitation or 35 column chromatography. This route is described by way of example for tBuOOC-CH 2 -(Boc)(D)Cha-OH below. Synthesis of D-cyclohexylalanine benzyl ester 40 A suspension of 100 g (481 mmol) of D-cyclohexylalanine hydrochloride, 104 g (962 mmol) of benzyl alcohol and 109.7 g (577 mmol) of p-toluenesulfonic acid monohydrate in 2200 ml of toluene was slowly heated to reflux in a water separator. In a temperature range from 80-900C,.evolution of hydrogen chloride and 45 the dissolution of the suspension to give a clear solution was observed. When water no longer separated (about 4 h), 500 ml of toluene were distilled off, the reaction mixture was allowed to 32 cool overnight, and the resulting residue was filtered off and washed twice with 1000 ml each of hexane. The resulting residue (195 g) was then suspended in 2000 ml of dichloromethane, treated with 1000 ml of water and adjusted to pH 9-9.5 with stirring by 5 successive addition of 50% strength sodium hydroxide solution. The organic phase was separated off, washed twice with 500 ml each of water, dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated, whereby 115 g (94%) of the title compound were obtained as a pale oil. 10 N-(tert-Butyloxycarbonylmethylene)-D-cyclohexylalanine benzyl ester 115 g (440 mmol) of D-cyclohexylalanine benzyl ester were 15 dissolved in 2000 ml of acetonitrile, treated at room temperature with 607.5 g (4.40 mmol) of potassium carbonate and 94.3 g (484 mmol) of tert-butyl bromoacetate and stirred at this temperature for 3 days. The carbonate was filtered off and washed with acetonitrile, the mother liquor was concentrated (300C, 20 20 mbar), the residue was taken up in 1000 ml of methyl tert-butyl ether and the organic phase was extracted with 5% strength citric acid and saturated sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate, the drying agent was filtered off, the filtrate was concentrated and 25 the oil obtained (168 g) was employed directly in the following reaction. N-Boc-N-(tert-Butyloxycarbonylmethylene)-D-cyclohexylalanine benzyl ester 30 The oil obtained in the previous synthesis (168 g, 447 mmol) was dissolved in 1400 ml of acetonitrile, treated with 618 g (4.47 mmol) of potassium carbonate powder and 107.3 g (492 mmol) of di-tert-butyl dicarbonate and the mixture was stirred at room 35 temperature for 6 days. The potassium carbonate was filtered off with suction, washed with about 1000 ml of acetonitrile and the filtrate was concentrated. 230 g of the desired product were obtained. L0 N-Boc-N-(tert-butyloxycarbonylmethylene)-D-cyclohexylalanine cyclohexylammonium salt 115 g of N-Boc-N-(tert-butyloxycarbonylmethylene)-D-cyclo hexylalanine benzyl ester were dissolved in 1000 ml of pure 5 ethanol and hydrogenated at normal pressure with hydrogen for 2 h at 25-300C in the presence of 9 g of 10% strength Pd on active carbon. After filtration and removal of the solvent in a rotary 33 evaporator, 100 g (260 mmol) of a yellow oil were obtained, which was taken up in 1600 ml of acetone and heated to reflux. The heating bath was removed and a solution of 27 g (273 mmol) of cyclohexylamine in acetone was added rapidly through a dropping 5 funnel. On cooling the reaction mixture to room temperature, the desired salt crystallized out. The solid was filtered off, washed with 200 ml of acetone and recrystallized once more from acetone for final purification. After drying the residue in a vacuum drying oven at 300C, 70.2 g of the desired salt were obtained as a 10 white powder. N-Boc-N-(tert-butyloxycarbonylmethylene-D-cyclohexylglycine cyclohexylammonium salt was prepared in an analogous manner from cyclohexylglycine as starting material. 15 N-Boc-N-(tert-butyloxycarbonylethylene)-D-cyclohexylalanine cyclohexylammonium salt a) tert-Butyl 3 -bromopropionate 20 16.64 g (109 mmol) of bromopropionic acid, 150 ml of condensed 2 -methylpropene and 2 ml of concentrated sulfuric acid were added at -30*C in a nitrogen countercurrent to a glass vessel suitable for an autoclave, the vessel was firmly 25 sealed and the mixture was stirred at room temperature for 72 h. For working-up, the reaction vessel was again cooled to -30 0 C and the reaction solution was cautiously poured into 200 ml of an ice-cold, saturated sodium hydrogencarbonate solution. Excess 2 -methylpropene was allowed to evaporate 30 with stirring, the residue was extracted three times with 50 ml each of dichloromethane, the combined organic phases were dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated in a water-jet vacuum. The oil residue was purified by column chromatography (eluent 35 N-hexane, later N-hexane/diethyl ether 9:1). 18.86 g of the title compound were obtained. b) N-(tert-Butyloxycarbonylethylene)-D--cyclohexylalanine benzyl ester 10 49.4 g (189 mmol) of D-cyclohexylalanine benzyl ester were dissolved in 250 ml of acetonitrile, treated at room temperature with 31.6 g (151 mmol) of tert-butyl bromopropionate and the mixture was refluxed for 5 days. The 5 resulting precipitate was filtered off, washed repeatedly with acetonitrile, the filtrate was concentrated in a water-jet vacuum, the residue was taken up in 350 ml of 34 dichloromethane and the organic phase was extracted with 5% strength citric acid and saturated sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate, the drying agent was filtered off and the filtrate was 5 concentrated. The oily residue was purified by column chromatography (eluent: dichloromethane, later dichloromethane/methanol 95:5). A slightly impure oil was obtained, which was employed directly in the following reaction. 10 c) N-Boc-N-(tert-butyloxycarbonylethylene)-D-cyclohexylalanine benzyl ester The oil obtained in the preceding synthesis (30 g, max. 15 70 mmol) was dissolved in 150 ml of acetonitrile, treated with 28 ml (160 mmol) of diisopropylethylamine and 19.2 (88 mmol) of di-tert-butyl dicarbonate and stirred at room temperature for 3 days. The reaction mixture was concentrated on the rotary evaporator in a water-jet vacuum, the residue 20 was taken up in n-hexane and washed five times with 3 ml each of a 5% strength citric acid solution, the combined organic phases were dried over sodium sulfate, the drying agent was filtered off, the filtrate was concentrated and the residue was subjected to purification by column chromatography 25 (eluent: hexane/ethyl acetate 95:5). 32.66 g (64 mmol) of the desired product were obtained. d) N-Boc-N-(tert-butyloxycarbonylethylene-D-cyclohexylalanine cyclohexylammonium salt 30 32.66 g (64 mmol) of N-Boc-N-(tert-butyloxycarbonylethylene) D-cyclohexylalanine benzyl ester were dissolved in 325 ml of pure ethanol and hydrogenated at 25 to 30 0 C with hydrogen at normal pressure for 14 h in the presence of 3 g of 10% 35 strength Pd on active carbon. After filtration of the solution through Celite&, washing with ethanol and removal of the solvent in a rotary evaporator, 26.7 g of a yellow oil were obtained, which was taken up in acetone and heated to reflux. The heating bath was removed and the solution of 7 g 40 (70 mmol) of cyclohexylamine in- acetone was added rapidly through a dropping funnel. On cooling the reaction mixture to room temperature, the desired salt crystallized out. The solid was filtered off, washed with 25 ml of acetone and recrystallized once more from acetone for final purification. 45 After drying the residue in a vacuum drying oven at 300C, 35 26.6 g (54 mmol) of the desired salt were obtained as a white powder. N-Boc-N-(tert-butyloxycarbonylmethylene ) -(D)-cyclohexylalanyl 5 3, 4-dehydroproline: a) N-Boc-Pyr-OH (5 g, 23.45 mmol) was dissolved in MeOH (50 ml) and treated with HCl in dioxane (4N, 30 ml). The mixture was then heated under reflux for 12 h. The solvent was removed in 10 a rotary evaporator and H-Pyr-OMe hydrochloride was obtained as the product. Yield: 3.84 g (100%). b) N-(t-BuO 2
C-CH
2 )-N-Boc-(D)-Cha-OH (8 g, 20.75 mmol) was dissolved in dichloromethane (75 ml) and treated at -10 0 C 15 with ethyldiisopropylamine (15.5 ml, 89.24 mmol). After storing at this temperature for 5 min., a solution of H-Pyr-OMe hydrochloride (3.4 g, 20.75 mmol) in dichloromethane (25 ml) was added dropwise. A solution of propanephosphonic anhydride in ethyl acetate (50% strength, 20 20 ml, 26.96 mmol) was then added dropwise and the mixture was stirred at -10 to 0"C for 2 h. The batch was diluted with dichloromethane and washed with saturated sodium hydrogencarbonate solution (2 x 80 ml, 5% strength citric acid solution (2 x 15 ml) and saturated sodium chloride 25 solution (1 x 20 ml). The organic phase was dried over sodium sulfate and the solvent was removed in a rotary evaporator. The crude product was purified by means of flash chromatography (silica gel, dichloromethane/methanol 95/5). -Yield: 6.2 g (60%). 30 c) N-(t-Bu 2
C-CH
2 )-N-Boc-(D)-Cha-Pyr-OMe (5.5 g, 11.12 mmol) was dissolved in dioxane (40 ml), treated with sodium hydroxide solution (1N, 22.2 ml, 22.24 mmol) and stirred at room . temperature for 2 h. The dioxane was removed in a rotary 35 evaporator, and the aqueous phase was washed with ethyl acetate and acidified to pH 1 to 2 with potassium hydrogensulfate solution (20% strength). The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over sodium sulfate. Yield: 5 g (94%), 40 colorless foam. Recrystallization from n-hexane saturated with water afforded colorless crystals (m.p.'= 158 to 160 0 C). N-Boc-N-(tert-butyloxycarbonylmethylene)-(D)-cyclohexylglycyl 3, 4-dehydroproline 45 36 This compound was prepared from N-Boc-N-(tert-butyloxycarbonyl methylene)-(D)-cyclohexylglycine and 3,4-dehydroproline methyl ester in an analogous manner. 5 The (L)3,4-dehydroproline employed as the D unit can be obtained commercially; the (D,L)-4,5-dehydropipecolic acid can be prepared according to A. Burgstahler, C.E. Aiman J. Org. Chem. 2 (1960), 489 or C. Herdeis, W. Engel Arch. Pharm 32S (1993), 297 and then converted into Boc-(D,L)-Dep-OH using (Boc) 2 0. 10 The synthesis of 3-(6-cyano)picolylamine has been described in WO 96/25426 and WO 96/24609. 3-(6-Cyano)picolylamine 15 The preparation of this component was carried out as described in WO 96/25426 and WO 96/24609. Example 1: 20 N-( tert-butoxycarbonylmethylene )-(D)-cyclohexylalanyl- 3 , 4 dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide A suspension of 1.22 g (17.6 mmol) of hydroxylamine hydrochloride in 50 ml of ethanol was treated with 1.3 g of conc. ammonia, 25 stirred for 30 min. and the deposited precipitate (ammonium chloride) was filtered off with suction. 4.3 g (8.9 mmol) of N-(tert-butoxycarbonylmethylene)-(D)-cyclohexylalanyl- 3 ,4 dehydroprolyl-(6-cyano-3-picolyl)amide (WO 96/25426, Example 93, stage a) were then added to the alcoholic hydroxylamine solution 30 and it was allowed to stand at room temperature for one hour. According to TLC (eluent: dichloromethane/ethanol = 9:1 or dichloromethane/methanol/conc. ammonia = 45:5:0.3), starting material was no longer detectable. After distilling off the solvent in vacuo, the residue was dissolved in 100 ml of 35 dichloromethane, and the solution was washed with water and aqueous sodium hydrogencarbonate solution and dried over sodium sulfate. After concentration, 4.1 g (87%) of an amorphous residue remained. FAB-MS (M+H+): 529 40 Example 2: N-(Hydroxycarbonylmethylene)-(D)-cyclohexylalanyl- 3 ,4-dehydro prolyl-(6-hydroxyamidino-3-picolyl)amide hydrochloride 45 3.5 g (6.6 mmol) of N-(tert-butoxycarbonylmethylene)-(D) cyclohexylalanyl- 3 ,4-dehydroprolyl-(6-hydroxyamidino-3-picolyl) amide (see Ex. 1) were dissolved in 15 ml of dichloromethane, 37 treated with 25 ml of a 4N solution of hydrogen chloride in dioxane and allowed to stand at room temperature overnight. After distilling off the solvent in vacuo (toward the end with addition of toluene), the amorphous residue was digested repeatedly with 5 diethyl ether. After drying, 3.1 g (90% of theory) of a white amorphous powder remained. FAB-MS (M+H+): 473 Example 3: 10 N-( Ethoxycarbonylmethylene )-(D )-cyclohexylalanyl-3, 4-dehydro prolyl-(6-hydroxyamidino-3-picolyl)amide 2.5 g (5.3 mmol) of N-(hydroxycarbonylmethylene)-(D)-cyclohexyl alanyl-3, 4-dehydroprolyl-(6-hydroxyamidino-3-picolyl) aide 15 hydrochloride (see Ex. 2) were dissolved in 50 ml of dry ethanol, treated with 3 ml of a 4N solution of hydrogen chloride in dioxane, refluxed for 4 hours and allowed to stand at room temperature for 2 days. After distilling off the solvent in vacuo at a bath temperature 20 of 35 0 C, the residue was digested repeatedly with diethyl ether, then taken up in ethyl acetate and extracted with saturated sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate and concentrated, and the residue was purified by column chromatography (eluent dichloromethane/ethanol 25 = 9:1, toward the end 4:1). After distilling off the solvent, 1.85 g (70% of theory) of a white amorphous powder remained, FAB-MS (M+H+): 501 Example 4: 30 N-(Methoxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro prolyl-(6-hydroxyamidino-3-picolyl)amide This compound was prepared analogously to Example 3, the residue digested with ether first being dissolved in methanol and 35 converted into the acetic acid salt by means of ion exchanger before it was purified by column chromatography (eluent dichloromethane/methanol = 9:1). FAB-MS (M+H+): 487 40 Example 5: N-(Isopropyloxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide This. compound was prepared analogously to Example 3, the starting 45 material N-(hydroxycarbonylmethylene)- (D)-cyclohexyl alanyl-3,4-dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide hydrochloride (see Ex. 2) being dissolved in isopropanol and 38 hydrogen chloride being introduced. The work-up and purification was carried out analogously to Example 4. FAB-MS (M+H+): 515 5 Example 6: N-(Benzyloxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro prolyl-(6-hydroxyamidino-3-picolyl)amide This compound was prepared analogously to Example 4 from 10 N-(hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro prolyl-(6-hydroxyamidino-3-picolyl)amide hydrochloride (see Ex. 2) and benzyl alcohol. FAB-MS (M+H+): 563 15 Example 7: N-( Ethyloxycarbonylmethylene )-( D )-cyclohexylalanyl-3, 4-dehydro prolyl-[ (6-amidino )-3-picolylamide ] hydrochloride
HO
2
C-CH
2 -(D)-Cha-Pyr-NH-3-(6-am)-pico (4.93 g, 10 mmol; 20 preparation: WO 96/25426, Example 93) was dissolved in 60 ml of ethanol, treated with HCl in ether (4.5N, 15 ml) and stirred at 60*C for 6 h. As according to TLC (methylene chloride/methanol/ acetic acid (50% strength in water): 35/15/7) the conversion was still not complete, a further 25 ml of 4.5N hydrogen chloride in 25 ether and 50 ml of ethanol were added and the mixture was stirred at 60*C again for 5 h. After concentrating the reaction mixture in vacuo in a rotary evaporator, it was codistilled a number of times with ethanol and ether in order to remove adhering hydrochloric acid. The product was then washed by stirring in a 30 little acetone/methylene chloride, and the residue was filtered off with suction and dried in vacuo. 5.4 g of the title compound were obtained as a white, hygroscopic solid substance. FAB-MS (M+H+): 485 35 Example 8: N-(Methyloxycarbonylmethylene )-( D )-cyclohexylalanyl-3, 4 dehydroprolyl-[ (6-amidino)-3-picolylamide] hydrochloride This compound was prepared analogously to Example 7 by 40 esterification of HO 2
C-CH
2 -(D)-Cha-Pyr-NH-3-(6-am)-pico with methanol. FAB-MS (M+H+): 471 45 39 Example 9: N-(n-Propyloxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 dehydroprolyl-[ (6-amidino)-3-picolylamide ] hydrochloride 5 This compound was prepared analogously to Example 7 by esterification of HO 2
C-CH
2 -(D)-Cha-Pyr-NH-3-(6-am)-pico with n-propanol. FAB-MS (M+H+): 499 10 Example 10: N-( Hydroxycarbonylmethylene )-(D)-cyclohexylalanyl-3, 4-dehydro prolyl-( 6-methoxy-amidino-3-picolyl) amide a) N-(tert-Butoxycarbonylmethylene)-(Boc)-(D)-cyclohexylalanyl 15 3,4-dehydroprolyl-(6-aminothiocarbonyl-3-picolyl)amide t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-CN)-pico (WO 96/25426, Ex. 93, stage b) was reacted with hydrogen sulfide in pyridine/triethylamine to give the corresponding thioamide 20 t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-CSNH 2 )-pico according to WO 96/25426, Ex. 93, stage c). b) N-(tert-Butoxycarbonylmethylene)-(Boc)-(D)-cyclohexylalanyl 3,4-dehydroprolyl-(6-S-methyliminothiocarbonyl-3-picolyl) 25 amide hydroiodide The product t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-CSNH 2 )-pico obtained from a) was reacted with methyl iodide to give t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-C=NH(SCH 3 ))-pico x HI 30 analogously to WO 96/25426, Ex. 93, Stage d. c) N-( tert-Butoxycarbonylmethylene )-( Boc )-( D)-cyclohexylalanyl 3,4-dehydroprolyl-(6-methoxyamidino-3-picolyl)amide 35 O-Methylhydroxylamine hydrochloride (0.9 g, 8.1 mmol) was dissolved in 30 ml of methanol and converted into the corresponding acetic acid salt by means of an ion exchanger (Fluka: acetate on polymeric support, 3.0 mmol of acetate per g). t-BuO 2
C-CH
2 -(Boc)-(D)-;-Cha-Pyr-NH-3-(6-C=NH(SCH 3 ))-pico x 40 HI (4.8 g, 6.2 mmol; see b) was added to this methanolic solution and the reaction mixture was stirred at room temperature overnight. After concentrating in vacuo, the residue was taken up in 200 ml of ethyl acetate, washed three times with 30 ml each of water, twice with 20 ml each of 20% 45 strength sodium hydrogensulfate solution and once with 30 ml of saturated sodium chloride solution and then purified by 40 column chromatography on silica gel, 0.9 g of the desired product being isolated. d) N-(Hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 5 dehydroprolyl-(6-methoxyamidino-3-picolyl)amide The product t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH 3-(6-C=NH(NHOCH 3 ))-pico (0.9 g, 0.7 mmol) obtained according to c) was dissolved in 10 ml of absolute dioxane, cooled to 10 0*C and treated with 5 ml of a 4N solution of hydrogen chloride in dioxane. The mixture was stirred at room temperature for 6 h with exclusion of moisture, then dissolved in water and subjected to salt exchange by means of an acetate exchanger and the aqueous phase was freeze-dried. 15 0.38 g of the title compound was obtained as a white powder. FAB-MS (M+H+): 487 Example 11: N-(Methoxycarbonylmethylene)-(D)-cyclohexylalanyl-3, 4-dehydro 20 prolyl-( 6-methoxy-amidino-3-picolyl) amide A solution of 1.5 g (2.9 mmol) of N-(hydroxycarbonylmethylene) (D)-cyclohexylalanyl-3,4-dehydroprolyl-(6-methoxyamidino-3 picolyl)amide (see Ex. 10 d) in methanol was treated with a 4N 25 solution of hydrogen chloride in dioxane and stirred at room temperature for 2 days. It was concentrated, the residue was codistilled twice with diethyl ether in order to remove excess acid and the crude product was purified by column chromatography. FAB-MS (M+H+): 501 30 Example 12: N-(Isopropyloxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydr oprolyl-(6-methoxyamidino-3-picolyl)amide 35 This compound was prepared analogously to Example 11 by esterification of N-(hydroxycarbonylmethylene)-(D) cyclohexylalanyl-3, 4-dehydroprolyl-( 6-methoxyamidino-3-picolyl) amide (see Ex. 10d) with isopropanol. FAB-MS (M+H+): 529 40 45 41 Example 13: N-(n-Octyloxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide 5 This compound was prepared analogously to Example 4 from N-(hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro prolyl-(6-hydroxyamidino-3-picolyl)amide hydrochloride (see Ex. 2) and n-octanol. FAB-MS (M+H+): 585 10 Example 14: N-( c-Hexyloxycarbonylmethylene )-(D)-cyclohexylalanyl-3, 4 dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide 15 This compound was prepared analogously to Example 3 from N-(hydroxycarbonylmethylene)-(D)-cyclohexylalanyl 3,4-dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide hydrochloride (see Ex. 2) and c-hexanol. FAB-MS (M+H+): 555 20 Example 15: N-(Neopentyloxycarbonylmethylene)-(D)-cyclohexylalanyl 3,4-dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide 25 This compound was prepared analogously to Example 3 from N-(Hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro prolyl-(6-hydroxyamidino-3-picolyl)amide hydrochloride (see Ex. 2) and neopentyl alcohol. FAB-MS (M+H+): 543 30 Example 16: N-(Methoxyethoxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide 35 This compound was prepared analogously to Example 4 from N-( hydroxycarbonylmethylene )-( D )-cyclohexylalanyl-3, 4 dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide-hydrochloride (see Ex. 2) and ethylene glycol monomethyl ether. FAB-MS (M+H+): 531 40 Example 17: N-(0-Methyldiethoxyoxycarbonylmethylene)-(D)-cyclohexylalanyl 3,4-dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide 45 42 This compound was prepared analogously to Example 4 from N-(hydroxycarbonylmethylene)-(D)-cyclohexylalanyl 3, 4-dehydroprolyl-(6-hydroxyamidino-3-picolyl) amide hydrochloride (see Ex. 2) and diethylene glycol monomethyl ether. 5 FAB-MS (M+H+): 575 Example 18: N-(Cyclohexylmethyloxycarbonylmethylene)-(D)-cyclohexylalanyl 3, 4-dehydroprolyl-(6-hydroxyamidino--3-picolyl) amide 10 This compound was prepared analogously to Example 4 from N-(hydroxycarbonylmethylene)-(D)-cyclohexylalanyl 3,4-dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide-hydro chloride (see Ex. 2) and cyclohexylmethanol, the residue digested 15 with ether being filtered off and purified by means of reversed phase HPLC. FAB-MS (M+H+): 569 Example 19: 20 N-(Cyclooctyloxycarbonylmethylene)-(D)-cyclohexylalanyl 3, 4-dehydroprolyl-( 6 -hydroxyamidino-3-picolyl ) amide This compound was prepared analogously to Example 4 from N-(hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro 25 prolyl-( 6 -hydroxyamidino-3-picolyl)amide hydrochloride (see Ex. 2) and cyclooctanol. As the purification by column chromatography using the eluent dichloromethane/methanol = 9:1 failed, a second purification was carried out (eluent ethyl acetate) by means of MPLC (silica gel). The title compound was 30 obtained as a white powder. FAB-MS (M+H+): 583 Example 20: N-(trans-4-Methylcyclohexyloxycarbonylmethylene)-(D) 35 cyclohexylalanyl-3,4-dehydroprolyl-(6-hydroxyamidino-3-picolyl) amide This compound was prepared analogously to Example 4 from N-(hydroxycarbonylmethylene)-(-D)-cyclohexylalanyl .0 3,4-dehydroprolyl-( 6 -hydroxyamidino-3-picolyl)amide hydrochloride (see Ex. 2) and trans-4-methylcyclohexanol. As the purification by column chromatography using the eluent dichloromethane/ methanol = 9:1 and 95:5 failed, a third purification was carried out (eluent ethyl acetate) by means of MPLC (silica gel). The 5 title compound was obtained as a white powder. FAB-MS (M+H+): 569 43 Example 21: N-(n-Hexyloxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide 5 This compound was prepared analogously to Example 4 from N-(hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 dehydroprolyl-( 6 -hydroxyamidino-3-picolyl)amide hydrochloride (see Ex. 2) and n-hexanol, the purification by column chromatography being carried out on silica gel (MPLC; eluent 10 ethyl acetate/n-hexane = 7:3). FAB-MS (M+H+): 557 Example 22: N-(c-Pentyloxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 15 dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide This compound was prepared analogously to Example 4 from N-(hydroxycarbonylmethylene)-(D)-cyclohexylalanyl 3, 4-dehydroprolyl-( 6 -hydroxyamidino-3-picolyl) amide hydro 20 chloride (see Ex. 2) and c-pentanol, the purification by column chromatography being carried out on silica gel (MPLC; eluent ethyl acetate/n-hexane = 1:1). FAB-MS (M+H+): 541 25 Example 23: N-(4-Methoxycyclohexyloxycarbonylmethylene)-(D)-cyclohexylalanyl 3,4-dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide This compound was prepared analogously to Example 4 from 30 N-(hydroxycarbonylmethylene)-(D)-<cyclohexylalanyl 3, 4-dehydroprolyl-( 6 -hydroxyamidino-3-picolyl) amide hydro chloride (see Ex. 2) and 4 -methoxycyclohexanol, the purification by column chromatography being carried out silica gel (MPLC:. eluent ethyl acetate/methanol = 99:1, with an increase in the 35 proportion of methanol of 0.1% per minute). The title compound was obtained as a cis/trans mixture (according to HPLC the ratio of the two isomers was 29:71). FAB-MS (M+H+): 585 40 Example 24: N-(1,1,2-Trimethylpropyloxycarbonylmethylene)-(D)-cyclo hexylalanyl-3, 4-dehydroprolyl-( 6 -hydroxyamidino-3-picolyl) amide a) 1,1, 2 -Trimethylpropyl bromoacetate 44 3.5 ml (1.1 equivalents) of pyridine and, at -5 0 C, 7.9 g (39 mmol) of bromoacetyl bromide were. added at room temperature to a solution of 4.0 g (39 mmol) of 2,3-dimethyl-2-butanol in 20 ml of dichloromethane. During 5 the addition of the bromide, which proceeded in a strongly exothermic manner, a pale precipitate was formed. During the course of this, the temperature rose to 20 0 C. The mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate and extracted three times with 5 ml each of saturated 10 sodium chloride solution. The ethyl acetate phase was dried .over magnesium sulfate and concentrated, and the residue obtained was employed in the next reaction without further purification. 15 b) N-(1,1,2-Trimethylpropyloxycarbonylmethylene)-(D)-cyclo hexylalanyl-3,4-dehydroprolyl-(6-cyano-3-picolyl)amide 30 ml of a 4N solution of hydrogen chloride in dioxane was added at -5*C to a solution of 14.1 g (29.3 mmol) of 20 Boc-(D)-Cha-Pyr-NH-3-(6-CN)-pico (WO 96/25426, Ex. 32, stage d) in 30 ml of dioxane. The mixture was stirred at room temperature for 3 hours and concentrated. The residue was taken up a total of three times in dichloromethane and concentrated again in order to remove the excess hydrogen 25 chloride. After the residue had been taken up in 50 ml of ethyl acetate and had been treated with 200 ml of diethyl ether, the product precipitated. It was filtered off and washed with diethyl ether. After drying, 12.0 g (98%) of the compound H-(D)-Cha-Pyr-NH-3-(6-CN)-pico were obtained as the 30 hydrochloride. 2.3 g (5.5 mmol) of H-(D)-Cha-Pyr-NH-3-(6-CN)-pico x HCl were dissolved in 20 ml of dichloromethane, and the solution -was treated at room temperature with 7.6 g (54.7 mmol) of 35 potassium carbonate and dropwise at -5*C with 1.22 g (5.5 mmol) of 1,1,2-trimethylpropyl bromoacetate. It was allowed to come to room temperature and stirred for 3 days. The reaction mixture was concentrated in vacuo in a rotary evaporator, taken up in ethyl acetate, and the solution was 40 washed three times with a little water and once with saturated sodium chloride solution. The organic phase was dried and concentrated. The residue was purified by column chromatography (eluent dichloromethane/methanol = 9:1) by means of MPLC (silica gel). 1.82 g (64%) of the title 45 compound were obtained as a white powder. FAB-MS (M+H+): 524 45 c) N-(1,1, 2-Trimethylpropyloxycarbonylethylene ) (D )-cyclohexylalanyl-3, 4-dehydroprolyl-( 6-hydroxy amidino-3-picolyl)amide 5 0.17 g (1.32 mmol) of diisopropylethylamine and 73 mg (1.05 mmol) of hydroxylamine hydrochloride were added at room temperature to a solution of 460 mg (0.88 mmol) of the compound obtained in b) in 10 ml of dichloromethane. The mixture was stirred at room temperature for 4 hours, diluted 10 with dichloromethane and extracted twice with 5 ml each of 5% strength citric acid solution. The organic phase was dried and concentrated. The residue was purified by column chromatography by means of reverse phase HPLC. The title compound was obtained as a white powder. 15 FAB-MS (M+H+): 557 Example 25: N-(2-Methyl-1,3-dioxan-5-yloxycarbonylmethylene)-(D)-cyclohexyl alanyl-3,4-dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide 20 This compound was prepared analogously to Example 24 starting from H-(D)-Cha-Pyr-NH-3-(6-CN)-pico x HCl and 2-methyl-1,3-dioxan-5-ol, the hydroxylamine addition being carried out in acetonitrile and the purification by column 25 chromatography on silica gel (MPLC; eluent ethyl acetate/methanol = 99:1, with an increase in the proportion of methanol of 0.1% per minute). The title compound was obtained as a white powder. FAB-MS (M+H+): 573 30 Example 26: N-(1-Isopropyl-2-methylpropyloxycarbonylmethylene)-(D )-cyclohexyl alanyl-3,4-dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide This compound was prepared analogously to Example 24 starting 35 from H-(D)-Cha-Pyr-NH-3-(6-CN)-pico x HCl and 2,4-dimethyl 3-pentanol, the hydroxylamine addition being carried out in acetonitrile and the purification by column chromatography on silica gel (MPLC; eluent ethyl acetate/methanol = 99:1, with an increase in the proportion of methanol of 0.1% per minute). The 40 title compound was obtained as a white powder. FAB-MS (M+H+): 571 45 46 Example 27: N-(2-Indanyloxycarbonylmethylene )-(D)-cyclohexylalanyl-3, 4-. dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide 5 This compound was prepared analogously to Example 25 starting from H-(D)-Cha-Pyr-NH-3-(6-CN)-pico x HCl and 2-indanol. FAB-MS (M+H+): 589 Example 28: 10 N-(1-Isobutyl-3-methyloxycarbonylmethylene)-(D)-cyclohexyl alanyl-3,4-dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide This compound was prepared analogously to Example 25 starting from H-(D)-Cha-Pyr-NH-3-(6-CN)-pico x HCl and 2,6-dimethyl 15 heptan-4-ol. FAB-MS (M+H+): 599 Example 29: N-[4-Oxo-4-(1-pyrrolidinyl)butyloxycarbonylmethylene]-(D)-cyclo 20 hexylalanyl-3,4-dehydroprolyl-(6-hydroxyamidino-3-picolyl)amide a) 4-Oxo-4-(1-pyrrolidinyl)-1-butanol A mixture of 7.1 g (82 mmol) of y-butyrolactone and 11.7 g 25 (164.5 mmol) of pyrrolidine was stirred at room temperature for 3 hours. The pyrrolidine was distilled off in vacuo in a rotary evaporator to the greatest possible extent, and the residue was dissolved in toluene a number of times and concentrated again in order to remove traces of the base. The 30 product obtained was employed in the following reaction without purification. b) 4-Oxo-4-(1-pyrrolidinyl)butyl bromoacetate 35 The product obtained a) was reacted with bromoacetyl bromide analogously to Example 24a), 4-dimethylaminopyridine being employed as a base instead of pyridine. The title compound was obtained analogously to Example 24 40 starting from H-(D)-Cha-Pyr-NH-3-(6-CN)-pico x HCl and the 4-oxo-4-(1-pyrrolidinyl)butyl bromoacetate prepared in b). FAB-MS (M+H+): 612 45 47 Example 30: N-[2-(Cyclohexylamino)- 2 -oxoethyloxycarbonylmethylene]-(D) cyclohexylalanyl-3, 4-dehydroprolyl-(6-hydroxyamidino-3-picolyl) amide 5 a) N-Cyclohexyl-2-hydroxyacetamide A mixture of 1.2 g (10 mmol) of 1,4-dioxane-2,5-dione and 4.0 g (40 mmol) of cyclohexylamine was stirred at a 10 temperature of 100*C for 3 hours.. The cyclohexylamine was distilled off in vacuo in a rotary evaporator to the greatest possible extent, and the residue was dissolved a number of times in toluene and concentrated again in order to remove traces of the base. The product obtained was dissolved in 15 diethyl ether and added dropwise to petroleum ether, a precipitate being deposited. The precipitate was filtered off and employed in the following reaction without further purification. 20 b) 2-(Cyclohexylamino)-2-oxoethyl bromoacetate The product obtained in a) was reacted with bromoacetyl bromide analogously to Example 24a), 4 -dimethylaminopyridine being employed as base instead of pyridine. 25 Analogously to Example 24, the title compound was obtained starting from H-(D)-Cha-Pyr-NH-3-(6-CN)-pico x HCl and the 2-(cyclohexylamino)-2-oxoethyl .bromoacetate prepared in b). FAB-MS (M+H+): 612 30 Example 31: N-(Hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro prolyl-{5-[ 2-(1,2, 4-oxadiazol-3-yl-5-on) ]-pyridyl}methylamide hydrochloride 35 a) N-(tert-butoxycarbonylmethylene )-(Boc ) -(D)-cyclohexylalanyl 3, 4-dehydroprolyl-( 6 -hydroxyamidino-3-picolyl) amide 11.9 g (20 mmol) of N-(tert-butoxycarbonylmethylene)-(Boc) 40 (D)-cyclohexylalanyl-3, 4-dehydroprolyl-(6-cyano-3-picolyl) amide (WO 96/25426, Example 93, Stage b), 2.78 g (40 mmol) of hydroxylamine hydrochloride and 4.65 g (36 mmol) of diisopropylethylamine were dissolved in 100 ml of ethanol and .heated at 55-60 0 C for 5 hours. The solution was concentrated 45 in vacuo, the residue was taken up in 100 ml of ethyl acetate and the mixture was washed twice with saturated sodium chloride solution. After drying and distilling off the 48 solvent, 11.3 g (90% of theory) of slightly yellowish, amorphous residue remained. b) N-(tert-Butoxycarbonylmethylene )-(Boc) -(D)-cyclohexyl 5 a-lanyl-3,4-dehydroprolyl-{5-[2-(1,2, 4 -oxadiazol-3-yl-5-one)] pyridyl}methylamide 10.2 g (16.2 mmol) of the above amidoxime were dissolved in 60 ml of pyridine and, after addition of 2.9 g (17.9 mmol) of 10 carbonyldiimidazole, heated under reflux for 3 hours. The pyridine was distilled off in vacuo, the residue was taken up in methyl tert-butyl ether, and the solution was washed with 5% strength citric acid solution and finally with saturated sodium chloride solution. After drying and distilling off the 15 solvent, 10 g (94% of theory) of amorphous residue remained). c) N-(Hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 dehydroprolyl-{S-[ 2-(1,2, 4 -oxadiazol-3-yl-5-one) ]-pyridyl} methylamide hydrochloride 20 10 g (15.3 mmol) of the compound obtained in b) were dissolved in 80 ml of glacial acetic acid, treated with 80 ml of a 4N solution of hydrogen chloride in dioxane and allowed to stand at room temperature overnight. 25 After distilling off the solvent in vacuo (toward the end with addition of toluene), the amorphous residue was purified by column chromatography (eluent: ethanol/25% strength ammonia = 50:2.5). The residue was dissolved in a mixture of 30 water and dioxane (ratio 3:7), treated with one equivalent of 32% strength hydrochloric acid and concentrated to dryness. The residue was digested with acetonitrile and then filtered off with suction. 3.9 g (48% of theory) of a white powder were isolated; 35 FAB-MS (M+H+): 499 Example 32: N-(Methoxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro prolyl-{5-[ 2-(1,2, 4 -oxadiazol-3-yl-5-one) ]-pyridyl}methylamide 0 hydrochloride 1.9 g (3.6 mmol)of N-(hydroxycarbonylmethylene)-(D) cyclohexylalanyl-3, 4-dehydroprolyl-{5-[ 2-(1,2, 4-oxadiazol-3-yl-5 one)]-pyridyl}methylamide hydrochloride (see Example 31) were 5 dissolved in 100 ml of methanol and, with addition of 10 ml of a 49 4N solution of hydrogen chloride in dioxane, heated under reflux for 8 hours. The residue was digested with acetonitrile and then filtered off 5 with suction. 1.65 g (85% of theory) of a white powder were. isolated; FAB-MS (M+H+): 513 Example 33: 10 N-(Neopentyloxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 dehydroprolyl-(6-amidino-3-picolyl) amide This compound was prepared analogously to Example 7 from N-(hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro 15 prolyl-(6-namidino-3-picolyl)amide hydrochloride (Preparation: WO 9625426, Example 93) and neopentyl alcohol. FAB-MS (M+H+): 527 Example 34: 20 N-(n-Hexyloxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 dehydroprolyl-( 6-amidino-3-picolyl ) amide This compound was prepared analogously to Example 7 from N-(hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro 25 prolyl-(6-amidino-3-picolyl)amide hydrochloride (Preparation: WO 9625426, Example 93) and n-hexanol. FAB-MS (M+H+): 541 Example 35: 30 N-(c-Hexyloxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro prolyl-(6-amidino-3-picolyl)amide This compound was prepared analogously to Example 7 from N-( hydroxycarbonylmethylene )-( D)-cyclohexylalanyl-3, 4-dehydro 35 prolyl-(6-amidino-3-picolyl)amide hydrochloride (Preparation: WO 9625426, Example 93) and c-hexanol. FAB-MS (M+H+): 539 Example 36: 40 N-(methoxyethoxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 dehydroprolyl-( 6-amidino-3-picolyl ) amide This compound was prepared analogously to Example 7 from N-(hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3, 4 45 dehydroprolyl-( 6-amidino-3-picolyl ) amide hydrochloride (Preparation: WO 9625426, Example '93) and ethylene glycol monomethyl ether.
50 FAB-MS (M+H+): 515 Example 37: N-(O-Methyldiethoxyoxycarbonylmethylene)-(D)-cyclohexylalanyl 5 3,4-dehydroprolyl-( 6 -amidino-3-picolyl)amide This compound was prepared analogously to Example 7 from N-(hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydroprol yl-(6-amidino-3-picolyl)amide hydrochloride (Preparation: 10 WO 9625426, Example 93) and diethylene glycol monomethyl ether. FAB-MS (M+H+): 559 Example 38: N-(Methoxyethoxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 15 dehydroprolyl-(6-methoxyamidino-3-picolyl)amide This compound was prepared starting from N-(tert-butoxycarbonyl methylene)-(Boc)-(D)-cyclohexylalanyl-3,4-dehydroprolyl-(6 methoxyamidino-3-picolyl)amide (see Ex. 10c). 20 The removal of the protective groups and the transesterification/ esterification of the carboxyl function in t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-C=NH(NHOCH 3 ))-pico was achieved by treating with a 4N solution of hydrogen chloride in 25 dioxane and a large excess of ethylene glycol monomethyl ether. The work-up and purification of the compound obtained was carried out analogously to Ex. 11. FAB-MS (M+H+): 545 30 Example 39: N-(n-Octyloxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 dehydroprolyl-( 6 -methoxyamidino-3-picolyl)amide This compound was prepared starting from N-(tert-butoxycarbonyl 35 methylene)-(Boc)-(D)-cyclohexylalanyl-3,4-dehydroprolyl
(
6 -methoxyamidino-3-picolyl)amide (see Ex. 10c). The removal of the protective groups and the transesterification/ esterification of the carboxyl- function in 40 t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-C=NH(NHOCH 3 ))-pico was achieved by treating with a 4N solution of hydrogen chloride in dioxane and a large excess of n-octanol. The work-up and purification of the compound obtained was carried out analogously to Ex. 11. 15 FAB-MS (M+H+): 599 51 Example 40: N-( c-Hexyloxycarbonylmethylene )-(D)-cyclohexylalanyl-3, 4 dehydroprolyl-(6-methoxyamidino-3-picolyl)amide 5 This compound was prepared starting from N-(tert-butoxycarbonyl methylene )-(Boc )-( D)-cyclohexylalanyl-3, 4-dehydroprolyl-(6 methoxyamidino-3-picolyl)amide (see Ex. 10c). The removal of the protective groups and the transesterification/esterification of the carboxyl function in 10 t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-C=NH(NHOCH 3 ))-pico was achieved by treating with a 4N solution of hydrogen chloride in dioxane and a large excess of cyclohexanol. The work-up and purification of the compound obtained was carried out analogously to Ex. 11. 15 FAB-MS (M+H+): 569 Example 41: N-( Hydroxycarbonylmethylene )-(D)-cyclohexylalanyl-3, 4-dehydro prolyl-(6-allyloxyamidino-3-picolyl)amide 20 a) N-(tert-butoxycarbonylmethylene)-(Boc)-(D)-cyclohexylalanyl 3, 4-dehydroprolyl-(6-aminothiocarbonyl-3-picolyl)amide t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-CN)-pico (WO 96/25426, Ex. 93, stage b) was reacted with hydrogen sulfide in 25 pyridine /triethylamine to give the corresponding thioamide t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-CSNH 2 )-pico according to WO 96/25426, Ex. 93, Stage c). b) N-(tert-Butoxycarbonylmethylene)-(Boc)-(D)-cyclohexylalanyl 30 3, 4-dehydroprolyl-( 6-S-methyliminothiocarbonyl-3-picolyl) amide hydroiodide The product t-BuO2C-CH2-(Boc)-(D)-Cha-Pyr-NH-3-(6-CSNH 2 ).-pico obtained from a) was reacted with methyl iodide to give 35 t-BuO 2
C-CH
2 -(Boc )-(D)-Cha-Pyr-NH-3-( 6-C=NH (SCH 3 ) )-pico x HI analogously to WO 96/25426, Ex. 93, Stage d). c) N-( tert-Butoxycarbonylmethylene )-( Boc )-( D )-cyclohexylalanyl 3, 4-dehydroprolyl-( 6-allyloxyamidino-3-picolyl) amide 40 O-Allylhydroxylamine hydrochloride (0.93 g, 7.0 mmol) were dissolved in 20 ml of methanol and converted into the corresponding acetic acid salt by means of an ion exchanger .(Fluka: acetate on polymeric support, 3.0 mmol of acetate per 45 g). t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-C=NH(SCH 3 ))-pico x HI (4.5 g, 5.8 mmol; see b) was added to this methanolic solution and the reaction mixture was stirred at room 52 temperature overnight. After concentrating in vacuo, the residue was taken up in ethyl acetate, washed three times with 30 ml each of water, twice with 20 ml each of 20% strength sodium hydrogensulfate solution and once with 30 ml 5 of saturated sodium chloride solution and then purified by column chromatography on silica gel, 2.1 g of the desired product being isolated. d) N-(Hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 10 dehydroprolyl-(6-allyloxyamidino-3-picolyl)amide The product t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH 3-(6-C=NH(NHO-allyl))-pico (2.1 g, 3.1 mmol) obtained as in c) was dissolved in 5 ml of absolute dioxane, cooled to 0*C 15 and treated with 5 ml of a 4N solution of hydrogen chloride in dioxane. The mixture was stirred at room temperature for 6 h with exclusion of moisture and concentrated, then the residue was dissolved in water, the solution was subjected to salt exchange by means of an acetate exchanger and the 20 aqueous phase was freeze dried. 0.69 g of the title compound was obtained as a white powder. FAB-MS (M+H+): 513 Example 42: 25 N-(Hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro prolyl-(6-benzyloxyamidino-3-picolyl)amide This compound was prepared analogously to Example 41, the product t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-C=NH(SCH 3 ))-pico x HI 30 obtained in 41c) being reacted with O-benzylhydroxylamine (corresponding to Ex. 40 subjected to salt exchange from the hydrochloride to the acetate) at 35*C in the course of 30 min. Work-up was carried out analogously to Ex. 41. As the purification by column chromatography by means of MPLC (silica 35 gel) using the eluent ethyl acetate/cyclohexnae = 1:1 failed, a second purification was carried out by means of MPLC (eluent ethyl acetate/cyclohexane = 3:7). 1.5 g of the title compound were obtained as a white powder. The removal of the Boc protective group and the hydrolysis of the tert-butyl ester were 40 carried out using a solution of hydrogen chloride in diethyl ether. FAB-MS (M+H+): 563 45 53 Example 43: N-(Hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro prolyl-[ 6-(m-methoxy-benzyloxy) amidino-3-picolyl ] amide 5 This compound was prepared analogously to Example 41, the product t-BuO 2
C-CH
2 -(Boc )-( D)-Cha-Pyr-NH-3-( 6-C=NH (SCH 3 ) )-pico x HI obtained in 41c) being reacted with 0-(m-methoxybenzyl) hydroxylamine (corresponding to Ex. 40 subjected to salt exchange from the hydrochloride to the acetate) at 35 0 C in the course of 30 10 min. Work-up was carried out analogously to Ex. 41. As the purification by column chromatography by means of MPLC (silica gel) using the eluent ethyl acetate/cyclohexnae = 1:1 failed, a second purification was carried out by means of MPLC (eluent ethylacetate/cyclohexane = 3:7). 1.5 g of the title compound were 15 obtained as a white powder. The removal of the Boc protective group and the hydrolysis of the tert-butyl ester were carried out using a solution of hydrogen chloride in diethyl ether. FAB-MS (M+H+): 563 20 Example 44: N-(Hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4 dehydroprolyl-[6-(4-chlorophenyl)hexyloxy)amidino-3-picolyl] amide 25 This compound was prepared analogously to Example 41, the product t-Bu0 2 C-CH2-(Boc)-(D)-Cha-Pyr-NH-3-(6-C=NH(SCH 3 ))-pico x HI obtained in 41 c) being reacted with O-[ 6
-(
4 -chlorophenyl)hexyl hydroxylamine at 20 0 C in the course of 10 hours. The removal of the -Boc protective group and the hydrolysis of the tert-butyl 30 ester were carried out using a 4N solution of hydrogen chloride in dioxane. FAB-MS (M+H+): 667 Example 45: 35 N-(Ethoxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro prolyl-[6-(4-chlorophenyl)hexyloxy)amidino-3-picolyl]amide This compound was prepared analogously to Example 11 by esterification of N-(hydroxycarbonylmethylene)-(D)-cyclohexyl 40 alanyl-3,4-dehydroprolyl-[6-(4-chlorophenyl)hexyloxy)-amidino-3 picolyllamide (Ex. 44) with ethanol in a 4N solution of hydrogen chloride in dioxane. FAB-MS (M+H+): 695 54 Example 46: N-(Hydroxycarbonylmethylene)-(D)-cyclohexylalanyl-3,4-dehydro prolyl-[ 6 -(p-methyl-benzyloxy)amidino-3-picolyl]amide 5 This compound was prepared analogously to Example 43, the product t-BuO 2 C-CH2-(Boc)-(D)-Cha-Pyr-NH-3-(6-C=NH(SCH 3 ))-pico x HI obtained in 41 c) being reacted with 0-(p-methylbenzyl) hydroxylamine. The removal of the Boc protective group and the hydrolysis of the tert-butyl ester were carried out using a 4N 10 solution of hydrogen chloride in dioxane. FAB-MS (M+H+): 577 Example 47: N-( Ethoxycarbonylmethylene )-( D )-cyclohexylalanyl-3, 4-dehydro 15 prolyl-[6-(p-methylbenzyloxy)amidino-3-picolyl]amide This compound was prepared analogously to Example 11 by esterification of N-(hydroxycarbonylmethylene)-(D) cyclohexylalanyl-3, 4-dehydroprolyl-[ 6 -(p-methylbenzyloxy) amidino 20 3 -picolyl]amide (Ex. 46) with ethanol in a 4N solution of hydrogen chloride in dioxane. FAB-MS (M+H+): 605 Example 48: 25 N-(Hydroxycarbonylmethylene)- (D)-cyclohexylalanyl-3,4-dehydro prolyl-[6-phenyloxyamidino-3-picolyl]amide This compound was prepared analogously to Example 43, the product t-Bu 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-C=NH(SCH 3 ))-pico x HI 30 obtained in 41c) being reacted with 0-phenylhydroxylamine hydrochloride in the presence of two equivalents of diisopropylethylamine. The removal of the Boc protective group and hydrolysis of the tert-butyl ester was carried out using a 4N solution of hydrogen chloride in dioxane. 35 FAB-MS (M+H+): 549 Example 49: N-( Ethoxycarbonylmethylene )-(D)-cyclohexylalanyl-3, 4 dehydroprolyl-[6-phenyloxyamidino--3-picolyl]amide This compound was prepared analogously to Example 11 by esterification of N-(hydroxycarbonylmethylene)-(D) cyclohexylalanyl-3, 4-dehydroprolyl-[ 6 -phenyloxyamidino-3 picolyl]amide (Ex. 48) with ethanol in a 4N solution of hydrogen 5 chloride in dioxane. FAB-MS (M+H+): 577 55 Example 50: N-(Hydroxycarbonylmethylene)-( D)-cyclohexylalanyl-3,4 dehydroprolyl-[ 6 -isopentyloxyinidino-3-picolyl]amide 5 This compound was prepared analogously to Example 43, the product t-BuO 2
C-CH
2 -(Boc)-(D)-Cha-Pyr-NH-3-(6-C=NH(SCH 3 ))-pico x HI obtained in 41c) being reacted with 0-isopentylhydroxylamine hydrochloride in the presence of six equivalents of diisopropylethylamine. The removal of the Boc protective group 10 and the hydrolysis of the tert-butyl ester was carried out using a solution of hydrogen chloride in diethyl ether. FAB-MS (M+H+): 543 Example 51: 15 N-( Ethoxycarbonylmethylene )-( D)-cyclohexylalanyl-3, 4 dehydroprolyl-[6-isopentyloxyamidino-3-picolyl]amide This compound was prepared analogously to Example 11 by esterification of N-(hydroxycarbonylmethylene)-(D) 20 cyclohexylalanyl-3, 4-dehydroprolyl-[ 6 -isopentyloxyamidino-3 picolyl]-amide (Ex. 50) with ethanol in a 4N solution of hydrogen chloride in dioxane. FAB-MS (M+H+): 571 25 30 35 40 45

Claims (7)

1. A compound of the formula I
5. N-G A-B-D-H- 2 -K 10 in which A, B, D, G and K have the following meanings: A is: R10OC-CH2-, R10OC-CH 2 -CH 2 -, R 1 00C-CH(CH 3 )-, HO-CH 2 -CH 2 -, 15 Ik2R 3 N(O)C-CH2-, R 2 R 3 N-0-CO-CH2-, R 2 N(OH)-CO-CH2-, where R 2 and R 3 independently of one another are H, Ci-C 6 -alkyl, C3-CS-cycloalkyl, C3-Cs-cycloalkyl-Ci-C3-alkyl, or benzyl, or R 2 and R 3 together form a C 4 -C 6 -alkylene chain, 20 in which R 1 is: H-, C 1 -C 16 -alkyl-, H 3 C-[O-CH2-CH2]q (q = 1-4), CIo-tricycloalkyl-, Clo-tricycloalkyl-CH2-, C 3 -CS-cycloalkyl-, C 3 -Cs-cycloalkyl-Ci-C3-alkyl-, where a phenyl ring can be 25 fused to the cycloalkyl ring, pyranyl-, piperidinyl-, aryl or phenyl-Ci-C3-alkyl-, where except for H all radicals mentioned can optionally carry up to 4 identical or different radicals selected from Ci-C 4 -alkyl, CF 3 , F, Cl, N02, HO or Ci-C 4 -alkoxy radicals, or 30 R 1 is ( 2 -oxo-1,3-ioxolen-4-yl)methyl-, which can be substituted in the 5-position by Ci-C 1 6 -alkyl or aryl, or 35 R 1 is: R4-C(O)O-C(Rs)2-, R4-C(O)NR 2 -C(RS)2-, where R 4 can be Ci-C 4 -alkyl-, C 3- CS-cycloalkyl-Ci-C 3 -alkyl-, C 3 -CS-cycloalkyl-, Ci-C 4 -alkyloxy-, C3-C8-cycloalkyl-Ci-C3-alkyloxy C 3 -C8-cycloalkyloxy-, aryl- or phenyl-Ci-C6-alkyl-, the two 40 radicals R 5 independently of one another are H, CH 3 or C 2 Hs, and R 2 has the meaning indicated above, R 6 00C-C1-C 6 -alkyl, R 6 R 7 N(0 )C-C 1 -C 6 -alkyl-, R 6 R7N-C 2 -C6-alkyl-, and in which R 6 and R 7 independently of one another are H or .Ci-C 6 -alkyl, or 45 57 if R 1 is R 6 R 7 N()C-CI-C 6 -alkyl-, R 6 and R 7 together form a C 4 -C 6 -alkylene chain, or A is: 5 Cl-C 4 -alkyl-SO2-(CH 2 )2-6- , HO 3 S-(CH 2 )4-6-, 5-tetrazolyl-(CH2)1-6-, Ci-C 4 -alkyl-O-(CH 2 )2-6-, R 2 R 3 N-(CH 2 )2-6-, R 2 S-(CH 2 ) 2-6-, R 2 R 3 NSO 2 -(CH 2 )2-6-, HO-(CH 2 )2-6-, 10 B is R 9 (CH 2 )p -N- -CO 15 8 H R p isO,1,2 20 R 8 is H-, R 10 00C- where R 10 = Ci- 16 -alkyl-, phenyl-, C 3 -C8-cycloalkyl-, phenyl-Ci-C 4 -alkyl-, RilC(O)-0-CH 2 -, R 1 lC(O)-O-CH(CH 3 )-, where R 11 can be Ci-C 4 -alkyl-, phenyl-, benzyl-, C 3 -CS-cycloalkyl- or cyclohexyl-CH2-, 25 R 9 is C3-0-cycloalkyl-, which can carry up to four identical or different CI_4-alkyl radicals, D is: 30 N N o d o 35 G is: -H, -OH, -OR 12 , in which R 12 is: -Ci-g-alkyl, -C 3 -Ce-cycloalkyl, -Ci-C 3 -alkyl-C 3 -C8-cycloalkyl, -aryl or -Ci-C 6 -alkylphenyl, 40 which can optionally carry up to three Ci-C 4 -alkyl, CF 3 , F, Cl, or CI-C 4 -alkoxy radicals, K is:H, or G. and K together form a -C(0)O-group, 45 their configurational isomers, tautomers and their salts with physiologically tolerable acids, 58 where the following applies: (i) 5 if D = (II) or (III) and G = -H, -OH, -OR 12 , in which R 12 is: -Ci-Cs-alkyl, -C 1 -C 3 -alkyl-C 3 -C8-cycloalkyl, -aryl or 10 -Ci-C 6 -alkylphenyl, which can optionally carry up to three Ci-C 4 -alkyl, CF 3 , F, Cl, or CI-C 4 -alkoxy radicals K is: H, 15 or G and K together form a -C(0)O-group, then A and B have the following meanings: A: R 1 0OC-CH 2 -, RIOOC-CH 2 -CH2-, R 1 0OC-CH(CH 3 )-, HO-CH 2 -CH 2 -, R 2 aR 3 aN(O)C-CH 2 -, R 2 R 3 N-0-CO-CH2-, R 2 N(OH)-CO-CH 2 -, where R 2 20 and R 3 independently of one another are H, C 1 -C 6 -alkyl, C 3 -CS-cycloalkyl or benzyl or R 2 and R 3 together form a C 4 -C 6 -alkylene chain, R 2 a is equal to H and R 3 a is C 5 -CS-alkyl, C 3 -C8-cycloalkyl or benzyl; 25 in which R 1 is: C 5 -C 1 6 -alkyl-, H 3 C-[0-CH2-CH2]q (q = 1-4), C 1 0 -tricycloalkyl-, Cio-tricycloalkyl-CH 2 -, C 3 -CB-cycloalkyl-, C 3 -Ce-cycloalkyl-Ci-C3-alkyl-, where the phenyl ring can be 30 fused to the cycloalkyl ring, pyranyl-, piperidinyl-, or aryl-, where except for H all radicals mentioned can optionally carry up to four identical or different radicals selected from Ci-C-alkyl, CF 3 , F, Cl, NO 2 , HO or Ci-C 4 -alkoxy radicals, or 35 R 1 is (2-oxo-1,3-dioxolen-4-yl)methyl which can be substituted in the 5-position by Ci-C 1 6 -alkyl or aryl, or 40 R 1 is: R 4 -C(O)O-C(R 5 ) 2 -, R 4 -C(O)NR 2 --C(R 5 ) 2 -, where R 4 can be Ci-C 4 -alkyl-, C 3 -C 8 -cycloalkyl-Ci-C 3 -alkyl-, C 3 -C 8 -cycloalkyl-, Ci-C 4 -alkyloxy-, C 3 -CS-cycloalkyl-Ci-C 3 -alkyloxy-, C 3 -C 8 -cycloalkyloxy-, aryl- or phenyl-C 1 -C 6 -alkyl-, the two radicals R 5 independently of one another are H, CH 3 or C 2 H 5 , 45 and R 2 has the meaning indicated above, 59 R 6 00C-Cj-C 6 -alkyl-, R 6 R 7 N(O)C-Ci-C 6 -alkyl-, R 6 R7N-C 2 -C 6 -alkyl-, and in which R 6 and R 7 independently of one another are H or Ci-C 6 -alkyl, or if R 1 is R6R 7 N()C-Ci-C6-alkyl-, R 6 and R 7 together form a 5 C-4-C 6 -alkylene chain, or A is C 1 -C 4 -alkyl-SO 2 -(CH2)2-6- , HO 3 S-(CH 2 )4-6-, 5-tetrazolyl-(CH 2 )1-6-i 10 C 1 -C 4 -alkyl-O-(CH2)2-6-, R 2 R 3 N-(CH 2 ) 2 -6-, R 2 S-(CH2)2-6-, R 2 R 3 NSO2-(CH 2 )2-6-, HO-(CH 2 )2-6, B is 15 ,R (CI-I P 20 p isO,1,2 R 8 is H-, R 1 0 00C- where R 1 0 = C 1 - 1 6 -alkyl-, phenyl-, C 3 -C 8 -cycloalkyl-, phenyl-C 1 -C 4 -alkyl-, R 1 1 C(O)-0-CH2-, 25 R11C(O)-O-CH(CH3)-, where R 1 1 can be Ci-C 4 -alkyl-, phenyl-, benzyl-, C 3 -C 8 -cyloalkyl- or cyclohexyl-CH2-, R 9 is C 3 -- cycloalkyl-, which can carry up to four identical or -different C 1 -4-alkyl radicals, 30 or (ii) 35 if D = (II) or (III) and G = -OR 1 2 , in which R 12 is: -CS-C 8 -alkyl, -C 3 -C 8 -cycloalkyl, 40 -C 1 -C 3 -alkyl-C 3 -C8-cycloalkyl, -aryl or -Ci-C 6 -alkylphenyl, which can optionally carry up to three Ci-C 4 -alkyl, CF 3 , F, Cl, or Ci-C 4 -alkoxy radicals, K is: H, 45 or G and K together form a -C(O)O-group, then A and B have the following meanings: 60 A is: R 1 0OC-CH 2 -, R 1 0OC-CH 2 -CH 2 -, R 1 0OC-CH(CH 3 )-, R 2 aR 3 aN(O)C-CH 2 -, where R 2 a and R3a independently of one another are H, Ci-C 6 -alkyl, C 3 -C9-cycloalkyl or benzyl or R2a and R3a together form a C 4 -C 6 -alkylene chain, 5 in which R 1 is: H-, Ci-C 4 -alkyl- or phenyl-Cl-C 4 -alkyl-, where except for H all radicals mentioned can optionally carry up to four 10 identical or different radicals selected from C 1 -C 4 -alkyl, CF 3 , F, Cl, N02, HO or Cl-C 4 -alkoxy radicals, B, p and R8, R 9 , R 10 and R 1 1 have the meaning indicated in i). 15 2. A compound of the formula I as claimed in claim 1 in i), in which A, B, D, G and K have the following meanings: A is: R 1 00C-CH 2 -, R10OC-CH 2 -CH2-, R 1 0OC-CH(CH 3 )-, 20 in which R 1 is: Cs-C 1 6 -alkyl-, H 3 C-[O-CH2-CH2]q (q = 1-4), C 1 0 -tricycloalkyl-, Cio-tricycloalkyl-CH 2 -, C 3 -Ce-cycloalkyl-, C 3 -C 8 -cycloalkyl-Cl-C3-alkyl-, where a phenyl ring can be 25 fused to the cycloalkyl ring, pyranyl-, piperidinyl-, where except for H all radicals mentioned can optionally carry up to four identical or different radicals selected from CH 3 , CF 3 , F, Cl, HO or methoxy radicals, or 30 R 1 is (2-oxo-1,3-dioxolen-4-yl)methyl-, which can be substituted in the 5-position by Ci-C 3 -alkyl or aryl, or 35 R 1 is: R 4 -C(O)O-C(R) 2 -, where R 4 C 1 -C 4 -alkyl-, C 3 -C-cycloalkyl-, Ci-C 4 -alkyloxy-, C 3 -C 8 -cycloalkyl-Ci-C 3 -alkyloxy-, C 3 -Ce-cycloalkyloxy-, or aryl- the two radicals R 5 independently of one another are H, CH 3 or C 2 Hs, R 6 0OC-C 1 -C 6 -alkyl-, R 6 R 7 N(0)C-Ci-C 6 -alkyl-, R 6 R 7 N-C 2 -C 6 -alkyl-, 40 and in which R 6 and R 7 independently of one another are H or Ci-C 6 -alkyl or, if R 1 is R 6 R 7 N(O)C-C 1 -C 6 -alkyl-, R 6 and R 7 together form a C 4 -C 6 -alkylene chain, 45 B is 61 I? --N-C-CO 5 .H p is 0,1 R8 is H-, R 10 0OC- and R 10 = Ci-a-alkyl-, phenyl-, C3-Cs-cycloalkyl-, 10 phenyl-Ci-C 4 -alkyl-, R 9 is C 3 - 8 -cycloalkyl-, which can carry up to four identical or different C 1 -4-alkyl radicals, 15 D = (II) and G = -H, -OH, -0-Ci-Ce-alkyl, K is: H 20 or G and K together form a -C(O)O-group. 3. A compound of the formula I as claimed in claim 1 in ii), in which A, B, D, G and K have the following meanings: 25 A is: RIOOC-CH 2 -, R 1 0OC-CH 2 --CH 2 -, R 1 0OC-CH(CH 3 )-, R 2 aR 3 aN(O)C-CH 2 -, where R 2 a and R 3 a independently of one another are H, Cl-C 6 -alkyl, C3-CB-cycloalkyl or benzyl, or R 2 a and R 3 a together form a C4-C6-alkylene chain, 30 in which RI is: H-, Cl-C 4 -alkyl- or phenyl-Ci-C 4 -alkyl-, where except for H all radicals mentioned can optionally carry up to four 35 identical or different radicals selected from CH 3 , CF 3 , F, Cl, HO or methoxy radicals, B is 40 (CH 2 )p R 45 p is 0, 1 62 R 8 is H-, R 1 0 0OC- and R 10 = CI-16-alkyl-, phenyl-, C3-Ce-cycloalkyl-, benzyl-, and R 9 has the meaning indicated in ii) 5 D = (II) G -OR 1 2 , 10 in which R 1 2 is: -C 5 -Ce-alkyl, -C3-C8-cycloalkyl, -Ci-C3-alky.-C3-Cq-cycloalkyl, -aryl or -Ci-C6-alkylphenyl, which can optionally carry up to three CH 3 -, CF 3 -, F-, Cl-, or 15 methoxy radicals, K is: H, or G and K together form a -C(0)O- group. 20 4. A compound of the formula I as claimed in claim 1, in which A, B, D, G and K have the following meanings: A is: RIOOC-CH 2 -, R 1 0OC-CH 2 -CH 2 -, R 1 0OC-CH(CH 3 )-, 25 in which RI is: C5-C 1 0 -alkyl-, C4-C7-cycloalkyl-, C4-C7.cycloalkyl-CH 2 -, where all radicals mentioned can optionally carry up to four 30 identical or different radicals selected from CH 3 - and methoxy-, B is R 9 2CHp -N-C-CO 1 8 H R 0 p isO,1, R 8 is H-, 5 R 9 is C4-7-cycloalkyl-, which can carry up to four identical or different methyl or ethyl radicals 63 D is: No '0 G is: -OH, K is: H. 10 5. A compound, its configurational isomers, tautomers and its salts with physiologically tolerable acids, selected from the group: 15 HOOC-CH2-(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico H 3 CO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico EtO-OC-CH 2 -(D)-Cha-Pyr-NH-3'-[6-am-(OH)]-pico nPrO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico iPrO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)] -pico 20 nBuO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH)]-pico iBuO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH) J-pico tBuO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH) ]-pico BnO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(OH) 3 -pico HOOC-CH 2 -(D) -Chg-Pyr-NH-3-[
6-am-(OH) ]-pico 25 H3CO-OC-CH 2 -(D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico EtO-OC-CH 2 -(D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico nPrO-OC-CH 2 -(D ) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico iPrO-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico nBuO-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(OH)]-pico 0 iBuO-OC-CH 2 -( D) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico tBuO-OC-CH 2 -( D ) -Chg-Pyr-NH-3-[ 6-am-(OH) ]-pico H 3 CO-OC-CH 2 -(D) -Cha-Pyr-NH-3-[ 6-am-(H)]-pico EtO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(H)]-pico nPrO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(H)]-pico 5 iPrO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(H)]-pico nBuO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(H)]-pico iBuO-OC-CH 2 -( D) -Cha-Pyr-NH-3-[6-am-( H) ]-pico tBuO-OC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(H)]-pico H3CO-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(H)]-pico EtO-OC-CH 2 -(D) -Chg-Pyr-NH-3-[ 6-am-(H) 3-pico nPrO-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(H)]-pico nBuO-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(H)]-pico iBuO-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(H)]-pico .tBuO-OC-CH 2 -( D) -Chg-Pyr-NH-3-[6-am-(H) ]-pico HOOC-CH 2 -(D)-Cha-Pyr-NH-3-[6-am-(O-allyl)]-pico H 3 CO-OC-CH 2 -(D)-Chg-Pyr-NH-3-[6-am-(OCH 3 )]-pico 64 iPrO-OC-CH 2 - (D) -Cha-Pyr-NH-3- [6-am- (OCH 3 ) I -Pico 6. A drug comprising, in addition to customary vehicles and excipients, compounds of the general formula I as claimed in 5 any one of claims 1 to 5.
7. The use of compounds of the general formula I as claimed in any one of claims 1 to 5 for the production of drugs for the therapy and prophylaxis of thrombin-dependent thromboembolic 10 events.
8. The use of compounds of the general formula I as claimed in any one of claims 1 to 5 for the production of drugs for the therapy and prophylaxis of 15 - disorders whose pathological mechanism is based directly or indirectly on the proteolytic action of thrombin, - disorders whose pathological mechanism is based on the 20 thrombin-dependent activation of receptors and signal transduction, - disorders which are accompanied by stimulation or inhibition of gene expression in body cells, 25 - disorders which are based on the mitogenic action of thrombin, - disorders which are based on a thrombin-dependent 30 contractility and permeability change in epithelial cells, - thrombin-dependent, thromboembolic events, - disseminated intravasal coagulation (DIC), 35 - reocclusion and for the reduction of the reperfusion time in the case of comedication with thrombolytics, - the occurrence of earlier reocclusion and later restenosis 40 after PTCA, - the thrombin-dependent proliferation of smooth muscle cells, - the accumulation of active .thrombin in the CNS, 45 65 tumor growth and against the adhesion and metastasis of tumor cells.
9. The use of the compounds of the general formula I (as claimed 5 in any on of claims 1 to 5 as prodrugs for the production of a drug for oral or parenteral administration.
10. The use of compounds of the general formula I as claimed in any one of claims 1 to 5 for the production of drugs having 10 improved absorption in the gastrointestinal tract or a flattening of the amplitude of the plasma concentration time profile over the dose range or an increase in the duration of action of the active compound, comparison in each case being made with the pharmacologically active compounds. 5 D
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