MXPA97005970A

MXPA97005970A - Tromb inhibitors

Info

Publication number: MXPA97005970A
Authority: MX

Abstract

The present invention relates to inhibitors of thrombosis of the formula I: wherein R 1, A, B and D have the meanings indicated in the description, and intermediates for the preparation thereof. The compounds I are suitable for controlling disease

Description

TROMBINE INHIBITORS The present invention relates to p-amidinsbenz and peptide licks with sulphonyl or N-terminal aminosulfone radicals, to the preparation thereof and the present invention also relates to the use thereof as inhibitors of the trina. EP 601 45 ?, EP 67 658, WO 94/29336 and WO 95/23609 describe peptide thrombin inhibitors. The present invention relates to thrombin inhibitors of the formula I NB Rl- S0 -A- B- NH- D- Z NH2 and to the stereoisomers thereof and the salts thereof with physiologically tolerated acids, wherein the functionality to idine may be in monoprotected or diprotected form and wherein the components have the following meanings: R1 is OH, C1-C20 alkyl , C1-C3 alkyl, C3-C8 cycloalkyl, C1-C10 arylalkyl, aryl, hetaryl, R200C- < CH2 > not just R 3 R 2 N, where R 2 and R 3 are identical or different and are hydrogen, C 1 -C 10 alkyl, aryl, arylalkyl C 1 -C 10 or together are a C 2 -C 7 alkylene chain to which an aryl or heteryl radical can be fused or which may contain a heteroatom < 0, S, NH or N substituted), and n is 1, 2, 3 or 4, A: a res id id of al fa-ami noá gone from the formula IIR «I NH - C CO II RI 5 where R4 is hydrogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, aryl or C 1 -C 3 arylalkyl, R 5 is hydrogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl-CH 2 -, it being possible for the CH 2 group in the ring it is replaced by 0, S, NR6, or bicycloalkyl- < CH2) 0.1 (sic), ada anti lo- (CH2) 0-1, (CH3> 3 Si-C1-C4 alkyl, aryl or arylalkyl C1-C3, hetaryl or heteroaryl C1-C3, if R4 is H, a C1-C8 alkyl radical wherein one hydrogen atom is replaced by SR6, 0R6, C0-0R6 <R6 = hydrogen, C1-C8 alkyl or C1-C3 alkylaryl) or C0NR7R8 (P.7 , R8 are identical or different and are H, C1-C4 alkyl, C3-C7 cycloalkyl or together are a C3-C6 alkylene chain), or R4 and R5 together are a C2-C6 alkylene chain which may contain a fused aryl radical, B: a cyclic alf-amino acid residue of the formula III III where it is 2, 3 or 4, and a hydrogen in the ring can be replaced by a hydrophilic group or Cl-C3 alkyl, and m is 3 or 4, a CH2 group in the ring can be replaced by or : < ígen > - > , sulfur, NH or N-C 1 -C 4 alkyl and / or two nearby hydrogen atoms can be replaced by a double bond either by a fused aromatic system or by a melamine chain with 4-6 carbon atoms, D: a structural fragment of formula IV, V or VI IV V VI where R9 is F, Cl, Br, N02, RISO, P.1500C, R150CH2, R15NH, R15C0NH, R15NH-C0 or R1500CCH20, where R15 is H, C1-C6 alkyl, benzyl or phenyl, RIO, RU are H, C1-C4 alkyl or R150, where R9 and RIO or Rll can together form a ring of fused phenylene or an alkylene chain consisting of 3 to 5 carbon atoms, wherein one or two carbon atoms may be replaced by oxygen, R12 is H or C1-C4 alkyl, R13 is alkyl C1-C4, phenylalkyl C1-C4, RISCO, CF3C0, C2F5C0, R150CH2, R1500C, R150CH2C0, R1500CCO or R15NHC0C0, R14 is H, C1-C4 alkyl, F, Cl, Br, N02, R150, R1500C, R150CH2, R15NH , R15C0NH, R15NH-C0 or R1500CCH20, and W, X, Y, Z are CH to either N, but at least one of the radicals W, X, Y or Z is N and the ring in VI can be substituted by 1 or 2 of the following radicals: C 1 -C 4 alkyl, OH, O-C 1 -C 4 alkyl, CF 3, F, Cl, Br, S-C 1 -C 4 alkyl, 0 (CH 2) n C00R 6 < n = 1-4). The term "aryl" everywhere means mannocyclic or bicyclic aromatic groups containing from 6 to 10 carbon atoms in a ring system, for example phenyl or naphthyl, and which can carry up to 3 identical or different substituents. The term "hetaryl" refers everywhere to 5-membered or 6-membered aromatic rings which may contain 1 or 2 heterethates as for example N, O or S and on which an aryl ring can be fused, for example a phenyl ring. The term "cycloalkyl" refers to cyclic hydrocarbon radicals saturated with 3 to 7 carbon atoms, for example cyclopentyl, cyclohexyl, cycloheptyl, it being possible for the rings to be substituted by halogen, C1-C4 alkyl and 0-alkyl. C1-C4. The following groups of compounds a to Ig are preferred: wherein, the R and the fragments A and B have the following meanings: Rl: OH, C1-C10 alkyl, CF3CH2, fepyl, naphthyl, phenyl-C1-C4 alkyl (especially benzyl and phenethyl), C1-C4-naphthylalkyl, pyridyl, isoquinone, NH2, monodium I-C1-C4 and cyhalkylamino C1-C4, piperidinii. A: glycine, alanine, valine, leucine, isoleucine, phenyl- and iclohe? Lgl icine, fsnii- and cyclohe: <i lalanina, tetrahi > dropirani Igl icina, tetrahidropi rani 1 val ina, alpha-meti lciclohe: < ilalanine, diphenyl- and dicycloexi lalanine, it being possible for the phenyl rings present in the residues to be replaced by up to three identical or different C1-C4 alkyl, 0-C1-C4 alkyl, OH, F, Cl or COOR6, aspartic acid , glutamic acid, aspargin, glutamine, the nitrogen atom possibly carrying, if required, one or two alkyl groups or being part of a C4-C8 ring, serine, homoserine, threonine, it being possible that the carboxyl group or hydroxyl group The latter is esterified or etherified by a C 1 -C 8 alkyl radical. The amino acids A preferably have the D configuration.

The fragments B z preferably have the configuration L. R9: is Cl, Br, N02, R150, R1500C, R150CH2, R15NH, R15C0NH or R1500CCH20, where R15 is H, C1-C6 alkyl, benzyl or phenyl, RIO: is H, C1-C4 alkyl or R150. Their particularly preferred components R and fragments A and B have the following meanings: R1: HO, CH3, CH3-CH2, CH3- < CH2 > 3, CF3CH2, fepyl, benzyl, phenethyl, pyridyl, (CH3) 2N, CH3-NH, NH2 and piperidini lo, A: cyclohexy lgl icine or cyclohexy lalanipa, tetrahydro-4-pirani Igl icine, tetrahydro-4-pirani 1 valine, dicyclohexyl or di feni lalanin or pheni lalanin, it being possible for the phenyl rings to be substituted by up to 3 identical or different CH30, CH3, HO, F or Cl radicals, serine or tert-butyl. Lensine The amino acids preferably have the D. B configuration: The B fragments preferably have the configuration L. R9: Cl, CH30 or HO RIO: H, CH3 or CH30 The meanings of the elements R 1, fragments A and B and X are the following: R 1 OH, C 1 -C 10 alkyl, CF 3 CH 2, phenyl, naphthyl, phenyl C 1 -C 4 alkyl (especially benzyl and phenethyl), n C 1 -C 4 uyl, pyridyl, isoquinolyl, NH 2, C 1 -C 4 alkyl, C 1 -C 4 dialkyl, piperidinium, glycine, naive, valine, leu, isoleucine , phenyl- or cyclohexylglycine, phenyl- or cyclosheyllanine, te rahi ropírani 1, tet ah ídropí ra ni Iva 1 ina, di feni 1 -or di-iclohe i lalapip , it being possible for the phenyl rings present in the residues to be substituted by up to 3 identical or different C1-C4 alkyl, 0-C1-C4 alkyl, OH, Fe, Cl or C00R6 radicals, aspartic acid, glutamic acid, asparagine, glutamine, the nitrogen atom possibly carrying, if required, one or two gi uμt > = 'alkyl b? .t? r. s? e? d?> part >: eu an lo C4-C8 , serine, homoserine, tre > 3nina, where the carboxyl or hydrophilic group can be esterified or etherified by a C 1 -C 8 alkyl radical. Amino acids A preferably have the D B configuration: The fragments B preferably have the configuration L X: CH or N. Especially preferred are the Rl fragments, fragments A and B and X with the following: R? : HO, CH3, rK "V- CH1", CH3- < CH? , 7,, CF-CHI, fenilu, be'fllo, feni le * lio, pipdilo, (CH3) 2N, CH3-NH, H pipe idini lo, A: cyclohem lgl ic ina or cyclohexyl lalanine, te ra idropi ran-4-? 1- li ina, te rahydropy ran-4-i 1-va 1 in, diciclohejíi 1- ob in di feni lalanina or feni lalanina, where the phenyl rings can be substituted by up to 3 radicals CH30, CH3, HO, F or else Cl identical or > J j -but i 1 be ina. The amino acids preferably have the D configuration.

B: The fragments; B preferably has the confi uration L. X: CH or N or the P itsants, the fragments A and B and X in the compounds T, Td e have the following meanings: Pli OH, C1-C10 alkyl, CF3CH2, phenyl, naphthyl, C1-C4-C1-C4-alkyl (especially benzyl and phenethyl), C1-C4-C1-C4-alkyl, pyriol, 1-chloro-1, NH2, C1-C4-onalkyl or 1-C4-cycloalkyl, pipen > I dini it A: c i lohe; * - i Igl ic ina or cyclohe? iinina (sic), tetrah ídropí r nilglicina, tetrah id or iranil alina, di feni 1- or dic ic lohe; < i the l ni na, feni la lanina sust ui a by 2 o 3 rad? »Tlf-, s?» "J» - ?? "? : I > .- •: > 'í > . > • f »" > ~ l yf-one >] -? CH30, CH3, HO, F or Cl, either serine or tert-but i 1 be ina. The disabled A have preference for the D configuration.

B: Fragment B preferably has the configuration L X: CH or N The substituents R, the fractions A and B and X here have the following meanings: Pl: OH, C1-C10 alkyl, CF3CH2, phenyl, naphtha, phenylalkyl C1-C4 (especially benzyl) and phenethyl ), naph and C1-C4 alkyl, pyridyl, isoquinolyl, NH2, • TKDnoa 1 qui la no C1-C4 or dialkylamino C1-C4, piperidinium, A: glycine, alanine, valma, leucine, isoleucine, phenyl-oi. »>; _- »> , > \ J >; 1 > "> i &. i 1? j 1 i -. i n H," •? • r111 - > 1 ... »n» zi • "1 ah" .- »i 1 .. I -i>. > - >? ~ The r: th i > J r» ~ »-4-pi ram 1»; »1 i> * t> -» - - t < H »" rah i ro-4-pir 3 n 11 31 i na, a 1 fa il -ciclohe: < i lalamine (sic), idifenil- or di »:: iclohe: < i lalanin, if possible that the phenyl rings present in the residues which are substituted by up to three C1-C4 alkyl radicals, 0-C1-C4 alkyl, OH, F, Cl or C00P6 i > different or different, acid aspart i > ™ »_), acid p» ?? t;! »? I? Ir, --isparagip., Jluinin. , the 5 volume > of a hydrogen atom possibly carrying, if required, one or two alkyl groups or forming part of "a C4-C8 ring, it being ina, ho oserine, threonine, s? end" 3 possible that the carboxyl or hydrophilic group is nified or etherified by a C 1 -C 8 alkyl radical. '3 ami north they have ot re eren the conf igg a > 'j ... n D B: The B fragments are preferably in the configuration LR ': CH3 or CH30 X: CH or N The following substances can be mentioned specifically: MeS02- (D) -alpha-Me-Cha ~ Pro-NH- (2-Me0) -4-amb EtS02- ( D, L) -Cog-Pro-NH- (2-MeO) -4-amb EtSD2-D- (3,4- or: < i) Phe ~ Pra-NH- (2-MeO) -4- amb MeS02- (D, L) - (l-Te ralinil 61y-Pro-NH- (2-MeO) -4-amb MeS02- (D, L) -Dpa-Pro-NH- (2-MeO) -4 -amb MeS02- (D, L) - (5-diben ?? suberil > Gly-Pro-NH- < 2-Me0) -4-amb EtS02-D- (4-methoxy) iPhe-Pro-NH (2-MeO) -4-amb MeS02- (D, L) - (3, 4, 5-1rimeto: < i) Phe-Pro -NH- (2-MeO) -4-amb CF2S02-D- (4-chloro) Phe-Pro-NH- (2-MeO) -4-amb CF3S02- (D, L) - (Me3Si) Ala-Pra -NH- (2-MeO) -4-amb MeS02- (D) -Chg-Pro-NH- (2-MeO) -4-amb CF3-CH2S02- (D) -Chg-P ro-NH- (2 -MeQ) -4-amb MeSD2- (D) -Phe-A2e-NH- (2-MeO) -4-amb MeS02- (D) - (tert-bu il) Ser-Pro-NH- (2-Me0) ) -4-amb MeS02- (D) -Cha-Pro-NH- (2-MeO) -4-amb Bz-P02- (D) -Cha-Pro-NH- < 2-Me0) -4-amb n-Bu-S02- (D) -Cha-Pro-NH- < 2-MeO) -4-amb H0-S02- (D) -Chg-Pro-NH- (2-NeO) -4-amb H2N-S02- < D) -Chg-Pro-NH- (2-MeO) -4-amb H2N-S0- (D) -Chg-P ra-NH- (2-MeO) -4-amb H00C-CH2-CH2-S02- (D > -Chg-P ra-NH- (2-MeO) -4-amb 2-Naph t. -S02- (D) -Phe-Pro-NH- (2-MeO) -4-amb MeS02- (D, L) - (beta-pheni 1) Pro-P ro-NH- (2-MeO) -4-amb MeS02- (D) -Chg-Aze-NH- (2-MeO) -4-amb MeS02 - (D) -Chg-Pic ~ NH- (2-MeO) -4-amb MeS02- (D) -Chg-Hyp-NH- (2-Me0) -4-amb MeS02- (D) -Chg-Pyr -NH- (2-Me0) -4-amb EtS02- (D) -Chg- (N-cyclopropyl) Gly-NH- (2-Me0) -4-amb MeS02 ~ (D) -Chg- 1-Tic- NH- (2-MeO) -4-amb MeS02- (D) -Chg-2-nd-NH- (2-MeO) -4-amb MeS02- (D) -Chg-2-Ph i -NH- (2-MeO) -4-amb EtS02- (D) -Chg- (Cy 1 o) Leu-NH- (2-MeO) -4-amb Pro-S02- (D) -Chg-Pro-NH- ( 2-iPrO) -4-amb Ph-S02- (D) -Chg-Pro-NH- (2-0H) -4-amb MeS02- (D) -Chg-Pro-NH- (2-0CH2-C00H) -4-amb MeS02- (D) -Chg-Pro-HN- (2-NH-CO e) -4-amb MeS02- (D) -Chg-P ro-NH- (2-NH2) -4-amb EtS02- (D) -Chg-Pro-NH- (2-C00H) -4-amb MeS02- (D) -Chg-Pro-NH- (2-C00Me) -4-amb MeS02- (D) -Chg- P ro-NH-2-CH20H) -4-amb EtS02- (D) -Chg-Pra-NH- (2-C1) -4-amb H0-S02- (D) -C hg-P rs-NH- (2-Br) -4-amb H2N-S0- (D) -Chg-Pr »3-NH- (2, -t: < i) -4 ~ amb MeSO- (D) -Chg-P ro-NH- (2, 3-d imetho < i) -4-amb EtSO- (D) -Chg-Pro-NH- (3- MeO) -4-amb H0S02- < D) -Chg-P ro-NH ~ (3-OH) -4-amb CF3S02- (D) -Chg-Pro-NH- < 3-iPrO) -4-amb MeS02- (D) -Chg-Pro-NH- (3-C1) -4-amb EtS02- (D) -Chg-Pro-NH- (4-am) -napme MeS02- < D) -Chg-Pro-NH-4-amb (ME) MeS02- (D) -Chg-Pro-NH-4-amb (COOH) MeSO- (D) -Chg-Pro-NH-4-amb (COOMe) ) MeS02- (D) -Phe-Pro-NH-4-amb (CH20H) MeS02- (D) -Phe-Pro-NH-4-amb (C0-CH2P) MeS02- (D) -Chg-Pro-NH -4-amb (C0-CF3) MeS02- (D) -Chg-Pro-NH-4-amb (CHO) -MeS02 ~ (D) -Chg-Pro-NH-4-amb (C0CH20H) MeS02- (D ) -Chg-Pro-NH-4-amb (C0C0NHCH3) MeS02- (D) Phe-Pro-NH- < -am) -3-pic MeS02- (D) Phe-Pro-NH- (2 ~ a-5-pyrim) met i lo MeS02- (D) Phe-Pro-NH- (5-am-2-pyr im ) met i lo MeSO- < D) Phe-Pro-NH- < ? -am-2-MeO) -3-p ic MeS02- (D) Phe-Pro-NH- (2-am-5-pyraz) me ilo EtS02 ~ (D) Phe-Pro-NH- (6-am -2-F) -3-p ic CF3-CH2-S02- (D) Phe-Pro-NH- (6-am ~ 2-0H) -3-pic n-BuS02- (D) -Phe-Pra- NH- (6-a ~ 2-BzO) -3-p ic n-BuS02- (D) -Phe-Pro-NH- (6-am-2-0H) -3-p ic n-oc i 1- S02- (D) -Phe-Pro-NH- (6-am-2-i-PrO) -3-pic Benc i 1-S02- (D) -Phe-Pro-NH- (6-am-2- OCH2-COOM) e-3-pic i-propi 1-S02- (D) Phe-Pro-NH- (S-am-6-Cl) -2-pic Feni 1-S02- (D) Phe-Pro -NH- (5-am-3-MeO) ~ 2-pic 2-naft i 1-S02- (D) Phe-Pro-NH- (5-am-3-0H) -2-pi 3-pi ri i 1 -S02- < D) Phe-Pro-NH- (5-am-3-Me) -2-pic 2-thienyl-S02 ~ (D) Phe-Pro-NH- (5-am-4-Me) -2-pic N -piperidinyl-S02- (D) Phe-Pro-NH- (5-am-3-MeO) -2-pic H2N-S02- (D) Phe-Pro-NH- (5-am-, -C12-2 -pyri) ethyl Me2N-S02- (D) Phe-Pro-NH- < 2-am-4, - (OH) 2-5-p and im) et i lo EtHN-S02- (D) Phe-Pro-NH- (2-am-4,6-C12-5-pyrim) me i MeS02- (D) Phe (4-0Me) -Pro-NH- (2-am-4, -Me2-5-pyr i) mti lo MeS02- (D) Phe < 3-0Me) -Pro-NH- (5-am-4, - (OH) 2-2-pyri) et i lo MeS02- (D) Fhe (4-Cl) -Pro-NH- (5-am- 4, 6-Me2-2-pyr im) me i lo MeS02- (D) Cha-Pro ~ NH- (6-am) -3-pic MeS02- (D) Cha-Pyr-NH- (6-am) -3-pi MeS02- (D) Cha-Pro-NH- (5-am) -2-pic MeS0- (D) Cha-Pra-NH- (2-am-5-pyrim) methyL MeS02- (D) Cha-Pro-NH- (5-am-2-p rim) eti lo MeS02- (D) Cha-Pro-NH- (6-am-2-Me) -3-p ic MeS02- (D >; Cha-Pro-NH- (-am-2-Me0) -3-pic MeS02 ~ (D) Cha-Pro-NH- (6-am-2-Cl) -3-pic MeS02- < D > Cha-Pra-NH- (2-am-4.6 <Me0) 2-5-pyrim) me ilo MeS02- (D) Cha-Prs-NH- (5-am-4,6- (MeO) 2 -2-pyrim) methyl MeS02- < D) Cha-P ra-NH- (2-a) -5-p and az MeS02- (D) Chg-Pro-NH- (6 m) -3-pic MeS02- (D) Chg-Pyr ~ NH- ( 6-am) -3 ~ pic MeS02 ~ (D) Chg-P ro-NH- (5-a) -2-p ic Me3 D2- (D) Chg-Pro-NH- < 2-am-5-p im) meti lo MeS02- (D) Chg-P ro-NH- (5-am-2-pyr im) met i MeS02- (D) Chg-Pro-NH- (6- am-2-Me) -3-pic MeS02 ~ (D) Chg-Pro-NH- (6-am-2-Me0) -3-pic MeS02- < D) Chg-Pro-NH- (-am-2-C1) -3-p ic MeS02- () Chg-Pro-NH- (2-am-4, o- < MeO) 2-5-p and im ) met i 1o MeS02- (D) Chg-Prs-NH- (5-am-4,6- (Me0) 2-2-pyrim) met i lo MeS02- (D) Dpa-Pro-NH- (6-) am) -3-pic MeS02- (D) Dpa-Pro-NH- (2-am-5-pyri) met i 1O MeS02- (D) Dpa (4,4'-MeO) -Pro-NH- ( 6-am) -3-pIC MeS02- (D) Dpa (4,4'-C12-Pro-NH- (6-am) -3-pic MeSO- (D, L) Phg (3, -C12) -Pro-NH- (5-a) -2-p ic MeS02- (D, L) Phg (3,4-C12) -Pro-NH- (5-am) -2-pytim) methyl MeS02- (D ) Tbg-Pro-NH- (6-am-2 ~ MeO) -3-pic MeS02- (D) Asp (0H) -Pro-NH- (2-am-4,6-C12-5-pyrim) methyl MeS02- (D) Asp (OMe) -Pro-NH- (2-am-5-pyrim) methyl MeS02- (D) Asp (OMe > -Pro-NH- (-am-2-Me) -3- p ic MeS02- (D) Asp (OtBu) -Pro-NH- < 6-am) -3-pic MeS02- (D) Asp (0tBu) -Pro-NH- (5-am-2-pyrim) ilo MeS02- (D) Phe-Aze-Pro-NH- (5-am) -2-pic MeS02- (D) Phe-Aze-Pro-NH- (2-am-4,6- (Me0) 2- 5-pyrim) me ilo MeS02 ~ (D) Phe-P ip-Pro-NH- (6-am) -3-p ic MeS02- (D) Phe-P ip-Pro-NH- (2-am-5 -pyrim) eti1o 1-nafti 1-S02-61y-Pro-NH- (5-am-) 2-pic l-naphthyl-S02-Gly-Pro-NH- (6-am-2-Me) -3- pic H00C- (CH2) 3-S02- (D) Chg-Pro-NH- (6-am) -3-pic HOOC- (CH2) 3-S02- < D) Chg-Pro-NH- (5-am) -2-p ic MeS02- (D) Ser (t-Bu) -P ro-NH- (6-am) -3-pic MeS02- (D) Ser (t-Bu) -Pra-NH- (5-am) -2 ~ pic H03S- (D) Chg-P ro-NH- (6-am) -3-p ic MeS02-TMS iA-P ro-NH - < 6-am) -3-p ic The following substances can be mentioned as preferred substances: 1. MeS02- (D) - (4-methoxy) Phe-Pro-NH- (2-MeO) -4 ~ amb 2. MeS02- (D) -Chg-P ro -NH-4-amb (Me) 3. MeS02- (D) -Cha-Pro-NH- (2-Me0) -4-amb 4. MeS02- (D, L) - Dpa-P ra-NH- (2-MeO) -4-amb 5. MeS02- (D) -Phe-Pro-NH- (6-am) -3-pic 6. MeS02- (D) -Chg-Pro -NH- (6-am) -3-pic 7. MeS02- (D) -Chg-P ro-NH- (5 -a) -2-p ic 8. MeS02- (D) -Cha-Pyr-NH - < 6-am) -3-p ic 9. MeS02- (D) -Chg-Pyr-NH- (6-am) -3-pic 10. H00C-CH2-S02- (D) -Cha-Pro-NH- (6-am) -3-p ic List of abbreviations: AIBN: Azobisisobuti rodini tri lo (sic) am: a idino Ala: alanine 4-amb: 4-amidinobenz i lo Asp: aspartic acid Aze: azet idincarboxy 1 ico acid Boc: tert-but i loxicarboni lo Bz: benzio Cbz: benci loxicarboni lo Cha: cic lohex i lalanina Chg: cyclohexi lgl icina Cog: cic1ooctilglicina Cpa: c iclopent i lalanina (Cyclo) Leu: 1-aminoc acid lohe; < ancarbo: < 1 1 DCM: dichloromethane Gly: glycine Hyp: hydra: < iprol ina 2-Ind: acid 2 indole in a rbo: < í 1 ico (sic) Leu: leucine napme: naphthylmethyl NBS: N-bromosucci imide Ph: phenyl Phe: phenylalanine 2-Phi: 2-perhydroindolcarboxy 1 icole foot: picolila pip: pipecolic acid Pro: proline Pyr: 3,4-pi rrol in-2 acid -carbo? í 1 ico pyri: piri idilo pyraz: pi rae i ni lo Tbg: tert-butilglicina I-Tic: acid 1-t trahidroi oquinol inc rboxi 1 ico 3-Tic: ácí »d > 3 3-tetrahi 'roi oquinol ipcarbo? í 1 ico TUSi A: »- r i '- i 1 s i 1 i 1.a 1 an i na 4-a» t, b (R13) is the structure R13 NH2 The invention relates to d i c. iana 1 to the compounds of the formulas, VII, VIII, IX and X NH H2N D CN VII H2N D-VIII NH2 NH R1 S02 AB NH -C \ NHOH where R1, A, B and D have the stated meanings, and where the amidene f in the formula VIII and in the formula I may be in the form or 'well diprotected. The intermediates are novel, and are used to prepare compounds I and are valuable building blocks for synthesizing serine protease inhibitors. The structural fragment of formula XI NH is novel and is widely used as a constituent of serine protease inhibitors and, particularly, of thrombin inhibitors. The compounds of the formula I can be used as such or in the form of their salts with physiologically tolerated acids. Examples of such acids are: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, allic acid, fumaric acid, maleic acid (sic), succinic acid, hydroxysuccinic acid, acid sulfuric acid, glutaric acid, aspartic acid, pyrovic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglin. The functionality of the compound in compounds I can be monoprotected or diprotected by a protective group amins. Groups Cbz and BOC are especially suitable as a protective group. The same applies to the amidine functionality in compounds VIII.

Compounds I can be prepared starting from the alpha-amino acid H-A-OH or from the cyclic amido acid N protein > gi > do B-OH com > : > It is shown in the schematics of Reflection I and 11"Esn and I Scheme I I B In the above reaction schemes, P.16 is H or C1-C4 alkyl, R17 is C1-C4 alkyl, preferably methyl or t-butyl, R18 is CN or - NH2 ^ H < ? N-P ^ '- C - C NHP NH-P NH2 and P is a protective group, preferably t-butoxycarboni the (Boc) or bec i lo: < i ca rboni lo (Cbz). Alternatively, the protected amino acids P-A-OH and H-B-CR17 uu-jd 'stat a »:. -. . . pa t a pr opor »; IGG ,; - »• 1 μéμ gone P-A-B-0R17 and then react, after elimination of P, with R1S02C1 or, after the elimination of R17 ion, with compounds of formula VII or HIV, with reaction sequence arbarria. R1-S02-A-0H can also be directly coupled with HB NH D R18 to give the final product I or .3 in 1 '3S intermediates VII or IC If intermediate groups containing amidine in protected form are used in the sequences of the previous reaction, the protective group (s) are eliminated in the final stage. If R18 is an amide, it can be converted, after linking to provide p B NH CH2 D C0NH2 or R1 S02 A B NH CH2 D C0NH2, in the nitrile and thereafter further converted to amidine. The required coupling reactions are carried out under standard conditions of peptide chemistry (see M. Bodansky, A. Bodansky "The Practice of Peptide Synthesis", Springer Verlag, ( 1084 (sic)) The Boc protecting groups are removed with HCl / dioxane or CF3C00H / ethylene chloride, and the Cbz protecting groups are removed by hydrogensis isis or with HF Ester functionalities are hydrolyzed with NaOH or LiOH in an alcoholic solvent such as methanol or ethanol, t-butyl esters are hydrolyzed with acids, for example CF3C00H. The reaction with the sulfonyl chlorides R1-SQ2C1 in the presence of an organic base such as, for example, triethyl, pyridine or N, N-i isopro i let and the ina is carried out in organic solvents such as CH2C12, THF or DMF. In the case of free earboxyl groups, the reaction is carried out in the presence of carbonate solutions or aqueous alkali metal hydroxide. The amidines are prepared from the precursors of ni rilo by means of the graphic synthesis, of Pinner (R. Roger and DG Neilson, Che. Rev. 61 (1961) 179) or, preferably, by means of a modified synthesis » of Pinner which is carried out by means of iminstyoster salts as intermediates (H. Vieweg et al., Pharmazie 39 (1984) 226). The in-catalytic hydrogenation of the N-hydroxyamidines, which are obtained by the addition of hydroxylamino on the cyano group, with Raney nickel or Pd / C in alcoholic solvents, also results in amidines (BJ Broughton et al., J Med Chem. 18 (1975) (1117) The novel components can be used for the therapy and prophylaxis of thrombin-dependent thrombinic events with, for example, deep vein thrombosis, pulmonary emboli, myocardial infarcts or cerebral infarcts. unstable angina, as well as for disseminated intravascular coagulation therapy (DIO) are also suitable for combination therapy with thrombolytic agents such as streptokinase, urokinase, prourokinase, t-PA, APSAC and other plasminogen activators to shorten the time of reperfusion and prolong reocclusion time Additional uses are prevention of initial reocclusion depending on thrombin and late restenosis after angina Percutaneous translumal coronary ioplasty, prevention of smooth muscle cell proliferation induced by thrombin, prevention of accumulation of active thrombin in the central nervous system (for example, in Alzheimer's disease), tumor control and prevention of mecarps that lead to the adherence and metasthesis of tumor cells. Its unique advantage is that they are effective even after oral administration. The compounds according to the present invention can be administered conventionally orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally, rectally). The administration can also be carried out with vapors or sprays through the nasopharyngeal space. The dosage depends on the age, condition and weight of the patient and the mode of administration. In general terms, the daily dose of active ingredient per person is approximately 10-2000 mg in the case of oral administration and approximately 1-200 mg in the case of parenteral administration. This dose can be administered in two or four single doses or once a day as a deposit. The novel compounds can be used in conventional solid dosage forms or in conventional forms, for example, in the form of uncoated or coated (film-coated) tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or tablets. . They are produced in a conventional manner. The active ingredients can be processed for this purpose with conventional pharmaceutical auxiliaries such as, for example, tablet binders, replenishers, preservatives, tablet disintegrants, flow regulators, plastifiants, wetting agents, dispersants, emu. Phosphate, solvents, sustained-release agents, antioxidants and / or booster gases (see H. Sucker et al., Pharmazeut ische Technologie (Pharmaceutical Technology), Thieme-Verlag, Stuttgart, 1978). The forms obtained in this way usually contain the active ingredient in a quantity of 0.1 to 9X by weight. EXAMPLE 1: Acetate of 2-methoxy-4-amidinobenzylamide of N- and i lsul foni 1- (D) -phenylalanyl-proline (a) 3-ni tro-4-met i Ibenzoni tr i lo 399 g were added (2.56 mol) of 4-met i lbenzoni tr i lo over the course of 90 minutes to 1 liter of smoking nitric acid at a temperature of -10 ° C. 1 hour >After the addition, the mixture was drained in 2.5 1 of ice water, then a solid was precipitated and said solid was separated in a melting filter funnel and washed to a pH of u with water. The yield was 363 g (88 * /,). 1H-NMR (CDC13; delta in ppm): 8.3 (d, 1H), 7.8 (dd, 1H); 7.5 (dd, 1H); 2.7 (2, 3H) (b) 3-amino-4-met i lbenzoni tri lo 120 g of 3-ni ro-4-met i lbenzoni lo was suspended in 1.2 1 of EtOH and hydrogenated in the presence of 7 g of Pd / C (10) with 50 1 of hydrogen at room temperature. After removal of the catalyst, the solvent was removed. Obtained 95 g of pure product (974 / «). 1 H-NMR (DMS0-d 6; delta in ppm): 7.1 (dd, 1H); 6.90 (d, 1H); 6.85 (dd, 1H); 5.35 < s, 2H, NH2 (sic)); 2.15 < s, 3H) (> ~) 3-hydroxy-4-met i. Ibenzoni tr i lo A solution of 49.2 g (0.72 mol) of NaN02 in 217 ml of water was added dropwise to 85 g (0.72 mol) of 3-amino-4-met i 1-benzoni tri lo in 1.8 1 of 6N HCl at a temperature of 0 ° C to 5 ° C over the course of a 0.5 hour period. The mixture was then stirred at a temperature between O'C and 5'C for an additional 30 minutes and subsequently at the boiling point for 1 hour. After cooling the solution, the product was extracted with ethyl acetate and, thereafter, in the form of the phenolate with 5N NaOH at ice temperature. The aqueous phase was then quenched to a pH of 3 with 6N HCl, and the product »3 was extracted with ethyl acetate. 41 g (43V «) were obtained. 1H-NMR < DMS0-d6; from a in ppm): 10.3 (s, OH); 7.25 (dd, 1H); 7.15 (d, 1H); (dd, 1H); 2.20 (s, 3H) (d) 3-methoxy-4-met i. Ibenzoni tri lo 15 g (0.11 mol) of 3-hydroxy-4-me i lbenzani ri dissolved in 30 ml of DMF were added dropwise to a suspension of 0.11 mol of NaH in 30 ml of DMF, and the mixture was stirred until no further evolution of H2 was observed. Then 10.6 ml (0.17 mol) of methyl iodide was added drop by drop, and the mixture was stirred at room temperature for 1 hour. The solution was poured into ice water, and the product was extracted with dichloromethane / ethyl acetate 7: 1. After removal of the solvent, the product began to crystallize slowly. 14.8 g (89X) were obtained. 1H-NMP. (CDC13? Delta in ppm): 7.2 < m, 2H); 7.02 (s, 1H); 3.85 (s, 3H); 2.25 (s, 3H) (e) 4-bromomet i-l-3-methoxybenzyl-3-one (sic) 14.7 g (0.1 mol) of 3-methoxy-4-met i lenzoni tri were dissolved. in 210 ml of 1,2-dichloroethane, brominads with 19.1 g (0.11 mole) of NBS in portions over the course of one hour in the presence of catalytic amounts of az »3b isisobut i G» D? C and after the addition was complete, it was stirred at 82 ° C for an additional 30 minutes. After the addition of n-heptane, the precipitated succiny was removed, and the solvent was removed. The yield was 18.5 (lagoon) (82 * /.). 1H-NMR (DMS0 ~ d6; delta in ppm): 7.60 (dd, 1H); 7.50 (d, 1H) | 7.40 (dd, 1H); 4.68 (s, 2H>; 3.96 (s, 3H) (f) 4-f ta 1 imidomet i-3-met> 3xibenz »3ni tr i lo 24.4 g (108 mol (sic)) of 4-bromomet i-3-etox ibenzoni tri lo, dissolved in 125 ml of DMF, and 20.0 g of potassium ph alimide were stirred at room temperature for 24 hours and then at 50 ° C for 1 hour. water, after which the product was precipitated as a solid, 21.5 g (68 '/,). 1H-NMR (DMS0-d6 $ delta in ppm): 7.9 (, 4H) j 7.5 were obtained. (d, 1H); 7.35-7.25 (m, 2H>, - 7.78 (s, 2H); 3.92 (s, 3H) (g) 4-ami nomet i 1-3-methox ibenzoni tri lo 10.6 ml of hydration at 21.2 g (73 mmol) of 4-phtal imidomet i 1-3-methoxybenzanitri dissolved in 290 ml of THF, and the mixture was stirred at room temperature for 20 hours, then 180 ml were added. of 2H (sic) HCl dropwise and, after 1.5 hours, the solvent was completely removed.The residue was collected in MTBE, extracted with 1 N HCl, adjusted The pH is 9-10 with 2N NaOH and extracted with methylene chloride. 8.0 g (68V.) Of product was obtained. 1H-NMR (DMS0-d6; delta in ppm): 7.55 (dd, ÍH); 7.40 (dd, 1H, 7.37 (d, 1H), - 3.85 (s, 3H), - 3.70 (s, 2H) j 2.5-1.6 (NH2). (h) 4-cians-2-methoxybenzene and boc-proline lick 16.0 g of Boc-proline (50 mmol), dissolved in 80 ml of THF, were stirred with 5.7 g of isocinimide hydroxide and 10.2 g of DDC in chloride I read O'C for 30 minutes. Then 8.0 g (50 mmol) of 4-aminomethyl-1-3-methoxybenzene tri. the di uelt > 3s in 50 ml of THF were added dropwise at a temperature of 0 ° C, and the mixture was stirred at room temperature for 20 hours. It is rem > The solid was filtered by filtration, the filtrate was mixed with the same volume of ethyl acetate and washed with an S > 3% NaHS04 5% solution and a saturated NaCl solution. 11.5 g (65 * / :) of product were obtained. 1 H-NMR (DMS0-d 6; delta in ppm): 8.38 (, NH); 7.50-7.35 (m, 3H); 4.40-4.05 (m, 3H, N-CH2-Ar / N-CH-CO); 3.87 (s, OCH3); 3.50-3.25 Cm, 2H, N-CH2); 2.2.5-2.00 (sic) (m, 1H); 1.90-1.65 (, 3H); 1.40 and 1.30 (2s; 9H) (i) 2-methoxy-4-cyanobenzyl proline lamide 11.4 g (31.7 mmol) of 2-methoxy-4-cyanobenzyl lamide from Boc-pralipa were dissolved in 130 ml of methylene chloride and, at a temperature between 0 ° C and 5 ° C, saturated with HCl. After 2 hours the > Boc group had been totally eliminated. The solvent was removed under reduced pressure, and the product was used without further purification in the next reaction. 1 H-NMR (DMS0-d 6; delta in ppm): 10.25 (s, 1H); 8.60 (s, 1H), 7.50 (d, 1H); 7.42 (dd, 1H); 7.39 (d, 1H); 4.40-4.20 (m, 3H); 3.88 (s, 3H); 3. 20 (m, 2H); 2.35 (m, 1H); 2.00-1.80 (m, 3H) (j) 2-methoxy-4-cyanobenzyl lamido Boc- (D) -4- ethoxylaepylalanylpropane 1.55 g (5.25 mmol) of Boc- (D) -Phe- (4- 0Me) -0H, 3.9 ml di isopropi. Let i lamina and 1.55 g (5.25 mmol) of proline 2-metaxy-4-cyanobenzylamide hydrochloride at a temperature of -5 ° C with 4.4 ml (5.9 mmol) of propane phosphonic anhydride (50 * A in ethyl acetate). ethyl) in 35 ml of methylene chloride and stirred at O'C for one hour. The reaction mixture was washed successively with NaOH 1 N, IN HCl and saturated brine and dried over Na 2 SO 4. The solvent was removed for > : lej r 2.4 g of a solid. 1 H-NMR (DMS0-d 6; delta in ppm): 8.72 and 7.87 (t, 2H); 7.42 (1H); 7. 35 (m, 3H); 7.15 (d, 2H); 6.85 (d, 2H); 7.00 + 6.70 (2d) 1H; 4.40-4-10 (, 4H); 3.85 (s, 3H, 3.70 (s, 3H &; 3.05-2.55) (m, 4H); 1.95-1.55 (m, 4H); 1.2 (s, 9H) (k) 2-methoxy-4-amidinobenzyl dihydrochloride of (D) -4-metho-phenylalanylproline The nitrile was converted by known processes (DE 4121947) through the thioa-ida stage into Amidine Starting from the nitrile, 2.2 g of the thioamide was obtained. 1H-NMR (DMS0-d6, delta in ppm): 9.85 (s, 1H); 9. 45 (s, 1H); 8.65 / 7.85 (2t, 1H); 7.55-6.65 (m, 7H, Ar-H); 4. 40-4.10 (, 4H); 3.86 / 3.85 (2s, 3H); 3.71 / 3.70 (2s, 3H); 3.05 / 2.60 (m, 4H); 2.10 / 1.55 (, 4H); 1.35 / 1.10 (s, 9H) Starting from 2.2 g of the thioamide and after reaction with methyl iodide and a solution of ethanolic ammonia and purification by column chromatography on silica gel (mobile phase: DCM / MeOH 9: 1) 1.7 g of the idina will be obtained in the form of h idroi »3duro. 1H-NMR (DMSO-d6; delta in ppm): 9.28 (s, 2H>; 8.87 (s, 2H); 8.75 / 7.95 (st, 1H); 7.40-6.65 (, 7H, Ar-H); -4.10 (m, 4H), 3.90 (s, 3H), 3.70 < s, 3H); 3.7-3.7 / 3.0-2.6 < m, 4H); 1.95-1.55 (, 4H); 1.30 / 1.22 (2s, 9H). The amidine hydroxide was converted to the amidine hydrochloride in an IRA 420 ion exchanger, then dissolved in 50 ml of methylene chloride and saturated with HCl at a temperature of O'C at 5 ° C. After stirring for one hour, the solvent was removed, 1.0 g of the amidine was obtained in the form of dihi.drocloru.ro. FAB-MS (M +) = 453 1 H-NMR (DMS0-d 6, delta in ppm); 9.50 (5 (wide (sic), 2H), 9.25 (s (broad), 2H), 8.85-8.65 (broad signa, 3H), 7.40 (s, 1H), 7.35 (d, 1H), 7.30 (d) , 1H), 7.15 (d, 2H), 6.90 (d, 2H), 4.35-4.10 (, 4H), 3.85 (s, 3H), 3.75 (s, 3H), 375-3.55 (, 2H), 3.20- 2.80 (m, 2H), 1.90-1.40 (m, 4H) (1) 2-methoxy-4-amid insbenzylamide of N- et i l sulfoni 1- (D) - (4-methoxy i) f ni lalani lprol ina 0.23 g (2 mmol) of methanesulphonic chloride was added to a solution of 0.9 g (2 mmol) of the above amidino hydrochloride (sic) in 20 ml of pyridine at a temperature of O'C., and the mixture was stirred at room temperature overnight. After removal of the solvent by distillation, the residue was purified by column chromatography (eluyepte: CH2C12 / methanol / 50 * / acetic acid, 45/5 / 1.5). The pure fractions eluate was distilled, adding toluene towards the end, and the residue was 1 i. 0.5 g of acetate was obtained in the form of a white amorphous powder. FAB-MS: 531 (M +). EXAMPLE 2: (alpha-meth i-l-4-amidino) -ben »~ i lamida of N-met iulsul foni 1- (D) -pheni lalanylproline (a) N- (p-cyanobenz 1) imine of benzophenone they added 270 g (2.0 mole) of anhydrous 2C03 to a solution of 150 g (0.8 mole) of benzophenone imine with a purity level of 97 * and 144.8 g (0.74 mole) of p-cynbenzene bromide in 450 ml of acetonitrile, and the mixture was stirred at room temperature for 6 hours. The inorganic salts were removed by filtration with suction and then most of the solvent was removed by distillation, 300 ml of water was added to the residue, and the mixture was extracted several times with ethyl acetate. The organic phase was washed twice with water, dried over Na 2 SO 4 and evaporated to dryness. Digestion with ether resulted in 180 g of white crystals, melting point 101-102'C (b) 1- (4-cyanopheni 1) et i. laminate Added >drop by drop 20.7 g (0.07 mol) of N- (p-ciansbenz i 1) benzophenone imine drop by drop to a solution of lithium diisopropylamide, prepared from 8.15 g (0.08 mol) of di is »3prop i lamina and 48.3 ml (0.08 mol) of a solution at 15 * /, of butyllithium in hexane, in 100 ml of tetrahydroflora abs. at a temperature of -70 * C, and the mixture was stirred for 15 minutes. Then 9.94 g (0.07 mol) of methyl iodide was added dropwise, and the temperature of the reaction mixture was allowed to rise to room temperature. After the addition of 100 ml of water and several extractions with ether, the ether phase was washed with a solution > from acid to 3% to 5%, a solution of 5% NaHC03 and water and dried over Na2SO4, and the ether was removed by distillation. The residue was dissolved in 150 ml of tetrahydrofuran, 100 ml of IN HCl was added, the mixture was stirred at room temperature overnight. Tetrahydrofuran was removed by distillation from the reaction mixture under reduced pressure, the remaining acid phase was extracted several times with ether to remove the benzophenone, and then the acid phase was made alkaline with an aqueous solution of K2C03 with ice cooling, and the oily base was extracted with methylene chloride. The extract was dried in K.2C03. 9.7 g (95 * /,) of an oil to oil were allowed "after the removal of methylene chloride and were used without further purification in the next reaction. (C) (at 1-4-c-fae) not) benc? lamí da Boc- (D) -feni 1 alam lpr »3l ina 16.2 g of di io rop i lamina and 22 mi (30 m sl) of propanfosfónico anhydride (solution of 5 * 4 in acetate of et? l> 3) were added dropwise to a solution of 3.65 g (25 mmol) of 1- (4-c? anophen? 1) et i lamina and 9.1 g (25 mmol) of Boc. D-Phe-Pro-OH in 150 ml of met chloride filled at a temperature of -5 ° C. The mixture was then stirred for 2 hours, during which period the temperature rose from -5 ° C. to 20 ° C. The organic phase was washed with water, a 5 * / sodium bicarbonate solution and a 5% citric acid solution, dried over Na2SO4 and evaporated to dryness.A pale crystalline residue was obtained and was used without no further purification in the next reaction. (d) > d? h? droclarurs de (al fa-met i l-4-a? d? no) benc? Lick of (D) -fen? lalan? lproline 4.1 g of the above compound and 4 ml of tpetila ina were dissolved in 40 ml of pipdma, saturated with H2S at a temperature of O'C, and allowed to stand at room temperature overnight. A reduction by TLC (CH2Cl / MeOH, 9/1) showed that the conversion to thioamide was complete. For isolation, most of the pyridyme was removed by distillation under reduced pressure, and the residue was taken up in 250 ml of ethyl acetate and washed with brine, a solution of citric acid to 5 * 4 a solution of NaHCO3. Mecha a and removal of the solvent by distillation afforded 4.1 g of pure crystalline thioamide. The thioamide was dissolved in 150 ml of acetone and, after the addition of 7 ml of methyl bromides, was allowed to stand at room temperature for 6 hours.The amorphous residue after removal of the solvent was removed by stirring with dry ether. and then dried, the methyl S-thioimidate hydroiodide was dissolved in 50 ml of ethanol, 15 ml of a 10 * 4 ammonium acetate solution was added, and the mixture was heated at 70 ° C. for 3 hours. isolation, the solvent was removed, the residue was dissolved in 100 ml of CH2C12, the insoluble parts were removed by filtering ion and then CH2C12 was removed by distillation Dissection with a mixture of ethyl acetate / diethyl ether removed the soluble impurities The remaining mixed iodide / acetate salt was dissolved in acetone / water (3/2) and converted to the pure acetate using an ion-exchanger IRA acetate, followed by 1 iof i lization. a melting point of 110-115'C. The above compound was dissolved in 70 ml of CH2C12, and 80 ml of ethyl acetate saturated with HCl was added. After a short period of time a precipitate separated and was completed by the addition of ether. The latter was removed by filtration with suction, washed with ether until it was free of HCl and dried under reduced pressure. White cpatles were obtained, melting point 190-195 ° C, FAB-MS: 407 (M- +). (e) acetate (a 1 fa-met 11-4-am? d tno) -bsnc? Lick of N- et 11 sul fom 1- (D) -fen? The title compound was obtained as a white amorphous powder as for le. FAB-MS: (M +) EXAMPLE 3 (2-meto? -4-am? D? No) ben i lamida of N-me i lulul foni 1- (D) -ci lohe i la laní lprol ina 1.70 g (6.26 mmol) of Boc- (D) -Cha-QH as in example lj with 1.85 g (6.26 mmol) of (2-methox? -4-c? An) ben »c? Hydrsclsride. roline lick (Example li) to provide 2.7 g of (2-MeO-4-CN) benz? Boc-L (D > -Cha-Pro, and subsequently the 'Boc protecting group was and immised with HC1 gas in DCM 2.0 g (4.45 mmol) hydrocarbon (2-M O-4-CN) benzyl hydrocarbon. H- (D) -Cha-Pro lime reacted in 40 ml of DCM and 8.9 mm »3 l of diisopropyltylamine at an O'C temperature with 0.7 ml of ethyl chloride to provide 2.0 g. of the corresponding sulfone ida.The nithop was converted by 58 a process with »3c: gone (DE 41 21 947) by means of the thioamide stage in the aniline. The inter > ambio del h idroiodur »D de a idina by the hidroaceta t > 3 of amidine (see Example 4b) resulted in 0.8 g of (2-methoxy-4-amino-dino) benzyl amide of Me-S02- (D) -Cha-Pr »3, which was purified by chromatography on column as in example 11. FAB-MS: (M + H) + = 496 EXAMPLE 4 (2-metaxy-4-aii no) benci li »da of N-met i Isul foni 1- (D, L) - di feni la lan i lprol ina (a) (2-MeO-4-CN) benci lick of Boc- (D, L) -Dpa-Pro 6.0 g (17.6 m al) of Boc- (D, L) - Dpa-0H and 5.2 g (17.6 mmol) of (2-Me0-4-CN) -benzyl amide hydrochloride of H-Pro reacted as in example lj and were subsequently purified by column chromatography on a gel-gel. ice (mobile ias-r: DCM / 4.5 * 4 MeOH). 5.6 g of product were obtained. 1 H-NMR (DMS0-d6; delta in ppm): 8.45 and 7.95 (1H, NH, (2 diastereomers or rat)), 7.5-6.9 (14H), 5.35-4.95 (m, 1H), 4.5-4.1 (3H), 4.0-3.0 (3H), 3.90 and 3.85 (s, 3H) (2 diastereomers)), 2.1-1.1 (13H) ) (b) (2-MeO-4-amidino) benzylamide of Me-S02- (D, L) -Dpa-Pro 3.55 g (6.0 mmol of the compound protected by Boc (Example 4a) were dissociated in 30 ml of DCM with gaseous HCl to provide 3.1 g of hydrochloride (2-Me0-4-CN) benzylamide of H- (D, L) -Dpa-Pro, and 1.5 g (2.9 mmol of this hydro-loride were stirred) in 30 ml of DCM and 1.1 ml of diisopropy, leti laminated with 0.24 ml of metallic chloride at a temperature of O'C for 2 hours, the organic phase was washed with 0.5 N HCl. , water and a solution Saturated NaCl and then dried, and the product was purified by silica gel column chromatography (mobile phase: DCM / 5 * /, MeOH). This resulted in 1.15 g of 5''Ji (2-MeO-4-CN) benzylamide of Me-S02- (D, L) -Dpa-Pro. 1.15 g * (2.1 mmol) of this nitrile were converted by a 10 known process (DE 41 21 947) through the thioamide stage in amidine. 2.3 g of the thioamy were obtained > and 0.95 g of the amidine hydroiodide, which was converted to the amidine hydroacetate in an ion exchanger (IRA 420). 0.77 g of (2-MeO-4- 15 amidino) benzylamide hydroacetate was obtained from Me-S02- (D, L) -Dpa-Pro (HPLC purity 95 * 4); FAB-MS: (M + H) + = 578 EXAMPLE 5 (6-amid ino) -3-picol acetate and 1-amide of N-met iulsul foni 1- (D) phenyl lani rol ina 20 ( a) 2-cyano-5- (acidomet i 1) pi idine 14.5 g (0.07 mmol) of trifluoroacetic anhydride dissolved in 20 ml of methylene chloride were added dropwise to a solution of 8.8 g (0.07 mmol) of 2-cyano-5- (hydroxyethyl) pyridine (WO 83/01446) and 6.9 g of The triet was laminated in 200 ml of methylene chloride at room temperature, and the mixture was then stirred for 2 hours. After removal of the methylene chloride by distillation, the residue was > dissolved in a mixture of 50 ml of toluene and 50 ml of dimethyl sulfoxide, were added 11.2 g (0.17 mol) of s-3d3-azide and 0.7 g of tetrabuti bromide onis, and the mixture was a > gited at room temperature overnight. * > The reaction mixture was poured into 300 ml of water and extracted several times with ether. After drying with Na 2 SO 4 and removal of the ether by distillation, 6.8 g of crystals were kept in an aryl lens and were used in the next reaction without further purification. (b) 2-cyano -5- (a inometi 1) pi ridine 15 The compound obtained in (a) was dissolved in 45 ml of tetrahydrofuran and 1.2 ml of water and, with stirring, 11.2 g of trif was added in portions. lfosf ina. The reaction mixture was allowed to stand at room temperature overnight. After the removal of the solvent through After distillation, the residue was taken up in 100 ml of ether, the precipitated tri-phenylphosphine oxide was removed by filtration with suction, and the filtrate was adjusted to a pH of 2 with hydrochloric acid et reo. The precipitated hydrochloride was removed by suction filtration, 25 washed with ether and digested successively with toluene and hot isopropanol. 4.7 g (40 * 4) of hydrochloride were isolated, melting point 253-256 ° C (decomposi tion). (c) (6-c iano) -3-p ic »3l i. Lick of Boc- (D) -feni la lani Iprol ina 8.12 g of di is »3prop i let i lamina, and subsequently 11 mi 5 (15 mm »3l) of propaphophosphonic anhydride (50 * 4 solution in ethyl acetate) were added dropwise to a solution of 2.11 g (12.5 mmol) of 2-cyano-5- (aminorae). ) pi ri ina and f -k 4.5 g (12.5 mmol) of Boc-D-Phe-Pro-OH in 70 ml of CH2C12 at a temperature of -5'C. The mixture was then stirred 10 for 2 hours, the temperature was allowed to rise from -5'C to 20'C. The organic phase was washed with water, solutions of bicarbonate, sodium hydroxide at 5 * 4 and citric acid at 5 * 4, washed in Na 2 SO 4 and evaporated to dryness, a pale yellow crystalline residue was obtained, mp 167 -170'C, that 15 was used in the next reaction without further purification. (d) (6-amidino) -3-picol acetate and N-methylsulfonyl- (D) -phenylalanyl-proline lick The above compound was dissolved in 100 ml of isopropanol 20 and, after the addition of a 2.3 g solution of HCl in 20 ml of isopropanol was heated at 50 ° C for 5 hours, during which the hydrochloride of the deprotected compound was separated. This was removed by suction filtration and washed with cold isopropanol until it was free of HCl. 2.5 g (6.5 mmol) of the above hydrochloride was suspended in 50 ml of CH2C12. The addition of 1.35 g (13.5 mmol) of tetylamine resulted in a solution to which, at a temperature of 0 to 5 ° C, drop was added to g> 3rd 0.7 g (6.1 5 mmol) of metansul foni 3 or > d? suel > 3 in 10 ml of CH2C12. The reaction mixture was stirred at room temperature for 5 hours and then extracted by ; f stirring with water, solutions of citric acid to 5 * 4 and of NaHC03 to 5 * 4. After drying in Na2S04 the removal of the After the solvent was removed by distillation, the viscous oily residue was recrystallized from a mixture of ethyl acetate / ether (1: 1). 4.1 g of the above compound and 4 ml of triethylamine were dissolved in 40 ml of pipdin, saturated with H2S at O'C, 15 and allowed to stand at room temperature overnight. Kfc A review with TLC (CH2C12 / MeOH, 9/1) showed that the conversion to thioamide was complete. For isolation, most of the pipdin was removed by distillation ba or reduced pressure, and the residue was collected in 250 ml. 20 ethyl acetate and washed with brine, a solution of citric acid at 5 * 4 and a solution of NaHCO3. Drying and removal of the solvent by distillation yielded 4.1 g of pure crystalline thiomide. The thioamide was dissolved in 150 ml of acetone, and after addition of 7 ml of methyl iside, it was allowed to stand at room temperature for 6 hours. The amorphous residue after removal of the solvent was removed by stirring with dry ether and then dried. The hydroiodide of S-met i 1 ioimidate was dissolved in 50 ml of ethanol, 15 ml of an ammonium acetate solution was added to the 10 * 4, and the mixture was heated at 70 ° C for 3 hours. For the isolation, the solvent was removed, the residue was dissolved in 100 ml of CH2C12, the insoluble particles were removed me > After filtration, the CH2C1.2 was then removed by distillation. Digestion with a mixture of ethyl acetate / diethyl ether removed the soluble impurities there. The remaining iodide / a-retata mixed salt was dissolved in acetone / water (3/2) and converted to the pure acetate using an ion IRA acetate exchanger, followed by 1 iof i lization. A white amorphous powder, melting point 128-137'C, FAB-MS: 473 (M + H +) was isolated. EXAMPLE 6 (6-amidino) -3-picolyl acetate of N-met iulse foni 1- (D) -c iclohexylglycylproline (a) Boc- (D) -cyclohexy lgl iciproline 29 g (0.113 mol) of Boc- (D) -cyclohexane and 18.7 g (0.113 mol) of proline methyl ester hydrochloride were suspended in 300 ml of CH2C12 and dissolved by the dropwise addition of 58.3 g (0.45 mol) of isopropi le i lamina. After cooling to -15 ° C, 113 ml (0.147 mol) of propanephosphonic anhydride (50 * 4 solution in ethyl acetate) was added dropwise, and the mixture was stirred for 1 hour. After the addition of 200 ml of water, the organic phase was separated and washed with an aqueous solution of K2CO3, 0.5 N hydrochloric acid and a 5 * 4 bicarbonate solution. After drying with Na 2 SO 4, the solvent was removed by distillation, the oily residue (41 g) was dissolved in 400 ml of ethanol, 120 ml of Na H 1 N was added, and the mixture was stirred at room temperature for 2 hours. After the alcohol was removed by distillation, the aqueous phase was diluted with water and extracted several times with tert-butyl methyl ether. The aqueous phase was acidified with a solution of HS04 and extracted 3 times with CH2C12. After drying and removal by distillation of methylene chloride, the oily residue was crystallized from diisopropyl ether / N-hexane (1/3). 28 g of white crystals were isolated, melting point 145-148'C. (b) (6-cyano) -3-picol and Boc- (D) -lacyclohe ylgl ici lprol ina lick 26.6 g (0.075 mol) of Boc- (D) -cyclohexy lgl ic i lprol ina and 12.7 were suspended. g (0.075 mol) of 6-cyano-3-picol hydrochloride i lamined in 300 ml of CH2C12, and 47 g (0.364 mol) of diisoprop i let i lamin were added. Then, at a temperature of -10 ° C, 66 ml of propanephosphonic anhydride (a solution of ethyl acetate at 50 * 4) were added dropwise., the mixture was stirred at O'C for 1 hour, 200 ml of water was added, and the CH2C12 phase was separated. The organic phase was washed with 0.1 N sodium hydroxide solution and water and then dried and the solvent was removed by distillation. The residue was taken up in 100 ml of ethyl acetate, so that the crystallization started rapidly and was completed by the addition of 150 ml of n-hexane. After filtration with suction and drying, 31.4 g (89 * 4 of the theoretical level) of white crystals, melting point 150-151'C, were isolated. (c) (6-amidino) -3-picol l acetate of N-methylsul foni 1- (D) -cyclohexyglycylproline The protective group was removed from the above Boc compound as in example 5d, the reaction was carried out with chloride of etansul fopi lo, and the cyano group was converted to amidine. The acetate was isolated in the form of white crystals, melting point 250-256 * C (decomposition), FAB-MS: 465 (M + H +). EXAMPLE 7 (5-amidino) -2-pi.col acetate and lime of N-met iulse foni 1- (D) -cyclohexylglycine (a) 5-carboxamido-2-icol and 3 g of Raney nickel to a solution of 3.5 g (24 mmol) of 2-c ian »3-5-carb >3xamidopi was added in 80 ml of methanol and 20 ml of concentrated ammonia, and the hydrogenation was carried out at room temperature. The hydrogen absorption was complete > after about 7 hours. The filtrate after removal by filtration with suction of the catalyst was concentrated and the residue dissolved in 20 ml of 2N hydrochloric acid and 20 ml of methanol. The addition of 150 ml of ethyl acetate resulted in the separation of the hydrochloride, which was removed by filtration with suction and drying (3.7 g). The free base melted at 198-202'C. (b) 5-cyano-2-picol and lamna 41 g (0.22 mol) of 5-carbaxamide-2-picol were suspended in 150 ml of methanol and 300 ml of methylene chloride, cooled to 10 ° C. , and dissolved by the addition of 150 ml of trie i lamina. Then a solution of 47.6 g (0.22 mol) of (Boc) 20 was added dropwise, and the mixture was stirred at room temperature for 4 hours. The residue, after removal of the solvent, was mixed with a saturated K2CQ3 solution and extracted 5 times with methylene chloride. The combined extracts were dried, and the solvent was removed by distillation, adding toluene towards the end. 5.4 of the residue were suspended in 40 ml of dioxane and 15 ml of methylene chloride, 4.3 g of pyridine were added, and then, at a temperature of 0.degree. C., 5.2 g of trifluoroacetic anhydride were added dropwise, which resulted in a clear solution. The addition of 100 ml of water was followed by extraction with ethyl acetate, and the organic phase was washed with dilute citric acid, NaHCO 3 solution and water. A yellow oil (approximately 5 g) remained after drying and removal of the solvent, was dissolved in 15 ml of isopropanol and 30 ml of ethyl acetate, and 35 ml of an ethereal solution of hydrochloric acid was added. After standing overnight, the precipitated hydrochloride was removed by suction filtration and dried. 4 g of white crystals were isolated. Melting point: 230-234'C. (c) (5-cyano) -2-picol ilamide of Boc- (D) -cyclohexylglycillipoline Boc- (D) -c iclahexi lg icin-prol ina (sic) was combined with 5-cyano-2-picol i lamina as in example 6b to result in white crystals, melting point 128-129'C. (d) (5-amino) -2-pi > acetate; role and lick of N-met i lsul foni 1- (D) -c ic 1ohex i 1g 1 ic i 1p ro1 i na The protective group was removed from the previous Boc compound as in example 5d, the reaction was carried out with Methane sulphide chloride, and the cyano group was converted to amidine. The acetate was isolated in the form of white crystals, melting point 149-150 ° C (decomposition), FAB-MS: 465 (M + H +). EXAMPLE 8 (6-amid i no) -3-picol i acetate. Lick of N-met i Isulfoni 1- (D) -ci lohexi llani 1-3, 4-dehidr »3pral ina (a) (6-carb > 3xamido) -3-picol &lick of Boc-3,4 - dehydroprol ina 5.0 g of Boc-3,4-deh-idroprol in (23.4 mmol) was suspended together with 5.25 g of 6-carbohydrochloride of 6-carb »3xamido-3-picsl 1 and 32.1 ml of diiscsprap i let i lamina (187 mmol) in 50 ml of CH2C12 and, under stirring at a temperature between 0 and 5 ° C, 23.5 ml of propanephosphonic anhydride (50 * 4 solution in ethyl acetate) were added dropwise. The mixture was then stirred at room temperature overnight. The solution was diluted to 150 ml with CH2C12, extracted successively with a solution of sodium bisulfate at 20 * 4 and a solution of citric acid at 5 * 4, dried over sodium sulfate and concentrated on a rotary evaporator. The aqueous phases were back-extracted 3 times with CH2C12, and the organic phase was dried, concentrated in a rotary evaporator and used together with the main product without further purification in the next reaction. (b) (6-carboxamido) -3-picol l-hydrochloride of H-3,4-dehydroprol ina The crude product of (a) was dissolved in 100 ml CH2C12 and, after addition of 10 ml of 5M HCl in ether, was stirred at room temperature for 2 hours (revision by TLC). The crude product after complete evaporation to dryness under reduced pressure and codest lac ion with low pressure under reduced pressure was recrystallized from 200 ml of ethanol. This resulted in 5.03 g and, after the concentration of the mother liquor, an additional 0.3 g of product. (80.4 * 4 of the theoretical level). An elemental analysis showed that the product was in the form of onoh idrochloride. (c) (6-carboxamido) -3-picol i lamida of Boc- (D) -cyclohexy lani 1-3,4-deh idrop al ina 5.06 g of Boc- (D) -cyclohexylalanine (18.66 m) were stirred. al) together with 5.28 g of (6-carboxamide) -3-picol l-hydrochloride of H-3, 4-dehydroprol ina (18.66 mmol) and 9.55 ml of diisopropyl leti (56 mmol) in 75 ml of CH2C12 and, at a temperature of 0 to 5 ° C, 18.6 ml of propanephosphonic anhydride (50 * 4 solution in ethyl acetate) were added dropwise. The mixture was then stirred at room temperature overnight, during which a precipitate separated. After removal by filtration, suction of the precipitate and after the solution has been extracted 5 times with 25 ml of citric acid at 5 * 4 each time (TLC did not show any di isapropi let and lamina in the organic phase): ), the organic phase was washed several times with a saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure. To minimize the byproduct of propanphosphonic acid, the residue was "recog".The mixture was taken up in ethyl acetate, extracted several times with a saturated bicarbonate solution and then dried in sodium sulfate and concentrated in a rotary evaporator. The yield was 7.0 g of product in the form of a solids foam (75 * 4 at the theoretical level). (d) (6-> iano) ~ 3-pic »3l i Lmida of B» 3c- (D) -cyclohexylalani 1-3, 4-dehydroprol ina - 7.0 g of (6-carboxamido) -3 were dissolved -p icol i lamida of ac- (D) -c iclohexi lalani 1-3, 4-deh idr »3prsl ina (14 mmol) together with 9.5 ml di isoprop i let i lamina (56 mmol) in 100 ml of chloride of methylene, cooled to a temperature of 0 to 100 ° C, and 3.5 ml of trichloroacetic anhydride (25.2 mmsl) were added dropwise. After stirring at room temperature for 2 hours, the precursor was completely converted (revision by TLC). The solution was then extracted 3 times with a 25 * 4 solution of sodium sulfate, 3 times with a saturated solution of sodium bicarbonate and 1 time with saturated brine, dried over sodium sulfate and concentrated in a rotary evaporadar. Yield: 6.6 g (98 * 4 theoretical level). (e) Preparation of (6-cyana) ~ 3-picsl ilamide of H- (D) -cyclohexyl lane 1-3,4-dihydroxya 6.6 g of (6- iano) -3-p were dissolved. The lick of Boc- (D) -ciclahe i lalani 1-3,4-deh idrsprol ina (13.75 mmol) in 15 ml of isopropanol, and after the addition of 12.5 ml of a solution of hydrochloric acid »3 isopropapol ico 4 N, was stirred at 40 ° C for 2 hours (revision by TLC). The reaction solution was concentrated under reduced pressure, the re i > Duo was collected in aq, the solution was extracted 3 times with ether, and the aqueous phase was adjusted to pH 9 with a solution of sodium hydroxide at 20 * 4 and extracted several times with CH2C12. The organic phase was washed with saturated brine, dried over sodium sulfate and concentrated on a rotary evaporator to obtain 4.3 g of product (82 * 4 at the theoretical level). (f) Preparation of (6-cyano) -3-picol i lamide of methylsulfoni 1- (D) -cylahex i lalani 1-3, 4-dehydroprol ina The compound was prepared as in example 5b from (6) -cyano) -3-picol and lick of H- (D) -cyclohexalai 1-3,4-dehydropral ina and metansulphonic chloride. Performance: 95 * 4 of the theoretical level. < g) Preparation of (6 ~ amidine) -3-picol and lime-metal lysis (D) -cyclshelalani 1-3, 4-dehydroxypropyl This compound was prepared as in Example 5d from of (6-cyano-3-picol i 1) methylsulfonyl amide 1- (D) -cyclohexylalani 1-3, -dehydroprolone by means of thiaamide in methyl S-methyl-1-thioamidate hydroiodide. A white amorphous powder was isolated. FAB-MS (M + H) - + = 477 EXAMPLE 9 (6-amidino) -3-picol acetate and lick of N-met i lsul foni 1- (D) -ciclahexi lgl ic i 1-3, -dehydraprol This compound was prepared as in Example 8. A white amorphous powder, FAB-MS (M + H) + = 463 was obtained. EXAMPLE 10 (6-amidino) -3-pic > : »L lick of N- (h idrox icarboni l et i lep) sul foni 1- (D) -cic 1 ohex i 1 g 1 ic i 1p ro1 i na (6-» iano) -3-picol and lick of H- (D) -cyclohexy lgl ic i lprol ina (Example 6b) reacted with metaxicarbonyl chloride lme i lensul foni lo (preparation presented in Tetrahedron Letters 30 (1989) 2869) to synthesize the corresponding sulfsamide. The nitrile functionality was converted to the amidine group by means of the thioamide step by known processes (DE 41 21 947). The resulting product of (6-cyano) -3-picol and lime of N- (meth »3-xyl-p-lyl-i-l-l-i-i-i-fon) 1- (D) -cic ohe and glycylproline was heated < In a mixture of 4 N hydrochloric acid and dioxans at a temperature of 80 ° C to hydrolyse the ester functionality (pairwise TLC revision), and then the solution was concentrated and the residue was purified by HPLC on a RP column the aqueous phases were 1 iof i 1; amorphous powder FAB-MS (M + H) + = 509.

Claims

1. An i nh ib i dor of the tr > 3mb i na of the f or rmu the I NH R1 S02 A B NH D ^ I 'NH2 and the sterols thereof and the salts thereof with physiologically tolerated acids, wherein the amidine functionality may be in monoprotext or dipyridine form and in d> 3nde 1 > : Substituents have the following: Rl is OH, C1-C20 alkyl, C1-C3, C1-C3, C3-C8 cycloalkyl, 3 * 3 Cl-ClO, aryl, hetaryl, R200C- (CH2) or R3E2N, where P2 and R3 are identical or different and are hydrogen, alkyl Cl-ClO, aryl, arylalkyl Cl-ClO or together are a " of C2-C7 alkylene to which an aryl or heteryl radical can be fused or which can contain a heteroatom (0, S, NH or substituted N), and n is 1, 2, 3 or 4, : a ra > dical to the amino acid of formula II R "I - NH - C CO II I R5 where R4 is hydrogen, C1-C8 alkyl, C6alkyl or C3-C7, aryl or C1-C3 arylalkyl, R5 is hi > hydrogen peroxide, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl or cycloalkyl C 3 -C 7 -CH 2 -, it being possible for the CH 2 group in the ring to be replaced by 0, S, NP 6, or bi ical ali 3.3- (CH 2) 0, 1 'sic), adamant i lo- (CH2) 0-1, (CH3) 3S? - lqu? C1-H4, ar i lo »3 well C1-C3 -lalkyl, heptaplo a good h > = > l a r i lalky 1 or C1-C3, =, x P _? = - H, a C1-C8 alkyl radical wherein one hydrogen atom is replaced by SR6, 0R6, C0-0R6 < P6 = hydrogen, C1-C8 alkyl or they alkylate Cl-C3 > or C0NR7R8 (R7, R8 are identical or "different and are H, C1-C4 alkyl, C3-C7 cycloalkyl or together are a chain of H1 qu i lf C3-C6 l), or P4 and R5 together = on a C2-C6 alkylene chain which may contain an aplo-fused radical, B: a cylic a-amino acid residue of the formula III »D» onde m is 2, 3 or 4, and a hydrogen in the ring can be replaced by a hydroxyl group »3 well Cl-C3 alkyl, and m is 3 or bi n 4, a CH2 group in the ring can be replaced by oxygen, sulfur, NH or N-C 1 -C 4 alkyl and / or two hydrogen atoms nearby can be replaced by a link either by a fused aromatic system or by a methylene chain with 4-6. atoms, carbon, D: a structural fragment of formula IV, V or VI IV V VI where R9 is F, Cl, Br, N02, P150, RISOOC, R150CH2, R15NH-C0, P15NH, P15C0NH, or R1500CCH20, where P15 is H, Cl- or alkyl, benzyl »3» p or phenyl, PIO, Pll are H, C1-C4 alkyl or BISO, where P9 and RIO or bi n Rll can together form a phenol ring fused to either an alkylene chain consisting of 3 to 5 carbon atoms, wherein one or two carbon atoms can be replaced by oxygen, Ptl is H > D bv n C1-C4 alkyl, R13 is C1-C4 alkyl, phenyl-C1-C4 alkyl, P15C0, CF3C0, C2F5C0, P150CH2, RISOOC, R150CH2C0, R1500CCO or P15NHC0C0, P4 is H, C1-C4 alkyl, F, Cl , Br, N02, R150, RISOOC, R150CH2, R15C0, R15C0NH, P15NH-C0 or R1500CCH20, and, X, Y, Z an CH or N, but a3 minus one > of the radicals W, X, Y or Z is N and the ring in VI can be substituted by 1 or 2 of the following radicals: C1-C4 alkyl, OH, O-C1-C4 alkyl, CF3, F, Cl, Br, S- C1-C4 alkyl, 0 (CH2) n C00P.6 < n = 1-4).

2. A compound of formula VII, VIII, IX or X NH H2N-D-CN VII H2N __ D _c VIII \ NH2 Rl s? 2 A B NH CN IX NB Rl - S02 A B NH D - C x NHOH where Rl - A, B, D, W (sic), X (sic), Y (sic) and Z (sic) have the ignited established in claim 1, and where the functionality amindine (sic) in the formula VIII can be in f > 3 monoprotected or diprotected.

3. A compound that ontien ». the structural fragment of the f or rmu 1 a NH where D has the meanings set forth in claim 1.

4. A thrombin inhibitor of formula I according to claim 1 for use in controlling diseases.