MXPA00002245A - Peptides containing an arginine mimetic for the treatment of bone metabolic disorders, their production, and drugs containing these compounds - Google Patents

Peptides containing an arginine mimetic for the treatment of bone metabolic disorders, their production, and drugs containing these compounds

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Publication number
MXPA00002245A
MXPA00002245A MXPA/A/2000/002245A MXPA00002245A MXPA00002245A MX PA00002245 A MXPA00002245 A MX PA00002245A MX PA00002245 A MXPA00002245 A MX PA00002245A MX PA00002245 A MXPA00002245 A MX PA00002245A
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Mexico
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acid
amino
propionylamino
dihydro
hydroxy
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MXPA/A/2000/002245A
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Spanish (es)
Inventor
Angelika Esswein
Silvia Konetschnyrapp
Lothar Kling
Eike Hoffmann
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Roche Diagnostics Gmbh
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Publication of MXPA00002245A publication Critical patent/MXPA00002245A/en

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Abstract

The present invention is directed to compounds of general formula (I), wherein R1, R2, R3 and X may be the same or different, and wherein R1, R2 represent hydrogen, an amino acid, peptidyl, alkyl or aryl residue;R3 represents hydroxy, lower alkoxy, or an -NR31R32 residue, where R31, R32 represent independently hydrogen, an aminoacid, peptidyl, alkyl or aryl residue;X represents an amino acid or a peptide;R4 represents hydrogen, hydroxy, amino or C1-C4 alkyl;m represents a number between 0 and 5;R5 represents an optionally substituted saturated or unsaturated mono- or bicyclic moiety which may contain one or more heteroatoms, a C1-C11 alkyl group which may have substitutions or intermittent heteroatoms, their tautomers, optical isomers, pharmaceutically acceptable salts and prodrugs as well as their production and their use as medicaments.

Description

P eptides containing an arginine mimetic for the treatment of bone metabolic disorders, their production and drugs containing these compounds.
The present invention relates to new peptide mimetics for the treatment of bone disorders, methods for their production and drugs containing these compounds.
In healthy individuals the processes of bone formation and degradation are virtually in balance, that is, the activity of osteoblasts and osteoclasts is balanced. However, if this balance is disturbed in favor of osteoclasts and / or disadvantaged by osteoblasts, a reduction in bone mass and a negative change in bone structure and function could result.
Until now, inhibitors of bone resorption such as estrogens, calcitonin and bisphosphates are primarily used in the treatment of bone metabolic disorders. However the use of these substances the limited and in addition, do not show the desired effects in all cases. Compounds that have a stimulating effect on bone formation and contribute to EEF .: 32843 increase an already diminished bone mass are therefore of particular importance in the treatment of bone disorders.
It is known that PTHrP (107-111) and the peptide derivatives thereof have a positive influence on the inhibition of bone resorption (WO 92/0511, WO 92/9424153). However, valin et al, in cell physiol. 170 (2), 209-15 (1997), describe an anti-proliferative effect of PTHrP (107-111) on UMR106 cells. Witfield et al. In J. Cell Physiol 166. { 1), 1-11 (1996) demonstrated a stimulating effect on PKC and a modulation of keratinocyte proliferation by PTHrP (107-111), whereas Kali et al. In Endocrinology 136 (3), 842-8 (1995) describes a stimulation of osteoclasts by PTHrP (107-111).
Surprisingly, it has now been found that the mimetic peptides of the present invention have a stimulating effect on bone formation and thus, are suitable for the general treatment of bone disorders. In particular, they can be used perfectly well in those cases where bone formation is disturbed, that is, they are particularly suitable for the treatment of osteopenic diseases of the skeletal system, such as osteoporosis, brittle bone disease, among others, such as for example , in orthopedic and orthodontic indications, in the healing of fractures, osteosynthesis, pseudodartrosis and for bone implants that become incorporated.
Due to these properties, they are also used in the prophylaxis of osteoporosis.
On the other hand, due to their influence on bone metabolism, the medicaments containing the mimetic peptide of the present invention as active substances constitute the basis for the local and systemic treatment of rheumatoid arthritis, osteoarthritis and degenerative osteoarthritis.
The present invention is directed to compounds of general formula (I) Where Ri, R2, R3 and X which can be the same or different and - where Ri, R2 represent hydrogen, an amino acid, peptidyl, alkyl or aryl radical; R3 represents hydroxide radical, lower alkoxide, or an -NR3? R32, wherein R31, R32 independently represent hydrogen, an amino acid, peptide, alkyl or aryl radical; X represents an amino acid or a peptide; R 4 represents hydrogen, hydroxide, amino or a C 1 -C 4 -alkyl; m represents a number between 0 and 5; Rs represents an optionally saturated or unsaturated mono- or bicyclic portion or may contain one or more heteroatoms, an alkyl group of CL-CH which may contain intermittent substitutions or heteroatoms; its tautomers, optical isomers, pharmaceutically acceptable salts and prodrugs.
X is preferably a D-amino acid or the dipeptide seryllalaryl; R4 preferably represents methyl or hydroxide; R1 and R2 are independently from each other preferably hydrogen; R3 is preferably hydroxide or amine; m is preferably 1 to 3, more preferably 1; The residue (CHR4) mR5 represents especially a preferred radical linked to Ca of a proteinogenic or non-proteinogenic amino acid.
Alkaline salts, alkaline earth salts such as Ca or Mg salts, ammonium salts, acetates or hydrochlorides are generally used as pharmaceutically acceptable salts which are produced in the usual manner for example by triple treatment of the compounds with organic or inorganic bases or inorganic acids such as for example sodium hydroxide, potassium hydroxide, aqueous ammonia, Cl-C4-alkyl-amines such as for example triethylamine or hydrochloric acid The salts are usually purified by reprecipitation from water / acetone.
The prodrugs of the compounds of the invention are those which are converted in vivo to the pharmacological active compound. The most common prodrugs are carboxylic acid, esters such as ethyl esters.
Representative peptides are residual peptides. It is understood that the peptide is a radical consisting of 2 to 10 identical or different proteinogenic or non-proteinogenic amino acids. Peptides having 2-5 amino acids are preferred; particularly preferred are those that have 2 amino acids.
The residual amino acids usually mean the radicals of a proteinogenic or non-proteinogenic amino acid. It is understood that non-proteinogenic amino acids are a, b,? and? -aminocarboxylics which may optionally have intermittent substitutions or heteroatoms.
The preferred α-amino acids are -HN- (CH 2) n -CO- with n = 1-10; the - (CH2) n- groups can be branched or unbranched.
Examples of such amino acids are L- and D-amino acids, such as 2-amino-3-hydroxy-4-methylpentanoic acid, 2-amino-3-hydroxy-4-methylpentanoic acid. 2-amino-3-methoxybutanoic acid, 2,3-diaminopropinoic acid, 2-amino-2-methyl-3-hydroxypropanoic acid; 2-amino-2-, methylbtanedioic acid, 2-amino-3-hydroxy-3-methylbutanoic acid, 2-amino-3-hydroxy-3-methylbutanoic acid, 2,3-diaminopropinoic acid, 2-amino-2-methyl acid -3-hydroxypropanoic acid, 2-amino-2-methylbutanedioic acid, 2-amino-2-methylbutanoic acid, 2-amino-2-methyl-4-pentenoic acid, 2-amino-3-methoxypropanoic acid, 1-amino-1 acid -cyclohexanecarboxylic acid, 1-amino-1-cyclopentanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminociclopropanecarboxylic acid, 2- (2-furyl) glycine, 2-amino-3-fluorobutanoic acid, 2-aminoisobutanoic acid, 3-chloroalanine, 3 -fluoronorleucine, 3-fluorovaline, 3-fluorolanine, 3-methoxy valine, alpha-cyanoalanine, alpha-methyleucine, beta-chloroalanine, beta-cyanoalanine, beta-hydroxyleucine, beta-hydroxyapartic acid, 3-hydroxyapartic acid, 2-aminobutyric acid, aliglicine, gamma-methyleucine, homoserine, norleucine, norvaline, tert-leucine, 2,3-diaminopropionic acid, 2,3-diaminosuccinic acid, 2-amino acid 4-pentenoic, 2-aminobutyric acid, 2-aminoheptanoic acid, 2-cyclopropyl-2-methylglycine, 4-thiaisoleucine, allotreonin, alpha-methylapartic acid, alpha-methylserine, beta-hydroxynorvaline, beta-methylapartic acid, homocysteine, homoserine, norleucine, 'norvaline, O-methylserine, penicillamine, propargaylglycine, beta-hydroxyapartic acid, vinylglycine, .beta-hydroxyapartic acid, H-4, 5-dehydro-LEU-OH. H-alpha-MeVAL-OH, H-propargayl-GLY-OH, H -allo-ILE-OH, H-PRA-OH, H-trans-4, 5-dehydroLYS-OH, 3-hydroxyapartic acid, 6-hydroxynorleucine , alo-isoleucine, allylic glycine, alpha-amino-butyric acid, gamma-methyleucine, homoserine, norvaline, penicilla ina, ter-leucine, vinylglycine, meso-alpha, beta-diaminosulfonic acid, O-carbonyl-serine, S-methylcystin , 2-amino-2-methylbutanedioic acid, 2-fluoro-beta alanine, beta-alanine, beta-aminobutyric acid, 2,3-dia inosuccinic acid, beta-aminoissbutyric acid, isoserin.
Preferred amino acids are alanine, serine, tryptophan, tyrosine, phenylalanine, threonine, histidine, citrulline, hocysteine, homoserine, hydroxyproline, hydroxymycin, ornithine, sarcosine, tranexamic acid, (cyclohexylalanine), aminobutyric acid, aminovaleric acid, and aminopropionic acid.
The lower alkyls denote methoxy, ethoxy, pr or toxic, preferably methoxy.
Alkyl usually means linear or branched residual alkyls having from one to six carbon atoms.
Aryl usually means a carbocyclic portion having from 6 to 14 carbon atoms or a heterocyclic portion of 5- or 6-membered having 1, 2 or 3 heteroatoms selected from 0, N, S whose portion may optionally have one or multiple substitutions, with phenyl or substituted naphthyl radicals or unsubstituted radicals that are preferred.
The term "monocyclic portion" is understood to be a saturated or unsaturated ring system having from 3 to 8, preferably from 5 to 7 carbon atoms, which may optionally have one or multiple intermittent heteroatoms such as nitrogen, oxygen or sulfur, particularly a cyclopentyl. cyclohexyl, cycloheptyl, morpholinyl, thiamorpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropynyl, phenyl, pyridyl, pyrimidinyl, pyridazylnyl, pyrazinyl, furyl, thiophenyl, imidazolium, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, or 1, 2, 4-triazolyl residual. In particular, lower alkyls, alkoxides and halogens are possible substituents.
Preferably, the bicyclic moiety referred to under R5 is a radical such as a naphthyl, tetrahydronaphthyl, decalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, idolyl, benzimidazolyl, indazolyl, oxindolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl or purinyl radical, but particularly a radical indolyl, naphthyl, benzamidazolyl, quinolinyl, tetrahydroquinolinyl, benzothiophenyl, and benzofuranyl.
The term "several" means in connection with monocyclic or bicyclic heteroatoms, preferably one, two or three, more preferably one or two and more preferably the heteroatom is nitrogen.
The term "several" means in connection with substituents or substitution preferably one to five, more preferably one, two or three, more preferably one or two.
Substitutions of monocycles or bicycles in R5 are halogens, nitro, hydroxide, alkoxides, amine, alkylamine, dialkylamine, halogenmethyl, dialogenomethyl, trihalogenomethyl, phosphone, alkylphosphone, dialkylphosphone, S02NH (alkyl), S02N (alkyl) 2, S02 (alkyl) , acetyl, formyl, nitrile, COOH, COOalkyl, -OC (O) alkyl, NHC (O) Oalkyl, OC (O) O-aryl, -NHC (S) NH2, -NHC (S) NHalkyl, -NHC (O) ) -arilo.
Preferred substituents are methyl, ethyl, propyl, isopropyl, halogenyl, especially chlorine, amine, acetyl, alkylammonium, dialkylammonium, alkoxide, hydroxyalkyl, and C0-C alkylcarbonic acids The preparation of the compounds of general formula (I) is achieved according to methods known per se. Advantageously, the preparation is carried out using the precursors (II), (III) and (IV), respectively.
Where Y represents a carboxyl group, according to the procedure outlined in Schemes 1, 2 and 3.
The compounds of general formula (IV) are novel and useful for the orthogonal synthesis of compounds that include the backbone of structure (IV). The preferred radical for R9 is Fmoc.
Scheme 1 (O (2) (3) («) i) ^ - e (12) (10) < l t) Steps a) to d) in scheme 1 represent the following reactions: a) NaBH3CN / MeOH / RT; b) PhCOCL / py / DMAP / RT; c) DBU / toluene / RT / 16 hrs; d) DIBAL-H / THF / -78 ° C; Where R6 represents a protected group, for example the benzoyl group, an alkyloxycarbonyl group or the benzylphenylcarbonyl group, and R7 represents hydrogen or a lower alkyl such as methyl, ethyl, propyl, butyl or tert-butyl, R8 represents an alkyl radical or aryl such as a residual methyl, ethyl, trifluoromethyl, phenyl, tosyl or 4-nitrophenyl, but preferably residual methyl or tosyl, and L usually represents a residual sulphonic acid such as methano- or trifluoromethanesulfonic acid or p-acid toluenesulfonic or residual p-toluenesulfonic acid, or halogen such as chlorine, bromine, iodine or acetate.
MHal represents a metal halide such as NaCl, NaBr, Kl, MgCl2 or MgBr2.
The compounds of formula (5) have been described (J.O.C. 48, 1129-31 (1983)). The conversion of a fatty alcohol to (5) a sulphonic or an ethic ester of formula (6) is carried out according to standard procedures. The conversion of an alcohol of formula (5) to a halide of formula (6) using N-chloro-, N-bromo- or N-iodosuccinamide (NCS, NBS, NIS) in the presence of triphenylphosfosine (Ph3P) is executed in analogy to the corresponding procedures of the literature (for example, Tetrahedrom Asy. 4 1619-2 A (1993)). The decarboxylation of manolic esters using metal halides in DMSO at elevated temperatures is well known. (T.L. 957 (1973)). The compounds of formula (9) have been described (JACS 114 7324-25 (1992)). The epoxy opening of a compound of formula (10) resulting in an alelic alcohol of formula (11) is carried out in analogy to the literature (Tetrahedron 2_4, 5827-30 (1968)). The conversion of a compound of formula (13) to a compound of general formula (II) by means of a rearrangement of Claisen is performed analogously to the literature (Tetrahedron 52, 941-54 (1996)).
Scheme 2 c) Ph (16) (19) (18) (17) Steps a) through f) in scheme 2 represent the following reactions: a) Ac20 / pyridine / DMAP b) 4 N HC1 / 16 hrs; (14) / EtN (i-Pr) 2 c) (16), R7 = Et / HMDS / n-BuLi / -78 ° C d) 1 N HC1 / THF / RT / 30 minutes e) Boc20 / etN (i-Pr) 2 / acetonitrile / 16 hrs f) LiOH / THF-MeOH-H20 Where R6 and R7 have the meanings mentioned above.
Scheme 3 (16) (6) (20) (21) Steps a) through e) in Scheme 3 represent the following reactions: a) HDMS / n-BuLi / -78 ° C b) CH3COOH / THF / RT / 30 minutes c) R9Cl / EtN (i-Pr) 2 / THF / 16hrs d) 4 N HCl / dioxane e) EtN (i-Pr) 2 / acetonitrile Where Re and R7 have the meanings mentioned above and R9 represents another protected group such as Fmoc or Troc.
The compounds of formula (I) can be administered in solid or liquid form or as aerosols on the oral, enteral, parenteral, topical, pulmonary or rectal routes in all pharmaceutically acceptable non-toxic carriers, auxiliaries and additives. The compounds of formula (I) can also be applied locally on / within the bones (optionally with surgical operation). The term "parenteral" includes delivery of subcutaneous, intravenous and intramuscular infusions. The forms of oral administration may be, for example, tablets, capsules, coated tablets, syrups, solutions, suspensions, emulsions, elixirs, etc., which may contain one or more additives from the following groups eg, flavoring substances, sweeteners , and condoms. The oral administration forms contain the active agent together with pharmaceutically acceptable non-toxic carriers suitable for the production of tablets, capsules, coated tablets, etc., such as calcium carbonate, sodium carbonate, sodium or sodium phosphate, starch. , mannitol, methylcellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as astearic acid), peanut oil, olive oil, paraffin, Miglyol, gelatin, agar agar, magnesium stearate, beeswax , cetyl alcohol, lecithin, glycerol, animal and vegetable fat, solid polymers of high molecular weight (such as polyethylene glycols). Tablets capsules, coated tablets etc, may be provided with an appropriate cover such as monoestereate glyceride or glyceride distereate, as well as prevent unwanted side effects in the stomach, or result in prolonged activity due to delayed absorption in the gastrointestinal tract. Aqueous or oily sterile injectable solutions or suspensions are preferably used in an injectable medium, containing common additives such as stabilizers and solubilizers. Such additives may be for example, water, isotonic saline, 1,3-butanedidol, fatty acids (such as oleic acid) mono- and diglycerides, or Miglyol. For rectal administration, all suitable non-irritating additives can be used that are solid at normal temperatures and liquids at rectal temperature. Such as cocoa butter and polyethylene glycol. For aerosol administration, the common pharmaceutical carrier media are used. For external applications, creams, tinctures, gels, solutions or suspensions are used with the pharmaceutically common additives the dose may depend on several factors such as the mode of application, species, age and / or conditions of the individual. The doses administered daily or at intervals are around 1-1000 mg / person, preferably around 10-250 mg / person and can be ingested continuously or distributed several times.
The compounds of formula (I) can be applied locally on / within the bones (optionally with surgical operation). The application directly on / within the bones (optionally with surgical operation) can be carried out any solution or suspension, conveniently by infusion or injection, locally or by allocating a carrier. For example, target compound carriers of formula (I) can be applied as gels, pastes, solids or as coatings or implants.
Biocompatible materials and preferably biodegradable materials are used as carriers. Preferably the materials are added materials that induce wound healing or osteogenesis.
For local application it is preferred to introduce the compounds of formula (I) into gels or polymeric films, and thereby immobilize them, and to apply these preparations directly on the point of the bone to be treated. These gels based on polymers or films consist, for example, of glycerol, methylcellulose, hyaluronic acid, polyethylene oxides and / or polyoxazoles. Collagen, gelatin and alginates are also suitable and are described in WO 93/00050 and WO 93/20859, for example. Other polymers are polylactic acid (PLA) and copolymers of lactic acid and glycolic acid (PLPG) (Hollinger et al., J. Bio ed, Mater.
Res 37, 71.82 (1983)), and the "demineralized bone matrix" (DBM) derived from bone (Gunterman et al, Kollagen Reí. Res _8, 419-4319 (1988)). Polymers such as those used for the adsorption of TGFB, for example are also suitable and are described in EP-A 0,6161,814 and EP-A 0,567,391 as well as synthetic bone matrices according to WO 91/18558.
Materials commonly used in the implantation of bone substitutes or other active therapeutic substances are also suitable as carriers for the compounds of formula (I). Such carriers are also based on, for example, calcium sulfate, tricalcium phosphate, hydroxylapatite and their biodegradable derivatives, and polymers. Apart from these biodegradable carriers, those non-biodegradable carriers that are biocompatible are suitable. For example, these carriers are synthetic hydroxylapatite, bioglass, aluminates or other ceramic materials (for example calcium aluminate phosphate). Preferably these materials are used in combination with said biodegradable materials, such as, in particular, polylactic acid, hydroxylapatite, collagen, or tricalcium phosphate. Other non-degradable polymers have been described in US Patent 4,164,560, for example. Particularly preferred is the use of carriers that continuously release the compound of formula (I) at the site of action. Especially suitable for this purpose are, for example, "slow release spheres" from Innovative research of America, Toledo, Ohio, USA. Particularly preferred is the use of spheres which release the compound of formula (I) for several days, preferably up to 100 days in a daily dose of 1-10 mg / kg per day.
Apart from the compounds mentioned in the examples, and the compounds which can be derived by the combination in all senses of the substituents mentioned in the claims, the following derivatives, as well as their pharmaceutically acceptable salts, particularly the hydrochlorides and trifluoroacetates are preferred in the sense of the present invention.
Index of abbreviations used: Aba = aminobutyric acid Ac = acetyl Ada = (l-midino-2,5-dihydro-lH-pyrrol-3-yl) alanine Ala = alanine Ava = aminovaleric acid Bn = benzyl Boc = tert-butyloxycarbonyl Bu = butyl Cbz = benzyloxycarbonyl Cha = cyclohexylalanine DBU 1, 8-diazabicyclo [5. 4. 0] undec-7-ene DIBAL-H = diisobutylaluminum hydride DMAP = 4-dimethylaminopyridine DMF di ethylformamide Et = ethyl Fmoc = 9-fluorenylmethoxycarbonyl Gly = glycine HMDS = hexa ethyldisilazane i-PR isopropyl Me methyl NMM = N-methylmorpholine Ph phenyl Phe = phenylalanine Pro proline Py pyridine RT room temperature Ser septa t-but = tert-butyl TBTU tetrafluoroborate 2-H1-bemzotriazole-1- il) -1,1,3, 3-tetramethyluronium TCP = trityl chloride-polystyrene THF = tetrahydrofuran Thr = threonine Troc = 2,2, 2-trichloroethoxycarbonyl Trp = tryptophan Tyr = tyrosine = residence time Val = valina In addition, the one-letter code for amino acids is used.
Within the meaning of the present invention, the following mimetic peptides are preferred in addition to the compounds mentioned in the examples and compounds that can be derived by the combination in all senses of the substituents mentioned in the claims in the preferred compounds.
Preferred compounds: 1) Acid 2-. { 5- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (indol-2-yl) -propionic. 2) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (7-methyl-indol-2-yl) -propionic) 2- Acid. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3-benzo [b] thiophen-2-yl-propionic 4) 2- Acid. { 5- [Amino-3- (l-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (6-Methyl-indol-2-yl) -propionic 5) 2- Acid. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2-5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (6-hydroxy-indol-2-yl) -propionic 6) 2- Acid. { 5- [2-Amino-3-l (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (3-methyl-indol-2-yl) -propionic 7) 2- Acid. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-, 5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (3-methyl-benzafuran-2-yl) -propionic 8) 2- Acid. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (3, 4-dimethyl-benzofuran-2-yl) -propionic acid 9) 2- acid. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (3,5-dimethylbenzofuran-2-yl) -propionic acid. 10) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propioylamino] -pentanoylamino} -3- (3, 6-dimethyl-benzofuran-2-yl) -propionic acid. 11) Acid 2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanylamino} -3- (5-ethyl-3-methylbenzofuran-2-yl) -propionic acid. 12) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} 3-hydroxy-3- (3-methyl-benzofuran-2-yl) -propionic acid. 13) - Acid 2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (3, 7-dimethylbenzafuran-2-yl-propionic acid. 14) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (7-ethyl-3-methyl-benzofuran-2-yl) -propionic acid. 15) Acid 2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (3, 6-dimethylbenzofuran-2-yl) -3-hydroxy-propionic acid. 16) Acid 2-. { 5- [2-Amino-3- (l-carbamimidyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (3,5-dimethyl-benzofuran-2-yl) -3-hydroxy-propionic acid. 17) Acid 2-. { 5- [2- (Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (3,4-dimethylbenzofuran-2-yl) -3-hydroxy-phoxypic-18) 2- Acid. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (3,7-dimethyl-benzofuran-2-yl) -3-hydroxy-propionic acid. 19) Acid 2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (7-Chloro-3-methylbenzofuran-2-yl) -3-hydroxy-propionic acid.
) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (5-ethyl-3-methyl-benzofuran-2-yl) -3-hydrox-propionic acid. 21) 2- Acid. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- . { 7-ethyl-3-methyl-benzofuran-2-yl) -3-hydroxy-propionic acid. 22) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3-furan-2-yl-pxopionic. 23) Acid 2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamines] -pentanoylamino} -3-furan-2-yl-3-hydroxypropionic acid. 24) Acid. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -thiophen-2-yl-acetic. 25) Acid 2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3-thiophene-2-yl-propionic acid. 26) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylimino] -pentanoylamino} -3- (pyrrol-2-yl) -propionic. 27) Acid 2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (5-methyl-thiophen-2-yl) -propionic acid. 28) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3-hydroxy-3- (5-methyl-thiophen-2-yl) -propionic acid. 29) Acid 2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (5-ethyl-thiophen-2-yl) -propionic acid. 30) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (5-propyl-thiophen-2-yl) -propionic. 31) Acid 2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbaminidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (5-Dihydroxymethyl-furan-2-yl) -propionic acid. 32) 5- (2- { 5- [2-Amino-3- (l-carbamimido-2, 5-dihydro-pyrrol-3-yl) -porpionylamino] -pentanoylamino} -2-carboxylic acid ethyl) -2-methyl-furan-3-carboxylic acid. 33) 5- (2- { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] pentanoylamino.) -2-carboxy-ethyl) -2-ethyl-furan-3-carboxylic acid. 34) 5- (2-. {5- [2-Amino-3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino] -2- ethyl ester. -carboxy-ethyl) -2-methyl-pyrrole -3-carboxylic acid. 35) 5- (2- { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino.} -2-carboxy-ethyl) -2-propyl-furan-3-carboxylic acid. 36) 3- (5-Acetylimino-4,5-dihydro-thiophen-2-yl) -2-i5- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) acid ) -propionylamino] -pentanoylamino} -3-hydroxy-propionic. 37) Acid 5-. { 2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -2-carboxy-ethyl) -2-isobutyl-furan-3-propionic. 38) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3-cyclopentane-1-enyl-propionic acid. 39) Acid 2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3-hydroxy-3-thiophen-2-yl-propionic acid. 40) Acid. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} - (3-methyl-benzo [b] thiophen-7-yl) -acetic. 41) Acid-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -phenyl-acetic. 42) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro, pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (3,4-dihydroxy-phenyl) -3-hydroxy-propionic acid. 43) Acid. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydroxy-pyrrol-3-yl) -propionylamino] -pentanoylamino} - (4-hydroxy-phenyl) -acetic. 44) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydroxy-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3-phenyl-butyric. 45) Acid 2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydroxy-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3- (3,4-bis-benzyloxy-phenyl) -3-hydroxy-propionic acid. 46) - Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} - 3-hydroxy-succinic. 47) 2- ( { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino acid .}. -carboxymethyl) -benzoic acid. 48) 5- [2-Amino-3- (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino acid} - (3-oxo-2, 3-dihydro-isoxasol-5-yl) -acetic .. 49) Acid. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl.}. -propionylamino] -pentanoylamino-cyclohexyl-acetic acid. 50) 1,4-dienyl acid. { 5- [2-Amino-3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl). Propionylamino] -pentanoylamino} -cyclohexa-1, 4-dienyl-acetic acid. 51) 1,5-dienyl acid. { 5- [2- (2-Amino-3-hydroxy-butyryl-ino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -cyclohexa-l, 5-dienyl-acetic acid. 52) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3-hydroxy-3-pyridine-3-yl-propionic acid. 53) Acid -2-. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -3-hydroxy-3-pyridine-4-yl-propionic acid. 54) 4- ( { 5- [2-Amino-3- (1-carbamimidoi'-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} -carboxymethyl) -2-hydroxybenzoic. 55) 4- ( { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino acid .}. -carboxymethyl) -benzoic acid. 56) Acid 2-. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} 3-phenylsulfanyl-butyric. 57) Acid. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} - (tetrazol-5-yl) -acetic. 58) Acid. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} - (indol-3-yl) -acetic, 59) Acid. { 5- [2- (2-Amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propylamino] -pentanoylamino} - (3,4-dihydroxy-phenyl) -acetic. 60) Acid. { 5- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -pentanoylamino} - (3, 5-dihydroxy-phenyl) -acetic 61) 2- Acid. { 4- [2-Amino-3- (l-carbamimidoyl-2, 5-hydroxy-phenol-3-yl) -propionylamino] -butyrylamino] -3- (indol-2-yl) -propionic acid. 62) Acid 2-. { 4- [2- (2-Amino-3-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (7-methyl-indol-2-yl) -propionic. 63) Acid 2-. { 4- [2-Amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3-benzo [b] thiophen-2-yl-propionic acid. 64) Acid 2-. { 4 - [- 2- (2-Amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (6-methyl-indol-2-yl) -propionic. 65) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (6-hydroxy-indol-2-yl) -propionic acid. 66) Acid 2-. { 4- [2- (2-amino-3-hydroxy-butylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butylamino} -3- (3-methyl-indol-2-yl) -propionic. 67) - Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (3-methyl-benzofuran-2-yl) -propionic acid. 68) Acid 2-. { 4- [2- (2-amino-3-hydro-butylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butylamino} -3- (3, 4-dimethyl-benzofuran-2-yl) -propionic acid. 69) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino-butylamino} -3- (3, 5-dimethyl-benzofuran-2-yl) -propionic acid. 70) Acid 2-. { 4-J2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (3, 6-dimethyl-benzofuran-2-yl) -propionic acid. 71) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (5-ethyl-3-methyl-benzofuran-2-yl) -propionic acid. 72) Acid 2-. { 4- [2- (2-amino-3-hydroxy-butylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3-hydroxy-3- (3-methyl-benzofuran-2-yl) -propionic acid. 73) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (3, 7-dimethyl-benzofuran-2-yl) -propionic acid. 74) Acid 2-. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (7-ethyl-3-methyl-benzofuran-2-yl) -propionic acid. 75) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (3, 6-dimethyl-benzofuran-2-yl) -3-hydroxy-propionic acid. 76) Acid 2-. { 4- [2- (2-amino-3-hydroxy-butylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (3, 5-dimethyl-benzofuran-2-yl) -3-hydroxy-propionic acid. 77) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (3, 4-dimethyl-benzofuran-2-yl) -3-hydroxy-propionic acid. 78) Acid 2-. { 4- [2- (2-amino-3-hydroxy-butylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (3, 7-dimethyl-benzofuran-2-yl) -3-hydroxy-propionic acid. 79) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (7-Chloro-3-methyl-benzofuran-2-yl) -3-hydroxy-propionic acid. 80) Acid 2-. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (5-ethyl-3-methyl-benzofuran-2-yl) -3-hydroxy-propionic acid. 81) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (7-ethyl-3-methyl-benzofuran-2-yl) -3-hydroxy-propionic acid. 82) Acid 2-. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3-furan-2-yl-propionic. 83) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3-furan-2-yl-3-hydroxy-propionic acid. 84) Acid. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -thiophen-2-yl-acetic. 85) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3-thiophene-2-yl-propionic acid. 86) Acid 2-. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (pyrrol-2-yl) -propionic. 87) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (5-methyl-thiophen-2-yl) -propionic acid. 88) Acid 2-. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3-hydroxy-3- (5-methyl-thiophen-2-yl) -propionic acid. 89) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (5-ethyl-thiophen-2-yl) -propionic acid. 90) Acid 2-. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (5-propyl-thiophen-2-yl) -propionic. 91) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (5-hydroxymethyl-furan-2-yl) -propionic acid. 92) 5- (2- { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino.) -2-carboxy-ethyl) -2-methyl-furan-3-carboxylic acid. 93) 5- (2-. {4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -2-carboxylic acid ethyl) -2-ethyl-furan-3-carboxylic acid. 94) - 5- (2-. {4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) ethyl ester ) -propionylamino] -butyrylamino.} -2-carboxy-ethyl) -2-methyl-pyrrole-3-carboxylic acid. 95) 5- (2-. {4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -2-carboxylic acid ethyl) -2-propyl-furan-3-carboxylic acid. 96) 3- (5-Aoethylimino-4, -dihydro-thiophen-2-yl) -2- acid. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3-hydroxá-propioni or 97) 5- (2- {4.4 { 2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino acid} -2- carboxy-ethyl) -2-isobutyl-furan-3-carboxylic acid 98) 2- Acid. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- cyclopent-1-enyl-propi or co 99) 2- Acid. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrole-3-yl]) -propylamino] -butylamino} -3-hydroxy-3-thiophen-2-yl-propionic acid 100) Acid. { - [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoi 1-2, 5-dihydro-pi-pyr-3-y1) -propionyl-mino] -butyrylamino} - (3-methyl-benzo [b] thiophen-7-yl) -acetic 101) Acid. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -phenyl-acetic 102) 2- Acid. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -butyralmino} -3- (3,4-dihydro-phenyl) -3-hydroxypropionic acid 103) Acid. { 4- [2-amino-3- (l-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylami o} - (4-hydroxy-phenyl) -acetic 104) 2- Acid. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3-phenyl-butyric 105) Acid 2-. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3- (3, 4-bis-benzi loxi-phenyl) -3-hydroxy-propionic acid 106) 2-. { 4- [2-. { 2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2), 5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3-hydroxy-succinic 107) 2- ( { 4- [2-amino-3- (l-carbamimidoyl-2,5-di-idro-pyrro] -3-yl) -propi or lamino] - butylamino.}. -carboxymethyl) -benzoic acid 108 '5- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoi 1-2, 5-dihydro-pyrrole-3-- il) -propionylamino] -bptyrylamino} - (3-oxo-2,3-dihydro-isoxazol-5-yl) -acetic-109) Acid. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -cyclohexyl-acetic acid 110). { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino} -butyrylamino} -cyclohexa-l, 4-dienyl-acetic 111) Acid. { 4- [2-amino-3- [l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -cyclohexa-1, 5-dienyl-acetic 112) 2- Acid. { 4- [2- (2-amino-3-hydroxy-butyryl-ino) -3- (l-carbamimidol-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3-hydroxy-3-pyridin-3-yl-propionic 113) 2- Acid. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3-hydroxy-3-pyridin-4-yl-propionic acid 114) 4- (. {4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2, 5 -dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino.} - carboxymethyl) -2-hydroxy-benzoic acid 115) 4- (. {4- [2-amino-3- (l-carbamimidoyl -2,5-dihydro-pyrrole -3-y1) -propioni mino] -butyrylamino.} - carboxymethyl) -benzoic acid 116) 2- Acid. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} -3-phenylsulfanyl-butyric 117) Acid. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} - (tetrazol-5-yl) -acetic 118) Acid. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} - (indol-3-il) -acetic 119) Acid. { 4- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} - (3,4-dihydroxy-phenyl) -acetic 120) Acid. { 4- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -butyrylamino} - (3, 5-dihydroxy-phenyl) -acetic 121) 2- Acid. { 3- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3- (indol-2-yl) -propionic 122) 2- Acid. { 6- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -hexanoylamino} -3- (7-methyl-indol-2-yl) -propionic 123) 2- (2- { 2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl) -2,5-dihydro-pyrrol-3-yl) -propionylamino] -3-hydroxy-propionylamino.]. -propionylamino) -3-benzo [b] thiophen-2-yl-propionic acid 124) Acid 2-. { 3- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3- (6-methyl-indol-2-yl) -propionic 125) 2- Acid. { 6- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -hexanoylamino} -3- (6-hydroxy-indol-2-yl) -propionic 126) 2- (2-. {2- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrole-3) acid -yl) -propionylamino] -3-hydroxy-propionylamino.]. -propionylamino) -3- (3-methyl-indol-2-yl) -propionic 127) 2- Acid. { 3- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3- (3-methyl-benzofuran-2-yl) -propionic 128) 2- (2- { 2- { 2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrole) -3-yl) -propionylamino.} - 3-hydroxy-propionylamino.]. -propionylamino) -3- (3,4-dimethyl-benzofuran-2-yl) -propionic 129) 2- Acid. { 6- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidol-2,5-dihydro-pyrrol-3-yl) -propionylamino] -hexanoylamino} -3- (3, 5-dimethyl-benzofuran-2-yl) -propionic 130) 2- (2- { 2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l -carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -3-hydroxy-propionylane, no.}. -propionylamino) -3- (5-ethyl-3-methyl-benzofuran-2-yl) - propionic 131) Acid 2-. { 3- [2-amino-3- (l-carbamimidol-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3-hydroxy-3- (3-methyl-l-benzofuran-2-yl) -propionic acid 132) 2- (2- { 2- [2- (2-amino-3-hydroxy-bpyrylamino) -3- (-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionic acid ] -3-hydroxy-propionylamino.} - propionylamino) -3- (3,7-dimethyl-benzofuran-2-yl) -propionic acid 133)? - acid? { 6- [2-am no-3- (l-carbamimidoyl-2, -dihydro-pi rrol -3-i 1) -propioni l mino] -hexanoi lo-3- (7-eti1 -3-meti 1-benzofuran -2-i 1) -propane 134) 2- (2- { 2- [2- (2-amino-3-hydroxy-bptylamino) -3- (_ -carbamimidoi 1-2, 5-dihydro) acid -pyrrole -3-i 1) -pro i ni 1 ami no] -3-nor droxi-propy nylo n.}. -propionylamino) -3- (3,6-dimethyl-benzofuran-2-yl) -3- hydroxy-propioni co 135) 2- Acid. { 3- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3- (3, 5-dimethyl-benzofuran-2-yl) -3-hydroxy-propionic acid 136) 2- (2- { 2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoi 1-2, 5-dihydro-pi-3-yl) - propionylamino] -3-hydroxy-propionylamino.]. -propionylamino) -3- (3,4-dimethyl-benzofuran-2-yl) -3-hydroxy-propionic acid 137) 2- Acid. { 6- [2-amino-3- (1-carbamimidoi 1-2, -dihydro-pyrrol-3-yl) -propionyl-mino] -hexanoyl} -3- (3,7-dimethyl-benzofuran-2-yl) -3-hydroxy-propionic acid 138) 2- (2- {2. {2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamyl-dodecyl-2,5-dihydro-pyridyl) -3- il) -propy or lamino] -3-hydroxy-propionylamino or.}. -propionylamino) -3- (7-chloro-3-methyl-benzofuran-2-yl) -3-hydroxy-propionic acid 139) Acid? . { 3- [2-amino-3- (1-carbamimidoi -2, -dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3- (5-ethyl-3-methyl-benzofuran-2-yl) -3-hydroxy-propy ni co 140) 2- Acid. { 6- [2- (2-amino-3-hydroxy-bufrylamino) -3- (-carbamimi doi 1 -2,5-dihydro-pyrrol-3-yl) -propioni 1 amino] -hexanoi lamino} -3- (7-ethyl-3-methyl-benzofuran-2-yl) -3-hydroxy-propionic acid 141) 2- Acid. { 6 [2-amino-3- (l-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -hexanoyl} -3-furan-2-yl-propionic 142) 2- Acid. { 3- [2-. { 2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3-furan-2-yl-3-hydroxy-propionic 143) Acid. { 3- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -thiophen-2-yl-acetic acid 144) 2- (2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) acid) -propionylamino] -3-hydroxy-propionylamino.}. -propionylamino) -3-thiophen-2-yl-propionic 145) 2- Acid. { 6- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -hexanoyl} -3- (pyrrol-2-yl) -propionic 146) 2- Acid. { 3- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3- (5-methyl-thiophen-2-yl) -propionic 147) 2- (2 { 2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl- 2, 5-dihydro-pyrrol-3-yl) -propionylamino] -3-hydroxy-propionylamino.]. -propionylamino) -3- (5-ethyl-thiophen-2-yl) -propionic 148) 2- Acid. { 3- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3- (5-propyl-thiophen-2-yl) -propionic 149) 2- (2- { 2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l- carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -3-hydroxy-propionylamino.]. -propionylamino) -3- (5-hydroxymethyl-furan-2-yl) -propionic 150) 5- Acid (2- { 6- { 2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -hexanoylamino.} -2-carboxy-ethyl) - 2-methyl-furan-3-carboxylic acid 151) 5- (2- (2-. {2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2, 5) acid -dihydro-pyrrol-3-yl) -propionylamino] -3-hydroxy-propionylamino.}. -propionylamino) -2-carboxy-ethyl) -2-ethyl-furan-3-carboxylic 152) ethyl ester of 5- ( 2- {3- [2-amino-3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -2-carboxy-ethyl) -2-methyl -pyrrole-3-carboxylic acid 153) 5- (2-. {6- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrole-3) acid -yl) -propionylamino] -hexanoylamino.} -2-carboxy-ethyl) -2-propyl furan-3-carboxylic 154) 5- (2-. { 3- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -2-carboxy-ethyl) -2-isobutyl-furan-3-carboxylic acid 155) (2- {2- [2-amino-3- (l-carbamimidoyl-2, 5-dihydro-pyrrole-3-} il) -propionylamino] -3-hydroxy-propionylamino.}. -propionylamino) -3-cyclopent-1-enyl-propionic 156) 2- Acid. { 3- [2-. { 2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3-hydroxy-3-thiophen-2-yl-propionic 157) 2- Acid. { 6- { 2-amino-3- (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -hexanoylamino} -3- (3, -dihydroxy-phenyl) -3-hydroxy-propionic 158) 2- Acid. { 3- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3-phenyl-butyric 159) 2- (2- { 2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrole-3) acid -yl) -propionylamino] -3-hydroxy-propionylamino.]. -propionylamino) -3- (3,4-bis-benzyloxy-phenyl) -3-hydroxy-propionic acid. 160) 2- Acid. { 6- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -hexanoylamino} -3-hydroxy-succinic 161) Acid. { 3-. { 2-amino-3- (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -cyclohexa-1,4-dienyl-acetic 162) 2- Acid. { 3- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3-hydroxy-3-pyridin-3-i1-propionic acid 163) 4- (. {6- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) - propionylamino] -hexanoylamino.} - carboxymethyl) -2-hydroxy-benzoic 164) 2- Acid. { 3- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -3-phenylsulphane-butyric 165) Acid. { 6- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -hexanoylamino} - (indol-3-yl) -acetic 166) Acid. { 3- [2-amino-3- (l-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} - (3, 5-dihydroxy-phenyl) -acetic 167) Acid (2. {2- 2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro- pyrrol-3-yl) -propionylamino] -propionylamino.]. -propionylamino) -3- (6-hydroxy-indol-2-yl) -propionic 168) (2- [2- [2-amino-3- (l -carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino.}. -propionylamino) -3- (3,6-dimethyl-benzofuran-2-yl) -propionic 169) 2- ( 2- { 2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino}. propionylamino) -3- (3,4-dimethyl-benzofuran-2-yl) -3-hydroxy-propionic acid 170) 2- (2- { 2- [2- (2-amino-3-hydroxy-butyrylamino ) -3- (l-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino.}. -propionylamino) -3- (7-ethyl-3-methyl-benzofuran-2-yl) -3-hydroxy-propionic 171) 2- (2- { 2- [2- (2-amino-3-hydroxy-butyryl-ino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol- 3-yl) -propionylamino] -propionylamino .}. -propionylamino) -3-thiophen-2-yl-propionic 172) 2- (2-. { 2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -propionylamino) -3- (5-methyl-thiophen-2-yl) -propionic 173) 2- (2- { 2- [2- (2-amino-3-hydroxy-butyrylamino) -3- ( l-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino.]. -propionylamino) -3- (5-hydroxymethyl-furan-2-yl) -propionic 174) Acid 3- (5 -acetylimino-4,5-dihydro-thiophen-2-yl) - (2-. {2- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] ] -propionylamino.}. -propionylamino] -3-hydroxy-propionic 175) (2- {2- [2- { 2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl- 2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} -propionylamino) -phenyl-acetic acid 176) (2- {2- [2-amino-3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -p-sprylamino] -propionylamino} acid. -propionylamino) -3- (3,4-dihydroxy-phenyl) -3-hydroxy-propionic acid 177) 2- (2- { 2- [2- (2-amino-3-hydroxy-butyrylamino) -3 acid - (1-carbamimidoyl-2, 5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino.]. -propionylamino) -3- (3, 4-bis-benzyloxy-phenyl) -3-hydroxy-propionic acid. ) 2- ((2- {2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (l-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] acid] -propionylamino.} - propionylamino) -carboxymethyl) -benzoic acid 179) 2- (2- { 2- [2- (2-amino-3-hydroxybutyrylamino) -3- (l-carbamimidoyl- 2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino.} - propionylamino) -3-hydroxy-3-pyridin-4-yl-propionic acid 180) Acid (2-. {2- 2- [2 - (2-amino-3-hydroxy-butyrylamino) -3- (l-carba? Aidoido-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino.} - propionylamino) - ( tetrazol-5-yl) -acetic 181) Acid (2-. { 2- [2- (2-amino-3-hydroxy-butyrylamino) -3- (1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl) -propionylamino] -propionylamino} - propionylamino) - (3,4-dihydroxy-phenyl) -acetic The following examples exemplify variants for the synthesis of the compounds of the invention. The structure of the compounds was obtained by ^? -, 13C-RM-s spectroscopy and optionally by mass spectroscopy. The purity of the substances was obtained by analysis of C, H, N and by chromatography.
Example 1 (±) -3- (2-tert-butoxycarbonyl-amino-2-hydroxycarbonyl) -ethyl-2,5-dihydropyrrole-l- (N, N'-di-tert-butoxycarbonyl) carboxy idine tBoc-Ada (Bos) 20H] a) 1-tert-Butyl ester 3-ethyl ester of 4-oxo-pyrrolidine-1,3-dicarboxylic acid (J. COOPER et al., J. Chem. Soc. Perkin Trans. 1, 1993t 1313-1318) To a reflux suspension of 1.58 g (66 mmol) of sodium Jiidride in 100 ml THF was added dropwise a solution of 12.79 g (60 mmol) of N-etrt-butyloxycarbonyl-glycine ethyl ester and 7.15 g (66 g). mmol) of ethyl acrylate in 100 ml of THF. After the addition was complete the mixture was heated to reflux for 2 h additional. The clear solution was cooled to room temperature, poured into 100 ml of ether / 100 ml of water and acidified under vigorous stirring with IN hydrochloric acid with methyl orange. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic phases were washed with saturated sodium bicarbonate in water and brine, dried with MgSO 4 and evaporated. Short path distillation of the residue gave 10.92 g (71%) of 1-tert acid.
Butylester 3-ethyl ester 4-sxo-pyrrolidine-1,3-dicarboxylic acid as a colored oil, p.fus 119-112 ° C (0.2 mbar), which solidifies in a prolonged stay in the refrigerator.
GC / MS (HP 5890 11/5972;, column: HP 5, film thickness 30 mx 25 mm x 0.25 Om, carrier gas: helium, temperature gradient: 50 ° C, 3 min, then with 20 ° C / min at 250 ° C) tR = 9.68 min m / z [%] = 185 (2), 130 (10), 112 (18), 85 (6), 57 (100). b) 1-tert. -butyl-3-ethyl ester of the acid-hydroxy-pyrroline-1,3-dicarboxylic acid To a solution of 5.15 g (20 mmol) of 4-oxo acid 1-tert-butyl ester 3-ethyl ester pyrrolidine-1,3-dicarboxylic acid in 30 ml of methanol was added to 1.88 g (30 mmol) of sodium cyanoborohydrate and small amounts of methyl orange. The pH was adjusted to 3 with stirring by the dropwise addition of hydrochloric acid IN (the color changes from yellow to orange). After no more acid was consumed, the mixture was stirred for one hour. The solvent was evaporated in vacuo and the residue was partitioned between a-cetate and water. The organic layer was washed twice with water then with brine, dried over magnesium sulfate and evaporated. The residual yellow oil was used in the next step without any further purification.
GC / MS ((HP 5890 11/5972;, column: HP 5, film thickness 30 x 25 mm x 0.25 Dm, carrier gas: helium, temperature gradient: 50 ° C, 3 min, then 20 ° C / min at 250 ° C) tR = 12.44 min (without separation of diastereomers) m / z [%] = 259 (M, 0.3), 241 (0.7), 202 (5), 186 (7), 158 (10), 112 (14), 68 (31), 57 (100). s) 1-tert. 4-Benzoyloxy-pyrrolidine-1,3-dicarboxylic acid 3-ethyl ester To a solution cooled with 1-tert ice. 3-ethyl ester of the 4-hydroxy-pyrrolidine-1,3-dicarboxylic acid of the reduction described above and 244 mg (2 mmol) of DMAP in 40 ml of pyridine were added dropwise 3.51 g (25 mmol 9 of benzoyl chloride) After the addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 2 h.The mixture was diluted with ethyl acetate and poured onto ice.The organic layer was separated, washed with Water CuS04 saturated in water, water and brine, dried over MgSO4 and evaporated The residual yellow oil was used the next step without further purification.
GC / MS ((HP 5890 11/5972;, column: HP 5, film thickness 30 x 25 mm x 0.25 Dm, carrier gas: helium; -temperature gradient: 50 ° C, 3 min, then at 20 ° C / min at 250 ° C) tR = 17.28 min and 17.38 min (1: 1 mixture of cis / trans isomers) m / z [%] = 318 (0.1), 290 (5), 262 (2), 241 (2), 185 (29), 141 (10), 112 (23), 105 (53), 77 (27 ), 68 (100), 57 (97). d) 1-tert. -butyl ester 3-ethyl ester of 2,5-dihydro-pyrrole-l, 3-dicarboxylism To a 1-tert solution. The crude 3-ethyl ester of 4-benzoyloxy-pyrrolidine-1,3-dicarboxylic acid of the benzolation described above in 75 ml of dry toluene was added 4.11 g (27 mmol) of DBU. The opaque heterogeneous mixture was stirred at room temperature for 16 h. After this time the original material was not detected by analysis with TLC and GC. The mixture was filtered through a short column of silica (eluted with petroleum ether / ethyl acetate 1: 1) and evaporated. Bulb-to-bulb distillation of the slightly yellow residual oil gave 4.16 g (86%) of 2,5-dihydro-pyrrole-1,3-dicarboxylic acid 1-tert.-butylester 3-ethyl ester as a b.p. 110 ° C / 0.2 mbar, which solidified slightly in a waxy mass while in the refrigerator.
GC / MS ((HP 5890 11/5972; column: HP 5, film thickness 3-0 - yes x 25 mm x 0.25 O, carrier gas: helium; Temperature gradient: 50 ° C, 3 min; then with 20 ° C / min at 250 ° C) tR = 11.94 min m / z [%] = 241 (M, 1.4), 196 (0.4), 185 (11), 168 (11), 140 (14), 112 (17), 68 (24), 57 (100) ^ -NMRÍCDCla, 300 MHz) d = 1.27 (t, = 7.1 Hz, 3H, OCH2CH3), 1.43, 1. 4 I2s, 9H, C (CH3) 3] / 4.25 (d, j = 7.1 Hz, 2H, OCH? CHs), 4.15-4.27 (br.
M, 4H7 2-H, 5-H), 6.66-6.71 (m, iH, 4-H) ppm. Double comma means due to impediment rotation. 134 C-NMR (CDCL3 / .75MHZ) d = 14.16, 14.20 (q, -CH2-CH3) ", 28.45 [q, -C (C (CH3) 3] 51. 715.51.39, 53.62, 53.84 (4t, C-2, C-5) ", 60 69 (t-CH2-CH3) 79.84 [s, - (CH3) 3], 132.29 (s, C-3), 136.44 , 136.55 (2d, C-4) ", 153.86, 154.08 (2s, -NCOO -) *, 162.75 (s, COOEt) ppm e) 1-tert.butyl ester of 3-hydroxymethyl-2,5-di-hydro-pyrrole-1-carboxylic acid To a solution of 5.43 g (22.5 mmol) of 1-tert. -butyl ester 3-ethyl ester of 2,5-dihydro-pyrrole-1,3-dicarboxylic acid in 50 ml of THF, cooled to -78 ° C were added dropwise 50 ml of a solution of DIBAL-H IN in hexane. The mixture was allowed to warm to room temperature overnight. As the TLC analysis indicated the total consumption of the original material, the mixture was cooled in an ice bath and 1.90 g of water were cautiously added, followed by 1.90 g of aqueous NaOH and 5.70 g of water. The white precipitate was filtered, thoroughly washed with ether and the combined filtrates were evaporated, the bulb-to-bulb distillation of the residual pale yellow oil yielded 4.13 g (93%) of 3-hideroxymethyl-2, 5-dihydro tert-butylester. -pyrrole-1-carboxylic acid as a bp coloring oil 130 ° C (0.2 mbar).
GC / MS (HP 5890 11/5972;, column: HP 5, film thickness 30 mx 25 mm x 0.25 ™ carrier gas: helium, temperature gradient: 50 ° C, 3 min, then with 20 ° C / min 250 ° C) tR = 11.34 min m / z [%] = 199 (M, I), 143 (10), 142 (13), 126 < 13), 112 (12), 80 (10), 68 (45), 57 (100) ^ -NMR (CDC13, 300 MHz) d = 1.44 (s, 9H.t-Bu), 4.09 (br, m.4H, 2-H, 4-H), 4.18 (br.S, 2H, CH20H), 5.63 (br.D, 1H, 4 -H) ppm. 13 C-NMR (CDCI3, 75 MHz) d = 28.5 [q, C (CH3) 3], 52.8, 53.0, 53.2, 53.3 (4t, C-2, C-5) ", 57.7, 59.8 (2d, CH2OH), 79.5 [s, C (CH3) 3], 120.0, L2Ü_3. &C-J, 135.6 (s, C-3), 154-4 (s, COOtBu) ppm.
"Double set of signs means impeded rotation. f) Ter-butyl ester of 3-acetoxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid.
To a solution of 4.13 g (20.7 mmol) cooled with ice of the 3-acetoxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert-butylester and 244 mg (2 mmol) of DMAP in 50 ml of pyridine were Aggregates 3.06 (30 mmol) of acetic anhydride, the mixture was stirred for 30 min. At 0 ° C then for 60 jain at room temperature. The mixture was drained on ice and extracted twice with ether, washed with saturated CuS04, water and brine and dried over MgSO4. Bulbo-bulb evaporation gave 4.82 g (97%) of the 3-acetoxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester as a colorless oil, b.p. 105 ° C (0.2 mbar).
GC / MS (HP 5890 11/5972;, column: HP 5, film thickness 30 mx 25 mm x 0.25 pm carrier gas: helium, temperature gradient: 50 ° C, 3 min, then with 20 ° C / min 250 ° C) tR = 11.87 min m / z [%] = 241 (M ", 0.2), 226 (0.1), 185 (5), 166 (5), 125 (18), 108 (3), 81 (13), 180 (23), 57 (100) 1H-NMR (CDC13, 300 MHz) d = 1.43.1.44 [2s, 9H, C (CH3) 3] *, 2.04, 2.06 (2S.3H, OOCCH3) *, 4.05-4.12 (br.m, 4H, 2 -H, 5-H), 4.61 (br.d, '= 5.7 Hz, 2H, CH20), 5.66-5.73 (br.,! H, 4-H) ppm. 13C-NRM (CDC13, 75MHz d = 20.7 (q, OOCCH3), 28.4 [q, C (CH3) 3], 53.0, 53.2, 53. 3 (3t, 2-C. 5-C) *, 60.8 (t, ^ Cft, 79.5 s, c (cfl ^, 123.4, 123.8 (23.0-4), 134.5,134.6 (2s, c-3) , 154.1 { S, mjD, 170.5 (s.caOT ^ ppn. g) 3-Acetoxy ethyl-2,5-dihydro-pyrrole-l- (N, N-di-tert-butoxyarbonyl) sarboxamidine.
To a solution of 1.21 g (5 mmol) of the 3-acetoxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert-butylester. For example 3f) in 10 ml of dry dioxane were added 10 ml of 4N hydrogen chloride in dioxane, the mixture was stirred at 0 ° C for 16 h. The mixture was evaporated to dry without heating and then evacuated to high vacuum for several hours. The opaque residue was suspended in 20 ml of dry acetonitrile and 776 mg (6 mmol) of ethyl diisopropylamine, followed by 1.71 g (5.5 mmol) of N, N '.bis-tert-butyloxycarbonyl-1H-pyrazole-1-carboxamidine were aggregates The mixture was stirred for 2 h at room temperature and then evaporated and purified by flash chromatography (petroleum ether / ethyl acetate 3: 1 to 2.1) to obtain 1.87 g (97%) of 3-acetoxymethyl-2, 5-dihydro- pyrrole-1- (N, N'-di-tert-butoxycarbonyl) carboxamidine, as a sticky solid.
XH-NMR (CDC13, 300 MHz) d = 1.45 (s, 18H, 2 t-Bu), 2.03 (s, 3H, Oac), 4, .38. { br. m, 4H, 2-H, 5-H), 4.61 (s, 2H, CHaOac), 5.72 (br.m, iH, 4-H), 10.22 (br.s, IH, NH) ppm. 13 C-NMR (CDC13, 75 MHz) d = 20.4 (q, OOCCH3), 27.7, 27.9 [2q, C (CH3) 3] ^ 55.0 (br.t, C-2, C-5), 60.2 (t, CH2OAc), 79.3, 81.8 [2br. s, C (CH3) 3], 122.4 (d, C-4), 133.5 (s, C-3), 150 (br.s, UcOO), 153.9 (s, NC = N), 162 (br. , NCOO), 170.2 (s, OOCH2CH3) ppm. h) 3- (2-Benzydryl-deneamin-2-ethoxycarbonyl-ethyl-2,5-dihydropyrrol-1- (N, '-di-tert-butoxycarbonyl) carboxamidine To a solution of fresh hexamethyldisilazide prepared at 0 ° C formed of 710 mg (4.4 mmol) of hexamethyldisilazone in 8 ml of THF and 1.92 g (4.4 mmol) of n-butyllithium (2.29 mmol / g in hexanes) and cooled to -78 ° C a solution of 1069 g (4 mmol) of N- (diphenylethylmethylene) -glycinate in ethyl in 8 ml of THF was added. The enolate orange solution was stirred for 30 min at -78 ° C, then a solution of 1.039 g (3.7 mmol) of 3-acetoxymethyl-2,5-dihydro-pyrrole-1- (N, N'-di- tert-butoxycarbonyl) carboxamidine and 426 mg (0.4 mmol) of Pd (PPh3) 4 in 12 ml of THF were added in the form of drops. The reaction mixture was allowed to reach room temperature for 2 hours and was stirred for 12 h. Additionally. The mixture was diluted with ether and cooled by addition of saturated NaHCO 3. The organic phase was washed with saturated NaHCO 3 and brine, dried over MgSO 4 and evaporated. Purification by flash chromatography (with ethyl acetate / petroleum ether 1: 5 + 1% triethylamine) gave 1.03 g (47%) of 3- (2-benzyldrilideneamino-2-ethoxycarbonyl-ethyl) -2,2-dihydropyrrole -1- (N, N '-di-tert-butoxycarbonyl) carboxamidine as an amorphous solid compound.
^ -NMRÍCDCls) d = 1.23 (t, j = 7.1 Hz, 3H, QCH2CH3), 1.46 [br.s, 18H, C (CH3) 3], 2.68 (br.m, 2H, 3-CH2-) 3.96 (br.m, 1H, CH-N), 4.15 (q, J = 1 .1 Hz, 2H, O R2C? .3), 4.16-4.29 (br.m, 4H, 2-H, 5-H) , 5.41 (br.m, 1H, 4-H), 7.07-7.60 (m, 10 H, Ar-H) ppm. 13 C-NMR (CDCl 3 75 MHz) d = 13.9 (q, OCH 2 CH 3), 28.0 [q, C (CH 3) 3], 32.5 (t, 3-CH 3), 55.2, 56.9 (2t, C-2, C-5 ), 60.9 (t, OCH2CH3), 63.6 (d, CH-NH2), 79, 81.6 [2 br. s, C (CH3) 3], 120.7 (d, C-4), 1-27.5, 127.8, 12-8.4, 128.6, 130.2 (-ßd, Ar-CH), 134.8 (s, C-NC = N) , 162 (br. S, NCOO), 170.7 (s, N = CPh2), 171.2 Is, OOCH2CH3) ppm. i) 3- (2-amino-2-ethoxysarbonyl-ethyl) -2,5, -dihydropyrrole-1 - (N, '-di-tert-butoxy-arylcarbonyl) carboxamidine To a solution of 118 mg (0.2 mmol) of 3- (2-benzyl-drilyneamino-2-ethoxycarbonyl-ethyl) -2,5-dihydropyrrole-1- (N, N'-di-tert-butoxycarbonyl) carboxamidine in 2 ml of THF was added 1 ml of IN hydrochloric acid. The mixture was stirred at room temperature for 30 min. Water (5 ml) was added. The aqueous phase was separated and washed twice with ether. The aqueous phase was adjusted to pH = 8.5 by adding NaHC03 IN and was extracted 5 times with ether. The combined ether phases were washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash chromatography (Chloroform / methanol 20: 1) to obtain 79 mg (93%) of 3- (2-amino-2-ethoxycarbonyl-ethyl) -2,5-dihydropyrrole-1- (NN '-di-). tert-butoxycarbonyl) carboxamidine, as a colorless oil.
^ -NMRÍCDCLs, 300 MHz) d = 1.22 (t, j = 7.1 Hz, 3H, OCH2CH3), 1.45 [s, 18H, C (CH3) 3], 2.33 (dd, 2J = 16.6 H2.3J = 8.1 Hz, IH, CHaHbCHNH2), 2, 54 (dd, 2J016.6 HZ, 3 J = 5.3 Hz, IH, CHaHbCHNH2), 3.54 (dd, 3"= £ __1-, 5 ^ 3 Hz, IH, CHaHbCHNH2) -, 4_ 13 (q, J = 7.1 Hz, 2H, ppm. d = 13.9 (q, OCH2CH3), 27.9 [q, C (CH3) 3], 34.1 (t, -CH2), 52.7 (d, CHNH2), 55.3, 56.9 (2d, C-2, C-5). 61.1 (t, OCH2 = CH3), ca 80 [2 br. s, C (CH3) 3], 120.7 (d, C-4), 134.6 (s, C-3) _, .53.8 (s, NC = N), 174.6 (s., OOCH2CH3) ppm. j) 3- (2-tert-butoxycarbonyl-amino-2-ethoxycarbonylethyl) -2,5-dihydropyrrole-1 - (N, N'-di-tert-butoxycarbonyl) carboxamidine To a solution of 79 mg (0.19 mmol) of 3-82-amino-2-ethoxycarbonyl-ethyl) -2,5-dihydropyrrole-1- (N, N'-di-tert-butoxycarbonyl) carboxamidine in 1 ml of acetonitrile dry were added 40 mg (0.3 mmol) of ethyl diisopropylamine and 65 mg of di-tert-butyl bicarbonate (Boc20) and the mixture was stirred for 16 h at room temperature. The solvent was evaporated and the residue was purified by flash chromatography (petroleum ether / ethyl acetate 2: 1) to obtain 83 mg (76%) of 3- (2-tert-butoxycarbonyl-amino-2-ethoxycarbonyl-ethyl) -2,5-dihydropyrrole-1- (N, N '-di-tert-butoxycarbonyl) carboxamidine, as a colorless oil.
^ -NMRÍCDCLs, 200 MHz) d = 1.22 (t, j = 7.1 Hz, 3H, OCH2CH3), 1.42, 1.47, 1.48 [3 s, 9H each, C (CH3.}. 3], 2.41-2.66 (br. m, 2, 3-CH2-), 4.17 (q, J = 7. 1 Hz, 2H, 0CH2CH3), 4. 32 (br.m, 4H, 2-H, 5-H), 5. 02 (br ., IH, CHNH) 5 .52 (br. S, 1H 4-H) ppm. 13 C-NMR (CDC13, 50 MHz) d = 14.1 (q, OCHCH3), 28.1, 28.3, 28.5 [3q, C.CHJJJ], 31.8 (t, 3-CH2), 48.3 (d, CHNH), 52.0, 55.3 (2t, C-2, C- 5) .61.6 (t, OCH2 = CH3), 121.3 (d and C-4), 133.5 (s, C-3), 153.9 (s, N = CN), 171.8 (s, COOEt) ppm.
NCOO-, C (CH3) 3-are not visible signs due to the extension line. ) 3- 2-tert-Butoxycarbonyl-amino-2-carboxy-ethyl) -2,5-dihydropyrrole-1- (N, NT-di-tert-butoxycarbonyl) Carboxamidine.
To a solution of 267 mg (0.63 mmol) of 3- (2-tert-butoxy-carbonyl-amino-2-ethoxycarbonyl-ethyl) -2,5-dihydropyrrole-1- (N, N'-di-tert-butoxycarbonyl) ) carboxamidine in 5 ml of THF / methanol / water 3: 1: 1 were added 50 mg (1.2 mmol) of LiOH * H20. After 30 minutes of stirring at room temperature the original material could not be detected by TLC. The mixture was made acidic by the addition of IN HCl, diluted with water and extracted 3 times with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and evaporated. The residue was purified by flash chromatography to give 98 mg (31%) of 3- (2-tert-Butoxycarbonyl-amino-2-carboxy-ethyl) -2,5-dihydropyrrole-1- (N, N'-di-tert-butoxycarbonyl) carboxamidine (Boc-Ada (B0C2 ) -OH) as a colorless amorphous solid. 1 H-NMR (CDCL3, 300 MHz) d = 1.39, 1.44 [2s, 9H, 18H, C (CH3) 3], 2.49-2.67 br. m, 2-H, 3-CH2) 4.33 (br., 4H, 2-H, 5-H), 5.30 (br.d, 1H, CHNH) 5.56 (br.s, 1H, 4-H) ppm. 6 = 27.7, 28.9, 28.0 [3q, C (CH3);.], 31.3 (t, 3-CH :), 52.0 (d, CHNH), 55.3, 56.9 (2t, C-2, C-5), 80.0, 80.9 [2s, (C_CH3), 121.1 (d, C-4), 133.6 (s, C-3), 153.2 (s, N = CN), 155 2 (br. S, NCOO), 176.5 (s) , COOH) ppm.
Example 2 (±) -3- (2-Fluorenylmethoxysarbonyl-amino-2-hydroxysarbonyl-1-ethyl) -2,5-dihydropyrrol-1- (N, N "-di-tert-butoxycarbonyl) carboxamidine [Fmoc-Ada (Boc) 2OH] a) tert-butyl ester of (±) -3- (2) acid Benchidriliden -2-tert-butoxycarbonyl-ethyl) -2,5-dihydropyrrole-l-carboxylic acid.
To a solution of lithium hexamethyldisilazide [fresh, prepared at 0 ° C from 1. 53 g (9.5 mmol) of hexamethyldisilazone and 4.09 g (9.5 mmol) of n-BuLi, (2.32 mmol / g in hexanes)] in 20 ml of THF was added a solution at -78 ° C of 2.79 g. (9.5 mmol) of tert-butyl-N- (diphenylmethylene) -glycinate in 20 ml of THF. The orange enolate solution was stirred for 30 minutes at -78 ° C, then a solution of 2.70 g (8.6 mmol) of 3-acetoxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester and 243 mg 80.21 mmol) of Pd (PPh3) 4 in 20 ml of THF was added in the form of drops. The reaction mixture was allowed to warm to room temperature again and was stirred for an additional 12 h. The mixture was diluted with ether and cooled by the addition of saturated NH 4 Cl. The organic layer was washed with saturated NH 4 Cl and brine, dried with MgSO 4. and evaporated. Purification by flash chromatography (ethyl acetate / petroleum ether 1: 10 + 0.5% triethylamine) gave 3.70 g (90%) of (+) - 3- (2-Benzydrylidene-2-ter-tert-butyl ester) butoxycarbonyl-ethyl) -2,5-dihydropyrrole-1-carboxylic acid, as a slightly yellow oil.
XH-NMR (CDC13 300 MHz) d = 1.41.1.42 [2s, 9H each, 2.62-2.71 (.2H, 3-CH2-), 3.80-4.10 (br.m, 4H, 2-H, 5-H, CHN), 5.41 (br.m, 1H, 4-H), 7.09-7.81 (m, 10H , Ar-H) ppm. 13 C-NMR (CDCl 3, 75 MHz; d = 27.8, 28.3 [2q, C (CH3) 3], 33.0 (t, 3-CH, 52.7, 53.1, 54.5, 55.0 (4t, C-2, C-5) *, 64.2, 64.4 (2d , CH-NH2) *, 78.9 [s, C (CH3) 3] *, 81.07, 81.13 {2s C (CH3) 3] *, 121.4, 121.5 (2d, C-4) *, 127.5, 127.6, 128.1, 128.2, 128.3, 128.4, 128.6, 128.7, 130.1 (9d, Ar-CH) *, 135.8, 135.9, 136.1 (3s, Ar ~ C) *, 139.3, 139.3 (s, C-3) *, 153.8, 153.9 (2s, NCOO) *, 170. 1, 170.2 [2s, C (CH3) 3], 170.4 (s, N = CPh2) ppm.
HR-MS (FAB) [M + H] C29H37 2? 4 cale: 477.2753 found: 477.2769 [M + Na] C2, HJ6N2? 4 at calc: 499.2573 found: 499.2570 b) (±) -3- (2-amino-2-tert-butoxycarbonyl-ethyl) -2,5-dihydropyrrole-l-carboxylic acid tert-butyl ester To a solution of 1.57 g (3.3 mmmol) of 3- (2-benzydrylinidene-2-tert-butoxycarbonyl-ethyl-2,5-dihydropyrrole-1-carboxylic acid tert-butyl ester in 10 ml of THF and 5 ml of 5 ml of glacial acetic acid were added and the mixture was stirred overnight at room temperature.
The THF was evaporated in vacuo, the residue was diluted with water and made alkaline by cautious additions of K2C03 (or NH solution). The mixture was extracted three times with ethyl acetate and dried over MgSO4. Purification by flash chromatography (elution with CH_: Cl 2 MeOH 20/1) gave 1.03 g (100%) of tert-butyl ester of 3- (2-amino-2-tert-butoxycarbonyl-ethyl) -2,5- dihydropyrrole-1-carboxylic acid, as a colorless waxy solid.
^ - MR (CDC13, 300 MHz) d = 1.41.1.42 [2s, 9H each, C (CH3) 3], 2.35 (dd, "= 14.6 Hz, 3_J = 7.4 Hz, IH, CHaHbCHNH), 2.49 (dd, 2J = 14.6 Hz, 3"= 5.8 Hz, IH, CHaHbCH Hz), 3.44 (dd, 3J = 7.4, 5.8, 5.3 Hz, IH, CHaHbCHNH2) , 4.04 (, 4H, 2-H, 5-H) ppm. 13 C-NMR (CDCI3, 75 MHz] d = 27.8, 28.3 [2q, C (CH _.], 34.46.34.52 (t, 3-CH) *, 52.7.53.0, 54.6, (4d, C-2, C-5) * 53.2 (d, CHNH2 ), 79.0, 79.1, L.lí 1.23 [4s, C (CH3) J] *, 121.6, 122.0 (2d, C-4; 135. 4, 135.6 (2s, C-3) *, 153.9 (s, NCOO), 174.2 (s, COOtBu) ppm.
HR-MS (FAB) [M + H] C? 6H29N2? 4 cale: 313 .2127 found: 313.2095 c) (±) -3- [2- (9-Fluorenylmethoxycarbonyl-amino) -2-tert-butoxycarbonyl-ethyl] -2,5-dihydropyrrole-l-carboxylic acid tert-butyl ester To an ice-cooled solution of 1.03 g (3.3 mmol 9) of 3- (2-amino-2-tert-butoxycarbonyl-ethyl) -2,5-dihydropyrrole-carboxylic acid ester and 0.46 g (4.3 mmol) of Diisopropyl ethylamine in 15 ml of THF, 0.98 g (3.8 mmol) of 9-fluoromethyl chloroformate was added in one portion, the mixture was stirred at room temperature overnight, the mixture was diluted with ether, poured over water ice The aqueous layer was extracted three times with ether, the combined organic phases were dried (MgSO) and evaporated, purification by flash chromatography (ethyl acetate / petroleum ether 1: 3) gave 1.70 g (97)% of the ter- 3- [2- (9-Fluorenyl-ethoxycarbonyl-amino) -2-tert-butoxycarbonyl-ethyl] -2,5-dihydropyrrole-carboxylic acid butyl ester, as a colorless amorphous solid.
^ - MR (CDC13, 300 MHz) d = 1.45, [s, 9H, C (0.3) 3] / 2.48-2.70 (br.m, 2H, CH¿.CHNH2). 4.05 (br.m, 4H, 2-H, 5-H), 4.20 (t, 1H, CHCH20), 4.41 (br.m, 3H, CHNH, CHCH2O), 5.36 (br.m, 1H, NH), 5.49 (br-, 1H, 4-H), 7.27-7.40 (m, 4H, Ar-H), 7.56-7.61 (m, 2H, Ar-H). 7.73-7.76 (, 2H, Ar-H) ppm. d = 27.7, 28.3 [2q, 0 (0.3)], 31.9.32.2 (2t, 3-CH2) *, 46.9 (d, CHCH20), 52.6 (d, CHNH2), 52.7, 53.0, 54.6 (lbr.d, 2d, C-2, C-5) *, 66.7 (t, CHCH20), 79.1, 79.2, 82.46, 82.51 [4s, C (CH3) 3] *, 119.8 (d, Ar-CH), 122.4, 122.8 ( 2d, C-4) *, 124.8, 127.3, 127.5 (3d, Ar-CH), 134.3 (br. S; C-3), 141.1, 143.6 (2s, Ar-C), 153.9, 155.4 (2s, NCOO ), 170.5 (s, COOtBu) ppm.
HR-MS (FAB) [M] C3_H38N2? 6 cale: 535.2808 found: 535.2789 [M] C. H.jgN.O.Na calc: 557.2628 found: 557.2643 d) hydrochloride? (±) -3- (2, 5-dihydro-lH-pyrrol-3-yl) -2-fluorenimethoxycarbonylamino-propionic acid to a solution of 588 mg (1.1 mmol) of tert-butyl é-st-er of 3- [2- (9-fluorenimethyl-methoxycarbonyl-amino) -2-tert-butoxycarbonyl-ethyl] -2,5-dihydropyrrole-1 Carboxylic acid and 376 mg (4mmol) of ethylendithiol in 5 ml of dioxane were added with 5 ml of 4N HCl in dioxane and the mixture was stirred at room temperature overnight. After 30 min a colorless solid began to precipitate. 20 ml of ether were added, the solid was filtered washed thoroughly with ether and dried in vacuo to give 433 mg (95%) of (±) -3- (2,5) dihydro-lH-pyrrole-3 hydrochloride. -yl) -2-fluorenylmethoxycarmonylamino-propionic, as a lightly colored powder.
H-NMR (CD30D, 300 MHz) d = 2.56-2.80 (m, 2H, CH.-CHNH ^), 3.99 (br.m, 4H, 2-H, 5-H), 4.21 (t, 1H, CHCH.O), 4.31-4". 42 (m, 3H, CHNH, CHCH? O), 5.36 (br., 1H, NH), 5.62 (br.s,! H. 4-H), 7.28-7.41 (m, 4H, Ar-H), 763-768 (m, 2H, Ar-H), 7.77-7.08 (m, 3H, Ar-H) ppm. 13 C-NMR (CD3OD, 75 MHz) d = 31.5, (t, CH;; CHNH;.), 48.3 (d, CHCHO), 53.3.53.5, 54.1 (3d, 2d, C-2, C-5, CH2CHNH), 67.9 (t, CHCH20), 120.9 (d, Ar-CH), 122.0 (d, C-4), 126.2, 128.1, 128.8 (3d, Ar-CH), 136. 6 (s, C-39, 142.6, 145.2 (2s, Ar-C), 158.5 (s, NCOOO), 17-4.4 (s, COOH) ppm. e) (±) -3- (2-f-uorenylmethoxycarbonyl-arnino-2-hydroxycarbonyl-1-ethyl) -2,5-dihydropyrrol-1- (N, N'-di-tert-butoxycarbonyl) carboxamidine A suspension of 400 mg (0.96 mmol) of acid hydrochloride (± 9-3- (2,5-dihydro-lH-pyrrol-3-yl) -2-fluorenylmethoxycarbonylamino-propionic acid in 5 ml of acetonitrile were added to it. 258 mg (2 mmol) of ethyl diisopropylamine were added, followed by 298 mg (0.96 mmol) of N, N'-bis-tert-butyloxycarbonyl-1H-pyrazole-1-carboxamidine The heterogeneous mixture was stirred at room temperature by a The mixture was acidified with acetic acid, the combined organic phases were washed with brine, dried and evaporated to dryness, flash chromatography (petroleum ether / ethyl acetate 1: 1 + 1% strength). acetic acid) gave 123 mg (21%) of (±) -3- (2-fluorenylmethoxycarbonyl-amino-2-hydroxycarbonyl-ethyl) -2,5-dihydropyrrole-1- (N, N'-di-tert-butoxycarbonyl) ) carboxamidine, as a slightly yellow amorphous solid.
^ -NMR (CD3OD, 300 MHz) d = 1.45, [s, 18H, C (CH3) 3], 2.57-2.79 (br.m, 2H, CH2CHNH2), 4.05 (br.m, 4H, 2-H, 5-H), 4.20 (t, 1H, CHCH20), 4 41 (br.m, 3H, CHNH, CHCH20), 5.36 (br.m, 1H, NH). 5.49 (br.m, 1H, 4-H), 7.24-7.37 (, 4H, Ar-H), 7.54-7.57 (, 2H, Ar-H). 7.70-7.73 (m, 2H, Ar-H) ppm. 13C-NMR (CD3OD, 75 MHz) d = 27.7, 27.9 [2q, C (CH3) 3], 31.3, (t, CHvCHNH), 46.9 (d, CHCH20), 52.6 (d, CH2CHNH), 55.5, 57.0, (2d, C-2, C- 5), 66.8 (t, CHCH20), 81.1 [br. s, C (CH3) 3], 119.7 (d, Ar-CH), 121.2 (d, C-4), 124.9, 126.9, 127.5 (3d, Ar-CH), 133.6 8s, C-3), 141.1, 143.6 (2s, Ar-C) 153.0, 155.8 2s, NCOO), 176.5 (s, COOtBu) ppm.
HR-MS (FAB) [M] C33H4XN4? 8 cale: 621.2924 found: 621.2881 Example 3 Ada-SAW The title compound was synthesized by a solid-phase methodology on a multiple SyRo II peptide synthesizer (Multisyn Tech, Bochum) on a 0.03 mmol scale using Fmoc-L-Trp-trityl-polystyrene (1%) divinylbenzene resin (Fmoc -1-trp-TCP; loading: 0.57 mmol / g; PepChem, Tübiguen) as starting material. The D-amino groups of the proteinogenic amino acids Ala and Ser were protected by 9-fluorenylmethoxycarbonyl (Fmoc), the side chain alkoxide group of Ser by tert-butyl. Ada non-proteinogenic amino acids were used as Boc-Ada (Boc2) -OH (from Example 1). The protected Fmoc amino acids were paired in an excess of 6 folds per 30 min in DMF. Tbtu (1 EQ) and NMM (1 EQ) were used as activating agents. The unfolding of the Fmoc group was carried out in Piperidine / dimethylformamide (1: 1 v / v) for 2 x 10 min. the Boc-Ada (Boc2) -OH kit was manually executed in DMF in lh by using = .048 mmol of the protected amino acid (in an excess of 1.6 folds) and equimolar amounts of TBTU and NMM for activation. The peptide was split from the resin with 750 ul of acetic acid / trifluoromethanol / dichloromethane (30:10:70) in two h. After washing five times with 150 ul of the same solvent mixture the filtrate was combined, diluted, with 10 ml of heptane and concentrated. This procedure was repeated twice to remove the acetic acid completely. The oily residue was dissolved in 5 ml of 4N hydrogen chloride in dioxane. To this solution were added 270 ul of ethanedithiol and the mixture was stirred 3 h at room temperature. Then the solvent was removed and the residue dissolved in heptane and concentrated again several times until the ethanedithiol was almost completely removed. The crude peptide was lyophilized from tert-butanol / water (1: 1) and purified by HPLC preparation to obtain 9.5 mg of Ada-SAW as a colorless lyophysylate (purity by HPLC> 90%) ESI-MS m / z 543.3 M + Example 4 Ada-ava- The title peptide was prepared in the same manner as in Example 3 starting from 50 mg (0.03 mmol) of the Fmoc-L-Trp-TCP resin using protected Fmoc aminovaleric acid. Obtaining 6.2 mg Ada-Ava-W as a colorless lyophilisate (purity by HPLC> 90%) ESI-MS m / z 484 .3 M + Example 5 Ada-Aba- The title peptide was prepared in the same manner as in the example starting from 50 mg (0.03 Mmol) of the Fmsc-L-Trp-TCP resin using protected Fmoc aminobutyric acid. Obtaining 4.8 mg Ada-Aba-W as a colorless lyophilisate (purity by HPLC> 90%).
ESI-MS m / z 470.3 Nf Example 6 T-Ada-SA The title compound was synthesized by a solid phase methodology on a Syro II multiple peptide synthesizer (MultiSynTeach, Bochum) on a 0.03 mmol scale using Fmoc-L-Trp_Trityl-polystyrene (1%) divinylbenzene resin (Fmoc-L -Trp-TCP, loaded 0.57 mmol / g PepChe, Tubigen) as starting material. The amines groups of the proteinogenic amino acids Ala and Ser were protected by 9-fluorenylmethoxycarbonyl (Fmoc), the side chain hydroxy groups of Ser by tert-butyl. Ada non-proteinogenic amino acids were used as Fmoc-ada (Boc2) -OH (from Example 2). The protected amino acids of the Fmoc were coupled in an excess of 6 for 30 minutes in DMF. TBTU (1 Eq) and NMM (1 eq) were used as activating reagents. The unfolding of the Fmoc group was carried out in piperidine / dimethylformamide (1: 1 v / v) for 2x10 min. the coupling of Boc-Ada (Boc2) -OH and Thr was performed manually in DMF in 1 h by using 0.048 mmol of the protected amino acid Boc-Ada- (Boc2) -OH (in excess of 1.65 times) an excess 6 times in the case of Thr. Equimolar amounts of TBTU and NMM were used for activation. The peptide was separated from the resin with 750 ul of acetic acid / trifluoromethanol / dichloromethane (30:10:70) in 2 h. After washing five times with 150 ul of the same mixture of solvents the filtrates were combined, diluted with 10 ml of heptane and concentrates. This procedure was repeated twice to remove the acetic acid completely. The oily residue was dissolved in 5 ml of 4N hydrogen chloride in dioxane. To this solution were added 270 ul of ethanedithiol and the mixture was stirred for 3 h at room temperature. Then the solvent was removed and the residue dissolved in heptane and concentrated again several times until the ethanedithiol was almost completely removed. The crude peptide was lyophilized from ter. -butanol / water (1: 1) and purified by preparative HPLC to obtain 2.6 mg of T-Ada-SAW as a colorless lifilizate (purity by HPLC> 90%) ESI-MS: m / z 644.3 M * Example 7 T-Ada-Ava-W The title peptide was prepared in the same manner as Example 6 starting from 50 mg (0.03 mmol) of Fmoc-L-Trp-TCP resin using aminovaleric acid protected with Fmoc. Obtaining: 2.7 mg of T-Ada-Ava-W as a colorless lyophilisate (purity by HPLC> 95%) ESI-MS: m / z585.3 M + Example 8 T-Ada-Aba-W The title peptide was prepared in the same manner as Example 6 starting from 50 mg (0.03 mmol) of the Fmoc-L-Trp-TCP resin using aminobutyric acid protected by Fmoc. Obtaining: 2.7 mg of T-Ada-Aba-W as a colorless lyophilisate (purity by HPLC> 95%).
ESI-MS: m / z 585.3 M * Example 9 Biological activity The compounds of general formula (I) were tested in an in vitro DNA synthesis assay. The cells -used were primary cultures of osteoblasts from fetuses of bald rats. The experiments were performed analogously as published in Pfeilschifter et al., Endocrinology 126, 703 (1990).
It is noted that in relation to this date, the best method known to the applicant, to carry out the aforementioned invention is that which is clear from the present description of the invention.
Having described the invention as an antecedent, the content of the following is claimed as property:

Claims (9)

Claims
1. - Compounds of general formula (i; characterized in that Ri, R2, R3 and X can be the same or different, and characterized in that Ri, R2, represent a hydrogen radical, an amino acid, peptide, alkyl or aryl. R3 represents hydroxide, lower alkoxide, or an NR31R3_ where R3i, and R32 independently represent hydrogen or an amino acid, peptide, alkyl or aryl radicals X represents an amino acid or a peptide; R4 represents hydrogen, hydroxide, amino or alkyl C? -C4; m represents a number between 0 and 5; R5 represents a mono- or bicyclic, unsaturated or saturated, optionally substituted moiety which may contain one or more heteroatoms, a C 1 -C 4 alkyl group which may have intermittent substitutions or heteroatoms, its tautomers, optical isomers, pharmaceutically acceptable salts and prodrugs .
2. Compounds of general formula I of claim 1, characterized in that Ri and R2 are hydrogen.
3. Compounds of general formula I of any of claims 1-2 characterized in that R 3 represents hydroxide or amino.
4. Compounds of general formula I of any of claims 1-4, characterized in that R 4 represents hydroxide or methyl.
5. The compounds of general formula I of any of claims 1-4, characterized in that m represents a number 1,2 or 3.
6. The compounds of the general formula I of any of claims 1-4, characterized in that (CHR4) _QR5 represents a radical linked to an o? ^ Of a proteinogenic or non-proteinogenic amino acid.
7. The compounds of general formula (IV) characterized in that Rd represents a protecting group, for example, the benzoyl group, an alkoxycarbonyl group or the benzyloxycarbonyl group. R9 represents .Fmoc or another protecting group useful for orthogonal synthesis, Y represents COOH or C00-C? -C4-alkyl.
8. A pharmaceutical product that includes at least one of the compounds of formula I of any of claims 1 to 6.
9. The use of a compound of general formula I of any of claims 1 to 6 in a method of preparing drugs for the treatment of bone disorders. P eptides that contain an arginine mimetic for the treatment of bone metabolic disorders, their production and medicines that contain these compounds. Summary of the invention. The present invention is directed to compounds of general formula (I), wherein R1, R1, R1 and X may be the same or different, and wherein Ri, R_ represent a hydrogen, an amino acid, peptide or an alkyl or aryl radical; R3 represents hydroxide, or lower alkoxide or aryl radical, or a radical -NR3? R32, where. R 31; R 32 independently represent hydrogens, an amino acid, peptidyl, alkyl or aryl radical; X represents an amino acid or a peptide; R4 represents hydrogen, hydroxide, amine or d-Cs, alkyl; m represents a number between '0 and 5; R5 represents an optional saturated or unsaturated mono- or bicyclic substitute portion which may contain one or more heteroatoms, a Ci-Cn alkyl group which may have intermittent substitutions or heteroatoms, its tautomers, optical isomers, pharmaceutically acceptable salts and prodrugs as well as its production and its use as medicines.
MXPA/A/2000/002245A 1997-09-05 2000-03-03 Peptides containing an arginine mimetic for the treatment of bone metabolic disorders, their production, and drugs containing these compounds MXPA00002245A (en)

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EP97115402 1997-09-05

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MXPA00002245A true MXPA00002245A (en) 2001-03-05

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