Classifications

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

Definitions

• the present invention relates to prodrugs of pharmacologically active, heterocyclic amidines, from which compounds are formed in vivo, which are competitive inhibitors of trypsin-like serine proteases, especially thrombin, their preparation and their use as medicaments.
• the invention also relates to pharmaceutical compositions containing the prodrugs of the active compounds as components, and the use of the compounds as thrombin inhibitors, anticoagulants and as anti-inflammatory agents.
• Thrombin belongs to the group of serine proteases and plays a central role as a terminal enzyme in the blood coagulation cascade. Both the intrinsic and the extrinsic coagulation cascade lead to the formation of thrombin from prothrombin over several amplification stages. The thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates blood coagulation and platelet aggregation, which in turn increases the formation of thrombin by binding platelet factor 3 and coagulation factor XIII and a whole series of highly active mediators.
• thromboin formation and action are central events in the development of both white, arterial and red, venous thrombi and therefore potentially effective targets for pharmaceuticals.
• thrombin inhibitors are able, independently of cofactors, to completely inhibit the effects of free thrombin as well as that bound to platelets. They can prevent thromboembolic events after percutaneous transluminal coronary angioplasty (PTCA) and lysis in the acute phase and serve as anticoagulants in the extracorporeal circulation (cardiopulmonary machine, hemodialysis). They can also be used in general for thrombosis prophylaxis, for example after surgery.
• PTCA percutaneous transluminal coronary angioplasty
• lysis in the acute phase and serve as anticoagulants in the extracorporeal circulation (cardiopulmonary machine, hemodialysis). They can also be used in general for thrombosis prophylaxis, for example after surgery.
• WO 94/29336 EP 0601459, WO 95/23609, EP 0672658, WO 97/23499, WO 98/06740 and WO 95/35309 represent a further development, the agmatine being replaced by an arylamidine residue.
• Active substance is understood to mean the pharmacologically active substance (drug) in comparison to the substance (prodrug), which must first be metabolically converted into the active substance.
• prodrugs over the drugs is that there are no high local concentrations of the drugs outside the destination.
• side effects are minimized with less selective drugs, e.g. no further serine proteases are inhibited in the gastrointestinal tract if the drug arises essentially only after or during the gastrointestinal passage due to metabolism of the prodrug.
• the aim of this invention is to improve the pharmacokinetic properties of the thrombin inhibitors mentioned in particular in WO 95/35309 and WO 96/25426 by means of suitable prodrugs.
• the invention relates to compounds of the formula I.
• R l 00C-CH 2 - R l 00C-CH 2 -CH 2 -, R ⁇ -OOC-CH (CH 3) -, R i OOC-C (CH 3) 2 -,
• R 2 and R 3 are independently H, Ci-C ⁇ -alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C ⁇ -C 3 alkyl, or benzyl, or R 2 and R 3 together are one Form a C 4 -C 6 alkylene chain,
• R 1 represents 2-oxo-l, 3-dioxolen-4-yl-methyl-, which can be substituted in the 5-position by C 1 -C 6 -alkyl or aryl,
• Rl R4-C (0) 0-C (R 5 ) 2 -, R 4 -C (0) NR-C (R 5 ) 2 -, where R 4 C ⁇ -C 4 -alkyl-, C 3 -C 8 - Cycloalkyl-C 3 alkyl, C 3 -C 8 cycloalkyl, C 4 C 4 alkyl oxy, C 3 -C 8 cycloalkyl C 3 -C 3 alkyloxy, C 3 -C 8 -Cycloalkyloxy-,
• R 8 H-, R 10 OOC- with R 10 C ⁇ _ ⁇ 6 alkyl, phenyl, C 3 -C 8 cycloalkyl, phenyl C ⁇ -C 4 alkyl, R 1: L C (0) - 0-CH 2 -, R 1: L C (0) -0-CH (CH 3 ) -, where R 11 -C-C 4 alkyl, phenyl, benzyl, C 3 -C 8 cycloalkyl or Cyclohexyl-CH 2 - can be
• R 9 is C 3 - 8 cycloalkyl, which can carry up to four identical or different C 4 alkyl radicals
• G -H, -OH, -OR 12 , wherein R 12 : -C ⁇ _s-alkyl, -C 3 -C 8 cycloalkyl, -C ⁇ -C 3 alkyl-C 3 -C 8 cycloalkyl, -aryl or - Ci-C ⁇ -alkylphenyl, which can optionally carry up to three -CC 4 alkyl, CF 3 -, F-, Cl-, or -CC 4 alkoxy radicals, K: H, or G and K together form one Form a -C (0) 0 group,
• -Ci-C ß -alkylphenyl which can optionally carry up to three -CC 4 alkyl, CF 3 -, F-, Cl- or -C ⁇ C 4 -alkoxy radicals,
• a and B have the following meanings:
• R 1 represents 2-oxo-l, 3-dioxolen-4-yl-methyl-, which can be substituted in the 5-position by C-Ci ß- alkyl or aryl,
• R 1 R 4 -C (0) 0-C (R5) 2 -, RC (0) NR 2 -C (R5) 2 -, where R 4 is C x -C 4 alkyl-, C 3 -C 8 -Cycloalkyl-C 3 -C 3 -alkyl-, C 3 -C 8 -cycloalkyl-, -C-C -alky- loxy-, C 3 -C 8 -cycloalkyl-C ⁇ -C 3 -alkyloxy-, C 3 -C 8 -Cycloalkyloxy-, aryl- or phenyl-Ci-C ß -alkyl-, the two radicals R 5 are independently H, CH 3 or C 2 Hs, and R 2 has the meaning given above,
• R ⁇ H-, R 10 OOC- with R 10 C ⁇ - 6 alkyl, phenyl, C 3 -C 8 cycloalkyl, phenyl-C 1 -C alkyl, R 1; C (0) -0-CH 2 -, R 1; L C (0) -0-CH (CH 3 ) -, where R 11 -C-C 4 alkyl, phenyl, benzyl, C 3 -C 8 -cycloalkyl- or cyclohexyl-CH - can be
• R9 C 3 _ 8 -cycloalkyl- which can carry up to four identical or different C ⁇ - 4 alkyl radicals
• R 1 R 4 -C (0) 0-C (R 5 ) 2 -, where R 4 is Cr ⁇ alkyl, C 3 -C 8 cycloalkyl,
• Ci-G ä alkyloxy-, C 3 -C 8 cycloalkyl-C ⁇ -C3-alkyloxy-, C3-C8-cyclo- alkyloxy, or aryl may be, the two radicals R 5 inde- are H, CH 3 or C 2 H 5 ,
• R 8 H, R 10 OOC with R 10 C 8 alkyl, phenyl, C 3 -C 8 cycloalkyl, phenyl C 4 alkyl,
• R 9 C 3 _ 8 -cycloalkyl-, which can carry up to four identical or different C ⁇ _ 4 -alkyl radicals,
• G -H, -OH, -0-C ⁇ -C 8 alkyl
• K H represents or G and K together form a -C (O) O group.
• R 2a R 3a N (0) C-CH 2 -, where R 2a and R 3a are independently H, Ci-C ⁇ -alkyl, C 3 -C 8 cycloalkyl or benzyl, or R 2a and R 3a together are a C Form a 4 -C 6 alkylene chain, wherein
• R 1 H, -CC 4 alkyl or phenyl -CC 4 -alkyl, with the exception of H all the radicals mentioned optionally up to four identical or different radicals selected from -C 4 -alkyl, CF. 3 -, F-, Cl-, N0 2 -, HO- or -CC 4 alkoxy radicals can be,
• Preferred under ii) are compounds of the formula I in which A, B, D, G and K have the following meaning:
• R 1 H-, C ⁇ -C 4 -alkyl or phenyl -CC-C 4 ⁇ alkyl-, with the exception of H all the radicals mentioned optionally up to four identical or different radicals selected from CH 3 -, CF 3 -, F, Cl, HO or methoxy radicals, can be
• R 8 H-, R 10 OOC- with R 10 C ⁇ _ ⁇ 6 alkyl, phenyl, C 3 -C 8 cycloalkyl, benzyl,
• G -OR 12 means where R 12 : -C 5 -C 8 alkyl, -C 3 -C 8 cycloalkyl, -C ⁇ -C 3 alkyl-C 3 -C 8 cycloalkyl, -aryl or -Ci-C ß -alkylphenyl, which are optional can carry up to three CH 3 , CF 3 , F, Cl or methoxy radicals, K: H, or G and K together form a -C (O) O group.
• R 1 C 5 -C ⁇ 0 alkyl, CC 7 -Cycloaikyl-, C 4 C 7 cycloalkyl-CH 2 -, wherein all said radicals may optionally up to four identical or different radicals selected from CH 3 - or may carry methoxy is is
• R 9 C 4 _ cycloalkyl which can carry up to four identical or different methyl or ethyl radicals
• the first group includes prodrugs of thrombin inhibitors (eg G equal to -OH, -OR 12 ) which as a substance have only a negligible antithrombotic effect, but which are converted into the corresponding active substance in the organism (G equal to H).
• thrombin inhibitors eg G equal to -OH, -OR 12
• G a negligible antithrombotic effect
• the second group includes prodrugs of thrombin inhibitors, which as prodrug already have a thrombin-inhibitory effect (for example A is R i OOC-CH ⁇ , R 1 OOC-CH-CH 2 -, R ⁇ -OOC-CH (CH 3 ) - etc. in combination with G equals -H).
• the active substance formed in the organism (drug; A equals HOOC-CH2-, HOOC-CH 2 -CH 2 -, HOOC-CH (CH 3 ) - etc., G equals -H)) also shows thrombin-inhibitory activity.
• These are partly compounds from claims 1 (i), 2 and 5.
• the advantage of these prodrugs is also their improved pharmacokinetic and pharmacodynamic behavior in the organism.
• the third group includes thrombin inhibitors, which per se exert their antithrombotic effect (e.g. A equals
• Aze Azetidine carboxylic acid
• Chg cyclohexylglycine
• Gly Glycine urine: Hydroxyamidino HOSucc: Hydroxysuccinimide
• PPA propylphosphonic anhydride
• TFAA trifluoroacetic anhydride thiaz: thiazole thioph: thiophene
• MeO tetraethoxy tetraethylene glycol yl monomethyl ether
• Ada-CH-0 1-adamanthyl ethyloxy
• 4-pyranyl-O 4-pyranyloxy nPrO: n-propyloxy nBu-0: n-butyloxy iBu-0: t-butyloxy
• cycloalkyl by itself or as part of another substituent contains saturated, cyclic hydrocarbon groups which contain the stated number of carbon atoms and in which up to two CH 2 groups can be replaced by oxygen, sulfur or nitrogen atoms.
• C 3 _ 8 cycloalkyl refers to saturated alicyclic rings with 3 to 8 C atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, cyclohexylmethylene, cycloheptyl or cyclooctyl, pyrrolidine, piperidine, morpholine . Pure carbocylene are preferred.
• alkyl by itself or as part of another substituent means a linear or branched alkyl chain radical of the length given in each case, which may be saturated or unsaturated and in which up to five CH 2 groups are replaced by oxygen, sulfur or nitrogen atoms could be.
• the heteroatoms are separated from one another by at least two carbon atoms.
• C 4 alkyl means methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 1-but-2-enyl, 2-butyl , C ⁇ _ 6 alkyl, for example C ⁇ _ alkyl, pentyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl or 3, 3- Dimethyl butyl.
• C ⁇ _ 8 alkyl means in addition to the radicals specified for Ci- 4 alkyl, for example Ci- ß- alkyl, heptyl, 2- (2-methoxyethoxy) ethyl or octyl.
• the saturated alkyl chains without heteroatoms are preferred.
• alkoxy by itself or as part of another substituent means a linear or branched alkyl chain radical of the length given in each case, which may be saturated or unsaturated and is bonded to the parent compound in question via an oxygen atom.
• C ⁇ _ 4 -alkoxy means, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy, 2-methyl-2-propoxy, 2-methyl-1-propoxy, 1-butoxy, 2-butoxy.
• aryl by itself or as part of another substituent includes mono- or tricyclic aromatic hydrocarbons, such as phenyl. Naphthyl, tetralinyl, indenyl, fluorenyl, indanyl, anthracenyl, phenanthrenyl.
• the compounds of the formula I can be present as such or in the form of their salts with physiologically tolerated acids.
• acids are: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, succinic acid, hydroxy succinic acid, sulfuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.
• platelet derived growth factor platelet derived growth factor
• P-selectin P-selectin
• ICAM-I tissue factor
• inhibition e.g. NO synthesis in smooth muscle cells
• epithelial cells e.g. vascular endothelial cells
• thrombin-dependent, thromboembolic events such as deep vein thrombosis, pulmonary embolism, myocardial or cerebral infarction, atrial fibrillation, bypass occlusion,
• DIC disseminated intravascular coagulation
• thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC, plasminogen activators from the
• the new compounds for the therapy and prophylaxis of thrombin-dependent thromboembolic events such as deep venous thrombosis, pulmonary embolism, myocardial or cerebral infarction and unstable angina can continue to be used for the therapy of disseminated intravascular coagulation (DIC).
• DIC disseminated intravascular coagulation
• thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC and other plasminogen activators to shorten the reperfusion time and extend the reocclusion time.
• Further preferred fields of application are the prevention of thrombin-dependent early reocclusion and late restenosis after percutaneous transluminal coronary angioplasia, the prevention of thrombin-induced proliferation of smooth muscle cells, the prevention of active thrombin accumulation in the CNS (e.g. in M. Alzheimer's disease), the fight against tumors and the prevention of mechanisms lead to adhesion and metastasis of tumor cells.
• the new compounds can also be used in diseases whose pathomechanism is based directly or indirectly on the proteolytic action of kininogenases, in particular kallikrein, e.g. for inflammatory diseases such as asthma, pancreatitis, rhinitis, arthritis, urticaria and other internal inflammatory diseases.
• diseases whose pathomechanism is based directly or indirectly on the proteolytic action of kininogenases, in particular kallikrein, e.g. for inflammatory diseases such as asthma, pancreatitis, rhinitis, arthritis, urticaria and other internal inflammatory diseases.
• the compounds of the invention can be administered orally in a conventional manner. It can also be applied with vapors or sprays through the nasopharynx.
• the dosage depends on the age, condition and weight of the patient and on the type of application.
• the daily dose of active ingredient per person is between about 10 and 2000 mg when administered orally. This dose can be given in 2 to 4 single doses or once a day as a slow-release form.
• the new compounds can be used in the customary pharmaceutical application forms in solid or liquid form, for example as tablets, film-coated tablets, capsules, powders, granules, dragées, solutions or sprays. These are manufactured in the usual way.
• the active ingredients can be combined with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents. mittein, retardants, antioxidants and / or propellants are processed (see H. Sucker et al.: Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1978).
• the application forms thus obtained normally contain the active ingredient in an amount of 0.1 to 99% by weight.
• GIT gastrointestinal tract
• the cells for 17- Cultivated on Transwell polycarbonate membranes for 24 days.
• the test chamber is arranged so that the membrane separates the apical from the basolateral compartment.
• the transport of the test substances from the apical side through the cell layer to the basolateral side can be measured depending on the pH gradient, e.g. apical (pH 6.0) basolateral (pH 8.0)
• test substance After the cells have been incubated with the test substance, samples are taken from the apical and basolateral sides after a defined time interval (for example 24 hours). The content of the test substance used and any metabolites in each of the two compartments is determined by HPLC (comparison of retention times) and HPLC-MS (elucidation of metabolites) analysis. The transport rate is calculated. Based on the values that these test s result, it is possible to divide the test substances into the following categories:
• test substances are dissolved in isotonic saline immediately before administration to awake Sprague Dawley rats.
• the application volumes are 1 ml / kg for intravenous bolus injection into the tail vein and 10 ml / kg for oral administration, which is carried out by gavage.
• blood samples are taken 1 h after oral administration of 21.5 mg-kg -1 or intravenous administration of 1.0 mg-kg -1 of the test substance or the corresponding vehicle (control).
• the animals are anesthetized by ip application of 25% urethane solution (dose 1 g-kg -1 ip) in physiological saline.
• the carotid artery is prepared and catheterized.
• Plasma samples (2 ml) are taken in citrate tubes (1.5 parts of citrate plus 8.5 parts of blood). Immediately after sampling, the ecarin clotting time (ECT) in whole blood is determined. After the plasma has been prepared by centrifugation, the plasma thrombin time and the activated partial thromboplastin time (APTT - activated partial thromboplastin time) are determined using a coagulometer. Coagulation parameters:
• PTT activated thromboplastin time
• Thrombin time 100 ⁇ l of citrate-treated plasma is incubated for 2 min at 37 ° C. in a coagulometer (CL 8, Kugel-Typ, Bender & Hobein, Kunststoff, FRG). After the addition of 100 ⁇ l of prewarmed (37 ° C.) thrombin reagent (Boehringer Mannheim), the time until a fibrin clot was formed was determined.
• test substances are dissolved in isotonic saline immediately before administration to watchful mongrel dogs.
• the application volumes are 0.1 ml / kg for intravenous bolus injection and 1 ml / kg for oral administration, which is carried out by gavage.
• 10 20, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min if necessary after 420, 480 min and 24 h
• intravenous administration 1.0 mg / kg or before and 10, 20, 30, 60, 120, 180, 240, 300, 360, 480 min and 24 h
• samples of venous blood (2 ml) are taken in citrate tubes.
• the ecarin clotting time (ECT) in whole blood is determined.
• the plasma thrombin time and the activated partial thromboplastin time are determined using a coagulometer.
• the anti-F Ila activity (ATU / ml) and the concentration of the substance are determined by their anti-F Ha activity in the plasma by means of a chromogenic (S-2238) thrombin assay, calibration curves using r-hirudin and the test substance were used.
• the plasma concentration of the test substance is the basis for
• T max time of maximum plasma concentration
• AUC Area under the curve
• F absorbed part of the test substance
• PTT activated thromboplastin time
• Thrombin time 100 ⁇ l of citrate-treated plasma is incubated for 2 min at 37 ° C. in a coagulometer (CL 8, Kugel-Typ, Bender & Hobein, Kunststoff, FRG). After the addition of 100 ⁇ l of prewarmed (37 ° C.) thrombin reagent (Boehringer Mannheim), the time until a fibrin clot was formed was determined.
• the determination of the coagulation parameters directly determines the proportion of active substance (drug) formed.
• the kinetics therefore include the absorption of the prodrug, its metabolism and excretion and the conversion into the active substance and its metabolism and excretion.
• the building blocks A, B and D are preferably constructed separately and used in a suitably protected form (see schemes I-III, use of orthogonal protective groups (P or P *) which are compatible with the synthetic method used).
• PDL L equals CONH 2 , CSNH 2 , CN
• Scheme II describes the linear structure of molecule I by coupling, alkylation, reductive amination or Michael addition
• the corresponding amidoximes are added with the addition of bases (e.g. NaOH, pyridine, tertiary amines) with carbonic acid derivatives such as e.g. Phosgene, di- and triphosgene, carbonyldiimidazole or chloroformate (R.E. Bolton et al., Tetrahedron Lett. 1995,
• bases e.g. NaOH, pyridine, tertiary amines
• carbonic acid derivatives such as e.g. Phosgene, di- and triphosgene, carbonyldiimidazole or chloroformate
• Scheme III describes a very efficient way of preparing compounds I by convergent synthesis.
• the correspondingly protected building blocks (P *) - AB-OH and HEDL * are coupled together and the resulting intermediates (P *) - ABEDL * analogous to Scheme I and Scheme II to the end product
• Boc, Cbz or Fmoc are used as N-terminal protective groups
• C-terminal protective groups are methyl, tert-butyl and benzyl ester.
• Amidine protecting groups are preferably BOC and Cbz. 25 If the intermediate products contain olefinic double bonds, protective groups which are split off by hydrogenolysis are unsuitable.
• Boc protective groups are removed by means of dioxane / HCl, diethyl ether / HCl, dichloromethane / HCl or TFA / DCM, Cbz protective groups hydrogenolytically or with HF, Fmoc protective groups with piperidine.
• the saponification of ester functions takes place with LiOH in an alcoholic solvent or in dioxane / water.
• esters are cleaved with TFA or dioxane / HCl.
• Reversed phase HPLC separations were carried out with acetonitrile / water and HOAc buffer.
• the output connections can be made using the following methods:
• building blocks A for the alkylation e.g. ⁇ -bromoacetic acid tert-butyl ester, ⁇ -bromoacetic acid adamantyl ester, b-bromopropionic acid tert-butyl ester, ⁇ -bromopropionic acid tert. -butyl ester, c- ⁇ bromobutyric acid tert. -butyl ester, bromoacetic acid-2, 3-dimethyl-2-butyl ester, THP-protected bromoethanol, tert-butylamide ⁇ -bromoacetic acid and diethylamide ⁇ -bromoacetic acid.
• reaction mixture was allowed to come to 0 ° C., stirred at this temperature for 90 min and 150-200 ml of 38% strength aqueous hydrochloric acid were carefully added. For complete hydrolysis, the mixture was stirred vigorously at room temperature for 15 hours. The organic phase was separated off and washed with 200 ml of water, saturated sodium bicarbonate solution and saturated sodium chloride solution. It was dried over magnesium sulfate, filtered off and concentrated on a rotary evaporator to remove the
• amino acids mentioned were converted into the Boc-protected form in each case using di-tert-butyl dicarbonate in water / dioxane and then recrystallized from ethyl acetate / hexane mixtures or column chromatographically on silica gel (mobile phase: ethyl acetate / petroleum ether - Mixtures) cleaned.
• N-Boc-N- (tert-butyloxycarbonylmethylene) -D-cyclohexylglycine-cyclohexylam onium salt was prepared in an analogous manner from cyclohexylglycine as a starting material.
• N-Boc-Pyr-OH (5 g, 23.45 mmol) was dissolved in MeOH (50 ml) and HC1 in dioxane (4N, 30 ml) was added. The mixture was then heated under reflux for 12 h. The solvent was spun off and H-Pyr-OMe hydrochloride was obtained as the product. Yield: 3.84 g (100%).
• This compound was prepared in an analogous manner from N-Boc-N- (tert-butyloxycarbonylmethylene) - (D) -cyclohexylglycine and 3,4-dehydroproline methyl ester.
• the (L) 3, 4-dehydroproline used as the D building block is commercially available; the (D, L) -4, 5-dehydropipecolic acid can be obtained according to A. Burgstahler, CE Aiman J. Org. Chem. 25 (1960) , 489 or C. Herdeis, W. Engel Arch. Pharm 326 (1993), 297 and then convert with (Boc) 2 0 into Boc- (D, L) -Dep-OH.
• the synthesis of 3- (6-cyano) -picolylamine has been described in WO 96/25426 and WO 96/24609.
• This compound was prepared analogously to Example 7 by esterification of H ⁇ 2C-CH- (D) -Cha-Pyr-NH-3- (6-am) -pico with n-propanol.
• O-methylhydroxylamine hydrochloride (0.9 g, 8.1 mmol was dissolved in 30 ml of methanol and converted into the corresponding acetic acid salt via an ion exchanger (Fluka: acetate on a polymeric carrier, 3.0 mmol acetate per g). See this for methanol Solution became t-Bu0 2 C-CH 2 - (Boc) - (D) -Cha-Pyr-NH-3-
• Example 24 Analogously to Example 24, the title compound was started from H- (D) -Cha-Pyr-NH-3- (6-CN) -pico x HC1 and the bromoacetic acid [2- (cyclohexylammo) -2-oxoethyl] shown in b) - received ester.
• Example 40 N- (c-Hexyloxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl- (6-methoxyamidino-3-picolyl) amide
• O-allylhydroxylamine hydrochloride (0.93 g, 7.0 mmol) was dissolved in 20 ml of methanol and converted into the corresponding acetic acid salt via an ion exchanger (Fluka: acetate on a polymer carrier, 3.0 mmol of acetate per g).
• ion exchanger Feluka: acetate on a polymer carrier, 3.0 mmol of acetate per g.
• To this methanolic solution was added t-Bu0 2 C-CH 2 - (Boc) - (D) -Cha-Pyr-NH- 3- (6-C NH (SCH 3 )) -pico x HI (4.5 g , 5.8 mmol; see b) and the reaction mixture was stirred overnight at room temperature.
• the processing was carried out analogously to Example 41.
• the processing was carried out analogously to Example 41.

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• 2000
  • 2000-04-05 HU HU0202431A patent/HUP0202431A3/hu unknown
  • 2000-04-05 KR KR1020017012802A patent/KR20020004995A/ko not_active Application Discontinuation
  • 2000-04-05 WO PCT/EP2000/003008 patent/WO2000061577A1/de not_active Application Discontinuation
  • 2000-04-05 AU AU36592/00A patent/AU3659200A/en not_active Abandoned
  • 2000-04-05 JP JP2000610850A patent/JP2002541254A/ja active Pending
  • 2000-04-05 SK SK1409-2001A patent/SK14092001A3/sk unknown
  • 2000-04-05 CN CN00807009A patent/CN1349526A/zh active Pending
  • 2000-04-05 EP EP00915197A patent/EP1169318A1/de not_active Ceased
  • 2000-04-05 BR BR0009653-9A patent/BR0009653A/pt not_active IP Right Cessation
  • 2000-04-05 CA CA002368830A patent/CA2368830A1/en not_active Abandoned
  • 2000-04-05 PL PL00352834A patent/PL352834A1/xx unknown
  • 2000-04-05 IL IL14567000A patent/IL145670A0/xx unknown
  • 2000-04-05 TR TR2001/02914T patent/TR200102914T2/xx unknown
• 2001
  • 2001-10-03 NO NO20014807A patent/NO20014807L/no not_active Application Discontinuation
  • 2001-10-05 BG BG105985A patent/BG105985A/xx unknown
• 2002
  • 2002-09-26 HK HK02107043.0A patent/HK1045516A1/zh unknown

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