EP0511347A1 - Derives de la phenylalanine metasubstitues - Google Patents

Derives de la phenylalanine metasubstitues

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Publication number
EP0511347A1
EP0511347A1 EP91919709A EP91919709A EP0511347A1 EP 0511347 A1 EP0511347 A1 EP 0511347A1 EP 91919709 A EP91919709 A EP 91919709A EP 91919709 A EP91919709 A EP 91919709A EP 0511347 A1 EP0511347 A1 EP 0511347A1
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EP
European Patent Office
Prior art keywords
radical
naphthylsulfonyl
phenylalanyl
compounds
group
Prior art date
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EP91919709A
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German (de)
English (en)
Inventor
Jörg STÜRZEBECHER
Helmut Vieweg
Peter Wikstroem
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DSM Nutritional Products AG
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Pentapharm AG
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Publication of EP0511347A1 publication Critical patent/EP0511347A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/58—Derivatives of thiocarboxylic acids, the doubly-bound oxygen atoms being replaced by nitrogen atoms, e.g. imino-thio ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • 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
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • 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
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • 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
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • 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
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • 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
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • 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 new proteinase inhibitors which contain a phenylalanine substituted on the phenyl radical.
  • a phenylalanine substituted on the phenyl radical is a substituent on the phenyl radical.
  • inhibitors with improved bioavailability have been found.
  • Proteinase inhibitors are potential drugs that can be used to control physiological processes that are triggered and maintained by proteinases. Numerous endogenous or naturally occurring inhibitors have been shown to influence the activity of proteinases in vivo and to dampen hyperproteolytic states [see Hörl, WH In: Design of Enzyme Inhibitors as Drugs, pp. 573-581, (Sandler, M and Smith, HJ, Eds.) Oxford, New York, Tokyo: Oxford University Press, 1989]. The therapeutic use of these relatively high molecular weight inhibitors is limited due to their special protein structure. Since, on the one hand, these inhibitors are not absorbable in the intestine after oral administration and, on the other hand, exert an antigenic activity, a look was made for synthetic small-molecule enzyme inhibitors.
  • the four classes of enzymes responsible for proteinase dependent processes include the serine, thiol, metallo, and aspartate proteinases.
  • Serine proteinases are proteolytic enzymes that have a reactive serine residue in the active center.
  • the trypsin family of serine proteinases includes enzymes which, like trypsin as such, cleave C-terminal peptide bonds of the basic amino acids arginine and lysine.
  • those enzymes are of particular physiological importance that are involved in the immune systems of the blood. These are in particular the enzymes of the coagulation system, but also those which trigger fibrinolysis, release kinin and bring about complement activation or those which are themselves components of the enzyme systems mentioned.
  • Factor X to serine proteinase Factor X a , which in turn catalyzes the activation of prothrombin to fibrinogen-coagulating serine proteinase thrombin.
  • factor X a appears as a preferred target enzyme for inhibitory interventions in the blood coagulation process.
  • the most potent thrombin inhibitor is the phenylalanine derivative
  • a first group contains peptidyl-arginine-chloromethyl ketones, for example Ile-Glu-Gly-Arg-CH 2 Cl, which inhibits factor Xa
  • HD-Phe-Pro-Arg-CH 2 Cl which selectively inhibits thrombin (C.
  • a second group includes peptidyl arginine aldehydes, e.g.
  • Inhibit thrombin Inhibit thrombin.
  • these inhibitors are relatively unstable and, due to their reactivity, can cause undesirable side reactions.
  • Further selective thrombin inhibitors are (2R, 4R) -4-methyl-1- [N ⁇ - (3-methyl-1,2,3,5-tetrahydro-8-quinoline sulfonyl) -L-arginine] -2-pipecolin-carboxylic acid (R. Kikumoto et al., Biochemistry 23, 85-90, 1984) and the boronic acid derivative BOC-D-Phe-Pro-Boro-Arg-C 10 H 16 (see European Patent Application No. 0 293 881) .
  • non-selective inhibitors of thrombin and the plasma coagulation factors X and XII and kallikreinen, enzymatic complement factors and trypsin are the methanesulfonic acid salt of the 4- (6-guanidino-hexanoyloxy) -benzoic acid ethyl ester (M. Muramatu et al., Biochim. Biophys. Acta 268, 221-224, 1972) and that Dimethanesulfonic acid salt of 6-amidino-2-naphthyl-p-guanidinobenzoic acid (see US Pat. No. 4,454,338).
  • Anti-factor Xa activity new inhibitor structures can be found.
  • the basic amidino group was changed or hydrophobically substituted secondary amino acids were introduced.
  • the compound N ⁇ -2-naphthylsulfonyl-3-amidinophenylalanyl-proline was prepared. It has now been found that this compound does not selectively inhibit factor X as expected, but surprisingly thrombin. It has also been found that this compound has excellent pharmacokinetic properties. After subcutaneous administration to rats, a relatively high blood level is obtained, which remains available in an effective, anticoagulant concentration over a longer period of time. After oral administration to rats, the compound is absorbed through the intestine. This also applies to analogous compounds in which the amidino group has been changed, for example in the case of derivatives with an oxamidino group. The new derivatives are also characterized by reduced toxicity.
  • Direct inhibitors of this type are therefore suitable for use as anticoagulants in a variety of types of application.
  • the present invention relates to novel proteinase-inhibiting D, L, L and D-phenylalanine derivatives of the formula
  • R 1 is a basic group of the formula
  • R 5 and R 6 in formulas (a) and (b) each denote hydrogen or a straight-chain or branched lower alkyl radical
  • R represents hydrogen or a straight-chain or branched lower alkyl radical and R 8 represents a straight-chain or branched lower alkyl radical, a 1- or 2-hydroxyethyl radical, a methylmercaptoethyl radical, an aminobutyl radical, a guanidinopropyl radical, a carboxy (lower) alkyl radical, a carboxamido ( low) alkyl radical, a Phenyl (lower) alkyl radical, the ring of which is optionally substituted with OH, halogen, lower alkyl or methoxy, a cyclohexyl or cyclohexylmethyl radical, the ring of which is optionally substituted with OH, halogen, lower alkyl or methoxy, or an N-heteroaryl ( denote lower) alkyl radical having 3 to 8 carbon atoms in heteroaryl, for example imidazolylmethyl or indolylmethyl, where group (e) can be race
  • n denotes the number 1 or 2, and in which one of the methylene groups optionally with a hydroxyl, carboxyl, lower alkyl or
  • Aralkyl radical, where group (h) can be racemic or D- or L-configured
  • (k) represents a piperidyl group which is optionally substituted in one of the positions 2, 3 and 4 with a lower alkyl or hydroxyl radical
  • a further aromatic or cycloaliphatic ring preferably phenyl or cyclohexyl, in the 2,3 or 3,4 position, based on the heteroatom, can be fused onto the heterocycloaliphatic rings of the formulas (h), (i), (k), (1) a piperazyl group which is optionally substituted in the p-position with a lower alkyl radical, an aryl radical or an alkoxycarbonyl radical, (m) a group of the formula
  • n ' represents the numbers 1 to 6 and R 10
  • R 3 represents hydrogen or a straight-chain or branched lower alkyl or a 1- or 2-hydroxyethyl radical, where n denotes the number 0 or 1,
  • R 4 is an aryl radical, for example phenyl, methylphenyl, ⁇ - or ⁇ -naphthyl or 5- (dimethylamino) -naphthyl, or one
  • Heteroaryl e.g. Quinolyl
  • Phenylalanine derivatives are compounds in which
  • R 9 in formulas (h) and (i) is a hydroxyl, straight-chain or branched lower alkoxy, cycloalkoxy or Aralkoxy group, represents, R 4 denotes an aryl or heteroaryl radical, preferably ⁇ -naphthyl, and
  • n the number 0
  • alk is preferably - CH 3 or - C 2 H 5
  • alk is preferably - CH 3 or - C 2 H 5
  • R 9 is a straight-chain or branched alkoxy or Benzyloxy group
  • R 9 is a straight-chain or branched alkoxy or Benzyloxy group
  • the compounds of the general formula IV are reacted with the corresponding amino acid esters by the DCC process by reacting the compounds IV in a suitable aprotic solvent with dicyclohexylcarbodiimide in the presence of 1-hydroxybenzotriazole and converting them to V with the amino acid esters or amines mentioned be implemented.
  • the compounds of structure IV are isolated after conversion into active esters with, for example, N-hydroxysuccinimide, 2,3,4,5,6, -pentafluorophenol or p-nitrophenol in the presence of dicyclohexylcarbodiimide or, without intermediate isolation, with corresponding amino acid esters or amines converted into compounds of the general formula V.
  • Compounds of structure V are the compounds having a carboxylic acid structure of the general formula V, where R 2 , R 3 and R 4 have the meanings given in the general formula I and the R 9 defined in R 2 is OH. Starting from the compounds with carboxylic acid structure V, further amino acids can be coupled using the methods described above.
  • n and R 2 to R 4 correspond to those of the general formula I, alk represents lower alkyl, preferably - CH 3 , and X represents halogen, generally iodine.
  • n and R 2 to R 4 correspond to those of the general formula I
  • alk represents lower alkyl, preferably -CH 3 or -C 2 H 5
  • X represents halogen, generally chlorine.
  • R 1 represents the oxamidino group (c).
  • the cyan compounds V become catalytic, for example with Raney nickel / hydrogen in alcoholic solution in the presence of ammonia
  • Bases are suitably in salts, preferably
  • n, R 2 , R 3 and R 4 are obtained in the same way as the corresponding cyano compounds IV and V, the meanings of n, R 2 , R 3 and R 4 also being corresponding.
  • lower alcohols preferably methanol
  • the biological activity of the compounds according to the invention was determined both in vitro and in vivo. To characterize the inhibitor activity in vitro, the dissociation constants K i for the inhibition of trypsin or the related enzymes thrombin, plasmin,
  • Plasma kallikrein according to the formula
  • K i value for a tested enzyme the greater the affinity of the inhibitor for the enzyme and the smaller the amount of inhibitor required to inhibit the enzyme, eg thrombin.
  • thrombin time TT
  • aPTT activated partial thromboplastin time
  • PT prothrombin time
  • IV intravenous
  • SC subcutaneous
  • PO oral
  • HPLC high pressure liquid chromatography
  • the substance to be tested was dissolved in rat plasma in vitro. This solution was also subjected to HPLC to determine whether the peak characteristic of the substance would reappear at the substance-specific retention time.
  • the substance to be tested was dissolved in physiological saline and in a dose of 1, 5 or 100 mg per kg body weight IV, SC. or p.o. administered to rats. Blood samples were taken at 15 minute intervals, from which plasma samples were produced by centrifugation, which in turn were subjected to HPLC to determine whether the peak characteristic of the substance would appear again at the substance-specific retention time.
  • the substance to be tested was dissolved in physiological saline and administered to rats in a dose of 1, 5 or 100 mg per kg body weight iv, sc or po. Blood samples were taken at intervals of 15 minutes, from which plasma samples were produced by centrifugation and tested in the coagulation test (thrombin-induced plasma coagulation).
  • racemates can optionally be present as pure enantiomers or diastereomers after appropriate separation.
  • HX salt form either hydrochloride (HCl) or
  • V method either A or B
  • MERCK thin-layer prefabricated plates with silica gel 60, F 254, as a coating and the following solvent systems (LS) were used to carry out the thin-layer chromatographic investigations:
  • the oily tosylates were dissolved in water, made alkaline with 0.5 N NaOH and the bases released were extracted with ethyl acetate. After the ethyl acetate solutions had been dried over Na 2 SO 4 , the solvent was distilled off to a residue of about 5 ml, acidified with 2 N ethyl acetate / HCl and the compounds 7-11 were precipitated by adding ether.
  • Method A 10 mmol of the corresponding piperidine carboxylic acid ester (AV, Table 6) were dissolved in 10 ml of DMF, mixed with 11 mmol of HOBT and cooled to 0 °. A solution of 9 mmol of compound 3 in 20 ml of THF and 11 mmol of DCC were added and the mixture was stirred overnight. The urea derivative formed was filtered off and the solvent was distilled off. The residue was dissolved in ethyl acetate, the solution was washed with water, 10% citric acid, saturated NaHCO 3 solution and saturated NaCl solution and then dried over MgSO 4 . After the solvent had been distilled off, the crude products were purified by recrystallization or column chromatography.
  • Method B 5.5 mmol of the corresponding piperidinecarboxylic acid ester (AV, Table 6) and 5 mmol of NMM were dissolved in 10 ml of ethyl acetate, a solution of 5 mmol of the acid chloride obtained from compound 3 and thionyl chloride in 20 ml of ethyl acetate was added dropwise, and the mixture was added for 2 hours stirred at room temperature. The solvent was then distilled off, the residue was taken up in ethyl acetate, extracted with 1N HCl, 10% Na 2 CO 3 solution and water, the organic phase was dried over MgSO 4 and the solvent was distilled off. After adding 20 ml of methanol, the mixture was left to crystallize.
  • thioimidate ester hydroiodides 72-82 were dissolved in 10 ml each of methanol, the solutions were mixed with the 1.5 molar amount of ammonium acetate and the batches were heated at 60 ° C. in a water bath for 3 hours. The mixture was then kept in the refrigerator for 24 hours, the crystallized betaines 83-93 were suction filtered, washed with methanol and ether and dried.
  • thioimidic acid methyl ester hydroiodides 108 and 109 were dissolved in 10 ml of methanol, the solutions were mixed with the 1.5 molar amount of ammonium acetate and the batches were heated for 3 hours at 60 ° C. in a water bath. After cooling, compounds 110 and 111 were precipitated by adding ether. It was reprecipitated from ethanol / ether for cleaning.
  • the betaine obtained was dissolved in methanolic hydrochloric acid and ether was added to the solution.
  • 3-cyano- (L) -phenylalanine (125) was also prepared starting with 3-cyano- (D, L) -phenylalanine methyl ester by chymotrypsin cleavage, which with 2-naphthylsulfonyl chloride in N ⁇ - (2-naphthylsulfonyl) -3- cyan (L) phenylalanine (126) was transferred.
  • 3-cyan- (D) -phenylalanine methyl ester could be obtained in an oily form, the acidic hydrolysis of which (25 ml 0.5N HCl, 6 hours reflux) to 3-cyan- (D ) phenylalanine hydrochloride. Yield: 72%, mp 210-212 ° C, [ ⁇ ] D 20 + 10.0 ° (3% in methanol).
  • Example 1 4 0.6 g each of the thioimidic acid methyl ester hydroiodides 163 and 164 were converted into the amidine hydroiodides 165 and 166 analogously to Example 2 (32-34).
  • Example 1 4 0.6 g each of the thioimidic acid methyl ester hydroiodides 163 and 164 were converted into the amidine hydroiodides 165 and 166 analogously to Example 2 (32-34).
  • Table 19-25 shows the inhibition of the coagulation enzymes thrombin and factor X based on the dissociation constant K i (expressed in ⁇ mol / 1) by the compounds mentioned. All investigated compounds competitively inhibit substrate cleavage caused by both enzymes.
  • K i dissociation constant
  • Table 26 also shows for some representative compounds according to the invention their inhibitory action against trypsin, plasmin, factor XII a , plasma kallikrein, tPA and glandular kallikrein. Trypsin is usually less inhibited, the K i values are an order of magnitude higher. The compounds are significantly less effective than plasmin, plasma kallikrein and factor X a (K i 2 orders of magnitude larger). The derivatives are practically ineffective against factor XII a , tPA and glandular kallikrein. For the majority of the compounds, one can therefore speak of selective thrombin inhibitors.
  • Plasma binding R 1 R 2 R 4 n thrombin trypsin plasmin Xa Xlla tPA Kaliikrein
  • Table 27 shows the mouse toxicity values of representative compounds according to the invention and, for comparison, NAPAP and TAPAM.
  • LD50 10 - 50 mg / kg after IV application Compared to previously tested derivatives of benzamidine-containing amino acids (LD50 10 - 50 mg / kg after IV application), the toxicity is significantly lower for a number of compounds according to the invention, i.e. values for the LD50 after IV administration of> 50 mg / kg were found. This becomes particularly clear when comparing NAPAP with those compounds that also show improved pharmacokinetic data (123, 83, 186 and 190).
  • Table 28-30 shows the results of studies on the pharmacokinetics of representative compounds according to the invention and, for comparison, the values with NAPAP.
  • the compounds to be tested were administered intravenously (Table 28), subcutaneously (Table 29) or orally (Table 30) to rats. After the administration, the test animals were at intervals of Blood samples are taken from 2 to a maximum of 360 minutes, in which the blood level of the compounds to be tested was determined by means of HPLC.
  • the tested derivatives show improved pharmacokinetic behavior compared to NAPAP.
  • the compounds are eliminated after intravenous administration at a comparable rate (Fig. 1), relatively high, long-lasting blood levels are found after subcutaneous administration (Fig. 2).
  • Fig. 2 After oral administration, NAPAP cannot be detected in plasma, while some of the compounds tested according to the invention reach relatively high concentrations (Fig. 3).
  • a number of representative compounds according to the invention are anticoagulant in vitro. In all cases, the thrombin time (TT) was most effectively prolonged. This corresponds to the selectivity of these inhibitors, which inhibit thrombin most strongly among the coagulation factors.
  • the anticoagulant effect of the compounds can also be demonstrated in vivo. After i.v., s.c and p.o. administration of the compounds to be tested, the anticoagulant effect was determined in the plasma of the test animals. This is shown as an example for connection 123 in Fig. 5. The antithrombin effect in the coagulation test must be demonstrated in accordance with the concentration curve in plasma determined by HPLC.
  • phenylalanine derivatives prepared by one of the processes according to the invention are expediently suitable as such or as salts with a physiologically tolerable inorganic or organic acid using suitable pharmaceutical auxiliaries Application forms transferred.
  • these are, in particular, transdermal therapy systems such as plasters, but also tablets, dragées, capsules, suppositories, solutions, etc.
  • the dosage depends on the antithrombin activity, the toxicity, the possible blood level values, the bioavailability and the type of application of the compound according to the invention used, and in general on the blood values, the weight and the general condition of the patient, so that the dosage must ultimately be determined by the practicing doctor .
  • the dosage corresponds to that of known thrombin-inhibiting compounds and is between approximately 0.2 mg / kg and approximately 20 mg / kg body weight, with higher doses possibly also being administered.
  • daily doses of a compound according to the invention of about 50 mg to about 1600 mg or more are thus obtained.
  • 1 tablet contains 50 mg active ingredient, 40 mg lactose, 30 mg
  • Corn starch 4 mg PVP and 1 mg magnesium stearate.
  • the active ingredient mixed with lactose and corn starch is moistened uniformly with a 20% ethanolic solution of polyvinylpyrrolidone, through a sieve
  • Example 2 Mesh size pressed 1.5 mm and dried at 40 ° C. The granules thus obtained are mixed with magnesium stearate and compressed into tablets.
  • Example 2
  • 1 dragee contains 25 mg of active ingredient, 20 mg of lactose and 15 mg of corn starch.
  • the active ingredient mixed with lactose and corn starch is granulated in the manner described in Example 1 and compressed into oval tablet cores, which are then coated.
  • a sugar mixture consisting of 36.09% powdered sugar, 13.54% gum arabic, 36.09% wheat starch and 3.00% magnesium stearate as well as a binder 11.28% of a mixture of equal parts of mucilage gum arabic and Water used.
  • 1 capsule contains 50 mg of active ingredient and 100 mg of lactose.
  • the finely powdered active ingredient is partly triturated with lactose and the mixture is introduced into the capsules in starch capsules, which are cylinders that can be pushed into one another and sealed on one side, in the dosage indicated.
  • 1 suppository contains 50 mg of active ingredient and 0.95 g of cetyl phthalate as the basis.
  • the finely powdered active ingredient is triturated with twice the amount of the liquefied base.
  • the trituration is partially mixed with the rest of the liquefied base and processed until it is uniform.
  • the mixture is close to the limit of pourability poured into a suitable mold and. left to cool.
  • the active ingredient is dissolved in 100 ml of aqua ad injection, the solution is filtered and, if appropriate, filled into ampoules of 2 ml each.
  • the vials filled and closed with the active ingredient solution are subjected to steam sterilization at 121 to 124 ° C.

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  • Life Sciences & Earth Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

On a découvert des dérivés de la D, L-, L- et D-phénylalanine de formule (I), définie dans la revendication 1, où R1 désigne un groupe amidine, guanidine, oxamidine, aminoéthyle ou amine, qui ont une action anticoagulante ou antithrombotique. Les composés à action antithrombotique présentent une faible toxicité et peuvent être administrés par les voies orale, sous-cutanée ou intraveineuse.
EP91919709A 1990-11-15 1991-11-15 Derives de la phenylalanine metasubstitues Withdrawn EP0511347A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
CH363490 1990-11-15
CH3634/90 1990-11-15
CH17191 1991-01-22
CH171/91 1991-01-22
CH79791 1991-03-15
CH797/91 1991-03-15
CH142491 1991-05-13
CH1424/91 1991-05-13

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EP0511347A1 true EP0511347A1 (fr) 1992-11-04

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EP91919709A Withdrawn EP0511347A1 (fr) 1990-11-15 1991-11-15 Derives de la phenylalanine metasubstitues

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US (1) US5518735A (fr)
EP (1) EP0511347A1 (fr)
JP (1) JPH05503300A (fr)
KR (1) KR920703558A (fr)
AU (1) AU8868991A (fr)
CA (1) CA2073776A1 (fr)
WO (1) WO1992008709A1 (fr)

Families Citing this family (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PH31294A (en) * 1992-02-13 1998-07-06 Thomae Gmbh Dr K Benzimidazolyl derivatives, pharmaceutical compositions containing these compounds and process for preparing them.
US5583146A (en) * 1992-12-02 1996-12-10 Bristol-Myers Squibb Company Heterocyclic thrombin inhibitors
DE4326465A1 (de) * 1993-01-20 1995-02-09 Thomae Gmbh Dr K Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
WO1994018185A1 (fr) * 1993-02-10 1994-08-18 Pentapharm Ag Piperazides de derives substitues de phenylalanine utilises comme inhibiteurs de la thrombine
CA2122397A1 (fr) * 1993-05-03 1994-11-04 Spencer D. Kimball Inhibiteurs heterocycliques de la thrombine a substituants guanidinyl ou amidinyl
US6984627B1 (en) 1993-06-03 2006-01-10 Astrazeneca Ab Peptide derivatives
SE9301916D0 (sv) * 1993-06-03 1993-06-03 Ab Astra New peptides derivatives
US5783563A (en) * 1993-06-03 1998-07-21 Astra Aktiebolag Method for treatment or prophylaxis of venous thrombosis
GB9322976D0 (en) * 1993-11-08 1994-01-05 Pfizer Ltd Therapeutic agents
DE4421052A1 (de) * 1994-06-17 1995-12-21 Basf Ag Neue Thrombininhibitoren, ihre Herstellung und Verwendung
AU3107795A (en) * 1994-08-09 1996-03-07 Pentapharm Ag Inhibitors of the benzamidine type
IL115420A0 (en) 1994-09-26 1995-12-31 Zeneca Ltd Aminoheterocyclic derivatives
SE9404196D0 (sv) * 1994-12-02 1994-12-02 Astra Ab New antithrombotic formulation
GB9426038D0 (en) 1994-12-22 1995-02-22 Iaf Biochem Int Low molecular weight bicyclic thrombin inhibitors
US5776718A (en) * 1995-03-24 1998-07-07 Arris Pharmaceutical Corporation Reversible protease inhibitors
GB9508622D0 (en) * 1995-04-28 1995-06-14 Pfizer Ltd Therapeutic agants
US5985899A (en) * 1995-04-28 1999-11-16 Lg Chemical Ltd. Selective thrombin inhibitors
TW438591B (en) * 1995-06-07 2001-06-07 Arris Pharm Corp Reversible cysteine protease inhibitors
RO118289B1 (ro) 1995-08-30 2003-04-30 Gd Searle & Co Chicago Derivati de fenilcarboniluree si compozitie farmaceutica
US6013651A (en) * 1995-08-30 2000-01-11 G. D. Searle & Co. Meta-azacyclic amino benzoic acid compounds and derivatives thereof
CA2236007A1 (fr) 1995-10-31 1997-07-17 Gerald Floyd Smith Diamines antithrombotiques
TW541316B (en) * 1995-12-21 2003-07-11 Astrazeneca Ab Prodrugs of thrombin inhibitors
US6057314A (en) * 1995-12-21 2000-05-02 Biochem Pharma Inc. Low molecular weight bicyclic thrombin inhibitors
US5785116A (en) * 1996-02-01 1998-07-28 Hewlett-Packard Company Fan assisted heat sink device
US6313127B1 (en) 1996-02-02 2001-11-06 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
GB9602294D0 (en) * 1996-02-05 1996-04-03 Zeneca Ltd Heterocyclic compounds
US5942544A (en) * 1996-02-22 1999-08-24 Dupont Pharmaceuticals Company α-branched anilines, toluenes, and analogs thereof as factor Xa inhibitors
US5740013A (en) * 1996-07-03 1998-04-14 Hewlett-Packard Company Electronic device enclosure having electromagnetic energy containment and heat removal characteristics
WO1998006396A1 (fr) * 1996-08-12 1998-02-19 Merck & Co., Inc. Inhibiteurs de la thrombine
ATE230399T1 (de) * 1996-08-14 2003-01-15 Astrazeneca Ab Substituierte pyrimidinderivate und ihre pharmazeutische anwendung
EP0927035A4 (fr) * 1996-09-13 2002-11-13 Merck & Co Inc Inhibiteurs de thrombine
US5872138A (en) * 1996-09-13 1999-02-16 Merck & Co., Inc. Thrombin inhibitors
US6004985A (en) * 1996-10-09 1999-12-21 Berlex Laboratories, Inc. Thio acid derived monocylic N-heterocyclics as anticoagulants
UA56197C2 (uk) 1996-11-08 2003-05-15 Зенека Лімітед Гетероциклічні похідні
TW542822B (en) 1997-01-17 2003-07-21 Ajinomoto Kk Benzamidine derivatives
AU5999798A (en) 1997-02-13 1998-09-08 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
JP2001511798A (ja) 1997-02-13 2001-08-14 ゼネカ・リミテッド オキシド−スクアレンシクラーゼ抑制剤として有用な複素環化合物
IL123986A (en) 1997-04-24 2011-10-31 Organon Nv Medicinal compounds
JP2002514217A (ja) 1997-04-30 2002-05-14 イーライ・リリー・アンド・カンパニー 抗血栓物質
JP2002513415A (ja) 1997-04-30 2002-05-08 イーライ・リリー・アンド・カンパニー 抗血栓剤
ES2232946T3 (es) 1997-04-30 2005-06-01 Eli Lilly And Company Agentes antitromboticos.
CA2295153A1 (fr) 1997-06-26 1999-01-07 Gerald Floyd Smith Agents antithrombotiques
AU8270698A (en) * 1997-06-26 1999-01-19 Eli Lilly And Company Antithrombotic agents
IL133621A0 (en) 1997-06-26 2001-04-30 Lilly Co Eli Antithrombotic agents
GB9715895D0 (en) 1997-07-29 1997-10-01 Zeneca Ltd Heterocyclic compounds
WO1999011658A1 (fr) * 1997-08-29 1999-03-11 Proteus Molecular Design Ltd. Derives de meta-benzamidine comme inhibiteurs de serine protease
US6740682B2 (en) 1997-08-29 2004-05-25 Tularik Limited Meta-benzamidine derivatives as serine protease inhibitors
US6133297A (en) * 1997-09-30 2000-10-17 Merck & Co., Inc. Thrombin inhibitors
DE19743435A1 (de) * 1997-10-01 1999-04-08 Merck Patent Gmbh Benzamidinderivate
US6284756B1 (en) 1998-04-30 2001-09-04 Eli Lilly And Company Antithrombotic agents
ES2189455T3 (es) 1998-07-20 2003-07-01 Wilex Ag Nuevos agentes inhibidores de la urocinasa.
US7342018B2 (en) 1998-07-20 2008-03-11 Wilex Ag Urokinase inhibitors and uses thereof
EP0997460B1 (fr) * 1998-10-28 2002-12-11 Eli Lilly And Company Dérivés de benzothiophène comme agents antithrombotiques et produits intermédiaires
EP1016663A1 (fr) * 1999-01-02 2000-07-05 Aventis Pharma Deutschland GmbH Dérivés de l'acide malonique, procédé pour leur préparation, leur utilisation comme médicaments et compositions les contenant (inhibiteurs du facteur Xa )
EP1140878A1 (fr) 1999-01-02 2001-10-10 Aventis Pharma Deutschland GmbH Nouveaux derives d'acide malonique, procedes de preparation de ces derives, leur utilisation et compositions pharmaceutiques les contenant (inhibition de l'activite du facteur xa)
GB9902989D0 (en) 1999-02-11 1999-03-31 Zeneca Ltd Heterocyclic derivatives
US20050032790A1 (en) * 1999-06-14 2005-02-10 Liebeschuetz John Walter Compounds
WO2000076971A2 (fr) 1999-06-14 2000-12-21 Eli Lilly And Company Composes
EP1127884A1 (fr) * 2000-02-26 2001-08-29 Aventis Pharma Deutschland GmbH Dérivés de l'acide malonique, procédés pour leur préparation, leur utilisation comme inhibiteur du facteur XA et compositions les contenants
US6610701B2 (en) 2001-02-09 2003-08-26 Merck & Co., Inc. Thrombin inhibitors
US20030114448A1 (en) * 2001-05-31 2003-06-19 Millennium Pharmaceuticals, Inc. Inhibitors of factor Xa
US6861424B2 (en) 2001-06-06 2005-03-01 Schering Aktiengesellschaft Platelet adenosine diphosphate receptor antagonists
US7115607B2 (en) * 2001-07-25 2006-10-03 Amgen Inc. Substituted piperazinyl amides and methods of use
SI21137A (sl) * 2002-01-24 2003-08-31 LEK, tovarna farmacevtskih in kemičnih izdelkov, d.d. Derivati azafenilalanina
CH695999A5 (de) * 2002-02-28 2006-11-15 Wilex Ag Verfahren zur Herstellung von 3- Amidinophenylalanin-Derivaten.
AU2003219039A1 (en) 2002-03-11 2003-09-22 Curacyte Ag Urokinase inhibitors, production and use thereof
DE10225876A1 (de) * 2002-06-11 2003-12-24 Wilex Ag Guanidinophenylalaninverbindungen als Urokinase-Inhibitoren
EP1525195A2 (fr) * 2002-07-25 2005-04-27 Wilex AG Procede de production de derives de phenylalanine
DE10238048A1 (de) 2002-07-25 2004-02-05 Wilex Ag Verfahren zur Herstellung von Phenylalanin-Derivaten
US7122580B2 (en) * 2002-08-09 2006-10-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds and methods to modulate coagulation
US7056923B2 (en) 2002-12-11 2006-06-06 Schering Aktiengesellschaft Platelet adenosine diphosphate receptor antagonists
DE10301300B4 (de) 2003-01-15 2009-07-16 Curacyte Chemistry Gmbh Verwendung von acylierten 4-Amidino- und 4-Guanidinobenzylaminen zur Inhibierung von Plasmakallikrein
DE10322191B4 (de) 2003-05-16 2014-02-27 The Medicines Company (Leipzig) Gmbh N-sulfonylierte Aminosäurederivate, Verfahren zu ihrer Herstellung und ihre Verwendung
US7208601B2 (en) * 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
JP2007501844A (ja) * 2003-08-08 2007-02-01 トランス　テック　ファーマ，インコーポレイテッド アリール及びヘテロアリール化合物、組成物並びに使用方法
WO2005014532A1 (fr) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Composes aryle et heteroaryle, compositions et procedes associes
DE10342108A1 (de) 2003-09-11 2005-04-14 Curacyte Chemistry Gmbh Basisch-substituierte Benzylaminanaloga als Inhibitoren des Gerinnungsfaktors Xa, ihre Herstellung und Verwendung
DE102005044319A1 (de) 2005-09-16 2007-03-22 Curacyte Chemistry Gmbh 2-(Aminomethyl)-5-Chlor-Benzylamid-Derivate und ihre Verwendung als Hemmstoffe des Gerinnungsfaktors Xa
DE102006050672A1 (de) 2006-10-24 2008-04-30 Curacyte Discovery Gmbh Hemmstoffe des Plasmins und des Plasmakallikreins
CN105566319B (zh) * 2014-10-09 2018-06-01 和鼎（南京）医药技术有限公司 一种(s,s)-2,8-二氮杂二环[4,3,0]壬烷的制备方法
US11130780B2 (en) 2015-03-09 2021-09-28 Washington University Inhibitors of growth factor activation enzymes
WO2018118838A1 (fr) * 2016-12-20 2018-06-28 Biomarin Pharmaceutical Inc. Inhibiteurs de la céramide galactosyltransférase pour le traitement de maladies
US20240130944A1 (en) 2021-02-16 2024-04-25 Dsm Ip Assets B.V. Lrat inhibitors for treating skin ageing

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4125604A (en) * 1974-11-08 1978-11-14 Mitsubishi Chemical Industries Limited N2-Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
DD142804A3 (de) * 1977-11-07 1980-07-16 Wagner Guenter Verfahren zur herstellung von na-alkyl-bzw.na-aryl-sulfonylierten omega-amidinophenyl-alpha-aminoalkylcarbonsaeureamiden
JPS60163855A (ja) * 1984-02-06 1985-08-26 Mitsubishi Chem Ind Ltd アルギニン誘導体および薬剤として許容され得るその酸付加塩

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9208709A1 *

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KR920703558A (ko) 1992-12-18
AU8868991A (en) 1992-06-11
WO1992008709A1 (fr) 1992-05-29
US5518735A (en) 1996-05-21
JPH05503300A (ja) 1993-06-03
CA2073776A1 (fr) 1992-05-16

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