WO1995009858A1 - Inhibiteurs de dipeptides d'acide boronique d'enzymes analogues a la trypsine - Google Patents

Inhibiteurs de dipeptides d'acide boronique d'enzymes analogues a la trypsine Download PDF

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Publication number
WO1995009858A1
WO1995009858A1 PCT/US1994/011048 US9411048W WO9509858A1 WO 1995009858 A1 WO1995009858 A1 WO 1995009858A1 US 9411048 W US9411048 W US 9411048W WO 9509858 A1 WO9509858 A1 WO 9509858A1
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Prior art keywords
alkyl
aryl
pro
nhch
nhc
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PCT/US1994/011048
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English (en)
Inventor
John Matthew Fevig
Matthew Mark Abelman
Eugene Cruz Amparo
Joseph Cacciola
Charles Adrian Kettner
Gregory James Pacofsky
Chia-Lin J. Wang
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The Du Pont Merck Pharmaceutical Company
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Priority claimed from US08/139,444 external-priority patent/US5462964A/en
Application filed by The Du Pont Merck Pharmaceutical Company filed Critical The Du Pont Merck Pharmaceutical Company
Priority to AU79226/94A priority Critical patent/AU7922694A/en
Publication of WO1995009858A1 publication Critical patent/WO1995009858A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/16—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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • 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
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • 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 the discovery of new C-terminal boronic acid dipeptide inhibitors of trypsin-like enzymes such as thrombin and pharmaceutical compositions thereof.
  • proteolytic enzymes which cleave precursor proteins at specific amino acid residues.
  • serine proteases One major type of these enzymes, the serine proteases, are so named because the initial step in their proteolysis reactions is the attack of the hydroxyl of an active site serine on the amide carbonyl at the scissile site of the protein. This results in a tetrahedral intermediate which subsequently breaks down into an acyl enzyme and the amino terminus of the cleaved sequence. Hydrolysis of the acyl enzyme releases the carboxyl terminus and the free enzyme.
  • a subclass of the serine proteases is composed of the trypsin-like enzymes, which cleave proteins site-specifically such that the liberated carboxyl terminus is arginine or lysine.
  • proteases exceeding inhibitors disclosed earlier by as much as three orders of magnitude in potency.
  • the trypsin-like protease thrombin is the final protease in both the intrinsic and extrinsic pathways of the blood coagulation cascade and thus is of crucial importance in the blood coagulation process.
  • Thrombin is responsible for the cleavage of fibrinogen to fibrin, which is then cross-linked by factor Xllla, thereby stabilizing a developing blood clot.
  • thrombin activates platelets and also factors V and
  • Inhibitors of thrombin are expected to be effective in the treatment of thrombosis, a condition in which unbalanced activity of the hemostatic mechanism leads to intravascular thrombus formation.
  • Direct thrombin inhibitors are also expected to be devoid of the side effects of bleeding and high interpatient variability which are common with heparin and vitamin K antagonist therapy (Green et al. Thromb. res. 1985, 37, 145-153).
  • This series of tripeptide thrombin inhibitors was expanded to include the boronic acid derivatives which are exemplified by Ac-D-Phe-Pro-boroArgOH in Kettner and Shenvi, European Patent Application EP 293 881.
  • Additional boronic acid inhibitors of thrombin have been disclosed: Elgendy et al., Tetrahedron Let t . 33, 4209 (1992) have described peptides containing ⁇ -aminoboronic acids with aliphatic neutral sidechains which are thrombin inhibitors.
  • Kakkar in PCT Application WO 92/07869 has claimed peptide thrombin inhibitors of the general structure, X-Aa 1 -Aa 2 -NH-CH(Y)-Z where Aa 1 and Aa 2 are unnatural amino acid residues, Z can be a variety of electrophilic groups including boronic acid, and Y can be a variety of basic
  • Tripeptide agents limited to ⁇ -alkyl and ⁇ -aryl or heteroaryl substituted glycines conjugated to -Pro-Arg-H have been disclosed by Lilly in European Patent Application EP 0 479 489 A2. Sandoz has
  • the present invention relates to an
  • aryl is limited to phenyl
  • R 4 and R 5 are independently selected at each occurrence from the group consisting of:
  • R 6 , R 7 , R 8 and R 9 are independently selected at each occurrence from the group consisiting of:
  • R 10 is phenyl, where phenyl is optionally substituted with one to three substituents selected from the group consisting of:
  • R 11 is hydrogen or -CO 2 R 4 ;
  • R 12 is:
  • ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O; n is independently selected at each occurence from 0 or 1; p is independently selected at each occurrence from 0 to 3; q is independently selected at each occurrence from 0 to 4; r is independently selected at each occurrence from 0 to 2; t is independently selected at each occurrence from 1 to 3.
  • Preferred compounds of formula (I) are those compounds wherein:
  • R 2 is hydrogen or C 1 -C 4 alkyl
  • aryl is limited to phenyl
  • R 4 is independently selected at each occurrence from the group consisting of:
  • R 6 , R 7 , R 8 , and R 9 are independently selected at each occurrence from the group consisting of:
  • R 10 is phenyl, where phenyl is optionally substituted with one to three substituents selected from the group consisting of:
  • Y 1 and Y 2 when taken together Y 1 and Y 2 form a c) cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O; r is independently selected at each occurrence from 0 to 2; t is 1.
  • More preferred compounds of formula (I) are those compounds wherein:
  • R 2 is hydrogen
  • R 4 is independently selected at each occurrence from the group consisting of:
  • R 6 , R 7 , R 8 , and R 9 are independently at each occurrence from the group consisiting of:
  • R 10 is phenyl, where phenyl is optionally substituted with one to three substituents selected from the group consisting of:
  • Trp L-tryptophan
  • D,L indicates the amino is present in mixture of the D-and the L-configuration.
  • the prefix "boro” indicates amino acid residues where the carboxyl is replaced by a boronic acid or a boronic acid ester. For example, if
  • R 1 is isopropyl and Y 1 and Y 2 are OH, the C-terminal residue is abbreviated "boroVal-OH” where "-OH"
  • Examples of other useful diols for esterification with the boronic acids are 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, and 1,2-dicyclohexylethanediol.
  • LRMS(NH 3 -CI) and HRMS(NH 3 -CI) are low and high resolution mass spectrometry, respectively, using NH 3 as an ion source.
  • amine-blocking group or "amine-protecting group” as used herein, refers to various acyl, thioacyl, alkyl, sulfonyl, phosphoryl, and
  • phosphinyl groups comprised of 1 to 20 carbon atoms. Substitutents on these groups maybe either alkyl, aryl, alkaryl which may contain the heteroatoms, O, S, and N as a substituent or as an in chain component.
  • amine-blocking groups are recognized by those skilled in the art of organic synthesis. Examples of suitable groups include formyl, acetyl, benzoyl, trifluoroacetyl, and methoxysuccinyl; aromatic urethane protecting groups, such as, benzyloxycarbonyl; and aliphatic urethane protecting groups, such as t-butoxycarbonyl or adamantyloxycarbonyl. Gross and Meienhofer, eds., The Peptides, Vol 3; 3-88 (1981), Academic Press, New York, and Greene and Wuts Protecti ve Groups in Organic
  • amino acid residues refers to natural or unnatural amino acids of either D- or L-configuration. Natural amino acids residues are Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val. Roberts and Vellaccio, The Peptides, Vol 5; 341-449 (1983), Academic Press, New York, discloses numerous suitable unnatural amino acids and is incorporated herein by reference for that purpose.
  • amino acids residues also refers to various amino acids where sidechain functional groups are coupled with appropriate protecting groups known to those skilled in the art.
  • the Peptides Vol 3, 3-88 (1981) discloses numerous suitable protecting groups and is incorporated herein by reference for that purpose.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic
  • hydrocarbon groups having the specified number of carbon atoms having the specified number of carbon atoms; "alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl” is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl, and so forth.
  • Alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
  • Hydrocarbon or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo.
  • aryl or is intended to mean phenyl, naphthyl, biphenyl or fluorenyl which may be unsubstituted or include optional substitution with one to five substituents.
  • heteroaryl is meant to include 5-, 6- or 10-membered mono- or bicyclic aromatic rings, which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of O, N, and S; said ring(s) may be unsubstituted or include optional substitution with one to three substituents.
  • heteroaryl include the following: 2-, or 3-, or 4-pyridyl, 2- or 3-furyl, thiophenyl, 2-, or 4-, or 5-imidazoyl, 2-, or 4-, or 5-oxazoyl, 2-, or 4-, or 5-thiazoyl, 2- or 3-benzofuranyl, 2- or 3-benzo[b]thiophenyl, 2-, or 3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1- or 2-benzimidazoyl, 2-benzoxazoyl, 1- or 2-benzothiazoyl, indolinoyl-2-onyl, indolinoyl, indolyl, pyrrolyl, 2- or 4- or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5-isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or 4- or 5-isothiazolyl;
  • heterocycle is meant to include 5-, 6-or 10-membered mono- or bicyclic rings, which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of O, N, and S; said ring(s) may be unsubstituted or include optional substitution with one to three substituents. Included in the definition of the group heterocycle, but not limited to, are
  • tetrahydrofuranyl tetrahydrothiophenyl
  • piperidinyl piperazinyl
  • morpholinyl Particularly preferred are 1-,3-, or 4-tetrahdroisoquinolinyl.
  • the substituents that may be attached to the aryl, heteroaryl or heterocycle ring(s) may be independently selected at each occurrence from the group consisting of:
  • the compounds of the present invention contain one or more chiral centers and that these stereoisomers may possess distinct physical and biological properties.
  • the present invention comprises all of the stereoisomers or mixtures thereof. If the pure enantiomers or diasteromers are desired, they may be prepared using starting materials with the appropriate stereochemistry, or may be separated from mixtures of undesired stereoisomers by standard
  • stable compound or “stable structure” is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound of formula (I) is modified by making acid or base salts of the compound of formula (I).
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of the compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds of formula (I) wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that , when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I); and the like.
  • compositions of the invention can be prepared by reacting the free acid or base forms of these compounds with a
  • Scheme 1 outlines the general procedure employed when R 3 in dipeptides of Formula (I) is an acyl group and the C-terminus is a boronic acid derivative of lysine, arginine or the isothiouronium derivative thereof.
  • R 3 in dipeptides of Formula (I) is an acyl group and the C-terminus is a boronic acid derivative of lysine, arginine or the isothiouronium derivative thereof.
  • hydrochlorides of which three methods are preferred.
  • a 0°C solution of the proline ester in a suitable solvent such as but not limited to tetrahydrofuran or dichloromethane, is treated with one equivalent of the desired acid chloride (IIa) and two equivalents of tertiary amine base, preferrably
  • the second method is the mixed anhydride procedure of Anderson, et. al. described in J. Am . Chem . Soc . 89, 5012 (1967).
  • a 0°C solution of the carboxylic acid (lib) in non-protic solvent, such as tetrahydrofuran is treated with one equivalent of tertiary amine base, preferrably N-methylmorpholine and one equivalent of isobutyl chloroformate .
  • the resulting isobutyl mixed anhydride is treated sequentially with the amine salt and one equivalent of triethylamine or N-methylmorpholine.
  • the resulting mixture is typically allowed to warm to room temperature, stirred for one to several hours and then subjected to standard aqueous workup.
  • the third method is the dicyclohexylcarbodiimide/ 1-hydroxybenzotriazole (DCC/HOBT) method of Konig and Geiger, Chem . Ber . 103, 788 (1970).
  • DCC/HOBT dicyclohexylcarbodiimide/ 1-hydroxybenzotriazole
  • a solution of amine salt and carboxylic acid (IIb) in N,N-dimethylformamide or tetrahydrofuran can be treated with one equivalent of DCC, HOBT and
  • the resulting mixture can be stirred for several hours or overnight and subjected to standard aqueous workup.
  • the standard aqueous workup referred to above typically involves removing the solvent in vacuo and then diluting the residue with a solvent such as ethyl acetate. This solution can be then washed sequentially with dilute aqueous acid, saturated aqueous sodium bicarbonate and brine. After drying over magnesium sulfate or sodium sulfate, the solution is concentrated in vacuo to afford the crude amide (III). In many cases this material is sufficiently pure to make unnecessary further purification. If purification of (III) is necessary, it is generally best done by flash column chromatography on silica gel.
  • the preferred method for preparing the borolysine analogs (VIIIb) and (IX) involves an azide displacement of the bromide (VIb) with sodium azide in DMF at 100°C to give (VIIb).
  • This azide can be reduced according any of the various methods for reduction of the azide to the corresponding amine found in Hudlicky, Reductions In Organic Synthesis, John Wiley and Sons, pp. 134 (1984).
  • a preferred method involves hydrogenation over
  • the preferred method for preparing the boroarginine analogs (XIa) and (XIIIa) involves the formamidation of the boroornithine derivative (Villa), derived from (Via) as described for the borolysine analog, with
  • the formamidino analog (XII) can also be prepared from the boroornithine (VIIIa) by treatment with ethyl formimidate. Transesterification with phenylboric acid then provides the boronic acid (XIIa).
  • Cleavage of the acid protecting group can be affected by a variety of conditions depending on the choice of R'.
  • R' a benzyl ester
  • hydrogenolysis of an alcohol solution of the compound may be effected under an atmosphere of hydrogen gas in the presence of platinum or palladium on carbon catalyst according to the reported by Hartney and Simonoff, Org. React . VII, 263 (1953).
  • the substituted phenoxyacetic acids (Table 1) are prepared by the general route shown in Scheme 5.
  • the substituted phenols (XXI) are deprotonated with a strong base, preferrably sodium hydride, and then alkylated with the appropriate bromoacetate (XXII) to give
  • XXXI The ⁇ , ⁇ -dimethylphenoxy- or ⁇ , ⁇ -dimethylthiophenoxy acetic acids (XXXI) (Table 1) can be prepared according to Scheme 7.
  • the phenol or thiophenol (XXIX) can be treated with 2-trichloromethyl-2-propanol (XXX) in the presence of sodium hydroxide, according to the method of Corey et. al. J. Am Chem Soc . 91, 4782 (1969) to produce the acid (XXXI).
  • azomethine ylide which can be generated in situ in two different ways .
  • the preferred method involves treating N-benzyl-N- (methoxymethyl)trimethylsilylmethylamine (XLIIIb) with trifluoroacetic acid, according to the method of Achiwa et. al. Chem . Pharm . Bull . 33, 2762 (1985).
  • N-benzyl-N- (cyanomethyl)trimethylsilylmethylamine (XLIIIa) can be treated with silver fluoride in the dark, according to the method of Padwa et. al. J. Org. Chem . 50, 4006 (1985).
  • Generation of the azomethine ylide by either method and reaction with (XLll) affords the pyrrolidine (XLIV).
  • Manipulation of the amine-protectiong group to give a more versatile carbamate-protected (CBZ or t-BOC) pyrrolidine followed by ester hydrolysis using alkaline hydrolysis can provide the carboxylic acid (XLV).
  • (XLVI) can be converted into its corresponding enol trifluoromethanesulfonate and subsequently coupled with phenylboric acid under palladium catalysis, according to the method of Suzuki et. al. Syn . Commun . 11, 513 (1981) to afford (XLVII).
  • Catalytic hydrogenation using the conditions previously described gives cis-(XLVIII), which can readily be isomerized to trans-(XLVIII) upon treatment with alkoxide in an alcoholic solvent. Ester hydrolysis as described above using alkoxide in an aqueous alcoholic solvent mixture can provide the acid (IL) of either stereoisomer.
  • This compound was prepared by coupling the acid
  • Part B Preparation of 3-[2-CF 3 C 6 H 4 CH(OH)]C 6 H 4 CO 2 H
  • Example 195 To a solution of Example 195 (0.30 g, 0.40 mmol) was added 12N HCI (about 0.5 mL). This solution was stirred at 25°C for 16 h. The mixture was partitioned between H 2 O and EtOAc. The aqueous layer was washed with EtOAc and concentrated to afford the product as a white solid. MS (DCI): m/z 619 (M+H)+.
  • the dipeptide boronic acids which are described in the present invention represent a novel class of potent, reversible inhibitors of trypsin-like enzymes.
  • Trypsin-like enzymes are a group of proteases which hydrolyze peptide bonds at basic residues liberating either a C-terminal arginyl or lysyl residue.
  • enzymes of the blood coagulation and fibrinolytic system required for hemostasis They are Factors II, X, VII, IX, XII, kallikrein, tissue plasminogen activators, urokinase-like plasminogen activator, and plasmin.
  • Enzymes of the complement system, acrosin (required for fertilization), pancreatic trypsin are also in this group. Elevated levels of proteolysis by these enzymes
  • proteases can result in disease states.
  • consumptive coagulopathy a condition marked by a decrease in the blood levels of enzymes of both the coagulation system, the fibrinolytic system and
  • anticoagulants such as heparin (and its complex with the protein inhibitor, antithrombin III) are ineffective in blocking arterial thrombosis associated with myocardial infractions and other clotting disorders.
  • heparin and its complex with the protein inhibitor, antithrombin III
  • antithrombin III a protein inhibitor
  • thrombin III a low molecular weight thrombin inhibitor, containing a different functionality, was effective in blocking arterial thrombosis [Hanson and Harker (1988) Proc .
  • Ki Ki-Valuent Values of Ki were determined by allowing thrombin (0.19 nM) to react with substrate (0.20 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to
  • v o is the velocity of the control in the absence of inhibitor
  • v s is the velocity in the presence of inhibitor
  • I is the concentration of inhibitor
  • Ki is the dissociation constant of enzyme: inhibitor complex
  • S is the concentration of substrate
  • K m is the Michaelis constant
  • Plasma was prepared by diluting blood 1:10 with 3.2% aqueous citric acid and centrifuging. Buffer consisted of 0.10 M Tris, pH 7.4, containing 0.9% sodium chloride, and 2.5 mg/mL bovine serum albumin. Bovine thrombin was obtained from Sigma and was diluted to 24 NIH units/mL. Plasma (200 ⁇ L) and buffer (50 ⁇ L) containing inhibitor were
  • Plasma 0.2 mL
  • buffer 0.05 mL, 0.10 M
  • Tris[hydroxymethyl]-aminomethane hydrochloride, pH 7.4, 0.9% (w/v) sodium chloride, and 2.5 mg/mL bovine serum albumin) containing inhibitor were incubated 3 min at 37°C in a fibrameter. Reactions were initiated by adding thrombin (0.05 mL) to achieve a final concentration of 4 NIH units/mL. The effectiveness of compounds as anticoagulants is reported as the level of inhibitor required to prolong clotting to that observed for 2 NIH units/mL thrombin in the absence of inhibitor. In this assay then, better inhibitors require lower
  • the compounds of formula (I) have anti-thrombogenic properties, they may be employed when an anti-thrombogenic agent is indicated, such as for the control of the coagulation of the fibrinolysis system in mammals or they may be added to blood for the purpose of preventing coagulation of the blood due to contact with blood collecting or distribution containers, tubing or apparatus.
  • these compounds may be administered orally, parenterally or intravenously to a host to obtain an anti-thrombogenic effect.
  • the dosage of the active compound depends on the mammalian species, body weight, age, and mode of administration as determined by one skilled in the art .
  • the compounds may be administered alone or in combination with pharmaceutical carriers or diluents at a dose of from 0.02 to 15 mg/kg to obtain the anti-thrombogenic effect, and may be given as a single dose or in divided doses or as a sustained release formulation.
  • Pharmaceutical carriers or diluents are well known and include sugars, starches and water, which may be used to make tablets, capsules, injectable solutions or the like which can serve as suitable dosage forms for administration of the compounds of this invention.
  • Remington's Pharmaceutical Sciences, A. Osol, is a standard reference text which discloses suitable pharmaceutical carriers and dosage forms.

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Abstract

L'invention concerne la découverte de nouveaux inhibiteurs de dipeptides d'acide boronique à terminaison C d'enzymes analogues à la trypsine, tels que la thrombine, ainsi que des compositions pharmaceutiques à base desdits inhibiteurs.
PCT/US1994/011048 1993-10-07 1994-10-06 Inhibiteurs de dipeptides d'acide boronique d'enzymes analogues a la trypsine WO1995009858A1 (fr)

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US13325293A 1993-10-07 1993-10-07
US08/133,252 1993-10-07
US08/139,444 US5462964A (en) 1993-10-20 1993-10-20 Dipeptide boronic acid inhibitors of trypsin-like enzymes
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US5578574A (en) * 1994-03-04 1996-11-26 Eli Lilly And Company Antithrombotic agents
US5599793A (en) * 1994-03-04 1997-02-04 Eli Lilly And Company Antithromobotic agents
US5602101A (en) * 1994-03-04 1997-02-11 Eli Lilly And Company Antithrombotic agents
US5693617A (en) * 1994-03-15 1997-12-02 Proscript, Inc. Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein
US5705487A (en) * 1994-03-04 1998-01-06 Eli Lilly And Company Antithrombotic agents
US5707966A (en) * 1994-03-04 1998-01-13 Eli Lilly And Company Antithrombotic agents
US5710130A (en) * 1995-02-27 1998-01-20 Eli Lilly And Company Antithrombotic agents
US5726159A (en) * 1994-03-04 1998-03-10 Eli Lilly And Company Antithrombotic agents
US5780454A (en) * 1994-10-28 1998-07-14 Proscript, Inc. Boronic ester and acid compounds
US5885967A (en) * 1994-03-04 1999-03-23 Eli Lilly And Company Antithrombotic agents
US5914319A (en) * 1995-02-27 1999-06-22 Eli Lilly And Company Antithrombotic agents
JP2006503903A (ja) * 2002-09-09 2006-02-02 トライジェン・リミテッド 血栓症の処置のためのボロン酸の多価金属塩
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids
US7378426B2 (en) 2004-03-01 2008-05-27 Bristol-Myers Squibb Company Fused heterotricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US7807709B2 (en) 2005-03-23 2010-10-05 Novartis Ag Organic compounds
US8129411B2 (en) 2005-12-30 2012-03-06 Novartis Ag Organic compounds
US8383650B2 (en) 2007-06-25 2013-02-26 Novartis Ag Organic compounds
EP2666772A1 (fr) * 2002-12-20 2013-11-27 Basf Se Synthèse d'amines et intermédiaires pour leur synthèse
US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives
US11851422B2 (en) 2021-07-09 2023-12-26 Aligos Therapeutics, Inc. Anti-viral compounds
US11952365B2 (en) 2020-06-10 2024-04-09 Aligos Therapeutics, Inc. Anti-viral compounds
US12065428B2 (en) 2021-09-17 2024-08-20 Aligos Therapeutics, Inc. Anti-viral compounds

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US6066730A (en) * 1994-10-28 2000-05-23 Proscript, Inc. Boronic ester and acid compounds, synthesis and uses
US6297217B1 (en) 1994-10-28 2001-10-02 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
US6465433B1 (en) 1994-10-28 2002-10-15 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
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US6617317B1 (en) 1994-10-28 2003-09-09 Millennium Pharmaceuticals, Inc. Boronic ester and acid compositions
US6747150B2 (en) 1994-10-28 2004-06-08 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
US8003791B2 (en) 1994-10-28 2011-08-23 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
US7119080B2 (en) 1994-10-28 2006-10-10 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
US5914319A (en) * 1995-02-27 1999-06-22 Eli Lilly And Company Antithrombotic agents
US5710130A (en) * 1995-02-27 1998-01-20 Eli Lilly And Company Antithrombotic agents
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids
US7371729B2 (en) 2002-09-09 2008-05-13 Trigen Limited Boronic acid salts useful in parenteral formulations
JP2006503903A (ja) * 2002-09-09 2006-02-02 トライジェン・リミテッド 血栓症の処置のためのボロン酸の多価金属塩
EP2666772A1 (fr) * 2002-12-20 2013-11-27 Basf Se Synthèse d'amines et intermédiaires pour leur synthèse
US8822702B2 (en) 2002-12-20 2014-09-02 Basf Se Synthesis of amines and intermediates for the synthesis thereof
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US7378426B2 (en) 2004-03-01 2008-05-27 Bristol-Myers Squibb Company Fused heterotricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US7807709B2 (en) 2005-03-23 2010-10-05 Novartis Ag Organic compounds
US8129411B2 (en) 2005-12-30 2012-03-06 Novartis Ag Organic compounds
US8497286B2 (en) 2007-06-25 2013-07-30 Novartis Ag Organic compounds
US8383650B2 (en) 2007-06-25 2013-02-26 Novartis Ag Organic compounds
US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives
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US11952365B2 (en) 2020-06-10 2024-04-09 Aligos Therapeutics, Inc. Anti-viral compounds
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