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WO1994021650A1 - Boronic acid and ester inhibitors of thrombin - Google Patents

Boronic acid and ester inhibitors of thrombin Download PDF

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Publication number
WO1994021650A1
WO1994021650A1 PCT/US1994/002965 US9402965W WO9421650A1 WO 1994021650 A1 WO1994021650 A1 WO 1994021650A1 US 9402965 W US9402965 W US 9402965W WO 9421650 A1 WO9421650 A1 WO 9421650A1
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WO
WIPO (PCT)
Prior art keywords
hydrochloride
boroarginine
pinanediol
phenyl
borothioarginine
Prior art date
Application number
PCT/US1994/002965
Other languages
French (fr)
Inventor
Eugene Cruz Amparo
William Henry Miller
Gregory James Pacofsky
John Wityak
Original Assignee
The Du Pont Merck Pharmaceutical Company
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Publication date
Application filed by The Du Pont Merck Pharmaceutical Company filed Critical The Du Pont Merck Pharmaceutical Company
Priority to AU64487/94A priority Critical patent/AU6448794A/en
Publication of WO1994021650A1 publication Critical patent/WO1994021650A1/en

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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

Definitions

  • This invention relates to the discovery of new boronic acid derivatives which are inhibitors of
  • thrombin and pharmaceutical compositions thereof.
  • Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which thrombin plays a key role. Blood coagulation may occur through either of two cascades of zymogen activations, the extrinsic and intrinsic pathways of the coagulation cascade. The last protease in each pathway is thrombin, which acts to hydrolyze four small peptides (two FpA and two FpB) from each molecule of fibrinogen, thus
  • the linear fibrin polymers may be cross-linked by factor Xllla, which is itself activated by thrombin.
  • thrombin is a potent activator of platelets, upon which it acts at specific receptors. Thrombin activation of platelets leads to aggregation of the cells and secretion of additional factors that further accelerate the creation of a hemostatic plug. Thrombin also potentiates its own production by the activation of factors V and VIII (see Hemker and Beguin in: Jolles, et. al., "Biology and Pathology of Platelet Vessel Wall Interactions," pp.
  • Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation.
  • Etiological factors such as the presence of
  • Atherosclerotic plaque, phlebitis and septicemia may cause thrombosis, leading to impaired blood flow to the effected tissues and possible serious pathological consequences.
  • heparins are ill-defined mixtures of sulfated polysaccharides that bind to, and thus potentiate the action of antithrombin III.
  • Antithrombin III is a naturally occurring inhibitor of the activated clotting factors IXa, Xa, XIa, thrombin and probably Xlla (see Jaques, Pharmacol . Rev. 1980, 31 , pp. 99-166).
  • the vitamin K antagonists act indirectly by inhibiting the post-ribosomal carboxylations of the vitamin K dependent coagulation factors II, VII, IX and X (see Hirsch, Semin . Thromb . Hemostasis 1986, 12, 1- 11). While effective therapies for the treatment of thrombosis, heparins and vitamin K antagonists have the unfortunate side effects of bleeding and marked
  • Thrombin is a serine protease having trypsin-like specificity for the cleavage of sequence-specific ArgXxx peptide bonds.
  • the cleavage event begins with an attack of the active site serine on the scissile bond of the substrate, resulting in the formation of a tetrahedral intermediate. This is followed by collapse of the tetrahedral intermediate to form an acyl enzyme and release of the amino terminus of the cleaved sequence. Hydrolysis of the acyl enzyme then releases the carboxy terminus.
  • thrombin inhibitors A number of naturally occurring thrombin inhibitors have been reported. These include josumamide A from Theonella sp . (see Fusetani, et.
  • Arylsulfonylarginine amides such as (2R, 4R) - 4-methyl-1- [N 2 - ⁇ (3-methyl-1,2,3,4-tetrahydro-8- quinolinyl)sulfonyl ⁇ -L-arginyl]-2-piperidinecarboxylate have been shown to be effective inhibitors of thrombin (see Okamoto, et. al. Thromb Res . 1976, 8, 77-82,
  • Inhibitor design has benefitted from the knowledge of the mechanism of action and of the peptide sequences which are thought to bind in the catalytic site of thrombin, e.g., -Gly-Val-Arg-Gly- of fibrinogen (see Blomback, et. al., J. Biol . Chem . , 1972, 247, 1496- 512) , Ile-Pro-Arg-Ser- of prothrombin (see Magnussen, et. al., in: Reich, et. al., "Proteases and Biological Control," pp. 123-149 (1975)) and -Val-Pro-Arg-Gly- of factor XIII (see Takagi and Doolittle, Biochemistry 1974, 13, 750-6 and Nakamura, et. al., Biochem .
  • Kettner and Shenvi disclose peptide boronic acid inhibitors of trypsin-like proteases of formula (1)
  • R 1 is a substituted alkyl selected from the group consisting of -(CH 2 ) Z -X, - CH (CH 3 ) - (CH 2 ) 2 -X, -CH 2 -CH (CH 3 )-CH 2 -X, -(CH 2 ) 2 -CH(CH 3 )-X and - (CH 2 ) 2 -CH (C H3 ) -X, wherein
  • W is an N-protecting group
  • Y is a sequence of n amino acids such that the n+1 amino acid peptide Y-Lys or Y-Arg has an affinity for the active site of a trypsin-like protease
  • n is an integer of from 1 to 10 and in which at least one amino acid is an
  • Q 1 and Q 2 are the same or different and are selected from -OH, -COR 1 , -CONR 1 R 2 , -NR 1 R 2 or -OR 3 of Q 1 and Q 2 taken together form a diol residue;
  • R 1 , R 2 and R 3 which may be the same or different, are C 1-10 alkyl, C 6-10 aryl, C 6- l oaralkyl, or phenyl substituted by up to three groups selected from C 1-4 alkyl, halogen and C 1-4 alkoxy;
  • R 4 is hydrogen or C 1-10 alkyl;
  • R 5 is a group -A-X; wherein A is -(CH 2 ) z - in which z is 2, 3, 4 or 5; -CH (CH 3 ) - (CH 2 ) 2 -; -CH 2 -CH(CH 3 )-CH 2 -; - (CH 2 ) 2 -CH (CH 3 ) -;
  • tripeptide thrombin inhibitors comprised of 1- aminoboronic and 1-aminophosphonic acid analogs of 3- methoxy-propylglycine (see Claeson, et. al., US 07- 245428) and pentylglycine (see Cheng, et. al.,
  • boropeptides have been disclosed with utility as a treatment for tumors, viral infections and arthritis (US 4963655A and EP
  • Kleemann, et. al. disclose renin-inhibiting 1-amino boronic acid derivatives of formula (3) A 1 -A 2 -HN-CHR 2 -BXR 3 (YR 4 ) (3) in which A 1 denotes a radical of formulae (4-8).
  • ⁇ l and Y 2 are independently
  • a heteroatom which can be N, S, or O
  • a divalent cyclic boro amide where said chain or ring contains from 2 to 20 carbon atoms
  • ring contains from 2 to 20 carbon atoms
  • aryl is phenyl, naphthyl or biphenyl substituted with one, two or three substituents selected from the group consisting of halo (F, Cl, Br, I), -CN, C1-C10-alkyl, C3-C8- cycloalkyl, C2-C10-alkenyl, C2-C10-alkynyl, methylenedioxy, -R 8 , -OR 8 , -NO 2 , -CF 3 , -S(O) r R 7 , -NR 8 R 9 , -COR 8 , -CO 2 R 8 ' -CONR 8 R 9 , NR 8 COR 9 ;
  • heteroaryl wherein heteroaryl is an
  • substituents are members selected from the group consisting of halo (F, Cl, Br, I) , -CN, C1-C10-alkyl, C3-C8-cycloalkyl, C2-C10-alkenyl, C2-C10-alkynyl, -R 8 , -OR 8 , -NO 2 , -CF 3 , -S(O) r R 7 , -NR 8 R 9 , -COR 8 , -CO 2 R 8 ' -CONR 8 R 9 , NR 8 COR 9 , NRCO 2 R 9 ,
  • R 3 is H, phenyl or C1-C4-alkyl
  • R 4 is H or phenylsulfonyl
  • R 5 and R 6 are hydrogen or when taken together from a six membered aromatic ring optionally substituted with one, two or three substituents selected from the group consisting of halo (F, Cl, Br, I), -CN, C1-C10-alkyl,
  • R 8 and R 9 are independently
  • R 10 and R 11 are independently
  • R 12 is
  • n 0 to 6;
  • n 3 or 4;
  • p 0 to 2;
  • r is 0 to 2;
  • t 1 to 5
  • E is -CO-, -SO 2 -, -CH 2 - or a single bond
  • F is -CO-; and pharmaceutically acceptable salts thereof.
  • Preferred compounds of formula (I) are those compounds wherein R 1 is phenyl and biphenyl containing
  • Trp tryptophan
  • pinanediol boronic acid ester and the pinacol boronic acid ester are abbreviated "-C 10 H 16 " and "-C 6 H 12 " respectively.
  • diols useful for deriving boronic acid esters are 1,2- ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3- butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol.
  • 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 diastereomers are desired, they may be prepared using starting materials with the appropriate stereochemistry, or may be separated from mixtures of undesired stereoisomers by standard
  • the compounds of formula (I) can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being affected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the chemical transformations proposed and this will sometimes require judgment as to the order of synthetic steps or selection of particular process scheme used from that shown below in order to obtain a desired compound of the invention.
  • Scheme 1 Synthesis of Thrombin Inhibitors
  • Reagents a. IBCF, NMM, RCO 2 H, Et 3 N, 0 °C, b. NaN 3 , c. H 2 , Pd(OH) 2 /C, HCl,d. DMAP, aminoiminomethanesulfonic acid, e. phenylboronic acid
  • Amine hydrochloride 1 is readily available via the procedure of Kettner and Shenvi (EP 0293881 A2). There are numerous synthetic methods by which to prepare amide 2, however, competing with amide formation is the cyclization of 1 to afford a complex mixture containing the desired amide and the corresponding N- acylboroproline. Since purification at this stage is unfeasible, choosing the correct method for amide formation is crucial to obtaining 2 in a purity suitable for subsequent synthetic transformations.
  • isobutyl mixed anhydride is generated by dissolving the carboxylic acid component in tetrahydrofuran and adding one equivalent of N-methylmorpholine. The solution is cooled to 0 °C and one equivalent of isobutyl
  • the preferred method for the preparation of azide 3 is by reaction of 2 with sodium azide (1.1 eq) in dimethylformamide at 70 °C for 2 hours.
  • the azide displacement may also be performed prior to amide formation. This is the preferred method in cases where the rate of amide formation is slow relative to the rate of cyclization.
  • Azide 4 is prepared by a modification of the procedure of Kettner and Shenvi (EP 0293881 A2) as shown in Scheme 2.
  • bromide 5 is reacted with sodium azide, followed by homologation to give 6, chloride displacement to afford 7 and acidic hydrolysis to give 4. Amide formation between 4 and the carboxylic acid component then affords 3 directly.
  • Reagents a . NaN 3 b . CHCl 2 Li, ZnCl 2 , c . LiN(TMS) 2 , d. 4M HCl, dioxane
  • Reduction of azide 3 to amine 8 may be accomplished by hydrogenation over precious metal catalysts.
  • the preferred catalyst for this transformation is Pearlman's catalyst (palladium hydroxide on carbon).
  • the amine is typically isolated as the hydrochloride salt. Isolation of 8 as the free base typically results in lowered yields. Salts of 8 which may confer superior physical properties may be preferred over the hydrochloride salt.
  • Formamidination of amine 8 may be accomplished using cyanamide. Due to the low reactivity of amine 8, however, the preferred method for this transformation is reaction with 4-dimethylaminopyridine (DMAP) and
  • Cleavage of pinanediol ester 9 may be accomplished using anhydrous boron trichloride according to the procedure of Matteson and Ray (J. Am . Chem . Soc . 1980, 102, 7588). This method, however, is strongly Lewis acidic and leads to partial destruction of the
  • the preferred method for water soluble boronic acids is a transesterification reaction that is run in the presence of excess phenylboronic acid.
  • the free boronic acid 10 may then be isolated using cation exchange chromatography.
  • the isothiouronium functionalized analogs 11/12 are prepared from bromide 2 according to the procedure of Kettner and Shenvi (EP 0293881 A2).
  • Inhibitors containing a sulfonamide in place of a carboxamide are prepared from either 1 or 4 by reaction with a sulfonyl chloride in the presence of a hindered amine (Scheme 3). The product sulfonamide 13 is then converted to the guanidinium 14 or isothiouronium 15 in the same manner as the corresponding carboxamides.
  • Inhibitors containing the borolysine moiety are prepared analogously to those containing boroarginine according to Kettner and Shenvi (EP 0293881 A2).
  • Novel biaryls synthesized in this invention are prepared through palladium catalyzed coupling of an appropriate arylmetal species to the aryl halide of choice using the methods described in Negishi, et. al., Org. Synth . 1987, 66, 61-14 , and references cited within.
  • Part B ( +) -Pinanediol 4-azido-1 (R) -(4-phenylbenzoyl) aminobutane-1-boronate.
  • (+)- pinanediol 4-azido-1 (R)-(4-phenylbenzoyl)aminobutane-1- boronate (3.04 g, 6.44 mmol) in methanol (30 mL) was added Pearlman' s catalyst Pd(OH) 2 /C, 200 mg) and 1 M hydrochloric acid (6.5 mL, 6.5 mmol).
  • the mixture was placed on a Parr apparatus and hydrogenated at 50 psi for 3 hours.
  • the mixture was filtered using CeliteTM, washed with methanol and the filtrate concentrated in vacuo .
  • the resulting amorphous solid was dissolved in water and washed with ether.
  • the compounds of formula (I) are useful as inhibitors of trypsin-like enzymes, notably human thrombin,
  • these compounds are indicated for use in the prevention or treatment of physiological reactions catalyzed by the aforesaid enzymes such as blood coagulation and inflammation.
  • substrate H-D-Phe-Pip-Arg-pNA (S-2238, Kabi) is cleaved by thrombin, liberating the p-nitroanalide group which absorbs light at 405 nm. Enzyme activity is measured in both the presence and absence of inhibitor. A decrease in absorbance at 405 nm in the presence of inhibitor is indicative of thrombin inhibition.
  • the compounds of formula (I) have anti- thrombogenic properties, they may be employed when an anti-thrombogenic agent is indicated, such as for control of the coagulation or the fibrinolysis system in mammals or they may be added to blood for the purpose of preventing coagulation or the blood due to contact with blood collecting or distribution containers, tubing or apparatus.
  • these compounds may be administered orally or parenterally 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 will be obvious to one skilled in the art. In the case of large mammals such as humans, 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
  • Osol is a standard reference text which discloses suitable pharmaceutical carriers and dosage forms .
  • the disclosure of this text is hereby incorporated by reference for a more complete teaching of suitable dosage forms for administration of the compounds of this invention.

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Abstract

Novel boronic acid derivatives of formula (I), which are useful inhibitors of trypsin-like enzymes, are disclosed: R?1-Z-CHR2-BY1Y2¿.

Description

Title
Boronic Acid and Ester Inhibitors of Thrombin
Field of the Invention
This invention relates to the discovery of new boronic acid derivatives which are inhibitors of
thrombin and pharmaceutical compositions thereof.
Background of the Invention
Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which thrombin plays a key role. Blood coagulation may occur through either of two cascades of zymogen activations, the extrinsic and intrinsic pathways of the coagulation cascade. The last protease in each pathway is thrombin, which acts to hydrolyze four small peptides (two FpA and two FpB) from each molecule of fibrinogen, thus
deprotecting its polymerization sites. Once formed, the linear fibrin polymers may be cross-linked by factor Xllla, which is itself activated by thrombin. In addition, thrombin is a potent activator of platelets, upon which it acts at specific receptors. Thrombin activation of platelets leads to aggregation of the cells and secretion of additional factors that further accelerate the creation of a hemostatic plug. Thrombin also potentiates its own production by the activation of factors V and VIII (see Hemker and Beguin in: Jolles, et. al., "Biology and Pathology of Platelet Vessel Wall Interactions," pp. 219-26 (1986), Crawford and Scrutton in: Bloom and Thomas, "Haemostasis and Thrombosis," pp. .47-77, (1987), Bevers, et. al., Eur. J. Biochem . 1982, 122, 429-36, Mann, Trends Biochem . Sci . 1987, 12, 229- 33).
Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation. Etiological factors such as the presence of
atherosclerotic plaque, phlebitis and septicemia may cause thrombosis, leading to impaired blood flow to the effected tissues and possible serious pathological consequences.
Currently, two of the most effective classes of drugs in clinical use as anticoagulants are the heparins and the vitamin K antagonists. The heparins are ill-defined mixtures of sulfated polysaccharides that bind to, and thus potentiate the action of antithrombin III.
Antithrombin III is a naturally occurring inhibitor of the activated clotting factors IXa, Xa, XIa, thrombin and probably Xlla (see Jaques, Pharmacol . Rev. 1980, 31 , pp. 99-166). The vitamin K antagonists, of which warfarin is the most well-known example, act indirectly by inhibiting the post-ribosomal carboxylations of the vitamin K dependent coagulation factors II, VII, IX and X (see Hirsch, Semin . Thromb . Hemostasis 1986, 12, 1- 11). While effective therapies for the treatment of thrombosis, heparins and vitamin K antagonists have the unfortunate side effects of bleeding and marked
interpatient variability, resulting in a small and unpredictable therapeutic safety margin. The use of direct acting thrombin inhibitors is expected to
alleviate these problems.
Thrombin is a serine protease having trypsin-like specificity for the cleavage of sequence-specific ArgXxx peptide bonds. As with other serine proteases, the cleavage event begins with an attack of the active site serine on the scissile bond of the substrate, resulting in the formation of a tetrahedral intermediate. This is followed by collapse of the tetrahedral intermediate to form an acyl enzyme and release of the amino terminus of the cleaved sequence. Hydrolysis of the acyl enzyme then releases the carboxy terminus. A number of naturally occurring thrombin inhibitors have been reported. These include nazumamide A from Theonella sp . (see Fusetani, et. al., Tetrahedron Lett . 1991, 32, 7073-4), cyclotheonamide A from Theonella sp . (see Fusetani, et. al., J. Am. Chem . Soc . 1990, 112, 7053-4), amblyommin from Amblyomma hebraeum (see Bonin, et. al., EP 345614), hirudin from Hirudo medicinalis, recombinant versions of hirudin and hirudin fragments (see Rigbl and Jackson, EP 352903, Koerwer, WO 9109946, Meyer, et. al., WO 9108233, Dawson, et. al., WO 9109125, Maraganore, et. al., WO 9102750 and Maraganore, EP
333356).
Synthetic thrombin inhibitors have also been
disclosed. Arylsulfonylarginine amides such as (2R, 4R) - 4-methyl-1- [N2- {(3-methyl-1,2,3,4-tetrahydro-8- quinolinyl)sulfonyl}-L-arginyl]-2-piperidinecarboxylate have been shown to be effective inhibitors of thrombin (see Okamoto, et. al. Thromb Res . 1976, 8, 77-82,
Ohshiro, et. al., Blood Vessel 1983, 14, 216-8), as have compounds containing constrained arginine mimics such as (2-naphthylsulfonylglycyl)-4-amidino- phenylalanyl piperidide (see Stuerzebecher, et. al., Thromb . Res . 1983, 29, 635-42), 1-[2-[5- (dimethylamino)naphth-1-ylsulfonamido]-3-(2- iminohexahydropyrimidin-5-yl)propanoyl]-4- methylpiperidine dihydrochloride (see Ishikawa, JP
88227572 and Ishikawa and Inamura, JP 88227573) , N- (trans-4-amino-methylcyclohexylcarbonyl)-4-0-(2- picolyl)-L-tyrosine 4-acetanilide dihydrochloride (see Okamoto, et. al., EP 217286) and 4- [(aminoiminomethyl)amino] benzoic acid esters (see Fuji, et. al., DE 3005580, Matsuoka, et. al., Jpn . J.
Pharmacol . 1989, 51 , 455-63, and Takeshita, et. al., EP 435235).
Inhibitor design has benefitted from the knowledge of the mechanism of action and of the peptide sequences which are thought to bind in the catalytic site of thrombin, e.g., -Gly-Val-Arg-Gly- of fibrinogen (see Blomback, et. al., J. Biol . Chem . , 1972, 247, 1496- 512) , Ile-Pro-Arg-Ser- of prothrombin (see Magnussen, et. al., in: Reich, et. al., "Proteases and Biological Control," pp. 123-149 (1975)) and -Val-Pro-Arg-Gly- of factor XIII (see Takagi and Doolittle, Biochemistry 1974, 13, 750-6 and Nakamura, et. al., Biochem .
Biophys . Res . Commun . 1974, 58, 250-256). This class of mechanism-based inhibitors are exemplified by the tripeptide aldehyde D-Phe-Pro-N-Me-Arg-H (see Bajusz, et. al., J. Med . Chem. 1990, 33, 1729-35), the
chloromethyl ketone Ac-(D)-Phe-Pro-ArgCH2Cl (see Kettner and Shaw, Thromb . Res . 1979, 14, 969-73) and the trifluoromethyl ketone D-Phe-Pro-ArgCF3 (see Kolb, et. al., US 697987).
Kettner and Shenvi (EP 293881, published June 12, 1988) , disclose peptide boronic acid inhibitors of trypsin-like proteases of formula (1)
R1-[(A3)q(A2)p(A1)o]n-ΝH-CHR2-BY1Y2 (1) wherein Y1 and Y2, independently, are hydroxyl or fluoro or, taken together, form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising 1 to about 20 carbon atoms and, optionally, a heteroatom which can be N, S, or 0; R2 is a substituted alkyl selected from the group consisting of -(CH2)Z-X, - CH (CH3) - (CH2) 2-X, -CH2-CH (CH3)-CH2-X, -(CH2)2-CH(CH3)-X and - (CH2) 2-CH (CH3) -X, where X is -NH2, -NH-C (NH)-NH2 or -S-C (NH)-NH2, and z is 3 to 5; n, o, p and q are, independently, either 0 or 1; A1, A2 and A3 are, independently, amino acids of L- or D-configuration selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, lle, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val; and R1 is a peptide comprised of 1 to about 20 amino acids, an acyl or a sulfonyl group comprised of 1 to about 20 carbon atoms, H, or an N-terminal protecting group. In this disclosure, Kettner and Shenvi demonstrated that the pinanediol esters of boropeptides are
pharmacologically equivalent to the corresponding boronic acids.
Metternich (EP 0471651 A2) discloses borolysine thrombin inhibitors of formula (2)
W-Y-NR4-CHR5-BQ1Q2 (2) wherein W is an N-protecting group; Y is a sequence of n amino acids such that the n+1 amino acid peptide Y-Lys or Y-Arg has an affinity for the active site of a trypsin-like protease; where n is an integer of from 1 to 10 and in which at least one amino acid is an
unnatural amino acid having a hydrophobic side chain; Q1 and Q2 are the same or different and are selected from -OH, -COR1, -CONR1R2, -NR1R2 or -OR3 of Q1 and Q2 taken together form a diol residue; R1, R2 and R3 which may be the same or different, are C1-10alkyl, C6-10aryl, C6- loaralkyl, or phenyl substituted by up to three groups selected from C1-4alkyl, halogen and C1-4alkoxy; R4 is hydrogen or C1-10alkyl; R5 is a group -A-X; wherein A is -(CH2)z- in which z is 2, 3, 4 or 5; -CH (CH3) - (CH2)2-; -CH2-CH(CH3)-CH2-; - (CH2) 2-CH (CH3) -; - (CH2) 2-C (CH3) 2-; CH(CH3)-(CH2)3-; -CH2-CH (CH3) - (CH2) 2-; -CH2-CH2-CH (CH3)- CH2-; -(CH2)3-CH(CH3)-; - (CH2) 3-C (CH3)2 : C6-10aryl C6- 10aralkyl and X is -NH2, -NH-C (NH) -NH2, -S-C (NH) -NH2, -N3, -C1-4alkoxy, C1-4alkylthio or Si(CH3)3 or R4 and R5 taken together form a trimethylene group and the asymmetric carbon atom may have the D- or L-configuration or represent any mixture of these.
Surprising for their lack of a basic residue at P1 are tripeptide thrombin inhibitors comprised of 1- aminoboronic and 1-aminophosphonic acid analogs of 3- methoxy-propylglycine (see Claeson, et. al., US 07- 245428) and pentylglycine (see Cheng, et. al.,
"Symposium on Thrombosis and Hemostasis," 1991,
Amsterdam, Abstract 2150).
In addition to thrombin inhibition, boropeptides have been disclosed with utility as a treatment for tumors, viral infections and arthritis (US 4963655A and EP
354522A) , emphysema (US 4499082A) , hypertension (EP 315574A) and as factor VII/Vila inhibitors (WO
8909612A). Kleemann, et. al. (AU A-24693/88) disclose renin-inhibiting 1-amino boronic acid derivatives of formula (3) A1-A2-HN-CHR2-BXR3(YR4) (3) in which A1 denotes a radical of formulae (4-8).
R1NR6-CHR5-CO- (4) R1CHR12-CHR5-CO- (5)
R1NR6-CHR5-CHR7-CHR8-CHR9-CO- (6)
R1CHR12-CHR5-CHR7-CHR8-CHR9-CO- (7)
R10-(CH2)n-CH(CH2)mR11-CO- (8) Despite the foregoing, more efficacious and specific thrombin inhibitors are needed as potentially valuable therapeutic agents for the treatment of thrombosis.
None of the cited references describe or suggest the new thrombin-inhibiting boronic acid derivatives of the present invention. Summary of Invention
The present invention pertains to novel compounds of formula (I):
R1-Z-CHR2-BY1Y2
(I)
wherein
γl and Y2 are independently
a) -OH,
b) -F,
c) -NR3R4, or
d) C1-C8-alkoxy;
Y1 and Y2 when taken together can form
a) a cyclic boron ester where said chain or ring
contains from 2 to 20 carbon atoms and,
optionally, a heteroatom which can be N, S, or O, b) a divalent cyclic boro amide where said chain or ring contains from 2 to 20 carbon atoms,
c) a cyclic boro amide-ester where said chain or
ring contains from 2 to 20 carbon atoms;
Z is
a) -(CH2)mCONR8-,
b) -(CH2)mCSNR8-,
c) -(CH2)mSO2NR8-,
d) -(CH2)mCO2-,
e) -(CH2)mC(S)O-, or
f) -(CH2)mSO2O-;
R1 is
a) -(CH2)p-aryl, wherein aryl is phenyl, naphthyl or biphenyl substituted with one, two or three substituents selected from the group consisting of halo (F, Cl, Br, I), -CN, C1-C10-alkyl, C3-C8- cycloalkyl, C2-C10-alkenyl, C2-C10-alkynyl, methylenedioxy, -R8, -OR8, -NO2, -CF3, -S(O)rR7, -NR8R9 , -COR8 , -CO2R8 ' -CONR8R9 , NR8COR9 ;
Figure imgf000010_0002
b) heteroaryl, wherein heteroaryl is an
unsubstituted, monosubstituted or disubstituted; i) 5- or 6-membered aromatic ring, which
contains from 1 to 3 heteroatoms selected from the group consisting of O, N, and S, ii) quinolinyl,
iii) isoquinolinyl,
iv) benzopyranyl,
v) benzothiophenyl,
vi) benzofuranyl,
vii) 5,6,7,8-tetrahydroquinolinyl
viii) 5,6,7,8-tetrahydroisoquinolinyl and wherein the substituents are members selected from the group consisting of halo (F, Cl, Br, I) , -CN, C1-C10-alkyl, C3-C8-cycloalkyl, C2-C10-alkenyl, C2-C10-alkynyl, -R8, -OR8, -NO2, -CF3, -S(O)rR7, -NR8R9, -COR8, -CO2R8' -CONR8R9, NR8COR9, NRCO2R9,
Figure imgf000010_0001
Figure imgf000011_0001
R2 is
a) -(CH2)n-NHC (NH)NH2, b) -(CH2)n-NHC (NH)NHCOCH3, c) -(CH2)n-SC(NH)NH2,
d) -(CH2)n-SC(NH)NHCOCH3,
e) -(CH2)n-NH2, or
f) -(CH2)n-NH(2-pyridyl);
R3 is H, phenyl or C1-C4-alkyl;
R4 is H or phenylsulfonyl;
R5 and R6 are hydrogen or when taken together from a six membered aromatic ring optionally substituted with one, two or three substituents selected from the group consisting of halo (F, Cl, Br, I), -CN, C1-C10-alkyl,
C3-C8-cycloalkyl, C2-C10-alkenyl, C2-C10-alkynyl, -OR8, -NO2, -CF3, -S(O)rR7, -NR8R9, -COR8, -CO2R8' -CONR8R9' phenyl, benzyl, phenylethyl'
R7 is
a) phenyl,
b) C1-C4-alkyl,
c) C1-C4-alkoxy, or
d) -CF3;
R8 and R9 are independently
a) H,
b)
Figure imgf000012_0001
c) C3-C7-cycloalkyl,
d) C1-C8-alkyl;
R10 and R11 are independently
a) halo (F, Cl, Br, I),
b) -CN,
c) C1-C10-alkyl,
d) C3-C8-cycloalkyl,
e) C2-C10-alkenyl,
f) C2-C10-alkynyl,
g) -OR8, h) -NO2,
i) -CF3,
j) -S(O)rR7,
k) -NR8R9,
l) -COR9,
m) -CO2R8
n) -CONR8R9''
R12 is
a) H,
b) C1-C4-alkyl,
c) phenyl,
d) benzyl
e) -COR7
f) -SO2R7
m is 0 to 6;
n is 3 or 4;
p is 0 to 2;
r is 0 to 2;
t is 1 to 5
E is -CO-, -SO2-, -CH2- or a single bond,
F is -CO-; and pharmaceutically acceptable salts thereof.
Preferred compounds of formula (I) are those compounds wherein R1 is phenyl and biphenyl containing
1-3 substituents selected from the series halo (F, Cl,
Br, I), C1-C10-alkyl, C3-C8-cycloalkyl, C2-C10-alkenyl,
C2-C10-alkynyl, -R8, -OR8, -NO2, -CF3, -S(O)rR7, -NR8R9,
-COR8, -CO2R8' -CONR8R9; NR8COR9;
R2 is
a) -(CH2)3-NHC(NH)NH2, or
b) -(CH2)3-SC(NH)NH2.
More preferred are those preferred compounds wherein Z is -(CH2)mCONR8-. Most preferred are those more preferred compounds listed below:
N1-(4-phenylbenzoyl)-(R)-boroarginine, hydrochloride N1-(3-phenoxybenzoyl)-(R)-boroarginine, hydrochloride N1-(1-fluorenonyl)-(R)-boroarginine, hydrochloride
N1-(4-[1-butyl]benzoyl)-(R)-boroarginine, hydrochloride N1-(2-benzoylbenzoyl)-(R)-boroarginine, hydrochloride N1-(5-phenyl-2-furoyl)-(R)-boroarginine, hydrochloride N1-(3-[N-benzyloxycarbonyl-N-methylamino]-4-[1-butyl]- benzoyl)-(R)-boroarginine, hydrochloride
N1-(2-phenyl-4-isoquinolyl)-(R)-boroarginine,
hydrochloride
N1-(4-cyclohexylbenzoyl)-(R)-boroarginine,
hydrochloride
N1-(2-methyl-4-phenylbenzoyl)-(R)-boroarginine,
hydrochloride
Illustrative of the compounds of this invention are the following:
N1-(4-phenylbenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(3-phenylbenzoyl)-(R)-b)roarginine (+)-pinanediol, bisulfite
N1-(3-phenoxybenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(4-[4-pyridyl]benzoyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-(2-benzoylbenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(3-benzoylbenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(4-benzoylbenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite N1-(3-[N-benzyloxycarbonyl ] aminobenzoyl )-(R) - boroarginine (+)-pinanediol, bisulfite
N1-(3-[N-benzyloxycarbonyl-N-methyl ]aminobenzoyl)-(R) - boroarginine (+)-pinanediol, bisulfite
N1-(4-ethylbenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(4-n-propylbenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(4-isopropylbenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(4-n-butylbenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(4-tert-butylbenzoyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-(4-n-hexylbenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(4-cyclohexylbenzoyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-(2-[N-(2-phenylethyl)carbonyl]aminobenzoyl)-(R) - boroarginine (+)-pinanediol, bisulfite
N1-(4-n-butyloxybenzoyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-(4-[N-cyclopropylcarbonyl ]aminobenzoyl)-(R) - boroarginine (+)-pinanediol, bisulfite
N1-(4-[N-cyclohexylcarbonyl]aminobenzoyl)-(R) - boroarginine (+)-pinanediol, bisulfite
N1-(4-[N-(4-methoxy)benzoyl]aminobenzoyl)-(R) - boroarginine (+)-pinanediol, bisulfite
N1-(4-[4-methoxy]phenylbenzoyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1- (2-[2-phenyl]benzyloxycarbonylbenzoyl)-(R) - boroarginine (+)-pinanediol, bisulfite
N1- (2-[1-naphthyl]benzoyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-(4-[4-carboxy]phenylbenzoyl)-(R)-boroarginine (+)- pinanediol, bisulfite N1-(4-phenylbenzoyl)-(R)-borothioarginine (+) - pinanediol, hydrobromide
N1-(3-phenylbenzoyl)-(R)-borothioarginine (+) - pinanediol, hydrobromide
N1-(3-phenoxybenzoyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(2-benzoylbenzoyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(3-benzoylbenzoyl)-(R)-borothioarginine ( +) - pinanediol, hydrobromide
N1-(4-benzoylbenzoyl)-(R)-borothioarginine ( +) - pinanediol, hydrobromide
N1-(3-[N-benzyloxycarbonyl ]aminobenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(3-[N-benzyloxycarbonyl-N-methyl ]aminobenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(4-ethylbenzoyl)-(R)-borothioarginine (+)-pinanediol, hydrobromide
N1-(4-n-propylbenzoyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(4-isopropylbenzoyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(4-n-butylbenzoyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(4-tert-butylbenzoyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(4-n-hexylbenzoyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(4-cyclohexylbenzoyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(2-[N-(2-phenylethyl)carbonyl]aminobenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(4-n-butyloxybenzoyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(4-[N-cyclopropylcarbonyl ]aminobenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide N1-(4-[N-cyclohexylcarbonyl ]aminobenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(4-[N-(4-methoxy)benzoyl]aminobenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(4-[4-methoxy]phenylbenzoyl)-(R)-borothioarginine
(+)-pinanediol, hydrobromide
N1-(2-[2-phenylbenzyloxycarbonyl]benzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(2-[1-naphthyl]benzoyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(4-[4-carboxy]phenylbenzoyl)-(R)-borothioarginine
(+)-pinanediol, hydrobromide
N1-([2-anthraquinonyl]carbonyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-([2-dioxothioxanthinonyl]carbonyl)-(R)-boroarginine
(+)-pinanediol, bisulfite
N1-([2-anthraquinony1]carbonyl)-(R)-borothioarginine
(+)-pinanediol, hydrobromide
N1-([2-dioxothioxanthinonyl]carbonyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-([2-fluoren-9-onyl]carbonyl)-(R)-borothiohomoarginine
(+)-pinanediol, hydrobromide
N1-([2-fluoren-9-onyl]carbonyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-([2-fluoren-9-onyl]carbonyl)-(R)-borothioarginine
(+)-pinanediol, hydrobromide
N1-([3-fluoren-9-onyl]carbonyl)-(R)-borothioarginine
(+)-pinanediol, hydrobromide
N1-([3-fluoren-9-onyl]carbonyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-([4-fluoren-9-onyl]carbonyl)-(R)-borothioarginine
(+)-pinanediol, hydrobromide
N1-([4-fluoren-9-onyl]carbonyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-(1-naphthoyl)-(R)-borothioarginine (+)-pinanediol, hydrobromide N1-(1-naphthoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(2-methyl-4-phenyl-5-methoxybenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(2-methyl-4-phenyl-5-carboxamidobenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(2-methyl-4-phenyl-5-fluorobenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(2-methyl-4-phenyl-5-trifluoromethylbenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(2-methyl-4-phenyl-5-chlorobenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(2-methyl-4-phenyl-5-hydroxybenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(2-methyl-4-[4-carboxy]phenyl-5-methoxybenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(2-methyl-4-[4-carboxy]phenyl-5-carboxamidobenzoyl)- (R)-borothioarginine (+)-pinanediol, hydrobromide N1-(2-methyl-4-[4-carboxy]phenyl-5-fluorobenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(2-methyl-4-[4-carboxy]phenyl-5- trifluoromethylbenzoyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(2-methyl-4-[4-carboxy]phenyl-5-chlorobenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(2-methyl-4-[4-carboxy]phenyl-5-hydroxybenzoyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(2-methyl-4-phenyl-5-methoxybenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(2-methyl-4-phenyl-5-carboxamidobenzoyl)-(R)- boroarginine (+)-pinanediol, bisulfite
N1-(2-methyl-4-phenyl-5-fluorobenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(2-methyl-4-phenyl-5-trifluoromethylbenzoyl)-(R)- boroarginine (+)-pinanediol, bisulfite N1-(2-methyl-4-phenyl-5-chlorobenzoyl)-(R)-boroarginine (+) -pinanediol, bisulfite
N1-(2-methyl-4-phenyl-5-hydroxybenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(2-methyl-4-[4-carboxy]phenyl-5-methoxybenzoyl)-(R)- boroarginine ( +)-pinanediol, bisulfite
N1-(2-methyl-4-[4-carboxy]phenyl-5-carboxamidobenzoyl)- (R)-boroarginine (+)-pinanediol, bisulfite
N1-(2-methyl-4-[4-carboxy]phenyl-5-fluorobenzoyl)-(R)- boroarginine (+)-pinanediol, bisulfite
N1-(2-methyl-4-[4-carboxy]phenyl-5- trifluoromethylbenzoyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(2-methyl-4-[4-carboxy]phenyl-5-chlorobenzoyl)-(R)- boroarginine (+)-pinanediol, bisulfite
N1-(2-methyl-4-[4-carboxy]phenyl-5-hydroxybenzoyl)-(R)- boroarginine (+)-pinanediol, bisulfite
N1-(2-[5-phenyl]furylcarbonyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-(2-[5-phenyl]thiophenylcarbonyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(2-[5-phenyl]furylcarbonyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(2-[5-phenyl]thiophen-ylcarbonyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(3-[6-phenyl]pyridylcarbonyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-(3-[5-benzyloxy]pyridylcarbonyl)-(R)-boroarginine
(+)-pinanediol, bisulfite
N1-(3-[6-phenyl]pyridylcarbonyl)-(R)-borothioarginine
(+)-pinanediol, hydrobromide
N1-(3-[5-benzyloxy]pyridylcarbonyl)-(R)-borothioarginine
(+)-pinanediol, hydrobromide
N1-(2-benzopyronylcarbonyl)-(R)-boroarginine (+)- pinanediol, bisulfite N1-(2-benzopyronylcarbonyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(3-isoquinolinylcarbonyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-(2-phenyl-4-isoquinolinylcarbonyl)-(R)-boroarginine (+)-pinanediol, bisulfite
N1-(3-isoquinolinylcarbonyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(2-phenyl-4-isoquinolinylcarbonyl)-(R)- borothioarginine (+)-pinanediol, hydrobromide
N1-(2-isoquinolinylcarbonyl)-(R)-boroarginine (+)- pinanediol, bisulfite
N1-(2-isoquinolinylcarbonyl)-(R)-borothioarginine (+)- pinanediol, hydrobromide
N1-(4-p-enylbenzoyl)-(R)-boroarginine, hydrochloride
N1-(3-phenylbenzoy1)-(R)-boroarginine, hydrochloride
N1-(3-phenoxybenzoyl)-(R)-boroarginine, hydrochloride
N1-(4-[4-pyridyl]benzoyl)-(R)-boroarginine,
hydrochloride
N1-(2-benzoylbenzoyl)-(R)-boroarginine, hydrochloride
N1-(3-benzoylbenzoyl)-(R)-boroarginine, hydrochloride N1-(4-benzoylbenzoyl)-(R)-boroarginine, hydrochloride
N1-(3-[N-benzyloxycarbonyl]aminobenzoyl)-(R)- boroarginine, hydrochloride
N1-(3-[N-benzyloxycarbonyl-N-methyl ]aminobenzoyl)-(R)- boroarginine, hydrochloride
N1-(4-ethylbenzoyl)-(R)-boroarginine, hydrochloride
N1-(4-n-propylbenzoyl)-(R)-boroarginine, hydrochloride
N1-(4-isopropylbenzoyl)-(R)-boroarginine, hydrochloride N1-(4-tert-butylbenzoyl)-(R)-boroarginine,
hydrochloride
N1-(4-n-hexylbenzoyl)-(R)-boroarginine, hydrochloride
N1-(4-cyclohexylbenzoyl)-(R)-boroarginine,
hydrochloride
N1-(2-[N-(2-phenylethyl)carbonyl]aminobenzoyl)-(R)- boroarginine, hydrochloride N1-(4-n-butyloxybenzoyl)-(R)-boroarginine,
hydrochloride
N1-(4-[N-cyclopropylcarbonyl]aminobenzoyl)-(R)- boroarginine, hydrochloride
N1-(4-[N-cyclohexylcarbonyl ]aminobenzoyl)-(R)- boroarginine, hydrochloride
N1-(4-[N-(4-methoxy)benzoyl]aminobenzoyl)-(R)- boroarginine, hydrochloride
N1-(4-[4-methoxy]phenylbenzoyl)-(R)-boroarginine, hydrochloride
N1-(2-[2-phenyl]benzyloxycarbonylbenzoyl)-(R)- boroarginine, hydrochloride
N1- (2-[1-naphthyl]benzoyl)-(R)-boroarginine,
hydrochloride
N1-(4-[4-carboxy]phenylbenzoyl)-(R)-boroarginine, hydrochloride
N1-([2-anthraquinonyl]carbonyl)-(R)-boroarginine, hydrochloride
N1-([2-dioxothioxanthinonyl]carbonyl)-(R)-boroarginine, hydrochloride
N1-([2-fluoren-9-onyl]carbonyl)-(R)-boroarginine, hydrochloride
N1-([3-fluoren-9-onyl]carbonyl)-(R)-boroarginine, hydrochloride
N1-(1-naphthoyl)-(R)-boroarginine, hydrochloride
N1-([4-fluoren-9-onyl]carbonyl)-(R)-boroarginine, hydrochloride
N1-(2-methyl-4-phenyl-5-methoxybenzoyl)-(R)- boroarginine, hydrochloride
N1-(2-methyl-4-phenyl-5-carboxamidobenzoyl)-(R)- boroarginine, hydrochloride
N1-(2-methyl-4-phenyl-5-fluorobenzoyl)-(R)-boroarginine, hydrochloride
N1-(2-methyl-4-phenyl-5-trifluoromethylbenzoyl)-(R)- boroarginine, hydrochloride N1-(2-methyl-4-phenyl-5-chlorobenzoyl)-(R)-boroarginine, hydrochloride
N1-(2-methyl-4-phenyl-5-hydroxybenzoyl)-(R)- boroarginine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-methoxybenzoyl)-(R) - boroarginine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-carboxamidobenzoyl)- (R)-boroarginine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-fluorobenzoyl)-(R)- boroarginine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5- trifluoromethylbenzoyl)-(R)-boroarginine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-chlorobenzoyl)-(R)- boroarginine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-hydroxybenzoyl)-(R)- boroarginine, hydrochloride
N1-(2-[5-phenyl]furylcarbonyl)-(R)-boroarginine, hydrochloride
N1-(2-[5-phenyl]thiophenylcarbonyl)-(R)-boroarginine, hydrochloride
N1-(2-benzopyronylcarbonyl)-(R)-boroarginine,
hydrochloride
N1-(2-isoquinolinylcarbonyl)-(R)-boroarginine,
hydrochloride
N1-(3-isoquinolinylcarbonyl)-(R)-boroarginine,
hydrochloride
N1-(2-phenyl-4-isoquinolinylcarbonyl)-(R)-boroarginine, hydrochloride
N1-(4-phenylbenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(3-phenylbenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(3-phenoxybenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(2-benzoylbenzoyl)-(R)-borothioarginine,
hydrochloride N1-(3-benzoylbenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(4-benzoylbenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(3-[N-benzyloxycarbonyl ]aminobenzoyl)-(R)- borothioarginine, hydrochloride
N1-(3-[N-benzyloxycarbonyl-N-methyl ]aminobenzoyl)-(R)- borothioarginine, hydrochloride
N1-(4-ethylbenzoyl)-(R)-borothioarginine, hydrochloride N1-(4-n-propylbenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(4-isopropylbenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(4-n-butylbenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(4-te.rt-butylbenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(4-n-hexylbenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(4-cyclohexylbenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(2-[N-(2-phenylethyl)carbonyl]aminobenzoyl)-(R)- borothioarginine, hydrochloride
N1-(4-n-butyloxybenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(4-[N-cyclopropylcarbonyl]aminobenzoyl)-(R)- borothioarginine, hydrochloride
N1-(4-[N-cyclohexylcarbonyl]aminobenzoyl)-(R)- borothioarginine, hydrochloride
N1-(4-[N-(4-methoxy)benzoyl]aminobenzoyl)-(R)- borothioarginine, hydrochloride
N1-(4-[4-methoxy]phenylbenzoyl)-(R)-borothioarginine, hydrochloride
N1-(2-[2-phenylbenzyloxycarbonyl]benzoyl)-(R)- borothioarginine, hydrochloride N1-(2-[1-naphthyl]benzoyl)-(R)-borothioarginine, hydrochloride
N1-(4-[4-carboxy]phenylbenzoyl)-(R)-borothioarginine, hydrochloride
N1-([2-anthraquinonyl]carbonyl)-(R)-borothioarginine, hydrochloride
N1-([2-dioxothioxanthinonyl]carbonyl)-(R)- borothioarginine, hydrochloride
N1-([2-fluoren-9-onyl]carbonyl)-(R)- borothiohomoarginine, hydrochloride
N1-([2-fluoren-9-onyl]carbonyl)-(R)-borothioarginine, hydrochloride
N1-([3-fluoren-9-onyl]carbonyl)-(R)-borothioarginine, hydrochloride
N1-([4-fluoren-9-onyl]carbonyl)-(R)-borothioarginine, hydrochloride
N1-(1-naphthoyl)-(R)-borothioarginine, hydrochloride
N1-(2-methyl-4-phenyl-5-methoxybenzoyl)-(R)- borothioarginine, hydrochloride
N1-(2-methyl-4-phenyl-5-carboxamidobenzoyl)-(R)- borothioarginine, hydrochloride
N1-(2-methyl-4-phenyl-5-fluorobenzoyl)-(R)- borothioarginine, hydrochloride
N1-(2-methyl-4-phenyl-5-trifluoromethylbenzoyl)-(R)- borothioarginine, hydrochloride
N1-(2-methyl-4-phenyl-5-chlorobenzoyl)-(R)- borothioarginine, hydrochloride
N1-(2-methyl-4-phenyl-5-hydroxybenzoyl)-(R)- borothioarginine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-methoxybenzoyl)-(R)- borothioarginine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-carboxamidobenzoyl)-
(R)-borothioarginine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-fluorobenzoyl)-(R)- borothioarginine, hydrochloride N1- (2-methyl-4-[4-carboxy]phenyl-5- trifluoromethylbenzoyl)-(R)-borothioarginine,
hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-chlorobenzoyl)-(R)- borothioarginine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-hydroxybenzoyl)-(R)- borothioarginine, hydrochloride
N1-(2-[5-phenyl]furylcarbonyl)-(R)-borothioarginine, hydrochloride
N1-(2-[5-phenyl]thiophenylcarbonyl)-(R)- borothioarginine, hydrochloride
N1-(3-[6-phenyl]pyridylcarbonyl)-(R)-boroarginine, hydrochloride
N1-(3-[5-benzyloxy]pyridylcarbonyl)-(R)-boroarginine, hydrochloride
N1-(3-[6-phenyl]pyridylcarbonyl)-(R)-borothioarginine, hydrochloride
N1-(3-[5-benzyloxy]pyridylcarbonyl)-(R)- borothioarginine, hydrochloride
N1-(2-benzopyronylcarbonyl)-(R)-borothioarginine, hydrochloride
N1-(3-isoquinolinylcarbonyl)-(R)-borothioarginine, hydrochloride
N1-(2-phenyl-4-isoquinolinylcarbonyl)-(R)- borothioarginine, hydrochloride
N1-(2-isoquinolinylcarbonyl)-(R)-borothioarginine, hydrochloride
N1-(4-phenylbenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(3-phenylbenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(3-phenoxybenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(4-[4-pyridyl]benzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride N1-(2-benzoylbenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(3-benzoylbenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(4-benzoylbenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(3-[N-benzyloxycarbonyl]aminobenzoyl)-(R)-borolysine
(+)-pinanediol, hydrochloride
N1-(3-[N-benzyloxycarbonyl-N-methyl ]aminobenzoyl)-(R)- borolysine (+)-pinanediol, hydrochloride
N1-(4-ethylbenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(4-n-propylbenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(4-isopropylbenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(4-tert-butylbenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(4-n-hexylbenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(4-cyclohexylbenzoyl)-(R)-borolysine ( +) -pinanediol, hydrochloride
N1- (2- [N-(2-phenylethyl)carbonyl]aminobenzoyl)-(R)- borolysine (+)-pinanediol, hydrochloride
N1-(4-n-butyloxybenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(4-[N-cyclopropylcarbonyl]aminobenzoyl)-(R)- borolysine (+)-pinanediol, hydrochloride
N1-(4-[N-cyclohexylcarbonyl ]aminobenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(4-[N-(4-methoxy)benzoyl]aminobenzoyl)-(R)-borolysine
(+)-pinanediol, hydrochloride
N1-(4-[4-methoxy]phenylbenzoyl)-(R)-borolysine (+)- pinanediol, hydrochloride
N1-(2-[2-phenyl]benzyloxycarbonylbenzoyl)-(R)-borolysine
(+)-pinanediol, hydrochloride N1-(2-[1-naphthyl]benzoyl)-(R)-borolysine (+)- pinanediol, hydrochloride
N1-(4-[4-carboxy]phenylbenzoyl)-(R)-borolysine (+)- pinanediol, hydrochloride
N1-([2-anthraquinonyl]carbonyl)-(R)-borolysine (+)- pinanediol, hydrochloride
N1-([2-dioxothioxanthinonyl]carbonyl)-(R)-borolysine
(+)-pinanediol, hydrochloride
N1-([2-fluoren-9-onyl]carbonyl)-(R)-borolysine (+)- pinanediol, hydrochloride
N1-([3-fluoren-9-onyl]carbonyl)-(R)-borolysine (+)- pinanediol, hydrochloride
N1-(1-naphthoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-([4-fluoren-9-onyl]carbonyl)-(R)-borolysine (+)- pinanediol, hydrochloride
N1-(2-methyl-4-phenyl-5-methoxybenzoyl)-(R)-borolysine
(+)-pinanediol, hydrochloride
N1-(2-methyl-4-phenyl-5-carboxamidobenzoyl)-(R)- borolysine (+)-pinanediol, hydrochloride
N1-(2-methyl-4-phenyl-5-fluorobenzoyl)-(R)-borolysine
(+)-pinanediol, hydrochloride
N1-(2-methyl-4-phenyl-5-trifluoromethylbenzoyl)-(R)- borolysine (+)-pinanediol, hydrochloride
N1-(2-methyl-4-phenyl-5-chlorobenzoyl)-(R)-borolysine
(+)-pinanediol, hydrochloride
N1-(2-methyl-4-phenyl-5-hydroxybenzoyl)-(R)-borolysine
(+)-pinanediol, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-methoxybenzoyl)-(R)- borolysine (+)-pinanediol, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-carboxamidobenzoyl)-
(R)-borolysine (+)-pinanediol, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-fluorobenzoyl)-(R)- borolysine (+)-pinanediol, hydrochloride N1-(2-methyl-4-[4-carboxy]phenyl-5- trifluoromethylbenzoyl)-(R)-borolysine (+)-pinanediol, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-chlorobenzoyl)-(R)- borolysine (+)-pinanediol, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-hydroxybenzoyl)-(R)- borolysine (+)-pinanediol, hydrochloride
N1-(2-[5-phenyl]furylcarbonyl)-(R)-borolysine (+)- pinanediol, hydrochloride
N1-(2-[5-phenyl]thiophen-ylcarbonyl)-(R)-borolysine (+)- pinanediol, hydrochloride
N1-(2-benzopyronylcarbonyl)-(R)-borolysine (+)- pinanediol, hydrochloride
N1-(2-isoquinolinylcarbonyl)-(R)-borolysine (+)- pinanediol, hydrochloride
N1-(3-isoquinolinylcarbonyl)-(R)-borolysine (+)- pinanediol, hydrochloride
N1-(2-phenyl-4-isoquinolinylcarbonyl)-(R)-borolysine
(+)-pinanediol, hydrochloride
N1-(4-phenylbenzoyl)-(R)-borolysine, hydrochloride
N1-(3-phenylbenzoyl)-(R)-borolysine, hydrochloride
N1-(3-phenoxybenzoyl)-(R)-borolysine, hydrochloride
N1-(4-[4-pyridyl]benzoyl)-(R)-borolysine, hydrochloride
N1-(2-benzoylbenzoyl)-(R)-borolysine, hydrochloride N1-(3-benzoylbenzoyl)-(R)-borolysine, hydrochloride
N1-(4-benzoylbenzoyl)-(R)-borolysine, hydrochloride
N1-(3-[N-benzyloxycarbonyl ]aminobenzoyl)-(R)-borolysine, hydrochloride
N1-(3-[N-benzyloxycarbonyl-W-methyl ]aminobenzoyl)-(R)- borolysine, hydrochloride
N1-(4-ethylbenzoyl)-(R)-borolysine, hydrochloride
N1-(4-n-propylbenzoyl)-(R)-borolysine, hydrochloride
N1-(4-isopropylbenzoyl)-(R)-borolysine, hydrochloride
N1-(4-tert-butylbenzoyl)-(R)-borolysine, hydrochloride N1-(4-n-hexylbenzoyl)-(R)-borolysine, hydrochloride
N1-(4-cyclohexylbenzoyl)-(R)-borolysine, hydrochloride N1-(2-[N-(2-phenylethyl)carbonyl]aminobenzoyl)-(R)- borolysine, hydrochloride
N1-(4-n-butyloxybenzoyl)-(R)-borolysine, hydrochloride
N1-(4-[N-cyclopropylcarbonyl ] aminobenzoyl)-(R)- borolysine, hydrochloride
N1-(4-[N-cyclohexylcarbonyl ] aminobenzoyl)-(R)- borolysine, hydrochloride
N1-(4-[N-(4-methoxy)benzoyl] aminobenzoyl)-(R)- borolysine, hydrochloride
N1-(4-[4-methoxy]phenylbenzoyl)-(R)-borolysine, hydrochloride
N1-(2-[2-phenyl]benzyloxycarbonylbenzoyl)-(R) - borolysine, hydrochloride
N1-(2-[1-naphthyl]benzoyl)-(R)-borolysine,
hydrochloride
N1-(4-[4-carboxy]phenylbenzoyl)-(R)-borolysine, hydrochloride
N1-([2-anthraquinonyl]carbonyl)-(R)-borolysine, hydrochloride
N1-([2-dioxothioxanthinonyl]carbonyl)-(R)-borolysine, hydrochloride
N1-([2-fluoren-9-onyl]carbonyl)-(R)-borolysine, hydrochloride
N1-([3-fluoren-9-onyl]carbonyl)-(R)-borolysine, hydrochloride
N2-(1-naphthoyl)-(R)-borolysine, hydrochloride
N1-([4-fluoren-9-onyl]carbonyl)-(R)-borolysine, hydrochloride
N1-(2-methyl-4-phenyl-5-methoxybenzoyl)-(R)-borolysine, hydrochloride
N1-(2-methyl-4-phenyl-5-carboxamidobenzoyl)-(R)- borolysine, hydrochloride
N1-(2-methyl-4-phenyl-5-fluorobenzoyl)-(R)-borolysine, hydrochloride
N1-(2-methyl-4-phenyl-5-trifluoromethylbenzoyl)-(R)- borolysine, hydrochloride N1-(2-methyl-4-phenyl-5-chlorobenzoyl)-(R)-borolysine, hydrochloride
N1-(2-methyl-4-phenyl-5-hydroxybenzoyl)-(R)-borolysine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-methoxybenzoyl)-(R) - borolysine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-carboxamidobenzoyl)-
(R)-borolysine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-fluorobenzoyl)-(R)- borolysine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5- trifluoromethylbenzoyl)-(R)-borolysine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-chlorobenzoyl)-(R)- borolysine, hydrochloride
N1-(2-methyl-4-[4-carboxy]phenyl-5-hydroxybenzoyl)-(R)- borolysine, hydrochloride
N1-(2-[5-phenyl]furylcarbonyl)-(R)-borolysine,
hydrochloride
N1-(2-[5-phenyl]thiophen-ylcarbonyl)-(R)-borolysine, hydrochloride
N1-(2-benzopyronylcarbonyl)-(R)-borolysine,
hydrochloride
N1-(2-isoquinolinylcarbonyl)-(R)-borolysine,
hydrochloride
N1-(3-isoquinolinylcarbonyl)-(R)-borolysine,
hydrochloride
N1-(2-phenyl-4-isoquinolinylcarbonyl)-(R)-borolysine, hydrochloride
N1-(2-methyl-4-phenylbenzoyl)-R-borolysine,
hydrochloride
N1-(2-methyl-4-phenylbenzoyl)-R-borolysine, (+)- pinanediol, hydrochloride
N1-(2-methyl-4-phenylbenzoyl)-R-borothioarginine (+)- hydrobromide
N1-(2-methyl-4-phenylbenzoyl)-R-borothioarginine (+)- pinanediol, hydrochloride N1-(2-methyl-4-phenylbenzoyl)-R-boroarginine (+)- hydrochloride
N1-(2-methyl-4-phenylbenzoyl)-R-boroarginine (+)- pinanediol, bisulfite
Detailed Description of the Invention
Throughout the specification, the following conventional three-letter abbreviations for amino acid residues or amino acids apply:
Ala = alanine
Arg = arginine
Asn = asparagine
Asp = aspartic acid
Cys = cysteine
Gln = glutamine
Glu = glutamic acid
Gly = glycine
His = histidine
lle = isoleucine
Leu = leucine
Lys = lysine
Met = methionine
Phe = phenylalanine
Pro = proline
Ser = serine
Thr = threonine
Trp = tryptophan
Tyr = tyrosine
Val = valine
The prefix "boro" indicates amino acid residues where the carboxy group is replaced by a boronic acid (Formula I, Y1 and Y2 = -OH).
The pinanediol boronic acid ester and the pinacol boronic acid ester are abbreviated "-C10H16" and "-C6H12" respectively. Other illustrations of diols useful for deriving boronic acid esters are 1,2- ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3- butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol.
Note that throughout the text when an alkyl substituent is mentioned, the normal alkyl structure is meant (e.g. butyl is n-butyl) unless otherwise
specified. However, in the definition of radicals above (e.g. R3) , both branched and straight chains are included in the scope of alkyl.
It is understood that many 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 diastereomers are desired, they may be prepared using starting materials with the appropriate stereochemistry, or may be separated from mixtures of undesired stereoisomers by standard
techniques, including chiral chromatography and
recrystallization of diastereomeric salts.
Synthesis
The compounds of formula (I) can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being affected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the chemical transformations proposed and this will sometimes require judgment as to the order of synthetic steps or selection of particular process scheme used from that shown below in order to obtain a desired compound of the invention. Scheme 1. Synthesis of Thrombin Inhibitors
Figure imgf000033_0001
Reagents: a. IBCF, NMM, RCO2H, Et3N, 0 °C, b. NaN3, c. H2, Pd(OH)2/C, HCl,d. DMAP, aminoiminomethanesulfonic acid, e. phenylboronic acid
Amine hydrochloride 1 is readily available via the procedure of Kettner and Shenvi (EP 0293881 A2). There are numerous synthetic methods by which to prepare amide 2, however, competing with amide formation is the cyclization of 1 to afford a complex mixture containing the desired amide and the corresponding N- acylboroproline. Since purification at this stage is unfeasible, choosing the correct method for amide formation is crucial to obtaining 2 in a purity suitable for subsequent synthetic transformations.
Three methods are preferred for the preparation of 2. In the first, a solution of 1 in tetrahydrofuran or dichloromethane at 0 °C is treated sequentially with the desired acid chloride followed by two equivalents of triethylamine. The mixture is then allowed to warm to room temperature overnight. The second method is the mixed anhydride procedure of Anderson, et. al. ( J. Am . Chem . Soc . 1967, 89, 5012). In this method the
isobutyl mixed anhydride is generated by dissolving the carboxylic acid component in tetrahydrofuran and adding one equivalent of N-methylmorpholine. The solution is cooled to 0 °C and one equivalent of isobutyl
chloroformate is added. After 5 minutes, a solution of 1 in chloroform is added, followed by the addition of one equivalent of triethylamine. The mixture is
typically stirred at 0 °C for one hour followed by one to several hours at room temperature. The third method for amide formation is the hydroxybenzotriazole/DCC method of König and Geiger ( Chem . Ber. 1970, 103, 788- 98). Thus, to a solution of 1 and the carboxylic acid component in dimethylformamide or tetrahydrofuran at 0 °C is added N-methylmorpholine , 1-hydroxybenzotriazole hydrate (2 eq) and DCC (1.05 eq). The solution is allowed to warm to room temperature overnight.
The preferred method for the preparation of azide 3 is by reaction of 2 with sodium azide (1.1 eq) in dimethylformamide at 70 °C for 2 hours. The azide displacement may also be performed prior to amide formation. This is the preferred method in cases where the rate of amide formation is slow relative to the rate of cyclization. Azide 4 is prepared by a modification of the procedure of Kettner and Shenvi (EP 0293881 A2) as shown in Scheme 2. Thus, bromide 5 is reacted with sodium azide, followed by homologation to give 6, chloride displacement to afford 7 and acidic hydrolysis to give 4. Amide formation between 4 and the carboxylic acid component then affords 3 directly.
Scheme 2. Synthesis of Azide 4
Figure imgf000035_0001
Reagents: a . NaN3 b . CHCl2Li, ZnCl2, c . LiN(TMS)2, d. 4M HCl, dioxane
Reduction of azide 3 to amine 8 may be accomplished by hydrogenation over precious metal catalysts. The preferred catalyst for this transformation is Pearlman's catalyst (palladium hydroxide on carbon). The amine is typically isolated as the hydrochloride salt. Isolation of 8 as the free base typically results in lowered yields. Salts of 8 which may confer superior physical properties may be preferred over the hydrochloride salt.
Formamidination of amine 8 may be accomplished using cyanamide. Due to the low reactivity of amine 8, however, the preferred method for this transformation is reaction with 4-dimethylaminopyridine (DMAP) and
aminoiminomethanesulfonic acid (AMSA, prepared by the method of Kim, et. al., Tetrahedron Lett . 1988, 29, 3183-6). This affords guanidine 9, which is isolated as the bisulfite or hydrochloride salt.
Cleavage of pinanediol ester 9 may be accomplished using anhydrous boron trichloride according to the procedure of Matteson and Ray (J. Am . Chem . Soc . 1980, 102, 7588). This method, however, is strongly Lewis acidic and leads to partial destruction of the
substrate. The preferred method for water soluble boronic acids is a transesterification reaction that is run in the presence of excess phenylboronic acid. The free boronic acid 10 may then be isolated using cation exchange chromatography.
The isothiouronium functionalized analogs 11/12 are prepared from bromide 2 according to the procedure of Kettner and Shenvi (EP 0293881 A2).
Inhibitors containing a sulfonamide in place of a carboxamide are prepared from either 1 or 4 by reaction with a sulfonyl chloride in the presence of a hindered amine (Scheme 3). The product sulfonamide 13 is then converted to the guanidinium 14 or isothiouronium 15 in the same manner as the corresponding carboxamides.
Scheme 3. Synthesis of Sulfonamides
Figure imgf000037_0001
Inhibitors containing the borolysine moiety are prepared analogously to those containing boroarginine according to Kettner and Shenvi (EP 0293881 A2).
Novel biaryls synthesized in this invention are prepared through palladium catalyzed coupling of an appropriate arylmetal species to the aryl halide of choice using the methods described in Negishi, et. al., Org. Synth . 1987, 66, 61-14 , and references cited within.
EXAMPLE 1: N1-(4-Phenylbenzoyl)boroarginine (+)- Pinanediol, Bisulfite Part A: ( +)-Pinanediol 4-bromo-1(R) -(4-phenylbenzoyl) aminobutane-1-boronate. To a solution of (+)- pinanediol 4-bromo-1 (R)-aminobutane-1-boronate
hydrochloride (5.00 g, 13.6 mmol) in dichloromethane (50 mL) at 0 °C was added 4-phenylbenzoyl chloride (4.97 g, 22.9 mmol) followed by N-methylmorpholine (4 mL, 36 mmol). After 1 hour, the cooling bath was removed and the mixture stirred at room temperature for 2 hours. The mixture was then diluted with ethyl acetate and washed with 0.1 M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford 3.37 g (48%) of the desired amide, mass spectrum: (M+H)+ = 510/512; 1H ΝMR (300 MHz, CDCI3) δ7.9 (2H, d, J
= 8.3), 7.84 (1H, bs), 7.6 (2H, d, J = 8.3), 7.44 (5H, m), 4.37 (1H, m) , 3.41 (1H, t, J = 6.9), 2.0 (10H, m) 1.49 (3H, s), 1.38 (1H, m) , 1.29 (3H, s) , 0.91 (3H, s). Part B: ( +) -Pinanediol 4-azido-1 (R) -(4-phenylbenzoyl) aminobutane-1-boronate. To a solution of (+)- pinanediol 4-bromo-1 (R)-(4-phenylbenzoyl) aminobutane-1- boronate (3.37 g, 6.60 mmol) in dimethylformamide (6 mL) was added sodium azide (547 mg, 8.41 mmol). The
resulting mixture was heated at 70 °C for 2 hours, cooled to room temperature, and diluted with ethyl acetate. The mixture was then washed with water, saturated sodium chloride and dried over anhydrous magnesium sulfate. Filtration, followed by
concentration of the filtrate in vacuo gave 3.04 g (97%) of the desired azide, mass spectrum: (M+H) + = 473; 1H ΝMR (300 MHz, CDCI3) δ7.89 (2H, d, J = 8.3), 7.75 (1H, bs), 7.3 (7H, m) , 4.32 (1H, m), 3.32 (1H, m), 2.0 (10H, m) 1.48 (3H, s) , 1.3 (4H, m) , 0.9 (3H, s). Part C : N1- (4-Phenylbenzoyl) boroornithine ( +) - pinanediol, hydrochloride. To a solution of (+)- pinanediol 4-azido-1 (R)-(4-phenylbenzoyl)aminobutane-1- boronate (3.04 g, 6.44 mmol) in methanol (30 mL) was added Pearlman' s catalyst Pd(OH)2/C, 200 mg) and 1 M hydrochloric acid (6.5 mL, 6.5 mmol). The mixture was placed on a Parr apparatus and hydrogenated at 50 psi for 3 hours. The mixture was filtered using Celite™, washed with methanol and the filtrate concentrated in vacuo . The resulting amorphous solid was dissolved in water and washed with ether. The aqueous phase was then concentrated in vacuo and crystallized from ethyl acetate-hexanes, giving 1.52 g (49%) of the desired amine hydrochloride, mass spectrum: (M+H) + = 447; mp : 157-170 °C; 1H NMR (400 MHz, CDCl3/DMSO-d6) δ9.88 (1H, bs), 8.18, (2H, d, J = 8.3), 8.13 (3H, bs) , 7.68 (2H, d, J = 8.3), 7.61 (2H, d J = 7.0), 7.45 (2H, d, J = 7.0), 7.37 (1H, d, J = 7.30), 4.20 (1H, d, J = 6.3), 2.99 (1H, m), 2.87 (2H, m) , 2.31 (1H, m) , 2.13 (1H, m), 1 . 84 (7H, m) , 1 . 56 ( 1H, d, J = 10 . 0) , 1 . 42 (3H, s ) , 1 .29 (3H, s) , 0.89 (3H, s).
Part D : N1- (4-Phenylbenzoyl)boroarginine ( +) - pinanediol, bisulfite. To a solution of N1-(4- phenylbenzoyl)boroornithine (+)-pinanediol,
hydrochloride (80 mg, 0.17 mmol) in ethanol (2 mL) was added 4-dimethylaminopyridine (40 mg, 0.33 mmol). After 15 minutes, aminoiminomethanesulfonic acid (40 mg, 0.32 mmol) was added and the resulting mixture heated at reflux for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate concentrated in vacuo . The residue was dissolved in chloroform and washed with 0.1 M hydrochloric acid, water and dried over anhydrous magnesium sulfate. Filtration, followed by concentration of the filtrate in vacuo afforded 73 mg (84%) of the desired guanidine, mass spectrum: (M+H)+ = 489; 1H NMR (400 MHz, CDCI3, 60 °C) δ9.48 (1H, bs) , 8.10
(2H, d, J = 8.1), 8.07 (1H, bs) , 7.75 (1H, bs) , 7.54
(2H, d, J = 8.3), 7.48 (2H, d, J = 7.0), 7.35 (3H, m) , 7.06 (4H, bs), 4.19 (1H, bd, J = 8.3), 3.1 (2H, m) , 2.84
(1H, m) , 2.29 (1H, m) , 2.12 (1H, m) , 1.96 (1H, m), 1.75
(6H, m) , 1.47 (1H, d, J = 10.2), 1.40 (3H, s) , 1.24 (3H, s) , 0.83 (3H, s). EXAMPLE 34: ( +) -Pinanediol 4-(Formamidino) thio-1 (R)-(4- phenylbenzoyl) aminobutane-1-boronate, Hydrobromide
( +) -Pinanediol 4-(formamidino)thio-1(R) - (A- phenylbenzoyl)aminobutane-1-boronate, hydrobromide. To a solution of (+)-pinanediol 4-bromo-1 (R)-(4-phenyl- benzoyl) aminobutane-1-boronate (200 mg, 0.392 mmol) in methanol (3 mL) was added thiourea (120 mg, 1.58 mmol). The reaction was stirred at room temperature for 3 days. The mixture was concentrated in vacuo, the residue dissolved in water and washed with ether. Concentration of the aqueous portion afforded 80 mg (35%) of the desired isothiourea, mass spectrum: (M+H)+ = 506; 1H NMR (300 MHz, CDCI3) δ8.15 (2H, d, J = 8.4), 7.61 (2H, d, J
= 8.4), 7.52 (2H, m), 7.38 (3H, m), 6.47 (1H, bs), 4.23 (1H, dd, J = 6.6, 1.9), 3.24 (1H, m), 3.14, (1H, m),
2.96, (1H, m), 2.32 (1H, m), 2.15 (1H, m), 1.99 (1H, m), 1.78 (6H, m), 1.48 (1H, d, J = 10.1), 1.42 (3H, s) , 1.27 (3H, s) , 0.86 (3H, s). The compounds listed in Tables 1-12 can be prepared using the above examples.
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Physical Data for Tables 1-14
A: MS (M+H)+ = 489; 1H NMR (400 MHz, CDCl3, 60 °C)
9.48 (1H, bs), 8.10 (2 H, d, J = 8.1), 8.07 (1 H, bs), 7.75 (1 H, bs) , 7.54 (2 H, d, J = 8.3), 7.48 (2 H, d, J = 7.0), 7.35 (3 H, m) , 7.06 (4 H, bs) , 4.19 (1 H, bd, J = 8.3), 3.1 (2 H, m), 2.84 (1 H, m), 2.29 (1 H, m) , 2.12 (1 H, m) , 1.96 (1 H, m), 1.75 (6 H, m), 1.47 (1 H, d, J = 10.2), 1.40 (3 H, s) , 1.24 (3 H, s) , 0.83 (3 H, s).
B: MS (DCI - NH3) , 505 (M + H)
C: MS (M+H) 490
D: MS (M+H)+ = 506; 1H NMR (300 MHz, CDCl3) 8.15 (2 H, d, J = 8.4), 7.61 (2 H, d, J = 8.4), 7.52 (2 H, m), 7.38 (3 H, m), 6.47 (1 H, bs) , 4.23 (1 H, dd, J = 6.6, 1.9), 3.24 (1 H, m) , 3.14, (1 H, m) , 2.96, (1 H, m) , 2.32 (1 H, m), 2.15 (1 H, m), 1.99 (1 H, m), 1.78 (6 H, m), 1.48 (1 H, d, J = 10.1), 1.42 (3 H, s) , 1.27 (3 H, s) , 0.86 (3 H, s).
E: mp 145-150 °C.
F: MS (DCI - NH3) , 522 (M + H)+.
G: HRMS (DCI - NH3), Calc: 534.2597, Found: 534.2609. H: HRMS (DCI - NH3), Calc: 534.2597, Found: 534.2605.
I: HRMS (DCI - NH3), Calc: 534.2597, Found: 534.2609.
J: [a]D = -14.85° (c = 0.606, MeOH) ; 1H NMR (300 MHz, DMSO - d6) 10.07 (br s, 1 H) , 10.05 (br s, 1 H), 8.96 (4 H, br s), 8.08 (1 H, s) , 7.71 (1 H, dd, J = 8.1, 1.1), 7.61 (1 H, d, J = 7.7), 7.30 - 7.50 (6 H, m) , 5.18 (2 H, s), 4.08 (1 H, br d), 3.08 - 3.25 (2 H, m), 2.50 - 2.65 (1 H, m), 2.15 - 2.30 (1 H, m), 1.97 - 2.10 (1 H, m), 1.40 - 1.90 (8 H, m), 1.31 (3 H, s), 1.24 (3 H, s), 0.84 (3 H, s); IR (KBr) 2500 - 3700 (br), 1734, 1646, 1578, 1550, 1440, 1222, 1058 cm-1; MS (Cl - NH3), m/e (%) 537.2 (10.2, M + H - H2NCN)+) ,
429.0 (42.8), 277.0 (100); Anal. Calcd for
C30H40BBrN4O5S: C, 54.64; H, 6.11; N, 8.50; B, 1.64. Found: C, 54.52; H, 6.16; N, 8.45; B, 1.60.
K: [a]D = -15.07° (c = 0.604, MeOH) ; 1H NMR (300 MHz, DMSO - d6) 9.98 (1 H, br s), 8.96 (4 H, br s), 7.93 (1 H, narrow m), 7.80 (1 H, app d), 7.64 (1 H, m), 7.56 (1 H, app t), 7.25 - 7.42 (5 H, m), 5.13 (2 H, s), 4.11 (1 H, dd, J = 8.3, 1.7), 3.30 (3 H, s), 3.10 - 3.25 (2 H, m), 2.57 - 2.68 (1 H, m), 2.15 - 2.30 (1 H, m), 1.97 - 2.10 (1 H, m), 1.48 - 1.90 (7 H, m), 1.44 (1 H, d, J = 9.9), 1.31 (3 H, s), 1.24 (3 H, s), 0.84 (3 H, s); IR (KBr) 2500 - 3700 (br), 1710,
1647, 1159 cm-1; MS (Cl - NH3), m/e (%) 593.2 (1.2, (M + H)+), 568.3 (22, (M + NH4 - H2NCN)+), 551.3 (100, (M + H - H2NCN)+); Anal. Calcd for C31H42BBrN4O5S : C, 55.29; H, 6.29; N, 8.32; B, 1.61. Found: C, 55.15; H, 6.21; N, 8.22; B, 1.47.
1: [a]D = -14.12° (c = 0.602, MeOH); 1H NMR (300 MHz, DMSO - d6) 10.09 (1 H, br s), 8.98 (4 H, br s), 7.90 (2 H, d, J = 8.3), 7.42 (2 H, d, J = 8.3), 4.06 (1 H, d, J = 7.0), 3.15 - 3.20 (2 H, m), 2.70 (2 H, q, J = 7.7), 2.54 (1 H, m), 2.18 - 2.28 (1 H, m), 1.98 - 2.08 (1 H, m), 1.44 - 1.84 (8 H, m), 1.30 (3 H, s), 1.24 (3 H, s), 1.20 (3 H, t, J = 7.7), 0.84 (3 H, s); IR (KBr) 2600 - 3700 (br), 1646, 1614, 1598, 1570, 1500, 1123 cm-1; MS (DCI - NH3), m/e (%) 458 (100, (M + H)+); Anal. Calcd for C24H37BBrN3O3S : C, 53.54; H, 6.93; N, 7.81; B, 2.01. Found: C, 53.75; H, 6.98; N, 7.74; B, 1.97. M: [a]D = -14.21° (c = 0.556, MeOH); 1H NMR (300 MHz, DMSO - d6) 10.06 (1 H, br s) , 8.95 (4 H, br s) , 7.88 (2 H, d, J = 8.1), 7.40 (2 H, d, J = 8.1), 4.06 (1 H, dd, J = 1.7, 8.3), 3.14 - 3.17 (2 H, m), 2.65 (2 H, t, J = 7.5), 2.50 - 2.60 (1 H, m) , 2.18 - 2.28 (1 H, m) , 1.98 - 2.08 (1 H, m), 1.45 - 1.84 (10 H, m), 1.30 (3 H, s), 1.24 (3 H, s) , 0.89 (3 H, t, J = 7.3), 0.84 (3 H, s); IR (KBr) 2500 - 3700 (br) , 1646, 1614, 1598, 1570, 1500, 1446, 1236, 1124, 1082 cm-1; MS (Cl - NH3), m/e (%) 472.2 (13.5, (M + H)+), 430.2 (100, (M + H - H2NCN)+), 278.0 (61.9); Anal. Calcd for
C25H39BBrN3O3S: C, 54.36; H, 7.12; N, 7.61; B, 1.96. Found: C, 54.50; H, 7.18; N, 7.83; B, 1.73.
N: [a]D = -13.79° (c = 0.602, MeOH); 1H NMR (300 MHz, DMSO - d6) 10.03 (1 H, br s) , 8.94 (4 H, br s) , 7.89 (2 H, d, J = 8.3), 7.45 (2 H, d, J = 8.3), 4.06 (1 H, br d) , 3.10 - 3.23 (2 H, m), 2.90 - 3.05 (1 H, m) , 2.50 - 2.60 (1 H, m) , 2.15 - 2.30 (1 H, m), 1.95 - 2.08 (1 H, m), 1.42 - 1.89 (8 H, m), 1.30 (3 H, s) , 1.24 (3 H, s), 1.23 (6 H, d, J = 7.0), 0.84 (3 H, s); IR (KBr) 2500 - 3700 (br), 1646, 1613, 1598, 1123 cm- 1 ; MS (DCI - NH3), m/e (%) 472 (100, (M + H)+), 430 (37, (M + H - H2NCN)+); Anal. Calcd for
C25H39BBrN3O3S: C, 54.36; H, 7.12; N, 7.61; B, 1.96. Found: C, 54.64; H, 7.17; N, 7.50; B, 1.74.
0: [a]D = -13.19° (c = 0.364, MeOH); 1H NMR (300 MHz, DMSO - d6) 10.03 (1 H, br s) , 8.93 (4 H, br s) , 7.88 (2 H, d, J = 8.5), 7.40 (2 H, d, J = 8.5), 4.06 (1 H, br d, J = 6.6), 3.15 - 3.20 (2 H, m) , 2.67 (2 H, t, J = 7.7), 2.50 - 2.60 (1 H, m), 2.18 - 2.28 (1 H, m), 1.95 - 2.08 (1 H, m), 1.24 - 1.84 (10 H, m), 1.23 - 1.35 (2 H, m), 1.30 (3 H, s), 1.24 (3 H, s), 0.90 (3 H, t, J = 7.3), 0.84 (3 H, s); IR (KBr) 2500 - 3700 (br), 1646, 1614, 1598, 1500, 1123 cm-1; MS (Cl -
NH3), m/e (%) 486.2 (3.3, (M + H)+), 444.2 (87.1, (M + H - H2NCN)+), 292.0 (100); Anal. Calcd for
C26H41BBrN3O3S: C, 55.13; H, 7.30; N, 7.42; B, 1.91. Found: C, 54.99; H, 7.22; N, 7.29; B, 2.07.
P: [a]D = -12.71° (c = 0.598, MeOH); 1H NMR (300 MHz, DMSO - d6) 10.05 (1 H, br s), 8.95 (4 H, br s), 7.90 (2 H, d, J = 8.6), 7.59 (2 H, d, J = 8.6), 4.06 (1 H, br d), 3.10 - 3.23 (2 H, m), 2.50 - 2.62 (1 H, m), 2.16 - 2.30 (1 H, m), 1.96 - 2.08 (1 H, m), 1.42 -
1.90 (8 H, m), 1.31 (9 H, s), 1.30 (3 H, s), 1.24 (3 H, s), 0.84 (3 H, s); IR (KBr) 2500 - 3700 (br), 1646, 1613, 1597, 1498, 1123 cm-1; MS (DCI - NH3), m/e (%) 486 (100, (M + H)+), 444 (16, (M + H - H2NCN)+); Anal. Calcd for C26H41BBrN3O3S : C, 55.13; H, 7.30; N, 7.42; B, 1.91. Found: C, 55.09; H, 7.45; N, 7.40; B, 1.67.
Q:1H NMR (300 MHz, DMSO - d6) §10.06 (1 H, br s), 8.95 (4 H, br s), 7.88 (2 H, d, J = 8.5), 7.40 (2 H, d, J = 8.5), 4.06 (1 H, br d, J = 6.6), 3.10 - 3.23 (2 H, m), 2.66 (2 H, t, J = 7.7), 2.50 - 2.60 (1 H, m), 2.15 - 2.30 (1 H, m), 1.95 - 2.08 (1 H, m), 1.40 - 1.90 (10 H, m), 1.20 - 1.38 (12 H, m), 0.80 - 0.90 (6 H, m); IR (KBr) 2500 - 3700 (br), 1646, 1614, 1598,
1500, 1124 cm-1; MS (DCI - NH3), m/e (%) 514 (100, (M + H)+), 472 (16, (M + H - H2NCN)+); Anal. Calcd for C28H45BBrN3O3S: C, 56.57; H, 7.63; N, 7.07; B, 1.82. Found: C, 56.19; H, 7.53; N, 6.97; B, 1.99. R: [a]D = -11.70° (c = 0.530, MeOH); 1H NMR (300 MHz, DMSO - d6) d10.05 (1 H, br s) , 8.83 - 9.13 (4 H, br d) , 7.88 (2 H, d, J = 8.3), 7.43 (2 H, d, J = 8.3), 4.06 (1 H, br d) , 3.05 - 3.25 (2 H, m), 2.45 - 2.67 (2 H, m), 2.13 - 2.30 (1 H, m) , 1.94 - 2.10 (1 H, m), 1.30 - 1.90 (18 H, m), 1.30 (3 H, s) , 1.24 (3 H, s), 0.84 (3 H, s); IR (KBr) 2500 - 3700 (br) , 1646, 1613, 1598, 1500, 1448, 1122 cm-1; MS (DCI - NH3) , m/e (%) 512 (100, (M + H)+), 470 (40, (M + H - H2NCN)+); Anal. Calcd for C28H43BBrN3O3S : C, 56.77; H, 7.32; N, 7.09; B, 1.82. Found: C, 56.49; H, 7.38; N, 6.96; B, 1.75.
S: HRMS (DCI - NH3), Calc: 577.3019, Found: 577.3025. T: [a]D = -8.31° (c = 0.614, MeOH); 1H NMR (300 MHz, DMSO - d6) d9.98 (1 H, br s) , 8.95 (4 H, br s) , 7.93 (2 H, d, J = 8.8), 7.11 (2 H, d, J = 8.8), 4.00 - 4.10 (3 H, m) , 3.10 - 3.23 (2 H, m) , 2.50 - 2.60 (1 H, m), 2.15 - 2.30 (1 H, m) , 1.95 - 2.08 (1 H, m), 1.37 - 1.90 (12 H, m), 1.29 (3 H, s) , 1.24 (3 H, s) , 0.94 (3 H, t, J = 7.4), 0.84 (3 H, s); IR (KBr) 2500 - 3700 (br), 1646, 1608, 1498, 1262, 1124 cm-1; MS (DCI - NH3), m/e (%) 502 (100, (M + H)+), 460 (28, (M + H - H2NCN)+); Anal. Calcd for C26H41BBrN3O4S : C, 53.62; H, 7.10; N, 7.21; B, 1.86. Found: C, 53.61; H, 7.09; N, 7.20; B, 1.78.
U: HRMS (DCI - NH3), Calc: 513.2707, Found: 513.2702. V: HRMS (DCI - NH3), Calc: 555.3165, Found: 555.3176. W: HRMS (DCI - NH3), Calc: 579.2812, Found: 579.2801.
X: HRMS (DCI - NH3), Calc: 450.2962, Found: 450.2958. Y: HRMS (DCI - NH3), Calc: 640.3016, Found: 640.3022. Z: [a]D = -8.80° (c = 0.602, MeOH) ; 1H NMR (300 MHz, DMSO - d6) 10.03 (1 H, br s), 9.25 (1 H, br s), 8.96
(4 H, br s) , 7.92 (1 H, d, J = 1.5), 7.72 (1 H, dd, J = 8.1, 1.5), 7.25 - 7.50 (6 H, m), 5.17 (2 H, s), 4.08 (1 H, dd, J = 8.1, 1.5), 3.08 - 3.27 (2 H, m), 2.65 (2 H, br t), 2.50 - 2.60 (1 H, m), 2.15 - 2.30
(1 H, m), 1.95 - 2.08 (1 H, m), 1.40 - 1.90 (10 H, m), 1.30 (3 H, s), 1.24 (3 H, s), 1.15 - 1.38 (2 H, m, buried underneath methyl absorptions), 0.77 - 0.95
(6 H, m); IR (KBr) 2500 - 3700 (br), 1704, 1646, 1572, 1539, 1453, 1234, 1123, 1056 cm-1; MS (Cl - NH3), m/e (%) 593.2 (1.3, (M + H - H2NCN)+), 485.2
(42.7), 333.0 (100); Anal. Calcd for C34H48BBrN4O5S: C, 57.07; H, 6.76; N, 7.83; B, 1.51. Found: C,
57.17; H, 6.84; N, 7.76; B, 1.41.
AA: 1H NMR (300 MHz, DMSO - d6) §9.98 (1 H, br s), 8.98 (4 H, br s), 7.77 - 7.92 (2 H, m), 7.08 - 7.55 (6 H, m), 4.90 - 5.30 (2 H, m), 4.09 (1 H, br d), 3.04 - 3.35 (5 H, m), 2.35 - 2.65 (3 H, m), 2.15 - 2.30 (1 H, m), 1.97- 2.10 (1 H, m), 1.37- 1.93 (10 H, m), 1.31 (3 H, s), 1.24 (3 H, s), 1.10 - 1.37 (2 H, m, buried underneath methyl absorptions), 0.72 - 0.93 (6 H, m); MS (Cl - NH3), m/e (%) 649.4 (1.9, (M +
H)+), 624.4 (31, (M + NH4 - H2NCN)+) , 607.2 (100, (M + H - H2NCN)+), 455.0 (39), 444.0 (29.8); Anal. Calcd for C35H50BBrN4O5S: C, 57.62; H, 6.91; N, 7.68; B, 1.48. Found:
C, 57.37; H, 6.86; N, 7.64; B, 1.40.
BB: HRMS (DCI - NH3), Calc: 520.2805, Found: 520.2796.
CC: HRMS (DCI - NH3), Calc: 560.2390, Found: 560.2407. DD: HRMS (DCI - NH3), Calc: 596.2060, Found: 596.2055. EE: HRMS (DCI - NH3), Calc: 546.2597, Found: 546.2604.
FF: HRMS (DCI - NH3), Calc: 534.2597, Found: 534.2609. GG: HRMS (DCI - NH3), Calc: 532.2441, Found: 532.2445.
HH: HRMS (DCI - NH3), Calc : 532.2441, Found: 532.2452.
II: HRMS (DCI - NH3), Calc: 480.2493, Found: 480.2492.
JJ: HRMS (DCI - NH3), Calc: 496.2441, Found: 496.2449.
KK: HRMS (DCI - NH3), Calc: 507.2601, Found: 507.2592. LL: HRMS (DCI - NH3), Calc: 537.2667, Found: 537.2685.
MM: HRMS (DCI - NH3), Calc: 498.2233, Found: 498.2231.
NN: HRMS (DCI - NH3), Calc: 481.2445, Found: 481.2442.
OO: HRMS (DCI - NH3), Calc: 557.2758, Found: 557.2754.
PP: HRMS (DCI - NH3), Calc: 5481.2445, Found: 481.2440. QQ: HRMS (NH3) - CI/DEP), Calc: 503.3193, Found: 503.3199.
RR: HRMS (DCI-NH3), Calc: 605.333; Found: 605.3325.
Utility
The compounds of formula (I) are useful as inhibitors of trypsin-like enzymes, notably human thrombin,
plasma kallikrein and plasmin. Because of their
inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions catalyzed by the aforesaid enzymes such as blood coagulation and inflammation.
As an illustration of the above, the biological activity of compounds of the present invention is demonstrated by their in vitro inhibition of
synthetic substrate hydrolysis by human thrombin S- 2238 Chromogenic Assay (IC50). The synthetic
substrate H-D-Phe-Pip-Arg-pNA (S-2238, Kabi) is cleaved by thrombin, liberating the p-nitroanalide group which absorbs light at 405 nm. Enzyme activity is measured in both the presence and absence of inhibitor. A decrease in absorbance at 405 nm in the presence of inhibitor is indicative of thrombin inhibition.
A mixture of 10 μL human thrombin (Enzyme Research Laboratories, Inc.) at an activity of approximately 7 units/mL, 10 μL of the inhibitor (normally at a concentration of 10-3 M or less), and 160 μL buffer (0.15 M NaCl, 10 mM HEPES, 10 mM Tris, 1 g/L PEG 8,000, pH 7.4) are incubated for 10 minutes at room temperature. To this mixture is added 20 μL of the synthetic substrate S-2238 at a concentration of 1 mM and the reaction allowed to occur for 10 minutes, after which absorbance at 405 nm is determined.
Using the methodology described above,
representative compounds of this invention were evaluated and found to exhibit an IC50 of less than 1 mM, thereby confirming the utility of the compounds of the invention as effective thrombin inhibitors.
Since the compounds of formula (I) have anti- thrombogenic properties, they may be employed when an anti-thrombogenic agent is indicated, such as for control of the coagulation or the fibrinolysis system in mammals or they may be added to blood for the purpose of preventing coagulation or the blood due to contact with blood collecting or distribution containers, tubing or apparatus.
Generally, these compounds may be administered orally or parenterally 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 will be obvious to one skilled in the art. In the case of large mammals such as humans, 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 . The disclosure of this text is hereby incorporated by reference for a more complete teaching of suitable dosage forms for administration of the compounds of this invention.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (I)
R1-Z-CCHR2-BY1Y2
(I) wherein
Y1 and Y2 are independently
a) -OH
b) -F,
c) - NR3R4, or
d) C1-C8- alkoxy;
Y1 and Y2 when taken together can form
a) a cyclic boron ester where said chain or
ring contains from 2 to 20 carbon atoms and, optionally, a heteroatom which can be N, S, or O,
b) a divalent cyclic boro amide where said chain or ring contains from 2 t 20 carbon atoms, c) a cyclic boro amide-ester where said chain or ring contains from 2 to 20 carbon atoms;
Z is
a) -(CH2)mCONR8-,
b) -(CH2)mCSNR8-,
c) -(CH2)mSO2NR8-,
d) -(CH2)mCO2-,
e) -(CH2)mC(S)O-, or
f) -(CH2)mSO2O-;
R1 is
a) - (CH2)p-aryl, wherein aryl is phenyl, naphthyl or biphenyl substituted with one, two or three substituents selected from the group consisting of halo (F, Cl, Br, I), CN, C1-C10- alkyl, C3-C8-cycloalkyl, C2-C10-alkenyl, C2--C10-alkynyl, -R8, -OR8, methylenedioxy, -NO2, -CF3, -S(O)rR7, NR8R9, -COR8, -CO2R8, -CONR8R9, NR8COR9, NR8CO2R9,
Figure imgf000068_0001
b) heteroaryl, wherein heteroaryl is an
unsubstituted or monosubstituted or
disubstituted
i) 5- or 6-membered aromatic ring, which
contains from 1 to 3 heteroatoms selected from the group consisting of O, N, and S, ii) quinolinyl,
iii) isoquinolinyl,
iv) benzopyranyl,
v) benzothiophenyl,
vi) benzofuranyl,
vii) 5,6,7,8-tetrahydroquinolinyl
viii) 5,6,7,8-tetrahydroisoquinolinyl and wherein the subtitutents are members selected from the group consisting of halo (F, Cl, Br, I, -CN, C1-C10-alkyl, C3-C8-cycloalkyl, C2-C10- alkenyl, C2-C10-alkynyl, -R8, OR8, NO2, -CF3,
-S(O)rR7, NR8R9, -COR8, -CONR8R9, NR8COR9,
NR8CO2R9,
Figure imgf000068_0002
Figure imgf000069_0001
R2 is
a) -(CH2) n-NHC (NH)NH2, b) -(CH2) n-NHC (NH)NHCOCH3, c) -(CH2)n-SC(NH)NH2, e) -(CH2)n-SC(NH)2,or f) - (CH) n-NH (2-pyridyl);
R3 is H, phenyl or C1-C4-alkyl; R4 is H, or phenylsulfonyl;
R5 and R6 are hydrogen or when taken together form a six membered aromatic ring optionally substituted with one, two or three substituents selected from the group consisting of halo (F, Cl, Br, I), -CN, C1-C10- alkyl, C3-C8-cycloalkyl, C2-C10-alkenyl, C2-C10- alkynyl, -OR8, -NO2, -CF3, -S(O)rR7, -NR8R9, -COR8, -COR2R8, -CONR8R9, phenyl, benzyl, phenylethyl;
R7 is
a) phenyl,
b) C1-C4-alkyl,
c) C1-C4-alkoxy, or
d) -CF3;
R8 and R9 are independently
a) H,
Figure imgf000070_0001
c) C3-C7-Cycloalkyl,
d) C1-C8-alkyl;
R10 and R11 are independently
a) halo (F, Cl, Br, I),
b) -CN,
c) C1-C10-alkyl,
d) C3-C8-cycloalkyl,
e) C2-C10-alkenyl,
f) C2-C10-alkynyl,
g) -OR8,
h) NO2,
i) -CF3,
j) -S(O)rR7,
k) -NR8R9,
l) -COR9,
m) -CO2R8, or
n) -CONR8R9; R12 is
a) H,
b) C1-C4-alkyl,
c) phenyl
d) benzyl,
e) -COR7
f) -SO2R7
m is 0 to 6;
n is 3 or 4,
p is 0 to 2,
r is 0 to 2,
t is 1 to 5
E is -CO-, -SO2-,-CH2- or a single bond,
F is -CO-, and
pharmaceutically acceptable salts thereof.
2. A compound of Claim 1 wherein:
Rl is phenyl containing 1-3
substituents selected from the series halo (F, CL, Br, I), Cl-ClO-alkyl, C3-C8-cycloalkyl, C2-C10- alkenyl, C2-C10-alkynyl, -R8, -OR8, -NO2, -CF3, -S(O)rR7, -NR8R9, -COR8, -CO2R8, CONR8R9, NR8COR9' and
Figure imgf000071_0001
; and
R2 is
a) -(CH2)3-NHC(NH)NH2, or
b) -(CH2)3-SC(NH)NH2.
3. A compound of Claim 2 wherein Z is - (CH2)mCONR8-.
4. A compound of Claim 3 selected from the group
consisting of
N1-(4-phenylbenzoyl)-(R)-boroarganine, hydrochloride, N1-(3-phenoxybenzoyl)-(R)-boroarganine, hydrochloride, N1-(1-fluorenonyl)-(R)-boroarginine, hydrochloride,N1-(4-[butyl]benzoyl)-(R)-boroarginine, hydrochloride, N1-(2-benzoylbenzoyl)-R-boroarginine, hydrochloride, N1-(5-phenyl-2-furol)-R-boroarginine, hydrochloride, N1-(3-[N-benzyloxycarbonyl-N-methylamino]-4-[1-butyl]- benzoyl)-(R)-boroarginine, hydrochloride,
N1-(2-phenyl-4-isoquinolyl)-(R)-boroarginine,
hydrochloride,
N1-(4-cyclohexylbenzoyl)-(R)-boroarginine, hydrochloride N1-(2-methyl-4-phenylbenzoyl)-(R)-boroarginine,
hydrochloride, or
5. A pharmaceutical composition comprising a
pharmaceutically suitable carrier and a
therapeutically effective amount of a compound of any one of claims 1 through 4.
6. A method of treating a physiological disorder in a warm blooded animal catalyzed by trypsin-like enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of any one of claims 1 through 4.
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EP0724446A1 (en) * 1993-10-07 1996-08-07 The Du Pont Merck Pharmaceutical Company Electrophilic peptide analogs as inhibitors of trypsin-like enzymes
FR2745288A1 (en) * 1996-02-27 1997-08-29 Adir NOVEL BORONIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
EP0810858A2 (en) * 1994-12-27 1997-12-10 The Du Pont Merck Pharmaceutical Company Boronic acid and ester inhibitors of thrombin
JP2006503903A (en) * 2002-09-09 2006-02-02 トライジェン・リミテッド Boronic acid polyvalent metal salt for the treatment of thrombosis
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids

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EP0293881A2 (en) * 1987-06-05 1988-12-07 The Du Pont Merck Pharmaceutical Company Peptide boronic acid inhibitors of trypsin-like proteases
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WO1992007869A1 (en) * 1990-11-06 1992-05-14 Thrombosis Research Institute Inhibitors and substrates of thrombin

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Publication number Priority date Publication date Assignee Title
EP0293881A2 (en) * 1987-06-05 1988-12-07 The Du Pont Merck Pharmaceutical Company Peptide boronic acid inhibitors of trypsin-like proteases
EP0471651A2 (en) * 1990-08-13 1992-02-19 Sandoz Ltd. Peptide boronic acid derivatives having protease inhibiting activity
WO1992007869A1 (en) * 1990-11-06 1992-05-14 Thrombosis Research Institute Inhibitors and substrates of thrombin

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0724446A1 (en) * 1993-10-07 1996-08-07 The Du Pont Merck Pharmaceutical Company Electrophilic peptide analogs as inhibitors of trypsin-like enzymes
EP0724446A4 (en) * 1993-10-07 1998-01-07 Du Pont Merck Pharma Electrophilic peptide analogs as inhibitors of trypsin-like enzymes
EP0810858A2 (en) * 1994-12-27 1997-12-10 The Du Pont Merck Pharmaceutical Company Boronic acid and ester inhibitors of thrombin
EP0810858A4 (en) * 1994-12-27 2000-11-15 Du Pont Pharm Co Boronic acid and ester inhibitors of thrombin
FR2745288A1 (en) * 1996-02-27 1997-08-29 Adir NOVEL BORONIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
EP0792883A1 (en) * 1996-02-27 1997-09-03 Adir Et Compagnie Novel derivates of boronic acid, process for their preparation and pharmaceutical compositions containing them
CN1076353C (en) * 1996-02-27 2001-12-19 阿迪尔公司 New compounds derived from boronic acid, process for their preparation and pharmaceutical compositions containing them
JP2006503903A (en) * 2002-09-09 2006-02-02 トライジェン・リミテッド Boronic acid polyvalent metal salt for the treatment of thrombosis
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

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AU6448794A (en) 1994-10-11

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