| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 09.99 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 07.09.99 |
| PATENT TITLE |
Synthesis of bisindolylmaleimides |
| PATENT ABSTRACT |
The present invention provides for the reaction of optionally substituted indole-3-acetamides with optionally substituted methyl indole-3-glyoxyl reagent to prepare potent PKC inhibitors. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 19.05.98 |
| PATENT REFERENCES CITED | Davis et al., Inhibitors of Protein Kinase C. 1. 2,3-Bisarylmaleimides, J. Med. Chem. Jan. 1992, vol. 35, No. 1, pp. 177-184. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. A process of preparing compounds of Formula Ia: ##STR26## wherein: R.sub.1 and R.sub.2 independently are optionally substituted 3-indolyl, which comprises, reacting a compound of the formula IV: ##STR27## wherein: W represents a C.sub.4 to C.sub.8 optionally substituted alkylene moiety optionally having an internal ether (--O--), amino (--NH--) or amide (--CONH--) linkage; R.sub.3 is hydrogen, I, Cl, Br, or OR.sub.4 ; R.sub.4 is C.sub.1 -C.sub.4 alkyl; R.sub.8 is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, (CH.sub.2).sub.m hydroxy, acetyl, carboxy, halo, haloalkyl, nitro, and (CH.sub.2).sub.m NR.sub.5 R.sub.6, where R.sub.5 and R.sub.6 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, or benzyl; and m is independently 0, 1, 2, or 3; in the presence of a base sufficiently strong to deprotonate the amide and methylene at the C-3 position of the indolyl-3-acetamide. 2. The process of claim 1, wherein the compound of formula IV is ##STR28## Z is --(CH.sub.2).sub.p --; R.sub.9 is halo, protected hydroxy, protected amino, NR.sub.5 R.sub.6, NH(CF.sub.3), or N(CH.sub.3)(CF.sub.3); R.sub.5 and R.sub.6 are independently H or C.sub.1 -C.sub.4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3. 3. The process of claim 2, wherein m is 2 and p is 2. 4. The process of claim 1, wherein the base is selected from the group consisting of alkali metal alkoxides, sodium hydride, lithium diisopropylamide, or n-butyllithium. 5. The process of claim 2, wherein the base is selected from the group consisting of alkali metal alkoxides, sodium hydride, lithium diisopropylamide, or n-butyllithium. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The present invention relates to bis-indolylmaleimides which are useful as protein kinase C inhibitors. More specifically, the invention provides a robust and efficient process of preparing bis-indolylmaleimides. The compounds prepared by the process are useful in those disorders associated with abnormal levels of protein kinase C, including cardiovascular disease, diabetes mellitus and its complications, and cancer. BACKGROUND OF THE INVENTION The bis-indolylmaleimide subunit is present in a number of biologically active metabolites isolated from Streptomycetes including Staurosporine, (Tamaoki et al., Biochem. Biophys. Res. Commun. 135: 397-402 (1986); Gross et al., Biochem. Pharmacol. 40: 343-350 (1990)) and Rebeccamycin, (Steglich et al., Angw Chem. Int. Ed. Engl. 19:459 (1980)). The simplest members of this class of compounds are the arcyriarubins, a family of pigments produced by slime molds (Myxomycetes). Id. Bis-indolylmaleimides are selective inhibitors of PKC and show promise as a novel potential therapy for auto immune diseases (Bit, R. A. et al., J. Med. Chem. 361:21 (1993)). The bisindolylmaleimide GF109303X has been recognized as a PKC kinase selective agent, (Bit, R. A. et al., Tetrahedron Letters 34:5623 (1993)) as has the conformational restricted analog, Ro 32-0432 (Wilkinson, S. E., J. Med. Chem. 36:21 (1993)) and also N,N' bridged bisindolylmaleimide macrocycles (Jirousek et al., J. Med. Chem. 39 (14):2664-2671 (1996)). Several methods are available in the literature to prepare the bis-indolylmaleimide framework including reaction of dihalomaleimides with indole Grignard reagents (Faul et al., Synthesis 12:1511 (1995) and Steglich, W. Tetradron 44: 2887 (1988)), oxidative coupling of indole-3-acetic acid trianions (Bergman et al., Tetrahedron Letters 28:1444 (1987)), and reaction of indolyl-3-glyoxyl chlorides with either indole-3-acetic acid in a Perkin condensation approach or with indole-3-acetimidates (Specter et al., J. Am. Chem. Soc. 76:6208 (1954); Davis, P. D., et al., Tetrahedron Letters 31:5201 (1990), Bit, R. A., Tetrahedron Letters 34:5623 (1993)) to prepare a bisindolylmaleic anhydride which is then converted to a bisindolylmaleimide in a two-step synthesis. Although all of these procedures can be utilized to prepare bisindolylmaleimides, one must use different procedures or multiple steps to prepare unsymmetrical vs. symmetrically substituted bisindolylmaleimides. Thus, there remains a need for a general and efficient method of preparing bis-indolylmaleimides. The present invention provides a general and very efficient method for the synthesis of these substrates. The syntheses provides a flexibile and powerful methodology for the synthesis of bisindolylmaleimides. SUMMARY OF THE INVENTION This invention provides a process of preparing compounds of Formula I: ##STR1## wherein: R.sub.1 and R.sub.2 independently are optionally substituted 3-indolyl and R.sub.11 is H or CH.sub.3 ; which comprises, reacting an optionally substituted indole-3-acetamide of the formula: ##STR2## with optionally substituted indolyl-3-glyoxyl reagent of the formula: ##STR3## wherein: R.sub.3 is I, Cl, Br, or OR.sub.4 ; and R.sub.4 is C.sub.1 -C.sub.4 alkyl; in the presence of a base sufficiently strong to deprotonate the amide and methylene at the C-3 position of indolyl-3-acetamide. DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS For purposes of the present invention, as disclosed and claimed herein, the following terms and abbreviations are defined as follows. The term "halo" represents fluorine, chlorine, bromine, or iodine. The term "alkyl" represents a cyclo, straight or branched chain alkyl group having from one to ten carbon atoms such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and the like. A haloalkyl is one such alkyl substituted with one or more halo atoms, preferably one to three halo atoms. An example of a haloalkyl is trifluoromethyl. A C.sub.1 -C.sub.4 alkyl is an alkyl limited to one to four carbon atoms. A C.sub.1 -C.sub.4 alkoxy is a C.sub.1 -C.sub.4 alkyl group covalently bonded by an --O-linkage. The term "C.sub.1 -C.sub.4 alkylene" represents a one to four carbon, straight alkylene moiety. Examples of C.sub.1 -C.sub.4 alkylene include methylene, ethylene, trimethylene, methylethylene, tetramethylene, and the like. Similarly, a "C.sub.4 -C.sub.8 alkylene" represents a four to eight carbon, straight alkylene moiety. The term "aryl" represents a phenyl or naphthyl. The term "alkali alkoxides" refers to bases, generally lithium, potassium, or sodium bases, of an alkoxide, generally a C.sub.1 -C.sub.4 alkoxy. Alkali alkoxides therefore include potassium t-butoxide, sodium methoxide, sodium ethoxide. The term "heterocycle" represents a stable, optionally substituted, saturated or unsaturated 5 or 6 membered ring, said ring having from one to four heteroatoms that are the same or different and that are selected from the group consisting of sulfur, oxygen, and nitrogen; and when the heterocycle contains two adjacent carbon atoms, the adjacent carbon atoms may be structured to form a group of the formula --CH.dbd.CH--; provided that (1) when the heterocyclic ring contains 5 members, the heteroatoms comprise not more than two sulfur or two oxygen atoms but not both; and (2) when the heterocyclic ring contains 6 members and is aromatic, sulfur and oxygen are not present. The heterocycle may be attached at any carbon or nitrogen which affords a stable structure. The term "optionally substituted alkylene" optionally substituted heterocycle, "or optionally substituted aryl" refers to substitution by one to three groups independently selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, (CH.sub.2).sub.m hydroxy, acetyl, carboxy, halo, haloalkyl, nitro, and (CH.sub.2).sub.m NR.sub.5 R.sub.6 ; wherein m is 0, 1, 2, or 3; and R.sub.5 and R.sub.6 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring. Said groups particularly the hydroxy or amino, are optionally protected during the claimed reaction. The term "leaving group" as used in the specification is understood by those skilled in the art. Generally, a leaving group is any group or atom that enhances the electrophilicity of the atom to which it is attached for displacement. Preferred leaving groups are triflate, mesylate, tosylate, imidate, chloride, bromide, and iodide. The term "hydroxy protecting group" as used in the specification refers to one of the ether or ester derivatives of the hydroxy group commonly employed to block or protect the hydroxy group while reactions are carried out on other functional groups on the compound. The species of hydroxy protecting group employed is not critical so long as the derivatized hydroxy group is stable to the condition of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. T. W. Greene and P. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, N.Y., 1991, provide a list of commonly employed protecting groups. Preferred hydroxy protecting groups are tert-butyldiphenylsilyloxy (TBDPS), tert-butyldimethylsilyloxy (TBDMS), triphenylmethyl (trityl), methoxytrityl, or an alkyl or aryl ester. A related term is "protected hydroxy," which refers to a hydroxy protecting group. The term "amino protecting group" as used in the specification refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. T. W. Greene and P. Wuts, Protective Groups in Organic Synthesis, Chapter 7, provide a list of commonly employed protecting groups. See also J. W. Barton, Protective Groups in Organic Chemistry, Chapter 2. Preferred amino-protecting groups are t-butoxycarbonyl, pthalimide, a cyclic alkyl, and benzyloxycarbonyl. The related term "protected amino" defines an amino group substituted with an amino protecting group as defined. The term "--NH protective groups" as used in the specification refers to sub-class of amino protecting groups that are commonly employed to block or protect the --NH functionality while reacting other functional groups on the compound. The species of protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) and may be removed at the appropriate point without disrupting the remainder of the molecule. T. W. Greene and P. Wuts, Protective Groups in Organic Synthesis, Chapter 7, page 362-385, provide a list of commonly employed protecting groups. Preferred --NH protecting groups are carbamate, amide, alkyl or aryl sulfonamide. The related term "protected --NH" defines a group substituted with an --NH protecting group as defined. The notation "*" designates the methylene at the 3-position of indolyl-3-acetamide. As previously noted, the invention provides a process of preparing compounds of Formula I: ##STR4## wherein: R.sub.1 and R.sub.2 independently are optionally substituted 3-indolyl and R.sub.11 is H or CH.sub.3, which comprises, reacting an optionally substituted indolyl-3-acetamide with an optionally substituted indolyl-3-glyoxyl reagent in the presence of a base. An advantage of the present invention is that the reaction is robust. Both the indole-3-acetamide and the indolyl-3-glyoxyl reagent may be optionally substituted with a wide variety of substituents recognized and disclosed in the prior art, provided that the substitution does not interfere with the reaction of the present invention. Preferred moieties are N-substituted, substituted on the fused 6-membered aromatic ring of the indolyl, and/or substituted at the 2-position of the indolyl. Also included are those bisindolylmaleimides wherein the N-substituents of the indolyl are linked together through a bridging moiety as hereinafter described. Substituents recognized as being desirable on a bis-indolylmaleimide include, for example, those disclosed in U.S. Pat. Nos. 5,057,614, 5,380,746, EPO 470 490 A1, WP 91/13071, EPO 397 060 A2, EPO 384 349 A1, EPO 624 586, WO 94/14798, EP 0 657 458, U.S. Pat. No. 5,481,003, and U.S. Pat. No. 5,545,636, all of which are herein incorporated by reference. Preferably, an optionally substituted indolyl-3-acetamide is a compound of the formula II: ##STR5## wherein: R.sub.7 is hydrogen, alkyl, haloalkyl, arylalkyl, C.sub.1 -C.sub.4 alkoxyalkyl, optionally protected hydroxyalkyl, optionally protected aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, or COO(C.sub.1 -C.sub.4 alkyl); R.sub.8 is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, (CH.sub.2).sub.m hydroxy, acetyl, carboxy, halo, haloalkyl, nitro, and (CH.sub.2).sub.m NR.sub.5 R.sub.6 ; wherein m is 0, 1, 2, or 3; and R.sub.5 and R.sub.6 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring. Preferred moieties include those wherein R.sub.7 is hydrogen, alkyl, optionally protected hydroxyalkyl, or optionally protected aminoalkyl; and R.sub.8 is hydrogen. Other preferred compounds include those wherein R.sub.8 is appendage at the 2-position of the indolyl and combines with R.sub.7 to form a moiety of the formula (IIa): ##STR6## wherein X is an optionally substituted C.sub.1 -C.sub.4 alkylene. Preferably, X is methylene substituted with --CH.sub.2 N(CH.sub.3).sub.2, a protected hydroxy or a protected amino. Preferably, R.sub.11 is H. An optionally substituted indolyl-3-glyoxyl reagent is preferably a compound of the formula (III): ##STR7## wherein: R.sub.3 is I, Cl, Br,or OR.sub.4 ; R.sub.4 is C.sub.1 -C.sub.4 alkyl; R.sub.7 ' is hydrogen, alkyl, haloalkyl, arylalkyl, alkoxyalkyl, optionally protected hydroxyalkyl, optionally protected aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, or trialkylaminoalkyl or COO(C.sub.1 -C.sub.4 alkyl); R.sub.8 is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, (CH.sub.2).sub.m hydroxy, acetyl, carboxy, halo, haloalkyl, nitro, and (CH.sub.2).sub.m NR.sub.5 R.sub.6 ; and m is 0, 1, 2, or 3. Preferably, R.sub.3 is Cl, Br, or OR.sub.4 and most preferably OR.sub.4. R.sub.7' is preferably hydrogen, alkyl, haloalkyl, alkoxyalkyl, optionally protected hydroxyalkyl, optionally protected aminoalkyl, monoalkylaminoalkyl, or dialkylaminoalkyl. Also included are compounds wherein R.sub.7 and R.sub.7' combine to form a bridging moiety linking the indolyl of the glyoxalyl reagent and the acetamide. Such compounds are of the formula (IV): ##STR8## wherein W represents a C.sub.4 to C.sub.8 optionally substituted alkylene moiety, and optionally having an internal ether (--O--), amino (--NH--) or amide (--CONH--) linkage. Most preferred compounds are compounds wherein W has an internal ether linkage and are represented by Formula (IVa): ##STR9## wherein Z is --(CH.sub.2).sub.p --; R.sub.9 is halo, protected hydroxy, protected amino, NR.sub.5 R.sub.6, NH(CF.sub.3), or N(CH.sub.3) (CF.sub.3); R.sub.5 and R.sub.6 are independently H or C.sub.1 -C.sub.4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3. Most preferred compounds of the Formula IVa are those wherein p is 1; and R.sub.5 and R.sub.6 are methyl. Yet another preferred indolyl-3-acetamide is a compound of the formula: ##STR10## wherein: m, Z, and R.sub.9 are the same as previously defined, and R.sub.10 is a leaving group, hydroxy, or protected hydroxy. Compound (IVb) is preferably reacted with glyoxyl reagent (III) to yield a compound of the formula: ##STR11## If a desired, compound IVc may be isolated from the reaction mixture; a macrocycle is then formed by the intramolecular alkylation of R.sub.10 by techniques appreciated in the art and described in (EP 0 657 458 (Jun. 14, 1995)). Preferably, a macrocycle of the formula: ##STR12## is prepared by reacting Compound IVc in the presense of base such as K.sub.2 CO.sub.3, Na.sub.2 CO.sub.3, NaOH, KOH, NaH, and Cs.sub.2 Co.sub.3. Similarly, the reaction may be carried out with substitution on the glyoxyl reagent. That is, an analogous compound of the Formula IVb: ##STR13## may be reacted with an unsubstituted indolyl-3-acetamide to form a compound of IVa. The reaction of glyoxyl reagent (IVb1) with indolyl-3-acetamide, or the reaction of indolyl-3-acetamide (IVb) with an unsubstituted indolyl-3-glyoxyl reagent may be controlled to yield macrocycle (IVd) in a one-step reaction. Presumably, N-alkylation to intermediate (IX) (below) takes advantage of intramolecular condensation to affect efficient maleimide formation. Both the bisindolylmaleimide and the macrocycle are formed in one step under mild conditions with no dimerization. For example, the following reaction ##STR14## was carried out with about 5 equivalents of NaH at room temperature in about 20 volumes of DMF to yield (IVd1) in 58% yield. The reaction was unsuccessful when using NaH in THF under these conditions while potassium t-butoxide in DMF was also operable. Thus, a substituted or unsubstituted bis-indolylmaleimide macrocycle may be formed in an efficient one-stop reaction. Such a robust synthesis was previously unknown in the art. It is recognized that various stereoisomeric forms of the compounds described herein may exist; compounds of the Formula (IVd) may contain a chiral carbon atom in the substituted alkylene moiety. The compounds are normally prepared as racemates and can conveniently be used as such, but individual enantiomers can be isolated or synthesized by the techniques described herein if so desired. Preparation of such racemates and individual enantiomers and mixtures thereof form part of the present invention. The present invention is based on the discovery that an indole-3-acetamide reacts with an indolyl-3-glyoxyl reagent upon treatment with a base sufficiently strong to deprotonate the amide of the indolyl-3-acetamide and to deprotonate the methylene at the methylene carbon at the 3-position of the indolyl. Preferred bases are selected from the group consisting of alkali metal alkoxides, sodium hydride, lithium diisopropylamide, or n-butyllithium and are most preferably alkali alkoxides such as potassium tert-butoxide (KOBu.sup.t). The reaction is carried out with a molar excess of base, preferably from about 0.5 to 10 equivalents of base, most preferably about 3.0 to 5.5 equivalents. However, one skilled in the art would recognize that the equivalents of base is dependent on the number of acidic hydrogens in the molecules. The reaction may be carried out in an organic solvent which is inert under the conditions of the reaction. Such solvents include, but are not limited to, ether solvents such as tetrahydrofuran, tert-butyl methyl ether, ether, and dimethoxyethane; alcohol solvents such as ethanol or butanol; or polar solvents such as dimethylformide, dimethylsulfoxide, or acetonitrile. A preferred solvent is tetrahydrofuran. Alcohol solvents are least preferred due to the solvent's possible quenching effect on the base. The reaction usually involves approximately equimolar amounts of the two reagents although other reagent equivalents are operative. The temperature of the reaction is preferably about 0.degree. C. to about the reflux temperature of the reaction mixture. The indolol-3-glyoxyl reagent utilized in this invention is prepared by conditions appreciated in the art. Generally, the glyoxyl reagent is prepared by techniques described in Feldman P. L., et al. Synthesis-Stuttgart 9: 735-37 (1986), Downie I. M. et al., Tetrahedron 49 (19): 4015-34 (1993), Rone N. et al. Synthetic Commun 25 (5): 681-90 (1995), Oikawa Y. et al. Heterocycles 4: 1859 (1976), DaSettimo JOC 35: 2546 (1970), and Rawal U. H. Tetrahedron Lett. 26: 6141 (1985), herein incorporated by reference. Preferably the glyoxyl reagent is prepared from an indole by sequential treatment of indole with oxalyl chloride followed by sodium methoxide (25% wt. solution in methanol) at low temperature (<-60.degree. C.). The indolyl-3-acetamide is prepared by conditions appreciated in the art or purchased from Aldrich Chemical Company, (Aldrich Chemical, Milwaukee, Wis., catalog, page 725 (1992-1993). Substitution to the acetamide is carried out by technique appreciated in the art and described in Rubottm G. et al., Synthesis 566 (1972), herein incorporated by reference. Though not wishing to be limited to any technical explanation, applicants believe the mechanism of the claimed reaction is as illustrated in Scheme 1. ##STR15## Compound (VI) and (VII) (trans and cis) can be isolated from the reaction mixture. These intermediates have been characterized by NMR, mass spectroscopy, and IR. Elimination (dehydration of (VII) to Compound I) can be achieved with an acid or a base. Preferably HCl is used when the indole-3-acetamide is unsubstituted. When a substituted indole-3-acetamide is employed, the reaction is preferably quenched with excess base. Accordingly, an advantage of the present invention is that an indole containing acid sensitive functionality could be cyclized readily by placing the substitution on the indole-3-acetamide. Preferably, Compound (VII) is converted to the final product in the same pot by quenching the reaction with HCl. When the indole-3-acetamide (II) is substituted complete elimination is achieved in about 1 to 5 hours to produce the bis-indolylmaleimide without the need to add acid. This elimination could be further enhanced by using more base, preferably 4 to 5 eq. of base, in the reaction which lead to complete cyclization in about 15 minutes to 1 hour. For example, acid sensitive ketal and trityl containing indole-3-acetamides may be cyclized with Compound III in one pot to give bis-indolylmaleimides in excess of 90% yield without the need to add an acid to quench the reaction and complete the elimination. Surprisingly, even hydroxyl and amino substituted indole-3-acetamides could be cyclized to give bis-indolylmaleimides in 98% and 84% yields respectively. The following examples of the claimed syntheses demonstrate the flexibility and power of this methodology for the synthesis of bisindolylmaleimides. The examples are offered to illustrate the invention and are not to limit the scope of the invention to the following examples. In the following examples, the designation "NMR" or "MS" means that the structure was confirmed by NMR or mass spectroscopy. GENERAL Infrared spectra were recorded on a Perkin Elmer 781 spectrometer. .sup.1 H NMR spectra were recorded on a QE 300 MHz spectrometer at ambient temperature. Data are reported as follows: chemical shift in ppm from internal standard tetramethylsilane on the d scale, multiplicity (b=broad, s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet and m=multiplet), integration, coupling constant (Hz) and assignment. .sup.13 C NMR were recorded on a QE 300 MHz (75.5 MHz) spectrometer at ambient temperature. Chemical shifts are reported in ppm from tetramethylsilane on the d scale, with the solvent resonance employed as the internal standard (deuterochloroform at 77.0 ppm and DMSO-d.sub.6 at 39.5 ppm). Combustion analyses were performed by Eli Lilly & Company Microanalytical Laboratory. High resolution mass spectra were obtained on VG ZAB 3F or VG 70 SE spectrometers. Analytical thin layer chromatography was performed on EM Reagent 0.25 mm silica gel 60-F plates. Visualization was accomplished with UV light. |
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