Title of Invention

A PROCESS FOR PREPARE INDOLYLMALEIMIDES

Abstract The present invention discloses a process for the preparation of indolylmaleimides of general formula (I) i, wherein, R1 and R1 are each independently either hydrogen or an optional substituent selected from halo, formyl, C1C10 alkyl, C1-C10 haloalkyi, C2-C10 alkenyl, C2-C10 alkynyl, aryl, alkylaryl, aminoalkyi, aminoaryl, heteroaryl, aralkyi, hydroxyalkyi, alkoxyalkyl, carbonylalkyi, monoalkylaminoalkyi, diaikylaminoalkyi, trialkylaminoalkyi, aminoalkylaminoalkyi, azidoalkyi, acyiaminoalkyi, acylthioalkyi, acyloxyalkyi, carboxyalkyi, alkoxycarbonylalkyl, alkylcarbonyloxyalkyl, aminocarbonylalkyl, cyanoalkyi, amidinoalkyi, alkylsulphonylaminoalkyl, * arylsulphonylaminoalkyl, mercaptoalkyi, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl, alkylsulphonyloxyalkyl, hydroxyalkylthioaikyi, mercaptoalkylthioalkyi, aryithioalkyi, carboxyalkylthioalkyi amidinothioalkyl, nitroguanidinoalkyi, a amino protecting group, an alkylglycose residue, and the like; R2 and R2 are each independently either hydrogen or an optionally substituted CrCio alkyl, haloalkyi, aminoalkyi, hydroxyalkyi, alkoxyalkyl, carboxyalkyi, carbonylalkyi, monoalkylaminoalkyi, diaikylaminoalkyi, acyiaminoalkyi, alkoxycarbonylalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyi, alkylthioalkyl, carbonylalkyi, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulphinyl and the like; or either of Ri and R1; R 2 and R2; R1 and R1 are joined via an optionally substituted alkylene moiety, optionally having an internal ether, amino or amide linkage;
Full Text

FIELD OF INVENTION
The present invention relates to a process for the preparation of indolylmaleimides.
BACKGROUND OF THE INVENTION
Protein kinase C (PKC), and particularly its various isozymes, have been associated with a variety of diseased states including cancer, central nervous system disorders, Alzheimer's, cardiovascular disease, dermatological diseases, inflammation, auto-immune diseases such as rheumatoid arthritis and also diabetic complications. As a result, there is a high level of research aimed at identifying therapeutic agents for inhibiting PKC activity as a way of treating these various conditions, and especially PKC inhibitors that are isozyme selective. Substituted indolylmaleimides, particularly the substituted bis-indolylmaleimides, are one major class of compounds which have been found to be selective PKC inhibitors (Steglich et. al., Angew. Chem. Ed. Engl., 1980, 19, 459).
Various symmetrical and non-symmetrical bis-indolylmaleimide derivatives are reported in literature. Examples include, US 5,043,335; US 5,380,746; US 5,491,242; US 5,516,915; US 5,821,365; EP 0 657 458; and PCT applications, WO 91/13071, WO 93/18765, WO 93/18766, WO 98/04551 and WO 00/47575. Further, bis-indolylmaleimide macrocycles are reported in US 6,057,440; US 5,821,365 and US 5,624,949.
Another class of indolylmaleimide derivatives described in US 5,057,614; are reported to be useful in control or prevention of inflammatory, immunological, bronchopulmonary or cardiovascular disorders; while indolylmaleimide derivatives described in WO 93/18765 and WO 93/18766 (US 5,547,976) are mentioned to have anti-viral activity.
The process to prepare such indolylmaleimide derivatives is a known art and is included in patents like US 4,785,085; US 5,057,614; US 5,380,746; US 5,547,976; US 5,516,915; US 5,665,877; US 6,037,475 and US 6,228,877. Also some research articles describe alternative approaches to synthesize various indolylmalemide derivatives, for example, Davis P. et. al. J. Med. Chem. 1992, 35, 177-184; Bit et. al. J. Med. Chem. 1993, 36, 21-29; Bit et. al.. Tetrahedron Lett, 1993, 34, 5623, Bergman et. al., Tetrahedron Lett., 1987, 28, 4441-4444; Davis et. al.. Tetrahedron Lett., 1990, 31, 2353, Davis et. al.. Tetrahedron Lett., 1990, 31, 5201-5204, and Bemner et. al.. Tetrahedron, 1988,44,2887-2892.

The general approach has been to prepare the title compoudns by using suitable mole ratio of indolyl magnesium halide with dihalomaleimide in appropriate solvent mixture. In most of the methods, ratio of indolyl grignard reagent: 2,3-dihalomaleimide is 4:1. Here we discuss in brief the prior art as found in the literature.
Another approach employs 1:2 ratio of N-benzyloxymethyl 2,3-dibromomaleimide : optionally substituted indolyl magnesium iodide as described in US patent 4,785,085.
US patent 5,057,614, gives preparation for 3,4-bis(3-indolyl)-1H-pyrrole-2,5-dione wherein indolyl magnesium bromide and 2,3-dibromomaleimide in 4:1 mole ratio were heated to reflux in benzene for 65 hours to obtain the bis-product.
US patent 5,380,746, gives preparation for 4-bromo-3-(3-indolyl)-1H-pyrrole-2,5-dione wherein indolyl magnesium bromide and 2,3-dibromomaleimide are reacted in 5:1 mole ratio and the time required for this reaction is 30 hrs under reflux.
US patent 5,547,976, gives preparation for 3,4-bis(3-indolyl)-1H-pyrrole-2,5-dione wherein indolyl magnesium bromide and 2,3-dibromomaleimide are reacted according to the procedure given in Bernner et. al., Tetrahedron, 1988, 44, 2887-2892. Further it also reports that the reaction is significantly dependent on solvent conditions (same as given in. Synthesis, 1995 (12), 1511-1516).
US patent 5,516,915 gives various schemes to prepare differently substituted bis-indolyl derivatives using an indole grignard reagent and dibromomaleimide. In the method 3:1 to 5:1 molar ratios of optionally substituted indole: 2,3-dibromomaleimide is used, and the reaction is completed in about 30 hours for unsubstituted monoindolylmaleimide and in about 20 hours for symmetrical bis-5-methoxyindolylmaleimide derivative. Sometimes, formation of an impurity is reported, the exact structure of which is not disclosed.
US patent 5,665,877, gives preparation for 3,4-bis(3-indolyl)-1H-pyrrole-2,5-dione wherein indolyl magnesium bromide and 2,3-dichloromaleimide are reacted in 4:1 mole ratio.
According to US patent 5,821,365, it is preferable to use 2,3-dichloromaleimide in the synthesis of bis-indolylmaleimide. It also describes method of preparation of 2,3-dichloro-N-methylmaleimide. This is the closest known prior art of the present invention. The process of the present invention is different from the method disclosed in the following respects:

1. Molar ratio of indolyl magnesium bromide and N-methyl-2,3-dichloromaleimide is 4.28:1 moles in the process of the US Patent.
2. Solvent : solid (reaction mass) ratio are higher in the process of the US Patent..
3. The present invention envisages shorter reaction time for identical reaction.
4. The process of the present invention is more economical y as relatively smaller amounts of indole, solvent, 2,3-dichloromaleimide are required to produce same amount of final product.
5. Method of isolation of product is different in the two processes.
6. Yields are higher in the process of the present invention.
7. The purity of the cmde product of the present invention is more than 98.50 %, with less than 0.5 % of indole in it. These impurities are easily removed during recrystalization to increase the purity > 99.5 %.
8. Solvent recovery is different in the two cases.
To prepare such indolyl derivatives, most of patent and literature including those cited above, refer to Bernner et. al., in Tetrahedron, 1988, 44, 2887-2892. According to this process indolyl magnesium bromide and N-methyl-2,3-dibromomaleimide in 5:1 mole ratio when refluxed for 2 hrs yield the corresponding bis-indolyl derivative. However, when we attempted to reproduce the same, the reaction mixture at the end of 25 hrs contained mostly the mono indolylmaleimide.
It is reportedly confirmed, a number of times that synthesis of bis-indolylmaleimides is sensitive to the solvent composition (for example in, Synthesis, 1995 (12), 1511-1516). This is the only process we found in literature wherein the ratios of indolyl magnesium bromide : 2,3-dichloromaleimide is about 2:1 moles. According to their observation when toluene:tetrahydrofuran is used as solvent in the ratios between 10:1 to 1:1 there is increase in the percentage proportion of unreacted 2-chloro-3-indolylmaleimide as impurity from 9 % to 65 % in the corresponding bis-derivative. It also states that in presence of toulene:diethylether tetrahydrofuran leads to increase in 1,2-carbonyl adduct, while the same reaction in toluene:tetrahydrofuran:diethylether (5:1:1) leads to decrease in the impurity. Hence, most of the methods found in patents literature prefer to use above solvent mixture. The paper also states that yield of reaction is also

affected by the ratio of reactants and solvent. Increase in reactant concentration leads to increase in amount of the said impurity and consequent decrease in the yield. It also states that there exists no difference in the reactivity of 2,3-dichloromaleimide and 2,3-dibromomaleimide.
No data on the effect of molar ratio of the two reactants on the formation of impurity and formation of polar impurity in the Toluene:Tetrahydrofuran is described in the literature.
Our attempts to reproduce the most widely reported process i.e. Bemner et. al., in Tetrahedron, 1988, 44, 2887-2892 resulted in formation of mostly monosubstituted derivative even at the end of 25 hrs of reaction.
Thus, there is a need for a straight forward process to prepare indolylmaleimides useful as either an intermediate or as a bio-active molecule. Alternative method should be a simplified process with higher yields, shorter reaction time, easier (e.g. milder) reaction conditions, inexpensive reagents and the like.
The present process involves the general approach of condensation of an organometallic-3-indole with dihalomaleimide. The process gives exact science of preparing the indolyl maleimide derivatives in most convenient way. It has optimized the molar ratios of reactants, solvents, reduced formation of 1,2-addition product and shortened reaction time and thus conserves energy and reduces the overall cost of production. This reaction is also versatile and the principle can be applied to obtain wide variety of products. Further, on completion of reaction, the mass left behind contains product along with excess amount of indole added, which can easily be washed off and recycled without any elaborate procedure. Thus, the process of this invention offers simple procedure to obtain a pharmaceutical grade intermediate or a drug, which can easily fit the regulatory requirements.
The main advantage is that both the steps involved in the preparation of bis-indolylmalemides have relatively faster reaction kinetics than ever reported before in the prior art. This increased rate of reaction does not adversely affect the yield and purity of the various bis-indolylmalemides formed; rather, certain side-products were not formed in the experiments done by us.
The principle of this invention can be essentially applied to other indolylmaleimides derivatives wherein there is at least one-indolylnitrogen unsubstituted

in the intermediate formed. Such compounds are known to be useful intermediates, for example bis-indolylmaleimides macrocycles, non-symmetrical bis-indolylmaleimides etc.
Further, this is a single-pot synthesis for symmetrical bis-indolylmalemide derivatives starting with the preparation of grignard reagent.
The present invention involves formation of ethyl magnesium halide, followed by indolyl magnesium halide and the final bis-indolyl maleimide, sequentially in the same pot.
Mono-substituted maleimides can also be prepared by this approach, potentially permeating the eventual synthesis of non-symmetrical bis-indolyl maleimides.
The advantages of the present invention as envisaged by us are as follows:
1. The present process is a one-pot synthesis, wherein the desired substituted symmetrical bis-indolylmaleimide is made using the appropriately substituted indole, ethyl magnesium bromide and dihalomaleimide.
2. The approach of this process can also be extended to monosubstituted maleimides as well as monosubstituted pyrrole indoles and non-symmetrical bis-indolylmaleimides.
3. Further the reaction time for the entire process as such is considerably short, without incurring any additional operational changes or costly equipment.
4. This process has smoother temperature gradient and hence reduced energy costs.
5. Along with all of the above advantages, the process does not compromise on yield and purity of the product. It provides bis-indolylmaleimides in greater than 65 % yield, with more than 99 percent purity.
6. The recovery of organic solvent/s used, is upto 80 %.
SUMMARY OF THE INVENTION
The present invention relates to the process for the preparation of compounds of general formula (I),


wherein, Ri and Rr are each independently either hydrogen or an optional substituent
selected, from halo, formyl, d-Cio alkyl, C1-C10 haloalkyi, C2-C10 alkenyl, C2-C10 alkynyl,
aryl, alkylaryl, aminoalkyi, aminoaryl, heteroaryl, aralkyi, hydroxyalkyi, alkoxyalkyl,
carbonylalkyi, monoalkylaminoalkyi, dialkylaminoalkyl, trialkylaminoalkyl,
aminoalkylaminoalkyi, azidoalkyl, acylaminoalkyi, acylthioalkyi, acyloxyalkyi, carboxyaikyi,
alkoxycarbonylalkyl, aikylcarbonyloxyalkyi, aminocarbonylalkyl, cyanoalkyl, amidinoalkyl,
alkylsulphonylaminoalkyl, arylsulphonylaminoalkyi, mercaptoalkyi, aikylthioalkyi,
alkylsulphinylalkyl, alkylsulphonylalkyl, alkylsulphonyloxyalkyl, hydroxyalkylthioalkyi,
mercaptoalkylthioalkyi, arylthioalkyi, carboxyalkylthioalkyi amidinothioalkyi,
nitroguanidinoalkyi, a amino protecting group, an alkylglycose residue, and the like;
R2 and R2' are each independently either hydrogen or an optionally substituted CrCio alkyl, haloalkyi, aminoalkyi, hydroxyalkyi, alkoxyalkyl, carboxyaikyi, carbonylalkyi, monoalkylaminoalkyi, dialkylaminoalkyl, acylaminoalkyi, alkoxycarbonylalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyi, mercaptoalkyi, aikylthioalkyi, carbonylalkyi, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulphinyl and the like; or either of Ri and Rr; R2 and R2-; Ri and Rr are joined via an optionally substituted alkylene moiety, optionally having an internal ether, amino or amide linkage;
R3 is either a leaving group; or an aryl or heteroaryl group, preferably a phenyl or indol-3-yl, which may be further substituted by Rr, R2', R4', Rs-, Rff and Rr independently and as defined above;

R4, Rs, Re, R7, R4', Rs', Re' and R7 each independently represents hydrogen or an optionally substituents selected from, for example, halogen, C1-C10 alkyl, hydroxy, CrCio alkoxy, aryloxy, haloalkyi, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, "NHCO(alkyl), alkylthio, alkylsulphinyl or alkylsulphonyl;
Z either represents -N(Rc) where Re is independently hydrogen, a substituted or unsubstituted CrC4 alkyl, C1-C4 alkanoyl group, or any other -NH-protecting group that can be split off;
Q and W either of them represents O or independently represents either O, S, (H.OH) or (H,H); or salt, esters and a solvate thereof;

which comprises reacting about specific mole equivalents of indolyl magnesium halide of a general formula (II), with a particular dihalomaleimide represented by a general formula (111), in a suitable solvent mixture and refluxing generally above 100 'C, and continuing the reaction till dihalomaleimide in the reaction is exhausted, but prior to formation of any polar impurity and, if desired, in an inert atmosphere.
A particular aspect of this invention includes reacting about 3 moles of indolyl magnesium halide with 1 mole of 2,3-dichloromaleimide when it is desired to prepare a symmetrical bis-indolyl derivative.
Another aspect of this invention includes reacting about 1.2 moles of indolyl magnesium halide with 1 mole of 2,3-dibromomaleimide when it is desired to prepare a mono substituted indolyl maleimide derivative. This derivative can react further with another differently substituted indolyl derivative preferably indolyl magnesium halide to obtain non-symmetrical bis-indolylmaleimide.
The terms "halo" and "halogen" as used herein to identify substituent moieties, represent fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
The compounds of formulae (1) may have one or more asymmetric carbons. The process of invention also includes preparation of such chiral compounds of formula (1)

using the corresponding chiral oxo amines wherein the reaction proceeds wWcomplete retention of configuration at the asymmetric carbon atom.
The reaction of dihalomaleimide of formula (III) with an optionally substituted organometallic-3-indole of formula (II), is conveniently carried out in an inert organic solvent, such as toluene, 1,4-dioxane, benzene, tetrahydrofuran or diethylether; or a mixture thereof, preferably mixture of toluene and tetrahydrofuran in the ratio of 2 :1 to 5 :1 at the reflux temperature of the reaction mixture preferably above 100 'C in an inert atmosphere, for example in an argon or nitrogen atmosphere. The indole grignard reagent is preferably prepared in situ from the indole and an alky! magnesium halide such as ethyl magnesium iodide or ethyl magnesium bromide in a manner known in the art.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to the process for the preparation of compounds of general formula (I),

wherein, Ri or Rr is hydrogen or an optionally substituent selected, for example, halo,
formyl, C1-C10 alkyl, CrCio haloalkyi, C2-C10 alkenyl, C2-C10 alkynyl, aryl, alkylaryl,
aminoalkyi, aminoaryl, heteroaryl, aralkyl, hydroxyalkyi, alkoxyalkyl, carbonylalkyi,
monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, aminoalkylaminoalkyi,
azidoalkyi, acylaminoalkyi, acylthioalkyi, acyloxyalkyi, carboxyalkyi, alkoxycarbonylaikyl,
alkylcarbonyloxy alkyl, aminocarbonylalkyi, cyanoalkyi, amidinoalkyi,
alkylsulphonylaminoalkyl, arylsulphonylaminoalkyi, mercaptoalkyi, alkylthioalkyl,

alkylsulphinylalkyl, alkylsulphonylalkyl, alkylsulphonyloxyalkyl, hydroxyalkylthioalkyl,
mercaptoalkylthioalkyi, arylthioalkyi, carboxyalkylthioalkyi amidinothioalkyi,
nitroguanidinoalkyi, a amino protecting group, an alkylglycose residue, and the like;
R2 or R2' is hydrogen or an optionally substituted C1C10 alkyl, haloalkyl, aminoalkyi, hydroxyalkyi, alkoxyalkyl, carboxyalkyi, carbonylalkyl, monoalkylaminoalkyi, dialkylaminoalkyi, acylaminoalkyi, alkoxycarbonylalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyi, mercaptoalkyl, alkylthioalkyl, carbonylalkyl, alkoxycarbonylalkyl, aminocarbonylalkyi, alkylthio or alkylsulphinyl and the like; or either of Ri and Rr; R 2 and R2'; Ri and Rr are joined via an optionally substituted alkylene moiety, optionally having an internal ether, amino or amide linkage;
R3 is either a leaving group, or an aryl or heteroaryl group, preferably a phenyl or indol-3-yl, v\^hich may be further substituted by Rr, Rr, R4', R5, Re* and R7 independently and as defined above;
R4, Rs, Re, R7, R4', Rss Re- and R7 each independently represents hydrogen or an optionally substituents selected from, for example, halogen, CrCio alkyl, hydroxy, C1-C10 alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, -NHCO(alkyl), alkylthio, alkylsulphinyl or alkylsulphonyl;
Z either represents Oxygen or -N(Rc) where Re is independently hydrogen, a substituted or unsubstituted C1-C4 alkyl, CrC4 alkanoyl group, or any other protecting group that can be split off;
Q and W either of them represents O or independently represents either O, S, {H,OH) or (H,H);
or salt, esters and a solvate thereof;

which comprises reacting about specific mole equivalents of indolyl magnesium halide of a general formula (II), with a particular dihalomaleimide represented by a general formula (111), in a suitable solvent mixture and refluxing generally above 100 °C, and continuing

the reaction till dihalomaleimide in the reaction is exhausted, but prior to formation of any polar impurity and, if desired, in an inert atmosphere.
Suitable substituents on the indole ring are such, which do not interfere In the reaction. The list includes,
1. 5-aminoindole
2. 6-aminoindole
3. 5-benzyloxyindole
4. 4-chloroindole
5. 5-chloroindole
6. indole
7. 4-methoxyindole
8. 5-methoxyindole
9. 4-methylindole
10. 5-methy!indole and 11.6-methylindole
Suitable dihalomaleimides are dichloromaleimide and dibromomaleimide. The process to prepare dihalomaleimides of formula (III), especially those in which either one or both of the R3 groups are bromine, are well known. {Edge, S. et ai, Chemistry & Industry (1991), p. 130.) The procedure for the corresponding chloro compounds is also reported in literature, for example, in US 5,821,365.
The term "alkyl", alone or in combination, represents a cyclic, straight or branched chain saturated hydrocarbon group, which in the case of straight and branched chains, preferably has from one to ten carbon atoms (d-Cio alkyl) such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like and in the case of a cyclic hydrocarbon preferably has from three to ten carbon atoms, such as cyclopropyl and cyclohexyl. The term "substituted alkyl" is intended to include an alkyl group substituted with a substituent that does not prevent or interfere with the desired synthesis step.
The term "haloalkyi" is one such substituted alkyl, substituted with one or more halo atoms, and preferably is a C1C10 alkyl substituted with one to three halo atoms. One example of a haloalkyi is trifluoromethyl.
The term "alkoxy", used alone or in combination, is an alkyl, preferably a CrCio alkyl, covalently bonded to the parent molecule through an --O- linkage alone or in combination. Examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy,

butoxy and t-butoxy. An alkoxyalkyl is, for example, CH3(CH2)-0-(CH2)m- wherein m is from one to seven or preferably one to four. The term alkoxycarbonyl is, for example, t-butoxycarbonyl or BOC.
The term "aryl" when used alone or in combination represents a substituted or unsubstituted phenyl or naphthyl. Aryl may optionally be substituted with any substituent that does not prevent or interfere with the desired synthesis step and generally includes substitution with up to four and usually with one or two groups independently selected from hydroxy, carboxy, alkoxy, preferably a d-Cioalkoxy, an alkyl, preferably a Cr Cioalkyl, a haloalkyi, nitro, monoalkylaminoalkyi, dialkylaminoalkyi, trialkylaminoalkyi, -NHCO{Ci-Cioalkyl), -NHC0(ben2yl), -NHCO(Phenyl), -SH, -S(C1C10alkyl), -OCO(Ci-Cioalkyl), -SO2 (NR4 R5), -SO2 (C1C10 alkyl), -S02(phenyl), or halo. The term aryloxy is one such aryl covalently bonded through an -O- linkage. The term arylalkyi can be considered a substituted alkyl and represents -(CH2)aryl with m being an integer of generally 1 to 3, and preferably is benzyl. In contrast, the term alkylaryl can be considered a substituted aryl and may, for example, represent a moiety such as -aryl(CH2)m-CH3 where m is an integer of generally 0 to 2.
The term "alkenyl" means a two to seven carbon, straight or branched hydrocarbon containing one or more double bonds, preferably one or two double bonds. Examples of alkenyl include ethenyl, propenyl, 1, 3-butadienyl, and 1, 3, 5-hexatrienyl.
The acyl moiety of an acylamino or acylaminoalkyi group is derived from an alkanoic acid containing a maximum of 7, preferably a maximum of 4, carbon atoms (e.g., acetyl, propionyl or butyryl) or from an aromatic carboxylic acid (e.g. benzoyl). An acyloxy is one such acyl bonded by an -O- linkage, for example, acetyloxy, CH3C(=0)0-. An acylamino is, for example, CH3 (C=0)NH-- (acetylamino). Likewise, an acylaminoalkyi is
CH3(C=0)NH(CH2)m.
The heterocyclic group denoted by "Het" or "heterocyclyl" can be a stable, saturated, partially unsaturated, or aromatic 5- or 6-membered heterocyclic group. The heterocyclic ring consists of carbon atoms and from one to three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The heterocyclic group can be optionally substituted with one to three substituents independently selected from halogen, alkyl, hydroxy, alkoxy, haloalkyi, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulfinyl and alkylsulfonyl or, when the heterocyclyl group is an aromatic nitrogen-containing heterocyclic group, the

nitrogen atom can carry an oxide group. Examples of such heterocyclyl groups are imidazolyl, imidazolinyl, thiazotinyl, pyridyl, indolyl, furyl, and pyrimidinyl.
The term "leaving group" (LG) as used in the specification and claims is readily 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 easy displacement. Preferred leaving groups are triflate ("OSO2CF3), mesylate, tosylate, imidate, chloride, bromide, and iodide. Triflate is particularly preferred.
The term "alkylglycose residue" represents a glycose moiety linked in the C-1 position to the indolyl via a (C2- C4)alkyl. Glycoses included in alkylglycose residue are natural or unnatural 5 or 6 carbon sugars, preferably selected from allosyl, altrosyl, glucosyl, mannosyl, gulosyl, idosyl, galactosyl, talosyl, arabinosyl, xylosyl, lyxosyl, rhamnosly, ribosyl, deoxyfurananosyl, deoxypyranosyl, and deoxyribosyl. The glycose may be azide substituted, 0-acetylated, 0-methylated, amino, mono, and di-alkylamino substituted, or acylamino substituted.
Under certain circumstances it is at least desired and often required to protect the nitrogen (N) of intermediates during the synthesis of the compounds of formulae (I) and (II) with suitable "protecting groups" which are known. Introduction and removal of such nitrogen protecting groups are well-known to those skilled in the art.
In this regard, the term "--NH protective groups" and "protecting group" when used in a similar context, and as used in the specification and claims, 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 in carrying out the method of the present invention is not critical so long as the derivatized --NH group is stable to the condition(s) of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Prior art (T. W. Greene and P. Wats, Protective Groups in Organic Synthesis, Chapter 7, pages 385-394 and 397-403), provide a list of commonly employed protecting groups for indoles and maleimides. Preferred indole protecting groups are trimethylsilylethoxymethyl, benzyl, tosyl, carbamate, amide, alkyl or aryl sulfonamide, while maleimide protecting groups include alkoxy, benzyl, dialkoxybenzyl, benzyioxyalkyi or allyl. The related term "protected ~NH" defines a group substituted with an -NH protecting group as defined.
In certain circumstances there may also be a need to protect hydroxy groups and amino groups during the synthetic processes of the present invention. Those skilled in the

art are familiar with such "hydroxy protecting groups" and such "amino protecting groups." The term "hydroxy protecting group" 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 a 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 disoipting the remainder of the molecule. Preferred hydroxy protecting groups are tert-butyldiphenylsilyloxy (TBDPS), tert-butyldimethylsilyloxy (TBDMS), triphenylmethyl (trityl), mono- or di- methoxytrityl, or an alkyl or aryl ester.
The term "amino protecting group'* refers to substituents of an 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 in carrying out the method of the present invention is not critical so long as the derivatized amino group is stable to the condition(s) of subsequent reaction(s) and can be removed at the appropriate point without dismpting the remainder of the molecule. Preferred amino-protecting groups are t-butoxycarbonyl, phthalimide, a cyclic alkyl, and benzyloxycarbonyl.
The term "indolylmaleimide" embraces a genus of compounds having as their root structure a 3-(indol-3-yl)-pyrrolyl-2,5-dione and includes the subgenus of "bisindolylmaleimides" having as their root stoicture a 3,4-(indol-3-yl)"pyrrolyl-2,5-dione", wherein the indol-3-yi moiety or moieties is/are optionally N-substituted, may optionally be substituted on the fused 6-membered aromatic ring of the indolyl moiety and may optionally be substituted at position 2 of the indol-3-yl moiety or moieties. Compounds falling within this definition of indolylmaleimide are described, inter alia, in U.S. Pat. No. 5,491,242 (PCT publication WO 95/35294), PCT publication WO 95/17182, and published European patent application EP 0657458, which are all incorporated herein by reference.
The prior art describes a wide range of such optionally substituted indolylmaleimides and the present invention can advantageously be used to make such compounds as will be understood by those skilled in the art. Compounds of formula (1) are themselves useful as PKC inhibitors or represent intermediates useful for the preparation of compounds exhibiting PKC inhibitory activity. A particularly preferred feature of this aspect of the invention is the use of an indolylmaleimide of the following formula (I) for preparing other compounds of formula (I) by reaction with an organometallic reagent: (II) wherein the substitutents are as defined above in connection

with formula (I). These compounds are useful for preparing compounds of formula (I) or (II) having PKC inhibitory activity or for preparing intermediates of PKC inhibitors.
The preferred aspect of the present invention involves a process suitable for producing bisindolylmaleimides, including non-symmetrical bisindolylmalemides starting from commercially available materials. In a particulariy preferred approach, an optionally substituted indolyl magnesium halide, is prepared in situ according to the general procedures available in the prior art. The grignard reaction can be conducted in two steps, introducing the maleimide substituents for the halogen atoms one at a time. In such case, it is preferable to use 2,3-dibromomaleimide in a 1:1.2 molar ratios with indolyl magnesium halide. If needed, the protecting groups are subsequently de-protected, using known techniques and procedures, and additional steps may be performed to introduce, for example, a hydrogen, alkyl, aryl, substituted«aryl, alkylaryl, aminoalkyi, heteroaryl, carbonylalkyi, amidinothioalkyi, nitroguanidinoalkyi or another desired moiety. The general approach is described in US patent 5,516,915 and is incorporated herein by reference.
For example, a indolyl magnesium halide can be treated with 2,3-dibromomaleimide to yield an optionally substituted 3-bromo-4-(indol-3-yl)pyrrole-2,5-dione. This may be further alkylated, halogenated and the resulting product be subjected to another cycle of grignard reacted with a differently substituted indolyl magnesium halide according to the novel process of this invention to obtain non-symmetrical bisindolylmalemides.
Another aspect of this invention involves a process suitable for producing bisindolylmaleimides, including symmetrical bisindolylmalemides. The general method involves reacting about 3 moles of indolyl magnesium halide with 1 mole of 2,3-dichloromaleimide according to the novel process of this invention when it is desired to prepare a symmetrical bis-indolyl derivative. Similar to above, the protecting groups are subsequently de-protected, using known techniques and procedures, and additional steps may be performed to introduce, for example, a hydrogen, alkyl, aryl, substituted-aryl, alkylaryl, aminoalkyi, heteroaryl, carbonylalkyi, amidinothioalkyi, nitroguanidinoalkyi or another desired moiety. The general approach is described in US patent 5,516,915 and is incorporated herein by reference.
Another particular aspect of this invention includes reacting about 1 mole of indolyl magnesium halide with 1 mole of 2,3-dibromomaleimide when it is desired to prepare either a mono substituted indolyl maleimide derivative.

The reaction may be monitored by conventional techniques such as gas chromatography, thin layer chromatography etc or any other convenient technique known in the field of art. After it is confirmed that the reaction is complete the reaction mixture is allowed to cool slowly to room temperature.
The products of various reactions contemplated by the practice of this invention can be isolated using conventional procedures including precipitation, extraction, distillation, chromatography and the like.
The product preferably is isolated by addition of reaction solvent to an aqueous solvent, which may contain pH-modifying agents. Water is such preferred solvent, and the reaction mixture is later neutralized with a suitable acid such as citric acid, ammonium chloride and the like. Later the residue obtained after filtration, if needed, may be further purified by using column chromatography over a silica gel column using a solvent system containing ether, hexane, pentane, ethyl acetate, alcohols etc. or mixtures thereof. The solvent/s may be evaporated in an inert atmosphere under vacuum to obtain pure product.
The process of this invention has been demonstrated with the following examples:
• 3-bromo-4-(indol-3-yI)-1H"pyrrole2,5-dione
• 3-chloro-4-(indol-3-yl)-1H"pyrrole2,5-dione
• 3,4-bis-(indol-3-yl)-1H-pyrrole2,5-dione
The following preparation and examples are presented to illustrate and explain the invention. Unless otherwise indicated, all references to parts and percentages are based on weight and all temperatures are expressed in degrees Celsius. The scope of this invention is not construed as merely consisting of the following examples. In the following example and preparations, melting point, nuclear magnetic resonance spectra, mass spectra, high pressure liquid chromatography over silica gel and tetrahydrofuran are abbreviated as M. Pt, NMR, MS, HPLC and THF respectively.
Commercial reagents were utilized without further purification. Melting points are uncorrected. NMR data are reported in parts per million (8) and are referenced to the deuterium lock signal from the sample solvent. Unless othenA/ise stated, all mass spectra were performed using ESI conditions. IR spectra were taken using KBr pellet. Room temperature refers to 25-30 °C. Chromatography refers to column chromatography performed using 60 - 120 mesh silica gel and executed under nitrogen pressure (flash chromatography) conditions. The "NMR"spectra and "MS" indicate that the spectrum was

consistent with the desired structure the product. This is further confirmed by characteristic IR spectra and melting point.
ILLUSTRATIVE EXAMPLE
Example 1:
3-bromo-4-(indol-3-yl)-1H-pyrrole-2,5-dione
Tetrahydrofuran (80mL), magnesium turnings (80.25 g, 0.33 moles) and iodine (0.5 g) were charged and stirred in a reaction flask equipped with mechanical stirrer, thermometer pocket, heating mantle, condenser, 500 mL addition funnel and nitrogen inlet. Slowly, ethyl bromide solution (30 mL, 0.40 moles) was added over one hour, maintaining the temperature below 40 °C. the reaction mixture was further stirred at the mass temperature of 30 - 40 °C, for another 30 minutes.
Substituted indole (38.8 g, 0.333 moles) dissolved in toluene (81 mL) was charged to the addition funnel and was added dropwise over next one hour at temperature of 30 -40 X.
A solution of dibromo-N-methylmaleimide (73.9 g, 0.275 moles) in toluene (450 mL) was prepared and added slowly, during which time a dark heterogenous mixture resulted. The mixture was heated to reflux (temperature = 110 ""C) for one hour and monitored by TLC till the completion of the reaction (usually, 1-2 hours, mobile phase: Chloroform: ethyl acetate = 6:1).
The reaction mixture was cooled to 20-30 ""C. 20 % aqueous solution of citric acid (200 mL) slowly, at temperature below 5 °C, in one hour. The slurry was further stirred at 0 °C for 30 minutes. The red colored solid separates out. The product was isolated by filtration, rinsed with water and toluene, then dried in air. The product was obtained in 87 % yield.
The product obtained is characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.

Example 2: 3-chloro-4-(indol-3-yl)-1H-pyrrole-2,5-dione
Tetrahydrofuran (80mL), magnesium tumings (80.25 g, 0.33 moles) and iodine (0.5 g) were charged and stirred in a reaction flask equipped with mechanical stirrer, thermometer pocket, heating mantle, condenser, 500 mL addition funnel and nitrogen inlet. Slowly, ethyl bromide solution (30 mL, 0.40 moles) was added over one hour, maintaining the temperature below 40 °C. the reaction mixture was further stirred at the mass temperature of 30 - 40 °C, for another 30 minutes.
Substituted indole (38.8 g, 0.333 moles) dissolved in toluene (81 mL) was charged to the addition funnel and was added dropwise over next one hour at temperature of 30 -40 °C.
A solution of dibromo-N-methylmaleimide (49.49 g, 0.275 moles) in toluene (300 mL) was prepared and added slowly, during which time a dark heterogenous mixture resulted. The mixture was heated to reflux (temperature = 110 °C) for one hour and monitored by TLC till the completion of the reaction (mobile phase: Chloroform: ethyl acetate = 6:1).
The reaction mixture was cooled to 20-30 °C. 20 % aqueous solution of citric acid (200 mL) slowly, at temperature below 5 °C, in one hour. The slurry was further stirred at 0 °C for 30 minutes. The red colored solid separates out. The product was isolated by filtration, rinsed with water and toluene, then dried in air. The product was obtained in 85 % yield.
The product obtained is characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.
Example 3:
3,4-bis-(indol-3-yl)-1H-pyrrole-2,5-dione.
Tetrahydrofuran (80mL), magnesium turnings (80.25 g, 0.33 moles) and iodine (0.5 g) were charged and stirred in a reaction flask equipped with mechanical stirrer, thermometer pocket, heating mantle, condenser, 500 mL addition funnel and nitrogen inlet. Slowly, ethyl bromide solution (30 mL, 0.40 moles) was added over one hour, maintaining the temperature below 40 °C. the reaction mixture was further stirred at the mass temperature of 30 - 40 ""C, for another 30 minutes.

Substituted indole (38.8 g, 0.333 moles) dissolved in toluene (81 mL) was cnargea to the addition funnel and was added dropwise over next one hour at temperature of 30 -40 °C.
A solution of dichloro-N-methylmaleimide (20.05 g, 0.1114 moles) in toluene (150 mL) was prepared and added slowly, during which time a dark heterogenous mixture resulted. The mixture was heated to reflux (temperature =110 °C) for one hour and monitored by TLC till the completion of the reaction (mobile phase: Chloroform: ethyl acetate = 6:1).
The reaction mixture was cooled to 20-30 ^C. 20 % aqueous solution of citric acid (200 mL) slowly, at temperature below 5 °C, in one hour. The slurry was further stirred at 0 °C for 30 minutes. The red colored solid separates out. The product was isolated by filtration, rinsed with water and toluene, then dried in air. 28.7 g (69.5 %) of product was obtained, melting range: 280 °C (DSC), H.P.L.C. purity = 98.7 %.
If desired, the above product can be further recrystallised from acetone to obtain the pharmaceutically acceptable purity of more than 99.5 % (yield = 65 % overall yield).
The product obtained is characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.



The principles preferred embodiments and modes of operation of tl^e present invention have been described in the foregoing specification. The invention, which is intended to be protected herein, however, is not to be construed as limited to the particular forms disclosed, since they are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art without departing from the spirit of the invention. Those skilled in the art will recognize variations in the processes as described above and will recognize appropriate modifications of the reaction conditions based on the above disclosure of making the compounds of formula
(I).

























WE CLAIM:
1. A process for the preparation of indolylmaleimides of general formula (I),

wherein, R1 and R1 are each independently either hydrogen or an optional substituent
selected from halo, formyl, C1-C10 alkyl, C1C10 haloalkyi, C2-C10 alkenyl, C2-C10 alkynyl,
aryl, alkylaryl, aminoalkyl, aminoaryl, heteroaryl, aralkyi, hydroxyalkyi, alkoxyalkyl,
carbonylalkyl, monoalkylaminoalkyi, dialkylaminoaikyi, triaikylaminoalkyl.
aminoalkylaminoalkyi, azidoalkyl. acylaminoalkyi, acylthioalkyi, acyloxyalkyi, carboxyalkyi,
alkoxycarbonylalkyl, alkylcarbonyloxyalkyl, aminocarbonylalkyl, cyanoalkyi, amidinoalkyi,
alkylsulphonylaminoalkyl, arylsulphonylaminoalkyi, mercaptoalkyi, alkylthioalkyl,
alkylsulphinylalkyl, alkylsulphonylalkyl, alkylsulphonyioxyalkyl, hydroxyalkylthioalkyi,
mercaptoalkylthioalkyi, arylthioalkyi, ' carboxyalkylthioalkyi amidinothioalkyi,
nitroguanidinoalkyj, a amino protecting group, an alkylglycose residue, and the like;
R2 and R2 are each independently either hydrogen or an optionally substituted C1-C10 alkyl, haloalkyi, aminoalkyl, hydroxyalkyi, alkoxyalkyl, carboxyalkyi, carbonylalkyl, monoalkylaminoalkyl, dialkylaminoaikyi, acylaminoalkyi, alkoxycarbonylalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyi, mercaptoalkyi, alkylthioalkyl, carbonylalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkyisulphinyl and the like; or either of Ri and Rr; R 2 and R2, R1 and R1 are joined via an optionally substituted alkylene moiety, optionally having an internal ether, amino or amide linkage;

Ra is either a leaving group; or an aryl or heteroaryl group, preferably a phenyl or indol-3-yl, which may be further substituted by Rr, R1 R4, Rs', Re- and Ry- independently and as defined above;
R4, R5. R6, R7. R4', R5,. R6 and R7 are each independently represents hydrogen or an optionally substituents selected from, for example, halogen, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, aryloxy, haloalkyi, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, -NHCO(alkyl), alkylthio, alkylsulphinyl or alkylsulphonyl;
Z either represents -N(Rc) where Rc is independently hydrogen, a substituted or unsubstituted C1C4 alkyl, C1C4 alkanoyl group, or any other -NH-protecting group that can be split off;
Q and W either of them represents O or independently represents either O, S, (H,OH) or (H,H); or salt, esters and a solvate thereof;

which comprises reacting about specific mole equivalents of indolyl magnesium halide of a general formula (il), with a particular dihalomaleimide represented by a general formula (III), wherein R2, R3, R4. Rs. Re and Ryare as defined above, in a suitable solvent mixture of the kind such as herein described and refluxing generally above 100 °C, and continuing the reaction till dihalomaleimide in the reaction is exhausted, but prior to formation of any polar impurity and, if desired, in an inert atmosphere.
2. The process according to claim 1, wherein the said compound of formula (II) is used in
the range of 0.9 to 1.2 moles, and compound of general formula I comprises a
monosubstituted indolylmaleimide..
3. The process according to claim 2, wherein said compound of formula III comprises
dibromomaleimide.
4. The process according to claim 1, wherein the said compound of formula (II) is used in
the range of 0.28 to 0.32 moles and said compound of formula I is symmetrical bis-
indolylmaleimide.

5. The process according to claim 4, wherein wherein said compound of formula 111
comprises dichloromaleimide.
6. The process according to claim 1, wherein in said compound of formula (III), Z is N-
methyl, W and Q each are oxygen, and Rais either chloro or bromo.
7. The process according to claim 1, wherein in said compound of formula (11), R4, R5, R6
and R7 are all hydrogens.
8. The process according to claims 3 and 5, wherein the reaction mixture contains organic
solvents such as toluene, tetrahydrofuran, and the mixtures thereof in the molar ratio of
2:1 to 5:1
9. The process according to claims 3 and 5, wherein the reaction of said compound of
formula (II) and the said compound of formula (III) is conducted at a temperature above
100 °C.
ID. The process according to claim 1, wherein the ratio of total solids to the solvent is between 1 : 2.5 to 1 : 3.5.
11. The process according to claim 1, wherein the compound of formulae (I) is selected from:
a. 3"bromo-4-(indol-3-yl)-1 H-pyrrole-2,5-dione
b. 3"Chloro-4-(indol-3-yl)-1 H-pyrrole-2,5-dione
c. 3,4-bis-(indol-3-yl)-1H-pynrole-2,5-dione


Documents:

0224-che-2003 claims-duplicate.pdf

0224-che-2003 description (complete)-duplicate.pdf

224-che-2003-abstract.pdf

224-che-2003-claims.pdf

224-che-2003-correspondnece-others.pdf

224-che-2003-correspondnece-po.pdf

224-che-2003-description(complete).pdf

224-che-2003-form 1.pdf

224-che-2003-form 13.pdf

224-che-2003-form 3.pdf

abs 224. 1.jpg

abs 224.2.jpg

abs 224.3.jpg


Patent Number 197987
Indian Patent Application Number 224/CHE/2003
PG Journal Number 08/2007
Publication Date 23-Feb-2007
Grant Date 23-Jan-2006
Date of Filing 19-Mar-2003
Name of Patentee M/S. SUVEN LIFE SCIENCE LIMITED
Applicant Address ROAD NO. 7, BANJARA HILLS, HYDERABAD 500 034
Inventors:
# Inventor's Name Inventor's Address
1 RAMAKRISHNA, VENKATA SATYA NIROGI SUVEN PHARMACEUTICALS, SERENE CHAMBERS, ROAD NO. 7, BANJARA HILLS, HYDERABAD 500 034
2 SHIRSATH, VIKAS SHREEKRISHNA SUVEN PHARMACEUTICALS, SERENE CHAMBERS, ROAD NO. 7, BANJARA HILLS, HYDERABAD 500 034Q
3 KAMBHAMPATI, RAMA SASTRI SUVEN PHARMACEUTICALS, SERENE CHAMBERS, ROAD NO. 7, BANJARA HILLS, HYDERABAD 500 034
PCT International Classification Number C07D 498/22
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA