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    • 专利摘要:
    PURPOSE: Substituted bisindolylmaleimides are anti-proliferative agents useful in the treatment or control of cancer, particularly in the treatment or control of solid tumors. The compounds are especially useful in the treatment or control of breast tumors. CONSTITUTION: Compounds of formula (I) wherein: R1 and R1' are independently alkyl, aryl, alkenyl or alkynyl; R2 and R2' are independently hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonyl-aminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxy alkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulfinyl; R4, R5, R6, R7, R4', R5', R6' and R7' each independently are hydrogen, formula (II), CO2R9, CH2OR10, CHO, CH2NR11R12, CON(R13)2, halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, azide, phosphate or phosphonate provided that at least one of R4, R5, R6 and R7 and at least one of R4', R5', R6' and R7' are other than hydrogen, with the proviso that when R6 is method, R5 or R5' are not method; R8 is alkyl or aryl; R9 is alkyl or aryl; R10 is hydrogen, alkyl or aryl; R11 and R12 are independently hydrogen, alkyl, aryl, aralkyl or acyl; R13 is hydrogen, alkyl, aryl or aralkyl; and one of X and Y signifies O and the other signifies O, S, (H,OH) or (H,H); as well as pharmaceutically acceptable prod rugs therefor or pharmaceutically acceptable salts of acidic compounds of formula (I) with basis or basic compounds of formula (I) with acids are anti proliferative agents useful in the treatment of cancer.
    公开号:KR20000029640A
    申请号:KR1019997000711
    申请日:1997-07-19
    公开日:2000-05-25
    发明作者:딩그라우르바쉬후다；허린도나메리；키이쓰데니스달톤
    申请人:프리돌린 클라우스너;롤란드 비. 보레르；에프. 호프만-라 로슈 아게；
    IPC主号:
    专利说明:

    Substituted Bisindolylmaleimides for the Inhibition of Cell Proliferation
    The present invention relates to substituted pyrroles. More particularly, the present invention relates to pharmaceutically acceptable prodrugs of the following formula (I) as well as to pharmaceutically acceptable prodrugs thereof, or to acidic compounds and bases of formula (I) or to basic compounds and acids of formula (I) Possible salts are:
    Where
    R 1 and R 1 ′ are independently alkyl, aryl, alkenyl or alkynyl;
    R 2 and R 2 ' are independently hydrogen or alkyl;
    R 4 , R 5 , R 6 , R 7 , R 4 ' , R 5' , R 6 ' and R 7' are each independently hydrogen, , CO 2 R 9 , CH 2 OR 10 , CHO, CH 2 NR 11 R 12 , CON (R 13 ) 2 , halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino , Aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, azide, phosphate or phosphonate, provided that R 4 , R 5 , At least one of R 6 and R 7 and at least one of R 4 ′ , R 5 ′ , R 6 ′ and R 7 ′ is not hydrogen;
    R 8 is alkyl or aryl;
    R 9 is alkyl or aryl;
    R 10 is hydrogen, alkyl or aryl;
    R 11 and R 12 are independently hydrogen, alkyl, aryl, aralkyl or acyl;
    R 13 is hydrogen, alkyl, aryl or aralkyl;
    One of X and Y represents O and the other represents O, S, (H, OH) or (H, H);
    Provided that if R 6 is methoxy then R 5 or R 5 ' is not methoxy.
    The compounds of the present invention are antiproliferative agents useful for the treatment or inhibition of cancer, particularly for the treatment or inhibition of hard tumors. The compounds of the present invention are particularly useful for the treatment or inhibition of prothoracic tumors.
    As used herein, the term "alkyl", alone or in combination, is substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, amino, halogen, thioalkyl or alkylsulfinyl, or unsubstituted to the maximum carbon number 10, preferably up to 5 straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, secondary-butyl, t-butyl and pentyl. The term "alkoxy" denotes a group in which the alkyl moiety is as defined above, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like. Haloalkyl groups can have one or more halogen atoms, examples of which groups are chloromethyl and trifluoromethyl. The term "acyl", alone or in combination, refers to a group derived from alkanoic acids having up to 10, preferably up to 5 carbon atoms, such as acetyl, propionyl or butyryl, or from aromatic carboxylic acids, such as benzoyl. it means. Examples of substituents on alkanoic acid include one or more of the following: hydroxy, alkoxy, amino, halogen, thioalkyl, carboxy, carboxylic acid derivative or alkyl sulfinyl and the like. Examples of substituents on aromatic carboxylic acids include one or more of the following: halogen, alkyl, hydroxy, benzyloxy, alkoxy, haloalkyl, nitro, amino, cyano and the like. The term "aryl", alone or in combination, means a phenyl group or unsubstituted phenyl group having one or more, preferably 1 to 3 substituents, examples of which include halogen, alkyl, hydroxy, benzyloxy, Alkoxy, haloalkyl, nitro, amino and cyano. The term "halogen" means fluorine, chlorine, bromine or iodine. The term "amino", alone or in combination, refers to an amine or unsubstituted amine group substituted by one or more substituents selected from alkyl, aryl, acyl, alkylsulfonyl or arylsulfonyl. The term "alkenyl" refers to a straight or branched chain hydrocarbon group of 2 to 5 carbon atoms having one or more double bonds. Groups having 3 to 5 carbon atoms are preferred. The term "alkynyl" refers to a straight or branched chain having 2 to 5 carbon atoms having one or more triple bonds. Groups having 3 to 5 carbon atoms are preferred.
    The term "amino protecting group" means any conventional amino protecting group such as alkyl, preferably methyl, substituted alkyl such as trityl and trialkylsilylethyl, acyl and the like.
    As used herein, the term "pharmaceutically acceptable precursor" means a compound that can be converted into a compound of formula (I) or a pharmaceutically acceptable salt thereof under physiological conditions or by solubilization.
    In the above formula (I), R 1 and R 1 ′ are preferably alkyl. In a particularly preferred embodiment, R 1 and R 1 ′ are methyl. Preferably, R 2 and R 2 ' are hydrogen.
    At least one of R 4 , R 5 , R 6 and R 7 , and at least one of R 4 ′ , R 5 ′ , R 6 ′ and R 7 ′ is preferably nitro, alkoxy, alkyl, halogen, cyano, , CO 2 R 9 , CH 2 OR 10 , CH 2 NR 11 R 12 , CHO, CON (R 13 ) 2 , alkylthio or aralkyloxy.
    In a preferred embodiment, at least one of R 4 , R 5 , R 6 and R 7 , and R 4 ′ , R 5 ′ , R 6 ′ and R 7 ′
    At least one of cyano, , CO 2 R 9 , CH 2 OR 10 , CH 2 NR 11 R 12 , CHO or CON (R 13 ) 2 .
    In a particularly preferred embodiment, one of R 4 , R 5 , R 6 and R 7 , and one of R 4 ′ , R 5 ′ , R 6 ′ and R 7 ′ is nitro, alkoxy, alkyl, halogen, cyano, , CO 2 R 9 , CH 2 OR 10 , CH 2 NR 11 R 12 , CHO, CON (R 13 ) 2 , alkylthio or aralkyloxy, and the other is hydrogen.
    In a particularly preferred embodiment, R 6 and R 6 ′ are independently nitro, alkoxy, alkyl, halogen, cyano, , CO 2 R 9 , CH 2 OR 10 , CH 2 NR 11 R 12 , alkylthio or aralkyloxy, CHO, CON (R 13 ) 2 , one of R 4 , R 5 and R 7 , and R 4 ′ , R 5 ' and R 7' are hydrogen.
    Preferably, R 8 and R 9 are independently alkyl, in particular methyl, with R 10 being hydrogen or alkyl, preferably methyl, R 11 and R 12 being hydrogen or alkyl, R 13 being hydrogen or alkyl to be.
    Preferred compounds of formula (I) are those in which R 1 and R 1 ′ are alkyl; R 2 and R 2 ' are hydrogen, at least one of R 4 , R 5 , R 6 and R 7 , and at least one of R 4' , R 5 ' , R 6' and R 7 ' are nitro, alkoxy, alkyl Halogen, cyano, , CO 2 R 9 , CH 2 OR 10 , CH 2 NR 11 R 12 , CHO, CON (R 13 ) 2 , alkylthio or aralkyloxy, R 8 and R 9 are alkyl; R 10 is alkyl; R 11 and R 12 are alkyl; R 13 is alkyl.
    In a particularly preferred embodiment, R 1 and R 1 ′ are alkyl; R 2 and R 2 ' are hydrogen, one of R 4 , R 5 , R 6 and R 7 , and one of R 4' , R 5 ' , R 6' and R 7 ' is nitro, alkoxy, alkyl, halogen , Cyano, , CO 2 R 9 , CH 2 OR 10 , alkylthio, aralkyloxy, CH 2 NR 11 R 12 , CHO or CON (R 13 ) 2 , the other is hydrogen; R 8 and R 9 are methyl; R 10 is methyl; R 11 and R 12 are methyl; R 13 is methyl.
    In another preferred embodiment, R 1 and R 1 ′ are alkyl; R 2 and R 2 ' are hydrogen and one of R 4 , R 5 , R 6 and R 7 is amino, acylamino, monoalkylamino or dialkylamino.
    In a particularly preferred embodiment, R 1 and R 1 ′ are alkyl; R 2 and R 2 ' are hydrogen, R 6 is amino, acylamino, monoalkylamino or dialkylamino and at least one of R 4' , R 5 ' and R 6' is , CO 2 R 9 , CH 2 OR 10 , CHO, CH 2 NR 11 R 12 , CON (R 13 ) 2 , halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino , Aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, azide, phosphate or phosphonate.
    In a more preferred embodiment, R 1 and R 1 ′ are alkyl; R 2 and R 2 ' are hydrogen, R 6 is amino, acylamino, monoalkylamino or dialkylamino, and R 6' is , CO 2 R 9 , CH 2 OR 10 , CHO, CH 2 NR 11 R 12 , CON (R 13 ) 2 , halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino , Aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, azide, phosphate or phosphonate; Preferably R 6 ' is alkoxy, halogen, cyano, alkylthio, alkyl, nitro or acylamino.
    Compounds of formula (I), in which X and Y both represent O, are prepared by the following Schemes 1-3.
    Where
    R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are as defined above;
    Provided that when any of R 1 to R 7 is a substituent reacting with an acid chloride, for example when any of R 1 to R 7 is hydroxy, hydroxyalkyl, amino, monoalkylamino or aminoalkyl, Such substituents are protected by conventional protecting groups.
    As disclosed in Scheme 1, a compound of Formula II (known compound or compound prepared by a known method) is prepared at an inert solvent such as N, N-dimethylformamide at a temperature of about 0 ° C to about 25 ° C. Or reacted with NaH and CH 3 I in tetrahydrofuran to form the corresponding compound of formula III.
    The compound of formula III is reacted with oxalyl chloride in a solvent such as diethyl ether (Et 2 O) or dichloromethane (CH 2 Cl 2 ) at a temperature between 0 ° C. and 25 ° C. To form.
    Where
    R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 1 ' , R 2' , R 4 ' , R 5' , R 6 ' and R 7'' are as defined above;
    Provided that any of R 1 to R 7 or R 1 ' to R 7' is a substituent that reacts with an acid chloride, for example any of R 1 to R 7 or R 1 ' to R 7' is hydroxy When substituted, hydroxyalkyl, amino, monoalkylamino or aminoalkyl, these substituents are protected by conventional protecting groups.
    As disclosed in Scheme 2, a compound of Formula V (known compound or compound prepared by a known method) is reacted with POCl 3 in N, N-dimethylformamide (DMF) at a temperature of 0 ° C. to 60 ° C. To form the corresponding compound of formula VI.
    The compound of formula VI is reacted with NaH and CH 3 I in an inert solvent such as dimethylformamide or THF to form the corresponding compound of formula VII.
    Compounds of formula (VII) were dissolved in potassium, quaternary-butoxide (KOtBu) and toluene-4-sulfonyl methyl isocyanide in a solvent such as ethylene glycol-dimethylether (DME) at a temperature of -30 ° C to -60 ° C. Reaction with (TosMIC) and then treatment with methanol at a temperature of 65 ° C. to form the corresponding compound of formula VIII.
    The compound of formula VIII is reacted with HCl gas in isopropanol to form the corresponding compound of formula IX.
    The compound of formula IX is reacted with the compound of formula IV and Et 3 N in a solvent such as methylene chloride at a temperature between 0 ° C. and 25 ° C. The resulting product is then treated with para-toluene sulfonic acid (pTsOH) in a solvent such as toluene at a temperature of about 25 ° C. to form the corresponding compound of formula (I). If a protecting group was used during the reaction of a compound of Formula IX with a compound of Formula IV, the protecting group is removed at this point by methods known in the art.
    Alternatively, preferably, compounds of formula I, wherein R 4 , R 5 , R 6 , R 7 , R 4 ' , R 5' , R 6 ' and R 7' are amino, alkylamino, dialkylamino or acylamino To prepare a bis-indolylmaleimide precursor of formula (I) wherein R 4 , R 5 , R 6 , R 7 , R 4 ' , R 5' , R 6 ' or R 7' is nitro, Reduction by known methods forms the corresponding amino bis-indolylmaleimide. The amino group is then modified with the desired alkylamino, dialkyl or acylamino derivative by methods known in the art.
    R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are compounds of formula I wherein R 1 ' , R 2' , R 4 ' , R 5' , R 6 ' and R 7' It can be prepared by Scheme 3.
    Where
    R is an amino protecting group,
    W is halogen,
    R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are the same as R 1 ′ , R 2 ′ , R 4 ′ , R 5 ′ , R 6 ′ and R 7 ′ , as defined above .
    As disclosed in Scheme 3, a compound of Formula XI (known compound or a compound prepared by a known method) is prepared in a solvent such as toluene at a temperature of 25 ° C. to the reflux temperature of the solvent Compound or a compound prepared by a known method), a base such as methylmagnesium iodide, and a base such as sodium hydride to form the corresponding compound of formula XII.
    The compound of formula XII is reacted with a base such as potassium carbonate and an alkylating agent such as CH 3 I in a solvent such as N-methylpyrrolidinone at room temperature to form the corresponding compound of formula XIII.
    The protective group R was removed to react the compound of formula XIII with potassium hydroxide in a solvent such as ethanol and then 1,1,1,3,3,3-hexa-methyldisilazane and methanol in a solvent such as DMF at room temperature. The corresponding compounds of formula la are formed by conventional methods which may comprise treating with a mixture of
    Compounds of formula (I), in which one of X and Y represent O and the other represents S, are prepared by reacting a compound of formula (I) in which both X and Y represent O with a sulfiding agent.
    Conventional procedures can be used to carry out the sulfidation, which includes the protection of substituents prior to sulfidation and deprotection after sulfidation, known to those skilled in the art.
    Sulfides include phosphorus pentasulphide, Lawesson's reagent [2,4-bis (4-methoxyphenyl) -1,2-dithioxo-1,3,2,4, -dithiaphosphane; Bull. Soc. Chim. Belg. 87 (1987) 229-238] or Davy reagent [2,4-bis (methylthio) -1,3,2,4-dithiadiphosphane; Sulfur Lett. 1983, 1, 167])]. This reaction is carried out in an inert organic solvent, for example aliphatic or cyclic ethers (for example dimethoxyethane) or halogenated aromatic hydrocarbons (for example benzene, toluene or chlorobenzene) and at elevated temperatures, in particular in the reaction mixture Is carried out appropriately at a rereflux temperature
    Compounds of formula (I) in which one of X and Y represent O and the other represents (H, OH) are prepared by reducing a compound of formula (I) in which both X and Y represent O with a complex metal hydride.
    Reduction can be carried out by known techniques, including the protection of substituents on indole rings before reduction and deprotection after reduction according to known methods. Other hydrides such as diisobutylaluminum hydride and sodium dihydro-bis (2-methoxy-ethoxy) aluminate may also be used, but alkali metal aluminum hydrides such as lithium aluminum hydride are preferably complex Used as metal hydride. Suitable inert organic solvents in which this reduction can be carried out include aliphatic and cyclic ethers such as diethyl ether or tetrahydrofuran (THF) and hydrocarbons such as hexane, benzene and toluene. Conveniently, this reduction is performed near room temperature.
    Compounds of formula (I) wherein one of X and Y represents O and the other represents (H, H) catalyzes a compound of formula (I) wherein one of X and Y represents O and the other represents (H, OH) It can be produced by hydrogenation with.
    Conventional procedures can be used to carry out catalytic hydrogenation including the protection and deprotection of substituents on indole rings according to known procedures. Thus, catalytic hydrogenation can be carried out in the presence of a palladium or platinum catalyst, for example a noble metal catalyst such as palladium / carbon (Pd / C) and an inert organic solvent such as alkanol (eg methanol or ethanol). This catalytic hydrogenation is suitably carried out near room temperature and under atmospheric pressure.
    If desired, the acidic compound of formula (I) may be converted to a pharmaceutically acceptable salt using a base, or the basic compound of formula (I) may be converted to a pharmaceutically acceptable salt using an acid.
    The conversion of the acidic compound of formula I to a pharmaceutically acceptable salt can be carried out by treatment with a suitable base by known techniques. Suitable salts are salts derived from inorganic bases such as sodium, potassium or calcium salts as well as salts derived from organic bases such as ethylenediamine, monoethanolamine or diethanolamine. The conversion of the basic compound of formula I to a pharmaceutically acceptable salt can be carried out by treatment with a suitable acid by known techniques. Suitable salts are salts derived from inorganic acids such as hydrogen chloride, hydrogen bromide, phosphate or sulfates as well as organic acids such as acetate, citrate, fumarate, tartrate, maleate, methanesulfonate or p-toluene Salts derived from sulfonates.
    Pyrrole of formula (I) and pharmaceutically acceptable salts thereof can inhibit cellular processes, such as cell proliferation, and in combination with organ transplants, can also be used in oncology to treat or inhibit inflammatory diseases such as arthritis, immune diseases, etc. have.
    The epithelial prethoracic cancer cell line (MDAMB-435) was purchased from the ATCC (American Type Cell Culture Collection) and grown in culture in the medium recommended by ATCC. To analyze the effect of various compounds on these cell growth, cells were plated at a concentration of 1500 cells / well in 96 well tissue culture plates (test plates). The day after the cells were plated, the compound to be analyzed was dissolved in 100% DMSO (dimethyl sulfoxide) to obtain a 10 mM stock solution. Each compound was diluted to 1 mM in H 2 O and added to three wells in a first row of 96 well master plate containing medium to obtain a final concentration of 40 μM. The compound was then diluted in turn in the medium of the "master plate". The diluted compound (s) was then transferred to the test plate containing the cells. DMSO was added to ten "control cells" of excipients. The final concentration of DMSO in each well was 0.1%. Five days after the drug was added, the plates were analyzed as follows:
    MTT (3- (4,5 methyl thiazol-2-yl) -2,5-diphenyl tetrazolium bromide; thiazolyl blue) was added to each well to obtain a final concentration of 1 mg / ml. The plates were then incubated at 37 ° C. for 2.5-3 hours. The MTT containing medium was then removed and 50 μl of 100% ethanol was added to each well to dissolve formazan. Absorbance was then read using an automated plate reader (Bio-tek microplate reader). IC 50 was calculated using the Reed and Munsch equation (see Am. J. Hygiene Vol. 27 pgs. 493-497, 1938).
    The results are provided in Tables 1a and 1b below for compounds of Formula Ia.
    Pyrroles of formula (I) and their aforementioned salts can be used as medicaments, for example in the form of pharmaceutical preparations, for example of tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions, emulsions or suspensions It may be administered orally in the form. They may also be administered parenterally, for example in the form of suppositories, or for example in the form of injection solutions.
    For the preparation of pharmaceutical preparations, these compounds may be combined with therapeutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, steric acid or salts thereof can be used as carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft capsules are vegetable oils, waxes, fats, semisolid or liquid polyols. However, depending on the nature of the active substance, no carrier is necessary in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are water, polyols, saccharose, invert sugar and glucose. Suitable carriers for injection solutions are water, alcohols, polyols, glycerin and vegetable oils. Suitable carriers for suppositories are natural or cured oils, waxes, fats and semisolid polyols.
    The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, coatings or antioxidants. They may also contain other pharmaceutically valuable substances.
    As mentioned above, the pyrroles of formula I and their aforementioned salts can be used for the treatment or inhibition of oncological, inflammatory, immunological, bronchial and cardiovascular diseases. Dosages may vary within wide limits and will, of course, be adjusted to the individual needs in each particular case. In general, in the case of oral administration to adults, a daily dosage of about 5 mg to 5000 mg is suitable, although it may exceed the upper limit if appropriate. The daily dose may be administered as a single dose or in divided doses.
    The following examples illustrate the invention:
    Example 1
    3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione
    a) A solution of known 6-nitro-1H-indole (5 g, 31 mM) in dimethylformamide (DMF) (50 ml) was cooled to 0 ° C. and treated with NaH (1 g, 37 mM). After stirring at 0 ° C. for 2 h, CH 3 I (2.3 ml, 37 mM) was added and the reaction stirred overnight while warming to room temperature. After pouring into H 2 O (500 ml), the mixture was extracted with ethyl acetate (EtOAc, 200 ml × 4). The combined organic fractions were dried over MgSO 4 , filtered and evaporated. Purification by flash column chromatography yielded 1-methyl-6-nitro-1H-indole (5.34 g, 97%).
    b) A stirred solution of 1-methyl-6-nitro-1H-indole in diethyl ether (Et 2 O, 5 ml) was cooled to 0 ° C. and treated with oxalyl chloride (0.15 ml, 1.7 mM). After stirring overnight at room temperature, the solids were collected, washed with ether and dried to give (1-methyl-6-nitro-1H-indol-3-yl) -oxo-acetyl chloride (225 mg, 96%). .
    c) A mixture of DMF (7 ml, 90 mM) and POCl 3 (2.25 ml, 24.5 mM) was cooled to 5 ° C. and treated with known 6-methoxy-1H-indole. After stirring for 1 hour at room temperature, the mixture was heated at 45 ° C. for 1 hour and then cooled to room temperature overnight. The reaction mixture was poured onto ice (100 ml) and stirred for 30 minutes, during which time a solution of KOH (9.6 g, 171 mM) in H 2 O (20 ml) was added dropwise. After stirring for 30 minutes, it was then heated at 60 ° C. for 1 hour, the reaction was cooled to 30 ° C. and the pH adjusted to 7 with 1 N HCl. The mixture was extracted with EtOAc (50 ml × 3) and the organic fractions mixed, dried over MgSO 4 , filtered and evaporated. The residue was purified by crystallization from methanol to give 6-methoxy-1H-indole-3-carboxaldehyde (1.65 g, 69%).
    d) A solution of 6-methoxy-1H-indole-3-carboxaldehyde (1.65, 9.4 mmM) in DMF (10 ml) was cooled to 0 ° C. and treated with NaH (11.3 mM). After stirring at room temperature for 1 hour, the mixture was cooled to 0 ° C., treated with CH 3 I (0.7 ml, 11.3 mM) and then warmed at room temperature overnight. After poured into H 2 O (200 ml), the mixture was acidified with HCl and extracted with EtOAc (100 ml × 2). The combined organic fractions were dried over MgSO 4 , filtered and evaporated to give 6-methoxy-1-methoxy-1H-indole-3-carboxaldehyde (1.78 g, 99%).
    e) Toluene-4-sulfonylmethyl in DME (15 ml) in a cooled (-30 ° C) suspension of potassium tert-butoxide (KOtBu, 1.62 g, 14.4 mM) in dimethoxyethane (DME; 25 ml) A solution of isocyanide (TosMIC, 1.45 g, 7.4 mM) was added. After the mixture was further cooled to -60 ° C, a solution of 6-methoxy-1-methyl-1H-indole-3-carboxaldehyde (800 mg, 4.23 mM) was slowly added and the reaction mixture was allowed to 1.5 hours. Stirred. After treatment with methanol (11 ml), the mixture was heated to the reflux temperature for 15 minutes and then the solvent was evaporated. The residue was treated with H 2 O (15 ml) containing acetic acid (HOAc, 55 ml) and then extracted with CH 2 Cl 2 (50 ml × 3). The combined organic layers were washed with saturated NaHCO 3 solution (50 ml), dried over MgSO 4 , filtered and evaporated. Purification by flash column chromatography yielded (6-methoxy-1-methyl-1H-indol-3-yl) -acetonitrile (0.6 g, 70%).
    f) HCl gas was sent to a suspension of (6-methoxy-1-methyl-1H-indol-3-yl) -acetonitrile in isopropanol (25 ml). After 3 h the solvent was evaporated and the residue was evaporated from diethyl ether (Et 2 O, 50 ml × 2). The tan residue was further dried under high vacuum to afford 2- (6-methoxy-1-methyl-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride (1.6 g, 82%). Obtained.
    g) (1-methyl-6-nitro-1H-indol-3-yl) -oxo-acetyl chloride (251 mg, 0.94 mM) and 2- (6-methoxy-1) in CH 2 Cl 2 (25 ml) A suspension of -methyl-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride (280 mg, 0.94 mM) was cooled to 0 ° C. and treated with Et 2 N (0.53 ml, 3.7 mM), Stir at room temperature overnight while warming to room temperature. The mixture was then diluted with CH 2 Cl 2 (25 ml) and washed with H 2 O (25 ml) and 0.5 N HCl (20 ml). The combined organic layer was dried over MgSO 4 , filtered and evaporated. The residue was then mixed with toluene (4 ml), cooled to 0 ° C., treated with pTsOH (197 mg, 1 mM) and stirred for 3 hours. The precipitated red solid was collected and partitioned between CH 2 Cl 2 (50 ml) and H 2 O (25 ml). The organic fractions were washed with saturated NaHCO 3 solution (25 ml), then dried over MgSO 4 , filtered and evaporated. The residue was rinsed with tetrahydrofuran (THF) to yield 3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (1- with a melting point of 308-310 ° C. in 31% yield. Methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione was obtained.
    Example 2
    By a technique similar to that described in Example 1g), the following compounds were prepared. Starting materials were prepared by techniques similar to those described in 1b) and 1f).
    a) 3- (6-benzyloxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl)-having a melting point of 160 to 165 ° C Pyrrole-2,5-dione (6-benzyloxy-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl ) -Acetimide acid isopropyl ester hydrochloride.
    b) 3- (6-chloro-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole having a melting point of 300 to 302 ° C -2,5-dione (6-chloro-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl)- Prepared from acetimide acid isopropyl ester hydrochloride.
    c) 3- (1,6-dimethyl-1H-indol-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -pyrrole having a melting point of 240 to 245 ° C. 2,5-dione (6-methoxy-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1,6-dimethyl-1H-indol-3-yl) -acetimide Prepared from acid isopropyl ester hydrochloride.
    d) 3- (1,6-dimethyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2 having a melting point of 268 to 272 ° C. , 5-dione (1-methyl-6-nitro-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1,6-dimethyl-1H-indol-3-yl) -acetimidic acid iso Prepared from propyl ester hydrochloride.
    e) 3,4-bis- (6-methoxy-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione having a melting point of 258-260 ° C. (6-methoxy-1- Prepared from methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (6-methoxy-1-methyl-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    f) 3- (6-fluoro-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl)-having a melting point of 270 to 272 ° C. Pyrrole-2,5-dione (6-fluoro-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl ) -Acetimide acid isopropyl ester hydrochloride.
    g) 3,4-bis- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione having a melting point of 360 ° C. or higher is converted to (1-methyl-6-nitro-1H- Prepared from indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    h) 3- (6-fluoro-1-methyl-1H-indol-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) having a melting point of 255 to 257 ° C. Pyrrole-2,5-dione (6-fluoro-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (6-methoxy-1-methyl-1H-indole-3 Prepared from -yl) -acetimide acid isopropyl ester hydrochloride.
    i) 3- (6-chloro-1-methyl-1H-indol-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl)-having a melting point of 283-285 ° C.- Pyrrole-2,5-dione (6-chloro-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (6-methoxy-1-methyl-1H-indol-3-yl ) -Acetimide acid isopropyl ester hydrochloride.
    j) 1-methyl-3- [4- (1-methyl-6-nitro-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro- having a melting point of 294 to 296 ° C. 1H-Pyrrole-3-yl] -1H-indole-6-carboxylic acid methyl ester (1-methyl-6-methoxycarbonyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1- Prepared from methyl-6-nitro-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    k) 1-methyl-3- [4- (1-methyl-6-nitro-1H-indol-3-yl) -2,5-dioxo-2,5- having a melting point of 253 to 255 ° C. (decomposition) Dihydro-1H-pyrrole-3-yl] -1H-indole-6-carbonitrile (6-cyano-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1- Prepared from methyl-6-nitro-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    l) 3- [4- (1,6-dimethyl-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrole-3- having a melting point of 310 to 312 ° C. Il] -1-methyl-1H-indole-6-carbonitrile (6-cyano-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1,6-dimethyl-1H Prepared from -indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    m) 3- [4- (6-methoxy-1-methyl-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrole having a melting point of 261 to 263 ° C. -3-yl] -1-methyl-indol-6-carbonitrile (6-cyano-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (6-methoxy-1 Prepared from -methyl-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    n) 3- (1-methyl-6-methylsulfanyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) with a melting point of 273-275 ° C -Pyrrole-2,5-dione (1-methyl-6-methylsulfanyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indole-3 Prepared from -yl) -acetimide acid isopropyl ester hydrochloride.
    o) 3- (6-bromo-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) having a melting point of 319 to 321 ° C. Pyrrole-2,5-dione (6-bromo-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl ) -Acetimide acid isopropyl ester hydrochloride.
    p) 3- (6-iodo-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) having a melting point of 317 to 321 ° C; Pyrrole-2,5-dione (6-iodo-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl ) -Acetimide acid isopropyl ester hydrochloride.
    q) 3- (6-azido-1-methyl-1H-indol-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -pyrrole-2,5- Dione to (6-azido-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (6-methoxy-1-methyl-1H-indol-3-yl) -acetimide acid Prepared from isopropyl ester hydrochloride.
    r) 3- (4-methoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl)-having a melting point of 290 to 292 ° C. Pyrrole-2,5-dione (4-methoxy-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl ) -Acetimide acid isopropyl ester hydrochloride.
    s) 3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (4-methoxy-1-methyl-1H-indol-3-yl) with a melting point of 270-273 ° C. -Pyrrole-2,5-dione (4-methoxy-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (6-methoxy-1-methyl-1H-indole-3 Prepared from -yl) -acetimide acid isopropyl ester hydrochloride.
    t) 3- (4-fluoro-1-methyl-1H-indol-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) having a melting point of 283 to 285 ° C. -Pyrrole-2,5-dione (4-fluoro-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (6-methoxy-1-methyl-1H-indole-3 Prepared from -yl) -acetimide acid isopropyl ester hydrochloride.
    u) 3- (4-Fluoro-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione To (4-Fluoro-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl) -acetimide acid isopropyl Prepared from ester hydrochloride.
    v) 3- [4- (5-methoxy-1-methyl-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrole having a melting point of 326 to 328 ° C. 3-yl] -1-methyl-1H-indole-6-carbonitrile (6-cyano-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (5-methoxy Prepared from -1-methyl-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    w) 3- (6-chloro-1-methyl-1H-indol-3-yl) -4- (5-methoxy-1-methyl-1H-indol-3-yl)-having a melting point of 289 to 292 ° C. Pyrrole-2,5-dione (6-chloro-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (5-methoxy-1-methyl-1H-indol-3-yl ) -Acetimide acid isopropyl ester hydrochloride.
    x) 3- (5-methoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-methylsulfanyl-1H-indol-3-yl having a melting point of 261 to 264 ° C. ) -Pyrrole-2,5-dione (1-methyl-6-methylsulfanyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (5-methoxy-1-methyl-1H-indole Prepared from 3-yl) -acetimide acid isopropyl ester hydrochloride.
    y) 3- (6-ethoxy-1-methyl-1H-indol-3-yl) -4- (5-methoxy-1-methyl-1H-indol-3-yl) having a melting point of 229 to 232 ° C. -Pyrrole-2,5-dione (6-ethoxy-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (5-methoxy-1-methyl-1H-indole-3 Prepared from -yl) -acetimide acid isopropyl ester hydrochloride.
    z) 3- (1,6-dimethyl-1H-indol-3-yl) -4- (1,5-dimethyl-1H-indol-3-yl) -pyrrole-2,5 having a melting point of 248-250 ° C. -Dione (1,6-dimethyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1,5-dimethyl-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride Prepared from.
    aa) 3- (5-chloro-1-methyl-1H-indol-3-yl) -4- (1,6-dimethyl-1H-indol-3-yl) -pyrrole-2 having a melting point of 247 to 249 ° C , 5-dione to (5-chloro-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1,6-dimethyl-1H-indol-3-yl) -acetimidic acid iso Prepared from propyl ester hydrochloride.
    bb) 3- [4- (1,6-dimethyl-1H-indol-3-yl] -2,5-dioxo-2,5-dihydro-1H-pyrrole-3- having a melting point of 269 to 271 ° C. Yl] -1-methyl-1H-indole-5-carbonitrile (5-cyano-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1,6-dimethyl-1H Prepared from -indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    cc) 3- (1,5-dimethyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2 having a melting point of 248 to 250 ° C. , 5-dione to (1,5-dimethyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl) -acetimide acid iso Prepared from propyl ester hydrochloride.
    dd) 1-methyl-3- [4- (1-methyl-6-nitro-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro- having a melting point of 257 to 260 ° C. 1H-Pyrrole-3-yl] -1H-indole-5-carbonitrile was converted to (5-cyano-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6) -Nitro-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    ee) 3- (5-chloro-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole having a melting point of 301 to 303 ° C. -2,5-dione (5-chloro-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl)- Prepared from acetimide acid isopropyl ester hydrochloride.
    ff) 3- (1-methyl-5-nitro-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2 having a melting point of 270 ° C. , 5-dione (1-methyl-5-nitro-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl) -acetimide Prepared from acid isopropyl ester hydrochloride.
    gg) 3- (5-methoxy-1-methyl-1H-indol-3-yl) -4- (4-methoxy-1-methyl-1H-indol-3-yl) having a melting point of 250 to 254 ° C. -Pyrrole-2,5-dione (4-methoxy-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (5-methoxy-1-methyl-1H-indole-3 Prepared from -yl) -acetimide acid isopropyl ester hydrochloride.
    hh) 3,4-bis- (5-methoxy-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione having a melting point of 236 to 238 ° C. (5-methoxy-1- Prepared from methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (5-methoxy-1-methyl-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    ii) 3- (1,5-dimethyl-1H-indol-3-yl) -4- (5-methoxy-1-methyl-1H-indol-3-yl) -pyrrole having a melting point of 217 to 220 ° C. 2,5-dione (1,5-dimethyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (5-methoxy-1-methyl-1H-indol-3-yl) -acetimide Prepared from acid isopropyl ester hydrochloride.
    jj) 3- (5-chloro-1-methyl-1H-indol-3-yl) -4- (5-methoxy-1-methyl-1H-indol-3-yl)-having a melting point of 245 to 248 ° C. Pyrrole-2,5-dione (5-chloro-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (5-methoxy-1-methyl-1H-indol-3-yl ) -Acetimide acid isopropyl ester hydrochloride.
    kk) 3- [4- (5-methoxy-1-methyl-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrole having a melting point of 252 to 255 ° C. -3-yl] -1-methyl-1H-indole-5-carbonitrile (5-cyano-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (5-methoxy Prepared from -1-methyl-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    ll) 3- (1-methyl-6-nitro-1H-indol-3-yl) -4- (1-methyl-7-nitro-1H-indol-3-yl) -pyrrole-2,5-dione (1-Methyl-6-nitro-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-7-nitro-1H-indol-3-yl) -acetimide acid isopropyl ester hydro Prepared from chloride.
    mm) 3- (6-Fluoro-1-methyl-1H-indol-3-yl) -4- (1-methyl-7-nitro-1H-indol-3-yl) -pyrrole-2,5-dione (6-Fluoro-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-7-nitro-1H-indol-3-yl) -acetimide acid isopropyl Prepared from ester hydrochloride.
    nn) 3- (1,6-dimethyl-1H-indol-3-yl) -4- (1-methyl-7-nitro-1H-indol-3-yl) -pyrrole-2 having a melting point of 259 to 261 ° C. , 5-dione (1-methyl-7-nitro-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1,6-dimethyl-1H-indol-3-yl) -acetimide acid iso Prepared from propyl ester hydrochloride.
    oo) 3- (4-fluoro-1-methyl-1H-indol-3-yl) -4- (6-ethoxy-1-methyl-1H-indol-3-yl) -pyrrole having a melting point of at least 280 ° C -2,5-dione (4-fluoro-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (6-ethoxy-1-methyl-1H-indol-3-yl ) -Acetimide acid isopropyl ester hydrochloride.
    pp) 3- (4-bromo-1-methyl-1H-indol-3-yl) -4- (6-ethoxy-1-methyl-1H-indol-3-yl) -pyrrole having a melting point of at least 266 ° C. -2,5-dione (4-bromo-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (6-ethoxy-1-methyl-1H-indol-3-yl ) -Acetimide acid isopropyl ester hydrochloride.
    qq) 3- (6-ethoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole- having a melting point of 260 ° C. 2,5-dione (1-methyl-6-nitro-1H-indol-3-yl) -oxo-acetyl chloride and 2- (6-ethoxy-1-methyl-1H-indol-3-yl)- Prepared from acetimide acid isopropyl ester hydrochloride.
    rr) 3- [6- [2- (2-ethoxy-ethoxy) -ethoxy] -1-methyl-1H-indol-3-yl] -4- (1-methyl-6 with a melting point of 124 ° C -Nitro-1H-indol-3-yl) -pyrrole-2,5-dione to [6- [2- (2-ethoxy-ethoxy) -ethoxy] -1-methyl-1H-indole-3- Prepared from Ill] -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    ss) N- [1-methyl-3- [4- (1-methyl-6-nitro-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrole- 3-yl] -acetimide with (6-acetylamino-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro-1H-indol-3-yl ) -Acetimide acid isopropyl ester hydrochloride.
    Example 3
    3- (1-methyl-6-methylsulfanyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione
    a) 4- (methylthio) -benzaldehyde (12.6 ml, in methanol (30 ml) to a solution of sodium methoxide prepared from Na metal (8.65 g, 0.38 M) in methanol (200 ml) at 0-5 ° C. 94.7 mM) and methyl azidoacetate (44 g, 0.382 M) were added. After stirring at the same temperature for 3 hours, the suspension was diluted with H 2 O (300 ml). The solid was filtered, washed with water and dried under vacuum to afford 19.4 g (82.0%) of methyl-2-azido-3- (4-methylthio-phenyl) -propenoate as a yellow solid.
    A solution of methyl-2-azido-3- (4-methylthiophenyl) -propenoate (20.6 g, 83 mM) in xylene (200 ml) was added dropwise to boiling xylene (250 ml) for 2 hours. The reaction mixture was heated at reflux for an additional 2 hours, then cooled slowly and placed in the freezer overnight. The solid was filtered, washed with a small amount of CH 2 Cl 2 / hexanes (1: 3) and dried to afford 11.2 g (61.0%) of methyl-6-methylsulfanyl-1H-indole-2-carboxylate. .
    A mixture of methyl-6-methylsulfanyl-1H-indole-2-carboxylate (11.2 g, 51 mM) and 2N NaOH (125 ml) was heated to reflux for 30 minutes. The clear solution was cooled and extracted with EtOAc. The aqueous fraction was acidified with concentrated HCl until pH was 1 and the precipitate formed was filtered and dried to give 6-methylsulfanyl-1H-indole-2-carboxylic acid (9.6 g, 91.0%).
    A mixture of 6-methylsulfanyl-1H-indole-2-carboxylic acid (9.6 g, 46 mM), Cu powder (2.1 g, 33 mM) and quinoline (100 ml) was heated at 215 ° C. for 3 hours. The mixture was cooled to rt, filtered through celite and the filtrate diluted with H 2 O (500 ml). The cooled mixture was acidified with concentrated HCl (pH = 1) and extracted with EtOAc. The organic fractions were washed with saturated NaCl solution, dried over MgSO 4 , filtered and evaporated to give 6-methyl-sulfanyl-1H-indole (6.8 g, 90%) after purification by flash column chromatography. .
    b) In a technique similar to Example 1f), 2- (1-methyl-6-nitro-1H-indol-3-yl) -acetimide acid isopropyl hydrochloride is converted to (1-methyl-6-nitro-1H- Prepared from indol-3-yl) -acetonitrile.
    c) In a similar manner to Example 1 g), 3- (1-methyl-6-methylsulfanyl-1H-indol-3-yl) -4- (1-methyl-6-nitro having a melting point of 273 to 275 ° C. -1H-indol-3-yl) -pyrrole-2,5-dione (1-methyl-6-methylsulfanyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl- Prepared from 6-nitro-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride.
    Example 4
    3,4-bis- (6-methoxy-1-methyl-indol-3-yl) -pyrrole-2,5-dione
    a) A solution of CH 3 MgI (15 mM, in Et 2 O) was treated with a solution of 6-methoxy-1H-indole (2.21 g, 15 mM) in toluene (20 ml). After stirring at room temperature for 3.5 hours, a solution of 3,4-dichloro-1-methylmaleimide (1.2 g, 6.5 mM) in toluene (20 ml) was added dropwise to the suspension. After heating at reflux for 2 hours, the mixture was cooled to room temperature and treated with NaH (26 mM). After heating the mixture at the reflux temperature for 15 hours, the mixture was poured into 20% aqueous citric acid solution and extracted with EtOAc (100 ml × 3). The combined organic fractions were washed with H 2 O, saturated NaCl solution and dried over MgSO 4 . After filtration and evaporation of the solvent, the residue was purified by flash column chromatography to give 3,4-bis- (6-methoxy-1H-indol-3-yl) -1-methyl maleimide (3.65 g, 70% ) Was obtained.
    b) K, a solution of 3,4-bis- (6-methoxy-1H-indol-3-yl) -1-methylmaleimide (0.97 g, 24 mM) and N-methylpyrrolidinone (25 ml) Treated with 2 CO 3 (5.8 g, 42 mM) and CH 3 I (2.13 g, 15 mM). After stirring for 15 hours, the volatile liquid was removed and the product precipitated by the addition of H 2 O (50 ml), collected and washed with H 2 O (20 ml) and hexane (10 ml) 3.4- Bis- (6-methoxy-1-methyl-indol-3-yl) -1-methylmaleimide (1 g, 96%) was obtained.
    c) A suspension of 3.4-bis- (6-methoxy-1-methyl-indol-3-yl) -1-methylmaleimide (0.96 g, 2.23 mM) in ethanol (30 ml) was charged with 5 N KOH (30 ml). ) And heated to the reflux temperature until tlc indicated the disappearance of starting material (after about 22 hours). After removing most of the methanol, the pH of the solution was adjusted to 2 by the addition of 2N HCl. The solid was collected by filtration and washed with H 2 O. This material (0.92 g) in DMF (16 ml) was prepared with 1,1,1,3,3,3-hexamethyldisilazane (4 g, 25 mM) and CH 3 OH (4 g, 12.5 mM). Treated with mixed solution. After stirring the solution for 15 h at room temperature, H 2 O (20 ml) is added and the precipitated solid is collected by filtration and further washed with H 2 O to give 3,4-bis with a melting point of 350 ° C. or higher. -(6-methoxy-1-methyl-indol-3-yl) -pyrrole-2,5-dione was obtained.
    Example 5
    The following three procedures illustrate the method of reducing nitro-bisindolemaleimide to amino bis-indolylmaleimide.
    a) 3- [4- (6-amino-1-methyl-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl] -1- Methyl-1H-indole-6-carbonitrile
    3- (6-cyano-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione (9.0 g, 21 mM) was suspended in ethanol (1.8 l) and treated with tin (II) chloride dihydrate (35 g, 156 mM). This was mechanically stirred for 16 hours at reflux. The reaction was cooled down and the volume reduced to 1 l. This was poured into a mixture of ethyl acetate (2 l) and saturated sodium bicarbonate solution (1 l) and mixed well. Decanted organic layer. Washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, evaporated and then purified by flash column chromatography (ethyl acetate). The product was further purified by crystallization from tetrahydrofuran / hexanes to give 6.5 g of 3- [4- (6-amino-1-methyl-1H-indol-3-yl) -2, having a melting point of 255 to 260 ° C., 5-dihydro-1H-pyrrol-3-yl] -1-methyl-1H-indole-6-carbonitrile is obtained.
    b) 3,4-bis- (6-amino-1 H-indol-3-yl) -pyrrole-2,5-dione
    3,4-bis- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione (50 mg, 0.11 mM) prepared in Example 2g was replaced with N, N-dimethyl Dissolved in formamide (10 ml), a catalytic amount of activated Raney nickel was added and the reaction was shaken in a Parr hydrogenator at 45 psi for 20 hours. The reaction mixture was filtered through ethyl bed with ethyl acetate and concentrated. The product was purified by recrystallization from acetone and hexanes to give 3,4-bis- (1-methyl-6-amino-1H-indol-3-yl) -pyrrole-2,5-dione (35 mg).
    c) 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (6-fluoro-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione
    1.0 g (2.39 mM) 3- (6-fluoro-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro) in 20 ml of ethanol and 10 ml of tetrahydrofuran To a suspension of -1H-indol-3-yl) -pyrrole-2,5-dione was added 0.55 g of 10% Pd / C and 0.54 ml of 5% hydrochloric acid. The mixture was cooled in an ice bath and 0.54 ml (14.34 mM) hydrazine hydrate (85%) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The catalyst was removed by filtration through celite. The filtrate was evaporated and the residue was crystallized from ethyl acetate / tetrahydrofuran / hexane to give 708 mg (76%) of 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (6 -Fluoro-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione was obtained.
    Example 6
    Following the general procedure indicated in Example 5, the following compounds were prepared:
    a) 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (6-chloro-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione 3- (6-Chloro-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl)-using the procedure c) of Example 5 Prepared from pyrrole-2,5-dione.
    b) 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (6-bromo-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione 3- (6-bromo-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) using procedure a) of Example 5 Prepared from) -pyrrole-2,5-dione.
    c) 3- [4- (6-amino-1-methyl-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl] -1- Methyl-1H-indole-6-carboxylic acid methyl ester was prepared using the procedure a) in Example 5.
    3- [4- (1-Methyl-6-nitro-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl] -1-methyl- Prepared from 1H-indole-6-carboxylic acid methyl ester.
    d) 3- (6-amino-1-methyl-1 H-indol-3-yl) -4- (1-methyl-6-methylsulfanyl-1 H-indol-3-yl) -pyrrole-2,5- Dion was prepared using the procedure a) in Example 5, 3- (1-methyl-6-methylsulfanyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indole-3 Prepared from -yl) -pyrrole-2,5-dione.
    e) Example 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (1,6-dimethyl-1H-indol-3-yl) -pyrrole-2,5-dione 5, using process c) 3- (1,6-dimethyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2, Prepared from 5-dione.
    f) 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione 3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) using procedure b) of Example 5 Prepared from) -pyrrole-2,5-dione.
    Example 7
    General procedure for preparing the hydrochloride salt of amino bis indolylmaleimide:
    3- (6-amino-1-methyl-1H-indol-3-yl) -4- (6-fluoro-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione hydrochloride salt
    75 mg (0.193 mM) of 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (6-fluoro-1-methyl-1H-indole-3 in 2 ml of acetonitrile To the mixture of -yl) -pyrrole-2,5-dione 10 ml of water were added and the solid precipitated. 0.64 ml (0.772 mM) of 1.2 M hydrochloric acid was added to the mixture to form a clear solution. After 10 minutes, the mixture was concentrated to dryness. It was redissolved in acetonitrile, concentrated to dryness. The residue was dissolved in 4 ml of water and lyophilized overnight to give 80 mg (97%) of 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (6-fluoro- 1-Methyl-1H-indol-3-yl) -pyrrole-2,5-dione hydrochloride salt was obtained.
    In a similar technique, hydrochloride salts of other amines were prepared.
    Example 8
    3- (6-amino-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione
    a) 5.29 g of 1-methyl-6-nitroindole and 7.5 g of 10% Pd / C in 400 ml of ethanol were treated with 30 ml of 2N hydrochloric acid and 2.04 ml of 85% hydrazine hydrate at 0 ° C. It was stirred at room temperature and treated by dividing with 1 ml of hydrazine hydrate. The mixture was filtered through a bed of celite and washed with ethanol. The filtrate was concentrated to 50 ml and cooled to 0 ° C. for 1 hour. Fine needle-like crystals were filtered off as hydrazine hydro-chloride. The filtrate was concentrated to 25 ml, frozen and filtered to further remove byproducts. The filtrate was treated by dividing with cold 6 N hydrochloric acid, concentrated to about 25 ml, frozen and the burnt crystals of the product collected. The filtrate was again concentrated to about 10 ml, again treated with cold 6 N hydrochloric acid, concentrated and redissolved in 5 ml of ethanol and hexane to further crystallize the product. The carbon crystals were collected and the mixed yield was 2.80 g of 6-amino-1-methylindole hydrochloride.
    b) 2.5 g of 6-amino-1-methylindole hydrochloride was added to 30 ml of anhydrous pyridine and treated with 1.93 ml of trifluoroacetic anhydride at 0 ° C. This was stored in the refrigerator overnight. It was taken up in cold water, extracted with ethyl acetate and washed with cold 5% phosphoric acid and 5% brine. The organic extract was dried over magnesium sulfate and the concentrated crude product was further purified by flash silica chromatography. The product was crystallized from methylene chloride / hexanes to yield 1.1 g of 1-methyl-6-trifluoroacetylaminoindole.
    c) 200 mg of 1-methyl-6-trifluoroacetylaminoindole was placed in 5 ml of ether and cooled to 0 ° C. This was treated with 0.485 ml of 2.0 M oxalyl chloride / methylene dichloride and stirred at 0 ° C. for 2 hours. The yellow crystals were collected, washed with ether and dried in vacuo to yield 240 mg (6-trifluoroacetylamino-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride.
    d) 240 mg of (6-fluoroacetylamino-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 181 mg of 2- (1-methyl-6-nitro-1H-indole-3 -Yl) -acetimide acid isopropyl ester hydrochloride was stirred in methylene chloride with 494 mg of triethylamine at 0 ° C. for 2 hours and then at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with cold 0.5 N hydrochloric acid and 5% brine. This was extracted again with methylene chloride, and the organic extract was passed through a plug of magnesium sulfate and concentrated. The crude residue was taken up in methylene chloride and treated with 244 mg of p-toluene sulfonic acid at room temperature for 5 hours. It was diluted with methylene chloride and dissolved by adding a few drops of methanol. It was washed with 10% sodium bicarbonate and water and extracted again with methylene chloride. The organic extract was dried over magnesium sulfate and concentrated. The crude was further purified by precipitating LC (20% ethyl acetate / methylene chloride) to give 48 mg of N- [1-methyl-3- [4- (1-methyl-6- as a red-orange solid). Obtain nitro-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl] -1H-indol-3-yl] -trifluoroacetamide did.
    e) 120 mg of N- [1-methyl-3- [4- (1-methyl-6-nitro-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H -Pyrrole-3-yl] -1H-indol-3-yl] -trifluoroacetamide was added to 8 ml of water / methanol (1/1), treated with 240 mg of potassium carbonate, 45 for 5 hours. Warmed to ° C. It was cooled to room temperature, placed in methylene chloride, washed with water and extracted again with methylene chloride. The organic extract is dried over magnesium sulfate, filtered, concentrated to near dryness. 25 ml of acetonitrile were added and it was concentrated to 5 ml, diluted with 25 ml of acetonitrile / water (1/1) and acidified with 0.25 ml of 1.0 N hydrochloric acid. It was concentrated to remove acetonitrile, and freeze-dried to give 50 mg of 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro- as a red orange solid. 1H-indol-3-yl) -pyrrole-2,5-dione was obtained.
    Example 9
    N- [1-methyl-3- [4- (1-methyl-6-nitro-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrole-3- Yl] -1H-indol-3-yl] -acetamide
    (6-acetylamino-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride was prepared using 6-amino-1-methyl-1H- using a procedure similar to that described in Examples 8b) and 8c). Made from indole. This was followed by N- [1-methyl-3- [4- (1-methyl-6-nitro-1H-indol-3-yl) -2,5- using a procedure similar to that described in Example 8d). Dioxo-2,5-dihydro-1H-pyrrol-3-yl] -1H-indol-3-yl] -acetamide.
    Example 10
    3- (6-amino-1-methyl-1H-indol-3-yl) -4- (6- [4-azido-3-iodo-phenyl) -2-oxo-butyl] -1-methyl- 1H-indol-3-yl) -pyrrole-2,5-dione
    3,4-bis- (1-methyl-6-amino-1 H-indol-3-yl) -pyrrole-2,5-dione (40 mg, 0.1 mM) was dissolved in tetrahydrofuran (3 ml), Cool to 0 ° C. After addition of 3- (4-azido-3-iodo-phenyl) -propionic acid (29.6 mg, 0.09 mM) N-hydroxybenztriazole (16 mg, 0.1 mM) and diisopropylcarbodiimide ( 16 μl, 0.1 mM) was added. The reaction mixture was stirred for 5 h at 0 ° C., then concentrated and purified by column chromatography in 3% methanol / methylene chloride to give 3- (6-amino-1-methyl-1H-indol-3-yl) 4- (6- [4-azido-3-iodo-phenyl) -2-oxo-butyl] -1-methyl-1 H-indol-3-yl) -pyrrole-2,5-dione (18.7 mg , 29%) was obtained.
    Example 11
    In a technique similar to that described in Example 10, the following compounds were prepared:
    a) 3- (6-fluoro-1-methyl-1H-indol-3-yl) -4- (6- [4-azido-3-iodo-phenyl) -2-oxo-butyl] -1 -Methyl-1H-indol-3-yl) -pyrrole-2,5-dione to 3- (6-fluoro-1-methyl-1H-indol-3-yl) -4- (1-methyl-6- Prepared from amino-1 H-indol-3-yl) -pyrrole-2,5-dione.
    b) 3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (6- [4-azido-3-iodo-phenyl) -2-oxo-butyl] -1 -Methyl-1H-indol-3-yl) -pyrrole-2,5-dione to 3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6- Prepared from amino-1 H-indol-3-yl) -pyrrole-2,5-dione.
    c) N- [3- [4- (6-formylamino-1-methyl-1 H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1 H-pyrrol-3-yl ] -1-methyl-1H-indol-6-yl] -formamide was substituted with 3,4-bis- (1-methyl-6-amino-1H-indol-3-yl) -pyrrole-2,5-dione and Prepared from formic acid.
    d) N- [3- [4- (6-methoxy-1-methyl-1 H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1 H-pyrrol-3-yl ] -1-methyl-1H-indol-6-yl] -formamide 3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-amino- Prepared from 1H-indol-3-yl) -pyrrole-2,5-dione and formic acid.
    Example 12
    N- [3- [4- (6-acetylamino-1-methyl-1 H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1 H-pyrrol-3-yl]- 1-methyl-1H-indol-6-yl] -acetamide
    3,4-bis- (1-methyl-6-amino-1 H-indol-3-yl) -pyrrole-2,5-dione (50 mg, 0.13 mM) was dissolved in tetrahydrofuran (2.5 ml), Cool to 0 ° C. Triethylamine (38.5 μl, 0.27 mM) was added followed by acetyl chloride (19.4 μl, 0.27 mM). The reaction was stirred for 30 minutes and then concentrated. The reaction mixture was dissolved in chloroform, washed with 0.1 N hydrochloric acid, and the organic layer was dried over magnesium sulfate, filtered and concentrated. The product was purified by column chromatography in 5% methanol / ethyl acetate to give N- [3- [4- (6-acetylamino-1-methyl-1H-indol-3-yl) -2,5-dioxo -2,5-dihydro-1H-pyrrol-3-yl] -1-methyl-1H-indol-6-yl] -acetamide (14 mg, 23%) was obtained.
    Example 13
    N- [3- [4- (6-methoxy-1-methyl-1 H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1 H-pyrrol-3-yl]- 1-methyl-1H-indol-6-yl] -acetamide
    In a technique similar to that described in Example 12, N- [3- [4- (6-methoxy-1-methyl-1H-indol-3-yl) -2,5-dioxo-2,5-di Hydro-1H-pyrrole-3-yl] -1-methyl-1H-indol-6-yl] -acetamide 3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (1-Methyl-6-amino-1 H-indol-3yl) -pyrrole-2,5-dione was obtained.
    Example 14
    3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-methyl-amino-1H-indol-3-yl) -pyrrole-2,5-dione
    a) 6-aminoindole was prepared from 6-nitroindole by a technique similar to that described in Example 5b.
    b) N-methyl- (1-methyl-1H-indol-6-yl) -amine was prepared from 6-aminoindole by a technique similar to that described in Example 1a.
    c) Methyl- (1-methyl-1H-indol-6-yl) -amine (50 mg, 0.31 mM) was dissolved in methylene chloride (2 ml) and cooled to 0 ° C. Triethylamine (55 μl, 0.39 mM) was added followed by benzylchloroformate (52 μl, 0.39 mM). The reaction was stirred at rt for 1 h. The reaction mixture was washed with 0.1 N hydrochloric acid and the organic layer was dried over magnesium sulfate, filtered and concentrated. The product was purified by column chromatography in 25% ethyl acetate / hexanes to give methyl- (1-methyl-1H-indol-6-yl) -carbamic acid benzyl ester (67 mg, 73%).
    d) (3-Chlorooxalyl-1-methyl-1H-indol-6-yl) -methyl-carbamic acid benzyl ester was subjected to methyl- (1-methyl-1H-indole- in a similar manner as described in Example 1b. 6-yl) -carbamic acid benzyl ester.
    e) 2- (6-methoxy-1-methyl-1H-indol-3-yl) -acetimide acid isopropyl ester hydrochloride and (3-chlorocarbononecarbonyl-1-methyl prepared in Example 1f -1H-indol-6-yl) -methyl-carbamic acid benzyl ester was coupled using a technique similar to that described in Example 1g to give [3- [4- (6-methoxy-1-methyl-1H-indole- 3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl] -1-methyl-1H-indol-6-yl] -methyl-carbamic acid benzyl ester was obtained .
    f) [3- [4- (6-methoxy-1-methyl-1 H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1 H-pyrrol-3-yl]- 1-Methyl-1H-indol-6-yl] -methyl-carbamic acid benzyl ester (26 mg, 0.048 mM) was dissolved in toluene (4 ml). Pd / C (10 mg × 10%, 0.009 mM) was added and the reaction mixture was shaken on a Parr hydrogenator at 50 psi for 13 hours. The crude reaction mixture was filtered through a bed of celite and concentrated to 3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-methylamino-1H- Indol-3-yl) -pyrrole-2,5-dione (16 mg, 81%) was obtained.
    Example 15
    Tablet formulation
    Itemingredientmg / tablet 5 mg25 mg100 mg250 mg500 mg750 mg OneCompound A525100250500750 2Anhydrous lactose1038335193857 3Croscarmellose sodium668163248 4Povidone K30556122436 5Magnesium stearateOneOneOne369Total weight120120150300600900
    Compound A represents a compound of the present invention.
    Manufacturing process:
    1. Mix items 1, 2 and 3 in a suitable mixer for 15 minutes.
    2. Granulate the powder mixture from step 1 with 20% povidone K30 solution (item 4).
    3. Dry the granules from step 2 at 50 ° C.
    4. Pass the granules from step 3 through a suitable milling apparatus.
    5. Add item 5 to the milled granules from step 4 and mix for 3 minutes.
    6. The granules from step 5 are compressed in a suitable compression device.
    Example 16
    Capsule Blend
    Itemingredientmg / tablet 5 mg25 mg100 mg250 mg500 mg OneCompound A525100250500 2Function lactose159123148-- 3Corn starch2535403570 4talc1015101224 5Magnesium stearateOne2236Total weight200200300300600
    Manufacturing process:
    1. Mix items 1, 2 and 3 in a suitable mixer for 15 minutes.
    2. Add items 4 and 5 and mix for 3 minutes.
    3. Fill in a suitable capsule.
    Example 17
    Injection Solution / Emulsion Formulations
    Itemingredientmg / ml OneCompound A1 mg 2PEG 40010-50 mg 3lecithin20-50 mg 4Soybean oil1-5 mg 5Glycerol8-12 mg 6waterAdd in an amount of 1 ml
    Manufacturing process:
    1. Dissolve item 1 in item 2.
    2. Add items 3, 4, and 5 to item 6, mix until dispersed, and then homogenize.
    3. Add the solution from step 1 to the mixture from step 2 and homogenize until the dispersion is translucent.
    4. Sterilize the solution through a 0.2 μm filter and fill the vial.
    Example 18
    Injection Solution / Emulsion Formulations
    Itemingredientmg / ml OneCompound A1 mg 2Glycofurol10-50 mg 3lecithin20-50 mg 4Soybean oil1-5 mg 5Glycerol8-12 mg 6waterAdd in an amount of 1 ml
    Manufacturing process:
    1. Dissolve item 1 in item 2.
    2. Add items 3, 4, and 5 to item 6, mix until dispersed, and then homogenize.
    3. Add the solution from step 1 to the mixture from step 2 and homogenize until the dispersion is translucent.
    4. Sterilize the solution through a 0.2 μm filter and fill the vial.
    权利要求:
    Claims (39)
    [1" claim-type="Currently amended] A compound of formula (I) and a pharmaceutically acceptable precursor thereof, or an acidic compound of formula (I) and a base or a pharmaceutically acceptable salt of a basic compound of formula (I) and an acid:
    Formula I

    Where
    R 1 and R 1 ′ are independently alkyl, aryl, alkenyl or alkynyl;
    R 2 and R 2 ' are independently hydrogen or alkyl;
    R 4 , R 5 , R 6 , R 7 , R 4 ' , R 5' , R 6 ' and R 7' are each independently hydrogen, , CO 2 R 9 , CH 2 OR 10 , CHO, CH 2 NR 11 R 12 , CON (R 13 ) 2 , halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino , Aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, azide, phosphate or phosphonate, provided that R 4 , R 5 , At least one of R 6 and R 7 , and at least one of R 4 ′ , R 5 ′ , R 6 ′ and R 7 ′ is not hydrogen, and if R 6 is methoxy then R 5 or R 5 ′ is not methoxy ;
    R 8 is alkyl or aryl;
    R 9 is alkyl or aryl;
    R 10 is hydrogen, alkyl or aryl;
    R 11 and R 12 are independently hydrogen, alkyl, aryl, aralkyl or acyl;
    R 13 is hydrogen, alkyl, aryl or aralkyl;
    One of X and Y represents O and the other represents O, S, (H, OH) or (H, H).
    [2" claim-type="Currently amended] The method of claim 1,
    R 1 and R 1 ′ are independently alkyl.
    [3" claim-type="Currently amended] The method of claim 2,
    R 1 and R 1 ′ are methyl.
    [4" claim-type="Currently amended] The method of claim 1,
    R 2 and R 2 ' are each hydrogen.
    [5" claim-type="Currently amended] The method of claim 1,
    One or more of R 4 , R 5 , R 6 and R 7 , and one or more of R 4 ′ , R 5 ′ , R 6 ′ and R 7 ′ are independently nitro, alkoxy, alkyl, halogen, cyano, , CO 2 R 9 , CH 2 OR 10 , CH 2 NR 11 R 12 , CHO, CON (R 13 ) 2 , alkylthio or aralkyloxy.
    [6" claim-type="Currently amended] The method of claim 5,
    At least one of R 4 , R 5 , R 6 and R 7 , and at least one of R 4 ′ , R 5 ′ , R 6 ′ and R 7 ′ is cyano, , CO 2 R 9 , CH 2 OR 10 , CH 2 NR 11 R 12 , CHO or CON (R 13 ) 2 .
    [7" claim-type="Currently amended] The method of claim 5,
    One of R 4 , R 5 , R 6 and R 7 , and one of R 4 ′ , R 5 ′ , R 6 ′ and R 7 ′ is nitro, alkoxy, alkyl, halogen, cyano, , CO 2 R 9 , CH 2 OR 10 , CH 2 NR 11 R 12 , CHO, alkylthio, aralkyloxy or CON (R 13 ) 2 , the other being hydrogen.
    [8" claim-type="Currently amended] The method of claim 5,
    R 1 and R 1 ′ are alkyl and R 2 and R 2 ′ are hydrogen.
    [9" claim-type="Currently amended] The method of claim 7, wherein
    R 8 is alkyl, R 9 is alkyl, R 10 is hydrogen or alkyl, R 11 is alkyl, R 12 is alkyl and R 13 is alkyl.
    [10" claim-type="Currently amended] The method of claim 6,
    R 1 and R 1 ′ are alkyl and R 2 and R 2 ′ are hydrogen.
    [11" claim-type="Currently amended] The method of claim 9,
    R 10 is alkyl.
    [12" claim-type="Currently amended] The method of claim 9,
    R 6 and R 6 ' are nitro, alkoxy, alkyl, halogen, cyano, , CO 2 R 9 , CH 2 OR 10 , CH 2 NR 11 R 12 , alkylthio or aralkyloxy, CHO or CON (R 13 ) 2 , R 4 , R 5 , R 7 , R 4 ′ , R 5 ' And R 7' are hydrogen.
    [13" claim-type="Currently amended] The method of claim 8,
    R 6 and R 6 ' are nitro, alkoxy, alkyl, halogen, cyano, , CO 2 R 9 , CH 2 OR 10 , CH 2 NR 11 R 12 , alkylthio or aralkyloxy, CHO, CON (R 13 ) 2 , R 4 , R 5 , R 7 , R 4 ′ , R 5 ' And R 7' are hydrogen.
    [14" claim-type="Currently amended] The method of claim 2,
    R 2 and R 2 ' are each hydrogen and at least one of R 4 , R 5 , R 6 and R 7 is amino, acylamino, monoalkylamino or dialkylamino.
    [15" claim-type="Currently amended] The method of claim 14,
    R 6 is amino, acylamino, monoalkylamino or dialkylamino, and at least one of R 4 ' , R 5' and R 6 ' is , CO 2 R 9 , CH 2 OR 10 , CHO, CH 2 NR 11 R 12 , CON (R 13 ) 2 , halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino , Aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, azide, phosphate or phosphonate.
    [16" claim-type="Currently amended] The method of claim 15,
    R 6 is amino, acylamino, monoalkylamino or dialkylamino, and R 6 ' is , CO 2 R 9 , CH 2 OR 10 , CHO, CH 2 NR 11 R 12 , CON (R 13 ) 2 , halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino , Aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, azide, phosphate or phosphonate.
    [17" claim-type="Currently amended] The method of claim 1,
    3- (6-Amino-1-methyl-1H-indol-3-yl) -4- (6-fluoro-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione .
    [18" claim-type="Currently amended] The method of claim 1,
    3- (6-Amino-1-methyl-1H-indol-3-yl) -4- (6-bromo-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione .
    [19" claim-type="Currently amended] The method of claim 1,
    3- (6-Amino-1-methyl-1H-indol-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione .
    [20" claim-type="Currently amended] The method of claim 1,
    3- (6-Amino-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione.
    [21" claim-type="Currently amended] The method of claim 1,
    3- [4- (6-amino-1-methyl-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl] -1-methyl- 1H-indole-6-carbonitrile.
    [22" claim-type="Currently amended] The method of claim 1,
    3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione .
    [23" claim-type="Currently amended] The method of claim 1,
    3- (6-benzyloxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione .
    [24" claim-type="Currently amended] The method of claim 1,
    3- (6-Chloro-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione.
    [25" claim-type="Currently amended] The method of claim 1,
    3- (1,6-dimethyl-1H-indol-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione.
    [26" claim-type="Currently amended] The method of claim 1,
    3- (1,6-dimethyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione.
    [27" claim-type="Currently amended] The method of claim 1,
    3,4-bis- (6-methoxy-1-methyl-1H-indol-3-yl) -pyrrole-2,5-dione.
    [28" claim-type="Currently amended] The method of claim 1,
    3- (6-Fluoro-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione .
    [29" claim-type="Currently amended] The method of claim 1,
    3,4-bis- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione.
    [30" claim-type="Currently amended] The method of claim 1,
    3- (6-amino-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-methylsulfanyl-1H-indol-3-yl) -pyrrole-2,5-dione compound.
    [31" claim-type="Currently amended] The method of claim 1,
    3- (6-Amino-1-methyl-1H-indol-3-yl) -4- (1,6-dimethyl-1H-indol-3-yl) -pyrrole-2,5-dione.
    [32" claim-type="Currently amended] The method of claim 1,
    N- [3- [4- (6-methoxy-1-methyl-1 H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1 H-pyrrol-3-yl]- 1-methyl-1H-indol-6-yl] -acetamide.
    [33" claim-type="Currently amended] The method of claim 1,
    3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-methyl-amino-1H-indol-3-yl) -pyrrole-2,5-dione Phosphorus compounds.
    [34" claim-type="Currently amended] The method of claim 1,
    3- [4- (1,6-dimethyl-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl] -1-methyl-1H- Indole-6-carbonitrile compound.
    [35" claim-type="Currently amended] The method of claim 1,
    3- (1-methyl-6-methylsulfanyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione compound.
    [36" claim-type="Currently amended] The method of claim 1,
    3- [6- [2- (2-ethoxy-ethoxy) -ethoxy] -1-methyl-1H-indol-3-yl] -4- (1-methyl-6-nitro-1H-indole- 3-yl) -pyrrole-2,5-dione.
    [37" claim-type="Currently amended] An effective amount of a compound of formula (I) or a pharmaceutically acceptable precursor thereof, or an acidic compound of formula (I) and a base or a pharmaceutically acceptable salt of a basic compound of formula (I) and an acid And a inert carrier.
    [38" claim-type="Currently amended] Use of a compound of any one of claims 1 to 36 for the inhibition of cell proliferation or for the preparation of a corresponding medicament.
    [39" claim-type="Currently amended] Invention as described herein above.
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    同族专利:
    公开号 | 公开日
    DE69715870D1|2002-10-31|
    AR007969A1|1999-11-24|
    CN1077571C|2002-01-09|
    AU740011B2|2001-10-25|
    CA2262089A1|1998-02-05|
    ES2183163T3|2003-03-16|
    DE69715870T2|2003-06-18|
    CO4900054A1|2000-03-27|
    EP0915870A1|1999-05-19|
    TR199900186T2|1999-03-22|
    WO1998004551A1|1998-02-05|
    DK0915870T3|2003-02-03|
    PE91598A1|1998-12-24|
    DK915870T3|
    BR9711607A|1999-08-24|
    MA24354A1|1998-07-01|
    CN1226248A|1999-08-18|
    US6228877B1|2001-05-08|
    AU4296397A|1998-02-20|
    AT224889T|2002-10-15|
    PT915870E|2003-01-31|
    HRP970415A2|1998-08-31|
    JP2000516588A|2000-12-12|
    EP0915870B1|2002-09-25|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-07-29|Priority to US2207896P
    1996-07-29|Priority to US60/022,078
    1997-06-03|Priority to US4849697P
    1997-06-03|Priority to US60/048,496
    1997-07-19|Application filed by 프리돌린 클라우스너;롤란드 비. 보레르, 에프. 호프만-라 로슈 아게
    2000-05-25|Publication of KR20000029640A
    优先权:
    申请号 | 申请日 | 专利标题
    US2207896P| true| 1996-07-29|1996-07-29|
    US60/022,078|1996-07-29|
    US4849697P| true| 1997-06-03|1997-06-03|
    US60/048,496|1997-06-03|
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