EP1011665A1 - Heterocyclische mittel - Google Patents

Heterocyclische mittel

Info

Publication number
EP1011665A1
EP1011665A1 EP98906687A EP98906687A EP1011665A1 EP 1011665 A1 EP1011665 A1 EP 1011665A1 EP 98906687 A EP98906687 A EP 98906687A EP 98906687 A EP98906687 A EP 98906687A EP 1011665 A1 EP1011665 A1 EP 1011665A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
group
hydrogen
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98906687A
Other languages
English (en)
French (fr)
Other versions
EP1011665A4 (de
Inventor
Fariborz Mohamadi
Vinod F. Patel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9706304.4A external-priority patent/GB9706304D0/en
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP1011665A1 publication Critical patent/EP1011665A1/de
Publication of EP1011665A4 publication Critical patent/EP1011665A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • This invention relates to heterocyclic antineoplastic agents, as well as to processes for their preparation, pharmaceutical compositions comprising the heterocyclic agents and methods for their use.
  • the heterocyclic agents are substituted furano [3 , 2-e] indole-7-carboxylic acid derivatives .
  • DNA interactive agents which interact in a base- specific and sequence-specific manner in the minor groove and bind covalently by alkylation show promise as antineoplastic agents.
  • Reported agents include pyrrole [3 , 2-e] indole derivatives and furano [3 , 2-e] indole derivatives. See, for example, Annual Reports in Medicinal Chemistry, vol 25, p 134 (1990) and vol 28, p 176 (1993), as well as US patent 5,248,691 and Mohamadi, F., et al . , J. Med . Chem. (1994), 37(2), 232-239. Despite the continuing promise of this class of compounds, there still exists a need for an agent which provides an improved separation between the antineoplastic effect and dose-limiting toxicity in other tissues .
  • the present invention is directed to the discovery of a new antineoplastic agent, as defined below, with improved properties for use in oncolytic therapy. According to the invention, there is provided a compound of formula I
  • A is O or S
  • L is a pharmaceutically acceptable leaving group
  • -CO-Q is a group which binds in the minor groove of duplex DNA
  • R 1 is (1-4C) alkyl
  • R ⁇ is hydrogen or a prodrug residue; or (when said compound is acidic or basic) a pharmaceutically acceptable salt thereof.
  • This invention also relates to a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, together with a suitable diluent or carrier.
  • this invention provides a method for treating a susceptible neoplasm, particularly a susceptible solid tumor, which comprises administering to an animal (particularly a mammal, more particularly a human or a companion mammal) in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • a companion mammal is, for example, a cat or a dog.
  • Halo is fluoro, chloro, bromo or iodo .
  • Alkyl, alkoxy etc. denote both straight and branched groups; but reference to an individual residue such as “propyl” embraces only the straight chain ("normal") residue, a branched chain isomer such as "isopropyl” being referred to specifically.
  • the compound of formula I contains a chiral center at the position indicated by "*" in formula I. Accordingly, it may exist in, and be isolated in optically active and racemic forms.
  • a compound of formula I contains an additional chiral element, such a compound of formula I may exist in, and be isolated in, the form of a diastereomeric mixture or as a single diastereomer. It is to be understood that the present invention encompasses a compound of formula I as a mixture of diastereomers, as well as in the form of an individual diastereomer, and that the present invention encompasses a compound of formula I as a mixture of enantiomers, as well as in the form of an individual enantiomer.
  • a compound of formula I, or a pharmaceutically acceptable salt thereof may form a solvate.
  • the compound, pharmaceutically acceptable salt or solvate may exhibit poly-morphism. It is to be understood, therefore, that the present invention encompasses any mixture of isomers, any racemic or optically active form, any pharmaceutically active salt, any solvate or any mixture thereof, which form possesses oncolytic properties, it being known in the art and described hereinbelow how to prepare optically active forms (for example, by resolution of the racemic form or by synthesis from optically active starting materials) and how to determine the oncolytic properties by standard tests including those described below.
  • the groups L, R1, R ⁇ and Q not contain or introduce an element of chirality into the compound of formula I.
  • a pharmaceutically acceptable leaving group L is one which provides a compound of formula I which is sufficiently stable for formulation and administration and which provides a nontoxic anion when the group is released.
  • Particular values for L include chloro, bromo, iodo, -OSO3H and -OS ⁇ 2R a in which R a is (1-4C) alkyl, phenyl, phenyl bearing one or more methyl or halo substituents, and the like.
  • a preferred value of is chloro.
  • a particular compound of formula I is one wherein -CO-Q is
  • ⁇ t , R c , and R& independently, are methoxy or hydrogen, provided that at least one of them is methoxy; or wherein -CO-Q is
  • E and G are independently NH, 0 or S; and R e is hydrogen, dimethylamino or diethylamino .
  • a preferred value for -CO-Q is
  • R , R c , and R ⁇ are each methoxy, or in which Rp is methoxy and R c and R°- are each hydrogen.
  • R ⁇ is methyl.
  • R ⁇ is hydrogen.
  • R ⁇ is a prodrug residue
  • it may be any conventional prodrug residue for a phenolic moiety, particularly an acyl residue of formula -C0R f , -C00R9 or -CONR 1 ⁇ 1 in which HO-COR f is a nontoxic carboxylic acid, H-0R9 is a nontoxic alcohol, and H-NR ⁇ R 1 is a nontoxic amine.
  • R ⁇ includes - (CH2) n -C00H, - (CH2 ) n -S03H, - (CH2 ) n -CONH-CH2-S03H, -(CH2)n-NR-JR , -C (CH3 ) 2CH2NH2 , -CH2C (CH3 ) 2NH2 , -CH2OCH2COOH, -CH2SCH2COOH, -CH2S(02)CH2COOH, or - (CH2 ) n"CONH- (PEG) wherein n is 1, 2 or 3 ; R-- is hydrogen or (1-2C) alkyl; Rp is hydrogen, (1-2C) alkyl or -CH(R s )COOH, wherein R s denotes the side chain of a naturally occurring cc-amino acid; or -NR- ⁇ R- ⁇ is a morpholino, piperazino or 4-methylpiperazino group; and (CH2)
  • Rf is 2- (diethylamino) ethyl or (4-methylpiperazino) - methyl.
  • a particular value for -0R9 is (1-3C) alkoxy, chloromethoxy, vinyloxy, benzyloxy, 2- [ (1-4C) alkylsulfonyl] - ethyl or 2- (phenylsulfonyl) ethyl .
  • a particular value for R or R 1 is, independently, hydrogen or (1-2C) alkyl or -NR- ⁇ R 1 is anilino, morpholino, piperazino, 4- ( 1-piperidino) -
  • R- when it is a prodrug residue is, for example, 4-methylpiperazinocarbonyl .
  • the preferred enantiomer of a compound of formula I is the one of the formula I- ⁇
  • A, , Q, R! and R 2 have any of the values described above .
  • a particular value for a defined group either alone or as part of another group (such as alkoxy or alkylsulfonyl, for example) for
  • (1-2C) alkyl is methyl or ethyl; for (1-3C) alkyl is methyl, ethyl, propyl or isopropyl; for (1-4C) alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; and for (l-5C)acyl is formyl, acetyl, propanoyl, butanoyl,
  • a preferred compound of formula I is methyl 5-hydroxy-
  • a more preferred compound of formula I is (+)-(lS) methyl 5-hydroxy-l- (chloromethyl) -1, 2-dihydro-3- [(5,6,7- trimethoxy-lH-indole-2-yl) carbonyl] -3H-furano [3 , 2-e] indole-
  • I such as the enantiomer of formula I- ⁇ , or the above named (+)-(lS) species, is characterized as having an enantiomeric excess of at least 90%, and preferably an enantiomeric excess of at least 95%.
  • a compound of formula I includes an acidic moiety, for example when L is -OSO3H or R 2 includes an acidic group, the acidic compound of formula I will form a salt with a pharmaceutically acceptable base.
  • Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium) , alkaline earth metal salts (especially calcium and magnesium) , aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as triethylamine, morpholine, piperidine and triethanolamine .
  • the potassium and sodium salt forms are particularly preferred.
  • a compound of formula I includes a basic moiety, for example when R e is a substituted amino group or R 2 includes a basic moiety, the basic compound of formula I will form a pharmaceutically acceptable acid addition salt with a pharmaceutically acceptable acid.
  • Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, citric acid and methanesulfonic acid.
  • a compound of formula I may be made by a process which is analogous to one known in the chemical art for the production of structurally related heterocyclic compounds or by a novel process described herein. Novel processes and intermediates useful for the manufacture of a compound of formula I as defined above are provided as further features of the invention and are illustrated by the following procedures in which, unless otherwise specified, the meanings of the generic groups are as defined above. It will be recognized that it may be preferred or necessary to prepare a compound of formula I in which a functional group is protected using a conventional protecting group, then to remove the protecting group to provide the compound of formula I .
  • acylation is carried out using a conventional procedure, for example using a coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, for example as described in the examples below.
  • a coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, for example as described in the examples below.
  • RP is a conventional protecting group for a phenolic hydroxy group, for example RP is benzyl, by using a conventional method, such as hydrogenolysis of the benzyl group using ammonium formate and palladium on carbon in aqueous tetrahydrofuran .
  • the activated derivative is the chlorocarbonate or an activated ester such as the 4- nitrophenyl ester, and is conveniently prepared from the corresponding compound of formula I in which R 2 is hydrogen using a conventional method.
  • R 2 is hydrogen using a conventional method.
  • a pharmaceutically acceptable salt of a compound of formula I when required, it is obtained by reacting the acidic or basic form of such a compound of formula I with a base or an acid affording a physiologically acceptable counterion or by any other conventional procedure, such as, for example, exchanging the counterion of a salt.
  • the leaving group L of a compound of formula I may be converted into a different leaving group L by a conventional method of functional group interchange. It will be clear to one skilled in the art that a protecting group RP also may serve as a value of R 2 wherein R 2 is a prodrug residue.
  • a protected compound of formula Ip may be prepared using a similar procedure to that described above in process (A) , using an amine corresponding to that of formula II, but in which the phenolic hydroxy group is protected, which may be denoted as an amine of formula Up
  • RP is a conventional protecting group for a phenolic hydroxy group, for example RP is benzyl.
  • R is hydrogen
  • R n is a protecting group for an anilino nitrogen
  • R°- is a value of R 2 or RP which is stable to the subsequent reaction conditions
  • R r is a group which will afford the corresponding aryl radical when subjected to a radical generating reagent or condition.
  • the compound of formula IV provides another aspect of the invention and may be prepared using a process such as that outlined in the examples and which provides a further aspect of the invention.
  • R m is hydrogen, from 2-hydroxy-3-methoxy-5-nitrobenzaldehyde which comprises alkylating the phenolic hydroxy group with an ester of formula X-CH2 ⁇ C00R-'- a wherein R ⁇ a is a carboxy-protecting residue [for example, R ⁇ a is (1-4C) alkyl or benzyl and, more particularly, R-*- a is methyl or ethyl] and X is a leaving group [for example, X is bromo or iodo] using a base and an inert solvent [for example, forming the potassium salt using potassium carbonate in methanol followed by alkylating with ethyl bromoacetate in dimethylformamide] ; cyclizing the resulting ester to a benzofuran using a basic
  • a preferred process for preparing an amine of formula II or of formula lip from a corresponding ester of formula IV in which R m is hydrogen comprises using the novel process for preparing a 3-substituted indoline which is further discussed below and is illustrated in parts I-K of Example 1 for a compound of formula Up in which A is 0, L is chloro, Ri is methyl and RP is benzyl (preferably isolated as its hydrochloride salt) .
  • X is a leaving group, such as chloro, bromo, iodo or a sulfonyloxy group such as methylsulfonyloxy
  • Y denotes a group which has one of the values defined for and which is stable to the subsequent cyclization conditions, for example Y is chloro, bromo or
  • X and Y are each chloro.
  • Cyclizing the substituted vinyl compound of formula IV is effected by subjecting it to a radical generating reagent or condition in an inert solvent in the presence of a radical reducing agent to afford a corresponding substituted indoline of formula V.
  • Resolution of the alcohol of formula VII conveniently may be effected by preparing the ester with a chiral acid, such as for example the (R) - (-) -O-acetylmandelate ester, chromatographically separating the resulting diastereomers, and liberating the resolved alcohol of formula VII.
  • a chiral acid such as for example the (R) - (-) -O-acetylmandelate ester
  • R°i is a value of R 2
  • conversion of the alcohol of formula VII into an amine of formula II may be effected conveniently by converting the hydroxy group into the required value of L by using a conventional method (for example using triphenylphosphine and carbon tetrachloride in dichloromethane to afford the corresponding compound of formula V in which Y is chloro) , followed by removing the N-protecting group R n to afford the amine, conveniently isolated as its acid addition salt, such as the hydro- chloride.
  • R°i is a value of RP
  • a similar procedure affords an amine of formula lip.
  • R 0 - is a value of RP
  • the O-protecting group RP may be removed and the required O-substituent R 2 obtained using conventional methods before removal of the N-protecting group R n to afford the amine of formula II.
  • An amide of formula III in which R ⁇ is hydroxy may be obtained by using a process similar to that described above at (A) , using an amine corresponding to the amine of formula II, but in which the value (R ⁇ ) corresponding to is a hydroxy group or a protected hydroxy group (followed by deprotection) .
  • the amine conveniently is obtained from a corresponding primary alcohol of formula VII, which also may be obtained from a protected amine of formula V by converting the leaving group Y into hydroxy using a conventional method.
  • a preferred process for preparing a compound of the invention is the novel one illustrated in parts I-K of Example 1 for a compound of formula Up in which A is 0, L is chloro, R ⁇ is methyl and RP is benzyl.
  • another aspect of the invention is a process for the preparation of an indoline of formula VIII
  • each of R 4 , R 5 , R ⁇ , R 7 t Rn anc j z is a group which is stable to the reaction conditions of the process (or, further, in which R n is hydrogen) from a corresponding aniline of formula IX
  • R m is hydrogen
  • This novel process for the preparation of a 3-substituted indoline has the advantage that the substituent Y or Z is introduced directly, with no requirement of modification of a different group to obtain it. Moreover, the novel process avoids the intermediacy of the olefin such as that of formula VI, which readily may isomerize into the corresponding 3-methylindole derivative.
  • the values of the residues R 4 , R 5 , R ⁇ , R 7 , R n and Y are limited only by stability to the reaction conditions .
  • a pair of neighboring residues together may form a fused ring, for example as exemplified by compounds of formula IV and formula V.
  • a particular value for a residue is one independently selected from hydrogen, (1-4C) alkyl, hydroxy, ( 1-4C) alkoxy, benzyloxy, (1-5C) acyloxy, benzoyloxy, (1- 4C) alkoxycarbonyloxy, phenoxycarbonyloxy, (l-5C)acyl, benzoyl, cyano, (1-5C) acylamino, benzoylamino, (1- 4C) alkoxycarbonylamino or benzyloxycarbonylamino or a pair of neighboring residues together (such as, for example, R 4 and R5 ) may form a fused ring, for example, a furano-, thiopheno-, pyrrolo- or benz-ring (for example, where the heteroatom, if present, is at the R 5 -position) , which fused ring may further bear one or more substituents
  • R n is, for example, tert-butyloxycarbonyl, formyl, acetyl, trichloroacetyl, 2, 2, 2-trichloroethoxycarbonyl, benzyloxycarbonyl , 9-fluorenylmethoxycarbonyl , 2- (p-tolylsulfonyl)ethoxycarbonyl, phenylsulfonyl, allyl, benzyl, triphenylmethyl or a value listed above for -CO-Q.
  • R r hydrogen also is a value for R r
  • a particular value for X is, for example, chloro, bromo, iodo or a sulfonyloxy group such as methylsulfonyloxy .
  • a particular value of Z includes one defined above for Y, such as chloro, bromo or iodo, as well as methylsulfonyloxy, p-tolylsulfonyloxy, -S(0) m R u wherein m is 0, 1 or 2 and R u is, for example, methyl or phenyl.
  • Typical values for the novel process include those in which R 4 and R ⁇ together form a furano- , thiopheno- or pyrrolo-ring where the heteroatom is at the R ⁇ -position; R ⁇ is (1-4C) alkoxy or benzyloxy; R 7 is hydrogen, (1-4C) alkoxy or benzyloxy; R r is bromo or iodo; R n is tert- butyloxycarbonyl; and Z is chloro or bromo.
  • Values for the residue R r and the corresponding radical generating reagent or condition, inert solvent and radical reducing agent include those known in the art.
  • the inert solvent will depend upon the mode of generation of the radical and the solubility of the compound.
  • Values for R r and the corresponding conditions for radical generation and reductive trapping are provided, for example, in Giese, B. Radicals in Organic Syntheses : Formation of Carbon-Carbon
  • R r is, for example, halo, phenylsulfanyl, phenyselanyl, nitro, or the ester derived from treatment of a compound in which R r is hydroxy with carbon disulfide and methyl iodide
  • the cyclization may be effected using, for example, a conventional azo-type radical initiator, such as AIBN, a trialkyltin hydride, for example tributyltin hydride, and benzene as a solvent at reflux.
  • a conventional azo-type radical initiator such as AIBN
  • a trialkyltin hydride for example tributyltin hydride
  • benzene as a solvent at reflux.
  • R r is bromo or iodo and the radical generating reagent or condition is AIBN and tributyltin hydride in benzene at reflux.
  • each of -CO-Q, R 4 , R ⁇ , R6 , R 7 and Z has any of the values defined above, from a corresponding aniline of formula IX in which R n is a nitrogen protecting group which comprises converting the aniline of formula IX into the corresponding substituted indoline of formula VIII using the process described above, removing the N-protecting group R n using a conventional method, and, further, acylating the resulting indoline of formula VIII wherein R n is hydrogen with an acid of formula Q-COOH, or an activated derivative thereof.
  • the acylation is carried out using a conventional procedure, for example using a coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. It may be desired to use a protecting group during all or portions of the above-described processes; the protecting group then may be removed when the final compound or a required starting material is to be formed. As will be clear to one skilled in the art, the order of steps in the sequences leading to the starting materials and products of the invention may be altered if appropriate consideration relating to coupling methods, racemization, deprotection methods, etc., are followed.
  • Compound a compound of the invention or a pharmaceutically acceptable salt thereof (hereinafter, collectively referred to as a "Compound”) may be demonstrated by standard tests and clinical studies, including those described below.
  • T222 human squamous cell lung carcinoma
  • X 10 4 target cells were distributed in each well of 96 well tissue culture plates and incubated in leucine deficient medium (leucine free DMEM plus 13 ⁇ g/mL L-leucine, 29.2 ⁇ g/mL L-glutamine, 50 ⁇ g/mL gentamicin and 10% dialyzed fetal calf serum) for 16 hours at 37°C in 5% C0 2 .
  • leucine deficient medium leucine free DMEM plus 13 ⁇ g/mL L-leucine, 29.2 ⁇ g/mL L-glutamine, 50 ⁇ g/mL gentamicin and 10% dialyzed fetal calf serum
  • the medium was then removed aseptically and compound dilutions were added in 200 ⁇ l of leucine deficient medium.
  • 4 ⁇ Ci 3 H-leucine (NEN, Boston, MA) were added to each well and the plates were returned to the incubator for 24 hours.
  • Radioactivity incorporated into macromolecules was determined using an automated cell harvester and liquid scintillation techniques . Data were evaluated as percent reduction in incorporation of radioactivity relative to controls incubated in medium without compound to yield an 50% cytotoxic concentration (IC 50 ).
  • IC 50 cytotoxic concentration
  • the respective ICso's of the compounds of Examples 1, 2 and 3 in this assay were 0.39, 0.39 and 19.4 nM (indicating the enantiomer of Example 2 is the more active isomer) .
  • Dose dependent antitumor efficacy for the compound of Example 2 also was demonstrated in other xenograft protocols, including with GC3 colon tumor and MX-1 mammary tumor xenografts. While observed lethality was variable and delayed, a total dose of 5 mg/kg resulted in little lethality.
  • the compounds of formula I are antineoplastic agents and the invention provides a method of treating susceptible neoplasms.
  • the present compounds are useful in treating solid tumors including carcinomas such as ovarian, non-small cell lung, gastric, pancreatic, prostate, renal cell, breast, colorectal, small cell lung, melanoma and head and neck; and sarcomas such as Kaposi's sarcoma and rhabdomyosarcom .
  • a compound of formula I is administered using a parenteral route, such as an injection, for example, as an intravenous infusion; however, it may be preferred to administer the compound of formula I by another route, such as orally.
  • the compound may be administered individually or in combination with one or more other agents, either simultaneously or in a sequence. The clinician will determine the exact dose depending upon the size and age of the patient, the neoplasm being treated and the treatment regime.
  • the compound may be given as a bolus or as a constant intravenous infusion.
  • An intravenous dose for example, may be in the range of 0.05 to 20 mg/m 2 as a bolus once a week or in the range of 0.01 to 4 mg/m 2 /day for 5 days.
  • An oral dose may be, for example, from 0.01 to 50 mg/kg/day, possibly in divided doses .
  • the pharmaceutical composition comprising a compound of formula I will be appropriate for the elected mode of administration, and may be prepared using a conventional method.
  • any suitable carrier known in the art can be used.
  • the carrier may be a solid, liquid, or mixture of a solid and a liquid.
  • Solid form formulations include powders, tablets and capsules .
  • a solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel compound of this invention.
  • Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter.
  • Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both (for example in polyethylene glycol 400/absolute ethanol/polyoxyethylenesor-bitan monooleate, 6:3:1, v/v/v) .
  • a pharmaceutically acceptable carrier such as sterile water, sterile organic solvent or a mixture of both (for example in polyethylene glycol 400/absolute ethanol/polyoxyethylenesor-bitan monooleate, 6:3:1, v/v/v) .
  • a pharmaceutically acceptable carrier such as sterile water, sterile organic solvent or a mixture of both (for example in polyethylene glycol 400/absolute ethanol/polyoxyethylenesor-bitan monooleate, 6:3:1, v/v/v) .
  • Useful carriers for a solution, suspension or emulsion include polysorbate 80, polyoxyethylated castor oil, and
  • the pharmaceutical formulation is in unit dosage form.
  • the unit dosage form can be an ampoule containing the active ingredient in a form suitable for dissolution or dilution prior to administration or can be a prefilled syringe or bag containing a solution of the active ingredient.
  • the unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these.
  • the quantity of active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.
  • composition according to the invention may be made for oral, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation, either through the mouth or nose.
  • Active ingredient refers to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.
  • Hard gelatin capsules are prepared using the following ingredients:
  • Formulation 2 A tablet is prepared using the ingredients below:
  • the components are blended and compressed to form tablets each weighing 133 mg.
  • Formulation 3 Tablets, each containing 60 mg of active ingredient, are made as follows:
  • the active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50 °C and passed through a No . 18 mesh U.S. Sieve.
  • the sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No . 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Capsules each containing 80 mg of active ingredient, are made as follows:
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No . 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities .
  • Formulation 5 Suppositories, each containing 225 mg of active ingredient, are made as follows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
  • Formulation 6 Suspensions, each containing 50 mg of active ingredient per 5 ml dose, are made as follows:
  • the active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume .
  • Formulation 7 An intravenous formulation may be prepared as follows :
  • the solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 mL/min.
  • Acetyl chloride (13 mL, 186 mmol) was added dropwise to dry methanol (1.5 L) at 0 °C and then stirred at room temperature for 0.5 h.
  • 7-Hydroxy-5-nitrobenzofuran-2- carboxylic acid (39.6 g, 177 mmol) was added to the resulting acidic methanol and the mixture heated at reflux under a nitrogen atmosphere for 18 h.
  • the reaction mixture was cooled to room temperature and the resulting precipitated solid filtered, washed with cold methanol (500 mL) and dried to give the methyl ester as a light tan solid (41.2 g, 98%) .
  • reaction mixture was stirred at room temperature for 18 h and then evaporated to provide a solid, which was purified by flash chromatography (gradient: 5-20% ethyl acetate / hexanes) to furnish the benzyl ether as a white solid (57 g, 90%) .
  • the 5, 6, 7-trimethoxy-lH-indole-2-carboxylic acid used in part L above was prepared as follows .
  • the preparative chromatographic system consisted of a semi- automated integrated system Model LC80.600.VE.70 from
  • the column pumping system was a diaphragm Lewa model EKM2 and the sample pump was a Lewa model FC1.
  • the system had a 10 port fraction collector and Rainin Dynamax model UV-1 variable UV-VIS detector with full flow cell.
  • the preparative column was an 8 cm x 70 cm Dynamic Axial Compression (DAC) configuration.
  • the maximum bed length was 40 cm with a maximum working pressure of 70 bar [1000 psi] .
  • the hydraulic pump used to compress the column bed was a Haskel model MS-36.
  • the optimized run time was 13 min. Ten plus grams of the racemate was separated in 35 runs on the 8 cm column. The 5.1 gm (Isomer 1) and 5.0 p (Isomer 2) of enantiomers isolated from the preparatory chromatography represented a 98% recovery from the racemate. Enantiomeric excess of the separated isomers was 97.6% (Isomer 1) and 95.5% (Isomer 2), respectively .
  • the analytical chromatograph consisted of an integrated Shimadzu Scientific Instruments system [Columbia, MD, USA] with gradient pump model LC-10AD, variable wavelength detector model SPD-10A, autosampler model SIL-10A, fraction collector model FRC-10A, and system controller model SCL- 10A.
  • the enantiomers were separated on a 10 micron 4.6 x 250 mm Chiralcel OD-R column using acetonitrile and perchlorate buffer.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP98906687A 1997-03-10 1998-02-26 Heterocyclische mittel Withdrawn EP1011665A4 (de)

Applications Claiming Priority (5)

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US4026597P 1997-03-10 1997-03-10
US40265P 1997-03-10
GB9706304 1997-03-26
GBGB9706304.4A GB9706304D0 (en) 1997-03-26 1997-03-26 Heterocyclic agents
PCT/US1998/003612 WO1998040068A1 (en) 1997-03-10 1998-02-26 Heterocyclic agents

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WO (1) WO1998040068A1 (de)

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US5248691A (en) * 1992-09-03 1993-09-28 Eli Lilly And Company Furanoindolines

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BOGER D L ET AL: "DESIGN, SYNTHESIS, AND EVALUATION OF CC-1065 AND DUOCARMYCIN ANALOGS INCORPORATING THE 2,3,10,10A-TETRAHYDRO-1H-CYCLOPROPAUD BENZOUFQUINOL-5-ONE (CBQ) ALKYLATION SUBUNIT: IDENTICATION AND STRUCTURAL ORIGIN OF SUBTLE STEREOELECTRONIC FEATURES THAT GOVERN REACTIVITY AND REGIOSELECTIVITY" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,US,AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, vol. 116, no. 25, 1994, pages 11335-11348, XP002914133 ISSN: 0002-7863 *
BOGER D L ET AL: "TOTAL SYNTHESIS AND PRELIMINARY EVVALUATION OF (+)- AND ENT-(-)- DUOCARMYCIN SA" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,US,AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, vol. 115, no. 20, 1993, pages 9025-9036, XP002914132 ISSN: 0002-7863 *
MOHAMADI F ET AL: "Total synthesis and biological properties of novel antineoplastic (chloromethyl)furanoindolines: an asymmetric hydroboration mediated synthesis of the alkylation subunits" JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 37, 1994, pages 232-239, XP002086068 ISSN: 0022-2623 *
PATEL ET AL: "Total Synthesis of Seco (+)- and ent-(-)-Oxaduocarmycin SA: Construction of the (Chloromethyl)indoline Alkylating Subunit by a Novel Intramolecular Aryl Radical Cyclization onto a Vinyl Chloride" JOURNAL OF ORGANIC CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. EASTON, vol. 62, no. 25, 1997, pages 8868-8874, XP002142466 ISSN: 0022-3263 *
See also references of WO9840068A1 *
TIETZE L F ET AL: "SYNTHESIS OF THE REDUCED A-UNIT (CI) OF THE ANTITUMOR ANTIBIOTIC CC-1065" CHEMISCHE BERICHTE,DE,VERLAG CHEMIE GMBH. WEINHEIM, vol. 126, no. 12, 1 December 1993 (1993-12-01), pages 2733-2737, XP002041813 ISSN: 0009-2940 *

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AU6184898A (en) 1998-09-29
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CA2283127A1 (en) 1998-09-17
EP1011665A4 (de) 2001-09-12

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