Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
  • C07D493/14—Ortho-condensed systems
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to a process for preparing certain pyrrolo-[3,4-b]quinolines, certain 1H-pyrano[3',4':6,7] indolizino[3,4-b]quinolin-3,14(4H,12H)-diones, specifically camptothecin and its analogs, and certain 8-methyl-7-(oxopropyl)-indolizino[3,2-b]quinolin-9(11H)-ones, specifically mappicine ketones and mappicines.
• camptothecin itself is known to be cytotoxic at levels which inhibit tumor growth
• certain water-soluble camptothecin analogs which exhibit litde or no cytotoxicity are efficacious against solid tumor types normally refractory to known treatments.
• (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7] indolizino[1,2-b]quinolin-3,14(4H,12H)-dione commonly known as topotecan (Formula lb), which is disclosed in U.S. Pat No.5,004,758, issued to Boehm et al.
• tumors include, but are not limited to, ovarian, esophageal, non-small cell lung and colorectal carcinomas.
• topotecan is also useful for the preparation of a combination chemotherapeutic pharmaceutical composition which also comprises a platinum coordination compound, most preferably cis-platin.
• a platinum coordination compound most preferably cis-platin.
• the 4-(piperidino)-piperidinyl carbamate analogue of 7-ethyl-10-hydroxycamptothecin, commonly known as irinotecan (or CPT- 11) (Formula Ic) has also been shown to be efficacious against certain tumors. Both compounds are presently undergoing human clinical testing in refractory tumor types. Additionally, the 9-amino and 10,11-methylenedioxy analogs: of camptothecin (Formula Id) have shown promising antitumor activity in preclinical testing.
• camptothecin molecule results in compounds possessing antiviral activity while exhibiting little or no cytotoxicity.
• examples of such compounds include derivatives in which the E ring lactone has been replaced by some other functionality, i.e., two broad classes of compounds commonly called mappicine ketones and mappicines, of Formulas IIa and IIb respectively.
• mappicine ketones and mappicines of Formulas IIa and IIb respectively.
• These compounds which are useful in treating infections in humans and animals caused by a variety of viruses, (for example, Herpes simplex virus types 1 and 2, cytomegalovirus, and Varicella zoster virus) are disclosed in U.S. Ser. No. 07/606,216, filed by S. Petteway et al. on October 31,1990; U.S. Ser. No.
• Camptothecins have also been recently shown to possess antiretroviral activity, specifically the ability to inhibit the replication of Human
• HTV-1 Immunodeficiency Virus
• HTV-1 at dosages non-cytotoxic to mammalian cells, and thus may be useful in the treatment of patients suffering from Acquired Immune Deficiency Syndrome (AIDS, see AIDS Res. Hum. Retr., 1991, 7, 65).
• topoisomerase I is a monomeric enzyme with a molecular weight of approximately 100,000.
• Camptothecin is known to exert its antitumor activity by stabilization of the covalently bound topoisomerase I - DNA complex. As a result, progression of the DNA replication sequence proceeds only as far as induction of a single strand break. The ultimate result of this inhibition of the DNA transcription/replication process is cell death. Camptothecin and a few of its close congeners are the only agents in clinical drug development which inhibit topoisomerase I.
• Topoisomerase II consists of two identical subunits of molecular weight 170,000. Topoisomerase II induces transient breaks of both strands of the DNA helix and passes another double-stranded segment through the break.
• Several commercially important oncolytic agents e.g., etoposide, doxorubicin and mitoxantrone
• camptothecin does not inhibit topoisomerase ⁇
• mappicines and mappicine ketones are known to inhibit topoisomerase II As such these compounds are of interest both as potential antineoplastic and antiviral agents.
• camptothecin discloses a semisynthetic method of preparing certain water-soluble camptothecin analogs from camptothecin.
• the only practical method for obtaining preparative- and commercial-scale quantities of camptothecin is by extraction of the tissues of the Camptotheca acuminata tree indigenous to the People's Republic of China or the Nothapodytes foetida shrub indigenous to India.
• reliance on such natural sources has certain inherent disadvantages, including very high starting material cost (about $28,000/kg) and lack of a dependable source. Camptothecin has also been prepared from readily available materials by various totally synthetic approaches.
• strategy A a tricyclic CDE ring system is prepared by known methods and is coupled with ortho-aminobenzaldehyde via a Friedlander quinoline synthesis.
• the critical bond disconnection strategy is shown by the dashed line labelled A.
• strategy B tricyclic ABC and bicyclic DE ring components are prepared separately by known methods and are coupled using a two-step, standard procedure to form the D ring pyridone.
• the critical bond disconnection strategy is shown by the dashed line labelled B.
• the tricyclic ABC ring fragment for strategy B is ultimately prepared via a Friedlander quinoline synthesis requiring several steps. The Friedlander quinoline synthesis is therefore a basic component of many of the known approaches.
• the present invention provides an efficient general route for the facile synthesis of pyrrolo[3,4-b]quinolines, 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones and 1H-pyrano[3',4':6,7]indolizmo[1,2-b]qumolin-3,14(4H,12H)-diones, preferably camptothecin analogs.
• the present invention provides a process for preparing pyrrolo[3,4-b]quinolines, 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones; and 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-diones, preferably camptothecin analogs , more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, most preferably topotecan, said process comprising the step of intramolecular [4+2] cycloaddition of the N-arylimidate portion of a compound of Formula IV with the unactivated acetylene portion of said compound, the compound of Formula IV being generated from compounds of Formula III (shown in Scheme 2 below and having the same substitutions as compounds of Formula IV), which are derived from generally available compounds.
• R 1 H, OH, or OR, where R is an ester protecting group
• R 2 H, NO 2 , or a protected amine function
• R 3 H, C 2 H 5 , or a trialkylsilyl
• R 4 H or CH 2 COOEt
• R 5 COOMe or tosyl
• R 4 and R 5 are joined together to form a substituted pyridone IIa:
• A H, COOR, or a functionality for preparation of the hydroxymethyl (C-17) portion of an E ring lactone
• B H, OH, an appropriate leaving group such as halide or
• the present invention also provides a process for the preparation of 7-(1,1-bis-alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-ones, 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones; and 1H- pyrano[3 , ,4 , :6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-diones, preferably camptothecin analogs, more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, most preferably topotecan, said process comprising the step of coupling a vinyl triflate derived from a 7-hydroxy-5,6-dihydroindolizino[1,2-b]quinolin-9(11
• the resulting 7-(1,1-bis-alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-one may be conveniently elaborated into a 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-dione or a 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one as disclosed elsewhere in the present application.
• the present invention also provides a process for the preparation of pyrrolo[3,4-b]quinolines, 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones; and 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-diones, preferably camptothecin analogs, more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, most preferably topotecan, said process comprising the steps of:
• the present invention also provides a process for the preparation of camptothecin analogs which lack the lactone E ring, preferably 8-methyl-7-(oxopropyl)-indolizino[1,2-b]quinolin-9(11H)-ones, most preferably mappicines and mappicine ketones, said process comprising the steps of:
• the present invention provides a process for the total synthesis of, depending upon choice of termination step, 4-ethyl-4-hydroxy-9-methoxy-1H-pyrano[3',4':6,7] indolizino[1,2-b]quinolin-3,14(4H, 12H)-dione, more commonly known as 10-methoxycamptothecin, 4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7] indolizino[1,2-b]quinolin-3,14(4H,12H)-dione, more commonly known as 10-hydroxycamptothecin, as well as of 10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4 , :6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-dione, more commonly known as topotecan, said process comprising the
• tetrahydrofuran N,N-dimethylformamide, acetonitrile, acetone or N-methylpyrrolidinone, most preferably acetonitrile;at a temperature of about 20 -85°C, preferably about 60 - 85°C, most preferably at about the reflux temperature of acetonitrile; in the presence of a strong alkylatmg agent or such agent as is capable of transforming an amide into its corresponding O-alkylimidate or imidate ester, imidoyl halide, or a strong acid (such as aluminum chloride) capable of initiating a cyclodehydration, preferably trifluoromethanesulfonic anhydride, dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O-benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or triphenylphosphine/carbon tetrabromid
• a camptothecin includes camptothecin and and any derivative thereof the structure of which is based on the 1H-pyrano[3',4':6,7] indolizino-[1,2-b]quinolin-3,14(4H,12H)-dione ring system.
• pyrrolo[3,4-b]quinoline refers generally to compounds based on these ring systems.
• camptothecin analog includes camptothecins as defined above and also includes derivatives of camptothecin wherein the E ring has been replaced with another functionality.
• esteer protecting group is defined to include C 1 -C 6 alkyl groups as well as allyl, benzyl, phenyl and ⁇ , ⁇ , ⁇ -trichloroethyl.
• amine protecting group is defined to include alkyl and arylsulfonate esters, carbamates of common alkyl groups such as methyl, ethyl, ⁇ , ⁇ , ⁇ -trichloroethyl, allyl, tert-butyl and phenyl, amides such as acetamido and propionamido, as well as common alkyl groups such as methyl and benzyl.
• trimerkylsilyl is defined to include trimethyl, triethyl, triisopropyl and tripropylsilyl, as well as phenyldimethylsilyl and tert-butyldimethylsilyl.
• the present invention provides a process for preparing pyrrolo[3,4-b]quinolines, 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones; and 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-diones, preferably camptothecin analogs, more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, most preferably topotecan, the process comprising the step of intramolecular [4+2] cycloaddition of the N-arylimidate portion of a compound of Formula IV, generated from a starting material of Formula III, with the unactivated acetylene portion of said compound.
• Scheme 2 illustrates one embodiment of the present process wherein R 4 and R 5 of the compound of Formula IV are not joined together to form a pyridone
• X, R 1 -R 5 and Y are as defined for Formula IV;
• the starting material of Formula III is heated in a polar solvent, preferably methylene chloride, 1,2-dichloroethane, 1,2-dimethoxyethane tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone or N-methylpy ⁇ olidinone, most preferably acetonitrile; at a temperature of about 20 - 85 °C, preferably 60 - 85 °C, most preferably at the reflux temperature of acetonitrile; in the presence of a strong alkylating agent or such agent as is capable of producing either an O-alkylimidate or imidate ester, imidoyl halide, or such imide derivative as is capable of
• cyclodehydration preferably trifluoromethanesulfonic anhydride, dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O-benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or triphenylphosphine/carbon tetrabromide, most preferably trimethyloxonium tetrafluoroborate, thereby generating the compound of Formula IV which then undergoes [4 + 2] cycloaddition to yield a pyrrolo[3,4-b]quinoline.
• Compounds of Formula IV have not been isolated, but have been detected.
• the products of the present process are either pharmaceutically useful themselves, e.g. topotecan, or are intermediates, e.g. 10-methoxycamptothecin, useful for elaboration into pharmaceutically useful compounds, particularly camptothecin analogs.
• the present invention also provides a process for the preparation of 7-(1,1-bis-alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-ones, 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones; and1H-pyrano [3',4': 6,7] indolizino [1,2-b] quinolin - 3,14 (4H, 12H - diones, preferably camptothecin analogs, more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, yet more preferably topotecan and irinotecan, most preferably topotecan, said process, referring to Scheme 3, comprising the step of coupling a vinyl triflate dervived from a 7-hydroxy-5,6-dihydroindoli
• the resulting 7-(1,1-bis-alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-one may be conveniently elaborated into a 1H-pyrano[3',4':6,7]indolizino-[1,2-b]quinolin-3,14(4H,12H)-dione or a 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one as disclosed elsewhere in the present application.
• R 4 H or CH 2 COOEt
• R 5 COOMe, toluenesulfonyl, benzyl, COCH 3 ; or COCH 2 CH 3
• Y M.
• this embodiment of the present process may be conveniently used to provide a variety of useful
• the compounds of Formula IV are readily prepared by known methods, for example as shown in Scheme 5 and Steps 1-3 of Scheme 7, below, and as is exemplified in me Example (Steps 1-3 ).
• a polar solvent such as methylene chloride, 1,2-dichl ⁇ roethane, 1,2-dimethoxyethane tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone or N-methylpyrrolidinone, but preferably acetonitrile; at a temperature of about 20 - 85 °C, preferably at 60 - 85 °C, most preferably at the reflux temperature of acetonitrile; in the presence of a strong alkylating agent or an agent capable of transforming an amide into its corresponding O-alkylimidate or imidate ester, or an imidoyl halide, e.g.
• trifluoromethanesulfonic anhydride dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O-benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or
• triphenylphosphine/carbon tetrabromide preferably trimethyloxonium
• step (b) the substituted pyrrolo[3,4-b]quinoline resulting from step (a) is cyclized to a 7-hydroxy-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-one as follows.
• the carbamate function protecting the C-ring nitrogen is hydrolytically cleaved, preferably with acetic acid saturated with HBr, to give the resulting tricyclic amine.
• the amine is then coupled at the C-ring nitrogen with a monoalkyl malonyl chloride, preferably monomethyl malonyl chloride, to give the resulting malonate half-amide.
• the D ring is formed when the malonate half-amide undergoes a Dieckmann condensation in the presence of base, preferably methoxide, to give a 7-hydroxy-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-one.
• step (c) the vinyl triflate of the 7-hydroxy-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-one is coupled with a tertiary malonate anion to form a 7-(1,1-di-tert-butoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-one.
• step (d) the diester is cyclized to form the lactone E ring of an indolizino[1,2-b]quinolinone, preferably a camptothecin analog.
• 1,2 elimination of the tertiary hydrogen ⁇ to the quinolino nitrogen by oxidation in the presence of sodium nitrite or other oxidizing agents such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gives the analogous indolizino[1,2-b]quinolin-9(11H)-one, followed by reduction of the carbomethoxy group at C-8 to a hydroxymemyl function and hydrolysis/decarboxylation of the malonate diester to give the resulting 4-ethyl- 1H- pyrano[3',4':6,7] indolizino[1,2-b]quinolin-3,14(4H,12H)-dione.
• DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
• the 4-ethyl-1H-pyrano[3',4':6,7] indolizino[1,2-b]quinolin-3,14(4H,12H)-dione may be further reacted to form a tertiary alcohol ⁇ to the E ring carbonyl by air-oxidation, thus giving a camptothecin.
• camptothecin may be further elaborated to give a variety of
• camptothecin analogs For instance, cleavage of the methoxy group of 4-ethyl-4-hydroxy-9-methoxy-1H-pyrano[3',4 , :6,7] indolizino[1,2-b]quinolin-3,14(4H,12H)-dione (10-methoxycamptothecin) with HBr yields 10-hydroxycamptothecin, which is itself pharmaceutically useful. 10-Hydroxycamptothecin may be conveniently converted to topotecan by reaction with N.N.N'.N'-tetramethyldiaminomemane (BDAM).
• BDAM N.N.N'.N'-tetramethyldiaminomemane
• camptothecin products of the present process may further be converted to camptothecin analogs in which the E ring has been replaced by some other functionality, e.g., mappicines and mappicine ketones, for instance by the process described in our recently allowed U.S. Ser. No. 07/589,848, which discloses a semisynthetic method of preparing certain 8-methyl-7-(-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones from camptothecin or derivitized camptothecins.
• some other functionality e.g., mappicines and mappicine ketones
• the starting material is a compound of Formula in wherein R 4 and R 5 are joined together to form a substituted pyridone.
• the present invention provides a process for the preparation of camptothecin analogs which lack the lactone E ring, preferably 8-methyl-7-(oxopropyl)-indolizino [1,2-b]quinolin-9(11H)-ones, most preferably mappicines (1ib) and mappicine ketone (11a), said process comprising the steps of:
• camptothecin analog which lacks the lactone E ring, preferably a 8-methyl-7-(oxopropyl)-indolizino[1,2-b]quinolin-9(11H)-one, most preferably a mappicine or mappicine ketone.
• the present invention provides a process, as shown in Scheme 7, for the total synthesis of, depending upon choice of termination step, 4-ethyl-4-hydroxy-9-memoxy-1H-pyrano[3',4':6,7] indolizino[1,2-b]quinolin-3,14(4H, 12H)-dione, more commonly known as 10-methoxycamptothecin, 4-ethyl-4,9-dihydroxy-1H-pyrano[3',4 , :6,7] indolizino[1,2-b]quinolin-3,14(4H,12H)-dione, more commonly known as 10-hydroxycamptothecin, as well as of 10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-dione, more commonly known as topotecan, said
• tetrahydrofuran N,N-dimeti ⁇ ylformamide, acetonitrile, acetone or N-methylpyrrolidinone, most preferably acetonitrile;at a temperature of about 20 -85°C, preferably about 60 - 85°C, most preferably at about the reflux temperature of acetonitrile; in the presence of a strong alkylating agent or such agent as is capable of transforming an amide into its corresponding O-alkylimidate or imidate ester, imidoyl halide, or a strong acid (such as aluminum chloride) capable of initiating a cyclodehydration, preferably trifluoromethanesulfonic anhydride, dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O-benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or triphenylphosphine/carbon tetra
• step (b) hydrolyzing the carbamate function of the C-2 substituted pyrrolo[3,4-b]quinoline from step (a) with acetic acid saturated with HBr to give a tricyclic amine (X);
• Soduim borohydride (200 mg, 3 eq.) was added in small portions to this stirred solution and the resulting mixture was stirred for 15 minutes after addition was complete.
• the solvent was removed on a rotavapor and dilute hydrochloric acid (50 ml of 0.4% solution) was added to the residue.
• the mixture was extracted with 3 ⁇ 100 ml of methylene chloride.
• the combined organic layers were dried over magnesium sulfate and concentrated to give a dark solid to which trifluoroacetic acid (20 ml) was added.
• the mixture was stirred at ambient temperature for 1 h. Trifluoroacetic acid was removed on a rotavapor and water (50 ml) was added to the residue.
• the overall yield of topotecan for the total synthesis in 13 steps was about 5- 6%.

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