Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
  • C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine

Definitions

• R 2 is acetoxy or hydroxy
• R 5 is formyl or methyl
• vinblastine and vincristine which are anti-tumor agents widely used in the treatment of cancer. These agents have been prepared from extracts of the Vinca rosea plant. As these alkaloids are present in the plant only in very small concentrations and since they must be separated from many other companion alkaloids, their synthetic generation becomes particularly valuable.
• the Potier and Kutney coupling process has disadvantages.
• the yields are not satisfactory except for the coupling of catharanthine N-oxide with vindoline and even there the preparative yield is low.
• vindoline is the most abundant alkaloid of Vinca rosea and is thus readily available
• the other possible components of the Potier-Kutney coupling process catalogharanthine, allocatharanthine, voacangine,
• n is an integer of 0 to 1; A is the remaining portion of an aromatic carbocyclic or heterocyclic ring; B is an alkylene chain of from 1 to 4 carbon atoms; R 10 is -CH 2 Y, formyl or a formyl protected by formation of an acetal group; R 1 is lower alkyl and Y individually is a leaving group or a hydrolyzable ether group; X is halo and R 2 is amino protecting group; R 5 is hydrogen or lower alkyl; and R 6 is individually hydrogen, lower alkyl or taken together with Y forms lower alkylidenedioxy;
• Z is the residue of a vindoline ring system and n, A, B, R 1 , R 2 , R 5 , R 6 and R 10 are as above or mixtures thereof with the corresponding 7R diastereomer having the opposite configuration at the 5-position, are formed.
• n, A, B, Z and R 1 are as above; and R 5 is hydrogen or lower alkyl; and R 7 is hydrogen, hydroxy or lower alkyl; which have the "natural" conformational structure i.e. that of the alkaloids isolated from, plants. It is these alkaloids of the "natural" configuration which are active as anti-tumor agents.
• the process of this inventions produces for the first time alkaloids of the formula
• n, A, B, Z, R 1 , R 5 and R 7 are as above; which have a conformational structure different from the
• the compounds of formula I-B are intermediates for the "natural type” compounds of formula I-C and can be converted to the compounds of formula I-C by heating. While the compounds of formula I-B are not by themselves active as antifumor agents, they may be administered as "pro-drugs" and activated by transformation into the compounds of formula I-C at the tumor site by heating or by micro waves or by ultrasonics or by infra-red radiation.
• vinblastine- the compound of formula I where R 2 is acetoxy, R 5 is methyl, R 3 is hydroxy, R 4 is ethyl;
• vincristine- the compound of formula I where R 2 is acetoxy, R 4 is hydroxy, R 4 is ethyl, and R 5 is formyl.
• this synthesis provides a method for producing new vincristine and vinblastine type compounds which are active as anti-tumor agents, since it provides the correct relative and absolute configuration of the asymmetric carbon atoms at C18' and C2' respectively. Therefore, through the process of this invention not only can the known vincristine and vinblastine alkaloids be synthesized, but also new anti-tumor compounds having the following formula:
• n, B, and R 1 are as above; R 3 ' is hydrogen or lower alkyl; R 4 ' is hydrogen or lower alkyl; and R 5 is formyl or methyl.
• Compound A the compound of the formula I-D where R 5 is methyl and R 4 is ethyl and R 3 is hydrogen.
• Compound B the compound of formula I-D where R 5 is methyl and R 3 and R 4 are hydrogen.
• Compound C the compound of formula I-D where R 5 is formyl, and R 4 is ethyl and R 3 is hydrogen.
• Compound D the compound of formula I-D where R 5 is formyl, and R 3 and R 4 are hydrogen.
• the compounds of the formula I and I-C and I-D and their pharmaceutically acceptable salts are useful in inhibiting the growth of malignant tumors and may be utilized in this same manner as vinblastine and vincristine.
• the new analogues and conformational isomers of vinblastine and vincristine produced through the claimed synthesis of this invention such as the compounds of I-D, in particular Compound A, B, C and D, do not have the high toxicity of vincristine and vinblastine as will be seen from the results of Table 1 below.
• the effect of Compounds A and B on intraperitoneally transplanted tumors and their reduced toxicity can be seen from the results of the P-388 leukemia test.
• the compounds were administered in a saline solution.
• the P-388 leukemia test was performed on BDF hybrid mice. The tests were carried out on groups of six mice and 10 tumor cells/animal were transplanted intraperitoneally.
• test compounds were started in the 24th hour after transplantation. Treatment was performed intraperitoneally and the body weight and state of animals was determined every day. The effect obtained on the treated animals is expressed in % of the mean length of life of the control group, given in days. This increase over the control is expressed in Table 1 as %T/C, i.e. Treated/Control.
• the figures in parenthesis represent repeat determinations two months after the first determination.
• the tumor inhibitory effect of the new compounds on P-388 mouse tumor is evident at doses ranging from 0.01 to 100 mg/kg/day dose and is equal to the effect of the known indole-indoline alkaloids.
• the instant compounds are less toxic than these known alkaloid compounds
• the compounds can best be employed intravenously or as infusions.
• the parenteral route is ordinarily employed.
• the drug Prior to administration, the drug is customarily mixed with a pharmaceutically suitable carrier. With parenteral administration, the intravenous route is preferred although, with smaller mammals such as mice, the intraperitoneal route may be used.
• isotonic solutions containing 1-10 mg/ml. of a salt of an alkaloid of the formula I or salts thereof are employed.
• the drug is administered at a dose of from 0.01 to 10 mg/kg and preferably from 0.05 to 1 mg/kg of human body weight once or twice a week or every two weeks depending on both the activity and the toxicity of the drug.
• An alternative method of arriving at a therapeutic dose is based on body surface area with a dose in the range 0.1 to 10 mg/meter squared of human body surface administered thrice weekly or every 7 or 17 days.
• the novel compounds encompassed within formula I or I-D differ in their anti-tumor spectrum from that of vinblastine and vincristine as the anti-tumor spectra of those compounds differ among themselves, one drug being more effective against certain tumors or classes of tumors and less effective against others.
• an oncologist may administer them initially by the same route, in the same vehicle and against the same types of tumors as employed clinically with vincristine and vinblastine. Differences in dosage level would, of course, be based on relative oncolytic potency and toxicity.
• Tumors against which clinical trial candidates are screened include adenocarcinoma of the breast, adenocarcinoma of the colon, bronchogenic carcinoma, adenocarcinoma of the pancreas, ovarian cancer, malignant melanoma, acute myelocytic leukemia, acute lymphocytic leukemia, lymphomatous disease and malignant glioma.
• a compound of formula I would be tested clinically against one or more of these tumors as well as other tumors known to be susceptible to i.v. administration of vincristine and vinblastine. After its potency, nature and degree of side effects etc. had been established, the drug would be tried against tumors for which there is no therapy. After preliminary tests were concluded and the results published, the drug would be used against tumors susceptible to its action at relatively non-toxic dose levels.
• Useful non-toxic acids for forming acid addition salts with the bases of formula I include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and the like, as well as salts of non-toxic organic acids including aliphatic mono and dicarboxylates, phenylsubstiruted alkanoates, hydroxy alkanoates and alkandioates, aromatic acids, alphatic and aromatic sulfonic acids, etc.
• Such pharmaceutically acceptable salts thus include the sulfate, bisulfate. sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate.
• dihydrogen-phosphate metaphosphate.
• phosphite pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate.
• the substituent A in the compound of formula II can be any group which when connected to the ring system of the compound of formula II forms an aromatic carbocyclic or heterocyclic ring.
• Any conventional aromatic carbocyclic or heterocyclic ring structure can be formed by A.
• the aromatic carbocyclic ring substrates formed by A include the carbocyclic aromatic monocyclic or polycyclic ring structures containing 6 to 12 carbon atoms in the ring, most preferably benzene and naphthalene.
• any aromatic heterocyclic ring structure when connected to the remainder of the molecule in the compound of formula II forms an aromatic heterocyclic ring structure, any aromatic heterocyclic ring structure can be formed including those ring structures which contain from 1 to 3 nitrogen or sulfur atoms as the only hetero atoms in the ring structure.
• the heterocyclic ring structure is preferably monocyclic or bicyclic and can contain from 5 to 10 members in its ring.
• the aromatic heterocyclic ring structures formed by A are included pyridine, quinoline, pyrrole, thiophene etc.
• the ring structure formed by A can be unsubstituted or substituted with any conventional substituent.
• the use of these substituents does not affect the overall reaction to produce the compound of formula III with the stereoconfiguration of vinblastine.
• the ring formed by A is substituted, it can be substituted by any conventional substituent such as lower alkyl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, amino, nitro, lower alkylamino, halo, etc.
• B can be any alkylene chain of from 1 to 4 carbon atoms such as methylene, ethylene, propylene, butylene.
• the lower alkylene chain can be unsubstituted or substituted with any conventional substituent including those substituents mentioned hereinbefore in connection with the ring defined by A. Among the most preferred substituents are included hydroxy, lower alkyl, lower alkoxy, etc.
• the term lower alkylidenedioxy designates a lower alkylidenedioxy substituent where lower alkylidene contains from 1 to 7 carbon atoms. Among the preferred lower alkylidenedioxy substituents are included isopropylidenedioxy.
• R 10 is a formyl group protected through the formation of an acetal.
• the acetal can be formed with any conventional alcohol or glycol to produce an acetal which upon hydrolysis yields R 10 as formyl.
• the conventional alcohols used to produce the acetals are the mono-hydroxy alcohols such as methanol and ethanol as well as other lower alkanols and dihydroxy alcohols, or glycols which produce cyclic acetals such as lower alkylene glycols including ethylene glycol, etc and dihydroxy lower alkanes containing 2 to 7 carbon atoms such as 1,3-dihydroxypropane, 1,4-dihydroxy butane, etc.
• R 10 is -CH 2 Y and Y taken together with its attached carbon atom forms a hydrolyzable ether group
• Y can be any ether protecting groups, which when subjected to cleavage form a hydroxy group.
• a suitable ether protecting group is. for example, the tetrahydropyranyl ether, or 4-methyl-5, 6-dihydro-2H-pyranyl ether.
• arylmethyl ethers such as benzyl, benzylhydryl, or trityl ethers or alpha-lower alkoxy lower alkyl ether, for example, methoxymethyl, or tri(lower alkyl)silyl ethers such as trimethyl silyl ether or dimethyltert-butyl silyl ether.
• the preferred ethers which are removed by acid catalyzed cleavage are t-butyl and tetrahydropyranyl and the tri (lower alkyl)silyl ethers, particularly dimethyl-tert-butyl silyl ether, which may be removed by reaction with a fluoride such as tetrabutyl ammonium fluoride.
• Acid catalyzed cleavage is carried out by treatment with a strong organic or inorganic acid.
• the preferred inorganic acids are the mineral acids such as sulfuric acid, hydrohalic acid, etc.
• the preferred organic acids are lower alkanoic acids such as acetic acid, para-toluene sulfonic acid, etc.
• the acid catalyzed cleavage can be carried out in an aqueous medium or in an organic solvent medium.
• the organic acid can be the solvent medium.
• an organic acid is generally utilized with the acid forming the solvent medium.
• the cleavage is generally carried out in an aqueous medium. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure.
• the leaving group designated by Y can be any conventional leaving group.
• the conventional leaving groups which are preferred are tosyloxy, mesyloxy and halogen.
• R 2 which is an amino protecting group
• any conventional amino protecting group which can be removed by hydrogenolysis or photochemical cleavage can be utilized in accordance with this invention.
• the preferred amino protecting groups are included trityl, o-nitrobenzyl, benzyl, and diphenylmethyl, etc.
• lower alkyl designates monovalent saturated straight or branched chain alphatic hydrocarbon groups containing from 1 to 7 carbon atoms such as ethyl, methyl, n-propyl, isopropyl, n-butyl, isobutyl.
• lower alkylene designates a divalent saturated aliphatic straight or branched chain hydrocarbon radical containing 1 to 4 carbon atoms such as methylene or ethylene.
• halogen or halide includes all four halogens or halides such as chlorine, bromine, fluorine and iodine with chlorine, bromine and iodine being preferred.
• lower alkanoyl designates alkanoyl groups derived from alphatic monocarboxcylic acids containing from 1 to 7 carbon atoms such as acetyl, butyryl, pivaloyl. etc.
• the compound of formula III In condensing the compound of formula II with a compound containing the ring system of vindoline, one produces the compound of formula III with the configurations as shown at the 5 and 7 positions, which are necessary for obtaining vinblastine type compounds.
• the compound of formula III with the configuration as shown can be produced as a mixture thereof with the corresponding diastereomer having the opposite stereo-configuration at the 5 and 7 positions from that shown, depending upon the stereo-configuration at the 5 position of the compound of formula II.
• the compound of formula II has a 5 configuration as shown, condensation of the compound of formula II with a compound containing the ring system of vinblastine will produce the compound of formula III with the configuration at the 5 and 7 positions as shown.
• the compound of formula II contains a mixture of 5S and 5R isomers, the compound of formula III will be formed as a mixture of the 7 diastereomer as shown, with the corresponding diastereomer having the opposite configuration at both the 7 and 5 positions to that shown.
• the compound of formula III is produced as a mixture of the 7S diastereomer as shown with the corresponding 7R diastereomer having the opposite configuration at the 5-position to that shown.
• This diastereomeric mixture can be separated either at this stage or at some later stage in the reaction scheme utilizing conventional means such as chromatography.
• any organic compound which contains the structure shown in formula II can be utilized. It has been found that compound of formula II, when condensed with compounds containing the ring system of vindoline or salts thereof, produce the compound of formula III with the specific stereoconfiguration about the 5 and 7 position shown therein. Therefore, the substituents on A and B, as well as the substituent on the ring system of vindoline, are of no importance to the reaction of this invention. These substituents will be carried along to produce the compounds of formula III with stereo-configuration about the 5 and 7 position set forth above.
• any compound containing the ring system of vindoline can be condensed with the compounds of formula II to produce the compounds of formula III.
• preferred compounds which contain the ring system of vindoline for use in this invention are vindoline, 16-demethoxy vindoline and 2,3-dihydro N a methyl-tabersonine.
• the condensation of the compound of formula II with a vindoline ring system containing compound or salts thereof is carried out in the presence of an aprotic solvent.
• an aprotic solvent any conventional aprotic solvent can be utilized.
• the conventional aprotic solvents are aldehydes and ketones such as acetone, methyl ethyl ketone, etc.
• Other aprotic solvents which are also preferred include ethers such as dioxane and diethyl ether.
• this reaction takes place in the presence of a protic acid or with a salt of a vindoline ring system contain compound with a protic acid. Any conventional protic acid can be used in carrying out this reaction.
• protic acids are hydrohalic acids such as HCl and HBr as well as acids such as HBF 4 .
• condensation take place in the presence of a silver salt.
• Any conventional silver salt which reacts with halides can be utilized in carrying out this reaction.
• the preferred silver salts are silver nitrate, silver fluoroborate, silver perchlorate.
• temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. On the hand higher or lower temperatures can be utilized. Generally it is preferred to carry out this reaction at a temperature of from -10oC to +20oC.
• the compound of formula III can be converted to a compound of the formula
• n, A, B, Z, R 10 and R 10 are as above.
• This conversion is carried out by treating the compound of formula III with an alkali metal borohydride in an acid.
• Any conventional acid can be used in this conversion.
• the acids are included inorganic acids such as phosphoric acid, sulfuric acid as well as organic acids such as formic acid and acetic acid, with organic acids such as acetic acid being preferred.
• the organic acid can be utilized as the solvent.
• temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. On the other hand, if desired elevated or lower temperatures can be utilized.
• R 10 are as above with a compound containing the ring system of vindoline.
• This reaction can be carried out utilizing the same conditions described hereinbefore in connection with the conversion of a compound of formula II to a compound of formula III. However, it is generally preferred to carry out this reaction, without the presence of a silver salt, simply in the presence of an inert solvent. Generally it is preferred to carry out this reaction in a protic solvent in the presence of an acid, or in an acid halide. In carrying out this reaction with an acid, any protic solvent such as a lower alkanol i.e., methanol or ethanol can be utilized.
• the acids which are generally ut i l ized are the' organic acids such as the lower alkanoic acids i.e.
• acetic acid On the other hand mineral acids such as hydrochloric acid can be utilized as well.
• any conventional acid halide can be used such as lower alkanoic acid halides, i.e. acetyl chloride. In these procedures, temperature and pressure are not critical and room temperature can be utilized.
• n, R 1 , A, R 5 , Z, B, and R 7 are as above,
• the compound of formula V where R 10 is -CH 2 Y and Y is a leaving group can be converted to the compound of formula I-A by first subjecting the compound of formula V to hydrogenolysis or photochemical cleavage depending upon the substituent R 2 . In this manner the compound of formula V where R 2 is hydrogen is produced. In carrying out this reaction any conventional method of hydrogenolysis or photochemical cleavage to remove an amino protecting group can be utilized. In producing the compound of formula I-A, the compound of formula V where R 2 is hydrogen and R 10 is -CH 2 Y and
• Y is a leaving group, can be cyclized in an organic solvent to a temperature of 10oC to 100oC.
• any conventional hydrocarbon or ether solvent can be utilized with aromatic solvents such as toluene or benzene being preferred.
• aromatic solvents such as toluene or benzene being preferred.
• lower boiling solvents can be utilized. With these lower boiling solvents the cyclization occurs by heating in a sealed tube.
• n, R 1 , R 2 , A, R 5 , Z and B are as above
• R 7 is hydrogen or lower alkyl and Y' is an anion
• the compound of formula V where R 10 is CH 2 Y and Y is a leaving group is heated in a organic solvent to a temperature of from 35°C to 100oC.
• any conventional inert organic solvent can be utilized with aromatic hydrocarbons such as toluene and benzene or ether solvents being preferred.
• the solvents which can be utilized are solvents boiling above 35oC. However, lower boiling solvents can also be utilized if the reaction is carried out in a sealed tube.
• the leaving group Y in this reaction becomes the anion Y' upon formation of the quaternary salt.
• the compound of formula VI is converted to the compound of formula I-A by removal of the amino protection group as described above.
• the compound of formula V where R 10 is -CH 2 Y and Y is a hydrolizable ether group can be converted to the compound of formula V where R 10 is a leaving group by first removing the ether group by conventional ether hydrolysis to produce the compound of formula V where Y is -OH.
• This compound of formula V where Y is a hydroxy can be converted to the compound of formula V when Y is a leaving group such as mesyloxy, tosyloxy, or halogens such as chlorine or iodine by any conventional method of converting a hydroxy group to a leaving group.
• the compound of formula V where Y is a leaving group produced as above is converted to the compound of formula I-A as described above.
• the compound of formula V where R 10 is -CH 2 Y and Y and R 6 form a lower alkylidenedioxy, particularly isopropylidenedioxy, can be converted to the compound of formula I-A by first converting this compound to the corresponding compound of formula V where R 2 is hydrogen. This conversion is carried out by removing the amino protecting group as described above. After the amino protecting group has been removed the lower alkylidenedioxy groups may be removed by hydrolysis to produce the compound of formula V where R 10 is -CH 2 OH, R 2 is hydrogen and R 6 is hydroxy.
• this compound can be produced f rom the compound of formula V where R 10 is -CH 2 Y and Y and R 6 form lower alkylidenedioxy by first hydrolyzing the lower alkylidenedioxy groups to produce the compound of formula V where R 2 is an amino protecting group, R 10 is -CH 2 OH and R 6 is -OH and thereafter removin the amino protecting group.
• R 10 is hydrogen.
• R 10 -CH 2 OH and R 6 is
• OH can be converted to the compound of formula I-A by cyclization with a cyclization agent such as methyl triphenoxyphosphonium halide. Any of the conditions conventionally used with these agents can be utilized in this conversion.
• a cyclization agent such as methyl triphenoxyphosphonium halide. Any of the conditions conventionally used with these agents can be utilized in this conversion.
• this compound can be converted to the compound of formula I-A by first hydrolyzing the acetal group, by conventional acetal hydrolysis, to produce the corresponding compound of formula V where R 10 is formyl.
• n, R 1 , A, R 5 , Z, B, and R 7 are as above, and Y" is an anion of a lower alkanoic acid.
• any lower alkanoic acid can be utilized, with a acetic acid and formic acid being especially preferred.
• the compound of formula VII can be converted to the compound of formula I-A by reduction with sodium cyanoborohydride in a lower alkanoic acid at a temperature of from 20oC to 60oC.
• n, A, Z, B and R 1 are as above and R 7 is hydrogen or lower alkyl
• R 10 is formyl, and both of R 5 and R 7 are lower alkyl. is heated to a temperature of 35oC to 100oC in a neutral or basic organic solvent then a compound of the formula
• R 7 " are individually lower alkyl; is formed.
• the compounds of formula VII-A and VII-B can be converted to the corresponding compounds of formula I-A by reduction in the same manner as described in connection with the conversion of the compound of formula VII into the compound of formula I.
• any conventional neutral or basic organic solvent can be used or. if desired, mixtures of neutral and basic solvents.
• the preferred neutral solvents which can be utilized are included toluene, benzene, trichloromethane, etc.
• the preferred basic solvents are included pyridine, triethylamine, etc.
• the compounds of formulae III, V, VI, VII, VII-A and VII-B and I-A can be formed as either the 7S-diastereomer with the C5 configuration as shown or as a mixture thereof with its corresponding 7R diastereomer where the configuration at C5 is opposite to that shown.
• the formation of the 7S-diastereomer or its mixture with the corresponding 7R-diastereomer depends upon enantiomeric purity of the compound of formula II or II-A at the tertiary carbon attached to the tertiary nitrogen group contained therein. If a mixture of the 7S-diastereomer with the corresponding 7R-diastereomer is formed these diastereomers can be separated at any stage of the process by means of chromatography. In each instance, the stereochemistry at C5 will correspond uniquely to the stereochemistry at C7 and have the priority antireflective relationship (PARF) found in vinblastine.
• PARF priority antireflective relationship
• the compound of formula I-A can exist as one or the other or as a mixture of both of two conformational isomers, i.e. a compound of the formula I-B and I-C.
• the compound of formula I-C has the conformational structure of the natural product.
• a compound of structure I-B when a compound of structure I-B is heated at a temperature of from 30oC to 150oC it is converted to a compound having the natural conformational structure, i.e. a compound of the formula I-C.
• any conventional inert organic solvent can be utilized but this conformational conversion of I-B to I-C can be obtained in any medium. In fact heating the compound of formula I-B in solid form will accomplish this result.
• the preferred solvents are the aliphatic or aromatic hydrocarbons boiling above 30oC. Among these solvents are included toluene and benzene.
• a mixture of compounds of formula I-B and I-C can be converted to the "natural" conformational isomer by heating in the manner described above. If it is desired to obtain the compound of formula I-B in pure form, the compound of formula I-B can be separated from its mixture with the compound of formula I-C. Any conventional method of separation can be used to separate the compound of formula I-B from this mixture of conformational isomers.
• the compound of formula II is prepared by reacting a compound of the formula
• R 16 is hydrogen or an amino protecting group with any one of the following compounds:
• n, R 5 ' R 7 and B are as above; R 11 is hydrogen or lower alkyl; and R 12 is lower alkylidenedioxy.
• n, A, B, R 1 and R 5 are as above;
• R 15 is -CH 2 -R 9 or -CO 2 R 13 ;
• R 8 is hydrogen, or lower alkyl;
• R 9 is hydroxy or taken together with R 8 forms lower alkylidenedioxy and
• R 13 is lower alkyl, with the proviso that when R 9 is hydroxy, R 5 and R 8 are hydrogen;
• XIII-B or XIII-C to form the compound of formula XIII is carried out by a Mannich reaction. Any of the conditions conventional in Mannich reactions can be utilized in carrying out this reaction to form the compound of formula XIII.
• the reaction of this compound of formula XII with the compound of formula XIII-A produce the compound of formula XIII where R 5 and R 8 are hydrogen.
• R 15 is -CH 2 R 9 and R 9 is hydroxy.
• reaction of the compound of formula XII with the compound of formula XIII-B produces the compound of formula XIII where R 5 is hydrogen or lower alkyl; R 8 is hydrogen or lower alkyl and R 15 is -CO 2 R 13 .
• reaction of the compound of formula XII with the compound of formula XIII-C produces the compound of formula XIII where R 5 is hydrogen or lower alkyl, R 15 is -CH. where R 9 and R 8 form lower alkylidenedioxy
• n, Y' , A, B, R 1 R 2 , R 5 , R 6 , R 8 R 10 and R 15 are as above.
• the compound of formula XIII is converted to the compound of formula XIV by protecting the tertiary amine group.
• Any conventional method of protecting a tertiary amine group with any of the aforementioned tertiary amine protecting groups which can be removed by hydrogenolysis or by photochemical cleavage can be utilized to carry out the conversion of formula XIII to the compound of formula XIV.
• the amino protecting reagent containing a leaving group such as halide is reacted with the compound of formula XIII. This leaving group becomes the anion Y-.
• the compound of formula XIV is converted to the compound of formula XV by treating the compound of formula XIV with a amine or inorganic base.
• Any conventional amine base such as tri-lower alkylamine particularly triethylamine and diisopropylethylamine or an inorganic base such as sodium carbonate can be utilized.
• This reaction can be carried out in any conventional inert organic solvent.
• the preferred organic solvent are the alcohols, such as the lower alkanols including methanol.
• temperature and pressure are not critical. This reaction can be carried out at room temperature and atmospheric pressure. On the other hand, higher or lower temperatures can be utilized. Generally it is preferred to carry out this reaction at the reflux temperature of the solvent.
• the compound of formula XV where R 15 is -CH R 9 and R 9 is hydroxy can be converted to the compound of formula XVI where R 10 is CH 2 Y where Y is a hydrolyzable ether group by conventional etherification procedures.
• the preferred ether groups are the tri(lower alkyl silyl)oxy groups particularly t-butyldimethylsilyloxy.
• the hydroxy group can also be converted into a leaving group, such as mesyloxy, tosyloxy or a halide. particularly a chloride, bromide or iodide group, to produce the compound of formula XVI where Y is a leaving group.
• Reactions conventional for converting primary alcohols into the aforementioned leaving groups can be utilized to affect this conversion to form the compound of formula XVI.
• R 15 in the compound of formula XV is a -COOR this group can be converted to the compound of formula XVI where R 10 is formyl by reduction.
• Any conventional reducing agents such as diisobutyl aluminium hydride, which are utilized to reduce esters to their corresponding aldehydes, can be utilized in this conversion. If it is desired to prepare the compound of formula XVI where R 10 is formyl protected by formation of an acetal, the formyl group can be converted to an acetal by conventional means.
• the compound of formula XVI which includes the compound of XV when R 8 and R 9 form lower alkylidenedioxy, can be converted to the compound of formula II by treating the compound of formula XVI with a halogenating agent such as organic or inorganic hypohalite preferably calcium hypohalite, sodium hypohalite or t-butylhypohalite in the presence of a tertiary amine base.
• a halogenating agent such as organic or inorganic hypohalite preferably calcium hypohalite, sodium hypohalite or t-butylhypohalite in the presence of a tertiary amine base.
• Any conventional tertiary amine base can be utilized in carrying out this reaction.
• the preferred tertiary amine bases are the tri-lower alkyl amines and the cyclic tertiary amines.
• cyclic tertiary amines included N-lower alkylpyrrolidine, N-lower alkylpiperidine, N,N-di-lower alkylaniline, pyridine, etc.
• an inert organic solvent can be utilized.
• the amine base can act as the solvent medium.
• a solvent generally aprotic solvents , such as halogenated hydrocarbons, ethers and dimethylformamide are preferred.
• the compound of formula XVI can be converted to the intermediate of the formula XIX by reduction with an alkali metal borohydride, preferrably sodium borohydride in an inorganic or organic acid.
• This reaction can be carried out in the same manner described hereinbefore in converting the compound of formula III to the compound of formula V except that temperature of a t least 40oC, preferably 70oC to 100oC, are generally utilized for this conversion.
• the compound of formula XIX can be converted to the compound of formula II-B by chlorination with a hypohalite, such as t-butyl hypochlorite, sodium hypochlorite or calcium hypochlorite in the presence of a tertiary amine. This reaction is carried out in the same manner as described hereinbefore in connection with the formation of the compound of formula II.
• a hypohalite such as t-butyl hypochlorite, sodium hypochlorite or calcium hypochlorite
• the compounds of formula I wherein the vindoline ring contains a methyl group at R 5 can be converted to the corresponding compounds where R 5 is CHO, i.e. compounds of the vincristine type by oxidation procedures well known in the art.
• the ether is diethyl ether and Celite is diatomaceous earth.
• HPLC in the examples designates high pressure liquid chromatography.
• reaction mixture was basified (NH 4 OH) , 10% (aq) and extracted three times with CH 2 Cl 2
• the organic extracts were dried (Na 2 SO 4 ) and concentrated to a residue, which was immediately dissolved in THF (100 mL) .
• PARF 5,7-priority anti-reflective
• the 6S and 6R isomeric mixture of 4,6-priority antireflective (PARF) methyl 3-benzyl-1,2,3,3a,4,5-hexahydro-4-(3-p. toluenesulfonyloxy-propyl)-6-(15-vindolinyl)pyrrolo-(2, 3-d)carbazole-6-carboxylate was dissolved in 15 mL of acetic acid and, with stirring at room temperature, 0.54g (10 mmol) of sodium borohydride was added in six portions. After the final addition the reaction mixture was stirred for 10 min. and then poured onto ice. Adjustment of the pH to 9-10 with cone.
• PARF 4,6-priority antireflective
• the aqueous phase was basified with NH 4 OH (10% aq) and concentrated to a residue, which was chromatographed (SiO 2 , 2% methanol/CH 2 Cl 2 ) to yield the 7 ⁇ isomer of methyl 3-benzyl-1,2,3,4,5,6,7,8-octahydro-5 ⁇ (3-p.toluenesulfonyloxypropyl) azonino (6,7-b) indole-7-carboxylate (0.055g, 55%) and the 70 isomer of methyl-3-benzyl-1,2,3,4,5,6,7,8-octahydro-5 ⁇ (3-p.toluenesulfonyloxypropyl) azonino (6,7-b) indole-7-carboxylate (0.015g, 15%) as amorphous solids. These compounds tended to undergo, on standing, cyclization to the internal quaternary salt.
• PARF 5,7-priority anti-reflective
• reaction mixture was diluted with 20 mL of dichloromethane, washed with water (2 x 50 mL) and brine (1 x 20 mL) , dried (MgSO 4 ) and concentrated under vacuum to 0.61g (100%) of an orange foam. This material was used directly in the subsequent coupling reaction with vindoline.
• TLC then showed formation of the two diastereomeric products 4' -deethyl-4' -deoxyvinblastine (2'S,18'S) and 4' -deethyl-4' -deoxyvinblastine (2'R, 18'R) both with the 1' axially substituted piperidine ring conformation.
• TLC SiO 2 : 10% methanol in CH 2 Cl , CAS brown
• the above 1'-equatorial compound was conformationally inverted to the 2 , S,18 , S,1' axial 4' -deethyl-4'-deoxyvinblastine by heating in toluene at 95°C.
• This product had an HPLC retention of 8.8 min on the same column at the same flow rate.
• the 2'R, 18'R, 1' equatorial compound had HPLC retention of 35.1 min on a 250 x 4.6 mm C-18 reverse phase column with 1% triethylamine in 85:15 methanol:water at a 0.5 mL min flow rate.
• PARF 5,7-priority anti-reflective
• the epimeric mixture of tosylates could be separated by centrifugal chromatography on a 4 mm SiO 2 plate, with application in 10 mL of dichloromethane and elution with ethyl acetate: pentane (1:5). At 2.2 mL/min and with collection of 1 min fractions, the PREF isomer was obtained in fractions 6-26 and the 4,2' PARF isomer in fractions 99-170. Rechromatography of central fractions (5x) gave final 0.420 g combined PREF isomer and 0.391 g combined PARF isomer (total 0.811 g, 61% yield). Alternatively, separation of the diastereomeric tosylates was accomplished by preparative high pressure liquid chromatography.
• the crude reaction product was first passed through a 3 x 10 cm SiO 2 column, eluting with ethyl acetate: pentane (1:2).
• the concentrated eluates (200 mg) were then subjected to HPLC on a 22.1 mm x 50 cm 10 ⁇ m.
• Silica column with ethyl acetate: pentane 1:4, 20 mL/min. Collecting 24 mL fractions gave in fractions 6-9 76 mg and in fractions 12-17 112 mg of the respective diastereomers (94% recovery).
• TLC (SiO 2 , ethyl acetate) demonstrated the two imines 4,5-PARF and 4,6-PREF methyl 3-benzyl-1,2,3,3a,4,5-hexahydro-4-[2-(p.toluenesulfonyloxymethyl) butyl]-6-(15-vindolinyl)-pyrrolo (2, 3-d) carbazole-6-carboxylate (Rf 0.13 and 0.46) and the absence of vindoline (Rf 0.32).
• This imine mixture was dissolved in 25 mL of acetic acid and 0.571g (10.6 mmol) of potassium borohydride was added in. portions over 15 min. with rapid stirring.
• the reaction mixture was then poured into cold ammonium hydroxide solution and extracted with 3 x 50 mL of dichloromethane.
• the combined extracts were dried (MgSO 4 ) filtered and concentrated at 40°C at 15 mm and subsequently at 0.05 mm Hg to give 0.660g (85% yield based on vindoline used) of the two amines, i.e.
• Rechromatography of the fractions 31-51 provided additional separated compounds, for a combined 0.300 g of the 7S isomer and 0.271g of the 7R isomer (66% total yield based on vindoline).
• the resulting quaternary salt i.e. the 1'-equatorial piperidine ring conformational isomer of 6'-benzyl-4'-deoxy-vinblastinonium tosylate (2'S,18'S) (0.172g, 96%), which was free of starting amine by TLC, (ethyl acetate: ethanol, 1:1). was dissolved in 6 mL of methanol. Addition of 0.015g of 10% Pd/charcoal and stirring under a hydrogen atmosphere at -20°C for 40 min resulted in an uptake of 4 mL of hydrogen. The reaction mixture was filtered through a 1 x 3 cm plug of Celite 545.
• the compound 4'-deoxyvinblastine (191mg) was converted to its methane sulfonate salt by first dissolving this compound in 10 ml of ether. To this solution was added 31 ⁇ l of methane sulfonic acid. The resulting precipate was filtered and washed with 5ml of ether providing 212mg of the methane sulfonate salt of 4'deoxyvinblastine.

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• 1986
  • 1986-02-21 AU AU54594/86A patent/AU590873B2/en not_active Ceased
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• 1989
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