EP0923287A1 - Antifoliques non classiques de pyrrolo 2,3-d]pyrimidine - Google Patents

Antifoliques non classiques de pyrrolo 2,3-d]pyrimidine

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Publication number
EP0923287A1
EP0923287A1 EP97939567A EP97939567A EP0923287A1 EP 0923287 A1 EP0923287 A1 EP 0923287A1 EP 97939567 A EP97939567 A EP 97939567A EP 97939567 A EP97939567 A EP 97939567A EP 0923287 A1 EP0923287 A1 EP 0923287A1
Authority
EP
European Patent Office
Prior art keywords
eth
pyrimidin
amino
optionally substituted
ylcarbonyl
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Withdrawn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
EP97939567A
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German (de)
English (en)
Other versions
EP0923287A4 (fr
Inventor
Christopher L. Jordan
Vinod F. Patel
Daniel J. Soose
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
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Eli Lilly and Co
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Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0923287A1 publication Critical patent/EP0923287A1/fr
Publication of EP0923287A4 publication Critical patent/EP0923287A4/fr
Withdrawn legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the invention relates generally to the fields of pharmaceutical and synthetic organic chemistry. Specifically, the invention relates to the field of antifolate compounds which are useful in the treatment of various diseases.
  • folic acid is used by a number of cells to fuel cell replication.
  • Antifolate compounds mimic folic acid and its derived cofactors when taken up in a cell.
  • Antifolates interact with various folate requiring enzymes in cells to eventually cause the inhibition of cell replication.
  • Antifolate compounds are known to be useful in the treatment of cancer by providing a means to terminate the growth of malignant cells .
  • Classical antifolate compounds such as the multi-targeted antifolate LY 231514 (N- [4- [2- (2-amino-3H- 4-oxo-pyrrolo[2, 3-D]pyrimidin-5-yl ) ethyl] benzoyl] -L- glutamic acid)
  • FPGS folylpolyglutamate synthetase
  • DHFR dihydrofolate reductase
  • GAFT glycinamide ribonucleotide formyl transferase
  • TS thymidylate synthase
  • One way of increasing efficacy, in terms of inhibiting cell replication, is to provide an antifolate that does not contain a terminal glutamic acid moiety in the "L" configuration, thus avoiding the need for polyglutamation with FPGS.
  • the difficulty in providing such a compound is that the compound, in order to be effective in inhibiting cell replication, must still be able to effectively inhibit with other folate requiring enzymes even though it is not polyglutamated.
  • the concept of using a non-polyglutamatable inhibitor was suggested in 1983 as an approach to the design of novel DHFR inhibitors targeted against FPGS deficient tumors. See "Methotrexate Analogues. 20. Replacement of Glutamate by Longer-Chain Amino Diacids: Effects on Dihydrofolate Reductase Inhibition,
  • Non-polyglutamatable inhibitors were also described for the GARFT enzyme in "First Use of the Taylor Pteridine Synthesis as a Route to Polyglutamate Derivatives of Antifolates. 46. Side Chain Modified 5- deazafolate and 5-deazatetrahydrofolate Analogs as Mammalian Folypolyglutamate Synthetase and Glycinamide Ribonucleotide Formyl Transferase Inhibitors: Synthesis and in Vitro Biological Evaluation", Rosowsky, et al . , J ⁇ . Med. Chem. , (1992), 35(9), 1578-88.
  • the first aspect of the invention is a compound of formula (III) :
  • W and G are independently -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, -NR 3 R 4 , -SR 5 , -OR 6 or halo, R 3 and R 4 are independently -H, optionally substituted Ci-Cg alkyl, or a suitable amino protecting group, or together N, R 3 and R * -" are a phthalimido group,
  • R 5 is -H, optionally substituted C1-C6 alkyl or a suitable thiol protecting group
  • R 6 is -H, optionally substituted Ci-C ⁇ alkyl or a suitable hydroxy protecting group
  • L is -R 7 -Q(a)--
  • -CH2CH CH-, -CH2C ⁇ C- and -C ⁇ CCH2 ⁇ , and when R 7 is not -C ⁇ C-, R 7 may be substituted with C1-C2 alkyl, C1-C2 hydroxyalkyl, or C1-C2 hydroxyalkyl wherein the H on the hydroxy moiety has been replaced with a hydroxy protecting group, Q is -0-, -S- or -NR 8 -, a is zero or 1,
  • R 8 is -H, optionally substituted C1-C3 alkyl, alkoxycarbonyl or phenoxycarbonyl ;
  • B is selected from the group consisting of: optionally substituted 1,2-, 1,3-, or 1,4- phenylene, optionally substituted 2,3-, 2,4-, or 2,5- thiophenediyl , optionally substituted 2,3-, 2,4-, or 2,5- furandiyl, optionally substituted 1,2-, 1,3-, or 1,4- cyclohexanediyl, and optionally substituted -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-,
  • A) an ⁇ -amino acid residue selected from the group consisting of -alanine, -arginine, -asparagine, -aspartic acid, -cysteine, -cystine, -glutamine, -glycine, -histidine, -hydroxyproline, -isoleucine, -leucine, -lysine, -methionine, -phenylalanine, -proline, -serine, -threonine, -tryptophan, -tyrosine and -valine, OR
  • R ⁇ are each independently -H or a suitable carboxylic acid protecting group
  • R 11 is i) -COOR 10 , where R 10 is -H, optionally substituted alkyl or a suitable carboxylic acid protecting group, or ii) -H, -OH, 1-carboxyeth-l-yl , optionally substituted C1-C alkyl, optionally substituted cycloalkyl, carboxycycloalkyl, optionally substituted aryl, carboxyaryl, optionally substituted heteroaryl, optionally substituted alkyl (aryl), optionally substituted Ci-C ⁇ alkoxy, optionally substituted polycyclic, optionally substituted 5-tetrazolyl, or iii) -(CH2)e- where: e is 0, 1, 2, 3 or 4, U is -O-CH2-COOH, -S-CH2-COOH or -NR 12 R 25 ,
  • R1 is -H or a suitable amino protecting group
  • R 25 is benzoyl or carboxybenzoyl , or iv) -(CH2) e -T, where e is as above, T is phthalimido, -CO2R 10 , -SO(g)X, -NR 13 R 14 , -CONR 13 R 14 , CONHSO2R 15 , -PO3H2 or -CO- ⁇ - a ino acid residue
  • R-LO is as above, g is zero, 1, 2 or 3 , providing that when g is zero, 1 or 2 , X is optionally substituted Cj_-C6 alkyl, and when g is 3, X is -H,
  • R 13 is -H
  • R 14 is -H, optionally substituted C1-C6 alkyl
  • R 15 is optionally substituted alkyl, optionally substituted aryl, benzyl or carboxyaryl, and each R-'-'-' is independently -H or optionally substituted alkyl, and each ⁇ -amino acid residue is as above ; providing that all of R 11 is so configured such that
  • D- or L-glutamic acid is not D- or L-glutamic acid, -alanine, -arginine, -asparagine, -aspartic acid, -cysteine, -cystine, -glutamine, -glycine, -histidine, -hydroxyproline, -isoleucine, -leucine, -lysine, -methionine, -phenylalanine, -proline, -serine, -threonine, -tryptophan, -tyrosine or -valine; OR
  • each R 9 ' is independently -H or a suitable carboxylic acid protecting group
  • RU' is i) -COOR 10 ', where R 10 ' is -H, optionally substituted alkyl or a suitable carboxylic acid protecting group, ii) -H, -OH, 1-carboxyeth-l-yl , optionally substituted Ci-C ⁇ alkyl, optionally substituted cycloalkyl, carboxycycloalkyl, optionally substituted aryl, carboxy aryl, optionally substituted heteroaryl, optionally substituted aryl (alkyl), optionally substituted alkoxy, optionally substituted polycyclic, optionally substituted 5- tetrazolyl, or iii) -(CH2)e'-U ⁇ where: e' is zero, 1, 2, 3 or 4,
  • U' is -0-CH2 -COOH, -S-CH2 -COOH, or -NR 12, R 25 ',
  • R--- 2 ' is -H or a suitable amino protecting group
  • R ⁇ ' is benzoyl or carboxybenzoyl , iv) -(CH2)e'-T', where e 1 is as above,
  • T 1 is phthalimido, -CO2R 10 ', -S0( g ')X', -NR 1 'R 14 ', -CONR 13 'R 1 ' , -CONHSO2R 15 ' , -PO3H2 or -CO- ⁇ - amino acid residue, where
  • R-LO ' is as above, g' is zero, 2 or 3 , providing that when g' is zero or 2 , X' is optionally substituted C1-C alkyl, and when g' is 3, X' is -H, R 13 ' is -H,
  • R-*- 4 ' is -H, optionally substituted Ci-C ⁇ alkyl,
  • R 15 ' is optionally substituted alkyl, optionally substituted aryl, benzyl or carboxyaryl, and each R!6 ' is independently -H or optionally substituted alkyl;
  • R! is optionally substituted C3-C20 cycloalkyl or C3-C2O carboxycycloalkyl
  • R 2 is -H
  • J is optionally substituted 5-tetrazolyl or optionally substituted C1-C6 alkyl
  • y is zero or 1
  • y' is zero, 1, 2, 3, 4, 5 or 6 and R 11 is as above, and R 2 is -H;
  • j is zero, or an integer from 1 to 10
  • k is zero, or an integer from 1 to 10
  • R1 7 and R--- are independently -H or a suitable carboxylic acid protecting group
  • R 1 and R 2 are both - (CH2 ) n-COOR 17 , where n is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and
  • R 17 is as defined above;
  • R 2 is:
  • R- 1 - 7 is as above, and
  • Y is selected from the group consisting of halo, nitro, amino and optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a second aspect of the invention is an active ester intermediate of formula (I) :
  • a further aspect of the invention is a process to make the compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, by reacting an active ester of formula (I):
  • R 1 and R2 are as defined previously, in the presence of either a silylating agent or a suitable base.
  • a further aspect of this invention is a continuation of the process of the second aspect of the invention, further comprising a rapid work-up procedure wherein a compound or salt of formula (III) is isolated and purified by the following procedure: a) optionally adding a suitable diamine; b) adding a suitable aqueous acid; c) separating the product from its solvent; d) preparing the product physically for collecting, washing and drying; and e) collecting, washing and drying the product.
  • a further aspect of the invention is a pharmaceutical composition comprising a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, m combination with a pharmaceutically acceptable carrier, diluent or excipient.
  • a further aspect of the invention is a method of treating susceptible neoplasms in a mammal in need of such treatment comprising administering a neoplasm growth inhibiting amount of a compound of formula (III) , or a pharmaceutically acceptable salt or solvate thereof, to a mammal .
  • a further aspect of the invention is a method of treating arthritis in a mammal comprising administering an arthritis inhibiting amount of a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, to a mammal .
  • a further aspect of this invention is a method of treating psoriasis in a mammal comprising administering an arthritis inhibiting amount of a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, to a mammal.
  • alkyl refers to a fully saturated monovalent group having the stated number of carbon atoms containing only carbon and hydrogen, and which may be a straight chain or branched group. This term is exemplified by groups containing from 1-6 carbon atoms, such as, but not limited to, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, hexyl, and neohexyl . "Lower alkyl” refers to alkyl groups of from 1-3 carbon atoms .
  • cycloalkyl refers to a fully saturated monovalent ring which contains only carbon atoms in the ring.
  • the "cycloalkyl” groups used herein contain at least 3 and at most 20 carbon atoms in the ring.
  • Carboxycycloalkyl is a cycloalkyl structure that has from one to three -COOH groups in place of hydrogen (s) normally attached to carbon atoms in the ring.
  • C ⁇ -C6 alkoxy refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
  • Typical C ⁇ -C6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like.
  • C2 ⁇ C alkenyl refers to a monovalent, straight or branched chain containing only two to six carbon atoms with hydrogens attached and which contains at least one double bond.
  • Alkoxycarbonyl is the group RO-C- / where R is Ci-
  • Phenoxycarbonyl is the group PhO-C- t w ere Ph is phenyl .
  • ⁇ -Amino acid residues includes optionally substituted -alanine, -arginine, -asparagine, -aspartic acid, -cysteine, -cystine, -glutamine, -glycine, -histidine, -hydroxyproline, -isoleucine, -leucine, -lysine, -methionine, -phenylalanine, -proline, -serine, -threonine, -tryptophan, -tyrosine and -valine.
  • the preferred ⁇ -amino acid for the compounds of this invention is an ⁇ - amino acid in the L-configuration at the ⁇ carbon.
  • the amino acid residue group is bonded to the carbonyl group of Compound III through the ⁇ amino nitrogen.
  • Aryl refers to a monovalent aromatic structure.
  • aromatic refers to a structure containing one or more groups of carbon atoms in a cyclic array that contains clouds of delocalized ⁇ electrons above and below the plane of the atoms; furthermore, the ⁇ clouds must contain a total of (4q+2) ⁇ electrons, where q is any positive integer.
  • these aromatic rings can contain from six to ten carbon atoms. Within this range of possible numbers of carbon atoms present, each aromatic ring must retain its aromatic character and be sterically feasible.
  • Aromatic rings may optionally be substituted, with the proviso that only one to three of the hydrogens may be replaced.
  • heteroaryl refers to a monovalent aromatic structure containing from four to ten carbon atoms and at least one non-carbon atom selected from the group consisting of N, 0 or S, within the ring.
  • heteroaryl rings include single rings, such as pyrrolidino, pyridino, pyrimidino or fused rings such as quinolo, purino, pyrido or pyrrolo [2 , 3-d] pyrimidino .
  • An aryl (alkyl) group consists of at least one aryl group substituted with at least one alkyl group.
  • halo refers to fluoro, bromo, iodo and chloro .
  • a 5-tetrazolyl group is:
  • benzoyl refers to this structure
  • carboxybenzoyl refers to this structure
  • polycyclic refers to two or more rings that share two or more carbon atoms.
  • polycyclic compounds will be limited to monovalent ring systems that have only carbon atoms in the rings and that have either two or three rings.
  • the number of carbon atoms in each ring varies from 4 to 8.
  • substituted means one to three hydrogens on the structure have been replaced with one to three moieties independently selected from the group consisting of bromo, chloro, iodo, fluoro, C ⁇ -C6 alkyl, -N02, aryl, difluoromethoxy, and trihaloalkyl, wherein the halo can be bromo, chloro, iodo or fluoro and the alkyl is C1-C3 alkyl, with the proviso that any substituted structure must be so configured that it is sterically feasible, affords a stable structure and is capable of reacting as described herein.
  • a “pharmaceutically acceptable salt” may be any salt derived from an inorganic or organic acid that is suitable for administration as a drug.
  • the salts are derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate as acid salts), nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid, p-toluenesulfonic acid, hexanoic acid, heptanoic acid, cyclopent
  • a “pharmaceutically acceptable solvate” refers to a form of a compound that has one or more solvent molecules clinging to the molecules of the compound and which form is suitable for administration as a drug.
  • the solvent may be water, alcohol or any common organic solvent.
  • treatment means administering an appropriate therapeutic or prophylactic amount of a compound of the present invention to a mammal.
  • effective amount means a dosage sufficient to cause a positive change in the disease state being treated.
  • positive change will vary in meaning depending on the patient, the disease and the treatment.
  • an effective amount of an oncolytic could be an amount that causes a reduction in the size of a cancerous tumor, or where no reduction in tumor size occurs, an effective amount of an oncolytic could be defined simply as that amount that causes a decrease in analgesic consumption for the patient suffering from cancer.
  • protecting group refers to a group affixed to a substrate group for the purpose of preventing the substrate group from reacting at the wrong time or with a non-targeted reagent to yield an undesired product.
  • amino protecting group refers to substituents on an amino group commonly employed to block or protect the amino functionality while allowing other unprotected functional groups on the compounds to react .
  • amino protecting groups include the for yl group, the trityl group, the t-butoxy carbonyl (BOO group, the phthalimido group, the pivaloyl group, the trichloroacetyl group, the chloroacetyl, bromoacetyl and iodoacetyl groups, urethane- type blocking groups such as the benzoylmethylsulfonyl group, the 2-(nitro) phenylsulfenyl group, the diphenylphosphine oxide group and like amino protecting groups .
  • amino protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction ( ⁇ ) on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino protecting group (s) .
  • Further examples of amino protecting groups can be found in the references: J. W. Barton, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973 Chapter 2; and T. W. Greene, P.G.M. Wuts, "Protective Groups in Organic Synthesis-2nd Edition", John Wiley and Sons, New York, N.Y., 1991, Chapter 7.
  • carboxylic acid protecting group refers to groups commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
  • carboxylic acid protecting groups include 4-n ⁇ trobenzyl, 4-methoxybenzyl, 3 , 4-d ⁇ methoxybenzyl , 2,4- dimethoxybenzyl, 2 , 4, 6-tr ⁇ methoxybenzyl, 2,4,6- tnmethylbenzyl, pentamethylbenzyl , 3,4- methylenedioxybenzyl , benzhydryl , 4,4' -dimethoxybenzhydryl , 2,2 ' ,4, 4 ' -tetramethoxybenzhydryl, methyl, ethyl, propyl, isopropyl, t-butyl, t-amyl, t ⁇ tyl, 4-methoxytr ⁇ tyl , 4,4'- dimethoxytntyl
  • carboxylic acid protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction (s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of these groups are found in Chapter 5 of the Barton book, "Protective Groups in Organic Chemistry", and Chapter 5 of the Greene-Wuts book,
  • a related term is "protected carboxy", which refers to a carboxy group substituted with one of the above carboxy protecting groups.
  • Hydroxy protecting groups include C ⁇ -C6 alkyl, C -
  • hydroxy protecting groups can be found in the Greene-Wuts book.
  • Thiol protecting groups include benzyl, alkyl benzyl, hydroxybenzyl, acetoxybenzyl , nitrobenzyl, fluorenylmethyl , ferrocenylmethyl , diphenylmethyl, Bis (4- methoxyphenyl) methyl, 5-dibenzosuberyl, triphenylmethyl, diphenyl-4-pyridylmethyl, phenyl, 2 , 4-dinitrophenyl , t- butyl, 1-adamantyl, monothio, dithio and aminothioacetals, and thiazolidine. Further examples of thiol protecting groups can be found in the Greene-Wuts book.
  • protecting groups are chosen to perform their "protecting" function and are also chosen to be removable from the substrate group without the cleavage reaction affecting the remainder of the substrate group.
  • the compounds of this invention are herein described as embodying both the pyrrolo [2 , 3-d] pyrimidine heterocyclic ring system which ring system is numbered as follows :
  • the compounds of this invention can exist as an equilibrium mixture with their tautomeric isomers. Illustrated below are the partial structural formulae capable of undergoing tautomerism, with the equilibria among them being shown as well.
  • G , W NH2 , OH , or SH ;
  • G ' , W ' NH , 0 or S .
  • G A preferred group for G is -OH, with the understanding that the structure exists primarily in the G' keto form.
  • Preferred groups for W are -NH2 and -CH3.
  • a preferred group for L is optionally substituted -CH2CH2-.
  • Preferred groups for B are optionally substituted 1, 4-phenylene and 2 , 5-thiophenediyl .
  • Preferred groups for are as follows: -alanine,
  • amino acid residue group is bonded to the carbonyl group of Compound III through the ⁇ -amino nitrogen.
  • the group is bonded to the carbonyl group of Compound III through the preferred groups terminal nitrogen.
  • N- ⁇ [ (2 -methyl-4-hydroxypyrrolo [2 , 3- d]pyrimidin-5-yl) eth-2 -yl ] phen-4-ylcarbonyl ⁇ alanine is equivalent to N- ⁇ [ (2-methyl-3H-4-oxo-pyrrolo [2 , 3- d]pyrimidin-5-yl) eth-2 -yl] phen-4-ylcarbonyl) alanine .
  • the compounds of the present invention can be made via a process entitled "Rapid Analogue Process” or RAP.
  • the "rapid” part of the process refers to the relative rapid rate that non-classical antifolates can be synthesized, isolated and purified, when using this process.
  • R ⁇ O is selected from the group consisting of N-hydroxysuccinimidyl N-hydroxysulphosuccinimidyl and salts thereof, 2- nitrophenyl, 4-nitrophenyl and 2 , 4-dichlorophenyl, with an amine of formula (II) : HNR!R 2 ( I I )
  • Silylating agents are selected from any reagent capable of attaching a silyl group to a target group.
  • Typical silylating agents include any reagent with a trialkylsilyl group such as trimethylsilyl, triethylsilyl , triisopropylsilyl , dimethylisopropylsilyl , diethylisopropylsilyl, dimethylthexylsilyl, and t- butyldimethylsilyl, any reagent with an alkylarylsilyl group such as tribenzylsilyl , diphenylmethylsilyl , t- butylmethoxyphenylsilyl and tri-p-xylylsilyl , and any reagent with a triarylsilyl group such as triphenylsilyl .
  • a trialkylsilyl group such as trimethylsilyl, triethylsilyl , triisopropylsilyl , dimethylisopropylsilyl , diethylisopropylsilyl
  • the preferred silylating agent is a trimethyl silylating agent.
  • Typical trimethyl silylating agents include N,0- Bis (trimethylsilyl ) acetamide, allyltrimethylsilane, N,0- Bis (trimethylsilyl ) -carbamate, N, - Bis ( trimethylsilyl )methylamine, Bis (trimethylsilyl) sulfate, N, O-Bis (trimethylsilyl) trifluoroacetamide, N,N-
  • Bis (trimethylsilyl) rea trimethylsilane, ethyl trimethyl silylacetate, hexamethyldisilane, hexamethyldisilazane, hexamethyldisiloxane, hexamethyldisilylthiane, (isopropenyloxy) trimethyl silane, l-methoxy-2 -methyl-1- trimethyl-siloxy-propene, (methylthio) trimethylsilane, methyl 3-trimethylsiloxy-2-butenoate, N-methyl-N- trimethylsilylacetamide, methyl trimethylsilylacetate, N- methyl-N-trimethylsilylhepta-fluorobutyramide, N-methyl-N- trimethylsilyl-trifluoroacetamide, (phenylthio) trimethylsilane, trimethylbromosilane, trimethylchlorosilane, trimethyliodosilane, 4- trimethylsiloxy-3-penten
  • a more preferred silylating agent is N,0-bis- ( trimethylsilyl) acetamide.
  • the N,0-Bis (trimethylsilyl ) acetamide acts to protect carboxylic acid groups present, as well as any hydroxy group present, on the active ester and/or the amine of formula II.
  • trimethylsilyl protecting agent An added benefit of using a trimethylsilyl protecting agent is that the trimethylsilyl protected forms of the amine/active ester tend to be more soluble which leads to better yields in the reaction. It is also believed, without intending to be bound thereby, that the silylation of the N atoms activates the amino group towards nucleophilic attack. Protection of the carboxylic acid groups on the active ester of formula (I) and the amine of formula (II) permits the coupling of the active ester and amine to form the compounds of formula (III) .
  • the reaction takes place at a temperature preferably between about 25 C and about 100 C, more preferably between about 40 C and about 80 C, and most more preferably between about 50 C and about 60 C.
  • the reaction should take place in a solvent. Any non-reactive organic solvent such as dimethylformamide, ethyl acetate, methylene chloride, toluene or acetonitrile is suitable.
  • the preferred solvent is dimethylformamide . It takes between about 5 hours and 70 hours to make a measurable amount of product.
  • the reaction is run for about 10 hours to about 60 hours and more preferably the reaction is run for about 16 hours to about 48 hours.
  • ⁇ — ⁇ , L and B are as defined previously, with an alcohol under known conditions.
  • the active ester is a N-hydroxysuccinimide (NHS) ester
  • a compound of formula (IV) is reacted with N-hydroxysuccinimide (NHS) in a suitable solvent, such as dimethylformamide (DMF), under known conditions (such as room temperature stirring for approximately 24 hours after addition of 1,3-dicyclo- hexylcarbodimide) .
  • a suitable solvent such as dimethylformamide (DMF)
  • DMF dimethylformamide
  • the preferred active ester is a N- hydroxysuccinimide ester.
  • Compounds of formula (IV) can be made using known technology in the art of pyrrolo [ 2 , 3-d] pyrimidinyl fused ring system antifolate chemistry.
  • ⁇ -'- is the 5, 6-dihydropyrrolo [2, 3- d]pyrimidin-yl fused ring system
  • compounds of formula (IV) can be made by following the procedures described in, "The Synthesis of N- ⁇ 2-Amino-4-Substituted [ ( Pyrrolo [2 , 3- d] Pyrimidin-5-yl) Ethyl] Benzoyl ⁇ -L-Glutamic Acids as Antineoplastic Agents", Shih and Gossett, Heterocvcles . Vol. 35, No. 2, 1993.
  • Amines of formula (II) can be made by standard techniques known in the art. See for example, Organic Chemistry, pp.
  • reaction of compound (I) and compound (II) to make the compound of formula (III) can also take place in the presence of a suitable strong base.
  • suitable strong bases include NaOH, KOH, etc.
  • the preferred strong base is NaOH.
  • An advantage of the claimed process is that it includes a rapid work-up procedure wherein the compound of formula (III) is isolated from the reaction mixture by performing the following steps: a) optionally adding a suitable diamine; b) adding a suitable aqueous acid; c) separating the product from its solvent; d) preparing the product physically for collecting, washing and drying; and e) collecting, washing and drying the product.
  • a suitable diamine is any diamine capable of reacting with unreacted active ester to create a product with an amine functionality. This product with an amine functionality can then be washed out of the reaction mixture, along with unreacted HNRIR * -- .
  • One such suitable diamine is ethylene diamine. The addition of the diamine is optional, though preferred.
  • the suitable acid is a mineral acid selected from the group consisting of HCl, HBr, HI, and HF.
  • the preferred suitable acid is HCl.
  • the most preferred suitable acid is
  • aqueous HCl 1 Normal aqueous HCl .
  • Separating the product from its solvent can be done by any technique known in the art .
  • One such method is to strip the solvent from the product by heating the solvent.
  • the solvent is a high-boiling solvent
  • another solvent, or mixture of solvents can be added to form a lower-boiling azeotropic mixture which can be boiled off at a lower temperature.
  • Typical solvents used to create a lower boiling azeotropic solvent mixture can be selected from the group consisting of o-xylene, m-xylene, p-xylene, toluene, benzene, and mixtures thereof.
  • the most preferred solvent for this purpose is a mixture of o-xylene, m-xylene and p-xylene.
  • Preparing the product physically for collecting, washing and drying involves breaking up the clumped product into particles sufficiently small so that the particles may readily be collected by any suitable technique such as by filtration or evaporation. After collection, the product is washed and dried. Any method can be used to break up the product . A preferred method is sonicating the product in the presence of acid.
  • Collecting, washing, and drying can be accomplished using standard techniques in the art of organic chemistry.
  • the product can be collected by filtering it through a Buchner funnel, then washing it with water and then ether, and then drying it in a vacuum oven.
  • This invention includes pharmaceutically acceptable salts and solvates of all compounds.
  • the pharmaceutically acceptable salts of the invention are typically formed by reacting a compound of formula (III) which possesses one or more suitable acidic or basic functionalities with an equimolar or slight excess amount of base or acid.
  • the reactants generally are combined in a mutual solvent such as diethyl ether or benzene for acid addition salts, or water or alcohols for base addition salts .
  • the salt usually precipitates out of solution within about 1 hour to about 10 days, and can be isolated by filtration or other conventional means.
  • some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are included as compounds of this invention .
  • esters may be modified to form esters, using techniques known in the art. These ester compounds typically contain C1-C4 alkyl moieties in place of the acid hydrogen. These ester intermediates are also considered to be part of the invention.
  • the compounds of the present invention may be administered to any mammal. Of all mammals, it is believed that humans will benefit the most from administration of these compounds .
  • the compounds of the present invention are antineoplastic agents.
  • An embodiment of the present invention provides a method of treating susceptible neoplasms in mammals, preferably humans, in need of such treatment.
  • the present compounds are useful in inhibiting the growth of neoplasms or "cancers", including, but not limited to, carcinoma, sarcoma, melanoma, colorectal, choriocarcinoma, prostate, leukemia, breast, squamous or small cell lung cancer, non-small cell lung cancer, ovarian, testicular, adenocarcinoma, epidermal, lymphosarcoma, pancreatic, head and neck, kidney, bone and liver cancer.
  • the compounds are tested for their ability to inhibit the growth of certain tumor cell lines and data reported as standard ICso's and Ki inhibition constants.
  • the compounds of the present invention are also useful in the treatment of psoriasis and arthritis, in mammals, preferably humans.
  • the compounds of the present invention can be administered orally, parenterally, or by means of insufflation or by insertion of a suppository.
  • the compounds can be administered individually or in combination, preferably parenterally, and usually in the form of a pharmaceutical composition.
  • Parenteral routes of administration include intramuscular, intrathecal, subcutaneous, intravenous, intra-arterial , intraorbital , intracapsular, intraspinal, and intrasternal .
  • Oral dosage forms, including tablets and capsules, contain from 1 to 3000 mg of drug per unit dosage. Isotonic saline solutions containing 1-100 mg/mL can be used for parenteral administration .
  • compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Accordingly, the present invention also includes pharmaceutical compositions comprising as active ingredient one or more compounds of formula (III) associated with at least one pharmaceutically acceptable carrier, diluent or excipient .
  • the active ingredients are usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient.
  • the compositions can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidinone, cellulose, water, syrup, and methyl cellulose
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propyl - hydroxybenzoates, sweetening agents or flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions are preferably formulated in a unit dosage form with each dosage normally containing from about 0.1 milligrams per square meter of body surface area (mg/M 2 ) to about 3000 mg/M 2 , more usually about 10 mg/M 2 to about 250 mg/M 2 of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.
  • NMR nuclear magnetic resonance spectrum
  • IR infrared spectrum
  • UV ultraviolet spectrum
  • MS mass spectrometry
  • °C refers to degrees Celsius
  • DMF dimethylformamide
  • g refers to gram or grams
  • h refers to hour or hours
  • kPa refers to kiloPascals
  • L refers to liter or liters
  • mg refers to milligrams
  • ml refer to milliliter or milliliters
  • mol refers to moles,
  • mmol refers to millimole or millimoles
  • N refers to normal or normality
  • psi refers to pounds per square inch
  • RT refers to room temperature.
  • Step 1 Synthesis of ethyl 4 4-diethoxy-2-cyano-butanoate
  • Step 5 Synthesis of 2-methyl-3H-4-oxo-5- (trimethylsilylethyne) -pyrrolo[2, 3-d]pyrimidine
  • Step 7 Synthesis of 2-methyl-3H-4-oxo-5-(2-(4- carboxyphenyl ) ethynyl )pyrrolo [2,3-d]pyrimidine
  • Step 9 Synthesis of 4- ⁇ [2-methyl-4-oxo-3H-pyrrolo[2, 3- d]pyrimidin-5-yl]eth-2-yl ⁇ benzoic acid (N-succinimide ester) "Active Ester” (compound of formula (I))
  • Step 3 Synthesis of ⁇ 2- [ (2-methyl-3H-4-oxo-pyrrolo[2, 3- d]pyrimidin-5-yl)eth-2-yl]thiophen-5-yl ⁇ carboxylic acid (N- succinimide ester) "Active Ester” (compound of formula I)
  • step 2 To a stirred solution of the carboxylic acid from Preparation 2 , step 2 (1.2 g, 3.8 mmol) and N- hydroxysuccinimide (661 mg, 5.8 mmol) in N,N- dimethyl formamide (40 mL) was added 1,3- dicyclohexylcarbodiimide (1.2 g, 5.8 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature for 24 hours and then filtered to remove dicyclohexylurea.
  • Step 2 Synthesis of 2-t-butylacetamidyl-3H-4-oxo- pyrrolo [2 , 3-d] pyrimidine
  • Step 3 Synthesis of 2-t-butylacetamidyl-3H-4-oxo-5- (trimethylsilylethyne) -pyrrolo [2, 3-d]pyrimidine
  • Step 6 Synthesis of ⁇ 2-fluoro-4- [(2-t-butylacetamidyl-3H-4- oxo-pyrrolo [2, 3-d]pyrimidin-5-yl) -eth-2-yl] ⁇ benzoic acid methyl ester
  • Step 7 Synthesis of ⁇ 2-fluoro-4- [ (2-amino-3H-4-oxo- pyrrolo [2, 3-d]pyrimidin-5-yl) -eth-2-yl] ⁇ benzoic acid:
  • Step 8 Synthesis of ⁇ 2-f luoro-4- [ (2-amino-3H-4-oxo- pyrrolo [2, 3-d] pyrimidin- 5 -yl) -eth-2 -yl] ⁇ benzoic acid (N- succinimide ester) :
  • Step 1 Synthesis of 4- [ (2-t-butylacetamidyl-3H-4-oxo- pyrrolo [2, 3-d]pyrimidin-5-yl) -ethyn-2-yl] benzoic acid:
  • Step 4 To a solution of the acetylene from Preparation 3, Step 4 (258 mg, 1.0 mmol) and 4-iodobenzo ⁇ c acid (248 mg, 1.0 mmol) in CHCN (4 mL) was added N-O- bis (trimethylsilyl) acetamide (671 mg, 0.82 mL, 3.3 mmol) and the reaction was stirred at 40°C for 2 hours In a separate flask, a mixture of palladium(II) chloride (9 mg, 0.05 mmol) and triphenylphosphine (26 mg, 0.1 mmol) in DMF (1 mL) was stirred at RT for 90 minutes.
  • palladium(II) chloride 9 mg, 0.05 mmol
  • triphenylphosphine 26 mg, 0.1 mmol
  • Triethylamine (182 mg, 0.25 mL, 1.8 mmol) was added to acetylene mixture followed by the triphenylphosphine-palladium chloride mixture. The reaction was then refluxed for 2 hr, cooled and H;0 was added (1 mL containing 6-8 drops of IN HCl) . The resulting solid was filtered, washed with CH 3 CN and dried m vacuo. The crude product was purified by flash chromatography on silica gel (0.25% AcOH/10% MeOH/CH 2 Cl 2 ) to give 111 mg product (29%) as a tan solid.
  • Step 2 Synthesis of 4- [ (2-t-butylacetamidyl-3H-4-oxo- pyrrolo [2,3-d] yrimidin-5-yl ) -eth-2-yl]benzoic acid:
  • Step 1 To a solution of acetylene from Preparation 4, Step 1 (497 mg, 1.31 mmol) in methanol (15 mL) was added 5% Pd/C (250 mg) and the mixture was stirred under 60 psi (414 kPa) H at 50°C for 24 hours The reaction was filtered, concentrated in vacuo and triturated with methanol . The resulting solid was filtered and dried to give 232 mg product (46%) as off-white solid.
  • Step 3 Synthesis of 4- [ ⁇ 2-amino-3H-4-oxo-pyrrolo [2, 3- d]pyrimidin-5-yl) -eth-2-yl] benzoic acid:
  • Step 2 (5.76 g, 15.1 mmol) in EtOH (200 mL) was added p- toluenesulfonic acid monohydrate (6.30 g, 33.1 mmol) and the mixture was stirred at reflux for 16 hours The reaction was cooled and the resulting precipitate was filtered, washed with EtOH and dried in vacuo to give 5.22 g product as tosic acid salt (74%) .
  • a sample was dissolved in aqueous LiOH and the solution was acidified to pH 3 with IN HCl, the solid was filtered, washed with H0 and dried in vacuo to give product as a tan solid.
  • Step 4 Synthesis of 4- [ (2-amino-3H-4-oxo-pyrrolo[2,3- d]pyrimidin-5-yl) -eth-2-yl]benzoic acid (N-succinimide ester) :
  • Step 4 To a solution of acid from Preparation 4, Step 4 (10.0 g, 33.5 mmol) and N-hydroxysuccinimide (4.24 g, 36.9 mmol) in DMF (150 mL) was added 1 , 3-dicyclohexylcarbodiimide (7.61 g, 36.9 mmol) and the reaction was stirred at RT overnight. After 20 hr, the mixture was filtered and the clear solution concentrated in vacuo. The crude product was triturated with 20% iPrOH/EtOAc and filtered, then triturated again and dried in vacuo to give 10.36 g product (76%) as off-white solid.
  • active ester refers to succinimide ester made by the preparation described in any of Preparation 1, 2, 3 or 4 ; and the term amine refers to an amine of Formula II (namely: HNR---R 2 , where R 1 and R*-- are as described previously) .
  • Step 4 (75 mg, 0.19 mmol) and isopropyl amine (50 ⁇ L, 0.57 mmol) in CHCl /MeOH was stirred at room temperature under nitrogen for 2.5 hours. The reaction was concentrated in vacuo, and the crude product was sonicated in aqueous HCl and filtered. The solid was sonicated in H0, the solid was filtered and dried to give the product as an off-white solid (42 mg, 66%) .
  • Step 1 Synthesis of ⁇ -t-butyl- ⁇ -4- carboxymethylphenylsulfonamyl-N-4- [ (2-amino-3H-4-oxo- pyrrolo [2, 3-d]pyrimidin-5-y1) eth-2-y1]benzoylglutamate :
  • Step 2 Synthesis of ⁇ -t -butyl - ⁇ -4-carboxyphenylsulfonamyl- N-4- [ (2-amino-3H-4-oxo-pyrrolo[2, 3-d] pyrimidin- 5 -yl) eth-2 - yl] benzoyl -L-glutamic acid:
  • Step 3 Synthesis of ⁇ -4-carboxyphenylsulfonamyl-N-4- [ (2- amino-3H-4-oxo-pyrrolo[2,3-d]pyrimidin-5-yl)eth-2- yl]benzoyl-L-glutamic acid:
  • Step 2 Synthesis of ⁇ -t-butyl- ⁇ -3-carboxyphenylsulfonamyl- N-4- [ (2-amino-3H-4-oxo-pyrrolo [2, 3 -d] pyrimidin- 5 -yl) eth-2 - yl] benzoyl -L-glutamic acid:
  • Step 3 Synthesis of ⁇ -3-carboxyphenylsulfonamyl-N-4- [ (2- amino-3H-4-oxo-pyrrolo [2,3-d]pyrimidin-5-yl) eth-2- yl]benzoyl-L-glutamic acid:
  • the resulting dimethyl ester precursor of the above-depicted compound (61 mg, 0.12 mmol) was reacted with IN aqueous NaOH (0.36 mL, 0.36 mmol) in dioxane (3 mL) and H0 (2 mL) at 50°C for 4 hours The reaction was concentrated and the crude product was sonicated with IN aqueous HCl and the resulting solid was filtered, washed with H0, Et 0 and dried to give the product as a green solid (43 mg, 74%) .
  • Step 1 Synthesis of ⁇ -t-butyl- ⁇ -methylsulfonamyl-N-4- [ (2- amino-3H-4-oxo-pyrrolo [2,3-d]pyrimidin-5-yl ) eth-2- yl]b ⁇ nzoyl-glutamate:
  • Step 2 Synthesis of ⁇ -methylsulfonamyl-N-4- [ (2-amino-3H-4- oxo-pyrrolo [2, 3-d]pyrimidin-5-yl) eth-2-yl]benzoyl-L-glutamic acid:
  • Step 1 Synthesis of dimethyl-N-4- [ (2-amino-3H-4-oxo- pyrrolo [2, 3-d]pyrimidin-5-yl) eth-2-yl] -benzoyl-4- carboxyphenylglycinate
  • Step 2 Synthesis of N-4- [ (2-amino-3H-4-oxo-pyrrolo[2, 3- d]pyrimidin-5-yl) eth-2-yl] -benzoyl-4-carboxyphenylglycine
  • Step 1 Synthesis of ⁇ -t-butyl- ⁇ -ethanesulfonamyl-N-4- [ (2- amino-3H-4-oxo-pyrrolo[2,3-d] -pyrimidin-5-yl) eth-2- yl] benzoyl-gluta te :
  • Step 2 Synthesis of ⁇ -ethanesulfonamyl-N-4- [ (2-amino-3H-4- oxo-pyrrolo [2,3-d] -pyrimidin-5-yl ) eth-2-yl]benzoyl- - glutamic acid:
  • Step 1 Synthesis of ⁇ -t-butyl- ⁇ -n-butylsulfonamyl-N-4- [ (2- amino-3H-4-oxo-pyrrolo[2,3-d] -pyrimidin-5-yl)eth-2- yl]benzoyl glutamate:
  • Carboxylic acid 400 mg, 0.83 mmol
  • n- butylsulfonamide 340 mg, 2.48 mmol
  • Step 2 Synthesis of ⁇ -n-b tylsulfonamyl-N-4- [ (2-amino-3H-4- oxo-pyrrolo [2, 3-d] -pyrimidin-5-yl) eth-2-yl]benzoyl-L- glutamic acid:
  • Step 2 Synthesis of 4-isopropylsulfonamyl-N-4- [ (2-amino-3H- 4-oxo-pyrrolo [2,3-d]pyrimidin-5-yl ) eth-2-yl]benzoyl- - glutamic acid:
  • Step 1 Synthesis of ⁇ - ( -toluenesulfonamyl) -N-4- [ (2-amino-3H-4-oxo- pyrrolo[2, 3-d]pyrimidin-5-yl]eth-2-yl] -benzoyl-L-glutamic acid: Step 1: Synthesis of ⁇ -t-butyl- ⁇ - ( ⁇ -toluenesulfonamyl) -N-4- [ (2-amino-3H-4-oxo-pyrrolo [2,3-d]pyrimidin-5-yl] eth-2-yl] - benzoyl glutamate :
  • Step 2 Synthesis of ⁇ - ( ⁇ -toluenesulfonamyl) -N-4- [ (2-amino- 3H-4-oxo-pyrrolo[2,3-d]pyrimidin-5-yl]eth-2-yl]benzoyl-L- glutamic acid:
  • Step 1 Synthesis of ⁇ -t-butyl- ⁇ -4-benzenesulfonamyl-N-4- [ (2-amino-3H-4-oxo-pyrrolo [2, 3-d]pyrimidin-5-yl)eth-2- yl] benzoyl-glutamate :
  • Step 2 Synthesis of ⁇ -4-benzenesulfonamyl-N-4- [ (2-amino-3H- 4-oxo-pyrrolo [2,3-d]pyrimidin-5-yl) eth-2-yl] benzoyl-L- glutamic acid:
  • Carboxylic acid 500 mg, 1.03 mmol
  • methyl 2- (aminosulfonyl) benzoate 668 mg, 3.10 mmol
  • Sulfonamide Coupling Procedure for 18 hours to give the methyl benzoate ester/pivaloate ester of the above- depicted compound as a white solid (363 mg, 51%) .
  • Step 1 Synthesis of dimethyl-N-4- [ (2-amino-3H-4-oxo- pyrrolo [2, 3-d]pyrimidin-5-yl)eth-2-yl] -benzoyl-3- carboxyphenylglycinate :
  • Step 2 Synthesis of N-4- [ ( 2 -amino -3H- 4 -oxo -pyrrolo [2 , 3- d] pyrimidin-5 -yl ) eth-2 -yl ] -benzoyl - 3 -carboxyphenylglycine :

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Abstract

Cette invention se rapporte à des antifoliques non classiques de pyrrolo[2,3-d]pyrimidine. Elle se rapporte également à un procédé analogique rapide qui permet un examen rapide de l'antifolique et permet d'éviter le recours à des procédés de séparation chromatographique longs et coûteux. L'invention se rapporte en outre à des procédés de traitement de néoplasmes sensibles par ces antifoliques non classiques. L'invention se rapporte enfin à des procédés de traitement du psoriasis et de l'arthrite faisant usage de ces antifoliques non classiques.
EP97939567A 1996-08-30 1997-08-27 Antifoliques non classiques de pyrrolo 2,3-d]pyrimidine Withdrawn EP0923287A4 (fr)

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US2496496P 1996-08-30 1996-08-30
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PCT/US1997/015017 WO1998008382A1 (fr) 1996-08-30 1997-08-27 Antifoliques non classiques de pyrrolo[2,3-d]pyrimidine

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EP0400562A1 (fr) * 1989-05-29 1990-12-05 Takeda Chemical Industries, Ltd. Pyrrolopyrimidines, leur préparation et leur utilisation en tant qu'agents antitumoraux
EP0402903A1 (fr) * 1989-06-14 1990-12-19 Takeda Chemical Industries, Ltd. Préparation de pyrrolopyrimidines et produits intermédiaires
US4996206A (en) * 1989-12-11 1991-02-26 The Trustees Of Princeton University N-(pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivatives
EP0418924A2 (fr) * 1989-09-21 1991-03-27 Takeda Chemical Industries, Ltd. Pyrrolopyrimidines, leur préparation et utilisation
EP0431953A2 (fr) * 1989-12-08 1991-06-12 Takeda Chemical Industries, Ltd. Dérivés de pyrrolopyrimidine, leur préparation et utilisation
EP0434426A1 (fr) * 1989-12-20 1991-06-26 Takeda Chemical Industries, Ltd. Composés hétérocycliques condensés, leur production et utilisation
EP0438261A2 (fr) * 1990-01-16 1991-07-24 Takeda Chemical Industries, Ltd. Dérivés hétérocycliques condensés de l'acide glutamique, leur préparation et utilisation
EP0530537A1 (fr) * 1991-08-12 1993-03-10 Takeda Chemical Industries, Ltd. Dérivés de la pyrimidine condensés, leur préparation et leur utilisation comme agents antitumoraux
JPH0565286A (ja) * 1990-12-14 1993-03-19 Takeda Chem Ind Ltd 抗悪性腫瘍剤の測定法および試薬
EP0549291A1 (fr) * 1991-12-27 1993-06-30 Takeda Chemical Industries, Ltd. Inhibiteurs de la thymidylate synthase
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EP0400562A1 (fr) * 1989-05-29 1990-12-05 Takeda Chemical Industries, Ltd. Pyrrolopyrimidines, leur préparation et leur utilisation en tant qu'agents antitumoraux
EP0402903A1 (fr) * 1989-06-14 1990-12-19 Takeda Chemical Industries, Ltd. Préparation de pyrrolopyrimidines et produits intermédiaires
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US4996206A (en) * 1989-12-11 1991-02-26 The Trustees Of Princeton University N-(pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivatives
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JPH0565286A (ja) * 1990-12-14 1993-03-19 Takeda Chem Ind Ltd 抗悪性腫瘍剤の測定法および試薬
EP0530537A1 (fr) * 1991-08-12 1993-03-10 Takeda Chemical Industries, Ltd. Dérivés de la pyrimidine condensés, leur préparation et leur utilisation comme agents antitumoraux
EP0549291A1 (fr) * 1991-12-27 1993-06-30 Takeda Chemical Industries, Ltd. Inhibiteurs de la thymidylate synthase
EP0567223A1 (fr) * 1992-03-24 1993-10-27 Eli Lilly And Company Dérivés d'acide glutamique comme agents antineoplastiques
JPH069637A (ja) * 1992-04-17 1994-01-18 Takeda Chem Ind Ltd 縮合ピリミジン誘導体、その製造法および用途

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WO1998008382A1 (fr) 1998-03-05
EP0923287A4 (fr) 2001-08-01
AU4163197A (en) 1998-03-19
JP2000516961A (ja) 2000-12-19

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