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

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

Info

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Withdrawn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
Other languages
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
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Withdrawn legal-status Critical Current

Links

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 :

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US2496496P 1996-08-30 1996-08-30
US24964P 1996-08-30
PCT/US1997/015017 WO1998008382A1 (fr) 1996-08-30 1997-08-27 Antifoliques non classiques de pyrrolo[2,3-d]pyrimidine

Publications (2)

Publication Number Publication Date
EP0923287A1 true EP0923287A1 (fr) 1999-06-23
EP0923287A4 EP0923287A4 (fr) 2001-08-01

Family

ID=21823289

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97939567A Withdrawn EP0923287A4 (fr) 1996-08-30 1997-08-27 Antifoliques non classiques de pyrrolo 2,3-d]pyrimidine

Country Status (5)

Country Link
EP (1) EP0923287A4 (fr)
JP (1) JP2000516961A (fr)
AU (1) AU4163197A (fr)
CA (1) CA2263907A1 (fr)
WO (1) WO1998008382A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002232181B2 (en) * 2001-02-15 2004-03-04 Rheon Automatic Machinery Co., Ltd. Food dough rolling apparatus

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6686366B1 (en) 1998-06-02 2004-02-03 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
JP4611524B2 (ja) 1998-06-02 2011-01-12 オーエスアイ・ファーマスーティカルズ・インコーポレーテッド ピロロ［２，３ｄ］ピリミジン組成物およびその使用
US6878716B1 (en) 1998-06-02 2005-04-12 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptor and uses thereof
US6680322B2 (en) 1999-12-02 2004-01-20 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptors and uses thereof
US7160890B2 (en) 1999-12-02 2007-01-09 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
US6664252B2 (en) 1999-12-02 2003-12-16 Osi Pharmaceuticals, Inc. 4-aminopyrrolo[2,3-d]pyrimidine compounds specific to adenosine A2a receptor and uses thereof
CZ303772B6 (cs) * 2000-02-25 2013-05-02 Eli Lilly And Company Heptahydrátová krystalická forma disodné soli N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-benzoyl]L-glutamové kyseliny a zpusob její prípravy
US6680324B2 (en) 2000-12-01 2004-01-20 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptors and uses thereof
US6673802B2 (en) 2000-12-01 2004-01-06 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
US7504407B2 (en) 2001-11-30 2009-03-17 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 and A3 receptors and uses thereof
JP4440642B2 (ja) 2001-12-20 2010-03-24 オーエスアイ・ファーマスーティカルズ・インコーポレーテッド ピリミジンＡ２ｂ選択的アンタゴニスト化合物、それらの合成、及び使用
CN101973998A (zh) 2001-12-20 2011-02-16 Osi药物公司 吡咯并嘧啶A2b选择性拮抗剂化合物
KR100714519B1 (ko) 2002-03-07 2007-05-07 에프. 호프만-라 로슈 아게 이환 피리딘 및 피리미딘 ｐ38 키나아제 억제제
EP1462472A1 (fr) * 2003-03-26 2004-09-29 Sigma Kalon Services B.V. Procédé pour protéger des groupes acide dand des polymères
CN101098854B (zh) 2004-07-23 2012-12-05 恩多塞特公司 二价连接体及其轭合物
WO2008021385A2 (fr) * 2006-08-14 2008-02-21 Sicor Inc. Procédés de préparation de produits intermédiaires de pemetrexed
NZ599239A (en) 2007-03-14 2013-10-25 Endocyte Inc Binding ligand linked drug delivery conjugates of tubulysins
US9877965B2 (en) 2007-06-25 2018-01-30 Endocyte, Inc. Vitamin receptor drug delivery conjugates for treating inflammation
AU2008268432B2 (en) 2007-06-25 2015-01-15 Endocyte, Inc. Conjugates containing hydrophilic spacer linkers
CN101423524B (zh) * 2007-10-30 2010-12-22 齐鲁制药有限公司 二谷氨酸酯衍生物及其在培美曲塞制备中的应用
US20110082158A1 (en) * 2008-10-01 2011-04-07 Aleem Gangjee Selective proton coupled folate transporter and folate receptor, and garftase and/or other folate metabolizing enzymes inhibitor compounds and methods of using the same
US8252804B2 (en) * 2008-10-01 2012-08-28 Duquesne University Of The Holy Spirit Selective proton coupled folate transporter and folate receptor, and GARFTase inhibitor compounds and methods of using the same
US10080805B2 (en) 2012-02-24 2018-09-25 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
KR20150070318A (ko) 2012-10-16 2015-06-24 엔도사이트, 인코포레이티드 비천연 아미노산을 함유하는 약물 전달 컨쥬게이트 및 사용 방법
CN104955806B (zh) * 2013-02-06 2018-09-14 默克专利股份公司 用于治疗骨关节炎的作为聚蛋白聚糖酶抑制剂的取代羧酸衍生物
CN104341427A (zh) * 2014-10-01 2015-02-11 山东铂源药业有限公司 一种培美曲塞二钠杂质的合成方法
US9481678B2 (en) * 2015-02-09 2016-11-01 Duquesne University Of The Holy Ghost Substituted pyrrolo[2,3-D]dipyrimidines for selectively targeting tumor cells with FR-alpha and FR-beta type receptors
WO2016168637A2 (fr) * 2015-04-17 2016-10-20 Duquesne University Of The Holy Spirit Cyclopenta[d]pyrimidines et cyclopenta[d]pyrimidines substituées utilisées en tant qu'agents antitubuline et de ciblage de microtubules, pyrimidines monocycliques utilisées en tant qu'inhibiteurs de tubuline, et pyrrolopyrimidines utilisées en tant qu'antifolates ciblés et agents antitumoraux et d'inhibition de tubuline et de tyrosine kinase à récepteurs multiples
CN110305137A (zh) * 2018-03-20 2019-10-08 鲁南制药集团股份有限公司 一种培美曲塞二钠中间体及其制备方法
CN110305135B (zh) * 2018-03-20 2022-02-22 鲁南制药集团股份有限公司 一种培美曲塞二钠中间体及其制备方法
CN110305136A (zh) * 2018-03-20 2019-10-08 鲁南制药集团股份有限公司 一种培美曲塞二钠中间体及其制备方法
CN110305134B (zh) * 2018-03-20 2022-02-22 鲁南制药集团股份有限公司 一种培美曲塞二钠中间体及其制备方法

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0334636A2 (fr) * 1988-03-24 1989-09-27 Takeda Chemical Industries, Ltd. Dérivés de la pyrrolo pyrimidine, leur préparation et utilisation
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
US5248775A (en) * 1989-12-11 1993-09-28 The Trustees Of Princeton University Pyrrolo(2,3-d)pyrimidines
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

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5661148A (en) * 1989-09-19 1997-08-26 Teijin Limited Pyrrolo[2,3-d]pyrimidine derivatives, process for producing the same and pharmaceutical preparation comprising the same as active ingredient
CZ283281B6 (cs) * 1992-09-25 1998-02-18 Eli Lilly And Company Způsob přípravy v poloze 5 substituovaných pyrrolo(2,3-d)pyrimidinů
US5646152A (en) * 1994-06-15 1997-07-08 Pfizer Inc. Methods of administering CRF antagonists
US5650511A (en) * 1995-12-12 1997-07-22 Biocryst Pharmaceuticals, Inc. Process for the preparation of 9-deazaguanine derivatives

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0334636A2 (fr) * 1988-03-24 1989-09-27 Takeda Chemical Industries, Ltd. Dérivés de la pyrrolo pyrimidine, leur préparation et utilisation
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
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
US5248775A (en) * 1989-12-11 1993-09-28 The Trustees Of Princeton University Pyrrolo(2,3-d)pyrimidines
US4996206A (en) * 1989-12-11 1991-02-26 The Trustees Of Princeton University N-(pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivatives
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
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

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 017, no. 376 (C-1084), 15 July 1993 (1993-07-15) & JP 05 065286 A (TAKEDA CHEM IND LTD), 19 March 1993 (1993-03-19) *
PATENT ABSTRACTS OF JAPAN vol. 018, no. 209 (C-1190), 13 April 1994 (1994-04-13) & JP 06 009637 A (TAKEDA CHEM IND LTD), 18 January 1994 (1994-01-18) *
See also references of WO9808382A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002232181B2 (en) * 2001-02-15 2004-03-04 Rheon Automatic Machinery Co., Ltd. Food dough rolling apparatus

Also Published As

Publication number Publication date
EP0923287A4 (fr) 2001-08-01
JP2000516961A (ja) 2000-12-19
AU4163197A (en) 1998-03-19
CA2263907A1 (fr) 1998-03-05
WO1998008382A1 (fr) 1998-03-05

Similar Documents

Publication Publication Date Title
WO1998008382A1 (fr) Antifoliques non classiques de pyrrolo[2,3-d]pyrimidine
FI76791B (fi) Foerfarande foer framstaellning av 2-amino-4-hydroxikinazolinderivat med anticanceraktivitet.
CN113307811B (zh) 四氢吡喃基氨基-吡咯并嘧啶酮及其使用方法
US20170057972A1 (en) Lactam kinase inhibitors
TW201943712A (zh) 一種多功能化合物、其製備方法及其在醫藥上的應用
RU2633694C2 (ru) Дейтерированный фениламинопиримидин и фармацевтическая композиция, содержащая такое соединение
WO1995028387A1 (fr) Compose benzamide et utilisation medicale dudit compose
JP2001501216A (ja) ピリミジン誘導体およびその製造法
US5110818A (en) Anticonvulsive substituted-9-benzyl-9h-purines
EP2008210A1 (fr) Modulation de l'activite phosphoryl transferase de la glutamine synthetase
AU2020413997A1 (en) Pyridazinyl-thiazolecarboxamide compound
AU2019414550A1 (en) Fak inhibitor and drug combination thereof
CA2799764A1 (fr) Inhibiteurs selectifs de la mtor kinase
AU2019372121A1 (en) Heterocyclic compounds as BET inhibitors
KR20200089219A (ko) 아릴 또는 헤테로아릴 유도체, 및 이를 유효성분으로 포함하는 키나아제 관련 질환 치료용 약학적 조성물
JP7201800B2 (ja) Ｆｌｔ３およびａｘｌの阻害剤としての３，９－ジアザスピロ［５，５］ウンデカン系化合物
CZ195293A3 (en) PROCESS FOR PREPARING IN 5-POSITION SUBSTITUTED PYRROLO(2,3-d) PYRIMIDINES
CA3037971A1 (fr) Nouveaux derives de benzimidazole comme inhibiteurs de la famille des kinases tec
AU2020214351A1 (en) Indolo heptamyl oxime analogue as PARP inhibitor
AU2021394411A1 (en) Novel camptothecin derivative, composition containing same, and use thereof
AU2006281359B2 (en) Condensed pyrimidine derivatives as inhibitors of folic acid-dependent enzymes
WO2020077944A1 (fr) Dérivé de purine, son procédé de préparation et son utilisation
IE60038B1 (en) 4(3H)-oxo-5, 6, 7, 8-tetrahydropyrido-[2, 3-d]pyrimidine derivatives
JP2023503133A (ja) Ｃｄ７３を標的とするスルホンアミド化合物およびアデノシン受容体
EP4087845A1 (fr) Inhibiteurs de btk

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19990224

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

A4 Supplementary search report drawn up and despatched

Effective date: 20010615

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

RIC1 Information provided on ipc code assigned before grant

Free format text: 7A 01N 43/54 A, 7A 61K 31/505 B, 7C 07D 239/70 B, 7C 07D 487/00 B, 7C 07D 487/04 B, 7A 61P 35/00 B, 7C 07D 487/04 J, 7C 07D 239:00 J, 7C 07D 209:00 J

18D Application deemed to be withdrawn

Effective date: 20010301

RTI1 Title (correction)

Free format text: NONCLASSICAL PYRROLO 2,3-D PYRIMIDINE ANTIFOLATES