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WO1997049705A1 - DERIVES DE 5,6,7,8-TETRAHYDROPYRIDO[2,3-d]PYRIMIDINE - Google Patents

DERIVES DE 5,6,7,8-TETRAHYDROPYRIDO[2,3-d]PYRIMIDINE Download PDF

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Publication number
WO1997049705A1
WO1997049705A1 PCT/US1997/010952 US9710952W WO9749705A1 WO 1997049705 A1 WO1997049705 A1 WO 1997049705A1 US 9710952 W US9710952 W US 9710952W WO 9749705 A1 WO9749705 A1 WO 9749705A1
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WIPO (PCT)
Prior art keywords
tetrahydropyrido
compound according
ylcarbonyl
pyridin
pyrimidin
Prior art date
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Ceased
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PCT/US1997/010952
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English (en)
Inventor
Edward C. Taylor
Paul Gillespie
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Princeton University
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Princeton University
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Filing date
Publication date
Application filed by Princeton University filed Critical Princeton University
Priority to AU35009/97A priority Critical patent/AU3500997A/en
Publication of WO1997049705A1 publication Critical patent/WO1997049705A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to 5,6,7,8-tetrahydropyridof2,3-t7]pyrimidines of the formula:
  • R is hydroxy or amino
  • R is hydroxy or a carboxylic acid protecting group
  • R is hydrogen or an amino protecting group
  • Z is pyridinediyl in which the valence bonds originate from nonadjacent carbon atoms of the ring
  • n has a value of 2 or 3.
  • the present invention also pertains to the pharmaceutically acceptable salts of the 5,6,7,8-tetrahydropyrido[2,3-tf]pyrimidines of Formula I.
  • the invention pertains to a method of inhibiting neoplastic growth in a mammal in which the growth is dependent on folic acid, or a metabolic derivative of folic acid (such as N 5 ,N -methylenetetrahydrofolate), as a substrate.
  • the method comprises administering, in a single or multiple dose regimen, an effective amount of a compound according to Formula I to a mammal in need of such therapy.
  • the invention pertains to pharmaceutical compositions for inhibiting such neoplastic growth in a mammal through inhibition of folate enzymes which comprises a compound according to Formula I in combination with a pharmaceutically accept ⁇ able carrier.
  • pyrido[2,3-d]pyrimidines of Formula I are the tautomeric equivalent of the corresponding 3-H-4-oxo or 3-H-4-imino structures.
  • the compounds are depicted herein as 4-hydroxy and 4-amino com- pounds, it being understood the corresponding and tautomeric keto and imino struc ⁇ tures, respectively, are fully equivalent; e.g. :
  • the compounds of Formula I can be employed in the form of the free dicarbox- ylic acid, in which case both R groups are OH (hydroxy).
  • the compounds often can be employed in the form of a pharmaceutically acceptable salt, in which case the hydrogen atom when R is hydroxy is replaced by a pharmaceuti ⁇ cally acceptable cation.
  • Such salt forms, including hydrates thereof, are often crystal ⁇ line and advantageous for forming solutions or formulating pharmaceutical composi ⁇ tions.
  • Pharmaceutically acceptable salts with bases include those formed from the alkali metals, alkaline earth metals, non-toxic metals, ammonium, and mono-, di- and trisubstituted amines, such as for example the sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethanolammonium.
  • pyridinium, and substituted pyridinium salts are advantageous.
  • a second chiral center is present in the 6-position of the 5,6,7.8-tetrahy- dropyrido[2,3-d]pyrimidine ring system. Both the therapeutically active diastereo- meric mixtures and the individual diastereomers are included in the scope of this - 3 -
  • both individual diastereomers When both individual diastereomers are formed, they can be separated mechanically as by chromatography or chemically by forming salts with a chiral acid, such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and the like, and then freeing one or both of the indi ⁇ vidual diastereomeric bases, optionally repeating the process, so as obtain either or both substantially free of the other; i.e., in a form having an optical purity of >95%.
  • a chiral acid such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and
  • the protecting groups designated by R and R utilized herein denote groups which generally are not found in the final therapeutic compounds but which are inten- tionally introduced at some stage of the synthesis in order to protect groups which otherwise might be altered in the course of chemical manipulations. Such protecting groups are removed at a later stage of the synthesis and compounds bearing such pro ⁇ tecting groups thus are of importance primarily as chemical intermediates (although some derivatives also exhibit biological activity). Accordingly the precise structure of the protecting group is not critical. Numerous reactions for the formation and removal of such protecting groups are described in a number of standard works including, for example, "Protective Groups in Organic Chemistry", Plenum Press, London and New York, 1973; Greene, Th. W. "Protective Groups in Organic Synthesis".
  • a carboxy group can be protected as an ester group which is selectively removable under sufficiently mild conditions not to disrupt the desired structure of the molecule, especially a lower alkyl ester of 1 to 12 carbon atoms such as methyl or ethyl and particularly one which is branched at the 1 - or ⁇ position such as t-butyl; and such lower alkyl ester substituted in the 1- or 2-position with (/) lower alkoxy, such as for example, methoxymethyl, 1-methoxyethyl, and ethoxymethyl, (//) lower alkylthio, such as for example methylthiomethyl and 1-ethylthioethyl; (Hi) halogen, such as 2,2,2-trichloroethyl, 2-bromoethyl, and 2-iodoethoxycarbonyl; (z ' v) one or two phenyl groups each of which can be unsubstituted or mono-, di- or tri-
  • a carboxy group also can be protected in the form of an organic silyl group such as trimethylsilylethyl or tri-lower alkylsilyl, as for example tri-methylsilyloxy- carbonyl.
  • an amino group can be protected as an amide utilizing an acyl group which is selectively removable under mild conditions, especially formyl, a lower alkanoyl group which is branched in 1- or ⁇ position to the carbonyl group, particularly tertiary alkanoyl such as pivaloyl, or a lower alkanoyl group which is substituted in the position ⁇ to the carbonyl group, as for example trifiuoroacetyl.
  • an acyl group which is selectively removable under mild conditions, especially formyl, a lower alkanoyl group which is branched in 1- or ⁇ position to the carbonyl group, particularly tertiary alkanoyl such as pivaloyl, or a lower alkanoyl group which is substituted in the position ⁇ to the carbonyl group, as for example trifiuoroacetyl.
  • Z is pyridinediyl.
  • the depicted valence bonds of Z originate from nonadjacent carbon atoms of the ring.
  • Z thus can be, for example, pyridine-2,4-diyl, pyridine-2,5-diyl, pyridine-2,6-diyl, or pyridine-3,5-diyl.
  • the divalent group comprised by Z is asymmetric, as for exam ⁇ ple pyridine-2,5-diyl (as contrasted with the symmetrical pyridine-2,6-diyl), the single group can be oriented in either of two ways; e.g., (i) with the -C n H 2n - group depicted in Formula I in the 2-position and the carbonyl group in the 5- position, or (ii) with the carbonyl group in the 2-position and the -C n H 2n - group in the 5- position
  • Particularly preferred compounds are those wherein R and R are both hydroxy, R is hydrogen, and n has a value of 2; e.g., N- ⁇ 2-f2-(2-amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-dJpyrimidin-6-yl)ethyl]-pyridin-4-ylcarbonyl ⁇ -L-glutamic acid; N- ⁇ 2-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]- pyridin-5-ylcarbonyl ⁇ -L-glutamic acid; N- ⁇ 2-[2-(2-amino-4-hydroxy-5,6,7,8-tetra- hydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-pyridin-6-ylcarbonyl ⁇ -L-glutamic acid; N- ⁇ 4-[
  • the compounds of this invention can be prepared through catalytic hydrogenation of a compound of the formula:
  • R 2" is a carboxylic acid protecting group or HC(COR 2 )CII 9 CH 9 COR 2 in which R is a carboxylic acid protecting group; R 3' is an amino protecting group; and each Y when taken separately is hydrogen or both Y's when taken together are a carbon-carbon bond.
  • Suitable hydrogenation catalysts include noble metals and noble metal oxides such as palladium or platinum oxide, rhodium oxide, and the foregoing on a support such as carbon or calcium oxide.
  • the protecting groups encompassed by R , R , R , and R " can be removed following hydrogenation through acidic or basic hydrolysis, as for example with sodium hydroxide, thereby yielding the compounds of Formula I. Methods of remov ⁇ ing the various protective groups are described in the standard references noted above and incorporated herein by reference.
  • each of R , R , Y, and Z is as defined above and X is chloro, bromo, or iodo.
  • the 6-vinyl- and 6-ethynylpyrido[2,3-d]pyrimidine intermediates are known chemical intermediates being described, for example, in U.S. Patent No. 4,818,819, noted supra.
  • a 6-halopyrido[2,3-d]pyrimidine intermediate is allowed to react with a vinyl or ethynyl derivative of the pyridinedinyl comprised by Z, again the pres ⁇ ence of the same palladium/trisubstituted phosphine catalyst:
  • R 2" is -CONHCH(COR 2' )CH 2 CH 2 COR 2'
  • the product of this coupling reaction is hydrogenated as described above, and any protecting group removed, as also described above.
  • R is a carboxylic acid protecting group
  • the R protecting group can removed following hydrogenation as described above, and the resulting free carboxylic acid then coupled with a protected glutamic acid derivative in the manner described in U.S. Patent No. 4,684,653, the disclosure of which is incorporated herein by reference, using conventional condensation tech- niqucs for forming peptide bonds such as dicyclohexylcarbodiimide or diphenyl- chlorophosphonatc.
  • any remaining protecting groups are removed as discussed below.
  • the pyridinedinyl intermediates either are known or can be made from the known halopicolinic and halonicotinic acids.
  • a halopicolinic or halonicotinic acid can be treated with thionyl chloride and then reacted with dimethyl glutamate to yield a dimethyl halopyridinylcarboxyglutamate.
  • Reaction with trimethylsilylacet- ylene yields the corresponding dimethyl ethynylpyridinylcarboxyglutamate interme- diate which, after removal of the trimethylsilyl protecting group, can be coupled with a 6- halopyrido[2,3- ⁇ i]pyrimidine as described above.
  • the dimethyl halopyridinylcarboxyglutamate is allowed to react with a 6-ethynylpyrido[2,3- tfjpyrimidine or 6-vinylpyrido[2,3-t/
  • 6-ethynyl-, 6- vinyl-, and 6-halopyrido[2,3-t/)pyrimidine intermediates are known.
  • the compounds of this invention have an effect on one or more enzymes which utilize folic acid, and in particular metabolic derivatives of folic acid, as a substrate.
  • the action of the compounds appear to be similar in this regard to that of 6(R)-5,10- dideazatetrahydrofolic acid which is described in U.S. Patent No. 4,684,653.
  • the compounds exhibit particularly strong inhibitory activity against the enzyme glyci- namide ribonucleotide formyltransferase.
  • the compounds also exhibit inhibitory activity against folate enzymes such as dihydrofolate reductase and thymidylate synthetase.
  • the IC TM value against human T-cell derived lymphoblastic leukemia cells for N- ⁇ 3-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydro- pyrido[2,3-d]pyrimidin-6-yl)ethyl]-pyridin-5-ylcarbonyl ⁇ -L-glutamic acid is 0.1 ⁇ /mL while the glycinamide ribonucleotide formyltransferase/K/ is 0.126 ⁇ M.
  • the compounds can be used, under the supervision of qualified professionals, to inhibit the growth of neoplasms including choriocarcinoma, leukemia, adenocarci- noma of the female breast, epidermic cancers of the head and neck, squamous or small-cell lung cancer, and various lymphosarcomas.
  • the compounds can also be used to treat mycosis fungoides, arthritis, and psoriasis.
  • the compounds can be administered orally but preferably are administered parenterally, alone or in combina ⁇ tion with other therapeutic agents including other anti-neoplastic agents, steroids, etc., to a mammal suffering from neoplasm and in need of treatment.
  • Parenteral routes of administration include intramuscular, intrathecal, intravenous and intra-arterial. Dosage regimens must be titrated to the particular neoplasm, the condition of the patient, and the response but generally doses will be from about 10 to about 100 mg/day for 5-10 days or single daily administration of 250-500 mg, repeated periodi ⁇ cally; e.g. every 14 days. While having a low toxicity as compared to other anti- metabolites now in use, a toxic response often can be eliminated by either or both of reducing the daily dosage or administering the compound on alternative days or at longer intervals such as every three days. Concomitant administration of folic acid as a rescue therapy also may be indicated.
  • Oral dosage forms include tablets and cap ⁇ sules containing from 1-10 mg of drug per unit dosage.
  • Isotonic saline solutions con- taining 20-100 mg/ml can be used for parenteral administration.
  • the following examples will serve to further illustrate the invention.
  • “s” denotes singlet
  • “d” denotes doublet
  • “t” denotes triplet
  • "q” denotes quartet
  • "m” denotes multiplet
  • “br” denotes a broad peak.
  • the starting material can be obtained as follows: 5-Bromo-2-ethynylpyridine (3.20 g, 17.58 mmol) was added to a solution of potassium permanganate (5.60 g, 35.40 mmol) in water (500 mL). The solution was heated under reflux for 5 hours. Part of the 5-bromo-2-ethynylpyridine (450 mg, 2.47 mmol, 14%) was recovered from the condenser where it had sublimed. The solution was filtered through Celite to remove manganese dioxide, and the solvent was evaporated from the filtrate.
  • Potassium carbonate (220 mg, 1.59 mmol) was added to a solution of dimethyl N-(2-trimethylsilylethynylpyridin-5-ylcarbonyl)-L-glutamate (870 mg, 2.31 mmol) in methanol (100 mL). After stirring for 2 hours at room temperature under nitrogen, the solvent was evaporated under reduced pressure and the residue was taken up in chlor ⁇ oform (50 mL). This solution was washed with water (2 x 50 mL), dried over magnesium sulfate and evaporated.
  • Hard gelatin capsules are prepared using the following ingredients: Quantity
  • a tablet is prepared using the ingredients below:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des dérivés d'acide glutamique dans lesquels le groupe amine est remplacé par un groupe 2-amino-5,6,7,8-tétrahydropyrido[2,3-d]pyrimidine-6-ylalky-Z-carbonyle, dans lequel Z est un pyridinediyle dans lequel les liaisons de valence issues d'atomes de carbone non adjacents du noyau sont des agents antinéoplasiques. Un mode de réalisation type est l'acide N-{3-[2-¢2-amino-4-hydroxy-5,6,7,8-tétrahydropyrido[2,3-d]pyrimidine-6-yl)-éthyl]-pyridine-5-ylcarbonyl}-L-glutamique.
PCT/US1997/010952 1996-06-25 1997-06-24 DERIVES DE 5,6,7,8-TETRAHYDROPYRIDO[2,3-d]PYRIMIDINE Ceased WO1997049705A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU35009/97A AU3500997A (en) 1996-06-25 1997-06-24 5,6,7,8-tetrahydropyrido{2,3-d}pyrimidine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2039896P 1996-06-25 1996-06-25
US60/020,398 1996-06-25

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WO1997049705A1 true WO1997049705A1 (fr) 1997-12-31

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4684653A (en) * 1985-03-08 1987-08-04 The Trustees Of Princeton University Pyrido(2,3-d)pyrimidine derivatives
EP0327190A1 (fr) * 1988-02-05 1989-08-09 The Trustees Of Princeton University Dérivés de la pyrido[2,3-d]pyrimidine
EP0511792A2 (fr) * 1991-04-29 1992-11-04 Eli Lilly And Company Dérives de pyridopyrimidine comme agents antinéoplastiques
US5354751A (en) * 1992-03-03 1994-10-11 Sri International Heteroaroyl 10-deazaamino-pterine compounds and use for rheumatoid arthritis
EP0761668A2 (fr) * 1995-09-08 1997-03-12 The Trustees Of Princeton University Antifolates non-classiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4684653A (en) * 1985-03-08 1987-08-04 The Trustees Of Princeton University Pyrido(2,3-d)pyrimidine derivatives
EP0327190A1 (fr) * 1988-02-05 1989-08-09 The Trustees Of Princeton University Dérivés de la pyrido[2,3-d]pyrimidine
EP0511792A2 (fr) * 1991-04-29 1992-11-04 Eli Lilly And Company Dérives de pyridopyrimidine comme agents antinéoplastiques
US5354751A (en) * 1992-03-03 1994-10-11 Sri International Heteroaroyl 10-deazaamino-pterine compounds and use for rheumatoid arthritis
EP0761668A2 (fr) * 1995-09-08 1997-03-12 The Trustees Of Princeton University Antifolates non-classiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HABECK L L ET AL: "A novel class of monoglutamated antifolates exhibits tight-binding inhibition of human glycinamide ribonucleotide formyltransferase and potent activity against solid tumors", CANCER RES. (CNREA8,00085472);94; VOL.54 (4); PP.1021-6, ELI LILLY AND COM.;LILLY RES. LAB.; INDIANAPOLIS; 46285; IN; USA (US), XP002043960 *

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