Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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

Definitions

• This invention relates to folic acid antagonists that are metabolically inert exhibiting a high level of anti-inflammatory and anti-tumor activity. Metabolically inert classical antifolates are new and therefore they exhibit unexpected biological properties such as those recited in this invention. The field of this invention is confined to the anti-inflammatory, anti-neoplastic and anti-rheumatoid activity of new and novel folate antimetabolites.
• Antifolates are compounds that interfere at various stages of folate metabolism [ M. G. Nair. "The Chemistry of Antitumor Agents”. Chapter, 7; Blackie & Sons. London. 1991].
• Folate is a vitamin that is essential for the biosynthesis of purine and pyrimidine nucleotide precursors of DNA. Therefore antifolates are capable of inhibiting DNA biosynthesis and hence cell division.
• methotrexate (MTX) which is a powerful antifolate by virtue of its inhibition of Dihydrofolate Reductase (DHFR) mediated production of the active vitamin tetrahydrofolate is curative to Choriocarcinoma and Burkitt's lymphoma.
• MTX is also widely used as a single agent or in combination with other drugs for the treatment of various forms of human cancers [ M. G. Nair. "Cancer Growth and Progression: Cancer Management in Man” Volume 10, H. E. Kaiser (Ed); Kluwer Academic Publishers, Chapter, 7, 1989].
• the anti-rheumatoid properties of MTX is well documented and it is currently used as an arthritis remittive agent under the trade name Rheumatrex.
• MTX has also shown activity against asthma, but it has not yet been used clinically for this indication, except on an experimental basis.
• compound 1 When evaluated for inhibitory activity against the growth of a number of human cancer cells in culture, compound 1 was strikingly more active than either MTX or MDAM. Further evaluation in vitro using the enzyme folylpolyglutamate synthetase revealed that 1 and its analogs reported herein are not capable of elaboration to its polyglutamates due to the presence of the 4-methyleneglutamate moiety There fore the unexpected enhanced biological activity of 1 must have its origin in the complete lack of its in vivo metabolism [ Figure- 1]. Unlike trimetrexate, the compounds described in this invention are capable of transport to target tumor cells by the reduced folate transporter (RFT) due to the presence of the 4-methyleneglutamate moiety.
• RFT reduced folate transporter
• compound 1 was 4-5 times collaterally more sensitive in inhibiting the growth of leukemia cells that are resistant to MTX by virtue of defective polyglutamylation compared to the wild type MTX sensitive parental CCRF-CEM cell line. Accordingly, this invention demonstrates that metabolically inert classical folate analog inhibitors of dihydrofolate reductase are superior antitumor agents relative to the metabolizable classical antifolates such as methotrexate and aminopterin and to the 7-hydroxylatable but non-polyglutamylatable antifolates MDAM and MED AM.
• compound 1 As a model of metabolically ineffective DHFR inhibitor, compound 1 was evaluated as a potential anti-inflammatory agent relative to MTX and surprisingly it exhibited outstanding activity in this animal model of asthma substantiating the superiority of metabolically inert DHFR inhibitors.. In fact 1 was found to be not only superior to MTX but also to the well known anti-asthmatic drug theophylline in both early and late asthmatic responses and bronchial hyper responsiveness (BHR) when evaluated using allergic rabbits.
• BHR bronchial hyper responsiveness
• the anticancer and anti-inflammatory antifolates reported in this invention include close analogues of 1 bearing modified C9-10 region incapable of aldehyde oxidase mediated 7-hydroxylation and the 4-methyleneglutamate moiety that prevents polyglutamylation and modulation of binding to aldehyde oxidase.
• These quinazo line-based compounds [ 1, la , JLh, J-c_, and. lid ] may possess the racemic D,L-4-methyleneglutamate, enantiomerically pure D-4-methyleneglutamate [ "D" configuration ] or enantiomerically pure L-4-methyleneglutamate [ "L” configuration ] moieties.
• This invention accordingly provides a process for treating neoplastic diseases [ leukemia, ascetic and solid tumors ], a process for treating asthma and related inflammatory diseases and a process for treating rheumatoid arthritis and other auto immune diseases which comprises administering to a warm blooded animal with an abnormal proportion of leukocytes or other evidence of neoplastic disease, asthma or rheumatoid arthritis a therapeutically effective non-toxic amount of 5,8, 10-trideaza-4'-methyleneaminopterin (1) [herein referred to as compound 1] or its close analogues la - JLd as such or in the form of a pharmacologically acceptable salt thereof.
• compound 1 or its close analogues la - JLd as such or in the form of a pharmacologically acceptable salt thereof.
• leucovorin folinic acid; citrovorum factor
• other anticancer drugs including but not limited to tomudex, 5-FU; 5-FdUR; carboplatin, oxaloplatin or cis-platin; taxol, campothecins or cyclophosphamide to enhance efficacy.
• the salts of J- or its close analogues [ la - Id. ] may be formed with one or more of the amino groups of the quinazoline ring with acids such as acetic, hydrochloric, sulfuric, sulfonic, nitric, hydrobromic, phosphoric, citric, salicylic or methanesulfonic.
• Compound 1 or its close analogues and salts thereof may be administered to a warm blooded animal by oral or parenteral (intraperitoneal, intravenous, intrathecal, subcutaneous, intramuscular, etc.) routes.
• Higher dosage of 1 or its close analogues [ la - l ⁇ ] may be administered in conjunction with racemic leucovorin [6-(R,S) 5-formyltetrahydrofolate] and/or folic acid to further reduce toxicity.
• Compound 1 or its close analogues [ la - J-d ] may be provided in composite forms to facilitate administration to patients or in dosage unit form.
• a non-toxic and sterile carrier may be added to 1 and its close analogues.
• This carrier may be solid, liquid or semi-solid that may serve as a medium, vehicle or excipient.
• Methyl cellulose, polyhydroxybenzoate, talc, gelatin, lactose, dextrose, starch, mannitol, sorbitol, mineral oil, gum acacia, oil of theobroma or magnesium stearate may serve as a carrier
• Another useful and preferred formulation of these entities for administration to patients is their conversion to the corresponding sodium or potassium salts by dissolving in either sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate solution.
• the resulting solutions may be used as such or cryodessicated to the solid sodium or potassium salt and conveniently formulated in aqueous or non-aqueous vehicles or carriers.
• Compound 1, or its close analogues (la-Id) and a carrier or diluent can be encapsulated or enclosed in a paper or other container, cachet, gelatin, capsule or sachet when intended for use in dosage units.
• the process of the invention for the synthesis of compound 1 starts with the conversion of commercially available 5-methyl-2-nitrobenzoic acid to the corresponding amide 2 and its subsequent transformation to 5-methyl-2-nitrobenzonitrile (3) by standard procedures.
• Reaction of 1 in DMF under nitrogen with/?-formylmethylbenzoate in presence of an organic base such as diazabicyclo octane for several hours gave the olefin (4) after work up as a mixture of geometric isomers.
• Olefin 4 can also be prepared by reacting 2 withp-formylmethylbenzoate in methanol using sodium methoxide as a base. In general this reaction can be performed in any appropriate organic solvents using commonly used organic or inorganic bases.
• MTX and 1 were given as aerosol (5 mg/ml).
• Theophylline was given as aerosol (5 mg/ml)
• Dithionite Reduction of Product 4_ of Example-2 To a stirring solution of 1.0 gr of A in 40 mL of DMF maintained between 60-70 degrees was added portion-wise 5.0 gr of sodium dithionite followed by the addition of 60 mL of water during 20 minutes. About 15 minutes after the addition was complete, the mixture was evaporated to dryness under reduced pressure and 25 gr of ice was added whereupon a pink solid was formed. After all the ice had melted the precipitate was filtered, washed with water and dried to obtain 700 mg of the product. The reduction product showed a single spot on a TLC plate which was more polar than the starting compound, mp, 195-197°C; MS [C 17 H H N 2 O 2 ], Calcd, 278; Found, 279 [MH+].
• TGI Total Growth Inhibition
• the viscous product thus obtained was stirred with 25 mL of 5% sodium bicarbonate and filtered. After washing with water the solid was hydrolyzed with a mixture of 50 mL of 0.1 N NaOH and 20 mL of acetonitrile for 16 hrs , evaporated to ⁇ 30 mL, cooled in an ice-bath and acidified with glacial acetic acid to pH 4.0 to obtain a brown precipitate of Id which was washed, re-dissolved in 10.0 mL of 5% sodium carbonate and chromatographed on a C18 silica gel column using 12% acetonitrile in water as the eluting solvent.

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

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• 1998
  • 1998-01-17 US US09/008,613 patent/US5912251A/en not_active Expired - Lifetime
• 1999
  • 1999-01-13 JP JP2000540125A patent/JP4854850B2/ja not_active Expired - Lifetime
  • 1999-01-13 EP EP99903128A patent/EP1062209B1/en not_active Expired - Lifetime
  • 1999-01-13 EP EP05004632A patent/EP1535911A1/en not_active Withdrawn
  • 1999-01-13 DE DE69940881T patent/DE69940881D1/de not_active Expired - Lifetime
  • 1999-01-13 WO PCT/US1999/000948 patent/WO1999036409A1/en not_active Ceased

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