[go: up one dir, main page]

WO1992018118A1 - Medicaments - Google Patents

Medicaments Download PDF

Info

Publication number
WO1992018118A1
WO1992018118A1 PCT/US1992/003094 US9203094W WO9218118A1 WO 1992018118 A1 WO1992018118 A1 WO 1992018118A1 US 9203094 W US9203094 W US 9203094W WO 9218118 A1 WO9218118 A1 WO 9218118A1
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
mtr
methionine
kinase
tfmtr
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.)
Ceased
Application number
PCT/US1992/003094
Other languages
English (en)
Inventor
Michael K. Riscoe
Paula A. Tower
John H. Fitchen
Adolph J. Ferro
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.)
Oregon State Board of Higher Education
Oregon State
Original Assignee
Oregon State Board of Higher Education
Oregon State
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 Oregon State Board of Higher Education, Oregon State filed Critical Oregon State Board of Higher Education
Publication of WO1992018118A1 publication Critical patent/WO1992018118A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to pharmaceutical compositions comprising a methylthioribose (MTR) kinase inhibitor and an inhibitor of de novo methionine synthesis and their use as medicinal agents.
  • MTR methylthioribose
  • MTR-kinase is a microbial enzyme important in the recycling of methionine.
  • US-A-4820692 discloses analogues o MTR as a new class of antimicrobial drugs because of their ability to perturb the growth of MTR kinase-containing microorganisms. These analogs may act through inhibition of methionine recycling from MTR, resulting in methionine depletion, or by conversion to toxic products.
  • TFMTR 5-trifluoromethylthioribose
  • Microbial biosynthesis of cysteine and methionine proceeds along a branched convergent pathway in one arm of which sulfate is reduced to sulfide while serine is
  • the next step consists of formation of cysteine from sulfide and O-acetylserine by the enzyme O-acetylserine sulfhydrylase.
  • Methionine is then synthesised from cysteine via cystathionine in a sequence of reactions catalysed by cystathionine ⁇ -synthase,
  • cystathionine ⁇ -lyase and methionine synthase.
  • enteric bacteria derive methionine from cysteine.
  • Compound which inhibit O-acetylserine sulfhydrylase, cystathionine ⁇ -synthase, cystathionine ⁇ -lyase or methionine synthase inhibit the synthesis of methionine and can be termed
  • This invention is based upon the discovery that
  • inhibitors of de novo methionine synthesis act in synergy with MTR-kinase inhibitors to inhibit the growth of MTR-kinase containing microorganisms. Inhibition of de novo methionine synthesis would appear to increase reliance on the methionine salvage pathway for maintenance of methionine levels, thereby leading to increased efficacy of MTR-kinase inhibitors against such microorganisms by disruption of the methionine salvage pathway.
  • the present invention provides a pharmaceutical composition comprising an MTR-kinase inhibitor, and an inhibitor of de novo methionine synthesis and a
  • an MTR-kinase inhibitor is a compound of the formula (1) :
  • R is H, CI, F, Br, I or R 1 S in which R 1 is C 1-10 linear or branched chain alkyl or halogenated linear or branched chain alkyl and R 2 to R 4 are H or OH with the proviso that at least one of R 2 to R 4 is OH.
  • a preferred MTR-kinase inhibitor is TFMTR.
  • Preferred inhibitors of de novo methionine synthesis include inhibitors of O-acetylserine sulfhydrylase,
  • cystathionine ⁇ -synthase cystathionine ⁇ -lyase, methionine synthase or mixtures thereof.
  • O-acetylserine sulfhydrylase inhibitors are 1,2,4-triazole or azaserine (O-diazoacetylserine) .
  • An example of a cystathionine ⁇ -synthase inhibitor is propargylglycine (2-amino-4-pentynoate).
  • An example of a methionine synthase inhibitor is nitrous oxide (N 2 O).
  • this invention provides a method of treating a mammal infected with an MTR-kinase containing.
  • microorganism which comprises administering to said mammal an effective amount of an MTR-kinase inhibitor and an effective amount of an inhibitor of de novo methionine synthesis.
  • the MTR-kinase inhibitor and inhibitor of de novo methionine synthesis are administered concurrently either as a pharmaceutical composition as hereinbefore described or as separate pharmaceutical compositions.
  • MTR-kinase inhibitor and inhibitor of de novo methionine synthesis are administered non-concurrently (for example more than 1 hour apart) as separate
  • a pharmaceutical composition comprising both medicaments together and pharmaceutical compositions comprising the separate medicaments can be formulated in accordance with standard pharmaceutical practice.
  • They may be administered in standard manner, for example orally, sub-lingually, parenterally, transdermally, rectally, via inhalation, via buccal administration, or to the eye.
  • An oral liquid formulation will generally consist of a suspension or solution of the medicament in a liquid carrier for example, ethanol, glycerine or water with a liquid carrier for example, ethanol, glycerine or water with a liquid carrier for example, ethanol, glycerine or water with a liquid carrier for example, ethanol, glycerine or water with a liquid carrier for example, ethanol, glycerine or water with a liquid carrier for example, ethanol, glycerine or water with a
  • flavouring or colouring agent where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • examples of such carriers include magnesium stearate, starch,
  • compositions celluloses, lactose and sucrose.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of the medicament in a sterile aqueous or non-aqueous carrier optionally containing a parenterally
  • oil or solublising agent for example polyethylene glycol, polyvinylpyrrolidone, 2-pyrrolidone, cyclodextrin, lecithin, arachis oil, or sesame oil.
  • a typical suppository formulation comprises the
  • Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.
  • Formulations for administration to the eye include solutions, suspensions, ointments or creams as hereinbefore described.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.
  • Each dosage unit contains suitably from 150-1500 mg, preferably 100 to 500 mg, of an MTR-kinase inhibitor and from 50 to 1500 mg of an inhibitor of de novo methionine synthesis preferably from 500 to 1000 mg of an O-acetylserine
  • sulfhydrylase inhibitor or from 100 to 500 mg of a
  • cystathionine ⁇ -synthase inhibitor
  • the daily dosage regimen is suitably about 5-30 mg/kg of an MTR-kinase inhibitor and about 5 to 100 mg/kg of an MTR-kinase inhibitor
  • inhibitor of de novo methionine synthesis preferably about 10 to 50 mg/kg of an O-acetylserine sulfhydrylase inhibitor or about 5 to 30 mg/kg of cystathionine ⁇ -synthase inhibitor.
  • MTR-kinase containing microorganisms whose growth is inhibited by the compositions and methods of the present invention include Klebsiella pnenmoniae, Enterpbacter
  • the present invention provides a method of treating a mammal infected with an MTR-kinase containing protozoan which comprises administering to said mammal an effective amount of an MTR-kinase inhibitor and an effective amount of a methionine synthase inhibitor.
  • MTR-kinase inhibitors and methionine synthase inhibitors are as hereinbefore described.
  • MTR-kinase inhibitors are known from US-A-4820692 and can be prepared according to methods disclosed therein. TFMTR is suitably prepared according to the method disclosed in
  • 1,2,4-triazole or azaserine are commercially available and can be prepared as disclosed in Org. Syn. 40 : 99, 1960 and
  • propargylglycine are commercially available and can be
  • K. pneumoniae was maintained in a chemically-defined medium containing: 25mM NH 4 CI; 35mM glucose; 1.5mM KCl; 0.4mM MgSO 4 ; 0.045mM NaCl; 0.025mM FeSO 4 ,- 0.025 ⁇ g/ml thiamine; and 66.6mM Na 2 HPO 4 -NaH 2 PO 4 .
  • the following micronutrient solution was added with the indicated final concentrations : CaCl 2 (5 x 10 -7 M), CoCl 2 (5 ⁇ 10 -8 M), MnCl 2 (10 -7 M), HBO 3 (5 ⁇ 10 -7 M), ZnCl 2 (10 -8 M), CuCO 3 (10 -8 M), (NH 4 ) 6 Mo 7 O 24 (5 ⁇ 10 _9 M), and the pH was adjusted to 7.2.
  • Dose inhibition studies were conducted in 5ml cultures inoculated with ⁇ 10 4 cells per ml and maintained in a rotary shaker incubator at 37°C. Growth was monitored by optical density at 470nm 12-15 hrs after incubation when control cultures had reached an optical density of 0.4. Isoboles representing the activity of drug mixtures were performed and analysed as described by Hewlett, Biometrics, 25: 477-87, 1969. Briefly, TFMTR and 1,2,4-triazole, azaserine, or propargylglycine were serially-diluted so that the organisms were simultaneously exposed to drug mixtures. The ability of the various drug combinations to inhibit growth by 50% (IC50) relative to control values was measured.
  • isobologram As described by Hewlett, isoboles for two separately active drugs resemble: 1) a straight line for additive action; 2) a convex line for subadditive action; and 3) a concave line for potentiation.
  • K. pneumoniae was cultured in defined medium containing i ⁇ M TFMTR and varying amounts of methionine. The organisms were inoculated at a density of ⁇ 10 4 /ml and incubated for 15 hrs at 37°C. In the absence of added
  • TFMTR totally inhibited cell growth. Increasing the concentration of methionine to 100 ⁇ M restored growth to nearly 60% of control. The inhibitory action of TFMTR was completely abrogated by the addition of l,000 ⁇ M methionine.
  • 1,2,4-Triazole is a weak but
  • TFMTR bv azaserine - Azaserine is a substrate for O-acetylserine sulfhydrylase. Upon reaction of azaserine with this enzyme, diazoacetate, a highly-reactive and toxic product, is formed. Potentiation studies with TFMTR and azaserine demonstrated a striking synergy.
  • the IC 50 value for azaserine alone against K. pneumoniae was 2.0 ⁇ M. At all drug ratios, the amount of either drug required to produce 50 percent inhibition was less with the combination than with either drug alone, and became minimal when 0.05 ⁇ M TFMTR was combined with 0.25 ⁇ M azaserine.
  • the degree of potentiation for TFMTR and azaserine measured as the joint action ratio was 3.6.
  • TFMTR Potentiation of TFMTR by propargylglycine - Propargylglycine
  • Propargylglycine is an irreversible inhibitor of cystathionine ⁇ -synthase, a pyridoxal phosphatedependent enzyme involved in microbial methionine synthesis.
  • the growth inhibitory effects of propargylglycine are reversed by methionine.
  • 375 ⁇ M propargylglycine was required to inhibit Klebsiella growth by 50 percent.
  • Combining as little as 0.1 ⁇ M TFMTR with 20 ⁇ M propargylglycine produced the same degree of growth inhibition. All points from the TFMTR-propargylglycine combinations used in the study fell well below the line of addition.
  • the degree of potentiation between the two drugs was calculated to be 3.2.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compositions pharmaceutiques comprenant des inhibiteurs de méthylthioribose (MTR) kinase (par exemple trifluorométhylthioribose) et des inhibiteurs de synthèse de méthionine de novo (par exemple 1,2,4-triazole, azasérine ou propargylglycine).
PCT/US1992/003094 1991-04-18 1992-04-15 Medicaments Ceased WO1992018118A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9108348.5 1991-04-18
GB919108348A GB9108348D0 (en) 1991-04-18 1991-04-18 Medicaments

Publications (1)

Publication Number Publication Date
WO1992018118A1 true WO1992018118A1 (fr) 1992-10-29

Family

ID=10693536

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/003094 Ceased WO1992018118A1 (fr) 1991-04-18 1992-04-15 Medicaments

Country Status (4)

Country Link
GB (1) GB9108348D0 (fr)
IL (1) IL101455A0 (fr)
MX (1) MX9201791A (fr)
WO (1) WO1992018118A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0555352A4 (en) * 1990-10-31 1994-12-14 Health Research Inc Agents for the treatment of diseases caused by parasitic protozoa and neoplastic diseases
WO2010010383A1 (fr) * 2008-07-21 2010-01-28 Isis Innovation Limited Traitement de l’obésité

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4820692A (en) * 1986-01-30 1989-04-11 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And Oregon State University Methylthioribose analogs, their preparation and use as medicinal agents and biocides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4820692A (en) * 1986-01-30 1989-04-11 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And Oregon State University Methylthioribose analogs, their preparation and use as medicinal agents and biocides

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol. 35, No. 8, issued August 1991, P.A. TOWER et al., "Synergistic Activity of 5-Trifluoromethylthioribose and Inhibitors of Methionine Synthesis against Klebsiella Pneumoniae", pages 1557-1561. *
CHEMICAL ABSTRACTS, Vol. 108, No. 7, issued 15 February 1988, MIYAZAKI et al., "Inhibition of the Methionine Cycle Enzymes", see pages 337, abstract no. 51900z; & PHYTOCHEMISTRY, 1987, 26(10), 2655-60. *
PLANT PHYSIOLOGY, Vol. 71, No. 4, issued April 1983, A. GURANOWSKI, "Plant 5-Methylthioribose Kinase", pages 932-935. *
PLANT PHYSIOLOGY, Vol. 79, No. 2, issued October 1985, M.M KUSHAD et al., "5-Methylthioadenosine Nucleosidase and 5-Methylthioribose Kinase Activities and Ethylene Production during Tomato Fruit Development and Ripening", pages 525-529. *
THE JOURNAL OF BIOLOGICAL CHEMISTRY, Vol. 265, No. 2, issued 15 January 1990, A.J. GIANOTTI et al., "Selective Killing of Klebsiella Pheumoniae by 5-Trifluoromethylthioribose", pages 831-837. *
THE JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol. 76, issued 05 June 1954, S.A. FUSARI et al., "Azaserine, a New Tumor-Inhibitory Substance. Isolation and Characterization", pages 2878-2881. *
THE JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol. 95, No. 18, issued 05 September 1973, R.H. ABELES et al., "Acetylenic Enzyme Inactivators. Inactivation of Gamma-Cystathionase, in Vitro and in Vivo, by Propargylglycine", pages 6124-6125. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0555352A4 (en) * 1990-10-31 1994-12-14 Health Research Inc Agents for the treatment of diseases caused by parasitic protozoa and neoplastic diseases
US5563125A (en) * 1990-10-31 1996-10-08 Health Research, Inc. 5'-deoxy-5'-(substituted)alkylthioribose compounds and their pharmaceutical compositions
WO2010010383A1 (fr) * 2008-07-21 2010-01-28 Isis Innovation Limited Traitement de l’obésité

Also Published As

Publication number Publication date
MX9201791A (es) 1992-10-01
GB9108348D0 (en) 1991-06-05
IL101455A0 (en) 1992-12-30

Similar Documents

Publication Publication Date Title
EP0963219B1 (fr) Manipulations de stress nitrosant et oxydatif dans le traitement d'une maladie
US4898870A (en) Pyrroloquinoline quinone compounds useful as an enzyme inhibitor
JP2015078185A (ja) Ｎ−アセチルシステイン組成物及び薬剤毒性治療または防止方法
US20070197550A1 (en) Histone deacetylase inhibitors for enhancing activity of antifungal agents
CA2478094A1 (fr) Procedes d'induction de differenciation terminale
US9540336B2 (en) Therapeutic agents
AU675412B2 (en) Method of treating HIV infection
EP0768084B1 (fr) Inhibiteur de la metastase cancereuse
US20040157802A1 (en) Anti-microbial agents derived from methionine sulfoximine analogues
CA2862193A1 (fr) Composition anti-tuberculose contenant des composes a base d'oxazole
WO1992018118A1 (fr) Medicaments
US10065978B2 (en) Cysteine-modifying substrate analogue inhibitors of ribose 5-phosphate isomerase for parasitic diseases, along with methods of their formation and use
EP1909912B1 (fr) Utilisation de la collismycine A en tant qu'inhibiteur du stress oxydatif
AU7339898A (en) Use of aminothiol ester derivatives in the pharmaceutical field
WO2002055661A2 (fr) Inhibiteurs de la synthase des acides gras
NZ235914A (en) Immunosuppressant pharmaceutical composition
JP4491229B2 (ja) ミトコンドリアを保護するための医薬を調製するためのチアゾール誘導体の使用
US4125610A (en) Antibacterial compositions
NL194535C (nl) Farmaceutisch preparaat voor de behandeling van lepra dat diaminodifenylsulfon bevat.
EP2638902B1 (fr) Médicament antipaludique comprenant de l'alaremycine ou un dérivé de celle-ci comme principe actif
JPS63146820A (ja) マイコバクテリウム・アビウム−イントラセルレアコンプレツクス感染症の治療方法
NZ781587A (en) Mini softgel naproxen composition
HK1186655B (en) Antimalarial drug comprising alaremycin or derivative thereof as active ingredient
NZ781587B2 (en) Mini softgel naproxen composition
JP2009221113A (ja) 原虫病治療薬

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA