WO2001093866A1 - Composes a activite anti-virus herpes simplex - Google Patents

Composes a activite anti-virus herpes simplex Download PDF

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Publication number
WO2001093866A1
WO2001093866A1 PCT/EP2001/006347 EP0106347W WO0193866A1 WO 2001093866 A1 WO2001093866 A1 WO 2001093866A1 EP 0106347 W EP0106347 W EP 0106347W WO 0193866 A1 WO0193866 A1 WO 0193866A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethyl
hsv
viral
compounds
ibt
Prior art date
Application number
PCT/EP2001/006347
Other languages
English (en)
Inventor
Giulio Tarro
Original Assignee
Unihart Corporation
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 Unihart Corporation filed Critical Unihart Corporation
Priority to AU62342/01A priority Critical patent/AU6234201A/en
Publication of WO2001093866A1 publication Critical patent/WO2001093866A1/fr

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • the present invention relates to the use of isatin- ⁇ -thiosemicarbazone and of the corresponding 1-N-ethyl-derivative thereof, of formula
  • R H or ethyl
  • HSV virus is responsible for lesions at the oral, facial, ocular, genital and anal levels. It is present in two forms, named Types 1 and 2, and is preferably found in ectodermal tissues, from which it can induce lesions on the skin, oral cavity, vagina, conjunctiva and nervous system. HSV infections may, in some cases, induce blindness, infant death, encephalitis. An important characteristic of these viruses is that they can remain in a latent or quiescent form. HSV primary infections are contracted through openings in mucous membranes where the virus is locally replicated and then spreads to lymphonodes and, in some case, to blood circulation, inducing viremia.
  • the virus persists in a latent form in ganglia innerving the region where the primary infection took place. Latency can be interrupted with consequent viral multiplication which constitutes the recurrent form of the disease. Said recurrent form can be induced by heat, cold, ultraviolet light, hormonal disorders, or immunosuppressive agents.
  • a therapeutical treatment should selectively inhibit specific viral functions, such as adsorption, envelope removal, transcription, protein synthesis, nucleic acids replication, maturation and release.
  • IDU Idoxuridine
  • ARA-C cytosine arabinoside
  • ARA-A adenine arabinoside
  • TFT trifluorothymidine
  • Hep2 cells grown in milk bottles with BME added with 10% calf serum and 0.11% NaHC0 3 were used as experimental model. Cultures were infected at day 4 with the HSV Schooler strain. The Figure shows the inhibition of viral growth obtained with a 10 "40 ⁇ M concentration of IBT and N-ethyl-IBT. At these concentrations, viral progression after 24 hours is reduced to 31.25% for samples treated with IBT and to 6.25% for samples treated with the N-ethyl derivative. The compounds were found to be active when added 24 hours or 0.5-2 hours before infection. On the other hand, when the compounds were added after the infection, the inhibition decreased down to zero effect after the replication had started.
  • CPE cytopathogenic
  • the compounds of the invention exert their activity mainly through inhibition of the synthesis of novel infective viruses without changing the production of viral antigens. Therefore, parental viral genome is the cause of the residual cytopathogenic effect and of the observed production of viral antigens.
  • the experiments prove that in HSV-infected cells in the presence of IBT and N-ethyl-IBT, viral mRNA is usually transcripted until 3 hours after treatment, but not later, thereby preventing the production of the protein subunits necessary for mature virions to form.
  • the inhibition kinetics observed is likely due to the fact that viral mRNA which appears 3 hours after infection, is transcripted by the viral progeny genome and is sensitive to the effect di inhibitors which induce rupture of polyribosomes. It has in fact been observed that IBT has no effect on cells in which the formation of new viral DNA is prevented by fluorodeoxyuridine.
  • the mRNA transcripted by the viral progeny genome encodes for a protein, which is inhibited by addition of puromycin, on which protein IBT exerts its action.
  • the action mechanism of the compounds of the invention appears likely to be related with the control of translation of viral mRNAs, however such hypothesis does not limit the invention in any way.
  • the present invention relates to the use of IBT and its N-ethyl- derivative in the preparation of a medicament for the treatment of HSV infections.
  • said compounds will suitably be formulated with pharmaceutically acceptable carriers and excipients, and they will be administered through the oral, rectal, nasal, topical (transdermal, buccal and sublingual), vaginal, parenteral (subcutaneous, intramuscular, intravenous and intradermal), and pulmonary routes.
  • Suitable forms comprise, for example, tablets, lozenges, capsules, granulates, powders, suppositories, syrups, solutions, suspensions, creams, ointments, gel, pastes, lotions, emulsions, sprays.
  • the formulations will be preferably in the form of drops or collyriums and ointments or creams, respectively, having active ingredient content from 0.1 to about 20% by weight, preferably from 0.2 to 10% by weight.
  • an acceptable dosage of the active ingredient ranges from 0.1 to 250 mg / kg body weight daily, preferably from 1 to 100 mg/kg/day.
  • the desired dosage will preferably be divided in sub-doses administered at suitable intervals during the day.
  • the active compound should ideally reach plasma concentration peaks ranging from 0.25 to 100 ⁇ M, preferably from 1 to 50 ⁇ M.

Abstract

La présente invention concerne l'utilisation d'isatine-ß-thiosemi-carbazone et du dérivé de 1-N-éthyle correspondant dans le traitement des infections à virus herpès simplex (herpes simplex virus : HSV).
PCT/EP2001/006347 2000-06-09 2001-06-05 Composes a activite anti-virus herpes simplex WO2001093866A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU62342/01A AU6234201A (en) 2000-06-09 2001-06-05 Compounds with anti-hsv activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2000MI001288A IT1320767B1 (it) 2000-06-09 2000-06-09 Composti ad attivita' anti-hsv.
ITMI2000A001288 2000-06-09

Publications (1)

Publication Number Publication Date
WO2001093866A1 true WO2001093866A1 (fr) 2001-12-13

Family

ID=11445224

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2001/006347 WO2001093866A1 (fr) 2000-06-09 2001-06-05 Composes a activite anti-virus herpes simplex

Country Status (3)

Country Link
AU (1) AU6234201A (fr)
IT (1) IT1320767B1 (fr)
WO (1) WO2001093866A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102626408A (zh) * 2012-03-26 2012-08-08 天津市国际生物医药联合研究院 吲哚满二酮缩氨基硫脲类化合物在抑制ndm-1活性中的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB898855A (en) * 1960-03-11 1962-06-14 Wellcome Found Pharmaceutical antiviral compositions isatin-ª--thiosemicarbazone
GB975357A (en) * 1959-12-04 1964-11-18 Wellcome Found 1 substituted isatin-ª‰-thiosemicarbazones,their preparation and pharmaceutical preparations containing them
GB1298192A (en) * 1968-09-06 1972-11-29 Wellcome Found Isatin thiosemicarbazones
US4032659A (en) * 1969-03-20 1977-06-28 American Home Products Corporation Method of viral chemoprophylaxis
EP0270317A2 (fr) * 1986-11-29 1988-06-08 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Médicament pour le traitement des maladies virales

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB975357A (en) * 1959-12-04 1964-11-18 Wellcome Found 1 substituted isatin-ª‰-thiosemicarbazones,their preparation and pharmaceutical preparations containing them
GB898855A (en) * 1960-03-11 1962-06-14 Wellcome Found Pharmaceutical antiviral compositions isatin-ª--thiosemicarbazone
GB1298192A (en) * 1968-09-06 1972-11-29 Wellcome Found Isatin thiosemicarbazones
US4032659A (en) * 1969-03-20 1977-06-28 American Home Products Corporation Method of viral chemoprophylaxis
EP0270317A2 (fr) * 1986-11-29 1988-06-08 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Médicament pour le traitement des maladies virales

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TARRO, G. ET AL: "Effect of two methisazone derivatives on herpes simplex virus( HSV ) replication", ADVAN. ANTIMICROB. ANTINEOPLASTIC CHEMOTHER., PROC. INT. CONGR. CHEMOTHER., 7TH (1972), MEETING DATE 1971, VOLUME 1, ISSUE 1, 355-6. EDITOR(S): HEJZLAR, MIROSLAV. PUBLISHER: UNIV. PARK PRESS, BALTIMORE, MD., XP001030027 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102626408A (zh) * 2012-03-26 2012-08-08 天津市国际生物医药联合研究院 吲哚满二酮缩氨基硫脲类化合物在抑制ndm-1活性中的应用
CN102626408B (zh) * 2012-03-26 2013-10-16 天津市国际生物医药联合研究院 吲哚满二酮缩氨基硫脲类化合物在制备抑制ndm-1活性的药物中的应用

Also Published As

Publication number Publication date
AU6234201A (en) 2001-12-17
IT1320767B1 (it) 2003-12-10
ITMI20001288A1 (it) 2001-12-09
ITMI20001288A0 (it) 2000-06-09

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