EP1019063A1 - Modulation de reactions immunitaires - Google Patents

Modulation de reactions immunitaires

Info

Publication number
EP1019063A1
EP1019063A1 EP98946998A EP98946998A EP1019063A1 EP 1019063 A1 EP1019063 A1 EP 1019063A1 EP 98946998 A EP98946998 A EP 98946998A EP 98946998 A EP98946998 A EP 98946998A EP 1019063 A1 EP1019063 A1 EP 1019063A1
Authority
EP
European Patent Office
Prior art keywords
group
immune
animal
alkyl
alkenyl groups
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Withdrawn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
EP98946998A
Other languages
German (de)
English (en)
Other versions
EP1019063A4 (fr
Inventor
Carl John Landauer
Gabriel Johannes Du Preez
Volker Reinhard Schillack
Derrick Cecil Attfield
Johannes Beyers Van Den Bogaerde
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.)
Frangold Holdings Ltd
Original Assignee
Frangold Holdings Ltd
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 Frangold Holdings Ltd filed Critical Frangold Holdings Ltd
Publication of EP1019063A1 publication Critical patent/EP1019063A1/fr
Publication of EP1019063A4 publication Critical patent/EP1019063A4/fr
Withdrawn legal-status Critical Current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
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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 the treatment of conditions in the human body which are associated with inappropriate immune responses. More
  • this invention is concerned with the treatment of conditions in which the inappropriate immune response is associated with inappropriate-
  • Tyrosine Kinase hereinafter referred to as "PTK”
  • CDK Cycline Dependent Kinase
  • the invention consequently provides for the treatment of and for medicaments for use in the treatment of, a large variety of ailments
  • T lymphocytes also known as T-cells
  • B-cells the T lymphocytes
  • lymphocytes also known as B-cells, have been recognized for their important role in the immune response of the animal body against foreign
  • infection of the animal body or to endogenous immune stimulants, for example oncogenic transformation, is to cause the activation of the
  • immunological mediators including cytokines, lymphokines, chemokines, growth factors and cytotoxic cells and usually also gives rise to the
  • the response of the immune system is sometimes abnormal and
  • Such abnormality in immune cell activity may simply be
  • the present invention is directed at the treatment of such conditions as will appear below.
  • cytotoxic cells including the presence of cytotoxic cells, and/or of an
  • the immune response may persist even after the causative agent or stimulant, such as, for example, a viral or microbial
  • Immune cells and in particular T
  • lymphocytes are dependent for their biological function on signal transduction through the T cell receptor which is unique to, and present
  • the T cell receptor is a complex group of
  • CD 4 CD 8
  • Tyrosine Kinases phosphorilate certain proteins leading to the development
  • Tyrosine Kinase [PTK] plays an important role. This enzyme is a protein
  • Dimethylformamide or DMF is a volatile, non-ionic liquid at room temperature and is well known for its use as an industrial solvent. It is
  • Such toxicity as DMF has at high levels of concentration in the human body is attributed to its depletion of
  • R j is selected from the group consisting of H and lower [i.e. to C 3 ]
  • R 2 and R 3 are the same or different and each is selected from the
  • n is any number from 2 to 5, or the group -(CH 2 ) 2 -0-(CH 2 ) 2 and metabolites and prodrugs thereof.
  • the immune response to be affected by the above method may be an immune response of the immune cells forming part of the immune system of the body.
  • the immune cells may be T lymphocytes and or B lymphocytes.
  • the method may be performed to reduce the expression or secretion of immune cell products in the body.
  • R j is selected from the group consisting of H and lower [i.e. to C 3 ]
  • R 2 and R 3 are the same or different and each is selected from the group consisting of H, lower [i.e. C, to C 3 ] alkyl and C 2 to C 3 alkenyl groups which may optionally be halogenated or hydroxylated, or which may in combination with one another form a -(CH 2 ) n - group
  • n is any number from 2 to 5, or the group -(CH 2 ) 2 -0-(CH 2 ) 2 and metabolites and prodrugs thereof.
  • R is selected from the group consisting of H and lower [i.e. C, to C 3 ] alkyl and C 2 to C 3 alkenyl groups;
  • R 2 and R 3 are the same or different and each is selected from the group consisting of H, lower [i.e. C, to C 3 ] alkyl and C 2 to C 3 alkenyl
  • n is any number from 2 to 5, or the group -(CH 2 ) 2 -0-(CH 2 ) 2
  • composition comprising a compound selected from the group consisting of compounds of the general chemical formula (I)
  • R is selected from the group consisting of H and lower [i.e. C, to C 3 ] alkyl and C 2 to C 3 alkenyl groups;
  • R 2 and R 3 are the same or different and each is selected from the group consisting of H, lower [i.e. to C 3 ] alkyl and C 2 to C 3 alkenyl
  • n is any number from 2 to 5, or the group -(CH 2 ) 2 -0-(CH 2 ) 2
  • treated may be any one of the following:
  • Vasculitis Syndrome including Wagener's thrombosis and all forms of
  • SIRS Systemic Inflammatory Response Syndrome
  • the compounds of choice is dimethylformamide and its metabolites namely N-methylformamide, N-
  • the medicament according to the invention is adapted in use to administer to the patient a quantity of
  • the compound may be administered by
  • any route of administration such as orally, nasally, rectally, intravenously,
  • administration of the compound is transdermally. Preferably, however, it
  • transdermal patch is administered by a transdermal patch.
  • mixed lymphocytes were exposed to a non-specific stimulator of lymphocytes, such as PHA at 1 to 10 ⁇ g per
  • metabolic activity is not the result of direct cell toxicity as is evidenced by
  • T lymphocytes to certain T lymphocyte specific antigens and antigen,
  • transdermal administration system that is able to deliver a variety of drugs including DMF and the above-mentioned related compounds
  • the patch design parameters considered important include the following:
  • the patch must have pre-determined dimensions as it determines the amount of active ingredient [drug] absorbed over a certain time.
  • Drug concentration should be variable according to patient profile.
  • the patch must be stable, and deliver repeatable therapeutic
  • the patch and the drug must have a relative long shelf life.
  • Membrane pore size of 0.05-0.45 micron depending on which drug is administered.
  • Anti-irritation agent - Vitamin E (This agent can be applied before,
  • Indirect administration of the drug such as DMF may be done by
  • Therapeutic agent dosage can be predetermined according to patient's
  • Patch is very stable, has an unlimited shelf life, and agent administered from an ampoule has at least a two year expiry date,
  • Peripheral human lymphocytes were isolated from whole blood of healthy
  • peripheral whole blood is diluted 1:2 with phosphate buffered saline or cell culture media such as RPMI1640.
  • a density gradient such as
  • Histopaque 1077 [Sigma Cat # 1077] is then layered underneath the diluted peripheral blood, taking care to create a sharp interface. The density
  • This layer is then removed and further processed by placing the buffy coat in an additional tube and washing the cells washed 3 times
  • the cells are centrifuged at 400 g for 9 minutes. After the third wash the lymphocytes
  • the cells are collected from the pellet.
  • the cells are counted and diluted to the desired cell concentration.
  • DMF concentrations were prepared using complete cell culture
  • the isolated lymphocytes were diluted to the required concentration using
  • the prepared lymphocytes were placed in 96 well cell culture plates at a
  • PHA Phyto-Heame-Agglutinin
  • lymphocytes This demonstrates a significant inhibition of metabolic activity in the culture well which correlates very closely with the level of
  • AlamarBlue is observed for lymphocytes exposed to 0.05% DMF
  • lymphocytes were isolated the lymphocytes were exposed to DMF at various
  • the Tyrosine kinase activity was: 5, 15, 30, 75, 120 and 180 minutes.
  • the Tyrosine kinase activity was: 5, 15, 30, 75, 120 and 180 minutes.
  • tested lymphocytes might be the result of stimulation of certain tyrosine
  • the presented graphs are typical examples of many graphs obtained.
  • HELA a Cervix cancer cell line
  • HEP3B a liver cancer cell
  • the inhibitor was used in 10% DMSO solution. The test was carried under the following conditions and yielded the results

Landscapes

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

Abstract

L'invention concerne un procédé permettant d'influencer ou de moduler chez un animal une stimulation ou une suppression du produit de cellules immunitaires, suite à une réaction immunitaire à un stimulant immunitaire externe ou endogène. Le procédé comporte les étapes consistant à administrer à cet animal une quantité efficace du point de vue d'une modulation immunitaire, et non toxique, d'un composé sélectionné dans le groupe constitué par des composés représentés par la formule (I) chimique générale: R1-CO-NR2R3 (I), dans laquelle R1 est sélectionné dans le groupe constitué par H, un groupe alkyle inférieur (c.-à-d. C1 à C3) et un groupe alcényle C2 à C3; R2 et R3 sont les mêmes ou différents, et chacun est sélectionné dans le groupe constitué par H, un groupe alkyle inférieur (c.-à-d. C1 à C3) et un groupe alcényle C2 à C3 qui peuvent être éventuellement halogénés ou hydroxylés, ou lorsqu'ils sont combinés l'un avec l'autre, peuvent former un groupe -(CH2)n dans lequel n est un nombre compris entre 2 et 5, ou le groupe -(CH2)2-O-(CH2)2, des métabolites ou des promédicaments de ceux-ci. Le procédé est utile pour traiter diverses affections associées à des réactions immunitaires inappropriées. L'invention concerne l'utilisation de composés représentés par la formule (I) pour fabriquer des médicaments utiles pour le traitement de telles affections, et des préparations pharmaceutiques renfermant ceux-ci.
EP98946998A 1997-09-16 1998-09-16 Modulation de reactions immunitaires Withdrawn EP1019063A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ZA978319 1997-09-16
ZA9708319 1997-09-16
PCT/US1998/019126 WO1999013885A1 (fr) 1997-09-16 1998-09-16 Modulation de reactions immunitaires

Publications (2)

Publication Number Publication Date
EP1019063A1 true EP1019063A1 (fr) 2000-07-19
EP1019063A4 EP1019063A4 (fr) 2003-09-03

Family

ID=25586589

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98946998A Withdrawn EP1019063A4 (fr) 1997-09-16 1998-09-16 Modulation de reactions immunitaires

Country Status (10)

Country Link
EP (1) EP1019063A4 (fr)
JP (1) JP2001516721A (fr)
CN (1) CN1279612A (fr)
AU (1) AU737867B2 (fr)
BR (1) BR9812321A (fr)
CA (1) CA2304119A1 (fr)
IL (1) IL135091A0 (fr)
NO (1) NO20001341L (fr)
NZ (1) NZ503418A (fr)
WO (1) WO1999013885A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2324631A1 (fr) * 2000-10-26 2002-04-26 Virodene Pharmaceutical Holdings (Proprietary) Limited Substance ou composition pour le traitement du cancer
US20070212402A1 (en) * 2003-12-05 2007-09-13 Rooven Qainton V Patch

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5814659A (en) * 1996-04-23 1998-09-29 Dtr Dermal Therapy (Barbados) Inc. Topical analgesic composition

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
ABRAMS J S ET AL: "Phase II trial of N- methylformamide in advanced renal cancer." AMERICAN JOURNAL OF CLINICAL ONCOLOGY, (1989 FEB) 12 (1) 41-2. , XP008019185 *
BUFALO DEL D ET AL: "N-METHYLFORMAMIDE INDUCES CHANGES ON ADHESIVE PROPERTIES AND LUNG-COLONIZING POTENTIAL OF M14 MELANOMA CELLS" BRITISH JOURNAL OF CANCER, LONDON, GB, vol. 77, no. 2, January 1998 (1998-01), pages 210-215, XP001023799 ISSN: 0007-0920 *
CORDEIRO R F ET AL: "ROLE OF GLUTATHIONE DEPLETION IN THE MECHANISM OF ACTION OF N-METHYLFORMAMIDE AND N,N-DIMETHYLFORMAMIDE IN A CULTURED HUMAN COLON CARCINOMA CELL LINE" CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, BALTIMORE, MD, US, vol. 46, no. 3, March 1986 (1986-03), pages 1297-1305, XP001023787 ISSN: 0008-5472 *
DATABASE WPI Section Ch, Week 199916 Derwent Publications Ltd., London, GB; Class A96, AN 1998-541805 XP002246940 & CA 2 203 456 A (DTR DERMAL THERAPY BARBADOS INC), 23 October 1997 (1997-10-23) & US 5 814 659 A 29 September 1998 (1998-09-29) *
JINDAL S K ET AL: "Incidence and recognition of interstitial pulmonary fibrosis in developin countries." CURRENT OPINION IN PULMONARY MEDICINE, (1997 SEP) 3 (5) 378-83. REF: 51 , XP008019184 *
MINIKKAM SUTHANTHIRAN ET AL: "IMMUNOSUPPRESSIVE PROPERTIES OF POLAR ORGANIC COMPOUNDS THAT INDUCECELLULAR DIFFERENTIATION IN FRIEND ERYTHROLEUKEMIA CELLS" TRANSPLANTATION, WILLIAMS AND WILKINS, BALTIMORE, MD, US, vol. 33, no. 5, 1 May 1982 (1982-05-01), pages 534-540, XP000560858 ISSN: 0041-1337 *
MISRA, A N. ET AL: "Transdermal administration of insulin: effect of various penetration enhancers" INDIAN JOURNAL OF EXPERIMENTAL BIOLOGY (1996), 34(2), 171-3 , XP008019191 *
POELMANS L ET AL: "ÄToxic hepatitis due to dimethylformamide: case reports and literature reviewÜ. Toxische hepatitis op dimethylformamide: case reports en literatuurgegevens." ACTA CLINICA BELGICA, (1996) 51 (5) 360-6. , XP008019186 *
SCOTLANDI K ET AL: "PRE-TREATMENT OF HUMAN OSTEOSARCOMA CELLS WITH N-METHYLFORMAMIDE ENHANCES P-GLYCOPROTEIN EXPRESSION AND RESISTANCE TO DOXORUBICIN" INTERNATIONAL JOURNAL OF CANCER, NEW YORK, NY, US, vol. 58, no. 1, 1994, pages 95-101, XP001023781 ISSN: 0020-7136 *
See also references of WO9913885A1 *

Also Published As

Publication number Publication date
WO1999013885A1 (fr) 1999-03-25
NO20001341L (no) 2000-05-16
AU9389098A (en) 1999-04-05
NO20001341D0 (no) 2000-03-15
CA2304119A1 (fr) 1999-03-25
AU737867B2 (en) 2001-09-06
CN1279612A (zh) 2001-01-10
NZ503418A (en) 2001-02-23
IL135091A0 (en) 2001-05-20
JP2001516721A (ja) 2001-10-02
EP1019063A4 (fr) 2003-09-03
BR9812321A (pt) 2000-09-05

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