EP0920310A1 - Verwendung von aminothioleestern im pharmazeutischen bereich - Google Patents

Verwendung von aminothioleestern im pharmazeutischen bereich

Info

Publication number: EP0920310A1
Authority: EP; European Patent Office
Prior art keywords: cells; pharmaceutical composition; formula; represent; compound
Prior art date: 1997-04-08
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 Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn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

EP98920590A

Other languages

English (en)

French (fr)

Inventor

Gérard Anthony QUASH

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.)

Galderma Research and Development SNC

Original Assignee

Galderma Research and Development SNC

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.)

1997-04-08

Filing date

1998-04-08

Publication date

1999-06-09

1998-04-08 Application filed by Galderma Research and Development SNC filed Critical Galderma Research and Development SNC

1999-06-09 Publication of EP0920310A1 publication Critical patent/EP0920310A1/de

Status Withdrawn legal-status Critical Current

Links

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239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
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206010029260 Neuroblastoma Diseases 0.000 claims abstract description 5
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206010036832 Prolactinoma Diseases 0.000 claims abstract description 5
230000005764 inhibitory process Effects 0.000 claims abstract description 5
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239000000203 mixture Substances 0.000 claims description 13
238000002360 preparation method Methods 0.000 claims description 7
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 6
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102100020970 ATP-binding cassette sub-family D member 2 Human genes 0.000 description 1
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
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208000035404 Autolysis Diseases 0.000 description 1
101001074429 Bacillus subtilis (strain 168) Polyketide biosynthesis acyltransferase homolog PksD Proteins 0.000 description 1
101000936617 Bacillus velezensis (strain DSM 23117 / BGSC 10A6 / FZB42) Polyketide biosynthesis acyltransferase homolog BaeD Proteins 0.000 description 1
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- 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

the present invention relates to the use of ammothiolester derivatives in the preparation of a pharmaceutical composition with a view to removing the inhibition of apoptosis due to the presence of the bcl 2 gene in transformed cells.
necrosis Morphologically necrosis is characterized by swelling of the mitochond ⁇ es and the cytoplasm and by nuclear alteration, followed by the destruction of the cell and its autolysis, this being accompanied by an inflammation phenomenon
necrosis occurs passively and incidentally Tissue necrosis is generally due to a physical trauma of the cells or a chemical poison, for example
apoptosis The other form of cell death is called apoptosis [Kerr, JFR and Wyllie, AH, Br J Cancer, 265, 239 (1972)], but unlike necrosis apoptosis does not cause inflammation. It is described that apoptosis can be carried out under different physiological conditions. It is a highly selective form of cell suicide which is characterized by easily observable morphological and biochemical phenomena.
Apoptosis can be considered as a programmed death of cells involved in the development of tissue differentiation and renewal. It is also considered that cell differentiation, growth and maturation are closely linked to apoptosis and that substances capable of play a role in the differentiation, growth and maturation of cells are also linked to the phenomenon of apoptosis
4-methyith ⁇ o-2-oxobutanoic acid can be metabolized in vivo by the branched chain oxo-acid dehydrogenase complex present in the mitochond ⁇ es of liver, heart and heart cells.
E1 represents the decarboxylase of the branched chain oxo-acid dehydrogenase complex whose co-factor is thiamine pyrophosphate (TPP),
- E2 represents the transacylase of the branched chain oxo-acid dehydrogenase complex whose co-factor is thioctic acid (TA),
transaminase inhibitors involved in the transformation of MTOB into methionine which are compounds of L methionine esters and py ⁇ doxal selectively inhibit the growth of several types of transformed cells but not that of normal MRC5 cells and weakly induce apoptosis also in BAF3 lymphoid cells cultured in the presence of interleukin 3
bcl2 gene In the case of pathologies which are characterized by an overexpression of the bcl2 gene, such as in particular breast cancers, B cell lymphomas, leukemias, neuroblastomas, adenocarcmomas of the prostate, prolactinomas and other pituitary adenomas, this overexpression of the bcl2 gene gives cells resistance to apoptosis and therefore to chemotherapy or antiandrogens (Miyashita, T and Reed, JC (1993) Blood 81, 151-157, Furuya.Y et al (1996) Clinical Cancer Research 2, 389-398)
One of the aims of the present invention is therefore to partially or even completely inhibit this character resistant to the induction of apoptosis due to the bcl2 gene present in the transformed cells.
the present invention also relates to the use of at least one aminothiolester derivative of formula (I) for the preparation of a pharmaceutical composition intended to remove the inhibition of the character resistant to chemotherapy or to antiandrogens of transformed cells.
the aminothiolester derivatives have the following formula (I)
R1, R2 and R3, independently, represent an alkyl radical, linear or branched, saturated or unsaturated, of C1-C6.
saturated branched alkyl radicals having from 1 to 6 carbon atoms mention may be made in particular of the 2-methylbutyl, 2-methylpentyl, isopropyl and tert-butyl radicals
unsaturated alkyl radicals having from 1 to 6 carbon atoms there may be mentioned in particular the allyl radical
R1, R2 and R3, independently, represent an alkyl radical from C1 to C3
R1 and R2 represent a methyl radical and R3 a radical chosen from the methyl, ethyl and propyl radical.
R1, R2 and R3 represent the methyl radical
a compound of formula (I) is advantageously used in which the amine is in the form of ammonium, preferably in the form of organic ammonium and advantageously in the form of ammonium formate or acetate
the compounds of formula (I) have the advantage of being water-soluble, and therefore easily usable
FIG. 1 represents the percentage of DNA fragments obtained in BAF-bcl2 cells cultured for 6 hours with different compounds as a function of the concentrations (expressed in ⁇ M) of these different compounds which are 4-amino methyl-4 pentyne-2 al-1 (represented by D), S-methyl 4-am ⁇ no-4-methylpent-2-yne thioate (represented by M) and the mixture of 4-am ⁇ no-4-methylpent-2-yne thioate S-methyl (at different concentrations) and methional at 200 ⁇ M (represents by •)
FIG. 2 represents the percentage of DNA fragments obtained in BAF-bO cells cultured for 6 hours with different compounds as a function of the concentrations (expressed in ⁇ M) of these different compounds which are 4-amino 4-methyl pentyne-2 al-1 (represented by D), S-methyl 4-am ⁇ no-4-methylpent-2-yne thioate (represented by B) and the mixture of 4-am ⁇ no-4-methylpent-2-yne thioate S-methyl (at different concentrations) and methional at 200 ⁇ M (represented by *)
FIG. 3 represents the percentage of DNA fragments obtained in LNCaP cells (ATCC CRL 1740) cultured for 6 days with 4-am ⁇ no-4-methylpent-2-yne S-methyl thioate (represented by M) as a function of the concentrations of this compound (expressed in ⁇ M)
the pathologies which are characterized by an overexpression of the bcl2 gene are in particular breast cancers, B cell lymphomas, leukemias, neuroblastomas, adenocarcmomas of the prostate, prolactinomas and other pituitary adenomas
the pharmaceutical composition according to the invention comprises a physiologically acceptable medium
composition according to the invention can be carried out by enteral, parenteral, topical or ocular route.
pharmaceutical composition is packaged in a form suitable for application by a systemic route (for injection or infusion).
the composition By enteral route, the composition, more particularly the pharmaceutical composition, may be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles allowing controlled release
the composition By parenteral route, the composition may be in the form of solutions or suspensions for infusion or for injection
the compounds of formula (I) according to the invention are generally administered at a daily dose of approximately 0.001 mg / kg to 100 mg / kg in body weight in 1 to 3 doses
the pharmaceutical composition according to the invention is more particularly intended for the treatment of the skin and mucous membranes and may be in the form of ointments, creams, milks, ointments, powders, soaked tampons, solutions, gels, sprays, lotions or suspensions It can also be in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels allowing controlled release
This composition by topical route can be presented either in anhydrous form, either in aqueous form
the compounds of formula (I) are used topically or ocularly at a concentration generally between 0.0001% and 10% by weight, preferably between 0 01 and 1% by weight, relative to the total weight of the composition
compositions as described above can of course also contain inert or even pharmacodynamically active additives or combinations of these additives, and in particular methional, numerous antineoplastic agents, such as for example dexamethasone, cyclophosphamide, cisplatin, etoposide and BCNU (N, N-B ⁇ s (2-chloroethyl) -N-n ⁇ trosourea), which are also capable of inducing apoptosis
antineoplastic agents such as for example dexamethasone, cyclophosphamide, cisplatin, etoposide and BCNU (N, N-B ⁇ s (2-chloroethyl) -N-n ⁇ trosourea), which are also capable of inducing apoptosis
the present invention also relates to a pharmaceutical composition, characterized in that it comprises, in a physiologically acceptable carrier, at least one compound of formula (I), as described above, and at least one selected compound among methional and an antineoplastic agent
composition is therefore more particularly intended for treating, preventively or curatively, diseases linked to cellular hyperproliferation, such as cancers, autoimmune or allergic diseases
the pharmaceutical composition preferably comprises methional and at least one compound of formula (I), as described above
the antineoplastic agent is capable of inducing apoptosis and can thus be chosen from those mentioned above.
composition according to the invention may be in the form of a kit comprising at least one compound of formula (I), as described above, and at least one compound chosen from methional and an antineoplastic agent, the compounds of this kit being packaged separately
the cells used correspond to a BAF3 mouse lymphocyte cell line which requires interleukin 3 (IL3) to grow and which undergoes apoptosis (more than 80% of the cells) in the absence of IL3 in 16 hours [cf Collins, MKL, Marvel, J, Malde, P & Lopez-
IL3 interleukin 3
BAF3-bcl2 cells correspond to BAF3 cells transfected with the bcl2 gene
BAF3-bO cells correspond to BAF3 cells not transfected by the bcl2 gene
BAF3-bO cells undergo apoptosis (more than 80% cells) in the absence of IL3 in 16 hours
the BAF3-bcl2 cells which are therefore transfected with the bcl2 gene show no sign of apoptosis in the absence of IL3
the BAF3-bO or BAF3-bcl2 cells, cultured in the presence of IL3, are labeled by an adaptation of the method described in Wright, S et al (1992) J of Cell Biochem 48, 344-355, by incubating 2 , 5 10 5 cells / ml with 0.5 ⁇ Ci [3H] -thym ⁇ d ⁇ ne for 40 hours at 37 ° C.
% of fragments dpm of the culture medium + dpm of the DNA supernatant dpm of the culture medium + dpm of the supernatant + dpm of the pellet solubilized
the cells used correspond to a prostate adenocarcinoma cell line LNCaP (ATCC CRL 1740)
LNCaP prostate adenocarcinoma cell line
the LNCaP cells are cultured in a medium containing RPMI 1640 medium (marketed by the company GIBCO) and 7.5% serum of Ellles fetal calf are marked by an adaptation of the method described in Wright, S et al (1992) J of Cell Biochem 48, 344-355, by incubating 2.5 10 5 cells / ml with 0.5 ⁇ Ci [3H] - thymedene for 5 days at 37 ° C.

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Emergency Medicine (AREA)
Epidemiology (AREA)
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Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

EP98920590A 1997-04-08 1998-04-08 Verwendung von aminothioleestern im pharmazeutischen bereich Withdrawn EP0920310A1 (de)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
FR9704283		1997-04-08
FR9704283A FR2761606B1 (fr)	1997-04-08	1997-04-08	Utilisation de derives aminothiolesters dans le domaine pharmaceutique
PCT/FR1998/000712 WO1998044919A1 (fr)	1997-04-08	1998-04-08	Utilisation de derives aminothiolesters dans le domaine pharmaceutique

Publications (1)

Publication Number	Publication Date
EP0920310A1 true EP0920310A1 (de)	1999-06-09

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ID=9505645

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP98920590A Withdrawn EP0920310A1 (de)	1997-04-08	1998-04-08	Verwendung von aminothioleestern im pharmazeutischen bereich

Country Status (7)

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US (1)	US6028114A (de)
EP (1)	EP0920310A1 (de)
JP (1)	JP3190048B2 (de)
AU (1)	AU724253B2 (de)
CA (1)	CA2257898C (de)
FR (1)	FR2761606B1 (de)
WO (1)	WO1998044919A1 (de)

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US5994409A (en)	1997-12-09	1999-11-30	U.S. Bioscience, Inc.	Methods for treatment of neuro--and nephro--disorders and therapeutic toxicities using aminothiol compounds
US6489312B1 (en)	1999-06-15	2002-12-03	Medimmune Oncology, Inc.	Pharmaceutical formulations comprising aminoalkyl phosphorothioates
FR2809727B1 (fr) *	2000-05-31	2002-07-26	Galderma Res & Dev	Nouveaux composes aminothiolesters, compositions pharmaceutiques et cosmetiques les contenant et utilisations
US7078402B2 (en)	2000-05-31	2006-07-18	Centre National De La Recherche Scientifique (Cnrs)	Aminothiol ester compounds, pharmaceutical and cosmetics compositions containing same and uses thereof
US7053072B2 (en) *	2001-05-11	2006-05-30	Medimmune Oncology, Inc.	Methods for the administration of amifostine and related compounds
US6916892B2 (en) *	2001-12-03	2005-07-12	Fina Technology, Inc.	Method for transitioning between Ziegler-Natta and metallocene catalysts in a bulk loop reactor for the production of polypropylene
FR2983492B1 (fr) *	2011-12-06	2015-10-30	Advanced Biodesign	Procede ex vivo de purge tumorale d'un echantillon biologique
FR3047734B1 (fr) *	2016-02-17	2019-09-06	Advanced Biodesign	Procede de preparation de composes aminothiolester et leurs sels

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FR2550189B1 (fr) *	1983-08-04	1986-03-28	Centre Nat Rech Scient	Nouveaux derives acetyleniques possedant une activite d'inhibiteurs d'enzyme, leur preparation et leur application comme medicament
FR2728790B1 (fr) *	1994-12-29	1997-01-24	Cird Galderma	Composition modulant l'apoptose comprenant du methonial ou tout facteur influencant le taux intracellulaire de methonial

1997
- 1997-04-08 FR FR9704283A patent/FR2761606B1/fr not_active Expired - Lifetime
1998
- 1998-04-08 WO PCT/FR1998/000712 patent/WO1998044919A1/fr not_active Ceased
- 1998-04-08 AU AU73398/98A patent/AU724253B2/en not_active Ceased
- 1998-04-08 EP EP98920590A patent/EP0920310A1/de not_active Withdrawn
- 1998-04-08 US US09/202,068 patent/US6028114A/en not_active Expired - Fee Related
- 1998-04-08 JP JP54246398A patent/JP3190048B2/ja not_active Expired - Fee Related
- 1998-04-08 CA CA002257898A patent/CA2257898C/fr not_active Expired - Fee Related

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Title
See references of WO9844919A1 *

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JP3190048B2 (ja)	2001-07-16
WO1998044919A1 (fr)	1998-10-15
US6028114A (en)	2000-02-22
AU7339898A (en)	1998-10-30
JPH11513048A (ja)	1999-11-09
AU724253B2 (en)	2000-09-14
CA2257898A1 (fr)	1998-10-15
FR2761606B1 (fr)	1999-05-14
FR2761606A1 (fr)	1998-10-09
CA2257898C (fr)	2003-10-21

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