+

WO2008061647A1 - Use of a compound as vegf inhibitor - Google Patents

Use of a compound as vegf inhibitor Download PDF

Info

Publication number
WO2008061647A1
WO2008061647A1 PCT/EP2007/009767 EP2007009767W WO2008061647A1 WO 2008061647 A1 WO2008061647 A1 WO 2008061647A1 EP 2007009767 W EP2007009767 W EP 2007009767W WO 2008061647 A1 WO2008061647 A1 WO 2008061647A1
Authority
WO
WIPO (PCT)
Prior art keywords
chloro
guanidine
dimethoxybenzylideneamino
acceptable salt
pharmacologically acceptable
Prior art date
Application number
PCT/EP2007/009767
Other languages
French (fr)
Other versions
WO2008061647A8 (en
Inventor
Torbjörn Lundstedt
Gunilla EKSTRÖM
Original Assignee
Acure Pharma Ab
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 Acure Pharma Ab filed Critical Acure Pharma Ab
Publication of WO2008061647A1 publication Critical patent/WO2008061647A1/en
Publication of WO2008061647A8 publication Critical patent/WO2008061647A8/en

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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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

Definitions

  • the present invention relates to the use of N-(2-chloro-3,4-dimethoxybenzylidene- amino)-guanidine for the treatment, hindrance or prevention of blood vessel development and formation (angiogenesis).
  • benzylideneamino guanidines known in the art have shown anti- depressive effects (US 4060640). Examples of other pharmacologically active guanidines known in the art are described in patents US3982020, GBl 223491, WO02/11715, WO02/81430 and WO02/80896. Other application areas are also known in the art and are described in patents US3896332, DEl 165013, and US3941825. Even though the benzylideneamino guanidines known from the prior art are structurally similar to the compound in the present invention, they have never been reported as, and there is no suggestion that they might be, effective to inhibit vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • VEGF Vascular Endothelial Growth Factor
  • the invention provides N-(2-chloro-3,4-dimethoxybenzylideneamino)-guanidine and salts thereof for use as a VEGF inhibitor.
  • the invention further provides the use of N-(2-chloro-3,4-dimethoxybenzylidene- amino)-guanidine in the manufacture of a medicament for use as a VEGF inhibitor.
  • the invention also relates to methods for the manufacture of and pharmaceutical preparations comprising N-(2-chloro-3,4-dimethoxybenzylideneamino)-guanidine, and salts thereof, as well as to their use in medical and veterinary practice related to inhibition of vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • Such practice may include, but is not limited to, the inhibition or prevention of blood vessel formation and the treatment of angiogenesis.
  • This example illustrates the potency of N-(2-chloro-3,4-dimethoxybenzylidene- amino)-guanidine and its therapeutically active acid addition salts for treatment of blood vessel formation.
  • the tissue was digested with collagenase type I, and the cells were allowed to proliferate for 7-10 days before stimulation and exposure to the compounds.
  • the culture consisted of. a mixed cell population with the principal constituents being fibroblasts and macrophages (Andersson, S. E., Johansson, L. H., Lexmuller, K., and Ekstrom, G. M. 2000. Anti-arthritic effect of methotrexate: is it really mediated by adenosine? Eur J Pharm Sci 9:333-343).
  • the cells were stimulated with IL-I with simultaneous addition of AMAP 102. After three days of stimulation and compound exposure, the supernatants were collected, and the VEGF content measured using ELISA (DuoSet ® rat VEGF, R&D Systems, MN, USA). The cell viability was taken into account using the Cell Proliferation Reagent WST-I.
  • Suitable forms of pharmaceutical preparation for administration according to the invention include for example tablets, capsules, solutions, syrups, or emulsions.
  • the content of the pharmaceutically effective compound should desirably be in the range from 0.1 to 5 wt. % , of the total composition.
  • the preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine capsule), as a solution or suspension.
  • Suitable tablets may be obtained, for example, by mixing the active substance(s) with known carriers, diluents or excipients, such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • the tablets may also comprise several layers.
  • Coated tablets may suitably be prepared by coating cores produced similarly to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
  • Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as /7-hydroxybenzoates.
  • a sweetener such as saccharin, cyclamate, glycerol or sugar
  • a flavour enhancer e.g. a flavouring such as vanillin or orange extract.
  • suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as /7-hydroxybenzoates.
  • Capsules containing one the active substance may for example be prepared by mixing the active substance with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g.
  • kaolins kaolins, clays, talc, chalk
  • synthetic mineral powders e.g. highly dispersed silicic acid and silicates
  • sugars e.g. cane sugar, lactose and glucose
  • emulsifiers e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone
  • lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
  • the tablets may contain, in addition to the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like.
  • additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like.
  • lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process.
  • the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
  • a solution for parenteral administration by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable acid addition salt of the active substance preferably in a concentration of 0.1 % to about 5 % by weight.
  • These solutions may also contain stabilising agents and/or buffering agents.
  • Example of a preparation comprising a capsule
  • Example of a suitable tablet formulation Example of a suitable tablet formulation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

There is disclosed the use of N-(2-chloro-3,4-dimethoxybenzylideneamino)guanidine or a pharmacologically acceptable salt thereof as an agent for use in the inhibition of Vascular Endothelial Growth Factor (VEGF). Such an agent is likely to be of application in the treatment or prevention of undesired blood vessel formation during tumour growth and/or in inflammatory conditions.

Description

Use of a compound as VEGF inhibitor.
The present invention relates to the use of N-(2-chloro-3,4-dimethoxybenzylidene- amino)-guanidine for the treatment, hindrance or prevention of blood vessel development and formation (angiogenesis).
A number of benzylideneamino guanidines known in the art have shown anti- depressive effects (US 4060640). Examples of other pharmacologically active guanidines known in the art are described in patents US3982020, GBl 223491, WO02/11715, WO02/81430 and WO02/80896. Other application areas are also known in the art and are described in patents US3896332, DEl 165013, and US3941825. Even though the benzylideneamino guanidines known from the prior art are structurally similar to the compound in the present invention, they have never been reported as, and there is no suggestion that they might be, effective to inhibit vascular endothelial growth factor (VEGF).
Vascular Endothelial Growth Factor (VEGF) is a mitogen primarily for vascular endothelial cells and is structurally related to platelet-derived growth factor. It is a stimulator of endothelial cell proliferation that has been implicated in the vascularisation and growth of a variety of tumours, and is believed a major regulator of tumour angiogenesis in vivo. It is also implicated in some inflammatory conditions. For the treatment (reduction, prevention or hindrance) of undesired blood vessel formation during tumour growth and/or in inflammatory conditions, a VEGF inhibitor is likely to play a useful role.
We have now surprisingly found that N-(2-chloro-3,4-dimethoxybenzylideneamino)- guanidine and salts thereof can act as a VEGF inhibitor. Accordingly, in one aspect, the invention provides N-(2-chloro-3,4 dimethoxybenzylideneamino)-guanidine and salts thereof for use as a VEGF inhibitor. The invention further provides the use of N-(2-chloro-3,4-dimethoxybenzylidene- amino)-guanidine in the manufacture of a medicament for use as a VEGF inhibitor.
The invention also relates to methods for the manufacture of and pharmaceutical preparations comprising N-(2-chloro-3,4-dimethoxybenzylideneamino)-guanidine, and salts thereof, as well as to their use in medical and veterinary practice related to inhibition of vascular endothelial growth factor (VEGF). Such practice may include, but is not limited to, the inhibition or prevention of blood vessel formation and the treatment of angiogenesis.
EXAMPLES
The following examples are intended to illustrate but not to limit the scope of the invention.
Example 1
Preparation of N-(2-chloro-3,4-dimethoxybenzylideneamino)guanidine A solution of 2-chloro-3,4-dimethoxybenzaldehyde (1.0 g, 5 mmol), aminoguanidine bicarbonate (0.68 g, 5 mmol) and acetic acid (1 ml), in 15 ml of methanol was heated at reflux for 10 min. The reaction mixture was cooled down to 0 0C and the residue was filtered off.. The filtrate was evaporated under vacuum and the product was crystallised from ethanol. Yield of the title compound was 1.1 g (70%), M.p. 198-200 0C. Example 2
This example illustrates the potency of N-(2-chloro-3,4-dimethoxybenzylidene- amino)-guanidine and its therapeutically active acid addition salts for treatment of blood vessel formation.
Method
In rats with induced arthritis, antigen induced arthritis (AIA), pannus tissue from knee- joints was taken on day four after challenge. (Andersson, S. E., Lexmuller, K., and Ekstrom, G. M. 1998. Physiological characterization of mBSA antigen induced arthritis in the rat. I. Vascular leakiness and pannus growth. J Rheumatol 25:1772-1777).
The tissue was digested with collagenase type I, and the cells were allowed to proliferate for 7-10 days before stimulation and exposure to the compounds. The culture consisted of. a mixed cell population with the principal constituents being fibroblasts and macrophages (Andersson, S. E., Johansson, L. H., Lexmuller, K., and Ekstrom, G. M. 2000. Anti-arthritic effect of methotrexate: is it really mediated by adenosine? Eur J Pharm Sci 9:333-343).
The cells were stimulated with IL-I with simultaneous addition of AMAP 102. After three days of stimulation and compound exposure, the supernatants were collected, and the VEGF content measured using ELISA (DuoSet® rat VEGF, R&D Systems, MN, USA). The cell viability was taken into account using the Cell Proliferation Reagent WST-I.
The extent to which N-(2-chloro-3,4-dimethoxybenzylideneamino)guanidine reduced the ILl -induced VEGF production in primary rat synoviocytes in a dose-dependent manner in the 25-100 μM range is shown in Fig. l hereto.
Suitable forms of pharmaceutical preparation for administration according to the invention include for example tablets, capsules, solutions, syrups, or emulsions. The content of the pharmaceutically effective compound should desirably be in the range from 0.1 to 5 wt. % , of the total composition. The preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine capsule), as a solution or suspension.
It is preferable if the composition is administered orally. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known carriers, diluents or excipients, such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may suitably be prepared by coating cores produced similarly to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as /7-hydroxybenzoates.
Capsules containing one the active substance may for example be prepared by mixing the active substance with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
For oral administration the tablets may contain, in addition to the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions, the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
A solution for parenteral administration by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable acid addition salt of the active substance preferably in a concentration of 0.1 % to about 5 % by weight. These solutions may also contain stabilising agents and/or buffering agents.
EXAMPLE 3
Example of a preparation comprising a capsule
Per capsule Active ingredient, as salt 5 mg
Lactose 250 mg
Starch 120 mg Magnesium stearate 5 mg
Total up to 380 mg In case higher amounts of active ingredient, the amount of lactose used may be reduced. The ingredients are then packed into a gelatin capsule.
Example of a suitable tablet formulation.
Per tablet
Active ingredient, as salt 5 mg
Potato starch 238 mg
Colloidal Silica 10 mg
Talc 20 mg
Magnesium stearate 2 mg
5 % aqueous solution of gelatine 25 me
Total up to 300 mg

Claims

Claims:
1. N-(2-chloro-3,4-dimethoxybenzylideneamino)guanidine or a pharmacologically acceptable salt thereof for use as a VEGF inhibitor.
2. N-(2-chloro-3,4-dimethoxybenzylideneamino)guanidine or a pharmacologically acceptable salt thereof for use to inhibit or prevent blood vessel formation.
3. N-(2-chloro-3,4-dimethoxybenzylideneamino)guanidine or a pharmacologically acceptable salt thereof for the treatment of angiogenesis.
4. The use of N-(2-chloro-3,4-dimethoxybenzylideneamino)guanidine or a pharmacologically acceptable salt thereof in the preparation of a medicament for use as a VEGF inhibitor.
5. The use of N-(2-chloro-3,4-dimethoxybenzylideneamino)guanidine or a pharmacologically acceptable salt thereof in the preparation of a medicament for use to inhibit or prevent blood vessel formation.
6. The use of N-(2-chloro-3,4-dimethoxybenzylideneamino)guanidine or a pharmacologically acceptable salt thereof in the preparation of a medicament for the treatment of angiogenesis.
7. A method of inhibiting the action of VEGF in a subject which comprises administering to said subject an effective amount of N-(2-chloro-3,4- dimethoxybenzylideneamino)guanidine or a pharmacologically acceptable salt thereof.
8. A method of inhibiting or preventing blood vessel formation in a subject which comprises administering to said subject an effective amount of N-(2- chloro-3,4-dimethoxybenzylideneamino)guanidine or a pharmacologically acceptable salt thereof.
9. A method of treating angiogenesis in a subject which comprises administering to said subject an effective amount of N-(2-chloro-3,4- dimethoxybenzylideneamino)guanidine or a pharmacologically acceptable salt thereof.
PCT/EP2007/009767 2006-11-23 2007-11-12 Use of a compound as vegf inhibitor WO2008061647A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0623381.1 2006-11-23
GBGB0623381.1A GB0623381D0 (en) 2006-11-23 2006-11-23 Use of a compound as VEGF inhibitor

Publications (2)

Publication Number Publication Date
WO2008061647A1 true WO2008061647A1 (en) 2008-05-29
WO2008061647A8 WO2008061647A8 (en) 2008-11-27

Family

ID=37636386

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/009767 WO2008061647A1 (en) 2006-11-23 2007-11-12 Use of a compound as vegf inhibitor

Country Status (2)

Country Link
GB (1) GB0623381D0 (en)
WO (1) WO2008061647A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010108665A1 (en) 2009-03-24 2010-09-30 Life & Brain Gmbh Promotion of neuronal integration in neural stem cell grafts
WO2011012868A1 (en) * 2009-07-31 2011-02-03 Anamar Ab Compounds for treatment of inflammation
WO2016001390A1 (en) 2014-07-02 2016-01-07 Inflectis Bioscience O-alkyl-benzylideneguanidine derivatives and therapeutic use for the treatment of disorders associated an accumulation of misfolded proteins
WO2019215470A1 (en) 2018-05-09 2019-11-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of guanabenz or derivates thereof for the treatment of type i ifn-dependent pathologies
EP3721877A1 (en) 2014-07-02 2020-10-14 InFlectis BioScience Novel therapeutic uses of benzylideneguanidine derivatives for the treatment of proteopathies

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5599984A (en) * 1994-01-21 1997-02-04 The Picower Institute For Medical Research Guanylhydrazones and their use to treat inflammatory conditions
WO1998023267A1 (en) * 1996-11-26 1998-06-04 Wapharm Ab Use of hydroxyguanidines
WO2002011715A2 (en) * 2000-08-07 2002-02-14 Melacure Therapeutics Ab The use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5599984A (en) * 1994-01-21 1997-02-04 The Picower Institute For Medical Research Guanylhydrazones and their use to treat inflammatory conditions
WO1998023267A1 (en) * 1996-11-26 1998-06-04 Wapharm Ab Use of hydroxyguanidines
WO2002011715A2 (en) * 2000-08-07 2002-02-14 Melacure Therapeutics Ab The use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MACHADO R D P ET AL: "Mechanisms of angiotensin-(1-7)-induced inhibition of angiogenesis", AMERICAN JOURNAL OF PHYSIOLOGY - REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY 2001 US, vol. 280, no. 4 49-4, 2001, pages R994 - R1000, XP008089180, ISSN: 0363-6119 *
PHILLIPS P G ET AL: "Nitric oxide modulates capillary formation at the endothelial cell-tumor cell interface", AMERICAN JOURNAL OF PHYSIOLOGY - LUNG CELLULAR AND MOLECULAR PHYSIOLOGY 2001 US, vol. 281, no. 1 25-1, 2001, pages L278 - L290, XP008089179, ISSN: 1040-0605 *
PRUSIS, PETERIS ET AL: "Synthesis and Quantitative Structure-Activity Relationship of Hydrazones of N-Amino-N'-hydroxyguanidine as Electron Acceptors for Xanthine Oxidase", JOURNAL OF MEDICINAL CHEMISTRY , 47(12), 3105-3110 CODEN: JMCMAR; ISSN: 0022-2623, 2004, XP008089162 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010108665A1 (en) 2009-03-24 2010-09-30 Life & Brain Gmbh Promotion of neuronal integration in neural stem cell grafts
WO2011012868A1 (en) * 2009-07-31 2011-02-03 Anamar Ab Compounds for treatment of inflammation
GB2473095A (en) * 2009-07-31 2011-03-02 Anamar Ab 5-HT2B receptor antagonists for the treatment of inflammation or pain
WO2016001390A1 (en) 2014-07-02 2016-01-07 Inflectis Bioscience O-alkyl-benzylideneguanidine derivatives and therapeutic use for the treatment of disorders associated an accumulation of misfolded proteins
CN106488907A (en) * 2014-07-02 2017-03-08 英费列特斯生命科学公司 O alkyl benzylidene guanidine derivatives and its treatment have the therapeutic use of related disorders with the accumulation of misfolded protein matter
EP3721877A1 (en) 2014-07-02 2020-10-14 InFlectis BioScience Novel therapeutic uses of benzylideneguanidine derivatives for the treatment of proteopathies
CN106488907B (en) * 2014-07-02 2021-01-29 英费列特斯生命科学公司 O-alkyl-benzylidene guanidine derivatives and their therapeutic use for the treatment of diseases associated with accumulation of misfolded proteins
WO2019215470A1 (en) 2018-05-09 2019-11-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of guanabenz or derivates thereof for the treatment of type i ifn-dependent pathologies

Also Published As

Publication number Publication date
GB0623381D0 (en) 2007-01-03
WO2008061647A8 (en) 2008-11-27

Similar Documents

Publication Publication Date Title
EP1940364B1 (en) Capsule formulation of pirfenidone and pharmaceutically acceptable excipients
RU2723642C1 (en) Compounds of a metabolite of an angiotensin ii receptor antagonist and a nep inhibitor, and methods for preparing them
HU199302B (en) Process for producing synergic pharmaceutical compositions having hypotensive activity
BRPI0715492A2 (en) use of direct thrombin inhibitors
EP2595620A2 (en) Benzenesulfonamide-compound treatment of a pathological condition linked to an excessive effect of tnf
WO2002017913A1 (en) Medicinal compositions for preventing or treating heart failure
AU2012290987B2 (en) Left ventricular diastolic function improving agent
EA012594B1 (en) Amino acid salts of rosiglitazone
CN101412690A (en) Medicinal acid addition salt of silodosin, and preparation and medicament use thereof
WO2008061647A1 (en) Use of a compound as vegf inhibitor
WO1998027982A1 (en) Composition containing ascorbic acid
MXPA06004434A (en) Novel medical uses of compounds showing cb1.
CN108771662A (en) Application of pterostilbene in preparation of medicine for preventing and treating hyperuricemia nephropathy
CZ20001081A3 (en) Endothelin antagonist and beta-receptor blocker as compound preparations
EA007952B1 (en) Use of irbesartan for the preparation of medicaments that are used to prevent or treat pulmonary hypertension
CN118678960A (en) Methods and compositions for treating cancer
CN108774220B (en) Compounds for treating myocardial ischemia and uses thereof
SK227092A3 (en) Pharmaceutical agent against the high blood pressure
JPH0148245B2 (en)
EP4181873A1 (en) Modulation of drug-drug interactions of vadadustat
KR100817932B1 (en) Anti-vascular restenosis agent containing verbamin as an active ingredient
BRPI0611096A2 (en) (5z) -5- (6-quinoxalinylmethylidene) -2 - [(2,6-dichlorophenyl) mino] -1,3-thiazol-4 (5h) -one
AU2014240300C1 (en) Capsule Formulation of Pirfenidone and Pharmaceutically Acceptable Excipients
JPH0133084B2 (en)
JP3685508B2 (en) Anti-urease agent

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07819756

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07819756

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载