WO1984002908A1 - Carbostyriloximinopropanolamines utiles comme medicaments et procede pour leur preparation - Google Patents

Carbostyriloximinopropanolamines utiles comme medicaments et procede pour leur preparation Download PDF

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Publication number
WO1984002908A1
WO1984002908A1 PCT/FR1984/000007 FR8400007W WO8402908A1 WO 1984002908 A1 WO1984002908 A1 WO 1984002908A1 FR 8400007 W FR8400007 W FR 8400007W WO 8402908 A1 WO8402908 A1 WO 8402908A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbostyril
methyl ketone
ketone oxime
propyl
methyl
Prior art date
Application number
PCT/FR1984/000007
Other languages
English (en)
French (fr)
Inventor
Nourdine Amlaiky
Gerard Leclerc
Guy Andermann
Original Assignee
Pos Lab
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 Pos Lab filed Critical Pos Lab
Priority to AU24158/84A priority Critical patent/AU2415884A/en
Publication of WO1984002908A1 publication Critical patent/WO1984002908A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof

Definitions

  • the present invention relates to new beta-blocking compounds with a carbostyril nucleus, to their methods of preparation and to their applications in the therapeutic field, in particular as medicaments useful in the cardiovascular and ophthalmic fields.
  • the beta-blocking substances currently marketed belong to:
  • Ateolol of formula:
  • This product is used in the form of eye drops in the treatment of glaucoma and marketed in the form of tablets in the treatment of high blood pressure.
  • the subject of the invention is, as a new product, carbostyriloximinopropanolamines of general formula (A)
  • R 1 is a hydrogen atom, or an alkyl radical containing from 1 to 3 carbon atoms,
  • R 2 is a hydrogen atom, or an alkyloxy, aryloxy radical, containing from 1 to 10 carbon atoms, aliphatic or aromatic,
  • R 3 is an optionally substituted alkyl or arylalkyl radical containing from 2 to 30 carbon atoms, linear or branched, aliphatic or aromatic.
  • arylalkyl radical denotes above radicals preferably comprising from 1 to 6 carbon atoms in the aliphatic part, the aryl part preferably being the phenyl radical, for example benzyl radical, optionally substituted.
  • Compounds A can be saturated at 3,4 or have a double bond at this level.
  • a subject of the invention is also the therapeutically acceptable acid salts of these compounds.
  • These are salts of mineral acids such as phosphoric acid or organic acids, in particular monocarboxylic or dicarboxylic, maleic and fumaric, for example.
  • the salts may be the salts corresponding to the neutralization of one or more of the acid functions.
  • the compounds of the invention have beta-blocking properties. They find a particularly interesting application in the treatment of cardiovascular disorders and in the field of ophthalmology.
  • the compounds of the invention are obtained from the corresponding substituted acetyl-5, R 1 , R 2 (B) of formula
  • R 1 and R 2 are both a hydrogen atom.
  • Extract with chloroform dry over MgSO 4 .
  • Evaporate Chromatograph the product on silica using chloroform as the eluent.
  • Example 1 O- (tertbutylamino- & ol-2 propyl) (8-benzyloxy-carbostyril) -5 methyl ketone oxime.
  • Into a 250 ml flask add 3.6 g (0.01 mole of [(8-benzyloxy-corbostyril) -5 methyl ketone oxime] -3 epoxypropane -1.2 (X),
  • the base is converted into phosphate by dissolving it in water, adding phosphoric acid. Add acetonitrile, allow to crystallize.
  • Example 3 O- (isopropylamino-1 ol-2 propyl) (benzyloxy-8 carbostyril) -5 methyl ketone oxime. Made from [(8-benzyloxy-carbostyril) -5 methyl ketone oxime] -3 epoxypropane -1,2 (X) and isopropylamine, in accordance with Example 1. Yield 60%.
  • Example 5 O- [( ⁇ -methyl ⁇ -phenylethylamino-1) ol-2 propyl] (benzyloxy-8 carbos tyril) -5 methyl ketone oxime.
  • Example 6 Oxalate of O- [( ⁇ -methyl p-phenylethylamino-1) ol-2 propyl] (8-hydroxycarbostyril) -5 methyl ketone oxime (compound No. 5).
  • Example 8 O- [(3,4-dimethoxyphenylethylamino -1) ol-2 propyl] oxalate (8-hydroxy carbostyril) -5 methyl ketone oxime (compound No. 6).
  • Example 9 O- [(3,4-dimethoxyphenylethylamino) -1 ol-2 propyl] (8-benzyloxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime.
  • Example 11 O - [( ⁇ -methyl ⁇ -phenylethylamino) -1 ol-2 propyl] (benzyloxy-8 dihydro -3.4 carbos tyril) -5 methyl cetone oxime.
  • Example 14 O- (1-tertubylamino-2-ol-propyl) oxalate (8-methoxy-3,4-dihydro-carbos tyril) -5 methyl ketone oxime (compound No. 10). Made from (8-methoxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime -3 epoxypropane -1,2 (V) and tertbutylamine, in accordance with Example 1.
  • Example 17 O- (1-isopropylamino-2-ol-propyl) oxalate (8-methoxy-1-methyl-carbostyril) -5 methyl ketone oxime (compound No. 2).
  • the present invention also relates to the use of the compounds of formula A as a medicament, as well than pharmaceutical compositions containing these drugs.
  • compositions according to the present invention can comprise one or more compounds of formula A optionally in combination with other active ingredients.
  • compositions according to the invention are particularly suitable for use as eye drops.
  • the eye drops can contain various other constituents with various functions and playing in particular the roles: of isotonic agents, such as for example sodium chloride or chloride potassium; buffering agents, such as for example sodium or potassium phosphates, sodium borate; optionally preservatives such as non-toxic mercury salts, quaternary ammoniums, chlorhexidine salts.
  • isotonic agents such as for example sodium chloride or chloride potassium
  • buffering agents such as for example sodium or potassium phosphates, sodium borate
  • optionally preservatives such as non-toxic mercury salts, quaternary ammoniums, chlorhexidine salts.
  • the compositions are diluted with distilled water.
  • the usual dose which varies according to the subject to be treated and the condition in question, will be of the order of 1 to 4 applications per day of an eye drop containing 0.1% to 1% of active principle in humans. .
  • the efficacy of the compounds according to the invention is demonstrated by comparative tests which are described in more detail below.
  • the reference compound chosen is Timolol, that is to say the compound of basic formula:
  • the doses of the two compounds are equivalent to 0.5 g% of base.
  • the trials are carried out on series of New Zealand albino rabbits weighing 3.5 to 4.5 kg, operating in double-blind mode, with therapeutic rests between treatments. Measures without treatment were also made, by local anesthesia of the eye of rabbits with posicain, in order to be able to follow the evolution of the intraocular pressure (IOP) in animals.
  • Glaucoma was caused in the right eyes of rabbits by intraocular injection of: alpha-chymo tryps ine according to the SEARS method (Am. J. Ophtalmo 1974, 71p. 378) modified by VAREILLES & Al (Am. J / ophtalmo 1979, 210, P.561).
  • the presence of glaucoma is characterized by the determination of the flow coefficient, from tonographic measurements, the eye being considered to be glaucomatous when this coefficient is less than 0.12 (ZANEN, J .FR. Ophtalmol 1980, 3,9 , pp. 209-218).
  • the IOPs were measured every half hour during the first three hours and then every hour until the 7th hour.
  • the effect of local thesis donkeys was measured, each measurement being made on both eyes at the same time, the results of the left untreated eye being used as control tests.
  • STATISTICAL ANALYSIS determination of the mean and standard deviation of the local anesthetic effect (expressed in number of pulses on the cornea) obtained after instillation of the two compounds A and B in the healthy eye of 8 rabbits.
  • compositions according to the invention on the cornea is generally zero or very weak for the compounds of the invention unlike the case of timolol.
  • hypotensive action does not vary significantly with the concentration for all the products tested.
  • the new eye drops according to the invention have therefore been found to be, in general, excellent therapeutic agents for the treatment of glaucoma.
  • compositions of two eye drops according to the invention are given below, having given excellent results when they have been administered to patients with glaucoma, at the rate of two drops per 24 hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/FR1984/000007 1983-01-17 1984-01-10 Carbostyriloximinopropanolamines utiles comme medicaments et procede pour leur preparation WO1984002908A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU24158/84A AU2415884A (en) 1983-01-17 1984-01-10 Carbostyriloximinopropanolamines utiles comme medicaments et procede pour leur preparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR8300745A FR2539413A1 (fr) 1983-01-17 1983-01-17 Carbostyriloximinopropanolamines utiles comme medicaments et procede pour leur preparation

Publications (1)

Publication Number Publication Date
WO1984002908A1 true WO1984002908A1 (fr) 1984-08-02

Family

ID=9285057

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FR1984/000007 WO1984002908A1 (fr) 1983-01-17 1984-01-10 Carbostyriloximinopropanolamines utiles comme medicaments et procede pour leur preparation

Country Status (5)

Country Link
EP (1) EP0131595A1 (enrdf_load_stackoverflow)
FR (1) FR2539413A1 (enrdf_load_stackoverflow)
IN (1) IN161149B (enrdf_load_stackoverflow)
IT (1) IT1174468B (enrdf_load_stackoverflow)
WO (1) WO1984002908A1 (enrdf_load_stackoverflow)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0369944A1 (de) * 1988-11-18 1990-05-23 Ciba-Geigy Ag Substituierte Oxadiaminobutane
EP0240015A3 (en) * 1986-04-02 1990-10-24 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives, process for preparing them, pharmaceutical composition, and use
US5169867A (en) * 1990-04-11 1992-12-08 Ciba-Geigy Corporation Hydroxylamine compounds
US5434164A (en) * 1986-04-02 1995-07-18 Otsuka Pharmaceutical Co. Ltd. Carbostyril derivatives and salts thereof and pharmaceutical compositions for inhibiting adhesion of thrombocytes
WO2004050657A3 (en) * 2002-11-27 2004-11-25 Artesian Therapeutics Inc COMPOUNDS WITH MIXED PDE-INHIBITORY AND β-ADRENERGIC ANTAGONIST OR PARTIAL AGONIST ACTIVITY FOR TREATMENT OF HEART FAILURE

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2344538A1 (fr) * 1976-03-17 1977-10-14 Otsuka Pharma Co Ltd Nouveaux derives de carbostyrile, utiles notamment comme b-bloquants cardio-selectifs, et leur procede de preparation
FR2447721A1 (fr) * 1979-01-30 1980-08-29 Otsuka Pharma Co Ltd Compositions pour le traitement du glaucome, contenant un derive de carbostyrile comme constituant actif
EP0020765A1 (fr) * 1978-07-14 1981-01-07 Otsuka Pharmaceutical Co., Ltd. Remede contre le glaucome

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2344538A1 (fr) * 1976-03-17 1977-10-14 Otsuka Pharma Co Ltd Nouveaux derives de carbostyrile, utiles notamment comme b-bloquants cardio-selectifs, et leur procede de preparation
EP0020765A1 (fr) * 1978-07-14 1981-01-07 Otsuka Pharmaceutical Co., Ltd. Remede contre le glaucome
FR2447721A1 (fr) * 1979-01-30 1980-08-29 Otsuka Pharma Co Ltd Compositions pour le traitement du glaucome, contenant un derive de carbostyrile comme constituant actif

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0240015A3 (en) * 1986-04-02 1990-10-24 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives, process for preparing them, pharmaceutical composition, and use
US5008274A (en) * 1986-04-02 1991-04-16 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives and salts thereof and pharmaceutical composition for inhibiting adhesion of thrombocytes
US5434164A (en) * 1986-04-02 1995-07-18 Otsuka Pharmaceutical Co. Ltd. Carbostyril derivatives and salts thereof and pharmaceutical compositions for inhibiting adhesion of thrombocytes
EP0369944A1 (de) * 1988-11-18 1990-05-23 Ciba-Geigy Ag Substituierte Oxadiaminobutane
US5169867A (en) * 1990-04-11 1992-12-08 Ciba-Geigy Corporation Hydroxylamine compounds
WO2004050657A3 (en) * 2002-11-27 2004-11-25 Artesian Therapeutics Inc COMPOUNDS WITH MIXED PDE-INHIBITORY AND β-ADRENERGIC ANTAGONIST OR PARTIAL AGONIST ACTIVITY FOR TREATMENT OF HEART FAILURE

Also Published As

Publication number Publication date
IN161149B (enrdf_load_stackoverflow) 1987-10-10
FR2539413A1 (fr) 1984-07-20
IT1174468B (it) 1987-07-01
EP0131595A1 (fr) 1985-01-23
FR2539413B1 (enrdf_load_stackoverflow) 1985-05-03
IT8419167A0 (it) 1984-01-16

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