FR2522502A2 - N-Substd. 4-aminoethoxy-2-methyl-5-isopropyl-phenol derivs. - useful as alpha blockers and platelet aggregation inhibitors - Google Patents

N-Substd. 4-aminoethoxy-2-methyl-5-isopropyl-phenol derivs. - useful as alpha blockers and platelet aggregation inhibitors Download PDF

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Publication number
FR2522502A2
FR2522502A2 FR8203796A FR8203796A FR2522502A2 FR 2522502 A2 FR2522502 A2 FR 2522502A2 FR 8203796 A FR8203796 A FR 8203796A FR 8203796 A FR8203796 A FR 8203796A FR 2522502 A2 FR2522502 A2 FR 2522502A2
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France
Prior art keywords
sep
substd
isopropyl
platelet aggregation
aminoethoxy
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.)
Granted
Application number
FR8203796A
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French (fr)
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FR2522502B2 (en
Inventor
Christian Courtiol
Marie-Helene Creuzet
Claude Feniou
Gisele Prat
Henri Pontagnier
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Cortial SA
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Cortial SA
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Filing date
Publication date
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Priority to FR8203796A priority Critical patent/FR2522502A2/en
Priority to DE8282450006T priority patent/DE3264523D1/en
Priority to EP82450006A priority patent/EP0062596B1/en
Priority to PT74710A priority patent/PT74710B/en
Priority to CA000400482A priority patent/CA1196650A/en
Priority to ES511220A priority patent/ES8304062A1/en
Priority to OA57651A priority patent/OA07063A/en
Priority to US06/366,133 priority patent/US4818772A/en
Publication of FR2522502A2 publication Critical patent/FR2522502A2/en
Application granted granted Critical
Publication of FR2522502B2 publication Critical patent/FR2522502B2/fr
Granted legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring

Abstract

N-R2-N-CHR3-2-(2-isopropyl -4-OR1-5-methylphenoxy) ethylamines of formula (I) are new (where R1 is H, Me or COMe; R2 is H or Me; R3 is phenoxymethyl, 2,6-dimethoxyphenoxymethyl, 1,4-benzodioxan-2-yl or CH2CH2Ar, where Ar is phenyl opt. substd. by one or more substituents such as halogen, OH and OMe). (I) are alpha-1 blockers with long-lasting activity and low toxicity, and they also inhibit blood platelet aggregation. They can be used to treat arterial hypertension, peripheral vascular disease, asthma, glaucoma, thrombosis, etc. Effective doses are 1-100 mg/day (p.o.) and 0.1-10 mg (i.v.).

Description

te présent certificat d'addition au brevet français n 8106832 a pour objet l'application des produits de formule génerale (I)

Figure img00010001

avec R1 = H, CH3, COCH3
R2 = H, CH3
Figure img00010002

sous forme de base libre ou de sels pharmacologiquement compatibles, à la prévention et au traitement des thromboses.The present French patent application No. 8106832 relates to the application of the products of general formula (I)
Figure img00010001

with R1 = H, CH3, COCH3
R2 = H, CH3
Figure img00010002

as a free base or pharmacologically compatible salts, for the prevention and treatment of thromboses.

Les produits de formule (I) sont décrits dans le brevet n 8106832 pour leur application én thérapeutique alpha bloquante et antihypertensive. Nous avons maintenant découvert que ces produits présentaient une activité antiagrégante plaquettaire permettant leur emploi en thérapeutique thrombolytique. The products of formula (I) are described in patent No. 8106832 for their application in alpha blocking and antihypertensive therapy. We have now discovered that these products have antiplatelet platelet activity for use in thrombolytic therapy.

L'activité antiagrégante plaquettaire a été mise en évidence sur plaquettes humaines non lavées de sujet adulte normal etudiees dans leur milieu naturel (plasma riche en plaquettes). L'agent inhibiteur est teste en présence de 4 types d'agents agrégants (ADP, adrénaline, collagene, acide arachidonique) à diverses concentrations. Antiplatelet activity was detected in unwashed human platelets of normal adult subjects studied in their natural environment (platelet-rich plasma). The inhibitory agent is tested in the presence of 4 types of aggregating agents (ADP, adrenaline, collagen, arachidonic acid) at various concentrations.

Dans chaque cas on établit une courbe dose réponse. Le pouvoir inhibiteur de la substance est caractérisé par la dose correspondant à 50 Z d'inhibition ou 150
Le tableau ci-dessous indique pour certains produits de la présente invention les valeurs des 150 exprimées en M/1 vis à vis des 4 agents agrégats et comparativement a la ticlopidine prise comme référence.

Figure img00020001
In each case, a dose response curve is established. The inhibitory power of the substance is characterized by the dose corresponding to 50% inhibition or 150% inhibition.
The table below indicates for certain products of the present invention the values of the 150 expressed in M / 1 with respect to the 4 aggregating agents and compared to the ticlopidine taken as reference.
Figure img00020001

<tb> Produit <SEP> * <SEP> formule <SEP> I <SEP> avec <SEP> * <SEP> formule <SEP> I <SEP> avec <SEP> * <SEP> *
<tb> <SEP> R1 <SEP> CH, <SEP> *R1 <SEP> =H
<tb> * <SEP> testé <SEP> * <SEP> 1 <SEP> CH3 <SEP> * <SEP> R1 <SEP> H <SEP> * <SEP> Ticlopidine <SEP> *
<tb> * <SEP> * <SEP> R <SEP> = <SEP> CH3 <SEP> OMe <SEP> * <SEP> R2 <SEP> = <SEP> H <SEP> * <SEP> *
<tb> * <SEP> Agent <SEP> \ <SEP> R3 <SEP> = <SEP> -CH2-o <SEP> R3 <SEP> * <SEP> * <SEP> *
<tb> * <SEP> agre-gant <SEP> * <SEP> * <SEP> *
<tb> <SEP> HC1 <SEP> .<SEP> HCl
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> ADP <SEP> 1,25 <SEP> r <SEP> M/1 <SEP> * <SEP> 7.10 <SEP> * <SEP> 6.10-5 <SEP> * <SEP> 10-5 <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> ADP <SEP> 2,5 <SEP> P <SEP> M/1 <SEP> * <SEP> 7,4.10 <SEP> 5 <SEP> * <SEP> 5,8.10 <SEP> * <SEP> 5.10 <SEP> 5 <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> *adrénaline <SEP> lrM/l <SEP> * <SEP> 1,6.10 <SEP> 5 <SEP> * <SEP> 2,4.10 <SEP> 5 <SEP> * <SEP> 3,7.10-5 <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> *adrénaline <SEP> 5ru/1 <SEP> * <SEP> 4.10 <SEP> * <SEP> 5.10-5 <SEP> * <SEP> 5,2.10-5 <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> collagene <SEP> * <SEP> > <SEP> 10 <SEP> 4 <SEP> * <SEP> 5,2.10 <SEP> 5 <SEP> * <SEP> > <SEP> 10-4 <SEP> *
<tb> * <SEP> 50t <SEP> g/ml <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> acide <SEP> * <SEP> * <SEP> *
<tb> * <SEP> arachidonique <SEP> * <SEP> ) <SEP> > <SEP> ~4 <SEP> * <SEP> 1,5.10 <SEP> * <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> 5.1ou <SEP> 4 <SEP> M/1 <SEP> * <SEP> * <SEP> * <SEP> *
<tb> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> 10 <SEP> 3 <SEP> M/1 <SEP> * <SEP> > <SEP> 10-4 <SEP> * <SEP> 5,4.10 <SEP> 5 <SEP> * <SEP> *
<tb> <tb> Product <SEP> * <SEP> formula <SEP> I <SEP> with <SEP> * <SEP> formula <SEP> I <SEP> with <SEP> * <SEP> *
<tb><SEP> R1 <SEP> CH, <SEP> * R1 <SEP> = H
<tb> * <SEP> tested <SEP> * <SEP> 1 <SEP> CH3 <SEP> * <SEP> R1 <SEP> H <SEP> * <SEP> Ticlopidine <SEP> *
<tb> * <SEP> * <SEP> R <SEP> = <SEP> CH3 <SEP> OMe <SEP> * <SEP> R2 <SEP> = <SEP> H <SEP> * <SEP> *
<tb> * <SEP> Agent <SEP> \ <SEP> R3 <SEP> = <SEP> -CH2 -o <SEP> R3 <SEP> * <SEP> * <SEP> *
<tb> * <SEP> Aggressor <SEP> * <SEP> * <SEP> *
<tb><SEP> HC1 <SEP>. <SEP> HCl
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> ADP <SEP> 1.25 <SEP> r <SEP> M / 1 <SEP> * <SEP> 7.10 <SEP> * <SEP> 6.10-5 <SEP> * <SEP> 10 -5 <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> ADP <SEP> 2.5 <SEP> P <SEP> M / 1 <SEP> * <SEP> 7.4.10 <SEP> 5 <SEP> * <SEP> 5.8.10 <SEP > * <SEP> 5.10 <SEP> 5 <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * adrenaline <SEP> 1mM / l <SEP> * <SEP> 1.6.10 <SEP> 5 <SEP> * <SEP> 2.4.10 <SEP> 5 <SEP> * <SEP> 3.7.10- 5 <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * adrenaline <SEP> 5ru / 1 <SEP> * <SEP> 4.10 <SEP> * <SEP> 5.10-5 <SEP> * <SEP> 5.2.10-5 <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> collagen <SEP> * <SEP>><SEP> 10 <SEP> 4 <SEP> * <SEP> 5,2.10 <SEP> 5 <SEP> * <SEP>><SEP> 10 -4 <SEP> *
<tb> * <SEP> 50t <SEP> g / ml <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> acid <SEP> * <SEP> * <SEP> *
<tb> * <SEP> arachidonic <SEP> * <SEP>) <SEP>><SEP> ~ 4 <SEP> * <SEP> 1,5.10 <SEP> * <SEP> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> 5.1or <SEP> 4 <SEP> M / 1 <SEP> * <SEP> * <SEP> * <SEP> *
<tb> *
<tb> * <SEP> * <SEP> * <SEP> * <SEP> *
<tb> * <SEP> 10 <SEP> 3 <SEP> M / 1 <SEP> * <SEP>><SEP> 10-4 <SEP> * <SEP> 5,4.10 <SE> 5 <SEP> * <SEP> *
<Tb>

Compte-tenu de leurs propriétés pharmacologiques les produits selon la présente invention pourront être employés en traitement au long cours, seuls ou associés, dans la prophylaxie des accidents thrombotiques artériels (par exemple, chez les patients porteurs de valves cardiaques artificielles, dans la prévention des accidents vasculaires cérébraux, dans la prévention de l'infarctus du myocarde). Ils pourront être associés aux produits habituellement employés tels que l'héparine ou les fibrinolytiques dans le traitement des thromboses aigues. In view of their pharmacological properties, the products according to the present invention may be used in long-term treatment, alone or in combination, in the prophylaxis of arterial thrombotic accidents (for example, in patients with artificial heart valves, in the prevention of cerebrovascular accidents, in the prevention of myocardial infarction). They may be associated with commonly used products such as heparin or fibrinolytics in the treatment of acute thromboses.

Les doses et schémas thérapeutiques seront fonction du sujet et de l'affection à traiter. Les produits pourront être administrés par voie orale (par exemple sous forme de gélules, comprimés, gouttes buvables) ou par voie rectale (suppositoires). La posologie sera adaptée à chaque cas et pourra varier de 1 à 100 mg en une à trois prises pour la voie orale, ou de 1 à 100 mg en une ou deux prises pour la voie rectale.  Doses and regimens will depend on the subject and the condition being treated. The products may be administered orally (for example in the form of capsules, tablets, drinkable drops) or rectally (suppositories). The dosage will be adapted to each case and may vary from 1 to 100 mg in one to three doses for the oral route, or from 1 to 100 mg in one or two doses for the rectal route.

Claims (2)

R E V E N D I C A T I O N SR E V E N D I C A T IO N S 1 - Application des produits de formule générale selon la revendication 1 du brevet numéro 81,06,832 1 - Application of the products of general formula according to claim 1 of patent number 81,06,832
Figure img00040001
Figure img00040001
 avec R1 = H, CH3, COCH3 with R1 = H, CH3, COCH3
Figure img00040002
Figure img00040002
 sous forme de base libre ou de sols pharmacologiquement compatibles à la prévention et au traitement des thrornboses.  as a free base or as pharmacologically compatible soils for the prevention and treatment of thrombosis. 2 - Nouveaux médicaments administres par voie orale ou rectale destinés à la prévention et au traitement des thromboses et centenant une quantité thérapeutiquement efficace d?au moins un produit selon la revendication 1.  2 - New orally or rectally administered drugs for prevention and treatment of thromboses and centenant a therapeutically effective amount of at least one product according to claim 1.
FR8203796A 1981-04-06 1982-03-04 N-Substd. 4-aminoethoxy-2-methyl-5-isopropyl-phenol derivs. - useful as alpha blockers and platelet aggregation inhibitors Granted FR2522502A2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
FR8203796A FR2522502A2 (en) 1982-03-04 1982-03-04 N-Substd. 4-aminoethoxy-2-methyl-5-isopropyl-phenol derivs. - useful as alpha blockers and platelet aggregation inhibitors
EP82450006A EP0062596B1 (en) 1981-04-06 1982-04-01 Derivatives of 4-aminoethoxy-5-isopropyl-2-methyl phenol, process for their preparation and their use as medicines
DE8282450006T DE3264523D1 (en) 1981-04-06 1982-04-01 Derivatives of 4-aminoethoxy-5-isopropyl-2-methyl phenol, process for their preparation and their use as medicines
CA000400482A CA1196650A (en) 1981-04-06 1982-04-05 4-aminoethoxy-5-isopropyl-2-methyl phenyl derivatives; process for preparing the same and their use as therapeutic agents
PT74710A PT74710B (en) 1981-04-06 1982-04-05 NOVEL AMINOETHOXY-4 ISOPROPYL-5-METHYL-2-PHENOL DERIVATIVES
ES511220A ES8304062A1 (en) 1981-04-06 1982-04-06 Derivatives of 4-aminoethoxy-5-isopropyl-2-methyl phenol, process for their preparation and their use as medicines.
OA57651A OA07063A (en) 1981-04-06 1982-04-06 New derivatives of amineothoxy-4 isopropy-2-methyl-2-phenol, their preparation methods and their use as medicaments.
US06/366,133 US4818772A (en) 1981-04-06 1982-04-09 Derivatives of 4-aminoethoxy-5-isopropyl-2-methylbenzenes: methods of synthesis and utilization as medicines

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR8203796A FR2522502A2 (en) 1982-03-04 1982-03-04 N-Substd. 4-aminoethoxy-2-methyl-5-isopropyl-phenol derivs. - useful as alpha blockers and platelet aggregation inhibitors

Publications (2)

Publication Number Publication Date
FR2522502A2 true FR2522502A2 (en) 1983-09-09
FR2522502B2 FR2522502B2 (en) 1984-12-14

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FR8203796A Granted FR2522502A2 (en) 1981-04-06 1982-03-04 N-Substd. 4-aminoethoxy-2-methyl-5-isopropyl-phenol derivs. - useful as alpha blockers and platelet aggregation inhibitors

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