FR2533923A1 - New N-(5-aminomethyl-2-oxazolin-2-yl)-N'-phenylureas, method for preparing them and their therapeutic application - Google Patents

New N-(5-aminomethyl-2-oxazolin-2-yl)-N'-phenylureas, method for preparing them and their therapeutic application Download PDF

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FR2533923A1
FR2533923A1 FR8216783A FR8216783A FR2533923A1 FR 2533923 A1 FR2533923 A1 FR 2533923A1 FR 8216783 A FR8216783 A FR 8216783A FR 8216783 A FR8216783 A FR 8216783A FR 2533923 A1 FR2533923 A1 FR 2533923A1
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aminomethyl
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oxazolin
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FR2533923B1 (en
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Jarry
Marie-Helene Creuzet
Claude Feniou
Gisele Prat
Henri Pontagnier
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Cortial SA
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Priority to EP83450024A priority patent/EP0105821B1/en
Priority to OA58125A priority patent/OA08298A/en
Priority to JP58185794A priority patent/JPS5988476A/en
Priority to ES526276A priority patent/ES526276A0/en
Priority to US06/539,285 priority patent/US4499090A/en
Priority to CA000438408A priority patent/CA1219875A/en
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/28—Nitrogen atoms not forming part of a nitro radical

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Abstract

The invention relates to new N-(5-aminomethyl-2-oxazolin-2-yl)-N'-phenylureas, to a method for preparing them and to their therapeutic application. The products of the invention are of the general formula: in which R1 and R2, which may be identical or different, = alkyl (such as CH3, C2H5, C3H7, C4H9) or arylalkyl (such as benzyl) or aryl (such as phenyl); R1 and R2, with the nitrogen atom to which they are attached, can form a heterocycle such as piperidine, alkylpiperidine, pyrrolidine, morpholine or tetrahydroisoquinoline. They are obtained, in general, speaking, by a reaction employing phenyl isocyanate and a 2-amino-5-aminomethyl-2-oxazoline. These products are useful in therapy, for example in the treatment of disorders of cardiac rhythm, epilepsy, ulcerative disease and inflammatory or oedematous states.

Description

La présente invention concerne de nouvelles N-(aminométhyl-5 oxazolin-2 yl-2) N'-phénylurées, leur méthode de préparation ainsi que leur application thérapeutique. The present invention relates to novel N- (5-aminomethyl-2-oxazolin-yl-2) N'-phenylureas, their method of preparation and their therapeutic application.

Les produits de la présente invention ont pour formule générale

Figure img00010001

avec R1, R2 identiques ou différents = alkyl (tel que CH3, C2R5,
C3H7, C4H9) ou arylalkyl (tel que benzyl) ou aryl (tel que phényl) h et R2 peuvent former avec l'atome d'azote auquel ils sont rattachés un hétérocycle tel que pipéridine, alkylpipéridine, pyrrolidine, morpholine, tétrahydroisoquinoléine. The products of the present invention have the general formula
Figure img00010001

with R1, R2 identical or different = alkyl (such as CH3, C2R5,
C3H7, C4H9) or arylalkyl (such as benzyl) or aryl (such as phenyl) h and R2 can form with the nitrogen atom to which they are attached a heterocycle such as piperidine, alkylpiperidine, pyrrolidine, morpholine, tetrahydroisoquinoline.

On connait déjà des amino-2 oxazolines-2. Ainsi l'amino-2 phényl-5 oxazoline-2

Figure img00010002

a été brevetée par la société MacNeil Incorporated en France sous le nO 2448M pour ses propriétés de stimulation du systeme nerveux central et son activité anorexigène. L'amino-2 (dichloro-3,4 phénoxyméthyl)-5 oxazoline-2 a été testée par A.H. Abdallah et coll. pour son activité cardiovasculaire et anorexigene (Toxicol. appl. Pharmacol., 1973, 26, 513-22 ; 1973, 25, 344-53) et a été brevetée par la Société Dow Chemical aux Etats Unis sous le nO 3637726 le 9 avril 1970 pour son activité antimicrobienne.We already know 2-amino-2-oxazolines. Thus 2-amino-5-phenyl-oxazoline-2
Figure img00010002

was patented by the company MacNeil Incorporated in France under the number 2448M for its properties of stimulation of the central nervous system and its anorectic activity. Amino-2 (3,4-dichloro phenoxymethyl) -5 oxazoline-2 was tested by AH Abdallah et al. for its cardiovascular and anorectic activity (Toxicol. appl. Pharmacol., 1973, 26, 513-22; 1973, 25, 344-53) and was patented by the Dow Chemical Company in the United States under the number 3637726 on April 9, 1970 for its antimicrobial activity.

On connait également un dérivé de substitution de l'urée de formule

Figure img00010003

décrit par la Société Delalande dans le brevet français nO 7311985.We also know a urea substitution derivative of formula
Figure img00010003

described by Société Delalande in French patent no. 7311985.

Les produits de la présente invention se distinguent des dérivés déjà connus par la présence en position 5 du cycle oxazoline d'un substituant aminométhyl. Ils présentent des propriétés pharmacologiques permettant leur application en thérapeutique notamment dans le traitement des convulsions, des troubles du rythme, de la maladie ulcéreuse et des états inflammatoires ou oedémateux. The products of the present invention are distinguished from the derivatives already known by the presence in position 5 of the oxazoline ring of an aminomethyl substituent. They have pharmacological properties allowing their application in therapeutics in particular in the treatment of convulsions, arrhythmias, ulcerous disease and inflammatory or edematous states.

Les produits de la présente invention sont préparés de façon générale par réaction entre une amino-2 aminométhyl-5 oxazoline-2 et l'isocyanate de phényle dans un solvant tel que le benzene à la température d'ébullition du solvant. The products of the present invention are generally prepared by reaction between a 2-amino-5-aminomethyl-2-oxazoline and phenyl isocyanate in a solvent such as benzene at the boiling point of the solvent.

L'invention va être décrite plus précisément dans les exemples suivants sans toutefois que ceux ci ne limitent sa portée. The invention will be described more precisely in the following examples without, however, that these limit its scope.

Exemple 1
Préparation de la N-(diéthylaminométhyl-5 oxazolin-2 yl-2) N'-phénylurée.Example 1
Preparation of N- (5-diethylaminomethyl-oxazolin-2 yl-2) N'-phenylurea.

Produit de formule I avec R1 = R2 = C2H5. Product of formula I with R1 = R2 = C2H5.

Dans un réacteur muni d'un réfrigérant, d'une ampoule à brome et d'une agitation , on introduit 17,1 g d'amino-2 diéthylaminométllyl-5 oxazoline-2 préalablement dissoute dans 150 cm3 de benzène. Le mélange est porté à ébullition et 11,9 g d'isocyanate de phényle sont ajoutés goutte à goutte. Le chauffage est prolongé deux heures après la fin de l'addition d'isocyanate de pnényle. Lors du refroidissement il se forme un précipité qui est essoré et recristallisé dans Cl14. Rendement 92 %.Point de fusion 1480C. RNN dans D'fSOD6 (sont donnés les déplacements chimiques exprimés en ppm par rapport au
TMS pris comme étalon interne) 0,9 ppm, 6 protons, triplet (CH3) 2,3 -2,8 ppm, 6 protons, massif complexe, (CH2N) ; 3,2-4,0 ppm, 2 protons, massif complexe, (H en 4 du cycle oxazoline) ; 4,4-5,0 ppm, 1 proton, massif complexe (H en 5 du cycle oxazoline) ; 6,7-7,8 ppm, 5 protons, massif complexe, (protons aromatiques) ; 8,7 et 9,3 ppm, 2 protons, doues, (NHCONH).17.1 g of 2-amino-2-diethylaminometllyl-5-oxazoline-2 previously dissolved in 150 cm 3 of benzene are introduced into a reactor fitted with a condenser, a dropping funnel and a stirrer. The mixture is brought to the boil and 11.9 g of phenyl isocyanate are added dropwise. Heating is continued two hours after the end of the addition of pnenyl isocyanate. Upon cooling, a precipitate forms which is drained and recrystallized from Cl14. Yield 92%. Melting point 1480C. RNN in D'fSOD6 (the chemical shifts expressed in ppm with respect to the
TMS taken as internal standard) 0.9 ppm, 6 protons, triplet (CH3) 2.3-2.8 ppm, 6 protons, complex massif, (CH2N); 3.2-4.0 ppm, 2 protons, complex massif, (H in 4 of the oxazoline cycle); 4.4-5.0 ppm, 1 proton, complex massif (H in 5 of the oxazoline ring); 6.7-7.8 ppm, 5 protons, complex massif, (aromatic protons); 8.7 and 9.3 ppm, 2 protons, doues, (NHCONH).

Exemple 2
Préparation de la N-phényl N'-(pipéridinométhyl-5 oxazolin-2 yl-2) urée ;
Formule I avec R1 et R2 ensemble = -CH2-CH2-CH2-CH2-CH2-. Example 2
Preparation of N-phenyl N '- (piperidinomethyl-5 oxazolin-2 yl-2) urea;
Formula I with R1 and R2 together = -CH2-CH2-CH2-CH2-CH2-.

Ce produit est préparé selon la technique décrite dans l'exemple 1. Point de fusion 170 C. RMN dans CDC13 1,2-1,8 ppm, 6 protons, massif complexe (CH2C) ; 2,2-2,8 ppm, 6 protons, massif complexe (CH2N) ; 3,3-4,0 ppm, 2 protons, massif complexe (H en 4 du cycle oxazoline) ; 4,5-5,1 ppm, 1 proton, massif complexe (H en 5 du cycle oxazoline) ; 6,8-7,7 ppm, 5 protons, massif complexe (protons aromatiques) ; 8,2 et 8,8 ppm, 2 protons, dômes (NHCONH).  This product is prepared according to the technique described in Example 1. Melting point 170 C. NMR in CDC13 1.2-1.8 ppm, 6 protons, complex solid (CH2C); 2.2-2.8 ppm, 6 protons, complex massif (CH2N); 3.3-4.0 ppm, 2 protons, complex massif (H in 4 of the oxazoline cycle); 4.5-5.1 ppm, 1 proton, complex massif (H in 5 of the oxazoline ring); 6.8-7.7 ppm, 5 protons, complex massif (aromatic protons); 8.2 and 8.8 ppm, 2 protons, domes (NHCONH).

Exemple 3
Préparation de la N-phényl N'-(tétrahydro-1,2,3,4 isoquinoléinométhyl-5 oxazolin-2 yl-2) urée ; formule I avec R1 et R2 ensemble =

Figure img00020001
Example 3
Preparation of N-phenyl N '- (tetrahydro-1,2,3,4 isoquinolinomethyl-5 oxazolin-2 yl-2) urea; formula I with R1 and R2 together =
Figure img00020001

Ce produit est préparé selon la technique décrite dans l'exemple 1. Point de fusion 179cl. This product is prepared according to the technique described in Example 1. Melting point 179cl.

RMN dans DMSOD6

Figure img00030001

complexe (H en 3,4 du cycle isoquinoléine + CH2 en alpha) ; 3,2-4,0 ppm, 4 protons, massif complexe (H en 1 du cycle isoquinolélne + R en 4 du cycle oxazoline) ; 4,6-5,1 ppm, 1 proton, massif complexe (H en 5 du cycle oxazoline) ; 6,6-7,7 ppm, 9 protons, massif complexe (E aromatiques) 8,7-9,3 ppm, 2 protons, dômes (NHCONH).NMR in DMSOD6
Figure img00030001

complex (H in 3.4 of the isoquinoline cycle + CH2 in alpha); 3.2-4.0 ppm, 4 protons, complex massif (H in 1 of the isoquinoleline cycle + R in 4 of the oxazoline cycle); 4.6-5.1 ppm, 1 proton, complex massif (H in 5 of the oxazoline ring); 6.6-7.7 ppm, 9 protons, complex massif (E aromatics) 8.7-9.3 ppm, 2 protons, domes (NHCONH).

Les propriétés toxicopharmacologiques des produits de la présente invention sont exposées ci-après. The toxicopharmacological properties of the products of the present invention are set out below.

La toxicité a été déterminée chez la souris pour diverses voies d'administration. Ainsi les produits des exemples 1, 2 et 3 n'entraînent aucune mortalité quand ils sont administrés par voie orale à 300 mg/kg ou par voie intrapéritonéale à 200 mg/kg. Toxicity has been determined in mice for various routes of administration. Thus the products of Examples 1, 2 and 3 cause no mortality when they are administered orally at 300 mg / kg or intraperitoneally at 200 mg / kg.

Administrés par voie intrapéritonéale à la dose de 100 mg/kg les produits des exemples 1 et 2 empêchent l'apparition d'arythmies chez des souris soumises à des anesthésies au chloroforme. Administered intraperitoneally at a dose of 100 mg / kg, the products of Examples 1 and 2 prevent the appearance of arrhythmias in mice subjected to anesthesia with chloroform.

Administré par voie intrapéritonéale à la dose de 80 mg/kg le produit de l'exemple 3 entraine une inhibition des convulsions induites par une injection de 0,5 mg/kg de bicuculline 30 mn après. Le produit de l'exemple 3 n'agit pas sur la Gaba transaminase car il n'inhibe plus les convulsions induites par une seconde administration de bicuculline 5 h après Son activité est donc du type gabergique direct. Administered intraperitoneally at a dose of 80 mg / kg the product of Example 3 results in inhibition of the convulsions induced by an injection of 0.5 mg / kg of bicuculline 30 min after. The product of Example 3 does not act on Gaba transaminase because it no longer inhibits the convulsions induced by a second administration of bicuculline 5 hours after Its activity is therefore of the direct gabergic type.

A la concentration de 100 microg/ml le produit de l'exemple 1 inhibe à plus de 50 % l'effet chronotrope induit par 5 microg/ml d'hiatamine sur l'oreillette droite de cobaye battant spontanément. At a concentration of 100 microg / ml the product of Example 1 inhibits by more than 50% the chronotropic effect induced by 5 microg / ml of hiatamine on the right atrium of the guinea pig spontaneously beating.

Administré par voie orale à la dose de 200 mg/kg le produit de l'exemple 1 entraîne une inhibition de 51 % de l'oedème de la patte du rat induit par la carragénine. Administered orally at a dose of 200 mg / kg the product of Example 1 causes a 51% inhibition of edema of the rat's paw induced by carrageenan.

Compte tenu de leurs activités pharmacologiques, les produits de la présente invention peuvent être employés en thérapeutique humaine et vétérinaire. Associés aux excipients habituels ils pourront être utilisés par exemple pour traiter les troubles du rythme cardiaque,les épilepsies généralisées ou localisées, les convulsions fébriles de l'enfant, la maladie ulcéreuse, les états inflammatoires et oedémateux. Given their pharmacological activities, the products of the present invention can be used in human and veterinary therapy. Associated with the usual excipients, they can be used for example to treat cardiac arrhythmias, generalized or localized epilepsies, febrile convulsions in children, ulcerative disease, inflammatory and edematous states.

Ils seront administrés par exemple par voie orale sous forme de dragées, comprimés, sirop, ampoules, par voie rectale sous forme de suppositoires, par voie intramusculaire ou intraveineuse ou par voie topique sous forme de pommade ou de gel ; les doses administrées varieront selon l'indication et le sujet de 1 a 100 mg/j en 2 à 6 prises pour la voie orale, de 1 à 100 mg/j en 1 ou 2 prises pour la voie rectale, de 0,5 à 50 mg par injection pour les voies parentérales.  They will be administered for example orally in the form of dragees, tablets, syrup, ampoules, rectally in the form of suppositories, intramuscularly or intravenously or topically in the form of ointment or gel; the doses administered will vary according to the indication and the subject from 1 to 100 mg / d in 2 to 6 taken for the oral route, from 1 to 100 mg / d in 1 or 2 taken for the rectal route, from 0.5 to 50 mg per injection for the parenteral routes.

Claims (6)

REVENDICATIONS 1 - Nouveaux produits de formule génerale 1 - New products of general formula
Figure img00050001
Figure img00050001
 avec R1, R2 identiques ou différents = alkyl (tel que CH3, C2H5, C3, C4Hg) ou arylalkyl (tel que benzyl) ou aryl (tel que phényl) with R1, R2 identical or different = alkyl (such as CH3, C2H5, C3, C4Hg) or arylalkyl (such as benzyl) or aryl (such as phenyl) R1 et R2 peuvent former avec l'atome auquel ils sont rattachés un hétérocycle tel que pipéridine, alkylpipéridine, pyrrolidine, morpholine, tétrahydroisoquinoléine.R1 and R2 can form with the atom to which they are attached a heterocycle such as piperidine, alkylpiperidine, pyrrolidine, morpholine, tetrahydroisoquinoline. 2 - Méthode de préparation des produits selon la revendication l caractérisée en ce que l'on fait réagir dans un solvant tel que le benzène, à la température d'ébullition du solvant, l'isocyanate de phényle avec un dérivé de formule générale 2 - Method for preparing the products according to claim l characterized in that one reacts in a solvent such as benzene, at the boiling point of the solvent, phenyl isocyanate with a derivative of general formula
Figure img00050002
Figure img00050002
 dans laquelle R1, R2 identiques ou différents = alkyl(tel que CH3, C2H5, C3H7, C4H9) ou arylaîkyl (tel que benzyl) ou aryl (tel que phényl) ; R1 et R2 peuvent former avec l'atome d'azote auxquels ils sont rattachés un hétérocycle tel que pipéridine, alkylpipéridine, pyrrolidine, morpholine, tétrahydroisoquinolélne. wherein R1, R2 identical or different = alkyl (such as CH3, C2H5, C3H7, C4H9) or arylakyl (such as benzyl) or aryl (such as phenyl); R1 and R2 can form with the nitrogen atom to which they are attached a heterocycle such as piperidine, alkylpiperidine, pyrrolidine, morpholine, tetrahydroisoquinoline. 3 - Nouveau médicament caractérisé en ce que le principe actif est constitué par au moins un produit selon la revendication 1. 3 - New drug characterized in that the active principle consists of at least one product according to claim 1. 4 - Nouveau médicament selon la revendication 3 utile pour le traitement des troubles du rythme cardiaque. 4 - New drug according to claim 3 useful for the treatment of heart rhythm disorders. 5 - Nouveau médicament selon la revendication 3 utile pour le traitement des épilepsies et convulsions. 5 - New drug according to claim 3 useful for the treatment of epilepsies and convulsions. 6 - Composition pharmaceutique ou vétérinaire caractérisée en ce qu'elle contient à titre de principe actif au moins un produit selon la revendication 1 en association avec un véhicule pharmaceutique ou un excipient approprié.  6 - Pharmaceutical or veterinary composition characterized in that it contains as active principle at least one product according to claim 1 in combination with a pharmaceutical vehicle or an appropriate excipient.
FR8216783A 1982-10-05 1982-10-05 New N-(5-aminomethyl-2-oxazolin-2-yl)-N'-phenylureas, method for preparing them and their therapeutic application Granted FR2533923A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
FR8216783A FR2533923A1 (en) 1982-10-05 1982-10-05 New N-(5-aminomethyl-2-oxazolin-2-yl)-N'-phenylureas, method for preparing them and their therapeutic application
PT77429A PT77429B (en) 1982-10-05 1983-09-29 PROCESS FOR THE PREPARATION OF NOVEL N- (AMINO-METHYL-5-OXAZOLIN-2-YL) -N-PHENYLUREES AND COMPOSITIONS CONTAINING SAME
EP83450024A EP0105821B1 (en) 1982-10-05 1983-09-30 N-(aminomethyl-5-oxazolin-2-yl-2)-n'-phenyl ureas
DE8383450024T DE3362332D1 (en) 1982-10-05 1983-09-30 N- (AMINOMETHYL-5-OXAZOLIN-2-YL-2) -N'-PHENYL UREAS
OA58125A OA08298A (en) 1982-10-05 1983-10-03 New N- (5-aminomethyl oxazolin-2 yl-2) N'-phenylureas, their method of preparation and their therapeutic application.
JP58185794A JPS5988476A (en) 1982-10-05 1983-10-04 Novel n-(5-aminomethyl-2-oxazolin-2-yl)-n'-phenylurea, manufacture and application to therapy
ES526276A ES526276A0 (en) 1982-10-05 1983-10-05 PROCEDURE FOR THE PREPARATION OF NEW N- (5-AMINOMETIL 2-OXAZOLIN 2-IL) -N'-FENILUREAS
US06/539,285 US4499090A (en) 1982-10-05 1983-10-05 N-(5-aminomethyl-2-oxazolin-2-yl)-N'-phenylureas, compositions and use
CA000438408A CA1219875A (en) 1982-10-05 1983-10-05 N-(5-aminomethyl-2-oxazolin-2-y1) n'-phenylureas; process for preparing the same and their use as therapeutic agents

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GB1196544A (en) * 1967-06-28 1970-06-24 Abbott Lab Substituted (4-Oxo-2-Oxazolidinylidene)-Urea and -Thiourea Derivatives
DE1302662B (en) * 1971-02-04

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GB1196544A (en) * 1967-06-28 1970-06-24 Abbott Lab Substituted (4-Oxo-2-Oxazolidinylidene)-Urea and -Thiourea Derivatives

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