EP0119995A1 - Dihydro-orotsäure-acyl-derivate, ihre herstellung und ihre verwendung als arzneimittel - Google Patents

Dihydro-orotsäure-acyl-derivate, ihre herstellung und ihre verwendung als arzneimittel

Info

Publication number
EP0119995A1
EP0119995A1 EP19820902820 EP82902820A EP0119995A1 EP 0119995 A1 EP0119995 A1 EP 0119995A1 EP 19820902820 EP19820902820 EP 19820902820 EP 82902820 A EP82902820 A EP 82902820A EP 0119995 A1 EP0119995 A1 EP 0119995A1
Authority
EP
European Patent Office
Prior art keywords
general formula
methyl
hydrogen
trityl
compounds
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.)
Withdrawn
Application number
EP19820902820
Other languages
English (en)
French (fr)
Inventor
Jérôme CORBIERE
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.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP0119995A1 publication Critical patent/EP0119995A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms

Definitions

  • New acylated derivatives of dihydro orotic acid their preparation and their use as medicaments.
  • the invention relates to new derivatives of dihydroorotic acid, one of the nitrogen of which is acylated by a derivative of propionic acid.
  • orotic dihydro or thio orotic acid one of the nitrogen atoms of which is acylated by an amidinopropionic chain. It specifically relates to the N-acyl dihydro orotic acids of general formula I.
  • R is hydrogen or a lower alkyl radical
  • R 1 is oxygen, or sulfur
  • R 3 is hydrogen, the benzhydrile group or the trityl group
  • R 4 is hydrogen or a lower alkyl radical.
  • the invention also relates to the diastereoisomers and to the optical isomers of the compounds of general formula I.
  • the molecule of dihydro orotic acid or of dihydrothio orotic acid comprises two asymmetric carbon atoms giving rise to two diastereoisomers which can each be split.
  • the propionic chain has a chiral carbon atom when R 4 is different from hydrogen. This new center of symmetry can be split giving rise to two optical isomers.
  • the invention also relates to the salts of the compounds of general formula I with a mineral or organic acid, preferably therapeutically compatible.
  • the invention also relates to the esters of acids of general formula I corresponding to general formula I ',
  • R, R 1 , R 3 and R 4 are defined as above, and R 2 represents a lower alkyl, hydroxy-alkyl or polyhydroxy-lower alkyl, lower aralkyl radical.
  • the compounds according to The invention are inhibitors of the enzyme which converts the inactive decapeptide Angiotensin I to the active octapeptide angiotensin II.
  • Angiotensin II is the circulating hormone which can be considered to be responsible for essential hypertension when it is in excess.
  • the pharmacological tests below have shown that the compounds I of the invention are useful as antihypertensive agents having a prolonged effect or as medicaments for the treatment or prophylaxis of complications of diabetes.
  • these compounds can be administered in combination with diuretics such as hydroflumethiazide, furosemide and bumetanide, indapamide or chlortalidone.
  • these preparations may contain not only inert excipients, but also other antihypertensive agents such as reserpine, ⁇ - methyldopa, guanethidine, clonidine, hydralazine, etc., or beta-adrenergic receptor blockers such as propanolol, alprenolol pindolol, bufetolol, bupranolol, bunitr ⁇ lol, practolol, oxprenolol, indenolol, timolol, bunolol, etc.
  • antihypertensive agents such as reserpine, ⁇ - methyldopa, guanethidine, clonidine, hydralazine, etc.
  • beta-adrenergic receptor blockers such as propanolol, alprenolol pindolol, bufeto
  • the compounds of formula I are present in the form of pharmaceutical compositions suitable for administration by the oral, parenteral or rectal route.
  • the administration forms are tablets, capsules, powders, suppositories, injectable forms, ophthalmic solutions, ophthalmic ointments, etc. These preparations may also contain common excipients.
  • the doses are adjusted according to the therapeutic indications, the form of administration and the weight of the subject. In general, the daily doses are between 100 and 5000 mg, preferably between 250 and 1000 mg in a single dose or several divided doses.
  • the administration forms preferably contain between 125 and 500 mg of active principle per unit dose.
  • the subject of the invention is also a process for preparing the compounds of general formula I, characterized in that a dihydro orotic acid of general formula II is reacted
  • R and R 1 are defined as above, and R 3 is a benzhydryl or trityl radical, which is esterified with an alkanol or an arylalkanol to form an ester of general formula IV
  • R 2 is an alkyl or aralkyl radical
  • R, R 1 and R 3 are defined as above
  • the latter is reacted with a halide of an ⁇ -halogenated propionic acid of general formula V
  • R 3 is hydrogen or a lower alkyl X is chlorine or bromine
  • Hal is a halogen other than fluorine, to form the N-acylated derivative of dihydro orotic acid of general formula VI
  • the process of the invention also comprises the additional step which consists in unblocking the second nitrogen atom by acid hydrolysis using acetic acid or hydrochloric acid to form an N-acylated dihydro orotic acid of formula I '.
  • R 3 is hydrogen and the substituents R, R 1 , R 2 and R 4 are defined as above.
  • the process of the invention also comprises the step of hydrolysis of the esters of formula I 'into acids of formula I
  • the compounds of general formula I or I ′ can, if desired, be split into their isomeric diastero or split into their optical isomers by chemical or physical splitting agents.
  • the compounds of general formula I or I ′ can also be salified by addition of a mineral or organic acid such as hydrochloric acid, sulfuric acid, acetic acid, benzoic acid, nicotinic acid, methane sulfonic acid, isethionic acid, p. toluene sulfonic or glucose 1 - phosphoric acid.
  • a mineral or organic acid such as hydrochloric acid, sulfuric acid, acetic acid, benzoic acid, nicotinic acid, methane sulfonic acid, isethionic acid, p. toluene sulfonic or glucose 1 - phosphoric acid.
  • Stage B N'_trityl dihydro methyl orotate. 11 g15 of methyl dihydro orotate are dissolved in 40 ml of methylene chloride, then 2 ml of triethylamine and finally gradually a solution of 18g5 of trityl chloride in 60 ml of methylene chloride. The mixture is stirred at temperature for 6 hours. The triphenyl carbinol which has precipitated is separated by filtration and then the filtrate is washed with water until the washings are neutral. The methylene solution is then dried over magnesium sulfate and evaporated to dryness.
  • N '- trityl dihydro orotate of methyl is taken up in 50 ml of hot ethyl acetate. By cooling, the trityl derivative separates. The suspension is left to stand for 12 hours in a cooler and then the precipitate is separated by filtration. It is washed with cold ethyl acetate and then dried to constant weight.
  • the N '-trityl dihydro orotate of methyl is recrystallized from acetonitrile by hot and cold. It is in the form of colorless crystals melting at 237 - 240o.
  • Stage C N '-trityl N - (2 - chloropropionyl) dihydro orotate methyl.
  • 16g30 of 2-chloropropionic acid are dissolved in 45 ml of hexamethyl phosphorotriamide and then 20g 5 of freshly redistilled thionyl chloride is added in small portions.
  • the reaction mixture is kept at a temperature in the region of 5 ° for 2 hours.
  • the hydrochloric acid formed is removed by vacuum distillation.
  • the residual solution is added gradually to a solution of 62 g of N'-trityl dihydro orotate methyl in 125 ml of hexaphosphorotriamide previously cooled to 5o. Stirring is continued for 4 hours, then the excess reagent is decomposed by the addition of an aqueous solution of sodium carbonate at 20%. It is left in contact for one hour, then the aqueous phase is exhausted with isopropyl ether three times. The ethereal solutions are combined, washed with water until neutral, then dried and evaporated to dryness.
  • the residue of crude methyl N '- trityl N - (2-chloropropionyl) dihydro orotate is purified by dissolving in a minimum of hot ethyl acetate. By cooling, the N'-trityl N - (2-chloropropionyl) dihydro orotate of crystallized methyl is separated, which is filtered, drained and dried under vacuum. This compound melts at 251 - 252o.
  • Stage D N'-trityl N - (2-cyanopropionyl) dihydro methyl orotate.
  • N'-trityl N - (2-chloropropionyl) dihydro orotate methyl are dissolved in 120 ml of dimethyl sulfoxide. After complete dissolution, a solution of 4 g of potassium cyanide in 20 ml of water is carefully added. The mixture is brought to 40-45 ° and maintained at this temperature for 4 hours. The reaction mixture is allowed to return to room temperature and then diluted with an equal volume of water.
  • N '- trityl N - (2-cyanopropionyl) dihydro orotate of methyl precipitates progressively. It is left to stand for 12 hours and then the precipitate is separated, which is washed with water then with sodium bicarbonate and then again with water. It is then dried under vacuum.
  • Stage F N - (2-formamidino propionyl) methyl dihydro orotate.
  • Stage G N- (2,6 - dioxo 4-carboxy hexahydro pyrimidinyl -3) 2-carbonyl 2-methyl acetamidine.
  • hydrochloride or methane sulfonate is obtained.
  • salts with organic bases are obtained, for example the dicyclohexylamine salt, the benzothine, N-methyl-D-glucamine, and hydrabamine salts, salts with amino acids such as arginine, lysine, glycine, valine, ornithine or citrulline.
  • Example I By operating as in Example I, starting from 5 - methyl dihydro uracil 6-carboxylic acid, ethyl N-trityl 5 - methyl dihydro uracil 6-carboxylate is obtained which is condensed with chloride. ⁇ -chloropropionyl to form: N- trityl N '- ⁇ -chloropropionyl 5 -methyl dihydro uracil 6 - ethyl carboxylate
  • compositions compound of Example I 230 g lactose 150 g crystalline cellulose 50 g carboxymethylcellulose calcium 7 g magnesium stearate 3 g
  • the acute toxicity of the compounds of general formula I corresponds to an LD 50 of 2g50 / kg
  • the LD 50 was determined graphically as follows: 4-week old Rockland mice weighing 19 to 21 g are placed in a breeding room at constant temperature and humidity (23oC ⁇ 1.55oC - 5%) and they are provided with food pellets and water for a week at will. We choose for the experiment mice whose growth is normal. (Method of administration).
  • test compound is suspended in a 0.5% gum tragacanth solution and administered orally at a dose of 0.5 ml per 20 g body weight.
  • b Study of antihypertensive action.
  • compounds that inhibit the angiotensin I transforming enzyme may have curative activity vis-à-vis renal hypertension and essential hypertension.
  • the compounds of the invention were therefore evaluated as antihypertensive agents according to the following method: Male Wistar rats weighing 200 to 300 g are used. Under ether anesthesia, a polyethylene cannula is placed in the carotid artery and in the jugular vein. The cannula of the jugular vein is connected to a continuous perfusion device.
  • angiotensin I is infused intravenously at a dose of 300 g / kg using the continuous infusion set and the hypertensive response is recorded with a polygraph.
  • the compounds of the invention are administered in suspension in a 0.5% aqueous solution of tragacanth, orally at a dose of 0.3 ml / 100 g of body weight and the response of hypertension to the blood is measured. intravenous infusion of angiotensin I over time.
  • the inhibitory activity of the compounds with respect to the angiotensin I converting enzyme is expressed by the percentage inhibition of the hypertension response to angiotensin I.
  • the table shows the variations in the percentages d inhibition over time obtained with the compounds of the invention. (Results).
  • the table shows the results of the pharmacological tests when the compounds (I) of the invention and their salts are used as agents inhibiting the angiotensin I converting enzyme.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP19820902820 1982-09-28 1982-09-28 Dihydro-orotsäure-acyl-derivate, ihre herstellung und ihre verwendung als arzneimittel Withdrawn EP0119995A1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/FR1982/000159 WO1984001385A1 (fr) 1982-09-28 1982-09-28 Nouveaux derives acyles de l'acide dihydro orotique, leur preparation et leur emploi comme medicament

Publications (1)

Publication Number Publication Date
EP0119995A1 true EP0119995A1 (de) 1984-10-03

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP19820902820 Withdrawn EP0119995A1 (de) 1982-09-28 1982-09-28 Dihydro-orotsäure-acyl-derivate, ihre herstellung und ihre verwendung als arzneimittel

Country Status (2)

Country Link
EP (1) EP0119995A1 (de)
WO (1) WO1984001385A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4855301A (en) * 1986-10-09 1989-08-08 E. R. Squibb & Sons, Inc. 1,2,3,4-Tetrahydro-6-substituted-4-aryl(or heterocyclo)-3-((substituted amino)carbonyl)-2-thioxo (or oxo)-5-pyrimidinecarboxylic acids and esters

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2501205A1 (fr) * 1981-03-09 1982-09-10 Corbiere Jerome Nouveaux derives acyles de l'acide dihydro orotique, leur preparation et leur emploi comme medicament

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8401385A1 *

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Publication number Publication date
WO1984001385A1 (fr) 1984-04-12

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