FR2576214A1 - Pharmaceutical compositions based on diltiazem and an antihypertensive - Google Patents

Pharmaceutical compositions based on diltiazem and an antihypertensive Download PDF

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Publication number
FR2576214A1
FR2576214A1 FR8500678A FR8500678A FR2576214A1 FR 2576214 A1 FR2576214 A1 FR 2576214A1 FR 8500678 A FR8500678 A FR 8500678A FR 8500678 A FR8500678 A FR 8500678A FR 2576214 A1 FR2576214 A1 FR 2576214A1
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Prior art keywords
diltiazem
antihypertensive
pharmaceutical composition
pharmaceutical compositions
composition according
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FR8500678A
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French (fr)
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FR2576214B1 (en
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Icilio Cavero
Jean-Louis Cazor
Peter Hicks
Salomon Langer
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Synthelabo SA
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Synthelabo SA
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Priority to FR8500678A priority Critical patent/FR2576214B1/en
Priority to EP86400015A priority patent/EP0189336A1/en
Priority to DK22386A priority patent/DK22386A/en
Priority to JP61008820A priority patent/JPS61167626A/en
Priority to ZA86379A priority patent/ZA86379B/en
Priority to HU24386A priority patent/HUT39604A/en
Priority to AU52456/86A priority patent/AU5245686A/en
Publication of FR2576214A1 publication Critical patent/FR2576214A1/en
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Publication of FR2576214B1 publication Critical patent/FR2576214B1/en
Priority to US07/106,968 priority patent/US4925837A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Pharmaceutical composition containing diltiazem and an antihypertensive agent. Application in therapy.

Description

La présente invention a pour objet des compositions pharmaceutiques 9 base de diltiazem et d'un antihypertenseur, destinées au traitement de maladies cardiovasculaires, plus particulièrement de l'hypertension quelle que soit son origine.The present invention relates to pharmaceutical compositions 9 based on diltiazem and an antihypertensive agent, intended for the treatment of cardiovascular diseases, more particularly hypertension whatever its origin.

Le diltiazem de formule 1 donnée en annexe 1 est connu pour ses propriétés antiangineuses, antihypertensives et antagonistes du calcium.The diltiazem of formula 1 given in appendix 1 is known for its antianginal, antihypertensive and calcium antagonist properties.

Les agents antihypertenseurs que l'on associe eu diltiazem selon l'invention, sont les suivants la prazosine, la térazosine, la doxazosine, la trimazosine, la bunazosine, dont les formules 2, 3, 4, 5 et 6 sont données dans l'annexe 1, l'urapidil et llindoramine de formules 7 et 8.The antihypertensive agents which are combined with diltiazem according to the invention are the following prazosin, terazosin, doxazosin, trimazosin, bunazosin, the formulas 2, 3, 4, 5 and 6 of which are given in Annex 1, urapidil and lloramoram of formulas 7 and 8.

Les compositions pharmaceutiques de l'invention ont été soumises b une série d'essais pharmacologiques qui revèlent leurs intéressantes propriétés dans le domaine cardiovasculaire.The pharmaceutical compositions of the invention have been subjected to a series of pharmacological tests which reveal their advantageous properties in the cardiovascular field.

Le test utilisé est le suivant : de-s rats spontanément hypertendus âgés de plus de 5 mois, sont placés pendant 30 mn, dans une cage à air conditionné maintenue à 280C. La pression systolique des rats est mesurée selon la méthode décrite par Gerold et Tschirky (Arzneim. Forsch. 1968, 18, 1285).The test used is as follows: spontaneously hypertensive rats over 5 months of age are placed for 30 min in an air-conditioned cage maintained at 280C. The systolic pressure of the rats is measured according to the method described by Gerold and Tschirky (Arzneim. Forsch. 1968, 18, 1285).

On administre à un groupe de 6 rats SHR 12,5 mg/kg de diltiazem, 0,3 mg/kg de prazosine, 3,n mg/kg de trimazosine, 0,5 mg/kg de térazosine, 3,0 mg/kg d'urapidil séparément ou l'association de diltiazem et de l'un des autres agents antihypertenseurs.A group of 6 SHR rats are administered 12.5 mg / kg of diltiazem, 0.3 mg / kg of prazosin, 3, n mg / kg of trimazosin, 0.5 mg / kg of terazosin, 3.0 mg / kg of urapidil separately or the combination of diltiazem and one of the other antihypertensive agents.

La pression systolique est mesurde avant l'administration des agents thérapeutiques puis 3 à 5 heures aprbs l'administration d'un des composés ou de l'association de diltiazem et de l'un des agents antihypertenseurs. The systolic pressure is measured before the administration of the therapeutic agents and then 3 to 5 hours after the administration of one of the compounds or of the combination of diltiazem and one of the antihypertensive agents.

Les résultats sont donnés sous forme de diminutions de la pression sanguine par rapport à la pression de base.The results are given in the form of reductions in blood pressure relative to the baseline pressure.

Dans le tableau suivant sont donnés les résultats obtenus, et pour les composés administrés seuls, et pour les associations de diltiazem et d'un agent antihypertenseur. In the following table are given the results obtained, and for the compounds administered alone, and for combinations of diltiazem and an antihypertensive agent.

Tableau
dose pression Diminution de la
Composé mg/kg p.o. de base pression systolique
(mm Hg) (mm Hg) diltiazem 12.5 222 + 4 -1 + 2 prazosine 0.3 215 + 4 -26 + 5 prazosine + diltiazem 0.3+12.5 218 + 6 -62 + 5* trimazosine 3.0 210 + 3 -3 + 2 trimazosine + diltiazem 3.0+12.5 210 + 4 -44 + 6* térazosine 0.5 208 + 3 -28 + 4 térazosine+ diltiazem 0.5+12.5 212 + 5 -45 + 6* urapidil 3.0 -208 + 4 -13 + 7 urapidil+ diltiazem 3+12.5 208 + 3 -32 + 2* * Effet significativement différent (p < 0.05 : t-test) de celui obtenu pour chacun des composés administré seul. Board
dose pressure Decrease in
Compound mg / kg po basic systolic pressure
(mm Hg) (mm Hg) diltiazem 12.5 222 + 4 -1 + 2 prazosin 0.3 215 + 4 -26 + 5 prazosine + diltiazem 0.3 + 12.5 218 + 6 -62 + 5 * trimazosin 3.0 210 + 3 -3 + 2 trimazosin + diltiazem 3.0 + 12.5 210 + 4 -44 + 6 * terazosin 0.5 208 + 3 -28 + 4 terazosin + diltiazem 0.5 + 12.5 212 + 5 -45 + 6 * urapidil 3.0 -208 + 4 -13 + 7 urapidil + diltiazem 3 + 12.5 208 + 3 -32 + 2 * * Significantly different effect (p <0.05: t-test) from that obtained for each of the compounds administered alone.

Ces résultats montrent que l'association de diltiazem avec un des agents antihypertenseurs cités produit un effet antihypertenseur significativement plus important que la somme des effets engendrés par chacun des composés administré isolément.These results show that the combination of diltiazem with one of the antihypertensive agents cited produces a antihypertensive effect significantly greater than the sum of the effects produced by each of the compounds administered in isolation.

I1 existe donc une synergie entre les effets antihypertenseurs du -diltiazem et de l'un des agents antihypertenseurs cités par la Demanderesse. There is therefore a synergy between the antihypertensive effects of -diltiazem and of one of the antihypertensive agents cited by the Applicant.

Les compositions pharmaceutiques de l'invention contiennent de 5 à 120 mg de diltiazem et de 0,1 à 30 mg de l'un des agents antihypertenseurs cités, par unité de prise.The pharmaceutical compositions of the invention contain from 5 to 120 mg of diltiazem and from 0.1 to 30 mg of one of the antihypertensive agents mentioned, per dosage unit.

Les compositions pharmaceutiques de l'invention peuvent être présentées sous toute forme approprié pour l'administration par voie orale ou parentérale, en association avec tout excipient approprié.The pharmaceutical compositions of the invention can be presented in any form suitable for oral or parenteral administration, in combination with any suitable excipient.

Les compositions pharmaceutiques de l'invention peuvent être ut lisées pour le traitement de l'hypertension et pour le traitement d'autres maladies telles que l'asthme et les affections urologiques.The pharmaceutical compositions of the invention can be used for the treatment of hypertension and for the treatment of other diseases such as asthma and urological conditions.

La posologie quotidienne est telle que l'on administre de 5 à 240 mg de diltiazem et de 1 à 50 mg de l'un des agents antihypertenseurs. The daily dosage is such that 5 to 240 mg of diltiazem and 1 to 50 mg of one of the antihypertensive agents are administered.

Annexe 1 - diltiazem

Figure img00050001

- amino-4:.diméthoxy-6, 7 quinazolines
Figure img00050002

prazosine
Figure img00050003

térazosine
Figure img00050004

doxazosine
Figure img00050005
Annex 1 - diltiazem
Figure img00050001

- amino-4: .dimethoxy-6,7 quinazolines
Figure img00050002

prazosin
Figure img00050003

terazosin
Figure img00050004

doxazosin
Figure img00050005

Figure img00060001

- bunazosine
Figure img00060002
Figure img00060001

- bunazosin
Figure img00060002

Figure img00060003

- indoramine
Figure img00060004
Figure img00060003

- indoramine
Figure img00060004

Claims (6)

Revendications 1. Composition pharmaceutique contenant du diltiazem et un agent antihypertenseur choisi pafmi les composés suivants la prazosine, la térazosine, la doxazosine, la trimazosine, la bunazosine, l'urapidil et l'indoramine. Claims 1. Pharmaceutical composition containing diltiazem and a selected antihypertensive agent pafmi the following compounds prazosin, terazosin, doxazosin, trimazosin, bunazosin, urapidil and indoramin. 2. Composition pharmaceutique selon la revendication 1, contenant de 5 à 120 mg de diltiazem et de 0,1 à 30 mg de l'un des agents antihypertenseurs cités dans la revendication 1.2. Pharmaceutical composition according to claim 1, containing from 5 to 120 mg of diltiazem and from 0.1 to 30 mg of one of the antihypertensive agents cited in claim 1. 3. Composition pharmaceutique selon la revendication 1 ou la revendication 2, caractérisée par le fait qu'elle contient du diltiazem et de la prazosine.3. Pharmaceutical composition according to claim 1 or claim 2, characterized in that it contains diltiazem and prazosin. 4. Composition pharmaceutique selon la revendication 1 ou la revendication 2, caractérisée par le fait qu'elle contient du diltiazem et de la trimazosine.4. Pharmaceutical composition according to claim 1 or claim 2, characterized in that it contains diltiazem and trimazosin. 5. Composition pharmaceutique selon la revendication 1 ou la revendication 2, caractérisée par le fait qu'elle contient du diltiazem et de la térazosine.5. Pharmaceutical composition according to claim 1 or claim 2, characterized in that it contains diltiazem and terazosin. 6. Composition pharmaceutique selon la revendication 1 ou la revendication 2, caractérisée par le fait qu'elle contient du diltiazem et de l'urapidiî. 6. Pharmaceutical composition according to claim 1 or claim 2, characterized in that it contains diltiazem and urapidiî.
FR8500678A 1984-09-14 1985-01-18 PHARMACEUTICAL COMPOSITIONS BASED ON DILTIAZEM AND AN ANTIHYPERTENSOR Expired FR2576214B1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
FR8500678A FR2576214B1 (en) 1985-01-18 1985-01-18 PHARMACEUTICAL COMPOSITIONS BASED ON DILTIAZEM AND AN ANTIHYPERTENSOR
EP86400015A EP0189336A1 (en) 1985-01-18 1986-01-07 Pharmaceutical compositions containing an alpha-blocker and a calcium antagonist
JP61008820A JPS61167626A (en) 1985-01-18 1986-01-17 Hypotensive drug
ZA86379A ZA86379B (en) 1985-01-18 1986-01-17 Pharmaceutical composition
DK22386A DK22386A (en) 1985-01-18 1986-01-17 MEDICINE CONTAINING A COMBINATION OF AN ALFA BLOCKER AND A CALCIUM ANTAGONIST
HU24386A HUT39604A (en) 1985-01-18 1986-01-17 Process for producing pharmaceutical compositions containing alpha-blocking agents and calcium-antagonistic agents
AU52456/86A AU5245686A (en) 1985-01-18 1986-01-17 Compositions of alpha blocking and calcium-antagonistic compounds
US07/106,968 US4925837A (en) 1984-09-14 1987-10-13 Pharmaceutical compositions

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR8500678A FR2576214B1 (en) 1985-01-18 1985-01-18 PHARMACEUTICAL COMPOSITIONS BASED ON DILTIAZEM AND AN ANTIHYPERTENSOR

Publications (2)

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FR2576214A1 true FR2576214A1 (en) 1986-07-25
FR2576214B1 FR2576214B1 (en) 1987-02-20

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FR8500678A Expired FR2576214B1 (en) 1984-09-14 1985-01-18 PHARMACEUTICAL COMPOSITIONS BASED ON DILTIAZEM AND AN ANTIHYPERTENSOR

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JP (1) JPS61167626A (en)
FR (1) FR2576214B1 (en)
ZA (1) ZA86379B (en)

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 100, no. 5, 30 janvier 1984, réf. no. 29443r, page 24, Columbus, Ohio, US; J.L. REID et al.: "Pharmacokinetics and pharmacodynamics of trimazosin in man" & AM. HEART J. 1983, 106(5, Pt. 2) 1222-8 *
CHEMICAL ABSTRACTS, vol. 101, no. 11, 10 septembre 1984, réf. no. 83745z, page 39, Columbus, Ohio, US; I. KOBRIN et al.: "Urapidil in normotensive and spontaneously hypertensive rats: the effects on systemic and regional hemodynamics and cardiac mass" & J. HYPERTENS. 1984, 2(3), 317-20 *
CHEMICAL ABSTRACTS, vol. 96, no. 25, 21 juin 1982, réf. no. 210659e, page 52, Columbus, Ohio, US; P. THIEVANT et al.: "Effects of diltiazem on renovascular-hypertensive and on normotensive rats" & GEN. PHARMACOL. 1982, 13(2), 165-8 *
CHEMICAL ABSTRACTS, vol. 97, no. 3, 19 juillet 1982, réf. no. 16866a, page 51, Columbus, Ohio, US; M.A. WEBER et al.: "A vasodilator that avoids renin stimulation and fluid retention: antihypertensive treatment with trimazosin" & CLIN. PHARMACOL. THER. 1982, 31(5), 572-8 *

Also Published As

Publication number Publication date
FR2576214B1 (en) 1987-02-20
JPS61167626A (en) 1986-07-29
ZA86379B (en) 1986-10-29

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