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WO1996035420A1 - Utilisation de (s)-enantiomeres de derives de 1,4-dihydropyridine pour traiter l'insuffisance cardiaque - Google Patents

Utilisation de (s)-enantiomeres de derives de 1,4-dihydropyridine pour traiter l'insuffisance cardiaque Download PDF

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Publication number
WO1996035420A1
WO1996035420A1 PCT/EP1996/001978 EP9601978W WO9635420A1 WO 1996035420 A1 WO1996035420 A1 WO 1996035420A1 EP 9601978 W EP9601978 W EP 9601978W WO 9635420 A1 WO9635420 A1 WO 9635420A1
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WO
WIPO (PCT)
Prior art keywords
enantiomer
compound
general formula
preparation
medicament
Prior art date
Application number
PCT/EP1996/001978
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English (en)
Inventor
Amedeo Leonardi
Gianni Motta
Rodolfo Testa
Original Assignee
Recordati S.A., Chemical And Pharmaceutical Company
Recordati Industria Chimica E Farmaceutica S.P.A.
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 Recordati S.A., Chemical And Pharmaceutical Company, Recordati Industria Chimica E Farmaceutica S.P.A. filed Critical Recordati S.A., Chemical And Pharmaceutical Company
Priority to EP96919749A priority Critical patent/EP0825862A1/fr
Priority to AU58170/96A priority patent/AU5817096A/en
Priority to JP08533768A priority patent/JP2000514776A/ja
Publication of WO1996035420A1 publication Critical patent/WO1996035420A1/fr

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Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the invention relates to the preparation of (S)-enantiomers of 1,4-dihydropyridines, to their use in the treatment of heart failure and to their use in the manufacture of medicaments for such treatment.
  • 1 ,4-Dihydropyridines endowed with calcium antagonistic activity are widely used in the treatment of several cardiovascular diseases, for example hypertension and angina.
  • An important limiting factor in the use of these compounds is the negative inotropic effect exerted by some of them, see S. Goldmann et al., Angew Chem. Int. Ed. Engl. , 30, 1559, (1991). This effect suggests a careful administration of these compounds to patients suffering from cardiac diseases, although a reduction of cardiac work could result beneficial for some of them.
  • U.S. Patent 4,705,797 and U.S. Patent 4,772,621 disclose asymmetric diesters of l,4-dihydro-2,6-dimethyl-4-aryl-pyridine-3,5-dicarboxylic acids and the stereoisomers or pharmaceutically acceptable salts thereof as compounds having antihypertensive and coronary dilating activity.
  • the invention provides the use of an (S)-enantiomer of a compound having d e general formula I wherein
  • Ph represents a phenyl group
  • Ar represents a 2-nitrophenyl, 3-nitrophenyl, 2,3-dichlorophenyl or benzofurazan-4-yl group
  • A represents a branched chain alkylene group having from 3 to 6 carbon atoms
  • R represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, optionally mono-substituted by an alkoxy group having from 1 to 6 carbon atoms
  • Ri represents a hydrogen atom, a hydroxy group or an alkyl group having from 1 to 4 carbon atoms
  • R 2 represents a hydrogen atom or a methyl group or of a salt, hydrate or solvate of such an (S)-enantiomer for the preparation of a medicament for the treatment of heart failure.
  • the invention further provides a method for the treatment of a patient suffering from heart failure, the method comprising administering to the patient a therapeutically effective amount of an (S)-enantiomer of a compound having the general formula I as above defined or of a salt, hydrate or solvate of such an (S)-enantiomer.
  • the invention also provides a process for the preparation of the (S)-enantiomers of the compounds of the general formula I, the process comprising the esterification of the (R)-enantiomer of a compound of the general formula II
  • the (S)-enantiomer of the compound I may be administered to the patient as such, or in the form of any of its pharmaceutically acceptable salts, hydrates or solvates.
  • Preferred pharmaceutically acceptable acid addition salts include those formed with hydrochloric, sulphuric, maleic, succinic, citric, methanesulphonic and toluenesulphonic acids; they may be prepared from the free bases in conventional manner.
  • the active ingredient will usually be administered in admixture with a pharmaceutically acceptable carrier.
  • Suitable administration routes include oral, parenteral, rectal and transdermal routes.
  • Carriers can be solid, semisolid or liquid diluents as well as capsules and may optionally provide modified release of the active drug.
  • a preparation to be administered orally in the form of tablets can include, in addition to the active ingredient, solubilizers (e.g. a polyethoxylated fatty acid), components which modify the drug release (e.g. hydroxypropylmethyl cellulose), fillers (e.g. lactose), binders (e.g. hydroxypropylmethyl cellulose) and/or lubricants (e.g. sodium stearylfumarate).
  • solubilizers e.g. a polyethoxylated fatty acid
  • components which modify the drug release e.g. hydroxypropylmethyl cellulose
  • fillers e.g. lactose
  • binders e.g. hydroxypropylmethyl cellulose
  • lubricants
  • the tablets can be coated with suspensions of colouring pigments (e.g. iron oxide) and film forming agents (e.g. cellulose derivatives).
  • a preparation to be administered parenterally may be an aqueous solution of the active ingredient, possibly including a co-solvent such as polyethylene glycol.
  • the amount of the active ingredient usually ranges between 0.1 and 99% by weight of the total formulation, preferably between 0.5 and 20% by weight in formulations for injection and between 2 and 50% by weight in formulations for oral administration.
  • the daily dose of the active ingredient depends on individual needs (e.g. the patient's condition, body weight, age, gender etc.) as well as on the administration route.
  • the oral dosage may range from 0.1 to 100 mg, preferably 1 to 20 mg, of active ingredient per day.
  • an (R)-enantiomer of a compound II is esterified with a compound III.
  • the reaction may be performed in the presence of a coupling agent (e.g. dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole or diethyl cyanophosphonate) optionally in the presence of a promoting agent (e.g. N-hydroxysuccinimide or 4-dimethylaminopyridine) in aprotic or chlorinated solvents (e.g. dimethylformamide or chloroform) at temperatures ranging from -10 to 140°C according to well known synthetic methods: Albertson, Org.
  • the (R)-enantiomer of the compound II may first be reacted with an alkyl chloroformate in presence of a tertiary amine (e.g. triethylamine), subsequently adding the compound III at 0-80°C.
  • a promoting agent e.g. 1-hydroxypiperidine
  • a promoting agent may be added before the compound III, see Albertson, Org. React. , _12, 157 (1962).
  • Another alternative procedure is to convert the (R)-enantiomer of the compound II into the corresponding acyl halide using an inorganic halide (e.g. phosphorus pentachloride, phosphorus trichloride or thionyl chloride) in an aprotic solvent (e.g. chloroform, dichloroethane, dichloromethane, 1, 1, 1-trichloroethane or ethyl acetate), optionally in the presence of a promoting agent (e.g. dimethylformamide) at temperatures ranging between -10 and 65 °C, and then add the compound III. Isolation of the acyl halide before the addition of the compound III is optional.
  • an inorganic halide e.g. phosphorus pentachloride, phosphorus trichloride or thionyl chloride
  • an aprotic solvent e.g. chloroform, dichloroethane, dichloromethane, 1, 1, 1-trichlor
  • the homo-chiral (S)-enantiomers of the compounds I which are obtained may be purified according to known methods, either as bases (e.g. by column chromatography) or as salts (e.g. by re-precipitation or crystallization).
  • the (S)-enantiomers were investigated in vivo in dogs, at different doses in order to assess their pharmacological activity. Their effects on diastolic blood pressure and cardiac contractility were determined. The results show a positive inotropic effect on the heart contractility associated with the expected hypotensive effect. The positive inotropic effect suggests a potential use of these compounds as therapeutic agents for the treatment of heart failure.
  • the invention is illustrated by the following Examples.
  • the organic phase was washed sequentially with brine (4 ml), 10% aqueous sodium carbonate solution (5 x 4 ml), brine (4 ml), IN hydrochloric acid (5 x 5 ml), brine (4 ml), 10% aqueous sodium carbonate solution (2 x 5 ml) and finally with brine (4 ml).
  • the organic phase was dried over anhydrous sodium sulphate and evaporated to dryness in vacuo.
  • the residue was purified by flash chromatography on a silica gel column eluting with petroleum ethe ⁇ acetone 85: 15.
  • the title compound was prepared according to the method described in Example 1 , but using 2,2,N-trimethyl-N-(3,3-diphenylpropyl)-l-amino-3-propanol, prepared as described in Example 2, instead of 2,N-dimethyl-N-(3,3-diphenylpropyl)-l-amino- -2-propanol.
  • the crude was purified by flash chromatography on silica gel column eluting with n-hexane: ethyl acetate graduated from 70:30 to 65:35. The fractions containing the pure base were pooled, the solvents were evaporated in vacuo to dryness, and the residue was dissolved in diethyl ether. After filtration the solution was acidified with 3N ethereal hydrogen chloride and the precipitate was collected by suction and dried at 78°C/15 mmHg to give the title compound, m.p. 116-127°C.
  • the (S)-enantiomers of Examples 1 and 3 were tested for their in vivo pharmacological activity in dogs in comparison to the racemate of the compound of Example 1.
  • Intraventricular and arterial blood pressure were monitored by means of a Millar Mikro-Tip catheter with two pressor sensors inserted in the left ventricle via the left common carotid artery.
  • the right femoral vein was cannulated to allow drug infusion.
  • the following parameters were evaluated: systolic, diastolic and mean blood pressure, left ventricular systolic pressure and first derivative of left ventricular systolic pressure, dP/dt max as an index of cardiac contractility.
  • Figure 1 clearly shows that the racemate of the compound of Example 1 has a potent blood pressure lowering effect (DBP) accompanied by a slight reduction of cardiac contractility (dP/dt max).
  • DBP potent blood pressure lowering effect
  • dP/dt max cardiac contractility
  • Figures 2 and 3 show that the noticeable blood pressure lowering effects of the compounds of Examples 1 and 3 are associated with an increase of dP/dt max, supporting a positive inotropic effect.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

(S)-Enantiomères de composés de formule I dans laquelle Ph est phényle, Ar est 2-nitrophényle, 3-nitrophényle, 2,3-dichlorophényle ou benzofuran-4-yle, A est un groupe alkylène à chaîne ramifiée C3-C6, R est alkyle C1-C6 éventuellement substitué par alcoxy C1-C6, R1 est H, OH ou alkyle C1-C4, R2 est H ou CH3, qui ont un effet inotrope positif sur la contractilité cardiaque et sont utiles dans le traitement de l'insuffisance cardiaque et dans la préparation de médicaments utilisés dans ledit traitement. La préparation des (S)-énantiomères est également décrite.
PCT/EP1996/001978 1995-05-12 1996-05-09 Utilisation de (s)-enantiomeres de derives de 1,4-dihydropyridine pour traiter l'insuffisance cardiaque WO1996035420A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP96919749A EP0825862A1 (fr) 1995-05-12 1996-05-09 Utilisation de (s)-enantiomeres de derives de 1,4-dihydropyridine pour traiter l'insuffisance cardiaque
AU58170/96A AU5817096A (en) 1995-05-12 1996-05-09 Use of(s)-enantiomers of 1,4-dihydropyridine derivatives for treating heart failure
JP08533768A JP2000514776A (ja) 1995-05-12 1996-05-09 心不全を処置するための１，４−ジヒドロピリジン誘導体の（ｓ）−エナンチオマーの使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI95A000956 1995-05-12
IT95MI000956A IT1279529B1 (it) 1995-05-12 1995-05-12 Procedimento di preparazione ed uso degli enantiomeri (s) di derivati 1,4-diidropiridinici per il trattamento dell'insufficienza cardiaca

Publications (1)

Publication Number Publication Date
WO1996035420A1 true WO1996035420A1 (fr) 1996-11-14

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PCT/EP1996/001978 WO1996035420A1 (fr) 1995-05-12 1996-05-09 Utilisation de (s)-enantiomeres de derives de 1,4-dihydropyridine pour traiter l'insuffisance cardiaque

Country Status (5)

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EP (1) EP0825862A1 (fr)
JP (1) JP2000514776A (fr)
AU (1) AU5817096A (fr)
IT (1) IT1279529B1 (fr)
WO (1) WO1996035420A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0153016A2 (fr) * 1984-02-14 1985-08-28 RECORDATI S.A. CHEMICAL and PHARMACEUTICAL COMPANY Diesters asymétriques d'acide 1,4-dihydro-2,6-diméthyl-pyridine-3,5-dicarboxylique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0153016A2 (fr) * 1984-02-14 1985-08-28 RECORDATI S.A. CHEMICAL and PHARMACEUTICAL COMPANY Diesters asymétriques d'acide 1,4-dihydro-2,6-diméthyl-pyridine-3,5-dicarboxylique

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BIANCHI G. ET AL.: "Effects of a new calcium antagonist, Rec 15/2375, on cardiac contractility of conscious rabbits", PHARMACOL. RES., vol. 21, no. 2, 1989, pages 193 - 200, XP002010274 *
BIANCHI G. ET AL.: "Long lasting anti-hypertensive effects after oral Rec 15/2375, a new non-tachycardic calcium entry blocker, in conscious dogs", IRCS MED.SCI., vol. 14, no. 8, 1986, pages 817 - 818, XP002010273 *
DE LORENZI E. ET AL.: "Enantiomeric LC separation of calcium antagonists on protein-based chiral stationary phases", CHIRALITY, vol. 5, no. 8, 1993, pages 622 - 626, XP002010271 *
RECORDATI ET AL.: "Lercanidipine hydrochloride", DRUGS OF THE FUTURE, vol. 20, no. 12, 1995, pages 1284 - 1285, XP002010272 *

Also Published As

Publication number Publication date
EP0825862A1 (fr) 1998-03-04
AU5817096A (en) 1996-11-29
ITMI950956A1 (it) 1996-11-12
JP2000514776A (ja) 2000-11-07
IT1279529B1 (it) 1997-12-16
ITMI950956A0 (it) 1995-05-12

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