EP0594595A1 - Neue 4-methyl-thiazol-derivate, verfahren zur herstellung und diese verbindungen enthaltende arzneimittel - Google Patents

Neue 4-methyl-thiazol-derivate, verfahren zur herstellung und diese verbindungen enthaltende arzneimittel

Info

Publication number
EP0594595A1
EP0594595A1 EP91904815A EP91904815A EP0594595A1 EP 0594595 A1 EP0594595 A1 EP 0594595A1 EP 91904815 A EP91904815 A EP 91904815A EP 91904815 A EP91904815 A EP 91904815A EP 0594595 A1 EP0594595 A1 EP 0594595A1
Authority
EP
European Patent Office
Prior art keywords
methyl
piperazinyl
thiazole
thiazolyloxy
propanol
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Withdrawn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
EP91904815A
Other languages
English (en)
French (fr)
Inventor
Fabienne Jobart-Rouppert
Patrick Houziaux
Jean-Pierre Riffaud
Jean-Yves Lacolle
Patrick Saur
Bernard Danree
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.)
Institut de Recherches Chimiques et Biologiques Appliquees SARL IRCEBA
Original Assignee
Institut de Recherches Chimiques et Biologiques Appliquees SARL IRCEBA
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 Institut de Recherches Chimiques et Biologiques Appliquees SARL IRCEBA filed Critical Institut de Recherches Chimiques et Biologiques Appliquees SARL IRCEBA
Publication of EP0594595A1 publication Critical patent/EP0594595A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/34—Oxygen atoms
    • 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

Definitions

  • New derivatives of 4-methyl-thiazole processes for their preparation and pharmaceutical compositions containing them.
  • the subject of the present invention is new derivatives of 4-methyl-thiazole, more specifically amino derivatives of 4-methyl-5-thiazole, their methods of preparation and pharmaceutical compositions containing them.
  • the compounds according to the invention are derivatives of 4-methyl thiazole corresponding to the general formula:
  • R 1 and R 2 are chosen from a hydrogen atom, a halogen atom, a hydroxy group, a trifluoromethyl group, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms.
  • the invention also includes within its scope all the possible optical isomers of the compounds of formula (I) as well as their mixtures.
  • the invention also includes within its scope the salts of the above-mentioned compounds of formula (I).
  • a halogen atom is preferably a chlorine or fluorine atom.
  • the alkyl and alkoxy groups can be straight or branched chain groups.
  • An alkyl group having from 1 to 4 carbon atoms is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl group, preferably methyl or ethyl.
  • alkoxy group having from 1 to 5 carbon atoms is for example a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiobutoxy, n-pentoxy, isopentoxy or neopentoxy group, preferably methoxy, ethoxy, propoxy or isopropoxy.
  • the general process for the preparation of the compounds according to the invention, of formula (I), as defined above, in laguelle n is equal to 0 comprises the condensation reaction of 5-bromo-4-methyl-thiazole on the sodium salt d 'a (4-aryl piperazinyl-1) -2-ethanol of formula:
  • R 1 and R 2 have the same meaning as indicated above.
  • 5-bromo-4-methyl-thiazole is obtained by bromination of 2-amino-4-methyl-thiazole under conditions allowing the obtaining of 2-amino-5-bromo-4-methyl-thiazole;
  • Amino-2-methyl-4 thiazole is a known product, the preparation process of which is described in the literature (Merck Index, 10th edition, n ° 454).
  • R 1 and R 2 have the same meaning as indicated above.
  • (4-methyl-5 thiazolyloxy) -3-1,2-epoxy propane is obtained by:
  • Glycerol acetonide (or 2,2-dimethyl-1,3-dioxolane-4 methanol), sold by the company ALDRICH, is a known product whose preparation process is for example described in Beilstein 19, 65, Merck Index 10, 3236.
  • the compounds of formula (I) according to the invention and their pharmaceutically acceptable salts have advantageous pharmacological properties which suggest a therapeutic application of these compounds in particular in the treatment of cardiovascular manifestations linked to hyperactivity of the sympathetic nervous system of type ⁇ -adrenergic.
  • the invention also aims to cover new pharmaceutical compositions, characterized in that they contain, in combination with a pharmaceutically acceptable excipient, at least one compound of formula (I) or its non-toxic addition salt, as a principle active.
  • the pharmaceutically acceptable salts of the compounds of formula (I) are obtained in a manner known per se, by bringing the products of formula (I) into contact with a suitable quantity of pharmaceutically acceptable acid such as for example a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as citric, tartaric or fumaric acid.
  • a suitable quantity of pharmaceutically acceptable acid such as for example a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as citric, tartaric or fumaric acid.
  • compositions according to the invention can generally be prepared by conventional methods and administered in an appropriate pharmaceutical form.
  • the compounds can be administered, for example, orally in 1 to 3 doses per day, at a rate of 2 to 2 mg per dose depending on the compound, for example in the treatment of cardiovascular manifestations linked to hyperactivity of the sympathetic nervous system of ⁇ -adrenergic type.
  • the invention aims to cover a process for the preparation of a pharmaceutical composition, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) as defined above is incorporated, or a non-toxic addition salt of this compound, in a pharmaceutically acceptable excipient.
  • the invention aims to cover a method for the treatment of cardiovascular manifestations linked to hyperactivity of the sympathetic nervous system of the oc-adrenergic type, characterized in that it comprises administration to a mammal comprising man and l animal, of a therapeutically effective amount of at least minus a compound of formula (I) as defined above, or of a pharmaceutically acceptable addition salt of this compound.
  • Step 1 Synthesis of 2-amino-5-bromo-4-methyl-thiazole.
  • reaction medium is then filtered and the hydrobromide is washed with dichloromethane, then with pentane.
  • the hydrobromide is dissolved in 2000 ml of water, then basified by the addition of 850 ml of 10% aqueous sodium bicarbonate solution.
  • Step 2 Synthesis of 4-methyl-5-bromo thiazole.
  • the reaction medium is left under stirring at this temperature for 30 min.
  • the hypophosphorous acid (50%, 197 ml) is then added slowly to the reaction medium at -10 ° C.
  • the reaction medium supplemented with dichloromethane is centrifuged at 3000 rpm for 15 min. After decantation and evaporation under vacuum of the solvent, the (4-o-ethoxyphenyl-piperazinyl-1) -2 ethanol is removed by fractional distillation under reduced pressure. The distillation residue is purified by chromatography on a column of silica gel (AcOEt).
  • the hydrochloride is prepared in anhydrous ethyl ether by addition of dry HCl gas, then recrystallized from a mixture of isopropanol and pentane.
  • Step 1 Synthesis of (4-methyl-5 thiazolyloxy) -3-1,2-propanediol acetonide.
  • 5-bromo-4-methyl thiazole can be obtained by following the experimental process described in steps 1 and 2 of Example 1.
  • the reaction medium is stirred for 15 h.
  • the hydrochloride is crystallized from a mixture of isopropanol and ethyl ether.
  • the base is released by adding a 10% sodium bicarbonate solution, then purified by recrystallization from a mixture of ethyl acetate and pentane (80/20). 19.1 g of white crystals are obtained.
  • the reaction medium is heated for 10 h at 70 C.
  • the filtrate is concentrated to dryness under reduced pressure and the (methyl -4 thiazolyloxy-5) -3 epoxy-1,2 propane is purified by chromatography on a column of silica gel (AcOEt). 6.75 g of epoxide are obtained, in the form of a pale yellow oil.
  • Step 4 Synthesis of (4-o-propoxyphenyl-1 piperazinyl-1) -3 (4-methylthiazolyloxy-5) -1-propanol-2 monohydrochloride (B 1395).
  • the reaction medium is heated at 40 ° C for 21 h.
  • the solvent is removed by distillation under reduced pressure.
  • the monohydrochloride is obtained by adding a stoichiometric amount of an ethanolic solution of hydrochloric acid previously dosed, in an ethanolic solution of the base cooled by an ice bath. After 1 h of stirring and elimination of the ethanol by distillation under reduced pressure, the product is crystallized from a mixture of ethyl ether and acetone and then recrystallized from acetone.
  • mice I. Acute toxicity in mice.
  • the products were administered orally at a single dose in male mice weighing 22 g. Mortality was recorded after a 14-day observation period.
  • LD 50 lethal dose 50
  • the concentration of product is determined in the presence of which the concentration of noradrenaline must be multiplied by two to obtain the same effect as in the absence of said product.
  • the logarithm changed sign of this concentration constitutes the pA 2 of the products.
  • noradrenaline 0.4 mg.kg -1
  • the prior administration of a substance with an alpha-blocking property makes it possible to reduce this toxicity.
  • B 1431, B 1510, B 1525, B 1548 and B 1552 prove to be particularly active in the whole animal, thus confirming their action demonstrated in vitro.
  • Blood pressure is measured by catheterization of the left carotid artery in the anesthetized male rabbit.
  • the increase in blood pressure is induced by an intravenous injection of norepinephrine. This hypertension can be inhibited by the prior administration of molecules with alpha-blocking potential.
  • ID 50 50% inhibitory dose
  • ID 50 the dose of product which, administered by IV, inhibits by 50% the arterial hyperpressure.
  • Compound B 1395 is particularly effective with an active dose of less than 1 mg.kg V. Determination of cardiovascular activity
  • the products are administered intravenously in increasing doses. Three animals are tested per product. The dose causing a 25% drop in average blood pressure
  • the products have dose-dependent hypotensive effects but have little or no effect on the heart rate (Table 7).
  • the most hypotensive in terms of effective dose is B 1395 (DE 25 at 0.004 mg.kg -1 ).
  • the ED 25 evaluated 5 min after injection make it possible to locate the hypotensive potential of the products B 1395, B 1396, B 1431 and B1552 at the level of Nicardipine.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP91904815A 1990-02-19 1991-02-14 Neue 4-methyl-thiazol-derivate, verfahren zur herstellung und diese verbindungen enthaltende arzneimittel Withdrawn EP0594595A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9001979 1990-02-19
FR9001979A FR2658514B1 (fr) 1990-02-19 1990-02-19 Nouveaux derives du methyl-4 thiazole, leurs procedes de preparation et les compositions pharmaceutiques en contenant.
PCT/FR1991/000118 WO1991012246A1 (fr) 1990-02-19 1991-02-14 Nouveaux derives du methyl-4 thiazole, leurs procedes de preparation et les compositions pharmaceutiques en contenant

Publications (1)

Publication Number Publication Date
EP0594595A1 true EP0594595A1 (de) 1994-05-04

Family

ID=9393877

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91904815A Withdrawn EP0594595A1 (de) 1990-02-19 1991-02-14 Neue 4-methyl-thiazol-derivate, verfahren zur herstellung und diese verbindungen enthaltende arzneimittel

Country Status (8)

Country Link
US (1) US5322846A (de)
EP (1) EP0594595A1 (de)
JP (1) JPH05503537A (de)
CA (1) CA2075998A1 (de)
FR (1) FR2658514B1 (de)
IE (1) IE910540A1 (de)
PT (1) PT96808A (de)
WO (1) WO1991012246A1 (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE203012T1 (de) * 1994-03-30 2001-07-15 Zeria Pharm Co Ltd 4-indol-1-yl-buttersäure derivate, deren herstellung und deren verwendung als inhibitoren für alpha1-adrenerge rezeptoren und testosteron 5alpha-reduktasen
DE19728996A1 (de) 1997-07-07 1999-01-14 Basf Ag Triazolverbindungen und deren Verwendung

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE756127A (fr) * 1969-09-12 1971-03-15 Hoechst Ag Ethers heterocycliques et leur preparation
US3850946A (en) * 1972-07-10 1974-11-26 Syntex Inc 3-thiazol-5'-oxy-aminopropanol cardiovascular agents
FR2209557A1 (en) * 1972-12-12 1974-07-05 Roussel Uclaf Piperazo alkyl thiazolyl ketones/ethers - adrenolytics and antihypertensives prepd. from a piperazine and a halo alkyl thiazole
FR2637596B1 (fr) * 1988-10-11 1992-09-04 Irceba Methyl-4 ((aryl-4 piperazinyl-1)-2 ethyl)-5 thiazole et ses derives, leur procede de preparation et les medicaments en contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9112246A1 *

Also Published As

Publication number Publication date
CA2075998A1 (en) 1991-08-20
IE910540A1 (en) 1991-08-28
JPH05503537A (ja) 1993-06-10
US5322846A (en) 1994-06-21
FR2658514B1 (fr) 1992-06-19
PT96808A (pt) 1991-10-31
WO1991012246A1 (fr) 1991-08-22
FR2658514A1 (fr) 1991-08-23

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