EP0000032B1 - Thiazoles di- et tri-substitués; leur préparation, leur utilisation dans des médicaments et composés intermidiaires - Google Patents

Thiazoles di- et tri-substitués; leur préparation, leur utilisation dans des médicaments et composés intermidiaires Download PDF

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EP0000032B1
EP0000032B1 EP78100053A EP78100053A EP0000032B1 EP 0000032 B1 EP0000032 B1 EP 0000032B1 EP 78100053 A EP78100053 A EP 78100053A EP 78100053 A EP78100053 A EP 78100053A EP 0000032 B1 EP0000032 B1 EP 0000032B1
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alkyl
compounds
formula
hydrogen
thiazole
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EP0000032A1 (fr
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John James Baldwin
Gerald Salvatore Ponticello
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • 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
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
    • 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
    • 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
    • C07D277/36—Sulfur atoms
    • 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention involves novel di- and tri- substituted thiazoles having pharmaceutical activity and ⁇ -adrenergic blocking agents.
  • Thiazoles having an aminohydroxypropoxy substituent in the 2-position with or without a specific additional substituent in the 4 or 5-position are known and are taught to have ⁇ -adrenergic stimulating activity (U.S. 3,850,945).
  • Thiazoles having an aminohydroxypropoxy substituent in the 4 or 5-position with no additional substitution are also known and are taught to have ⁇ -adrenergic stimulating activity (U.S. 3,850,947, U.S. 3,850,946).
  • Thiazoles having the aminohydroxypropoxy substituent in the 2-position with an aminocarbonyl, formamido, substituted oxycarbonyl amino group in the 4 or 5-position are known and taught to have ⁇ -adrenergic blocking activity (U.S. 3,897,411).
  • Thiazoles having the following formula are known and are taught to be ⁇ -adrenergic blocking agents. (U.S. 3,897,442). Thiazoles of the formula are known and are taught to block ⁇ -adrenergic receptors (U.S. 3,932,400).
  • thiazoles having a 4(3-amino-2-OR-propoxy) substituent have been discovered.
  • the thiazoles are active as ⁇ -adrenergic blocking agents.
  • An embodiment of the present invention is compounds having the formula and pharmaceutically acceptable salts thereof or wherein
  • the pharmaceutically acceptable salts are the acid addition salts of the formula I free base.
  • Suitable acids include organic as well as inorganic acids.
  • useful organic acids are carboxylic acids such as acetic acid, 2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylic acid, maleic acid, succinic acid, citric acid, tartaric acid, oxalic acid, malic acid, pivalic acid, heptanoic acid, lauric acid, propanoic acid, pelargonic acid, oleic acid, and non-carboxylic acids such as isethionic acid.
  • useful inorganic acids are the hydrogen halides i.e., HCI, HBr and HI, phosphoric acid, sulfuric acid.
  • R may be hydrogen, C 2 ⁇ C 12 acyl or C 7 ⁇ C 12 aroyl.
  • the C 2 ⁇ C 12 groups include alkanoyl groups such as acetyl, pivaloyl, dodecanoyl, hexanoyl, succinoyl; carbocyclic aroyl groups include groups such as benzoyl, 1- or 2- naphthoyl, p-methylbenzoyl, p-phenylbenzoyl.
  • the C 2 ⁇ C 6 alkanoyl and benzoyl groups are preferred acyl groups and aroyl groups, respectively. Hydrogen is the most preferred R group.
  • the R i substituent comprises C 1 ⁇ C 12 alkyl groups and preferably the C 1 ⁇ C 6 alkyl groups.
  • the alkyl groups are exemplified by methyl, C 12 H 25 , hexyl, 2-ethylhexyl, isopropyl, sec-butyl,, heptyl.
  • the C 3-4 branched chain alkyl R 1 groups are more preferred, with t-butyl being the most preferred group.
  • R 2 includes H, CF 3 , C 6 ⁇ C 12 carbocyclic aryl such as phenyl, monosubstituted phenyl e.g. p-tolyl, o-halophenyl, p-nitrophenyl, p-methoxyphenyl and p-halophenyl; indanyl; 1- or 2-naphthyl, 6- membered-N-heteroaryl such as 2-, 3- or 4-pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, thienyl, furfuryl, C 1 ⁇ C 6 alkyl, e.g.
  • R 2 groups are hydrogen, C 1 ⁇ C 6 alkyl and C 1 ⁇ C 6 alkylthio, especially CH 3 ⁇ S.
  • the R 3 substituent includes CF 3 , C 1 ⁇ C 6 alkyl, CN, C 6 ⁇ C 12 carbocyclic aryl such as phenyl, carboxylic acid esters and amides.
  • the C 1 ⁇ C 6 alkyl groups are exemplified by CH 3 , isopropyl.
  • the ester group is C 1 ⁇ C 6 alkylester exemplified by ⁇ COOCH 3 , ⁇ COOC 6 H 13 , ⁇ COOCH(CH 3 ) 2 , ⁇ COOC 2 H 5 and C 6 ⁇ C 12 arylester, preferably carbocyclic aryl, exemplified by C 6 H 5 ⁇ OOC ⁇ , p ⁇ CH 3 ⁇ C 6 H 4 ⁇ OOC ⁇ , p ⁇ C 6 H 5 ⁇ C 6 H 4 ⁇ OOC ⁇ , C 9 H 9 ⁇ OOC ⁇ .
  • the amide group includes -CONH 2 , C 1 ⁇ C 6 substituted amide groups such as ⁇ CON(CH 3 ) 2 , ⁇ CON(C 6 H 13 ) 2 , ⁇ CONHC 2 H 5 , -CON (sec. butyl) 2 and carbonyl heterocyclic groups such as of the R 3 groups, CN, CF 3 and amide, especially CONH 2 , are preferred.
  • the formula I compounds have a chiral center (at the 2 carbon in the propoxy substituent) which confers optical activity.
  • the optical isomers are designated conventionally as L and D, 1 and d, + and -, S and R or by combinations of these symbols. Where the formula or compound name herein carries no specific designation, the formula or name includes the individual isomers, the mixtures thereof and racemates.
  • the thiazole compounds which are preferred have the formula Formula II. compounds where R 2 is H, C 1 ⁇ C 6 alkylthio, preferably CH 3 ⁇ S ⁇ , or said heteroaryl groups, especially pyridyl, R 3 is CN, CF 3 , amide, C 1 ⁇ C 6 alkyl or said ester groups and R 1 is C 1 ⁇ C 6 alkyl especially C 3 ⁇ C 4 branched alkyl are more preferred.
  • R 2 is said alkylthio or heteroaryl
  • R 3 is CN, CF 3 , CONH 2 , C 1 ⁇ C 6 alkyl or said ester groups and R 1 is C 3 ⁇ C 4 branched alkyl.
  • Another preferred group of thiazoles has the formula where R 2 is H, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkylthio or pyridyl, R 3 is CN, CF 3 , C 1 ⁇ C 6 alkyl or CONH 2 .
  • said branched alkyl is tert.-butyl
  • R 2 is H, CH 3 , CH 3 S or pyridyl
  • R 3 is CN, CH 3 , CONH 2 or CF 3
  • the thiazoles where said branched alkyl is tert.-butyl, R 2 is H, CH 3 S or pyridyl and R 3 is CN or CONH 2 are particularly preferred.
  • optical isomers those having the S-isomer configuration are preferred.
  • the thiazoles of the present invention have ⁇ -adrenergic blocking activity. This was determined in an in-vivo test using dogs as the test animals. In this test, representative thiazole compounds, were found to counteract the ⁇ -adrenergic stimulating effect of isoproterenol.
  • Certain of the present thiazoles also exhibit an antihypertensive effect of immediate onset when administered to a spontaneously hypertensive (SH) rat.
  • SH spontaneously hypertensive
  • the present thiazoles also show random vasodilator activity.
  • the present thiazole compounds will effect ⁇ -adrenergic blockade in humans.
  • This ⁇ -adrenergic blocking effect is useful in the therapeutic treatment of various cardiovascular conditions such as angina pectoris, arrhythmia etc.
  • the daily dosage may range from about 1.5 mg. to about 3000 mg.
  • Preferred daily dosages are about 6.5 mg. to about 200 mg.
  • Conventional dosage forms suitable for oral as well as parenteral, e.g. intravenous, intraperitoneal etc., administration are used.
  • Oral dosage forms include tablets, capsules, troches, liquid formulations e.g.
  • solutions, emulsions, elixirs, etc.-parenteral dosage forms include liquid formulations especially solutions.
  • the compositions are prepared using conventional procedures and compounding ingredients such as starch, sterile water, flavoring additivies, antioxidants, binders, vegetable oils, sweetening agents, glycerine.
  • Thiazoles which exhibit the immediate onset antihypertensive activity are useful for treating hypertensive humans at daily dosages ranging from about 100 to about 3000 mg. administered in oral or parenteral dosage forms.
  • the present thiazoles can be prepared by any convenient process.
  • Z is an alkyl sulfonyl or arylsulfonyl group.
  • sulfonyl groups are CH 3 ⁇ SO 2 , C 6 H 5 ⁇ SO 2 , NO 2 ⁇ C 6 H 4 SO 2 ⁇ , p ⁇ CH 3 ⁇ C 6 H 4 ⁇ SO 2 ⁇ , mesitylene ⁇ SO 2 ⁇ , CH 3 O ⁇ C 6 H 4 ⁇ SO 2 ⁇ , trichlorobenzene ⁇ SO 2 ⁇ ; C 16 H 33 ⁇ SO 2 ⁇ .
  • Suitable bases are alkali metal bases such as K 2 CO 3 , K ⁇ O ⁇ C(CH 3 ) 3 , NaH, organolithiums e.g. phenyllithium, n-butyllithium, lithium diisopropyl amide.
  • R 6 is hydrogen or a C 1 ⁇ C 12 alkyl or C 6 ⁇ C 12 carbocyclic aryl residue of any suitable aldehyde
  • suitable aldehydes are the aryl aldehydes such as benzaldehyde, naphthaldehyde 4-phenylbenzaldehyde, furfural, bromobenzaldehyde. tolualdehyde, mesitaldehyde or an alkanal such as acetaldehyde, butyraldehyde,
  • Z is hydrogen (and a related coupling reaction) is disclosed in U.S. 3,718,647 and U.S. 3,657,237.
  • the coupling reaction can be carried out at temperatures ranging from 0°C. to 130°C. A temperature range of 50°C. to 130°C. is preferred.
  • the reaction is generally carried out in a solvent. Any suitable solvent may be used. Examples of useful solvents are dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, tert, butanol, dioxane, toluene, acetone.
  • the hydrolysis is carried out using a conventional acid system e.g. by treatment with a solution of any suitable acid such as HCI, H z S0 4 , CH 3 COOH.
  • the hydrolysis product can be directly obtained as the salt of the acid used for the hydrolysis. Ordinarily, the product IA is recovered as the free base after conventional neutralization of the salt.
  • the coupling reaction is ordinarily carried out at atmospheric pressure. Higher pressures may be used if desired.
  • the product is obtained as a racemate.
  • the racemate may be separated into its individual enantiomers by conventional resolution techniques.
  • R 6 in the oxazolidine (e.g. formula V or VI) is other than hydrogen, in addition to the chiral center at oxazolidine position 5 there is a second chiral center at position 2.
  • R 6 in the oxazolidine e.g. formula V or VI
  • this designation refers only to the optical configuration around the carbon atom at the 5 position.
  • the thiazole product (IA) may be obtained directly as a single enantiomer. This provides a convenient way for directly preparing individual isomers of the present thiazoles.
  • Thiazoles represented by formula I wherein R is other than hydrogen are conveniently prepared by treating the corresponding thiazole where R is hydrogen with an appropriate acylating agent such as an acyl halide, e.g. undecanoyl chloride, pivaloyl chloride, benzoylchloride, p-methoxybenzoyl chloride, or an anhydride e.g. acetic anhydride.
  • an acylating agent such as an acyl halide, e.g. undecanoyl chloride, pivaloyl chloride, benzoylchloride, p-methoxybenzoyl chloride, or an anhydride e.g. acetic anhydride.
  • the compounds of the present invention also include the pharmaceutically acceptable salts of the novel thiazoles. These salts are conveniently prepared e.g. by treating the thiazole with an appropriate amount of a useful acid, generally in a suitable solvent.
  • the thiazoles having an alkylsulfonyl or alkylsulfonyl substituent are prepared by oxidizing the corresponding C 1 ⁇ C 6 alkylthio containing compound. Any suitable oxidizing agent, e.g. H 2 O 2 , may be used. The following equation illustrates the reaction
  • the solution is cooled to 0-10°C., poured into H 2 0 (100 ml.) and extracted with ether (3 x 100 ml.).
  • the organic layer is extracted with 1 N HCI (2 x 50 mi.) and the acid layer added to NaOAc (8.2 g., 0.1 m).
  • the solution is extracted with ether (2 x 50 ml.).
  • the aqueous layer is neutralized with saturated Na 2 CO 3 and extracted with CHCl 3 (3 x 100 ml.).
  • the organic layer is dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the residue is chromatographed on alumina (activity grade II, E.
  • ethyl-4-hydroxy-2-methylthiothiazole-5-carboxylate (20 g., 0.091 m), DMF (200 ml.) and NaH (50% mineral oil, 5.0 g., 0.104 m).
  • a solution of the tosylate of (S)-2-phenyl-3-tert.butylamino-5-hydroxymethyloxazolidine (0.106 m) in DMF (150 ml.) is added at room temperature and the solution heated on a steam bath with stirring. After 15 hours, the solution is cooled to 0-10°C., poured into H 2 0 (1 I.) and extracted with ether (3 x 300 ml.).
  • Example 1A Using the procedure of Example 1A, ethyl 4-hydroxy-2-methylthiazole-5-carboxylate (9.35 g., 0.05 m), DMF (100 ml.), NaH (57% mineral oil, 2.5 g., 0.052 m) and the tosylate of 2-phenyl-3-tert.butylamino-5-hydroxymethyloxazolidine (0.053 m) in DMF (100 ml.) are reacted to yield 4.7 g. (30%) of ethyl 3-methyl-4-(3-tert.butylamino - 2 - hydroxypropoxy)thiazole-5-carboxylate.
  • Example 2 Using the procedure of Example 1 B, ethyl 2-methyl-4(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate (4 g., 0.014 m), MeOH (90 mi.) and liquid NH 3 (33 g.) are heated to yield 1.3 g. (22%) of 5-carbamoyl-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogen maleate salt hemihydrate, m.p. 177-78°C.
  • Example 1A Using the procedure of Example 1A, ethyl 4-hydroxy-2-methylthiazole-5-carboxylate (28 g., 0.15 m), DMF (500 mi.), NaH (50% mineral oil, 7.5 g., 0.16 m) and the tosylate of (S) 2-phenyl-3-tert.butylamino-5-hydroxymethyloxazolidine (0.15 m) in DMF (100 ml.) are reacted to yield 9.8 g. (20%) of (S) ethyl 2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate.

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Claims (17)

1. Composés ayant la formule:
Figure imgb0031
et leurs sels pharmaceutiquement acceptables, ou
Figure imgb0032
où
R est de l'hydrogène, un groupe acyle en C2―C12 ou un groupe aroyle en C7―C12,
R1 est un groupe alcoyle en C1―C12.
R2 est de l'hydrogène, CF3, un groupe aryle carbocyclique en C6―C12, aryle monosubstitué, N-hétéroaryle hexagonal, alcoyle en C1―C6, alkoylthio en C1―C6, alcoylsulfinyle en C1―C6, alcoylsulfonyle en C1―C6, thiényle ou furfuryle,
R3 est un groupe alcoyle en C1―C6, -COO-alcoyle n C1―C6, -COO-aryle en C6―C12, cyano, aryle carbocyclique en C6―C12, CF3 ou
Figure imgb0033
où R4 et R5 sont choisis indépendamment parmi H et les groupes alcoyle en C1―C6 ou sont reliés pour former avec l'atome d'azote
Figure imgb0034
avec la condition que quand R2 est un groupe phényle, alors R3 est autre qu'un groupe alcoyle en C1―C6 ou ―COO-atcoyle en C1―C6; et
R6 dans la formule VI est de l'hydrogène, un groupe alcoyle en C1―C12 ou aryle carbocyclique en C6―C12, de sorte que quand R3 est ―COOC2H5, R2 doit être un groupe -S-alcoyle en C1―C6.
2. Composés selon la revendication 1, caractérisés en ce que R est de l'hydrogène et R, est un groupe alcoyle à chaîne ramifiée en C3―C4.
3. Composés selon la revendication 2, caractérisés en ce que R2 est un groupe alcoyle en C1―C6.
4. Composés selon la revendication 2, caractérisés en ce que R2 est un groupe aryle carbocyclique en C6―C12.
5. Composés selon la revendication 2, caractérisés en ce que R2 est un groupe alcoylthio en C1―C6.
6. Composés selon la revendication 5, caractérisés en ce que R2 est ―COOC2H5.
7. Composés selon la revendication 2, caractérisés en ce que R3 est CN,
Figure imgb0035
ou un groupe alcoyle en C1―C6.
8. Composés selon la revendication 7, caractérisés en ce que R3 est -CONH2.
9. Composés selon la revendication 2, caractérisés en ce que RI est un groupe t-butyle, R2 est un groupe phényle et R3 est un groupe
Figure imgb0036
ou -CN.
10. Composés selon la revendication 2, caractérisés en ce que RI est un groupe t-butyle, R2 est CH3―S― et R3 est ―COOC2H5 ou
Figure imgb0037
11. Composés selon la revendication 2, caractérisés en ce que R1 est un groupe t-butyle, R2 est ―CH3 et R3 est
Figure imgb0038
ou -CN.
12. Composés selon la revendication 2, caractérisés en ce que R1 est un groupe t-butyle, R2 est H et R3 est -CN.
13. Composés selon la revendication 1, caractérisés en ce qu'ils ont la configuration de l'isomère S.
14. Composition pharmaceutique pour effectuer un blocage bêta-adrénergique, caractérisées en ce qu'elles contiennent une quantité efficace d'un composé I de la revendication 1.
15. Composés selon la revendication 1, formule VI, caractérisés en ce que R1 est un groupe alcoyle à chaîne ramifiée en C3―C4 et R6 est H ou un groupe phényle.
16. Procédé pour la préparation des composés selon la revendication 1, formule I, dans lesquels R est de l'hydrogène, caractérisé en ce qu'on hydrolyse une oxazolidine de la formule:
Figure imgb0039
dans laquélle R1, R2 et R3 sont tels que définis dans la revendication 1 et R6 est de l'hydrogène, un groupe alcoyle en C1―C12 ou un groupe aryle carbocyclique en C6―C12.
17. Procédé pour la préparation des composés selon la revendication 1, formule I, dans lesquels R est un groupe acyle en C2―C12, caractérisé en ce qu'on acyle un composé ayant la formule:
Figure imgb0040
dans laquelle R1, R2 et R3 sont tels que définis dans la revendication 1.
EP78100053A 1977-06-01 1978-06-01 Thiazoles di- et tri-substitués; leur préparation, leur utilisation dans des médicaments et composés intermidiaires Expired EP0000032B1 (fr)

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US80240377A 1977-06-01 1977-06-01
US802403 1977-06-01
US05/897,075 US4260609A (en) 1977-06-01 1978-04-17 Di- and tri- substituted thiazoles

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EP0000032B1 true EP0000032B1 (fr) 1982-05-19

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Publication number Priority date Publication date Assignee Title
US4571402A (en) * 1982-06-22 1986-02-18 Schering Corporation Anti-bronchoconstriction 2-(4'-pyridinyl)-thiazole derivatives, composition, and method of use therefor
US4528291A (en) * 1982-06-22 1985-07-09 Schering Corporation 2-(4'-Pyridinyl)-thiazole compounds and their use in increasing cardiac contractility
US4446150A (en) * 1982-09-21 1984-05-01 Ayerst, Mckenna & Harrison, Inc. Naphthalenylthiazole derivatives
IE900394L (en) * 1989-02-08 1990-08-08 Abbott Lab Thiazole derivatives
EP2266607A3 (fr) 1999-10-01 2011-04-20 Immunogen, Inc. Des immunoconjugués pour le traitement des cancers.
CA2617953C (fr) * 2005-08-09 2013-12-17 Millennium Pharmaceuticals, Inc. Procede d'acylation de maytansinol a l'aide d'aminoacides chiraux
EP1806365A1 (fr) 2006-01-05 2007-07-11 Boehringer Ingelheim International GmbH Anticorps spécifiques pour la protéine alpha d'activation de fibroblastes et leurs immunoconjugués

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Publication number Priority date Publication date Assignee Title
BE790569A (fr) * 1971-10-27 1973-04-26 Syntex Corp Agents cardiovasculaires a base de thiazoles
US3850947A (en) * 1972-07-10 1974-11-26 Syntex Inc 3-thiazol-4'-oxy-aminopropanol cardiovascular agents
US3850946A (en) * 1972-07-10 1974-11-26 Syntex Inc 3-thiazol-5'-oxy-aminopropanol cardiovascular agents
GB1435139A (en) * 1972-08-17 1976-05-12 Sumitomo Chemical Co Thiazole derivatives

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US4260609A (en) 1981-04-07
JPS631308B2 (fr) 1988-01-12
EP0000032A1 (fr) 1978-12-20

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