Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1986-03-13
1988-08-23
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548195, 548197, C07D41704, A61K 31425
Patent
active
047661372
DESCRIPTION:
BRIEF SUMMARY
This invention relates to new compounds having antiallergic and antianaphylactic action and more particularly to derivatives of 4-(isoxazolyl)-thiazole-2-oxamic acids, their preparation and their use in the pharmaceutical field.
It is known that the disodium cromoglycate (Merck Index, IX ed., page 337) inhibits the release of mediators of allergic reactions provoked by antibody-antigen interactions.
Because of this property the disodium cromoglycate may be used in therapy as an antiallergic agent especially in asthamatic forms.
However, said compound is not absorbed orally and this drawback largely limits its field of applications.
To seek to overcome this drawback numerous other compounds were prepared which progressively modified the structure of the disodium cromoglycate until compounds structurally and chemically different from the parent compound were obtained.
Among these compounds may be mentioned the derivatives of phenyloxamic acid (J. Med. Chem., 21(9), 930, 1978) and 4-aryl-2-thiazole-oxamic acid (UK Patent Application No. 2,023,589--and European Patent Application No. 44442).
It has been now found that a valuable action is attained when the 4-position of a thiazole-2-oxamic acid is substituted by a 3 or a 5-isoxalyl group.
Therefor this invention relates to the compounds of formula: ##STR1## wherein Z is a group of formula ##STR2## in which
R and R.sub.1 which may be the same or different are a hydrogen or a halogen atom, a hydroxy group, a C.sub.1-3 alkoxycarbonyl group, a C.sub.1-3 alkyl group optionally substituted by hydroxy, C.sub.1-3 alkoxy or alkoxy(1-3 C.)oxalyloxy, a C.sub.1-3 alkoxy group optionally substituted by phenyl, or a phenyl group optionally substituted by halogen; and
R.sub.2 is a hydroxy group or OR.sub.3 where R.sub.3 is a C.sub.3-6 cycloalkyl group or a C.sub.1-3 alkyl group optionally substituted by phenyl or C.sub.1-3 alkoxy; and
R.sub.4 is a hydrogen atom or a C.sub.1-3 alkyl group; and when R.sub.2 is a hydroxy group, their pharmaceutically acceptable salts with organic or inorganic bases.
Typical examples of R and R.sub.1 include fluorine, chlorine, bromine, iodine, propoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, methyl, ethyl, propyl, isopropyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, propyloxypropyl, propyloxymethyl, methyloxyethyl, metoxymethyl, ethoxymethyl, ethoxalyloxypropyl (--C.sub.3 H.sub.6 OCOCOOC.sub.2 H.sub.5), propoxalyloxymethyl (--CH.sub.2 OCOCOOC.sub.3 H.sub.7), ethoxalyloxymethyl (--CH.sub.2 OCOCOOC.sub.2 H.sub.5), 2-bromophenyl, 2-iodophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2-chloro-6-fluorophenyl, methoxy, ethoxy, propoxy, phenylethoxy and benzyloxy.
Preferred meanings of R and R.sub.1 are hydrogen, bromine, chlorine, hydroxy, methyl, hydroxymethyl, methoxymethyl, ethoxalyloxymethyl, ethoxycarbonyl, phenyl, 2-chloro-6-fluorophenyl, benzyloxy and methoxy.
Typical examples of R.sub.3 include cyclopropyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, phenylmethyl, phenylethyl, phenylpropyl, methoxymethyl, propoxymethyl, ethoxyethyl, methoxyethyl and methoxypropyl.
Preferred meanings of R.sub.2 are hydroxy and OR.sub.3 wherein R.sub.3 is ethoxyethyl, ethyl, cyclohexyl and phenylmethyl.
Typical examples of organic bases useful for preparing the salts according to this invention are the primary and secondary aliphatic amines optionally substituted by hydroxy and carboxy groups.
Specific examples of said organic bases are methylamine, isopropylamine, hexylamine, diethylamine, ethanolamine, 2-hydroxymethyl-2-amino-1,3-propanediol, glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, arginine, lysine, cystine, cysteine, methionine, phenylalanine, tyrosine, tryptophan, histidine.
Depending on the meaning of the substituents, some of the compounds of formula I can exist in the form of isomers.
The isomers mixtures and the single isomers obtained by separation of the mixtures or by stereospecific synthesis are a further object of this invention.
The preparation of a compound of formula (I) comprises the reac
REFERENCES:
patent: 4246271 (1981-01-01), Cousse
Carenzi Angelo
Chiarino Dario
Della Bella Davide
Grancini Giancarlo
Gerstl Robert
Zambon S.p.A.
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