Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-02-07
1998-12-08
Fan, Jane
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548165, 548166, 548169, C07D27768, A61K 31395
Patent
active
058469893
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB96/02247 now WO 97/10227.
1. Field of the Invention
This invention relates to novel benzothiazolone derivatives, in particular novel 7-(2-aminoethyl)-benzothiazolone derivatives, and to processes for their preparation, pharmaceutical compositions containing them and methods of treatment involving their use. The novel compounds are dopamine DA.sub.2 - receptor agonists and .beta..sub.2 -adrenoreceptor agonists.
2. Background
Benzothiazolone derivatives are known. For example, international patent applications, publication numbers WO92/08708 and WO 93/23385 disclose biologically active amines, among them biologically active aminoethyl benzothiazolone derivatives which are .beta..sub.2 -adrenoreceptor agonists and dopamine DA.sub.2 -receptor agonists, and which are indicated in the treatment of obstructive airways diseases.
WO 93/24473 discloses 7-(2-aminoethyl)-benzothiazolone compounds of formula ##STR2## wherein X and Y are independently --S(O).sub.n --or --O--; n is 0, 1 or 2; p, q and r are independently 2 or 3; Z is phenyl optionally substituted by halogen, OR.sup.1, NO.sub.2 or NR.sup.2 R.sup.3 ; or Z is a 5 or 6 membered N, O or S containing heterocycle; and R.sup.1, R.sup.2 and R.sup.3 are independently hydrogen or alkyl C.sub.1-6. The compounds are .beta..sub.2 -adrenoreceptor agonists and dopamine DA.sub.2 -receptor agonists, and are indicated in the treatment of obstructive airways diseases. We have now found a group of novel 7-(2-aminoethyl)-benzothiazolone derivatives which are useful as dopamine DA.sub.2 -receptor agonists and .beta..sub.2 -adrenoreceptor agonists.
OUTLINE OF THE INVENTION
Accordingly, in one aspect of the present invention there are provided compounds of formula I, including optical isomers thereof, ##STR3## wherein X represents --SO.sub.2 NH-- or --NHSO.sub.2 --, phenylthio- or phenyl optionally substituted by alkyl or halogen, and
The compounds are pharmacologically active. They show both dopamine DA.sub.2 -receptor agonism and .beta..sub.2 -adrenoreceptor agonism. They exhibit little or no .alpha..sub.1 -adrenoreceptor agonism. The compounds have an advantageous duration of action and DA.sub.2 /B.sub.2 ratio.
Preferably, q in formula I above is 2. r is preferably 2.
When Y is phenyl substituted by alkyl, the alkyl group is preferably a C.sub.1-6, for example a C.sub.1 or C.sub.2 group, most preferably methyl.
When Y is phenyl substituted by halogen, the halogen substituent is preferably a chloro- or fluoro-substituent.
Preferred compounds of the present invention are compounds of formula I wherein X is SO.sub.2 NH, p is 3 and q and r are each 2. Other preferred compounds are compounds of formula I wherein X is NHSO.sub.2, and p, q and r are all 2.
Suitable pharmaceutically acceptable salts of the compounds of formula I include acid addition salts derived from inorganic and organic acids. The compounds may also form salts with suitable bases. Examples of suitable salts include the hydrochloride, citrate, D,L-lactate, hemisulphate, hemitatrate, D-gluconate, methanesulphonate, p-toluenesulphonate, hemifumarate, benzoate, xinafoate, hemisuccinate, 3-hydroxy-2-naphthoate, hemiembonate, hemimaleate, D-camphorsulphonate, 10-undecanoate, mandelate, naphthalene-l-sulphonate, naphthalene-2-sulphonate, 4-methoxybenzoate, 4-chlorobenzoate, 5-methylsalicylate, saccharinate, monomethyl suberate, hemisuberate and diphenyl acetate salts.
Suitable pharmaceutically acceptable esters of the compounds of formula I include phenylalkyl and alkyl esters.
Suitable amides include unsubstituted or mono- or di-substituted alkyl or phenyl amides.
The most preferred compounds of the invention are hoxy)ethyl!propanesulphonamide; 1,3-benzothiazol-7-yl)ethylamino!ethyl!-2-(2-phenylethoxy)ethanesulphonami de; -methyl -2-thienyl)ethoxy!ethyl!propanesulphonamide; azol-7-yl)ethylamino! propanesulphonamide; azol-7-yl)ethylamino!propanesulphonamide; -methylphenyl)ethoxy!ethyl!propanesulphonamide; phonamide; -methylphenyl)ethoxy!ethyl!propanesulphonamide; and phenylthioethox
REFERENCES:
"Synthesis and Evaluation of Non-Catechol D-1 and D-2 Dopamine Receptor Agonists: Benzimidazol-2-one, Benzoxazol-2-one, and the Hightly Potent Benzothiazol-2-one 7-Ethlamines" Joseph Weinstock et al., Journal of Chemistry, vol. 30, pp. 1166-1176.
Bonnert Roger Victor
Brown Roger Charles
Cage Peter Alan
Ince Francis
Pairaudeau Garry
Astra Pharmaceuticals Limited
Fan Jane
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