Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-03-03
1999-07-27
Ambrose, Michael G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548169, 548171, A61K 31425, C07D27768
Patent
active
059291001
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to novel benzothiazolone ethanamines, processes for their preparation, pharmaceutical compositions containing them and methods of treatment involving their use. The novel compounds are indicated for use as dopamine DA.sub.2 -receptor agonists and .beta..sub.2 -adrenoreceptor agonists.
BACKGROUND
Benzothiazolone derivatives are known. For example, international patent applications, publication numbers WO92/08708 and WO93/23385 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 reversible 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 reversible obstructive airways diseases.
We have now found a group of novel benzothiazolone ethanamines which are indicated for use as dopamine DA.sub.2 -receptor agonists and .beta.-adrenoreceptor agonists.
OUTLINE OF THE INVENTION
Accordingly, in one aspect of the present invention there are provided compounds of formula I, ##STR3## wherein X represents naphthyl 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 /.beta..sub.2 ratio.
Preferably, p in formula I above is 3. q is preferably 2. r is preferably 2. X is preferably unsubstituted naphthyl.
Where X is alkyl-substituted naphthyl, the substituent may be selected from straight- or branched-chain C.sub.1-6 alkyl, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, straight- or branched-chain pentyl or straight or branched-chain hexyl. Preferred halogen substituents are F, Cl and Br. Where the alkyl substituent is chiral, optical isomers may be formed and are included in the scope of the present invention. Also included in the scope of the present invention are tautomers of the compounds of formula I.
Pharmaceutically acceptable salts of the compound of formula I include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxybenzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, benzenesulphonates, p-toluenesulphonates, naphthalenesulphonates, methanesulphonates, sulphamates, ascorbates, salicylates, acetates, diphenylacetates, triphenylacetates, adipates, fumarates, succinates, lactates, glutarates, gluconates, hydroxy-naphthalenecarboxylates, e.g. 1-hydroxy or 3-hydroxy-2-naphthalenecarboxylates, or oleates. The compounds may also form salts with suitable bases. The compound of formula I may be obtained in the form of a salt, conveniently a pharmaceutically acceptable salt. Where desired, such salts may be converted to the free bases using conventional methods. Pharmaceutically acceptable salts may be prepared by reacting the compound of formula I with an appropriate acid or base in the presence of a suitable solvent.
The present invention also provides a process for preparing compounds of formula I, comprising the selective reduction of a compound of formula II, ##STR4## in which p, q, r, and X are as defined above.
Suitable reducing agents include electrophilic reducing agents, e.g., diborane and alane (aluminium hydride), or nucleophilic reducing agents,
REFERENCES:
patent: 5648370 (1997-07-01), Bonnert et al.
patent: 5763465 (1998-06-01), Bonnert et al.
"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
Brown Roger
Cage Peter
Cheshire David
Ince Francis
Ambrose Michael G.
Astra Pharmaceuticals Limited
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