Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1996-02-14
2004-02-24
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S925000, C514S926000, C514S972000
Reexamination Certificate
active
06696486
ABSTRACT:
This invention relates to a new medical use for certain chemical compounds and pharmaceutical compositions containing them. In particular it relates to the use in the treatment of gastrointestinal disorders of compounds which act as agonists at atypical beta-adrenoceptors (also known as beta-3-adrenoceptors). Such receptors have been described for example by J R S Arch et. al., Nature, 309, 163-165 (1984); C Wilson et. al., Eur. J. Pharmacol., 100, 309-319 (1984); L J Emorine et. al., Science, 245, 1118-1121 (1989); and A. Bianchetti et. al. Br. J. Pharmacol., 100, 831-839 (1990).
Atypical beta-adrenoceptors belong to the family of adrenoceptors which mediate the physiological actions of the hormones adrenaline and noradrenaline. Sub-types of the adrenoceptors, &agr;
1
-, &agr;
2
-, &bgr;
1
-, &bgr;
2
- and &bgr;
3
-(atypical) can be identified on the basis of their pharmacological properties and physiological effects. Chemical agents which stimulate or block these receptors (but not &bgr;
3
) are widely used in clinical medicine. More recently, emphasis has been placed upon specific receptor selectivity in order to reduce side effects caused, in part, by interactions with other receptors.
Atypical beta-adrenoceptors are known to occur in adipose tissue and the gastrointestinal tract. Compounds which act as agonists at atypical beta-adrenoceptors may be identified using standards tests (see for instance C Wilson et. al., supra).
A variety of compounds which act as agonists at atypical beta-adrenoceptors have been described in the art. These compounds are generally N-substituted arylethylamines in which the 2-carbon atom of the ethyl moiety is most commonly substituted by a hydroxy group.
Alternatively the 2-carbon atom may be cyclised via an oxygen atom and a methylene or ethylene linkage to the amine moiety to form oxazolidine or morpholine derivatives. The aryl group is most commonly an optionally substituted phenyl group, but may also be an optionally substituted benzofuranyl, indolyl, pyridinyl or thienyl group.
The N-substituents(s) is/are generally an aralkyl or aralkyloxy substituent in which the aryl group is commonly an optionally substituted phenyl group or an optionally substituted thienyl group.
Atypical beta-adrenoceptor agonists have been found to be particularly useful as thermogenic anti-obesity agents and as anti-diabetic agents.
Compounds having atypical beta-adrenoceptor agonist activity have also been described as being useful in the treatment of hyperglycaemia, as animal growth promoters, as blood platelet aggregation inhibitors, as positive inotropic agents and as antiathereosclerotic agents, and as being useful in the treatment of glaucoma.
It has now been found unexpectedly that compounds which act as agonists at atypical beta-adrenoceptors may be useful for the treatment of gastrointestinal disorders, especially, peptic ulceration, oesophagitis, gastritis and duodenitis (including that induced by
H.pylori
), intestinal ulcerations (including inflammatory bowel disease, especially, ulcerative colitis, Crohn's disease and proctitis) and gastrointestinal ulcerations, especially when induced by non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids.
Accordingly the present invention provides a method of treatment of a mammal, including man, suffering from a gastrointestinal disorder, such as peptic ulceration, oesophagitis, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations, which comprises administering to the subject an effective amount of a compound which acts as an agonist at atypical beta-adrenoceptors.
In a preferred aspect of the present invention, there is provided a method of treatment of a mammal, including man, suffering from a condition of intestinal ulcerations wherein said condition is an inflammatory bowel disease, such as ulcerative colitis, Crohn's disease or proctitis, which comprises administering to the subject an effective amount of a compound which acts as an agonist at atypical beta-adrenoceptors.
In a particularly preferred aspect of the present invention, there is provided a method of treatment of a mammal, including man, suffering from a condition of gastrointestinal ulcerations wherein said condition is induced by non-steroidal anti-inflammatory drugs, which comprises administering to the subject an effective amount of a compound which acts as an agonist at atypical beta-adrenoceptors.
References in this specification to treatment include prophylactic treatment as well as the acute alleviation of symptoms.
Preferred compounds for use according to the invention are those compounds which act as agonists at atypical beta-adrenoceptors described in published European Patent Specification Nos. 6735, 21636, 23385, 25331, 28105, 29320, 40000, 40915, 51917, 52963, 61907, 63004, 66351, 68669, 70133, 70134, 82665, 89154, 91749, 94595, 95827, 99707, 101069, 102213, 139921, 140243, 140359, 142102, 146392, 164700, 170121, 170135, 171519, 171702, 182533, 185814, 196849, 198412, 210849, 211721, 233686, 236624, 254532, 254856, 262785, 300290, 303546, 328251, 345591, 386603, 386920, 436435, 455006 and 500443; published UK Patent Specification No. 2133986; published PCT Patent Specification Nos. 84/00956, 84/03278, 84/04091, 90/13535 and 92/18461; U.S. Pat. Nos. 4,391,826 and 4,585,796; published Belgian Patent Specification No. 900983 and published Japanese Patent Specification No.86-145148.
A preferred group of atypical beta-adrenoceptor agonists for use according to the present invention is that represented by the formula (I):
or a physiologically acceptable salt, ester or amide thereof, wherein
R
1
and R
2
each independently represent a hydrogen atom or a methyl group;
R
3
represents a hydrogen, fluorine or chlorine atom or a trifluoromethyl group;
Z is an alkylene, alkenylene or alkynylene group of up to 10 carbon atoms; and m is 1, 2 or 3.
Another preferred group of atypical beta-adrenoceptor agonists for use according to the present invention is that represented by the formula (II):
or a physiologically acceptable salt or ester thereof, wherein
R
4
represents one or more groups which may be the same or different and are selected from the group consisting of hydrogen, halogen, trifluoromethyl, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylthio, alkoxycarbonyl, carboxyl, hydroxyalkyl, hydroxy, C
1-4
alkylsulphonyl and C
1-4
alkylsulphinyl;
R
5
and R
6
each independently represent a hydrogen atom or a C
1-4
alkyl group;
R
7
and R
8
each independently represent a group selected from the group consisting of hydrogen, carboxy, alkoxycarbonyl, hydroxymethyl, —CH
2
OCH
2
CO
2
R
9
and —CH
2
OCH
2
CH
2
OR
9
, with the proviso that R
7
and R
8
do not both represent hydrogen; and
R
9
is a hydrogen atom or a C
1-4
alkyl group.
A yet further preferred group of atypical beta-adrenoceptor agonists for use according to the present invention is that represented by the formula (III):
or a physiologically acceptable salt thereof, wherein
R
10
represents a hydrogen atom or a C
1-4
alkyl or a phenyl group;
R
11
represents a group of the formula —OR
13
or —NR
14
R
15
;
R
12
represents a group selected from C
1-3
alkyl, cyclohexyl, phenyl (optionally substituted by one or more groups selected from C
1-4
alkyl, hydroxy, methoxy, dimethylamino, trifluoromethyl, methylenedioxy or halogen atoms), naphthyl, pyridyl, furyl, thienyl or pyrrolyl;
R
13
represents a C
1-4
alkyl or carboC
1-2
alkoxymethyl group;
R
14
represents a hydrogen atom or a methyl, ethyl or amino group;
R
15
represents a hydrogen atom or methyl group; or the group —NR
14
R
15
form a cyclic amino group of the formula
wherein A and B each independently represent a single bond or an unsubstituted straight C
1-3
alkylene chain, or a straight C
1-3
alkylene chain substituted by carbomethoxy, hydroxymethyl or phenyl, and D is methylene, ethylene, 1,2-cyclohexylidine or 1,2-benzo;
X is a single bond or a straight C
1-4
alkylene chain; and
Y is a single bond, oxa, methylimino or —CONH—;
or R
10
—CH—X—Y—R
12
forms a tetrahydronaphthyl group.
Bacon & Thomas
Criares Theodore J.
Glaxo Group Limited
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