Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-06-07
2001-08-07
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S299000, C514S305000
Reexamination Certificate
active
06271229
ABSTRACT:
BACKGROUND OF THE INVENTION
The primary function of the gastrointestinal tract is the absorption of ingested nutrients. To achieve this primary function requires that transit along the esophagus and gastrointestinal tract is at a rate that allows for optimal digestion and absorption of water and electrolytes. Although the etiology and pathophysiology of esophageal and gastrointestinal motility disorders is incompletely understood, abnormal patterns of gastrointestinal motility that result in stimulated motility (hypermotility) may cause many of the symptoms of disorders such as Diffuse Esophageal Spasm (an esophageal obstructive disorder characterized by dysphagia), Achalasia (an obstructive disorder in which the lower esophageal sphincter fails to relax adequately resulting in dysphagia), noncardiac chest pain and Functional Bowel Disorders such as the Irritable Bowel Syndrome (IBS), non-ulcer dyspepsia, and idiopathic constipation.
The afore mentioned esophageal and gastrointestinal disorders are currently incompletely understood, they are however thought to be the result of abnormal motility (smooth muscle activity). Therefore, we believe a rationale therapy would be to reduce the hypermotility and restore normal patterns of esophageal and gastrointestinal motility. In the United States the only drugs approved for treating motility disorders are cisapride and metoclopramide, the latter a dopamine D2 receptor antagonist that releases acetylcholine from the myenteric plexus, consequently such as agent enhances motility which is not desirable in treating hypermotility disorders. Presently, no efficacious therapy exists for the therapy exists for the treatment of esophageal and gastrointestinal hypermotility disorders. Observations with anticholinergics and smooth muscle relaxants have been disappointing due to side effects such as dry mouth and blurred vision for the anticholinergics and headaches with smooth muscle relaxants such as nifedipine.
We have discovered a new class of selective muscarinic agents which have not previously been considered for the use in treating motility disorders of the gastrointestinal tract.
SUMMARY OF THE INVENTION
The method of this invention comprises administering to a patient suffering from gastrointestinal disorders an effective amount of a compound of the formula I
wherein
X is oxygen or sulphur;
R is hydrogen, amino, halogen, —CHO, —NO
2
, —R
4
, —Y, —NHCO—R
4
, —OR
4
, —SR
4
, —SOR
4
, —SO
2
R
4
, C
3-10
-cycloalkyl, C
4-10
-cycloalkenyl, C
4-10
-(cycloalkyl-alkyl), —Z
1
—C
3-10
-cycloalkyl, —Z
1
—C
4-10
-cycloalkenyl, —Z
1
—C
4-10
-(cycloalkylalkyl), —Z
1
—C
4-10
-(cycloalkenyalkyl), —Z
1
—C
4-10
-(methylenecycloalkylalkyl), —NH—R
4
, —NR
4
R
5
, —NH—OR
4
, —CH═NOR
4
, phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphthyl, naphtyl, indenyl, wherein each aromatic group is optionally substituted with halogen, —NO
2
, —CN, C
1-4
-alkyl, C
1-4
-alkoxy, —OCF
3
, —CONH
2
, —CSNH
2
, phenoxy or phenyl; or R is —Z
1
—R
6
—Z
2
—R
5
, —Z
1
—R
6
—Z
2
—R
7
—Z
3
—R
5
, —Z
1
—CO—R
5
, —Z
1
—R
6
—CO—R
5
, —Z
1
—R
6
—CO
2
—R
5
, —Z
1
—R
6
—O
2
C—R
5
, —Z
1
—R
6
—CONH—R
5
, —Z
1
—R
6
—NHCO—R
5
, —Z
1
—R
6
—Y, —Z
1
—R
6
—Z
2
—Y, wherein Z
1
and Z
2
independently are oxygen or sulphur, and R
4
and R
5
independently are straight or branched C
1-15
-alkyl, straight or branched C
2-15
-alkenyl, straight or branched C
2-15
-alkynyl, each of which is optionally substituted with one or more halogen(s), C
1-6
-alkoxy, —CF
3
, —CN, —COOH, —OH, —NH
2
, C
1-6
-alkyl ester, —SH, —NHR
4
, —NR
4
R
5
, phenyl or phenoxy, wherein each aromatic group is optionally substituted with halogen, —NO
2
, —CN, C
1-4
-alkyl, C
1-4
-alkoxy, —OCF
3
, —CONH
2
, —CSNH
2
, phenyl or phenoxy, and wherein R
6
and R
7
independently are straight or branched C
1-10
-alkylene, straight or branched C
2-10
-alkenylene, straight or branched C
2-10
-alkynylene, each of which is optionally substituted with one or more halogen(s), —CF
3
, —CN, —COOH, —OH, —NH
2
, C
1-6
-alkyl ester, —SH, —NHR
4
, —NR
4
R
5
, phenyl or phenoxy, and Y is a 5 or 6 membered heterocyclic group containing one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched C
1-6
-alkyl, phenyl or benzyl, or a carbon atom in the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group; and
G is selected from one of the following azabicyclic rings
wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R
1
and R
2
may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C
1-5
-alkyl, straight or branched C
2-5
-alkenyl, straight or branched C
2-5
-alkynyl, straight or branched C
1-10
-alkoxy, straight or branched C
1-5
-alkyl substituted with —OH, —OH, halogen, —NH
2
or carboxy; R
3
is H, straight or branched C
1-5
-alkyl, straight or branched C
2-5
-alkenyl or straight or branched C
2-5
-alkynyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; q is 1 or 2; and
is a single or double bond; or
a pharmaceutically acceptable salt thereof.
Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are hereby incorporated by reference.
Especially preferred salts include tartrate and hydrochloride.
As used herein, the term “patient” includes any mammal which could benefit from treatment of gastrointestinal disorders. The term particularly refers to a human patient, but is not intended to be so limited.
The thiadiazole and oxadiazole compounds used in the presently claimed method have been disclosed and claimed in PCT/DK91/00236. The thiadiazole and oxadiazole derivatives are known to be cholinergic muscarinic agents useful in the treatment of presenile and senile dementia. The compounds are believed to be useful for treating Alzheimer's disease, glaucoma, and painful conditions. Other disclosures suggest that thiadiazole compounds may be useful for the treatment of illnesses whose clinical manifestations are due to cholinergic deficiency, (European Patent Application 307142). Such illnesses include Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, and Tourette Syndrome.
The compounds of the present invention are chemically and biologically different from that previously reported by Schiavone et al. (1988) and the compounds inhibit small intestinal and colonic motility through a cholinergic mechanism since the inhibition of motility is blocked by atropine (10 and 100 &mgr;g/kg i.v.). In addition these motility inhibiting compounds have the desirable feature of having minimal effects on salivation and heart rate.
In addition, the compounds of this method have been found to have a favourable profile of activity in a number of in vitro binding assays, designed to measure the degree of binding to neural receptors.
The compounds have IC
50
levels of less than 1 &mgr;M in the
3
H-oxotremorine-M binding assay, indicating that the compounds have muscarinic receptor affinity.
This profile of activity in in vitro receptor binding assays, like that observed in the motility tests, would indicate that the compounds are effective in the treatment of gastrointestinal motility disorders.
Methods
Animals. Experiments were performed on fasted male ferret weighing 0.8-1.5 kg). Anaesthesia was induced with urethane (1.5 g/kg i.p.), a tracheal tube was inserted to provide a clear airway for spontaneous breathing and the body temperature was maintained at 38° C. using a homeothermic blanket. The left jugular vein was cannulated for the subsequen
Green, Esq. Reza
Gregg, Esq. Valeta A.
Novo Nordisk A S
Reamer James H.
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