Cyclobutene derivatives useful as antagonists of the motilin...

Details Cyclobutene derivatives useful as antagonists of the motilin... Cyclobutene derivatives useful as antagonists of the motilin...

2002-03-12

2003-12-23

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S255010, C514S329000, C514S357000, C544S165000, C544S382000, C546S223000, C546S316000

Reexamination Certificate

active

06667309

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a series of novel cyclobutene derivatives, pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention are useful as non-peptidyl antagonists of the motilin receptor. In addition, the compounds display efficacy and potency which are comparable to known motilin and erythromycin antagonists.
BACKGROUND
In mammals, the digestion of nutrients and the elimination of waste is controlled by the gastrointestinal system. This system is, to say the least, complicated. There are a number of natural peptides, ligands, enzymes, and receptors which play a vital role in this system and are potential targets for drug discovery. Modifying the production of, or responses to these endogenous substances can have an effect upon the physiological responses such as diarrhea, nausea, and abdominal cramping. One example of an endogenous substance which affects the gastrointestinal system is motilin.
Motilin is a peptide of 22 amino acids which is produced in the gastrointestinal system of a number of species. Although the sequence of the peptide varies from species to species, there are a great deal of similarities. For example, human motilin and porcine motilin are identical; while motilin isolated from the dog and the rabbit differ by five and four amino acids, respectively. Motilin induces smooth muscle contractions in the stomach tissue of dogs, rabbits, and humans as well as in the colon of rabbits. Apart from local gastrointestinal intestinal tissues, motilin and its receptors have been found in other tissues. For example, motilin has been found in circulating plasma, where a rise in the concentration of motilin has been associated with gastric effects which occur during fasting in dogs and humans (Itoh, Z. et al., 1976,
Scand. J. Gastroenterol.
11:93-110; Vantrappen, G. et al.
Dig.,
1979,
Dis Sci
24,497-500). In addition, when motilin was intravenously administered to humans it was found to increase gastric emptying and gut hormone release (Christofides, N. D. et al., 1979,
Gastroenterology
76:903-907).
Aside from motilin itself, there are other substances which are agonists of the motilin receptor and which elicit gastrointestinal emptying. One of those agents is the antibiotic erythromycin. Even though erythromycin is a useful drug, a great number of patients are affected by the drug's gastrointestinal side effects. Studies have shown that erythromycin elicits biological responses that are comparable to motilin itself and therefore may be useful in the treatment of diseases such as chronic idiopathic intestinal pseudo-obstruction and gastroparesis (Weber, F. et al., 1993,
The American Journal of Gastroenterology,
88:4, 485-90).
Although motilin and erythromycin are agonists of the motilin receptor, there is a need for antagonists of this receptor as well. The nausea, abdominal cramping, and diarrhea which are associated with motilin agonists are not always welcome physiological events. The increased gut motility induced by motilin has been implicated in diseases such as Irritable Bowel Syndrome and esophageal reflux. Therefore researchers have been searching for motilin antagonists.
One such antagonist is OHM-11526. This is a peptide derived from porcine motilin which competes with both motilin and erythromycin for the motilin receptor in a number of species, including rabbits and humans. In addition, this peptide is an antagonist of the contractile smooth muscle response to both erythromycin and motilin in an in vitro rabbit model (Depoortere, I. et al., 1995,
European Journal of Pharmacology,
286, 241-47). Although this substance is potent in that model, it is a peptide and as such it is susceptible to the enzymes of the digestive tract (Zen Itoh,
Motilin,
xvi, 1990). Therefore it is desirable to find other agents which are not peptides as potential motilin antagonists. The compounds of this invention are such agents.
U.S. Pat. No. 5,972,939 to Chen et al. describes cyclopentene derivatives which are useful in treating gastrointestinal disorders associated with antagonizing the motilin receptor.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of Formula I
wherein
R
1
is selected from hydrogen, C
1-5
alkyl optionally substituted with halogen, aminoC
1-5
alkyl, C
1-5
alkylaminoC
1-5
alkyl, di-C
1-5
alkylaminoC
1-5
alkyl, C
1-5
alkylcarbonyl, C
1-5
alkoxycarbonyl, aminocarbonyl, C
1-9
alkylaminocarbonyl, cycloC
3-9
alkylaminocarbonyl, heteroarylaminocarbonyl optionally substituted with one or more C
1-5
alkyl, pyridinylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen and C
1-5
alkyl, thiophenecarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen and C
1-5
alkyl, phenyl, phenylC
1-5
alkyl, phenoxycarbonyl, phenylcarbonyl, diphenylmethylcarbonyl, phenylaminocarbonyl, phenylthiocarbonyl, phenylaminothiocarbonyl, said phenyl, phenylC
1-5
alkyl, phenoxycarbonyl, phenylcarbonyl, diphenylmethylcarbonyl, phenylaminocarbonyl, phenylthiocarbonyl, phenylaminothiocarbonyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C
1-5
alkyl, trihalomethyl, C
1-5
alkoxy, amino, nitrile, nitro, C
1-5
alkylamino, and di-C
1-5
alkylamino, which substituents may be taken together to form a fused bicyclic aromatic ring or taken together with the phenyl ring to form a fused bicyclic 7-10 membered heterocyclic ring having one or two heteroatoms selected from oxygen, sulfur and nitrogen, and R
a
R
b
N—C
1-5
alkyl wherein R
a
and R
b
are independently selected from hydrogen and C
1-5
alkyl, or taken together to form a morpholine, piperazine, piperidine, or N-substituted piperidine wherein the N-substitutent is C
1-5
alkyl or phenylC
1-5
alkyl;
R
2
is selected from hydrogen, C
1-5
alkyl, C
1-5
alkoxy, phenyl optionally substituted with one or more substituents selected from the group consisting of halogen and C
1-5
alkyl, and phenylC
1-5
alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, C
1-5
alkyl, C
1-5
alkoxy, halo and di-C
1-5
alkylamino;
R
3
is selected from hydrogen, C
1-5
alkylcarbonyl optionally substituted with halogen, and phenylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen, C
1-5
alkyl, C
1-5
alkoxy, amino, C
1-5
alkylamino, and di-C
1-5
alkylamino;
R
4
is selected from hydrogen, C
1-5
alkyl, C
1-5
alkylcarbonyl optionally substituted with halogen, and phenylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen, C
1-5
alkyl, C
1-5
alkoxy, amino, C
1-5
alkylamino, and di-C
1-5
alkylamino;
n is 0-3;
m is 1-5;
R
5
is
 wherein:
q is 0-3;
t is 0-1;
X is oxygen, CH
2
, sulfur, hydroxy, thiol, or NR
c
wherein
R
c
is selected from hydrogen, C
1-5
alkyl, morpholinoC
1-5
alkyl, piperidinylC
1-5
alkyl, N-phenylmethylpiperidinyl, and piperazinylC
1-5
alkyl,
with the proviso that if q and t are 0, X is hydroxy, thiol, or amino;
A is C
1-5
alkoxycarbonyl, phenylcarbonyl, or R
7
R
8
N—wherin wherein R
7
and R
8
are independently selected from hydrogen, C
1-5
alkyl, and cycloC
1-9
alkyl, or R
7
and R
8
form a 5- or 6-membered heterocyclic ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and sulfoxides and N-oxides thereof; and
R
6
is selected from hydrogen, halogen, C
1-5
alkoxy, C
1-5
alkylamino, and di-C
1-5
alkylamino; or a pharmaceutically acceptable salt thereof.
The compounds of Formula I are useful in treating gastrointestinal disorders associated with the motilin receptor. The compounds compete with erythromycin and motilin for the motilin receptor. In addition, the compounds are antagonists of the contractile smooth muscle response to those ligands.
The present invention also comprises pharmaceutical compositions containing one or more of the compounds of Formula I a

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