Interphenylene 7-oxabicyclic [2.2.1] heptane...

Details Interphenylene 7-oxabicyclic [2.2.1] heptane... Interphenylene 7-oxabicyclic [2.2.1] heptane...

2000-09-14

2002-06-18

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S236000, C548S252000, C514S374000

Reexamination Certificate

active

06407250

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention provides novel Interphenylene 7-Oxabicyclo [2.2.1] heptane oxazoles useful as Prostaglandin F
2&agr;
(FP receptor) antagonists. The present invention also provides a method of synthesizing such novel compounds.
2. Description of Related Art
Prostaglandin F
2&agr;
antagonists are reported in U.S. Pat. Nos. 4,632,928; 5,747,660; and 5,955,575. The PGF
2&agr;
antagonists of U.S. Pat. No. 4,632,928 are pyrazole derivatives having an ergoline skeleton. The PGF
2&agr;
antagonist of U.S. Pat. No. 5,747,660 is a prostaglandin F
2&agr;
receptor regulatory protein (FPRP) which is able to inhibit the binding of PGF
2&agr;
to its receptor. The inventors of this patent state that the prostaglandin F
2&agr;
antagonist of their invention is believed to be the first selective prostaglandin F
2&agr;
antagonist discovered. U.S. Pat. No. 5,955,575 describes peptide sequences derived from the prostaglandin receptor F
2&agr;
and the G-protein, G&agr;q, as selective inhibitors of signal transduction involved in the stimulation of the prostaglandin receptor F
2&agr;
.
Interphenylene 7-Oxabicyclo [2.2.1] heptane oxazoles, useful as Thromboxane A
2
receptor antagonists are reported in U.S. Pat. Nos. 5,100,889 and 5,153,327, European Patent Application 0 391 652 and J. Med. Chem. 1993, 36, 1401-1417.
Thromboxane A
2
receptor antagonists, e.g. 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs, alone, or in combination with anti-inflammatory agents are useful in treating ulcerative gastrointestinal conditions and dysmenorrhea as disclosed in European Patent Application 0 448 274 and U.S. Pat. No. 5,605,917.
BRIEF SUMMARY OF THE INVENTION
The invention relates to novel Interphenylene 7-Oxabicyclo [2.2.1] heptane oxazoles useful as PGF
2&agr;
antagonists, the synthesis thereof, and their use in treating diseases and conditions, where PGF
2&agr;
is involved.
The novel compounds of the present invention are represented by the general formula I.
wherein
m is an integer of from 1 to 3, preferably 1 or 2;
n is 0 or an integer of from 1 to 4, preferably from 2 to 4;
R is selected from the group consisting of CO
2
H, CO
2
R
6
, CH
2
OH, CH
2
OR
6
 and CONR
3
R
4
;
R
1
and R
2
are independently selected from the group consisting of H, R
6
, C
1
-C
6
alkenyl, C
1
-C
6
alkynyl, C
3
-C
7
cycloalkyl, C
4
-C
12
alkylcycloalkyl, C
6
-C
10
aryl, C
7
-C
12
alkylaryl radicals and heteroatom-substituted derivatives thereof, wherein one or more of the hydrogen or carbon atoms in said radicals is replaced with a halogen, nitrogen or sulfur-containing radical;
R
3
and R
4
are independently selected from the group consisting of H and R
6
; and
X is selected from the group consisting of R
6
, hydroxy, halogen, COOR
6
, NO
2
, N(R
6
)
2
, CON(R
6
)
2
, SR
6
, sulfoxy, sulfone, CN and OR
6
wherein R
6
is C
1
-C
6
alkyl, and pharmaceutically acceptable salts thereof.
These compounds are especially useful for treating a number of PGF
2&agr;
-mediated disease responses. For instance, prostaglandins play an important role in inflammatory reactions relating to rheumatoid arthritis and psoriasis, reproductive disorders, bronchoconstrictive disorders (asthma), excessive bone breakdown (osteoporosis), peptic ulcers, heart disease, platelet aggregation and thrombosis.


REFERENCES:
patent: 4632928 (1986-12-01), Rettegi et al.
patent: 5100889 (1992-03-01), Misra et al.
patent: 5153327 (1992-10-01), Misra et al.
patent: 5260448 (1993-11-01), Das et al.
patent: 5347007 (1994-09-01), Das et al.
patent: 5605917 (1997-02-01), Ogletree
patent: 5747660 (1998-05-01), Orlicky
patent: 5955575 (1999-09-01), Peri et al.
patent: 0 391 652 (1990-10-01), None
patent: 0 448 274 (1991-09-01), None
patent: 575069 (1993-12-01), None
Misra et al, “Interphenylene 7-Oxabicyclo[2.2.1]heptane Oxazoles. Highly Potent, Selective, and Long-Acting Thromboxane A2 Receptor Antagonists”, J. Med. Chem. 1993, 36, 1401-1417.
Das et al, “Synthesis of Optically Active 7-Oxabicyclo[2.2.1]heptanes and Assignment of Absolute Configuration”, Communications, Dec. 1987, 1100-1103.

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