Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-20
2002-06-25
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S439000, C548S448000
Reexamination Certificate
active
06410583
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to compounds and methods for treating prostaglandin mediated diseases, and certain pharmaceutical compositions thereof. More particularly, the compounds of the invention are structurally different from steroids, antihistamines or adreneigic agonists, and are antagonists of the nasal and pulmonary congestion effects of D-type prostaglandins.
Two review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists:
Eicosanoids: From Biotechnology to Therapeutic Applications,
Folco, Samucisson, Maclouf, and Velo eds, Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87. An article from T. Tsuri et al. published in 1997 in Journal of Medicinal Chemistry, vol 40, pp.3504-3507 states that “PGD2 is considered to be an important mediator in various allergic diseases such allergic rhinitis, atopic asthma, allergic conjunctivitis and atopic dermatitis.” More recently, an article by Matsuoka et al. in
Science
(2000), 287:2013-7, describes PGD2 as being a key mediator in allergic asthma. In addition, patents such as U.S. Pat. No. 4,808,608 refer to prostaglandin antagonists as useful in the treatment of allergic diseases, and explicitly allergic asthma. PGD2 antagonists are described in, for example, European Patent Application 837,052 and PCT Application WO98/25919, as well as WO99/62555.
U.S. Pat. No. 4,808,608 discloses tetrahydrocarbazole-1-alkanoic acid derivatives as prostaglandin antagonists.
European Patent Application 468,785 discloses the compound 4-[(4-chlorophenyl)methyl]-1,2,3,4-tetrahydro-7-(2-quinolinylmethoxy)-cyclopent[b]indole-3-acetic acid, which is a species of a genus said to be leukotriene biosynthesis inhibitors.
U.S. Pat. No. 3,535,326 discloses antiphlogistic compounds of the formula:
SUMMARY OF THE INVENTION
The present invention provides novel compounds which are prostaglandin receptor antagonists, more particularly, they are prostaglandin D2 receptor (DP receptor) antagonists. Compounds of the present invention are useful for the treatment of various prostaglandin-mediated diseases and disorders; accordingly the present invention provides a method for the treatment of prostaglandin-mediated diseases using the novel compounds described herein, as well as pharmaceutical compositions containing them.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula I:
and pharmaceutically acceptable salts, hydrates and esters thereof, wherein:
R
1
, R
2
and R
3
are each independently selected from the group consisting of:
(1) hydrogen, and
(2) R
c
,
R
4
and R
5
are each independently selected from the group consisting of:
(1) H,
(2) F,
(3) CN,
(4) C
1-6
alkyl,
(5) OR
a
, and
(6) S(O)
n
C
1-6
alkyl,
wherein each of said alkyl group is optionally substituted with halogen, or
R
4
and R
5
on the same carbon atom may represent an oxo, or
R
4
and R
5
on the same carbon atom or on adjacent carbon atoms taken together form a 3- or 4-membered ring containing 0 or 1 heteroatom selected from N, S, or O optionally substituted with one or two groups selected from F, CF
3
and CH
3
;
R
6
is selected from the group consisting of:
(1) H,
(2) C
1-6
alkyl optionally substituted with one to six groups independently selected from OR
a
and halogen, and
(3) heterocyclyl optionally substituted with one to four halogen; or
R
5
and R
6
attached on adjacent carbon atoms together form a 3- or 4-membered ring containing 0 or 1 heteroatom selected from N, S, or O optionally substituted with one or two groups selected from F, CF
3
and CH
3
;
X is selected from the group consisting of: C═O, SO
2
, and C
1-4
alkyl wherein said alkyl is optionally substituted with one to six halogen;
Ar is aryl or heteroaryl each optionally substituted with one to four groups independently selected from R
c
;
Q is C
1-6
alkyl optionally substituted with one to six groups independently selected from:
(1) halogen,
(2) aryl,
(3) heteroaryl,
(4) OH,
(5) OC
1-6
alkyl,
(6) COOH,
(7) CONR
a
R
b
,
(8) C(O)NSO
2
R
7
,
(9) tetrazolyl,
wherein aryl, heteroaryl and alkyl are each optionally substituted with one to six groups independently selected from halogen, CF
3
, and
COOH; or
Q and R
6
together form a 3- or 4-membered ring optionally containing a heteroatom selected from N, S, and O, and optionally substituted with one or two groups independently selected from:
(1) halogen,
(2) oxo,
(3) OR
a
,
(4) COOH,
(5) C(O)NHSO
2
R
7
, and
(6) tetrazolyl,
R
7
is selected from the group consisting of:
(1) C
1-6
alkyl optionally substituted with one to six halogen,
(2) aryl, and
(3) heteroaryl,
wherein said aryl and heteroaryl are optionally substituted with halogen, OC
1-5
alkyl, C
1-5
alkyl and wherein said alkyl is optionally substituted with one to six halogen;
R
a
and R
b
are independently selected from hydrogen and C
1-6
alkyl optionally substituted with one to six halogen;
R
c
is
(1) halogen,
(2) CN,
(3) C
1-6
alkyl optionally substituted with one to six groups independently selected from halogen, NR
a
R
b
, C(O)R
a
, C(OR
a
)R
a
R
b
, and OR
a
,
(4) C
2-6
alkenyl optionally substituted with one to six groups independently selected from halogen and OR
a
,
(5) heterocyclyl,
(6) aryl,
(7) heteroaryl,
(8) C(O)R
a
,
(9) C(OR
a
)R
a
R
b
,
(10) C(O)OR
a
,
(11) CONR
a
R
b
,
(12) OCONR
a
R
b
,
(13) S(O)
n
R
7
,
(14) NR
a
C(O)OC
1-6
alkyl, wherein alkyl is optionally substituted with one to six halogen, and
(15) S(O)
n
NR
a
R
b
,
wherein heterocyclyl, aryl, heteroaryl are optionally substituted with one to four groups independently selected from halogen;
n is 0, 1 or 2.
The invention also encompasses pharmaceutical compositions containing a compound of formula I, and methods for treatment or prevention of prostaglandin mediated diseases using compounds of formula I.
The numbering of the core tricyclic ring system is as shown below:
The invention is described using the following definitions unless otherwise indicated.
The term “halogen” or “halo” includes F, Cl, Br, and I.
The term “alkyl” refers to linear, branched and cyclic and bicyclic structures and combinations thereof, containing the indicated number of atoms. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclopentylethyl, methyl substituted cyclopropyl, ethyl substituted cyclobutyl, adamantyl, cyclododecylmethyl, 2-ethyl-1-bicyclo[4.4.0]decyl and the like. The term C
1-6
alkyl encompasses acyclic alkyl groups having the indicated number of carbon atoms as well as —C
x
alkyl-C
z
cycloalkyl wherein x is 0 to 3 and z is 3 to 6 with the proviso that x+z=3 to 6.
“Haloalkyl” means an alkyl group as described above wherein one or more hydrogen atoms have been replaced by halogen atoms, with up to complete substitution of all hydrogen atoms with halo groups. C
1-6
haloalkyl, for example, includes —CF
3
, —CF
2
CF
3
and the like.
“Alkoxy” means alkoxy groups of a straight, branched or cyclic configuration having the indicated number of carbon atoms. C
1-6
alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
“Haloalkoxy” means an alkoxy group as described above in which one or more hydrogen atoms have been replaced by halogen atoms, with up to complete substitution of all hydrogen atoms with halo groups. C
1-6
haloalkoxy, for example, includes —OCF
3
, —OCF
2
CF
3
and the like.
“Alkenyl” means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon double bond, wherein hydrogen may be replaced by an additional carbon-to-carbon double bond. C
2-6
alkenyl, for example, includes ethenyl, propenyl, 1
Berthelette Carl
Boyd Michael
Labelle Marc
Lachance Nicolas
Roy Bruno
Merck Frosst Canada & Co.
Powers Fiona T.
Rose David L.
Yang Mollie M.
LandOfFree
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