Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-14
2002-04-09
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S183000, C514S241000, C514S242000, C514S252040, C514S255050, C514S256000, C514S336000, C514S340000, C544S179000, C544S180000, C544S182000, C544S238000, C544S333000, C544S405000, C546S256000, C546S268400, C546S269100, C546S280400, C546S281400
Reexamination Certificate
active
06369082
ABSTRACT:
BACKGROUND OF THE INVENTION
This 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 NSAIDs and opiates, and are antagonists of the pain and inflammatory effects of E-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, Samuelsson, 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 The British Journal of Pharmacology (1994, 112, 735-740) suggests that Prostaglandin E
2
(PGE
2
) exerts allodynia through the EP
1
receptor subtype and hyperalgesia through EP
2
and EP
3
receptors in the mouse spinal cord.
Thus, selective prostaglandin ligands, agonists or antagonists, depending on which prostaglandin E receptor subtype is being considered, have anti-inflammatory, antipyretic and analgesic properties similar to a conventional non-steroidal anti-inflammatory drug, and in addition, inhibit hormone-induced uterine contractions and have anti-cancer effects. These compounds have a diminished ability to induce some of the mechanism-based side effects of NSAIDs which are indiscriminate cyclooxygenase inhibitors. In particular, the compounds have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
In The American Physiological Society (1994, 267, R289-R-294), studies suggest that PGE2-induced hyperthermia in the rat is mediated predominantly through the EP1 receptor. World patent applications WO 96/06822 (Mar. 7, 1996), WO 96/11902 (Apr. 25, 1996) and EP 752421-A1 (Jan. 8, 1997) disclose compounds as being useful in the treatment of prostaglandin mediated diseases.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula A:
as well as pharmaceutically acceptable salts, hydrates and esters thereof, wherein:
y and z are independently 0-2, such that y+z=2;
R
a
is selected from the group consisting of:
1) heteroaryl, wherein heteroaryl is selected from the group consisting of:
a) furyl,
b) diazinyl, triazinyl or tetrazinyl,
c) imidazolyl,
d) isoxazolyl,
e) isothiazolyl,
f) oxadiazolyl,
g) oxazolyl,
h) pyrazolyl,
i) pyrrolyl,
j) thiadiazloyl,
k) thiazolyl
l) thienyl
m) triazolyl and
n) tetrazolyl, wherein heteroaryl is optionally substituted with 1-3 substituents independently selected from R
11
or C
1-4
alkyl,
2) —COR
6
,
3) —NR
7
R
8
,
4) —SO
2
R
9
,
5) hydroxy,
6) C
1-6
alkoxy, optionally substituted with 1-3 substituents independently selected from R
11
, and
7) C
1-6
alkyl, C
2-6
alkenyl or C
3-6
cycloalkyl, optionally substituted with 1-3 substituents independently selected from R
11
, and further substituted with 1-3 substituents independently selected from the group consisting of:
(a) —COR
6
(b) —NR
7
R
8
,
(c) —SO
2
R
9
,
(d) hydroxy,
(e) C
1-6
alkoxy or haloC
1-6
alkoxy, and
(f) heteroaryl,
such that R
a
is positioned on the pyridyl ring to which it is bonded in a 1,3 or 1,4 relationship relative to the thienyl group represented in formula A;
R
1
, R
2
, R
3
, R
4
and R
5
are independently selected from the group consisting of:
1) hydrogen,
2) halogen,
3) C
1-6
alkyl,
4) C
1-6
alkoxy,
5) C
1-6
alkylthio,
6) nitro,
7) carboxy and
8) CN, wherein items (3)-(5) above are optionally substituted with 1-3 substituents independently selected from R
11
;
R
6
is selected from the group consisting of hydrogen, hydroxy, C
1-6
alkyl, C
1-6
alkoxy and NR
7
R
8
, wherein C
1-6
alkyl or C
1-6
alkoxy are optionally substituted with 1-3 substituents independently selected from R
11
;
R
7
and R
8
are independently selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) SO
2
R
9
(4) C
1-6
alkyl,
(5) C
1-6
alkoxy,
(6) phenyl,
(7) naphthyl,
(8) furyl,
(9) thienyl and
(10) pyridyl, wherein items (4)-(5) above are optionally substituted with 1-3 substituents independently selected from R
11
, and items (6)-(10) above are optionally substituted with 1-3 substituents independently selected from R
11
or C
1-4
alkyl,
R
9
is selected from the group consisting of
(1) hydroxy,
(2) N(R
10
)
2
,
(3) C
1-6
alkyl, optionally substituted with 1-3 substituents independently selected from R
11
,
(4) phenyl,
(5) naphthyl,
(6) furyl,
(7) thienyl and
(8) pyridyl, wherein items (4)-(8) above are optionally substituted with 1-3 substituents independently selected from R
11
or C
1-4
alkyl;
R
10
is hydrogen or C
1-6
alkyl; and
R
11
is selected from the group consisting of: halogen, hydroxy, C
1-3
alkoxy, nitro, N(R
10
)
2
and pyridyl.
The invention also encompasses pharmaceutical compositions and methods for treatment or prevention of prostaglandin mediated diseases.
DETAILED DESCRIPTION OF THE INVENTION
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” means linear, branched or cyclic structures and combinations thereof, having the indicated number of carbon atoms. Thus, for example, C
1-6
alkyl includes methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
“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.
“Alkylthio” means alkylthio groups having the indicated number of carbon atoms of a straight, branched or cyclic configuration. C
1-6
alkylthio, for example, includes methylthio, propylthio, isopropylthio, etc.
“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.
“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-methylethenyl, butenyl and the like.
For purposes of this specification, the following abbreviations have the indicated meanings:
BOC=t-butyloxycarbonyl
CBZ=carbobenzoxy
DCC=1,3-dicyclohexylcarbodiimide
DIBAL=diisobutyl aluminum hydride
DIEA=N,N-diisoproylethylamine
DMAP=4-(dimethylamino)pyridine
EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EDTA=ethylenediaminetetraacetic acid, tetrasodium salt hydrate
FAB=fast atom bombardment
FMOC=9-fluorenylmethoxycarbonyl
HMPA=hexamethylphosphoramide
HATU=O-(7-Azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate
HOBt=1-hydroxybenzotriazole
HRMS=high resolution mass spectrometry
ICBF=isobutyl chloroformate
KHMDS=potassium hexamethyldisilazane
LDA=lithium diisopropylamide
MCPBA=metachloroperbenzoic acid
Ms=methanesulfonyl=mesyl
MsO=methanefulfonate=mesylate
NBS=N-bromosuccinimide
NMM=4-methylmorpholine
PCC=pyridinium chlorochromate
PDC=pyridinium dichromate
Ph=phenyl
PPTS=pyridinium p-toluene sulfonate
pTSA=p-toluene sulfonic acid
r.t.=room
Labelle Marc
Lacombe Patrick
Ruel Rejean
Billups Richard C.
Merck Frosst Canada & Co.
Rao Deepak
Raymond Richard L.
Rose David L.
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