Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-31
2004-09-07
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S351000, C514S535000, C514S568000, C546S297000, C546S300000, C546S301000, C560S042000, C560S043000, C562S465000
Reexamination Certificate
active
06787562
ABSTRACT:
This invention relates to novel, aromatic compounds and pharmaceutically-acceptable salts thereof which possess useful pharmacological properties. More particularly the compounds of the invention are antagonists of the pain enhancing effects of E-type prostaglandins. The invention also relates to processes for the manufacture of the aromatic compounds and pharmaceutically-acceptable salts thereof; to novel pharmaceutical compositions containing them; and to use of the compounds in pain relief.
The compounds of the invention are useful in the treatment of pain such as the pain associated with joint conditions (such as rheumatoid arthritis and osteoarthritis), postoperative pain, post-partum pain, the pain associated with dental conditions (such as dental caries and gingivitis), the pain associated with burns (including sunburn), the treatment of bone disorders (such as osteoporosis, hypercalcaemia of malignancy and Paget's disease), the pain associated with sports injuries and sprains and all other painful conditions in which E-type prostaglandins wholly or in part play a pathophysiological role.
Non-steroidal anti-inflammatory drugs (NSAIDS) and opiates are the main classes of drugs in pain relief. However both possess undesireable side effects. NSAIDS are known to cause gastrointestinal irritation and opiates are known to be addictive.
We have now found a class of compounds structurally different to NSAIDS and opiates, and useful in the relief of pain.
The compounds of the invention may also possess anti-inflammatory, anti-pyretic and anti-diarrhoeal properties and be effective in other conditions in which prostaglandin E
2
(PGE
2
) wholly or in part plays a pathophysiological role.
According to the invention there is provided a compound of the formula I;
wherein:
A is an optionally substituted:
phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, thienyl, thiazolyl, oxazolyl, thiadiazolyl having at least two adjacent ring carbon atoms or a bicyclic ring system of the formula:
wherein E is nitrogen or CH, F is nitrogen or CH, G is sulphur or oxygen and H is nitrogen or CH;
provided that the —Z—B—R
1
and —X—D linking groups are positioned in a 1,2 relationship to one another on ring carbon atoms and the ring atom positioned ortho to the —X— linking group (and therefore in the 3-position relative to the —Z— linking group) is not substituted;
B is an optionally substituted:
phenyl, pyridyl, thiazolyl, oxazolyl, thienyl, thiadiazolyl, isoxazole, pyrazole, furyl, pyrrolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridone, pyrimidone, pyrazinone or pyridazinone;
D is optionally substituted: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or phenyl;
R
1
is positioned on ring B in a 1,3 or 1,4 relationship with the —Z— linking group in 6-membered rings and in a 1,3-relationship with the —Z— linking group in 5-membered rings and is carboxy, carboxyC
1-3
alkyl, tetrazolyl, tetrazolylC
1-3
alkyl, tetronic acid, hydroxamic acid, sulphonic acid, or R
1
is of the formula —SO
2
NHR
e
wherein R
e
is hydrogen or C
1-6
alkyl; or R
1
is of the formula (IIA), (IIB) or (IIC):
wherein X″ is CH or nitrogen, Y is oxygen or sulphur Y′ is oxygen or NH, and Z is CH
2
, NH or oxygen provided that there is no more than one ring oxygen and there are at least two ring heteroatoms; or R
1
is of the formula —CONR
a
R
a1
or —C
1-3
alkylCONR
a
R
a1
wherein R
a
is hydrogen, C
1-6
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-3
alkyl, C
5-7
cycloalkenyl or C
5-7
cycloalkenylC
1-3
alkyl and R
a1
is hydrogen, hydroxy or optionally substituted: C
1-10
alkyl, C
2-10
alkenyl, C
2-10
alkynyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-6
alkyl, C
3-7
cycloalkylC
2-6
alkenyl, C
3-7
cycloalkylC
2-6
alkynyl, C
5-7
cycloalkenyl, C
3-7
cycloalkenylC
1-6
alkyl, C
5-7
cycloalkenylC
2-6
alkenyl, C
5-7
cycloalkenylC
2-6
alkynyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylC
1-6
alkyl, 5- or 6-membered saturated or partially saturated heterocyclyl or 5- or 6-membered saturated or partially saturated heterocyclylC
1-6
alkyl; or wherein R
a
and R
a1
together with the amide nitrogen to which they are attached (NR
a
R
a1
) form an amino acid residue or ester thereof; or R
1
is of the formula —CONHSO
2
R
b
or —C
1-3
alkylCONHSO
2
R
b
wherein R
b
is optionally substituted: C
1-10
alkyl, C
2-10
alkenyl, C
2-10
alkynyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-6
alkyl, C
3-7
cycloalkylC
2-6
alkenyl, C
3-7
cycloalkylC
2-6
alkynyl, C
5-7
cycloalkenyl, C
3-7
cycloalkenylC
1-6
alkyl, C
5-7
cycloalkenylC
2-6
alkenyl, C
5-7
cycloalkenylC
2-6
alkynyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroylarC
16
alkyl, phenyl, phenylC
1-6
alkyl, 5- or 6-membered saturated or partially saturated heterocyclyl or 5- or 6-membered saturated or partially saturated heterocyclylC
1-6
alkyl or R
1
is of the formula —CONR
a
N(R
c
)R
d
or —C
1-3
alkylCONR
a
N(R
c
)R
d
wherein R
a
is as hereinabove defined, R
c
is hydrogen or C
1-6
alkyl and R
d
is hydrogen, hydroxy or optionally substituted: C
1-10
alkyl, C
2-10
alkenyl, C
2-10
alkynyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-6
alkyl, C
3-7
cycloalkylC
2-6
alkenyl, C
3-7
cycloalkylC
2-6
alkynyl, C
5-7
cycloalkenyl, C
5-7
cycloalkenylC
1-6
alkyl, C
5-7
cycloalkenylC
2-6
alkenyl, C
5-7
cycloalkenylC
2-6
alkynyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylC
1-6
alkyl, 5- or 6-membered saturated or partially saturated heterocyclyl, 5- or 6-membered saturated or partially saturated heterocyclylC
1-6
alkyl, or R
c
and R
d
, together with the nitrogen atom to which they are attached, form a 4 to 8-membered saturated or partially saturated heterocyclic ring or form an amino acid residue or ester thereof;
X is —OCH
2
—, —SCH
2
—, —CH
2
CH
2
—, CH
2
—, —O—, —S— or —NH(R
4
)CH
2
wherein the left hand atom is attached to A and the right hand atom is attached to D;
Z is of the formula —CH(R
3
)CH(R
3
)N(R
2
)—, —N(R
2
)CH(R
3
)—, —CH(R
3
)P
1
—, —(CH(R
3
))m— or —CH(R
3
)N(R
2
)—
wherein
R
2
is hydrogen, C
1-6
alkyl (optionally substituted by hydroxy, cyano, nitro, amino, halo, C
1-4
alkanoyl, C
1-14
alkoxy or trifluoromethyl) C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl, C
3-6
cycloalkylC
1-3
alkyl, C
3-6
cycloalkylC
2-3
alkenyl, C
5-6
cycloalkenyl, C
5-6
cycloalkenylC
1-3
alkyl, C
5-6
cycloalkenylC
2-3
alkenyl, phenyl, phenylC
1-3
alkyl or 5- or 6-membered heteroarylC
1-3
alkyl;
R
3
is hydrogen or C
1-4
alkyl;
P
1
is oxygen or sulphur, m is 2 or 3 and R
4
is hydrogen or C
1-4
alkyl and wherein the left hand atom is attached to A and the right hand atom is attached to B; provided that when Z is —CH(R
3
)N(R
2
)— or —(CH(R
3
))m—, X is not —OCH
2
—; and N-oxides of —NR
2
where chemically possible;
and S-oxides of sulphur containing rings where chemically possible;
and pharmaceutically acceptable salts and in vivo hydrolysable esters and amides thereof, excluding 4-[4-acetyl-2-benzyl-3-hydroxyphenoxymethyl]-3-methoxybenzoic acid.
A 5- or 6-membered heteroaryl ring system is a monocyclic aryl ring system having 5 or 6 ring atoms wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen and sulphur.
A 5- or 6-membered saturated or partially saturated heterocyclic (heterocyclyl) ring is a ring system having 5 or 6 ring atoms wherein 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulphur.
Particular 5- or 6-membered monocyclic heteroaryl rings include pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, thienyl, furyl and oxazolyl.
Particular 5- or 6-membered saturated or partially saturated heterocyclic ring ring systems include pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl.
The linking group —CH(R
3
)N(R
2
)CH(R
3
)— includes —CH
2
N(R
2
)CH(Me)—, —CH
2
N(R
2
)CH
2—
and —CH(Me)N(R
2
)CH
2
—.
The linking group —CH(R
3
)CH(R
3
)N(R
2
)— includes —CH
2
CH(Me)N(R
2
)—, —CH(Me)CH
2
N(
Breault Gloria Anne
Oldfield John
Tucker Howard
Warner Peter
Mitchell Kenneth F.
Rao Deepak
Zeneca Ltd.
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