Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-13
2002-04-02
Kifle, Bruck (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S327000, C514S329000, C514S340000, C514S352000, C514S247000, C514S252050, C544S224000, C544S238000, C544S239000, C546S194000, C546S209000, C546S211000, C546S216000, C546S223000, C546S268400, C546S310000
Reexamination Certificate
active
06365603
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, postpartum pain, the pain associated with dental conditions (such as dental caries and gingivitis), the pain associated with bums (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 undesirable 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 relief of pain.
The compounds of the invention may also possess anti-inflammatory, anti-pyretic and anti-diarrheal 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 or thiadiazolyl having at least two adjacent ring carbon atoms; provided that the —CH(R
3
)N(R
2
)B—R
1
and —OR
4
groups are positioned in a 1,2 relationship to one another on ring carbon atoms and the ring atom positioned ortho to the OR
4
linking group (and therefore in the 3-position relative to the —CHR
3
NR
2
-linking group) is not substituted;
B is an optionally substituted: phenyl, pyridyl, thiazolyl, oxazolyl, thienyl, thiadiazolyl, imidazolyl, pyrazinyl, pyridazinyl or pyrimidyl;
R
1
is positioned on ring B in a 1,3 or 1,4 relationship with the —CH(R
3
)N(R
2
)-linking group 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 —CONR
a
R
a1
wherein R
a
is hydrogen or C
1-6
alkyl and R
a1
is hydrogen, C
1-6
alkyl (optionally substituted by halo, amino, C
1-4
alkylamino, di-C
1-4
alylamino, hydroxy, nitro, cyano, trifluoromethyl, C
1-4
alkoxy or C
1-4
alkoxycarbonyl), C
2-6
alkenyl (provided the double bond in not in the 1-position), C
2-6
alkynyl (provided the triple bond is not in the 1-position), carboxyphenyl, 5- or 6-membered heterocyclylC
1-3
alkyl, 5- or 6-membered heteroarylC
3
alkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl or 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
wherein R
b
is C
1-6
alkyl (optionally substituted by halo, hydroxy, nitro, cyano, trifluoromethyl, C
1-4
alkoxy, amino, C
1-4
alkylamino, di-C
1-4
alkylamino or C
1-4
alkoxycarbonyl), C
2-6
alkenyl (provided the double bond is not in the 1-position), C
2-6
alkynyl (provided the triple bond is not in the 1-position), 5- or 6-membered heterocyclylC
1-3
alkyl, 5- or 6-membered heteroarylC3alkyl, phenylC
1-3
alkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl or phenyl; wherein any heterocyclyl or heteroaryl group in R
a1
is optionally substituted by halo, hydroxy, nitro, cyano, trifluoromethyl, C
1-4
alkoxy or C
1-4
alkoxycarbonyl and any phenyl, heterocyclyl or heteroaryl group in R
b
is optionally substituted by halo, trifluoromethyl, nitro, hydroxy, amino, cyano, C
1-6
alkoxy, C
1-6
alkylS(O)p-(p is 0, 1 or 2), C
1-6
alkyl carbamoyl, C
1-4
alkylcarbamoyl, di(C
1-4
alkyl)carbamoyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-4
alkoxycarbonylamino, C
1-4
alkanoylamino, C
1-4
alkanoyl(N—C
1-4
alkyl)amino, C
1-4
alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C
1-4
alkylaminosulphonyl, di(C
1-4
alkyl)aminosulphonyl, C
1-4
alkoxycarbonyl, C
1-4
alkanoyloxy, C
1-6
alkanoyl, formylC
1-4
alkyl, hydroxyiminoC
1-6
alkyl, C
1-4
alkoxyiminoC
1-6
alkyl or C
1-6
alkylcarbamoylamino; or R
1
is of the formula —SO2N(R
c
)R
c1
wherein R
c
is hydrogen or C
1-4
alkyl and R
c1
is hydrogen or C
1-4
alkyl; or R
1
is of the formula (IA), (IB) or (IC):
wherein
X is CH or nitrogen, Y is oxygen or sulphur, Y′ is oxygen or NR
d
and Z is CH
2
, NR
d
or oxygen provided that there is no more than one ring oxygen and there are at least two ring heteroatoms and wherein R
d
is hydrogen or C
1-4
alkyl;
R
2
is hydrogen, C
1-6
alkyl, optionally substituted by hydroxy, cyano or trifluoromethyl, C
2-6
alkenyl (provided the double bond is not in the 1-position), C
2-6
alkynyl (provided the triple bond is not in the 1-position), phenylC
1-3
alkyl or pyridylC
1-3
alkyl;
R
3
is hydrogen, methyl or ethyl;
R
4
is optionally substituted: C
1-6
alkyl, C
3-7
cycloalkylC
1 3
alkyl or C
3-7
cycloalkyl; 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 2-[2-methoxybenzylamino]pyridine-5-carboxylic acid, 4-[2-methoxybenzylamino]benzoic acid, 5-[2,3-dimethoxybenzylamino]-2-chloro-3-aminosulphonylbenzoic acid and 5-[2,5-dimethoxybenzylamino]-2-hydroxybenzoic 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 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 systems include pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl.
Particular substituents for ring carbon atoms in A (heterocyclyl and heteroaryl rings) include halo, trifluoromethyl, nitro, hydroxy, amino, C
1-4
alkylamino, diC
1-4
alkylamino, cyano, C
1-6
alkoxy, C
1-6
alkylS(O)
p
- (p is 0, 1 or 2), C
1-6
alkyl (optionally substituted by hydroxy, amino, halo, nitro or cyano), CF
3
S(O)
p
-(p=0, or 2), carbamoyl, C
1-4
alkylcarbamoyl, di(C
1-4
alkyl)carbamoyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-4
alkoxycarbonylamino, C
1-4
alkanoylamino, C
1-4
alkanoyl(N—C
1-4
alkyl)amino, C
1-4
alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C
1-4
alkylaminosulphonyl, C
1-4
alkanoylaminosulphonyl, di(C
1-4
alkyl)aminosulphonyl, C
1-4
alkoxycarbonyl, C
1-4
alkanoyloxy, C
1-6
alkanoyl, formylC
1-4
alkyl, trifluoroC
1-3
alkylsulphonyl, hydroxyiminoC
1-6
alkyl, C
1-4
alkoxyiminoC
1-6
alkyl and C
1-6
alkylcarbamoylamino.
Where a ring nitrogen atom in A can be substituted without becoming quaternized, it is unsubstituted or substituted by C
1-4
alkyl.
Particular substituents for ring carbon atoms in B include halo, trifluoromethyl, nitro, hydroxy, C
1-6
alkoxy, C
1-6
alkyl, amino, C
1-4
alkylamino, di(C
1-4
alkyl)amino, cyano, C
1-6
alkyl S(O)p-(p is 0, 1 or 2), carbamoyl, C
1-4
alkylcarbamoyl and di(C
1-4
alkyl)carbamoyl.
Where a ring nitrogen atom in B can be substituted without becoming quaternized, it is unsubstituted
Kifle Bruck
Mitchell Kenneth F.
Truong Tamthom N.
Zeneca Ltd.
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