Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-03
2001-11-06
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...
C514S352000, C514S353000, C514S318000, C514S332000, C514S343000, C546S268400, C546S308000, C546S309000, C546S310000, C546S194000, C546S262000, C546S263000, C546S264000, C546S265000, C546S279100
Reexamination Certificate
active
06313148
ABSTRACT:
FIELD OF THE INVENTION
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 mild to moderate 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 mild to moderate pain relief. However both classes possess undesirable side effects. NSAIDS are known to cause gastrointestinal irritation and opiates are known to be addictive.
SUMMARY OF THE INVENTION
We have now found a class of compounds structurally different to NSAIDS and opiates, and useful in relief of mild to moderate 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 or naphthyl; provided that the —CH(R
3
)N(R
2
)B—R
1
and —OD groups are positioned in a 1,2 relationship to one another on ring carbon atoms and the ring atom positioned ortho to the —OD linking group (and therefore in the 3-position relative to the —CH(R
3
)N(R
2
)— linking group) is not substituted;
B is an optionally substituted pyridyl;
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
alkylamino, 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
1-3
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, amino, C
1-4
alkylamino, di-C
1-4
alkylamino, trifluoromethyl, C
1-4
alkoxy 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 heteroarylC
1-3
alkyl, 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, S(O)
p
C
1-6
alkyl (p is 0, 1 or 2), C
1-6
alkylcarbamoyl, 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 —SO
2
N(RC)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 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;
D is hydrogen, an optionally substituted 5-7 membered carbocyclic ring containing one double bond, C
1-3
alkyl substituted by an optionally substituted 5-7 membered carbocyclic ring containing one double bond or D is of the formula —(CH
2
)
n
CH(R
4
)C(R
5
)═C(R
6
)R
7
wherein:
R
4
is hydrogen, methyl or ethyl;
R
5
is hydrogen, methyl, bromo, chloro, fluoro or trifluoromethyl;
R
6
is hydrogen, C
1-4
alkyl, bromo, chloro, fluoro or trifluoromethyl;
R
7
is hydrogen, C
1-4
alkyl, bromo, chloro, fluoro or trifluoromethyl;
n is 0 or 1;
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-[5-carboxy-2-hydroxybenzylamino]benzoic acid, 4-[2,5-dihydroxybenzylamino]benzoic acid, 5-[2-hydroxybenzylamino]-2-hydroxybenzoic acid, 3-[2,5-dihydroxybenzylamino]benzoic acid, 4-[2,5-dihydroxybenzylamino]benzenecarboxamide, 3-[2-hydroxybenzylamino]benzoic acid, 4-[2,5-dihydroxybenzylamino]-2-hydroxybenzoic acid, 4-[2-hydroxybenzylamino]-2-hydroxybenzoic acid and 4-[2-hydroxybenzylamino]benzoic acid.
DETAILED DESCRIPTION OF THE INVENTION
The invention disclosed herein is disclosed in the commonly-owned parent of this application, U.S. patent application Ser. No. 09/455,096, allowed Mar. 10, 2000, the disclosure of which is incorporated herein by reference in its entirety.
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.
A 5-7 membered carbocyclic ring containing one double bond is monocyclic and contains only one double bond.
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.
Particular 5-7 membered carbocyclic ring systems containing one double bond include cyclohexen-3-yl, cyclopenten-2-yl and cyclopenten-3-yl.
Particular substituents for ring carbon atoms in A and heteroaryl or heterocyclyl rings include halo, trifluoromethyl, nitro, hydroxy, amino, C
1-4
alkylamino, diC
1-4
alkylamino, cyano, C
1-6
alkoxy, S(O)
p
C
1-6
alkyl (p is 0, 1 or 2), C
1-6
alkyl (optionally substit
Mitchel Kenneth F.
Raymond Richard L.
Zeneca Limited
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