Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-05-11
2001-10-09
Fan, Jane (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S277000, C514S235500, C546S334000, C546S336000, C546S339000, C546S340000, C544S131000
Reexamination Certificate
active
06300352
ABSTRACT:
This invention relates to novel pyridyl derivatives, their use as medicaments, pharmaceutical formulations including them and methods for their preparation.
European Patent Applications EP-A-0 264 114 and EP-A-0 267 439 disclose certain phenylalkyl- and phenylalkoxypyridine alkanol derivatives and their use as platelet-activating factor (PAF) antagonists.
A series of structurally distinct compounds have now been found to be useful for the modulation of inflammatory conditions. In a first aspect the present invention therefore provides a compound of formula I:
wherein:
X is O or S;
R
1
and R
2
are independently hydrogen, C
1-6
alkyl or C
3-6
cycloalkyl or R
1
and R
2
together with the carbon atom to which they are attached form a C
3-6
cycloalkyl group;
R
3
is hydrogen, and R
4
is C
1-6
alkyl or C
3-6
cycloalkyl or R
3
and R
4
together with the carbon atom to which they are attached form a C
3-6
cycloalkyl group;
Ar
1
is indanyl, tetrahydronaphthyl, naphthyl, phenyl, C
7-9
alkylphenyl or biphenyl, which latter four groups can be optionally substituted by one or more groups selected from halo, nitro, cyano, pyridyl, thiazinyl, C
1-10
alkyl (optionally substituted by one or more fluorine atoms), —Y—OR
5
, —Y—NR
6
C(O)NR
7
—R
8
,—O—Z—C(O)NR
7
R
8
, —O—Y—C(S)NR
7
R
8
, —Y—C(O)NR
7
R
8
, —Y—SO
2
NR
7
R
8
, —Y—NR
7
R
8
, —Y—OC(O)NR
7
R
8
, —Y—C(S)NR
7
R
8
, —Y—C(O)R
9
, —Y—OC(O)R
9
, —Y—CO
2
R
9
, Y—NR
10
C(O)NR
11
—Z—R
12
, SO
2
NR
10
C(O)NR
7
R
8
, —Y—SO
2
NHNR
7
R
8
, —Y—C(O)NR
11
—Z—R
12
, —Y—C(S)NR
11
—Z—R
12
, —Y—N(R
10
)SO
2
R
11
, —Y—N(R
10
)C(O)R
11
or —Y—N(R
10
)CO
2
R
11
;
where:
Y is a bond, C
1-6
alkylene or C
2-6
alkenylene;
R
7
and R
8
are independently hydrogen or C
1-6
alkyl or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur;
R
5
, R
6
, R
9
, R
10
and R
11
are independently hydrogen or C
1-10
alkyl (optionally substituted by one or more fluorine atoms);
Z is C
1-6
alkylene; and
R
12
is a group NR
10
C(O)R
11
, NR
10
CO
2
R
11
, OR
5
, NR
7
R
8
or CO
2
R
13
where R
5
, R
7
, R
8
, R
10
and R
11
are as defined above and R
13
is hydrogen, C
1-6
alkyl, C
1-6
alkylaryl or aryl optionally substituted by hydroxy,
or a salt or solvate thereof.
Alkyl, alkylene, alkenyl and alkenylene groups, whether alone or part of another group, can be straight chained or branched.
Suitably X is O or S, preferably X is O.
Suitably R
1
and R
2
are independently hydrogen, C
1-6
alkyl or C
3-6
cycloalkyl or R
1
and R
2
together with the carbon atom to which they are attached form a spiro linked C
3-6
cycloalkyl group. Preferably R
1
and R
2
are both hydrogen.
Suitably R
3
is hydrogen, and R
4
is C
1-6
alkyl or C
3-6
cycloalkyl or R
3
and R
4
together with the carbon atom to which they are attached form a C
3-6
cycloalkyl group. Preferably R
3
is hydrogen and R
4
is C
1-6
alkyl, in particular methyl, ethyl or isopropyl or R
3
and R
4
together with the carbon atom to which they are attached form a cyclopropyl group.
Suitably Ar
1
is indanyl, tetrahydronaphthyl, naphthyl, phenyl, C
7-9
alkylphenyl or biphenyl, which latter four groups can be optionally substituted by one or more groups selected from halo, nitro, cyano, pyridyl, thiazinyl, C
1-10
alkyl (optionally substituted by one or more fluorine atoms), —Y—OR
5
, —Y—NR
6
C(O)NR
7
—R
8
, —O—Z—C(O)NR
7
R
8
, —O—Y—C(S)NR
7
R
8
, —Y—C(O)NR
7
R
8
, —Y—SO
2
NR
7
R
8
, —Y—NR
7
R
8
, —Y—OC(O)NR
7
R
8
, —Y—C(S)NR
7
R
8
, —Y—C(O)R
9
, —Y—OC(O)R
9
, —Y—CO
2
R
9
, —Y—NR
10
C(O)NR
11
—Z—R
12
, SO
2
NR
10
C(O)NR
7
R
8
, —Y—SO
2
NHNR
7
R
8
, —Y—C(O)NR
11
—Z—R
12
, —Y—C(S)NR
11
—Z—R
12
, —Y—N(R
10
)SO
2
R
11
, —Y—N(R
10
)C(O)R
11
or —Y—N(R
10
)CO
2
R
11
; where Y is a bond, C
1-6
alkylene or C
2-6
alkenylene. More than one substituent can be present on the Ar
1
group and multiple substituents can be the same or different.
Preferably Ar
1
is a naphthyl or a biphenyl group. Preferred sustituents for Ar
1
groups include those groups exemplified herein.
More preferably Ar
1
is biphenyl optionally substituted by one or more substituents selected from halo, cyano, alkyl or SO
2
NR
7
R
8
. Most preferably Ar
1
is biphenyl substituted by cyano, halo, methyl or —SO
2
NH
2
.
Particularly preferred compounds of the invention include those exemplified herein in free base form as well as salts or solvates thereof.
Compounds of the invention can form pharmaceutically acceptable solvates and salts. The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, oxalic, mandelic, tartaric and methanesulfonic acids. Compounds of the invention may also form alkali metal salts such as magnesium, sodium, potassium and calcium salts.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.
According to the invention there is also provided a process for the preparation of compounds of formula I which comprises:
(a) reduction of a compound of formula (II):
in which R
3
, R
4
, X and Ar
1
are as defined in formula (I); or
(b) reduction of a compound of formula (III):
in which R
1
, R
2
, R
3
, R
4
, X and Ar
1
are as defined in formula (I); or
(c) preparation of compounds of formula (I) where Ar
1
is a substituted biphenyl group by reaction of a compound of formula (IV):
with a compound of formula (V):
where X, R
1
, R
2
, R
3
, and R
4
are as defined in formula (I), R
15
is an Ar
1
substituent as defined in formula (I), and R
16
is a suitable hydroxy protecting group, and one of R
17
/R
18
is triflate or halo and the other is B(OH)
2
or ZnHal, or and optionally thereafter in any order:
removing any protecting groups
converting a compound of formula (I) into another compound of formula (I)
forming a pharmaceutically acceptable salt or solvate.
Reduction of compounds of formula (II) is carried out using conventional procedures, for example by hydrogenation using a palladium catalyst in an inert solvent such as ethyl acetate. Reduction of compounds of formula (III) is carried out using conventional procedures, for example using sodium or zinc borohydride or other reducing agents in a suitable solvent such as ethanol.
Process (c) is carried out under the conditions of the Suzuki reaction (
Synthetic Communications
11(7), 513-519, 1081) for example at about 100° C. in the presence of a suitable catalyst and base (e.g. tetrakis(triphenylphosphine)palladium (0) and aqueous sodium carbonate) in a suitable solvent (e.g. ethanol/toluene).
Compounds of formula (II) can be prepared by oxidation of a compound of formula (VI):
in which X, Ar
1
, R
3
and R
4
are as defined in formula (I) followed by reaction of the resulting aldehyde with a compound of formula (VII):
in which M is lithium, sodium, potassium, MgX′ or ZnX′ where X′ is halogen optionally in the presence of additives such as boron trifluoride.
Oxidation of a compound of formula (VI) can be carried out under conventional conditions, for example by Swem oxidation.
Compounds of formula (VI) can be prepared by reduction of a compound of formula (VIII):
in which X, Ar
1
, R
3
and R
4
are as defined in formula (VI) and R
19
is hydrogen C
1-6
alkyl or benzyl using a suitable reducing agent such as lithium aluminium hydride or diborane.
Compounds of formula (VIII) can be prepared from compounds of formula (IX):
in which R
19
, R
3
and R
4
are as defined in formula (VIII) and L is a leaving group such as halogen o
Cheshire David
Cladingboel David
Hirst Simon
Manners Carol
Stocks Michael
Astrazeneca AB
Fan Jane
Nixon & Vanderhye
LandOfFree
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