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
2001-07-24
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, C514S357000, C546S339000, C546S332000, C546S340000, C544S360000
Reexamination Certificate
active
06265409
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 (CH
2
)
n
O, (CH
2
)
n
S or CH
2
CH
2
;
n is 1 or 2;
Ar
1
is naphthyl or biphenyl substituted by one or more groups selected from bromo, iodo, —Y—NR
1
C(O)NR
2
—R
3
, —O—Z—C(O)NR
2
R
3
, —O—Z—C(S)NR
2
R
3
, —Y—C(O)NR
2
R
3
, —Y—SO
2
NR
2
R
3
, —Y—NR
2
R
3
, —Y—C(S)NR
2
R
3
, —Y—C(O)R
4
, —Y—OC(O)R
4
, —Z—CH
2
—OR
4
, —Y—CO
2
R
4
, —Y—NR
5
C(O)NR
6
—Z—R
7
, —SO
2
NR
5
C(O)NR
2
R
3
, —Y—C(O)NR
6
—Z—R
7
, —Y—C(S)NR
6
—Z—R
7
, —Y—N(R
5
)SO
2
R
6
, —Y—N(R
5
)C(O)R
6
or —Y—N(R
5
)CO
2
R
6
; where:
Y is a bond, C
1-6
alkylene or C
2-6
alkenylene;
R
2
and R
3
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
1
, R
4
, R
5
and R
6
are independently hydrogen or C
1-10
alkyl (optionally substituted by one or more fluorine atoms);
Z is C
1-6
alkylene; and
R
7
is a group NR
5
C(O)R
6
, NR
5
CO
2
R
6
, NR
2
R
3
, CO
2
R
8
or OR
9
, where R
2
, R
3
, R
5
and R
6
are as defined above, R
8
is hydrogen, C
1-6
alkyl, C
1-6
alkylaryl or aryl optionally substituted by hydroxy, and R
9
is hydrogen or C
1-6
alkyl,
or a salt or solvate thereof,
provided that:
Ar
1
is not naphthyl substituted by O—Z—C(O)NR
2
R
3
or C(O)R
4
, and
Ar
1
is not biphenyl substituted by —SO
2
NR
2
R
3
, —NR
2
R
3
, SO
2
NR
2
R
3
, —C(O)R
4
, —OC(O)R
4
, —CO
2
R
4
, N(R
5
)SO
2
R
6
or —N(R
5
)C(O)R
6
Alkyl and alkenylene groups, whether alone or part of another group, can be straight chained or branched.
Suitably X is (CH
2
)
n
O, (CH
2
)
n
S or CH
2
CH
2
. Preferably X is CH
2
O, CH
2
S or CH
2
CH
2
. More preferably X is CH
2
O.
Suitably Ar
1
is naphthyl or biphenyl substituted by one or more groups selected from bromo, iodo, —Y—NR
1
C(O)NR
2
—R
3
, —O—Z—C(O)NR
2
R
3
, —O—Z—C(S)NR
2
R
3
, —Y—C(O)NR
2
R
3
, —Y—SO
2
NR
2
R
3
, —Y—NR
2
R
3
, —Y—C(S)NR
2
R
3
, —Y—C(O)R
4
, —Y—OC(O)R
4
, —Z—CH
2
—OR
4
, —Y—CO
2
R
4
, —Y—NR
5
C(O)NR
6
—Z—R
7
, —SO
2
NR
5
C(O)NR
2
R
3
, —Y—C(O)NR
6
—Z—R
7
, —Y—C(S)NR
6
—Z—R
7
, —Y—N(R
5
)SO
2
R
6
, —Y—N(R
5
)C(O)R
6
or —Y—N(R
5
)CO
2
R
6
. Preferably Y is C
1-6
alkylene or C
1-6
alkenylene. The substituent(s) can be present on any suitable position on the naphthyl and biphenyl groups.
Preferably Ar
1
is naphthyl or biphenyl substituted by one or more groups selected from bromo, —Y—C(O)OR
4
, —Y—C(O)NR
2
R
3
, Y—Z—NR
2
R
3
, —Y—NR
1
C(O)NR
2
R
3
, —Y—NR
5
C(O)NR
6
—Z—R
7
, or —Y—C(O)NR
6
—Z—R
7
where Y is CH═CH, CH
2
CH
2
. Preferably one substituent is present.
When Ar
1
is naphthyl or biphenyl substituted by —Y—C(O)OR
4
preferably R
4
is hydrogen or C
1-4
alkyl, in particular methyl.
When Ar
1
is naphthyl or biphenyl substituted by —Y—C(O)NR
2
R
3
, R
2
and R
3
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. Examples of such rings include piperazine, pyrrolidine and morpholine groups. Suitable optional substituents for such rings include C
1-6
alkyl and CO
2
C
1-6
alkyl. Preferably one of R
2
or R
3
is hydrogen and the other is C
1-4
alkyl, in particular methyl, or R
2
and R
3
are both C
1-4
alkyl, in particular methyl or R
2
and R
3
form a morpholine ring or a piperazine ring optionally substituted by C
1-6
alkyl in particular methyl, or CO
2
C
1-6
alkyl, in particular CO
2
Me and CO
2
t-butyl groups.
When Ar
1
is naphthyl or biphenyl substituted by —Y—NR
1
CONR
2
R
3
, R
1
and R
2
are preferably hydrogen and R
3
is preferably C
1-6
alkyl, in particular methyl.
When Ar
1
is naphthyl or biphenyl substituted by —Y—C(O)NR
6
—Z—R
7
, R
6
is preferably hydrogen. R
7
is suitably a group NR
5
C(O)R
6
, NR
5
CO
2
R
6
, CO
2
R
8
or OR
9
where R
5
and R
6
are independently hydrogen or C
1-6
alkyl and R
8
is hydrogen, C
1-6
alkyl, C
1-6
alkylaryl or aryl. When R
7
is NR
5
C(O)R
6
or NR
6
CO
2
R
6
, R
5
is preferably hydrogen and R
6
is preferably C
1-6
alkyl. Preferably R
7
is CO
2
R
8
or OR
9
. When R
7
is CO
2
R
8
suitable aryl groups include phenyl, preferably R
8
is hydrogen or benzyl.
Particularly preferred compounds of the invention include:
(2R)-1-[2-(6-Bromonaphthyloxy)]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-trans-Propenoic acid, methyl ester)naphthyloxy)]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-Propanoic acid, methyl ester)naphthyloxy)]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-(N-methyl)propanamide)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-trans-Propenoic acid)naphthyloxy)]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-(N-methyl)propenamide)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-(N,N-Dimethyl)propenamide)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-(N,N-Dimethyl)propanamide)naphthyloxy-]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-propanoic acid)naphthyloxy)]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-N-(benzyloxycarbonylmethyl)propanamide)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-N-(Ethanoic acid)propanamide)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-(N-Acetylpiperazino)-1-oxopropyl)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-(4-Morpholinyl)-1-oxopropyl)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-N-(2-Hydroxyethyl)propanamide)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-(4-(4-(1,1-Dimethylethoxycarbonyl))piperazine)-1-oxopropyl)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-(N-(Hexahydro-1,4-diazine)-1-oxopropyl)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-(N,N-Dimethyl)propanamide)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2S)-1-[2-(6-Bromonaphthyloxy)]-4-(3-pyridyl)-2-butanol,
(2S)-1-[2-(6-(3-(N,N-Dimethyl)propenamide)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2S)-1-[2-(6-(3-(N,N-Dimethyl)propanamide)naphthyloxy]-4-(3-pyridyl)-2-butanol,
(2R)-1-[3′-(N,N-Dimethylphenylacetamide)-4-biphenyl-4-yloxy]-4-(3-pyridyl)-2-butanol,
(2R)-1-[2-(6-(3-(N-6-(1,1-Dimethylethylcarbamoyl)hexyl)propanamide)naphthyl-oxy]-4-(3-pyridyl)-2-butanol,
or a salt or solvate 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, mandelic, tartaric and methanesulphonic 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 as hereinbefore defined which comprises:
(a) for comp
Cheshire David
Cladingboel David
Hirst Simon
Manners Carol
Stocks Michael
Astrazeneca AB
Fan Jane
Nixon & Vanderhye
LandOfFree
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