Quinuclidine derivatives and their use as muscarinic M3...

Details Quinuclidine derivatives and their use as muscarinic M3... Quinuclidine derivatives and their use as muscarinic M3...

2002-01-14

2004-06-15

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S133000, C546S134000, C546S135000

Reexamination Certificate

active

06750226

ABSTRACT:

This invention relates to new therapeutically useful quinuclidine derivatives, to some processes for their preparation and to pharmaceutical compositions containing them.
The novel structures according to the invention are antimuscarinic agents with a potent and long lasting effect. In particular, these compounds show high affinity for muscarinic M
3
receptors(Hm3).
In accordance with their nature as M
3
antagonists, the new compounds are suitable for treating the following diseases: respiratory disorders such as chronic obstructive pulmonary disease(COPD), chronic bronchitis, bronchial hyperreactivity, asthma and rhinitis; urological disorders such as urinary incontinence, pollakinuria in neuripenia pollakinuria, neurogenic or unstable bladder, cystospasm and chronic cystitis; and gastrointestinal disorders such as irritable bowel syndrome, spastic colitis, diverticulitis and peptic ulceration.
The compounds claimed are also useful for the treatment of the respiratory diseases detailed above in association with &bgr;
2
agonists, steroids, antiallergic drugs or phosphodiesterase IV inhibitors.
Compounds of the present invention may also be expected to have anti-tussive properties.
Depending on their nature the new compounds may be suitable for treating vagally induced sinus bradycardia.
Compounds with related structures have been described as anti-spasmodics and anti-cholinergic agents in several patents.
For example, in patent FR 2012964 are described quinuclidinol derivatives of the formula:
in which R is H, OH or an alkyl group having 1 to 4 carbon atoms; R
1
is a phenyl or thienyl group; and R
2
is a cyclohexyl, cyclopentyl or thienyl group, or, when R is H, R
1
and R
2
together with the carbon atom to which they are attached, form a tricyclic group of the formula:
in which X is —O—, —S— or —CH
2
—, or an acid addition or quaternary ammonium salt thereof.
EP-418716 describes thienyl carboxylate esters of formula
wherein A is a group
m and n=1 or 2
Q is a —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—, —CH═CH—, group
Q′ is a ═NR or NRR═ group; R
1
is a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl group, optionally substituted; R
2
is H, OH, C
1
-C
4
alkoxy or C
1
-C
4
alkyl and R
a
is H, F, Cl, CH
3
— or —NR.
U.S. Pat. No. 5,654,314 describes compounds of formula:
wherein R is an optionally halo- or hydroxy-substituted C
1-4
alkyl group; R is a C
1-4
alkyl group; or R and R═ together form a C
4-6
alkylene group; X
−
is an anion; and R
1
is H, OH, —CH
2
OH, C
1-4
alkyl or C
1-4
alkoxy.
The present invention provides new quinuclidine derivatives with potent antagonist activity at muscarinic M
3
receptors which have the chemical structure described in formula (I):
wherein:
is a phenyl ring, a C
4
to C
9
heteroaromatic group containing one or more heteroatoms (preferably selected from nitrogen, oxygen and sulphur atoms), or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group;
R
1
, R
2
and R
3
each independently represent a hydrogen or halogen atom, or a hydroxy group, or a phenyl, —OR
4
, —SR
4
, —NR
4
R
5
, —NHCOR
4
, —CONR
4
R
5
, —CN, —NO
2
, —COOR
4
or —CF
3
group, or a straight or branched lower alkyl group which may optionally be substituted, for example, with a hydroxy or alkoxy group, wherein R
4
and R
5
each independently represent a hydrogen atom, straight or branched lower alkyl group, or together form an alicyclic ring; or R
1
and R
2
together form an aromatic, alicyclic or heterocyclic ring;
n is an integer from 0 to 4;
A represents a —CH
2
—, —CH═CR
6
—, —CR
6
═CH—, —CR
6
R
7
—, —CO—, —O—, —S—, —S—(O)—, SO
2
or —NR
6
— group, wherein R
6
and R
7
each independently represent a hydrogen atom, straight or branched lower alkyl group, or R
6
and R
7
together form an alicyclic ring;
m is an integer from 0 to 8; provided that when m=0, A is not —CH
2
—;
p is an integer from 1 to 2 and the substitution in the azoniabicyclic ring may be in the 2, 3 or 4 position including all possible configurations of the asymmetric carbons;
B represents a group of formula i) or ii):
 wherein R
10
represents a hydrogen atom, a hydroxy or methyl group; and R
8
and R
9
each independently represents
 wherein R
11
represents a hydrogen or halogen atom, or a straight or branched lower alkyl group and Q represents a single bond, —CH
2
—, —CH
2
—CH
2
—, —O—, —O—CH
2
—, —S—, —S—CH
2
— or —CH═CH—, and when i) or ii) contain a chiral centre they may represent either configuration; X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.
In the quaternary ammonium compounds of the present invention represented by formula (I) an equivalent of an anion (X
−
)is associated with the positive charge of the N atom. X
−
may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate, and organic acids such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. X
−
is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate or succinate. More preferably X
−
is chloride, bromide or trifluoroacetate.
The compounds of the present invention represented by the formula (I) described above, which may have one or more assymetric carbons, include all the possible stereoisomers. The single isomers and mixtures of the isomers fall within the scope of the present invention.
If any of R
1
to R
7
or R
11
represents an alkyl group, it is preferred that said alkyl group contains 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms. In particular it is preferred that any alkyl group is represented by a methyl, ethyl, propyl, including i-propyl, butyl including a n-butyl, sec-butyl and tert-butyl.
The alicyclic and heterocyclic rings mentioned in relation to formula (I) preferably comprise from 3 to 10, preferably from 5 to 7 members. The aromatic rings mentioned in relation to formula (I) above preferably contain from 6 to 14, preferably 6 or 10 members.
Preferred compounds of formula (I) are those wherein
represents a phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl or benzothiazolyl group, in particular a phenyl, pyrrolyl, or thienyl group; R
1
, R
2
and R
3
each independently represent a hydrogen or halogen atom, or a hydroxyl, methyl, tert-butyl, —CH
2
OH, 3-hydroxypropyl, —OMe, —NMe
2
, —NHCOMe, —CONH
2
, —CN, —NO
2
, —COOMe or —CF
3
group, in particular a hydrogen atom, a hydroxy group or a halogen atom, wherein the halogen atom is preferably fluorine; n=0 or 1; m is an integer from 1 to 6, particularly 1, 2 or 3; A represents a —CH
2
—, —CH═CH—, —CO—, —NH—, —NMe—, —O— or —S— group, in particular a —CH
2
—, —CH═CH— or —O— group.
It is also preferred that p=2 and the substituent group —OC(O)B attached to the azoniabicyclo[2.2.2]octane is at the 3 position, preferably having the (R) configuration.
Further preferred compounds of formula I are those wherein B is a group of formula i) or ii) as defined above wherein, if B is a group of formula (i), R
8
and R
9
each independently represent a phenyl, 2-thienyl, 3-thienyl, 2-furyl or 3-furyl group, wherein R
11
is hydrogen atom; and, if B is a group of formula (Ii), Q represents a single bond, —CH
2
—, —CH
2
—CH
2
—, —O— or —S— group, in particular a single bond, —CH
2
—, —CH
2
—CH
2
— or —O— group, most preferably a single bond or —O— group; and in any case R
10
is a hydrogen atom or a hydroxy or methyl group; and when i) or ii) contain a chiral centre they may represent either the (R) or the (S) configuration.
Most preferably the —OC(O)B group in formula (I) is diphenylacetoxy, 2-hydroxy-2,2-diphenyl-acetoxy, 2,2-diphenylpropionyloxy, -hydroxy-2-phenyl-2-thien-2-yl-acetoxy, 2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-2-ylacetoxy,

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