Pharmaceutical formulations in dry form for the oral...

Details Pharmaceutical formulations in dry form for the oral... Pharmaceutical formulations in dry form for the oral...

1999-07-30

2001-10-16

Raymond, Richard L. (Department: 1615)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S316000, C514S323000, C514S331000, C546S135000

Reexamination Certificate

active

06303626

ABSTRACT:

The present invention relates to novel pharmaceutical formulations in dry form for oral administration, in which a cyclic quaternary ammonium compound is present as the active principle.
In particular, the invention relates to pharmaceutical formulations for oral administration which contain, as the active principle, a compound of the formula
in which:
AC
⊖
is a pharmaceutically acceptable anion;
Am
⊕
is:
i—either a group Am
1
⊕
of the formula
in which:
Ar
1
is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl. a (C
1
-C
4
)alkoxy, a (C
1
-C
4
)-alkyl and a trifluoromethyl, said substituents being identical or different;
x is zero or one; and
W
1
is a (C
1
-C
6
)alkyl or a benzyl group, the substituent W
1
being either in the axial position or in the equatorial position;
ii—or a group Am
2
⊕
of the formula
in which:
Ar
1
, x and W
1
are as defined above; and
R
1
is a hydroxyl, a (C
1
-C
4
)alkoxy, a formyloxy, a (C
1
-C
3
)alkylcarbonyloxy, a carboxyl, a (C
1
-C
4
)alkoxycarbonyl, a cyano, a ((C
1
-C
3
)alkylcarbonylamino, a mercapto or a (C
1
-C
4
)alkylthio;
iii—or a group Am
3
61
of the formula
in which:
Ar
1
and W
1
are as defined above; and
R
2
is hydrogen, a (C
1
-C
3
)alkyl or a (C
1
-C
3
)alkylcarbonyl;
iv—or a group Am
4
⊕
of the formula
in which:
Ar
1
and x are as defined above; and
p is one or two;
v—or a group Am
5
⊕
of the formula
in which:
Ar
1
and x are as defined above.
Ar is a phenyl which is unsubstituted or monosubstituted or disubstituted by a substituent selected from a halogen atom, a (C
1
-C
3
)alkoxy, a (C
1
-C
3
)alkyl and a trifluoromethyl, said substituents being identical or different; a naphthyl; or an indolyl;
Q and Y have one of the following groups of meanings:
a) Q
1
and Y
1
;
b) Q
2
and Y
2
when Am
⊕
is a group Am
1
⊕
, Am
2
⊕
, Am
4
⊕
or Am
5
⊕
;
c) Q
3
and Y
3
when Am
⊕
is a group Am
1
⊕
or Am
2
⊕
or a group Am
4
⊕
in which Ar
1
is a phenyl and p is two;
d) Q
4
and Y
4
when Am
⊕
is a group Am
1
⊕
, Am
3
⊕
, Am
4
⊕
or Am
5
⊕
;
Q
1
is hydrogen;
Y
1
is hydrogen, a (C
1
-C
4
)alkyl, an &ohgr;-(C
1
-C
4
)alkoxy-(C
2
-C
4
)alkylene, an &ohgr;-(C
1
-C
4
)alkylcarbonyloxy-(C
2
-C
4
)alkylene, an &ohgr;-benzoyloxy-(C
2
-C
4
)alkylene, an &ohgr;-hydroxy-(C
2
-C
4
)alkylene, an &ohgr;-(C
1
-C
4
)alkylthio-(C
2
-C
4
)alkylene, an &ohgr;-(C
1
-C
4
)-alkylcarbonyl-(C
2
-C
4
)alkylene, an &ohgr;-carboxy-(C
2
-C
4
)alkylene, an &ohgr;-(C
1
-C
4
)-alkoxycarbonyl-(C
2
-C
4
)alkylene, an co-benzyloxy-(C
2
-C
4
)alkylene, an &ohgr;-formyl-oxy-(C
2
-C
4
)alkylene, an &ohgr;-R
3
NHCOO—(C
2
-C
4
)alkylene, an &ohgr;-R
4
R
5
NCO—(C
2
-C
4
)-alkylene, an &ohgr;-R
6
CONR
7
—(C
2
-C
4
)alkylene, an &ohgr;-R
8
OCONR
7
—(C
2
-C
4
)alkylene, an &ohgr;-R
4
R
5
NCONR
7
—(C
2
-C
4
)alkylene, an &ohgr;-R
9
SO
2
NR
7
—(C
2
-C
4
)alkylene, an &ohgr;-cyano-(C
1
-C
3
)alkylene;
Q
2
and Y
2
together form an ethylene, trimethylene or tetramethylene group;
Q
3
and Y
3
together form a group
in which n is one, two or three;
Q
4
and Y
4
together form a radical selected from:
A
1
) —O—CH
2
—
A
2
) —O—CO—
A
3
) —CH
2
—O—CO—
A
4
) —O—CH
2
—CO—
A
5
) —O—CH
2
—CH
2
—
A
6
) —N(R
10
)—CO—
A
7
) —N(R
10
)—CO—CO—
A
8
) —N(R
10
)—CH
2
—CH
2
—
T is either a group —CO— when Q and Y are Q
1
and Y
1
, Q
2
and Y
2
or Q
4
and Y
4
when they together form a radical A
1
), A
5
) or A
8
); or a group —CH
2
— when Q and Y are Q
3
and Y
3
or Q
4
and Y
4
when they together form a radical A
2
), A
3
), A
4
), A
6
) or A
7
);
A is either a direct bond or a methylene group when T is —CO—, or a direct bond when T is —CH
2
—;
Z is:
a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which is unsubstituted or monosubstituted or polysubstituted by a (C
1
-C
4
)alkyl; a benzylamino; a carboxyl; a (C
1
-C
10
)alkyl; a (C
3
-C
7
)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C
1
-C
10
)alkoxy; a (C
3
-C
7
)cycloallcoxy which is unsubstituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C
1
-C
10
)alkylthio; a (C
1
-C
6
)alkylcarbonyloxy; a (C
1
-C
6
)alkylcarbonylamino; a benzoylamino; a (C
1
-C
4
)alkoxycarbonyl; a (C
3
-C
7
)cycloalkylcarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C
1
-C
4
)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C
1
-C
4
)alkyl or a (C
3
-C
7
)cycloalkyl; and a (pyrrolidin-1-yl)carbonylamino, said substituents being identical or different;
a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C
1
-C
4
)alkyl, a hydroxyl or a (C
1
-C
4
)alkoxy;
a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; an imidazolyl;
R
3
is a (C
1
-C
7
)alkyl or a phenyl;
R
4
and R
5
are each independently a hydrogen or a ((C
1
-C
7
)alkyl; R
5
can also be a (C
3
-C
7
)cycloalkyl, a (C
3
-C
7
)cycloalkylmethyl, a phenyl or a benzyl; or R
4
and R
5
, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, mnorpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C
1
-C
4
)alkyl;
R
6
is a hydrogen, a (C
1
-C
7
)alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or a (C
3
-C
7
)cycloalkyl which is unsubstituted or substituted ty one or more methyls;
R
7
is a hydrogen or a (C
1
-C
7
)alkyl;
R
8
is a (C
1
-C
7
)alkyl or a phenyl;
R
9
is a (C
1
-C
7
)alkyl; an amino which is unsubstituted or substituted by one or two (C
1
-C
7
)alkyls; a phenyl which is unsubstituted or monosubstituted or poly-substituted by a substituent selected from a halogen atom, a (C
1
-C
7
)alkyl, a trifluoromethyl, a hydroxyl, a (C
1
-C
7
)alkoxy, a carboxyl, a (C
1
-C
7
)alkoxycarbonyl, a (C
1
-C
7
)alkylcarbonyloxy, a cyano, a nitro and an amino which is unsubstituted or substituted by one or two (C
1
-C
7
)alkyls, said substituents being identical or different;
R
10
is hydrogen or a (C
1
-C
4
)alkyl, and its optional salts with mineral or organic acids and their optional solvates.
The compounds of formula (I) which are useful for the invention include both the racemates and the optically pure isomers, as well as the axial and equatorial isomers when Ams in the compound of formula (I) is a group Am
1
⊕
, a group Am
2
⊕
or a group Am
3
⊕
.
The compounds of formula (I) are described in patent applications FP-A-0 512 901, EP-A-0 515 240, EP-A-0 559 538, EP-A-0 591 040, WO 95/26 339, EP-A-0 700 382, EP-A-0 723 959 and WO 96/23 787.
Among the compounds of formula (I), those of the formula
in which:
Ar
1
, x and p are as defined for a compound of formula (I);
Ar′ is a 3,4-dichlorophenyl or a 3,4-difluorophenyl;
Z′ is a phenyl substituted in the 3-position by a halogen or a (C
1
-C
10
)alkoxy;
A
⊖
is a pharmaceutically acceptable anion, are preferred for the invention.
More particularly, the invention relates to pharmaceutical formulations in dry forms for the oral administration of (S)-1-{2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)piperidin-3-yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octane, or SR 140333, of the formula
in which A
⊖
is a pharmaceutically acceptable anion.
The benzenesulfonate of SR 140333, hereafter called compound A, is very particularly preferred. The international non-proprietary name of this compound is nolpitantium besilate.
The compounds of formula (1) have been described as antagonists of substance P, which is the natural ligand of the NK
1
receptors and hence have an affinity for the said receptors. For oral administration, such compounds must have a good absorption which entails both a good solubility in aqueo

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