Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-27
2001-11-06
Oswecki, Jane C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S365000, C514S372000, C514S375000, C514S379000, C514S315000, C514S396000, C514S408000, C514S438000, C514S471000, C514S603000, C546S184000, C546S290000, C546S348000, C548S202000, C548S217000, C548S241000, C548S346100, C548S578000, C549S074000, C549S491000, C564S316000
Reexamination Certificate
active
06313132
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel therapeutically active compounds, methods for their preparation, pharmaceutical compositions containing the novel compounds, and the use of the compounds for preparing drugs.
BACKGROUND OF THE INVENTION
WO 89/06644 and WO 94/11337 disclose tertiary 3,3-diphenylpropylamines having anticholinergic activity, especially for the treatment of urinary incontinence. SE-A-215499 discloses secondary 3,3-diphenylpropylamines having an advantageous effect on the heart and circulation. U.S. Pat. No. 3,446,901, GB-A-1,169,944 and GB-A-1,169,945 disclose 3,3-diphenylpropylamines having antidepressant activity. DE-B1-1216318 discloses preparation of diphenylalkylamines having effect on the heart and circulation.
SUMMARY OF THE INVENTION
In accordance with the present invention, novel therapeutically active diarylpropylamines have been found which like the 3,3-diphenylpropylamines known from WO 89/06644 and WO 94/11337 above have favourable anticholinergic properties, and which therefore also can be used for the control of events mediated by acetylcholine, like urination.
In one aspect, the present invention provides novel compounds represented by the general formula I:
wherein:
R
1
is hydrogen, hydroxy, alkyl, alkoxy, hydroxyalkyl, trifluoromethyl, amino, alkylcarbonylamino, alkylcarbonyloxy, halogen,
R
2
and R
3
independently are hydrogen, hydroxy, alkyl, alkoxy, hydroxyalkyl, halogen, alkoxycarbonylalkyl, carbamoyl, sulphamoyl,
R
4
is &ohgr;-hydroxyalkoxy, &ohgr;-aminoalkoxy, &ohgr;-aminoalkylamino, alkoxyalkyl, hydroxyalkoxyalkylaminoalkyl, dihydroxyalkyl, formyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, carbamoylalkyl, carboxamidoalkyl, carboxyl, amino, nitro, cyano, nitrilo, cyanoalkyl, azido, alkyl of at least two carbon atoms, alkoxy of at least two carbon atoms, hydroxyalkyl of at least two carbon atoms,
R
5
is hydrogen, halogen, alkyl,
Ar is aryl or heteroaryl which may be mono- or independently disubstituted by alkyl, alkoxy, hydroxy, hydroxyalkyl, halogen, alkoxycarbonylalkyl, carbamoyl, sulphamoyl, and
R
6
and R
7
are hydrocarbyl groups which may be the same or different, together containing at least three carbon atoms, and which may carry one or more hydroxy groups, and wherein carbon atoms may be interconnected by oxygen atoms, and wherein R
6
and R
7
may form a ring together with the amine nitrogen,
with the provisos that (a) when:
(i) at least two of R
2
, R
3
and R
5
are other than hydrogen, or
(ii) R
1
is other than hydroxy or methoxy, and Ar is other than phenyl that is ortho-substituted by hydroxy or methoxy, or
(iii) Ar is heteroaryl, or
(iv) at least one of R
6
and R
7
is aromatic hydrocarbyl or cycloalkyl, then
R
4
may also be hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, halogen, carbamoyl, sulphamoyl;
and (b), when Ar is unsubstituted phenyl, then R
1
, R
2
, R
3
, R
4
and R
5
can not all be hydrogen;
their salts with physiologically acceptable acids and, when the compounds can be in the form of optical isomers, the racemic mixture and the individual enantiomers.
In another aspect, the present invention provides the compounds having the general Formula I above for therapeutical use, especially for the treatment of urinary incontinence related disorders.
In still another aspect, the present invention provides a pharmaceutical composition comprising one or more compounds of the general Formula I above as the active ingredient, preferably together with a pharmaceutically acceptable carrier and, if desired, other pharmacologically active agents.
In yet another aspect, the present invention provides a method of treating a patient (animals, including humans) suffering from a disorder related to urinary incontinence, which method comprises the step of administering to the said patient an effective amount of a compound having the general Formula I above.
In another aspect, the present invention provides the compounds according to Formula I for use as a pharmaceutically active substance, especially as an anticholinergic agent.
In yet another aspect, the present invention provides the use of the compounds having the general Formula I above for the manufacture of a medicament for the treatment of urinary incontinence related disorders.
In still another aspect, the present invention provides processes for preparing compounds having the general Formula I above.
DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises novel 3,3-diarylpropylamines and their pharmaceutically acceptable salts which are characterized by Formula I above and which are useful as anticholinergic agents. The compounds are particularly useful for treatment of urinary incontinence.
One subgroup of compounds of Formula I is defined by the substituent R
4
being &ohgr;-hydroxyalkoxy, &ohgr;-aminoalkoxy, &ohgr;-aminoalkylamino, alkoxyalkyl, hydroxyalkoxyalkyl-aminoalkyl, dihydroxyalkyl, formyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyl-aminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, carbamoylalkyl, carboxamidoalkyl, carboxyl, amino, nitro, cyano, nitrilo, cyanoalkyl, or azido.
In a limited group of compounds within this subgroup, R
1
is hydrogen or methyl, R
2
, R
3
and R
5
are either all hydrogen or one of R
2
, R
3
and R
5
is methyl, methoxy, hydroxy, carbamoyl, sulphamoyl or halogen, and the others are hydrogen, and Ar is phenyl or phenyl which is mono- or independently disubstituted by methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen.
Another subgroup of the compounds of Formula I is defined by Ar being heteroaryl.
In a limited group of compounds within this subgroup, R
1
is hydrogen or methyl, and R
2
, R
3
, R
4
and R
5
are either all hydrogen or one of R
2
, R
3
, R
4
and R
5
is methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen, and the others are hydrogen.
Still another subgroup of the compounds of Formula I is defined by R
1
being hydrogen, alkyl, hydroxyalkyl, trifluoromethyl, amino, alkylcarbonylamino, alkylcarbonyloxy, or halogen. Preferaby, Ar is then other than phenyl that is ortho-substituted by hydroxy or alkoxy.
In a limited group of compounds within this subgroup, R
1
is hydrogen or methyl, R
2
, R
3
, R
4
and R
5
are either all hydrogen or one of R
2
, R
3
, R
4
and R
5
is methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen, and the others are hydrogen, and Ar is phenyl or phenyl which is mono- or independently disubstituted by methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen.
Yet another subgroup of the compounds of Formula I is defined by at least one of R
6
and R
7
being aromatic hydrocarbyl, cycloalkyl or a hydrocarbyl chain wherein carbon atoms are interconnected by an oxygen atom at one or more positions.
In a limited group of compounds within this subgroup, R
1
is hydrogen or methyl, R
2
, R
3
, R
4
and R
5
are either all hydrogen or one of R
2
, R
3
, R
4
and R
5
is methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen, and the others are hydrogen, and Ar is phenyl or phenyl which is mono- or independently disubstituted by methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen.
In the compounds of Formula I, “alkylo”, separately and in combinations, is preferably C
1-8
alkyl, i.e. methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomeric forms thereof, more preferably C
1-6
alkyl, especially C
1-4
alkyl.
Similarly, “alkoxy”, separately and in combinations, is preferably C
1-8
alkoxy, i.e. methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and isomeric forms thereof, more preferably C
1-6
alkoxy, especially C
1-4
alkoxy.
“Aryl” means phenyl or naphthyl. “Heteroaryl” refers to a 5- or 6-membered heteroaromatic ring having from one to three heteroatoms, and which optionally may be fused to a homoaromatic ring, such as a benzene ring. Exemplary heteroaryl groups are m
Beierlein Katarina
Emond Rikard
Haraldsson Martin
Johansson Rolf
Ringberg Erik
Birch & Stewart Kolasch & Birch, LLP
Oswecki Jane C.
Pharmacia AB
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