Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-24
2003-11-04
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S009000
Reexamination Certificate
active
06642269
ABSTRACT:
The invention relates to substituted benzothiepine 1,1-dioxide derivatives, their physiologically tolerable salts and physiologically functional derivatives.
The present application is a continuation of PCT application PCT/EP99/03743, which designates the United States, and was filed May 29, 1999. The present application and the PCT application claim priority to German patent No. 19825804.6, filed Jun. 10, 1998, and issued Apr. 16, 1999. Both prior applications are entirely incorporated by reference herein.
Benzothiepine 1,1-dioxide derivatives and their use for the treatment of hyperlipidemia as well as arteriosclerosis and hypercholesterolemia have already been described. PCT Application No. PCT/US97/04076, publication No. WO 97/33882. The disclosure of that publication is entirely incorporated by reference herein.
One object of the present invention is the improved availability of compounds which display a therapeutically utilizable hypolipidemia action. In particular, novel compounds satisfy this object when they bring about the same magnitude of fecal bile acid excretion at a significantly lower dosage than that required of currently-known compounds. A dose reduction of the ED
200
value by at least a factor of 5 compared with the compounds currently known is particularly desirable. The present invention unexepectedly satisfies this object.
The invention therefore relates to compounds of formula I:
in which
R
1
is methyl, ethyl, propyl, or butyl;
R
2
is H, OH, NH
2
, or NH—(C
1
-C
6
)-alkyl;
R
3
is a sugar radical, a disugar radical, a trisugar radical, or a tetrasugar radical, wherein said radicals are optionally mono- or polysubstituted by a sugar protective group;
R
4
is methyl, ethyl, propyl, or butyl;
R
5
is methyl, ethyl, propyl, or butyl;
Z is —(C═O)
n
—(C
0
-C
16
)-alkyl-, —(C═O)
n
—(C
0
-C
16
)-alkyl-NH—, —(C═O)
n
—(C
0
-C
16
)-alkyl-O—, —(C═O)
n
—(C
1
-C
16
)-alkyl-(C═O)
m
, or a covalent bond;
n is 0 or 1;
m is 0 or 1;
and their pharmaceutically tolerable salts and physiologically functional derivatives.
Preferred compounds of formula I are those in which one or more radicals have the following meaning:
R
1
is ethyl, propyl, or butyl;
R
2
is H, OH, NH
2
, or NH—(C
1
-C
6
)-alkyl;
R
3
is a sugar radical, or disugar radical, wherein said radicals are optionally mono- or polysubstituted by a sugar protective group;
R
4
is methyl, ethyl, propyl, or butyl;
R
5
is methyl, ethyl, propyl, or butyl;
Z is —(C═O)
n
—(C
0
-C
16
)-alkyl-, —(C═O)
n
—(C
0
-C
16
)-alkyl-NH—, —(C═O)
n
—(C
0
-C
16
)-alkyl-O—, —(C═O)
n
—(C
1
-C
16
)-alkyl-(C═O)
m
, or a covalent bond;
n is 0 or 1;
m is 0 or 1;
and their pharmaceutically tolerable salts.
Particularly preferred compounds of formula I are those in which one or more radicals have the following meaning:
R
1
is ethyl or butyl;
R
2
is OH;
R
3
is a sugar radical, wherein the sugar radical is optionally mono- or polysubstituted by a sugar protective group;
R
4
is methyl;
R
5
is methyl;
Z is —(C═O)—(C
0
-C
4
)-alkyl, or a covalent bond;
and their pharmaceutically tolerable salts.
On account of their higher water solubility compared with the starting or base compounds, pharmaceutically tolerable salts are particularly suitable for medicinal applications. These salts must have a pharmaceutically tolerable anion or cation. Suitable pharmaceutically tolerable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acid, and of organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acid. For medicinal purposes, the chlorine salt is particularly preferably used. Suitable pharmaceutically tolerable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
Salts with an anion or cation which is not pharmaceutically tolerable are likewise included in the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically-tolerable salts and/or for use in nontherapeutic, for example in-vitro, applications.
The term “physiologically functional derivative” used here indicates any physiologically tolerable derivative of a compound according to the invention, e.g. an ester which, on administration to a mammal, such as, for example, man, is able to form, directly or indirectly, such a compound or an active metabolite thereof.
A further aspect of this invention are prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to give a compound according to the invention. These prodrugs can themselves be active or inactive.
The compounds according to the invention can also be present in various polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention are included in the scope of the invention and are a further aspect of the invention.
Below, all references to “compound(s) according to formula I” refer to compound(s) of formula I as described above, and also their salts, solvates and physiologically functional derivatives as described herein.
The compounds of formula I and their pharmaceutically tolerable salts and physiologically functional derivatives are ideal pharmaceuticals for the prophylaxis and treatment of lipid metabolism disorders, in particular of hyperlipidemia. The compounds of formula I are likewise suitable for influencing, in particular, lowering, the serum cholesterol level and for the prophylaxis and treatment of one or more arteriosclerotic symptoms. When these compounds are used for prophylaxis, one skilled in the art has many means to determine or predict a patient's need for such prophylaxis. These methods are well-known in the art.
The compounds can optionally also be administered in combination with statins, such as, for example, simvastatin, fluvastatin, pravastatin, cerivastatin, lovastatin or atorvastatin.
The compounds according to the invention are also suitable for the prophylaxis or treatment-of gallstones.
The amount of a compound according to formula I which is necessary in order to achieve the desired biological effect is dependent on a number of factors, e.g. the specific compound selected, the intended use, in particular whether for prophylaxis or for treatment, the manner of administration and the clinical condition of the patient. In general, the daily dose is in the range from 0.1 mg to 100 mg (typically from 0.1 mg to 50 mg) per day per kilogram of body weight, e.g. 0.1-10 mg/kg/day. Tablets or capsules can contain, for example, from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically tolerable salts, the abovementioned weight data relate to the weight of the benzothiepine ion derived from the salt. For the prophylaxis or therapy of the abovementioned conditions, the compounds according to formula I can be used themselves as the compound, but preferably they are present in the form of a pharmaceutical composition with at least one pharmacologically tolerable excipient. The excipient must of course be tolerable in the sense that it is compatible with the other constituents of the composition and is not harmful to the health of the patient. The excipient can be a solid or a liquid or both and is preferably formulated with the compound as an individual dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the compound of formula I. Further pharmaceutically active substances can also be present, including further compounds according to formula I. The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consists in mixing the constituents with p
Enhsen Alfons
Frick Wendelin
Glombik Heiner
Heuer Hubert
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner LLP
Lambkin Deborah C.
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