Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-07
2002-05-14
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
06387944
ABSTRACT:
This application is a 371 of PCT/EP99/03701 May 28, 1999
The invention relates to substituted benzo(b)thiepine 1,1-dioxide derivatives, their physiologically tolerable salts and physiologically functional derivatives.
Benzo(b)thiepine 1,1-dioxide derivatives and their use for the treatment of hyperlipidemia as well as arteriosclerosis and hypercholesterolemia have already been described [cf. PCT Application No. PCT/US97104076, publication No. WO 97/33882].
The invention was based on the object of making available further compounds which display a therapeutically utilizable hypolipidemia action. In particular, the object consisted in finding novel compounds which, compared with the compounds described in the prior art, bring about a higher fecal bile acid excretion, even at a lower dose. A dose reduction of the ED
200
value by at least the factor 5 compared with the compounds described in the prior art was particularly desirable.
The invention therefore relates to compounds of the formula I
in which
R
1
is methyl, ethyl, propyl, butyl;
R
2
is H, OH, NH
2
, NH—(C
1
-C
6
)-alkyl;
R
3
is an amino acid radical, diamino acid radical, triamino acid radical, tetraamino acid radical, the amino acid radical, diamino acid radical, triamino acid radical or tetraamino acid radical optionally being mono or polysubstituted by an amino acid protective group;
R
4
is methyl, ethyl, propyl, butyl;
R
5
is methyl, ethyl, propyl, 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
, 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 the formula I are those in which one or more radical(s) has or have the following meaning:
R
1
is ethyl, propyl, butyl;
R
2
is H, OH, NH
2
, NH—(C
1
-C
6
)-alkyl;
R
3
is an amino acid radical, diamino acid radical, the amino acid radical or diamino acid radical optionally being mono- or polysubstituted by an amino acid protective group;
R
4
is methyl, ethyl, propyl, butyl;
R
5
is methyl, ethyl, propyl, 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
, a covalent bond;
n is 0 or 1;
m is 0 or 1;
and their pharmaceutically tolerable salts.
Particularly preferred compounds of the formula I are those in which one or more radical(s) has or have the following meaning:
R
1
is ethyl, butyl;
R
2
is OH;
R
3
is a diamino acid radical, the diamino acid radical optionally being mono- or polysubstituted by an amino protective group;
R
4
is methyl;
R
5
is methyl;
Z is —(C═O)—C
0
-C
4
-alkyl, 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, isothionic, 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 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 (directly or indirectly) to form 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 the formula (I) as described above, and also their salts, solvates and physiologically functional derivatives as described herein.
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, 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 and 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 benzo(b)thiepine 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 a 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 active compound. 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 pharmacologically tolerable excipients and/or auxiliaries.
Pharmaceutical compositions according to the invention are those which are suitable for oral and peroral (e.g. sublingual) administration, although the most suitable manner of administration is dependent-in each individual case on the nature and severity of the condition to be treated and on the type of the compound according to formula (I) used in each case. Coated formulations and coated delayed-release formulations are also included in the scope of the invention. Acid-resistant and enteric formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinal acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compounds for oral administration can be present in separate units, such as, for example, capsules, cachets, lozenges or tablets, which in each case contain a specific amount of the compound according to formula (I); as a powder or granules; as a solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared according to any suitable pharmaceutical method which includes a step in which th
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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