1,4-benzothiazepine-1,1-dioxide derivatives substituted by...

Details 1,4-benzothiazepine-1,1-dioxide derivatives substituted by... 1,4-benzothiazepine-1,1-dioxide derivatives substituted by...

2000-04-07

2001-08-21

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S211070, C536S029110, C540S551000, C540S552000

Reexamination Certificate

active

06277831

ABSTRACT:

The invention relates to substituted 1,4-benzothiazepine-1,1-dioxide derivatives, their physiologically tolerable salts and physiologically functional derivatives.
1,4-Benzothiazepine-1,1-dioxide derivatives and their use for the treatment of hyperlipidemia and also arteriosclerosis and hypercholesterolemia have already been described (PCT Application No. PCT/GB 95101884, Publication No. WO 96/05188).
The invention is based on the object of making available further compounds with therapeutically valuable hypolipidemic action. In particular, the object consists in finding novel compounds which cause a higher excretion of bile acid, even at a lower dosage, compared with compounds previously known.
The invention therefore relates to compounds of formula I
wherein:
R
1
is methyl, ethyl, propyl, or butyl;
R
2
is H or OH;
R
3
is a sugar residue, disugar residue, trisugar residue, or tetrasugar residue, wherein the sugar residue, disugar residue, trisugar residue, or tetrasugar residue are optionally mono- or polysubstituted by a sugar protective group;
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;
or a pharmaceutically tolerable salt, or a physiologically functional derivative thereof.
Preferred compounds of formula I are those wherein one or more radical(s) has, or have, the following meaning(s):
R
1
is ethyl, propyl, or butyl;
R
2
is H or OH;
R
3
is a sugar residue or disugar residue, wherein the sugar residue or disugar residue are optionally mono- or polysubstituted by a sugar protective group;
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;
or a pharmaceutically tolerable salt thereof.
Another embodiment of formula I are those wherein one or more radical(s) has, or have, the following meaning(s):
R
1
is ethyl or butyl;
R
2
is H or OH;
R
3
is a sugar residue, wherein the sugar residue is optionally mono- or polysubstituted by a sugar protective group;
Z is —(C═O)—C
0
-C
4
-alkyl or a covalent bond;
or a pharmaceutically tolerable salt thereof.
Because of their higher water solubility compared with the starting or base compounds, pharmaceutically tolerable salts are particularly suitable for medicinal applications, where 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, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and also organic acids, such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric, and trifluoroacetic acids. For medicinal purposes, the chlorine salt is preferably used. Suitable pharmaceutically tolerable basic salts are ammonium, alkali metal (such as sodium and potassium), and alkaline earth metal (such as magnesium and calcium).
Salts with a nonpharmaceutically tolerable anion are likewise within 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 designates any physiologically tolerable derivative of a compound according to the invention, e.g., an ester which on administration to a mammal, such as man, is able (directly or indirectly) to form such a compound or an active metabolite thereof.
A further aspect of this invention is 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 within the scope of the invention and are a further aspect of the invention.
Below, all references to “compound(s) according to formula I” relate to compound(s) of formula I as described above, and to 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 chosen specific compound, the intended use, the manner of administration, and the clinical condition of the patient.
In general, the daily dose lies 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 mg to 100 mg, typically from 0.02 mg to 50 mg. In the case of pharmaceutically tolerable salts, the abovementioned weight data relate to the weight of the benzothiazepine ion derived from the salt. For the prophylaxis or therapy of the abovementioned conditions, compounds according to formula I can be used directly, but they are preferably present with a tolerable carrier in the form of a pharmaceutical composition. The carrier 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 carrier 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 likewise 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 consist in mixing the constituents with pharmacologically tolerable carrier,and/or excipients.
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 in each individual case will be determined by the nature and the severity of the condition to be treated and on the type of the compound according to formula I used in each case. Sugar-coated formulations and sugar-coated sustained release formulations are also within the scope of the invention. Acid-resistant and enteric formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl 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 capsules, cachets, lozenges, or tablets, as powders or granules, as a solution or suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil emulsion, which in each case contain a certain amount of the compound according to formula I. These compositions can be prepared according to any suitable pharmaceutical method which comprises a step in which the active compound and the carrier (which can consist of one or more additional constituents) are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and/or finely divided solid carrier, after which the product, if necessary, is shaped. Thus, a tablet can be prepared by compressing or shaping a powder or granules of the compound, if appropriate with one or more additional constituents. Pressed tablets can be prepared by tableting the compound in free-flowing form, such as a powder or granules, if appropriate mixed with a binder, lubricant, inert diluent, and/or one or more surface-active/dispersing agent

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