CA2334775C

CA2334775C - Benzo(b)thiepine-1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use

Info

Publication number: CA2334775C
Application number: CA002334775A
Authority: CA
Inventors: Wendelin Frick; Alfons Enhsen; Heiner Glombik; Hubert Heuer
Original assignee: Sanofi Aventis Deutschland GmbH
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 1998-06-10
Filing date: 1999-05-28
Publication date: 2009-10-13
Anticipated expiration: 2019-05-28
Also published as: JP2002517491A; BR9912188A; ATE227715T1; TR200003632T2; WO1999064409A3; ZA200007061B; CA2334773C; ES2215387T3; NZ508681A; ZA200007060B; NO327075B1; ATE259372T1; HU229761B1; ID28695A; ES2182535T3; CZ297925B6; CN1152039C; DK1086113T3; WO1999064409A2; TR200003634T2

Abstract

The invention relates to substituted benzo(b)thiepine-1,1-dioxide derivatives and to the acid addition salts thereof. The invention relates to compounds of formula (1), wherein R1, R2, R3, R4, R5 and Z have the cited descriptions, to the physiologically compatible salts, to physiologically functional derivatives, and to a method for the production thereof. The compounds are suited, for example, as hypolipidemic agents.

Description

Description Benzo(b)thiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use 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-diox.ide derivatives and their use for the treatment of hyperlipidemia as well as; arteriosclerosis and hypercholesterolemia have already been described [cf. PCT Application . No. PCT/US97/04076, 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 ED200 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
O\S O

~ I
R~N \

\
I
,3 N R
~Z~
H
in which R is methyl, ethyl, propyl, butyl;

R2 is H, OH, NH2, NH-(C1-C6)-alky1;

R3 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;
R4 is mefhyl, ethyl, propyl, butyl;
R5 is methyl, ethyl, propyl, butyl;

Z is -(C=O)n-Cp-C1E3-alkyl-, -(C=O)n-Cp-C16-alkyl-NH-, -(C=O)n-Cp-C16-alkyl-O-, -(C=())n-C1-C16-alkyl-(C=O)m, a covalent bond;

n is0orl; -m is0orl;

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:

R1 is ethyl, propyl, butyl;

R2 is H, OH, NH2, NH-(C1-C6)-alkyl;

R3 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;
R4 is methyl, ethyl, propyl, butyl;
R5 is methyl, ethyl, propyl, butyl;

Z is -(C=O)n-Cp-Clg-alkyl-, -(C=O)n-Cp-C16-alkyl-NH-, -(C=O)n-Cp-C16-alkyl-O-, -(C=O)n-C1-C16-alkyl-(C=O)m, a covalent bond;

n is0orl;

m is0orl;

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:

R1 is ethyl, butyl;
R2 is OH;

R3 is a diamino acid radical, the diamino acid radical optionally being mono- or polysubstituted by an amino protective group;

R4 is methyl;
R5 is methyl;

Z is -(C=O)-C0-C4-al!kyl, 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 exaimple 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 accordinci 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 physiologicallly functional derivatives as described herein.

The amount of a compourid 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 kilograim 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 5 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 arrd/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 clelayed-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 the active compound and the excipient (which can consist of one or more additional c:onstituents) are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a Iiquid and/or finely divided solid excipient, after which the product, if necessary, is shaped. For example, a tablet can thus be prepared by pressing or shaping a powder or granules of the compound, if appropriate with one or more additional constituents. Pressed tablets can be produced by tableting the compound in free-flowing form, such as, for example, a powder or clranules, if appropriate mixed with a binder, lubricant, inert diluent arid/or a (number of) surface-active/dispersing agent(s) in a suitable machine. Shaped tablets can be produced by shaping the pulverulent compound moistened with an inert liquid diluent in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual) administration include lo:zenges which contain a compound accordirig to formula (I) _with a flavoring, customarily sucrose and gum arabic or tragacanth, and pastilles which include the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.

The invention furthermore relates both to isomer mixtures of the formula I, and the pure stereoisomers of the formula I, as well as diastereomer mixtures of the formula I and the pure diastereomers. The separation of the mixtures is carried out chromatographically.

Preferred racemic and eriantiomerically pure compounds of the formula I
are those having the follovving structure:

.R1 R
R 4 R 4 \ I '/
N
N

3Z 3iZ~
N R N
H H
The term amino acids or amino acid residues means, for example, the stereoisomeric forms, i.e. [) or L forms, of the following compounds:

alanine glycine proline cysteine histidirie glutamine aspartic acid isoleucine arginine glutamic acid lysine serine phenylalanine leucine threonine tryptophane methionine valine tyrosine asparaigine 2-aminoadipic acid 2-aminoisobutyric acid 3-aminoadipic acid 3-aminoisobutyric acid beta-alanine 2-aminopimelic acid 2-aminobutyric acid 2,4-diaminobutyric acid 4-aminobutyric acid desmosine piperidinic acid 2,2-diaminopimelic acid 6-aminocaproic acid 2,3-diaminopropionic acd 2-aminoheptanoic acid N-ethylglycine 2-(2-thienyl)glucine 3-(2-thienyl)alanine penicillamine sarcosine N-ethylasparagine N-methylisoleucine hydroxylysine 6-N-methyllysine.
allo-hydroxylysine N-methylvaline 3-hydroxyproline norvaline 4-hydroxyproline norleucine isodesmosine ornithine allo-isoleucine N-methylglycine The brief notation for the amino acids follow the generally customary notation (cf. Schroder, Lubke, The Peptides, Band I, New York 1965, pages XXII-XXIII; Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Volurne XV/1 and 2, Stuttgart 1974). The amino acid pGlu is pyroglytamyl, Nal is 3-(2-naphthyl)alanine, azagly-NH2 is a compound of the formula NH2-HN-CONH2 and D-Asp is the D form of aspartic acid. According tc- their chemical nature, peptides are acid amides and decompose into amino acids on hydrolysis.

Diamino acid residue, triamino acid residue, tetraamino acid residue are understood as meaning peptides which are synthesized from 2 to 4 of the abovementioned amino acids.

Suitable protective groups (see, for example, T.W. Greene, "Protective Groups in Organic Synthesis") employed for amino acids are primarily:
Arg(Tos), Arg(Mts), Arg(Mtr), Arg(PMV), Asp(OBzl), Asp(OBut), Cys(4-MeBzl), Cys(Acm), Cys(SBut), Glu(OBzl), Glu(OBut), His(Tos), His(Fmoc), His(Dnp), His(Trt), Lys(CI-,2), Lys(Boc), Met(O), Ser(Bzl), Ser(But), Thr(Bzl), Thr(But), Trp(Mts), Trp(CHO), Tyr(Br-Z), Tyr(Bzl) or Tyr(but).

Amino protective groups used are preferably the benzyloxycarbonyl(Z) radical which is removable by catalytic hydrogenation, the 2-(3,5-dimethyloxy-phenyl)prop-2-yloxycarbonyl (Ddz) or trityl (Trt) radical which can be cleaved by weak acids and the 9-fluorenylmethyloxycarbonyl (Fmoc) radical which can be removed by seconclary amines.

The invention furthermore relates to a process for the preparation of benzo(b)thiepine 1,1-dioxide derivatives of the formula I:

O\\ s i0 O\\ // 0 s R' / R' R, a N ~ ~ i III R 4 1 N ~ I

R5 R2 --~ R5 Rz HzO
NH NZR
z H
I I

A process for the preparation of compounds of the formula I, which comprises reacting an amiine of the formula II, in which R1, R2, R4 and R5 have the meanings indicated for formula I, with a compound of the formula III, in which R3 and Z have the meanings indicated for formula I, with elimination of water to give a compound of the formula I and optiorially converting the compound of the formula I obtained into a physiologically tolerable salt or a physiologically functional derivative. If the radical R3 is a monoamino acid, this raidical can optionally also still be lengthened stepwise so as to give the diamino acid radical, triamino acid radical or tetraamino acid radical after bonding to the amine of the formula II.

The compounds of the formula I and their pharmaceutically tolerable salts and physiologically functional derivatives are ideal pharmaceuticals for the treatment of lipid metabolism disorders, in particular of hyperlipidemia. The compounds of the formula I are likewise suitable for influencing the serum cholesterol level and for 1the prevention and treatment of arteriosclerotic symptoms. The compounds can optionally also be administered in combination with statins, such as, for example, simvastatatin, fluvastatin, pravastatin, cerivastatin, lovastatin or atorvastin. The following findings confirm the pharmacological efficacy of the compounds according to the invention.

The biological testing of the compounds according to the invention was carried out by determination of the ED200 excretion. This testing investigates the action of the compounds according to the invention ori the bile acid transport in the ileum and the fecal excretion of bile acids in the rat after oral administration twice daily. The diastereomer mixtures of the compounds were tested.

The test was carried out as follows:
1) Preparation of the test and reference substances The following recipe was used for the formulation of an aqueous solution:
the substances were dissolved in adequate volumes of an aqueous solution comprising Solutol (= polyethylene glycol 600 hydroxystearate;
BASF, Ludwigshafen, Germany; Batch No. 1763), so that a final concentration of 5% of Solutol is present in the aqueous solution. The solutions/suspensions were administered orally in a dose of 5 ml/kg.

2) Experimental conditions Male Wistar rats (Kastengrund, Hoechst AG, weight range 250-350 g) were kept in groups of 6 animals each and received a standard feed mixture (Altromin, Lage, Germany) from 10 days before the start of treatment (day 1) with a reversed day/night rhythm (4.00 - 16.00 dark, 16.00 - 4.00 light).
Three days before the stairt of the experiment (day 0), the animals were divided into groups of 4 animals each.

Division of the animals into treatment groups:

Number of the Animal No. / Test substance ~ Dose (mg/kg/d) group Analysiis No.

1 1-4 negative control Vehicle 2 5-8 Test substance 2 x 0.008 Dose 1 3 9-12 Test substance 2 x 0.02 Dose 2 4 13-16 Test substance 2 x 0.1 Dose 3 5 17-20 Test substance 2"x 0.5 Dose 4 1 dissolved/suspended in 5% Solutol HS 15/0.4% starch mucilage 3) Experimental course After intravenous or sulbcutaneous administration of 5 Ci of 14C-taurocholate per rat (day 0), the vehicles or test substances were given at 7.00-8.00 and at 15.00-16.00 on the following day (day 1) (treatment for one day).

10 Stool samples for the an,alysis of 14C-taurocholate were taken every 24 hours directly after the administration of the morning dose. The feces were weighed, stored at -18 C and later suspended in 100 ml of demineralized water and homogenized (IJltra Turrax, Janke & Kunkel, IKA-Werk). Aliquot parts (0.5 g) were weighed and combusted on combustion lids (Combusto Cones, Canberra Packard) in a combustion apparatus (Tri Carb@ 307 combuster Canberra Packard GmbH, Frankfurt am Main, Germany). The resulting 14C02 was absorbed with Carbo-Sorb (Canberra Packard). The following 14C radioactivity measurements were determined after addition of the scintillator (Perma-Fluor complete scintillation cocktail No. 6013187, Packard) to the samples with the aid of liquid scintillation counting (LSC).
The fecal excretion of 14C-taurocholic acid was calculated as a cumulative and/or percentage residual radioactivity (see below).

4) Observations and measurements The fecal excretion of 14C-TCA was determined in combusted aliquot parts of the stool samples taken at 24-hour intervals, calculated as the "cumulative percentage" of the administered activity and expressed as a %
of the residual activity (= remaining activity, i.e. administered activity rninus the already excreted activity). For the calculation of the dose-response curves, the excretion of i4C taurocholic acid was expressed as a percentage proportion of the corresponding values of the control group (treated with vehicle). Ttie ED200, i.e. the dose which increases the fecal excretion of 14C taurocholic acid to 200% of the control group, is calculated from a sigmoid or lin(aar dose-response curve by interpolation. The calculated ED200 corresponds to a dose which doubles the fecal excretion of bile acids.
5) Results Table 1 shows measurements of the ED200 excretion.
Table 1:
Compounds from Example ED200 excretion (mg/kg/d) p.o.

4 0.04 Comparison Examples 1 0.8 2 1.0 3 0.9 6) Discussion It can be inferred from the measured data that the compounds of the formula I according to the invention have an action which is better by the factor 20 compared with i:he compounds described in the prior art.

The following Examples serve to illustrate the invention in greater detail without restricting same to products and embodiments described in the Examples.

Example 4 o,, 0 s ~ . \
0 ;
0 _ OH o,,S o HN
O
O H O
N OH
NH HN
O O
O O H
NH2 8a ~N H
NH

O 8b C46H74N6O9S (887.20). MS (M + H)' = 887.5 Comparison Examples from W097/33882:
Comparison Example 1 O~~S O O~S O
~
N '''~,i N OH OH
( \
H2N \ / / ~

le ib Comparison Example 2 O~ ,O O~~ O
S S
I ,NN/
N
OH OH
O / I O

Br N \ Br N
H H
98 9b Comparison Example 3 ~N \ \ \ I '~~~
OH N
I OH
N
J F H ~ F N
O H
_ F FF

The Examples and Comparison Examples were prepared as follows (in the preparations only the synthesis of the a diastereomers is shown):

Reaction scheme 1 o, ,o o,o ; yOH
~ \ I TOTU H~ `
OH + Finac-D-Lys(Boc)-OH
/ ~ NH H
H-N \ O

1a ~ 6a O O

\' ~, EL~NH 7~ OH
/ H~ / I

Hi ~ 1- Fmoc-D Lys(Boc)-OH. TOTU
NH2 Z, EtNH

7a O" ', / ' \I _ ~ \
~ OH
"
H H
NH
o NHz 8a Synthesis of compound 6 as a diastereomer mixture:

150 mg (0.35 mmol) of 1Et/b and 245 mg (0.52 mmol) of Fmoc-D-Lys(Boc)-OH 5 (Fluka) in 6 ml of DMF are reacted with 169 mg of TOTU, 74 mg of 5 oxime and 0.5 ml of NEM anagously to the synthesis of compound 3. 'Yield 290 mg (94%) of 6a/b as an amorphous solid. TLC (ethylene acetate/n-heptane 2:1). Rf = 0.6. C50H64N408S (881.15). MS (M + H)+ = 881.5.
Synthesis of comgound 7 as a diastereomer mixture:
285 mg (0.32 mmol) of 6a/b are dissolved in 5 ml of DMF. After an addition of 0.6 ml of diethylamine, the mixture is allowed to stand for 30 minutes.
Working-up is carried out analogously to the synthesis of compound 3.
Yield 173 mg (81 %) of 7a/b as an amorphous solid. TLC (methylene chloride/methanol 15:1). Ftf = 0.2, starting material 6a/b Rf = 0.4.
C35H54N406S (658.91). AAS (M + H)+ = 659.4.
Synthesis of compound 8 as a diastereomer mixture:

168 mg (0.25 mmol) of 7'a/b are reacted analogously to the synthesis of compound 6 and 7 and 169 mg (75% over two stages) of 8a/b is obtained as an amorphous solid. TLC (methylene chloride/methanol 9:1). Rf = 0.3.
C46H74N609S (887.20). MS (M + H) + = 887.5.

Claims

1. A compound of the formula I, wherein R1 is ethyl or butyl;

R2 is OH;

R3 is a diamino acid radical, the diamino acid radical optionally being mono- or polysubstituted by an amino protective group;

R4 is methyl;
R5 is methyl;

Z is -(C=O)-C0-C4-alkyl or a covalent bond;
or its pharmaceutically tolerable salts.

2. A process for the preparation of a compound of the formula I as claimed in claim 1, which comprises reacting, according to the following equation, an amine of the formula II, in which R1, R2, R4 and R5 have the meanings indicated for formula I, with a compound of the formula III, in which R3 and Z

have the meanings indicated for formula I, with elimination of water to give a compound of the formula I and optionally converting the compound of the formula I obtained into a physiologically tolerable salt.

3. A pharmaceutical composition comprising one or more of the compound of formula I as claimed in claim 1 and a pharmaceutically tolerable excipient.

4. A pharmaceutical composition comprising one or more of the compound of formula I as claimed in claim 1 and a pharmaceutically tolerable excipient and one or more statins.

5. A use of a compound as claimed in claim 1 for the production of a medicament for the treatment of lipid metabolism disorders.

6. A process for the production of a pharmaceutical composition comprising mixing a compound of formula I according to claim 1, with a pharmaceutically suitable excipient and bringing this mixture into a form suitable for administration.

7. A use of a compound as claimed in claim 1 for the production of a medicament for the treatment of hyperlipidemia.

8. A use of a compound as claimed in claim 1 for the production of a medicament for influencing the serum cholesterol level.

9. A use of a compound as claimed in claim 1 for the production of a medicament for the prevention of arteriosclerotic symptoms.