Propanolamine derivatives linked to bile acids, processes...

Details Propanolamine derivatives linked to bile acids, processes... Propanolamine derivatives linked to bile acids, processes...

1999-09-29

2001-01-30

Badio, Barbara (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C540S107000, C540S109000, C540S112000, C540S113000

Reexamination Certificate

active

06180618

ABSTRACT:

Under the provisions of Section 119 of 35 U.S.C., Applicants hereby claim the benefit of the filing date of Federal Republic of Germany Patent Application Number 19845403.1, filed Oct. 2,1998, which Application is hereby incorporated by reference.
The present invention relates to novel substituted propanolamine derivatives, their pharmaceutically tolerated salts, their physiologically functional derivatives, and the preparation and use of such derivatives and salts.
Several classes of active compounds have been described for treatment of adiposity and disturbances in lipid metabolism, e.g.,
polymeric adsorbers, such as cholestyramine,
benzothiazepines (WO 93/16055),
bile acid dimers and conjugates (EP 0 489 423), and
4-amino-2-ureido-pyrimidine-5-carboxamides (EP 0 557 879).
The present invention was based on the need to provide further compounds with therapeutically valuable hypolipidemic action.
The present invention therefore relates to compounds of formula (I)
wherein:
GS is a bile acid group of the formula
R
1
is a bond to X or —OH;
R
2
is a bond to X, —OH, —O—(C
1
-C
6
)-alkyl, —NH—(C
2
-C
6
)-alkyl-SO
3
H, —N(CH
3
)—CH
2
—CH
2
—SO
3
H, —NH—(C
1
-C
6
)-alkyl-COOH, or —N(CH
3
)—(C
1
-C
6
)-alkyl-COOH;
with the proviso that R
1
and R
2
can not simultaneously be a bond to X;
R
3
, R
4
each independently of one another is H or OH;
 or a bond;
l, m, n each independently of one another is 0 or 1;
L is —(C
1
-C
6
)-alkyl or phenyl;
AA
1
, AA
2
each independently of one another is an amino acid radical or an amino acid radical which is mono or polysubstituted by an amino acid-protective group;
and pharmaceutically tolerated salts and physiologically functional derivatives thereof.
Preferred compounds of formula (I) are those in which one or more radical(s) has or have the following meaning:
GS is a bile acid group of the formula
R
1
is a bond to X or OH;
R
2
is a bond to X, —OH, —O—(C
1
-C
6
)-alkyl, —NH—(C
2
-C
6
)-alkyl-SO
3
H, —N(CH
3
)—CH
2
—CH
2
—SO
3
H, —N H—(C
1
-C
6
)-alkyl-COOH, or —N(CH
3
)—(C
1
-C
6
)-alkyl-COOH;
with the proviso that R
1
and R
2
can not simultaneously be a bond to X;
 or a bond;
l, m, n each independently of one another is 0 or 1;
L is —(C
1
-C
6
)-alkyl or phenyl;
AA
1, AA
2
, each independently of one another is an amino acid radical or an amino acid radical which is mono- or polysubstituted by an amino acid-protective group;
and pharmaceutically tolerated salts and physiologically functional derivatives thereof.
In certain currently preferable embodiments, compounds of formula (I) are those in which one or more radical(s) has or have the following meaning:
GS is a bile acid group of the formula
R
1
is a bond to X or —OH;
R
2
is a bond to X, —OH, —O—(C
1
-C
6
)-alkyl, —NH—(C
2
-C
6
)-alkyl-SO
3
H, or —NH—(C
1
-C
6
)-alkyl-COOH;
with proviso that R
1
and R
2
can not simultaneously be a bond to X;
 or a bond;
l, m, n, each independently of one another is 0 or 1;
L is —(C
1
-C
6
)-alkyl;
AA
1
, AA
2
, each independently of one another is an amino acid radical or an amino acid radical which is mono- or polysubstituted by an amino acid-protective group;
and pharmaceutically tolerated salts thereof.
The term alkyl is understood as meaning straight-chain or branched hydrocarbon chains.
The term amino acids or amino acid radicals indicates the stereoisomeric forms, i.e., D- or L-forms, of any of the following compounds:
alanine
glycine
proline
cysteine
histidine
glutamine
aspartic acid
isoleucine
arginine
glutamic acid
lysine
serine
phenylalanine
leucine
threonine
tryptophan
methionine
valine
tyrosine
asparagine
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
piperidic acid
2,2-diaminopimelic acid
6-aminocaproic acid
2,3-diaminopropionic acid
2-aminoheptanoic acid
N-ethylglycine
2-(2-thienyl)-glycine
3-(2-thienyl)-alanine
penicillamine
N-methylglycine
N-ethylasparagine
N-methylisoleucine
hydroxylysine
6-N-methyllysine
allo-hydroxylysine
N-methylvaline
3-hydroxyproline
norvaline
4-hydroxyproline
norleucine
isodesmosine
ornithine
allo-isoleucine
11-aminoundecanoic acid
The amino acids are abbreviated in accordance with customary nomenclature (e.g., Schröder, L{umlaut over (u)}bke,
The Peptides,
Volume I, New York 1965, pages XXII-XXIII; Houben-Weyl,
Methoden der Organischen Chemie
(
Methods of Organic Chemistry
), Volume XV/1 and 2, Stuttgart 1974). The amino acid D-Asp is the D-form of aspartic acid. Peptides are acid amides from their chemical nature and dissociate into amino acids on hydrolysis.
The term amino acid-protective groups is to be understood to mean suitable groups which protect the functional groups of the side chains of the amino acid radicals (see, e.g., T. W. Greene, P. G. M. Wuts,
Protective Groups in Organic Synthesis,
2nd Ed., John Wiley and Sons, New York 1991). Often utilized amino acid-protective groups are, for example, t-butyloxy-carbonyl (BOC), 9-fluorenylmethoxy-carbonyl (Fmoc), benzyloxy-carbonyl (Z), 2-(3,5-dimethoxyphenyl)prop-2-yloxycarbonyl (Ddz), methyl, t-butyl, trityl and S-t-butyl, and t-butylamino-carbonyl.
The present invention furthermore relates to processes for the preparation of compounds of formula (I) which proceed according to the following reaction equations (equations 1 to 4):
Process A
Compounds of type IV are obtained by reacting o-, m- or p-substituted imines of type 11 with ketone III. The reaction can be carried out, e.g., by mixing the two compounds in bulk without a solvent and then heating, or with a suitable solvent, such as ethanol, tetrahydrofuran (THF), toluene, diglyme or tetradecane, at temperatures of from 20° C. to 150° C.
The keto compounds of type IV are reduced to hydroxy compounds of type V with NaBH
4
or another suitable reducing agent in a suitable solvent, e.g., methanol, THF or THF/water, at temperatures between −30° C. and +40° C. Two isomer mixtures (racemates) are usually obtained as the main product in the reduction. The various racemates can be separated from one another by fractional crystallization or silica gel chromatography. The nitro group in compounds of type V can be reduced by known processes, e.g., catalytic hydrogenation with Pd or Pd-on-charcoal and H
2
in methanol.
The racemic compounds of type VI thus obtained can be separated further into their enantiomers. The racemate splitting of VI into enantiomers of type VII can be carried out by chromatography over chiral column material or by processes known from the literature using optically active auxiliary reagents (
J. Org. Chem.
44, 1979, 4891).
In accordance with equation 2, the aromatic amines of type VI or VII (as a racemate or as a pure enantiomer) can be reacted with an amino acid by known standard peptide coupling processes to give derivatives VIII. A suitable process is coupling with TOTU and triethylamine in DMF. Literature examples are illustrated in, e.g., G. Breipohl, W. König EP 0460446, W. König, G. Breipohl, P. Pokorny, and M. Birkner, in E. Giralt and D. Andreu (Eds.)
Peptides
1990, Escom, Leiden, 1991, 143-145. The radicals AA
1
and AA
2
have the meanings given according to formula (I). The amino function of the amino acid is provided with a protective group such as Fmoc, and the carboxylic acid is unprotected.
In amino acids with side chain functional groups, the functional groups are protected accordingly, either temporarily during the synthesis, or throughout the synthesis of the compounds according to the present invention.
To arrive at derivative VIII, the protective group of the amino function is split off. In the case of Fmoc, this is accomplished in a mixture of DMF and piperidine. Dipeptide conjugates IX are obtained if, starting from compounds of type VIII, the reaction sequence (a) coupling of an amino acid and (b) deprotection is repeated.
Bile acid derivatives of type X can be prepared from 3-amino-bile acid esters by linking with alkyl- or aryidicarboxylic acids or derivatives thereof, s

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