Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-07
2001-07-31
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S131000, C546S015000, C546S285000
Reexamination Certificate
active
06268362
ABSTRACT:
The present invention relates to anthracyclinone derivatives, to their use for the treatment of amyloidoses, to the methods for their preparation and to the pharmaceutical compositions containing them.
Our previous PCT Patent Application WO 96/04895 provides the new use of anthracyclinone derivatives in the treatment of amyloidosis, some novel compounds, processes for their .preparation and pharmaceutical compositions containing them.
Unexpectedly, we found that the presence of a particular heterocyclic residue on the anthracyclinone skeleton is associated with a better activity of this class of compounds as inhibitors of the aggregation process of amyloidogenic peptides.
The present invention provides anthracyclinone derivatives of formula 1
wherein R
1
represents:
hydrogen,
hydroxy,
a group of formula OR
7
wherein R
7
is C
1
-C
6
alkyl, C
2
-C
6
alkenyl;
R
2
represents:
hydrogen,
hydroxy,
diethylamino, piperidino, tetrahydropyridino or morpholino;
either R
3
, taken alone, represents hydrogen or hydroxy; and R
4
and R
5
, taken alone, independently represent hydrogen, hydroxy or, taken together with the carbon atom, represent a carbonyl group;
or R
3
and R
4
, taken together, represent a group of formula
wherein R
8
and R
9
represent a C
1
-C
6
alkyl, and R
5
represents hydrogen;
R
6
represents:
hydrogen or
a phenyl group, optionally substituted by methyl, methoxy or halogen,
and the pharmaceutically acceptable salt thereof
Preferred compounds of formula 1 are those wherein:
R, represents:
hydrogen,
hydroxy or
methoxy;
R
2
represents:
hydrogen,
hydroxy or
morpholino
R
3
represents hydroxy;
R
4
, taken alone, represents hydroxy;
R
5
, taken alone, represents hydrogen or
R
4
and R
5
taken together with the carbon atom represent a carbonyl group;
R
6
represents hydrogen, and the pharmaceutically acceptable salt thereof.
The term C
1
-C
6
“alkyl” as used herein includes both straight and branched chain alkyl groups or moieties such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and, in case of pentyl and hexyl, a branched chain isomer thereof.
The term C
2
-C
6
“alkenyl” as used herein includes both straight and branched chain radicals of up to 6 carbons such as, for example, vinyl, allyl, butenyl, pentenyl and hexenyl.
The term “halogen” as used herein means fluorine, chlorine, bromine or iodine.
This invention also includes all the possible isomers of compounds of formula 1 and mixtures thereof, for example diastereoisomeric mixtures and racemic mixtures. Thus, the stereocenter at position 9, and the possible stereocenters at positions 7 and 13, may have the (R) configuration or the (S) configuration or both, ie. a mixture of stereoisomers is present.
The present invention also provides the salts of compounds of formula 1. The salts are, typically, physiologically tolerable or pharmaceutically acceptable salts formed with suitable inorganic or organic acids. Examples of inorganic acids are, for instance, hydrochloric and sulfuric acid, while organic acids may be mono-, di- and tricarboxylic acids, like, for examples, acetic, trifluoroacetic, tartaric or citric acid, and sulfonic acids like, for example, methanesulfonic or ptoluensulphonic acid.
Compounds of formula 1, wherein R
3
, R
3
, R
4
, R
5
and R
6
are as defined above and R
2
is hydrogen or hydroxy, can be prepared by the following procedures:
(a) reacting a compound of formula 2,
wherein R
1
, and R
3
are as defined above and R
2
is hydrogen or hydroxy, with acompound of formula 3
(b) converting a compound of formula 1 as defined above into a different compound of formula 1 by appropriate chemical reactions, such as reduction, substitution or condensation.
Compounds of formula 1 obtained according to procedures a) or b) can be transformed into pharmaceutically acceptable salts thereof.
A compound of formula 1, wherein R
1
, R
3
and R
6
are as defined above, R
2
is hydrogen or hydroxy and R
4
and R
5
taken together represent a carbonyl group, is obtained according to procedure a) by reacting a compound of formula 2 with a compound of formula 3 in a proper organic solvent like dichloromethane, chloroform, acetone, dioxane or dimethylformamide at a temperature ranging from −10° C. to room temperature and for a period of from 6 to 48 hours. An organic base such as diethylamine or ethyl-diisopropylamine may be present. Preferred reaction conditions encompass the use of equimolar amounts of compound 2 and 3 and ethyldiisopropylamine in dichloromethane at room temperature for a period of 6 to 24 hours.
Compounds of formula 2, wherein R
1
and R
3
are as defined above and R
2
is hydrogen or hydroxy, can be prepared by bromination of a compound of formula 4,
wherein R
1
and R
3
are as defined above and R
2
is hydrogen or hydroxy, in analogy to known procedures reported in the literature (see, for instance, T. H. Smith et al.,
J. Org. Chem.
1977, vol. 42, p. 3653).
Compounds of formula 4, wherein R
1
and R
3
are as defined above and R
2
is hydrogen or hydroxy, may be prepared, depending on the nature of the substituents, starting from known anthracyclinones by appropriate chemical modifications (see: F. Arcamone in
Doxorubicin Anticancer Antibiotics, Medicinal Chemistry,
a series of monographs, vol. 17, Academic Press, 1981).
According to procedure b), a compound of formula 1 as defined above, may be converted into a different compound of formula 1 by appropriate synthetic procedures described for the anthracyclines or anthracyclinones (see: F. Arcamone in
Doxorubicin Anticancer Antibiotics,
Medicinal Chemistry, a series of monographs, vol. 17, Academic Press, 1981) or by general synthetic procedures (see: J. March,
Advanced Organic Chemistry,
IV Ed., J. Wiley & Sons, 1992).
As an example, a compound of formula 1, wherein R
1
, R
2
, R
3
and R
6
are as defined above and R
4
and R
5
taken together represent a carbonyl group can be converted into a compound of formula 1, wherein R
1
, R
2
, R
3
and R
6
are as defined above, R
4
represents hydroxy and R. represents hydrogen by reduction with sodium borohydride or sodium cyanoborohydride.
In another example, a compound of formula 1, wherein R
1
, R
3
and R
6
are as defined above, and
either R
2
represents hydroxy and R
4
and R
5
are taken together represent a carbonyl group,
or R
2
and R
4
represent hydroxy and R
5
represents hydrogen, can be converted into a compound of formula 1, wherein R
1
, R
3
and R
6
are as defined above, and
either R
2
represents hydrogen and R
4
and R
5
taken together represent a carbonyl group,
or R
4
represents hydroxy and R
2
and R
5
represent hydrogen, by treatment with sodium dithionite.
In another example, a compound of formula 1, wherein R
1
and R
6
are as defined above, R
2
and R
5
represent hydrogen and R
3
and R
4
represent hydroxy, can be converted into a compound of formula 1, wherein R
1
and R
6
are as defined above, R
2
and R
5
represent hydrogen, R
3
and R
4
taken together represent a group of formula
wherein R
8
and R
9
are as above defined, by condensation with a compound of the formula R
8
COR
9
or R
8
C (OCH
3
)
2
OR
9
wherein R
8
and R
9
are as above defined, for example acetone or 2,2-dimethoxy propane, in the presence of an acid catalyst.
In a further example, a compound of formula 1, wherein R
1
, R
3
and R
6
are as defined above, R
4
and R
5
are taken together to represent a carbonyl group and R
2
represents diethylamino, piperidino, tetrahydropyridino or morpholino, can be prepared by reacting a compound of formula 1, wherein R
1
, R
3
and R
6
are as defined above, R
2
represents hydroxy, R
4
and R
5
taken together represent a carbonyl group, by reaction with ethylchlorocarbonate to give an intermediate compound of formula 5,
wherein R
1
, R
3
and R
6
are as defined above in analogy to a procedure described in the literature (see: L. Bernardi et al.
Il Farmaco Ed. Sc.
1979, vol. 34, p. 884), followed by substitution with excess diethylamine, piperidine, tetrahydropyridine or morpholine.
Co
Bandiera Tiziano
Caruso Michele
Fancelli Daniele
Lansen Jacqueline
Suarato Antonino
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Pharmacia & Upjohn SpA
Ramsuer Robert W.
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