Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-26
2001-11-13
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...
C514S235800, C514S236800, C514S326000, C514S341000, C514S254040, C514S370000, C132S133000, C132S327000, C132S327000, C209S210000, C209S270001, C209S274000, C193S038000
Reexamination Certificate
active
06316451
ABSTRACT:
The present invention relates to 9-heterocyclyl anthracyclinone derivatives, to their use for the treatment of amyloidoses, to methods for their preparation and to pharmaceutical compositions containing them. More particularly, the present invention provides anthracyclinone derivatives which are characterized by the presence of a penta-atomic heterocyclic system linked to the position 9 of the anthracyclinone system and that are represented by the general formula 1
wherein:
R
1
is selected from:
hydrogen,
hydroxy,
a group of formula OR
5
wherein R
5
is C
1
-C
6
alkyl, C
2
-C
6
alkenyl or C
3
-C
8
cycloalkyl,
halogen,
and amino which may be unsubstituted or mono or disubstituted by C
1
-C
6
alkyl, C
2
-C
6
alkenyl, aralkyl, acyl or trifluoroacetyl;
R
2
is selected from:
hydrogen,
hydroxy, and
a group NR
6
R
7
wherein R
6
and R
7
independently represent hydrogen, an optionally substituted C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
3
-C
8
cycloalkyl or, taken together with the nitrogen atom, represent an optionally substituted C
3
-C
8
heterocyclic ring;
R
3
is selected from:
hydrogen and
hydroxy;
R
4
is a 2-substituted thiazolyl or imidazolyl system of formula A:
wherein z represents sulfur or nitrogen and R
6
and R
7
are as defined above, and the pharmaceutically acceptable salt thereof.
The term “alkyl” as used herein includes both straight and branched chain radicals of up to 6 carbons, for example methyl, ethyl, propyl, butyl, pentyl, hexyl and the various branched chain isomers thereof, as well as straight and branched chain radicals optionally carrying one or more substituents selected from aryl, cycloalkyl, halogen, trifluoromethyl, hydroxy, alkoxy, aralkoxyl, amino, mono or dialkylamino, carboxy.
The term “alkenyl” as used herein includes both straight and branched chain radicals of up to 6 carbons such as, for example, allyl, butenyl, pentenyl, hexenyl, optionally subsituted as the alkyl groups above.
The term “cycloalkyl” as used herein means a cycloalkyl group having 3 to 8 carbons, for example cyclopropyl, cyclobutl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, optionally subsituted as the alkyl groups above. The term “aryl” as used herein includes both monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion such as phenyl or naphthyl, optionally substituted by one or more substituents selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxyl, trifluoromethyl, halogen or hydroxy. The term “heterocyclyl” as used herein is a 3- to 7-membered, saturated or unsaturated heterocyclic ring containing at least one heteroatom selected from N, O and S and which is optionally fused to a second 5- or 6-membered, saturated or unsaturated heterocyclic ring or to an aryl ring, optionally substituted by one or more substituents selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxyl, trifluoromethyl, halogen or hydroxy.
The term “halogen” as used herein means fluorine, chlorine, bromine and iodine.
The term “aralkyl” as used herein refers to alkyl groups as previously defined having an aryl substituent, for example benzyl, phenethyl, diphenylmethyl and triphenylmethyl.
The term “alkoxyl” or “aralkoxyl” as used herein includes any of the above alkyl, cycloalkyl or aralkyl groups linked to an oxygen atom.
The term “acyl” as employed herein includes alkyl, aryl and heterocyclyl as described above linked to a carbonyl group.
This invention also includes all the possible isomers and mixture thereof, including diastereoisomeric mixtures and racemic mixtures, resulting from the possible combination of (R) and (S) stereochemistry at position 9 and, when substituents are present, at position 7. The present invention also provides the salts of those compounds of formula 1 that have salt forming groups, such as an acidic or a basic group (e.g. an amino group).
The salts are physiologically tolerable salts. In the case of compounds containing a basic amino group, the salts are formed with suitable inorganic or organic acids Inorganic acids are, for example, hydrochloric or sulfuric acid. Organic acids comprise mono-, di- and tricarboxylic acids, such as acetic, trifluoroacetic, tartaric and citric acid, or sulfonic acids like, for example, methansulfonic, trifluoromethansulfonic or p-toluensulfonic acid.
Preferred compounds of formula 1 are those wherein:
R
1
is selected from:
hydrogen,
hydroxy and
methoxy;
R
2
is selected from:
hydrogen,
hydroxy and
a group of formula NR
6
R
7
, wherein one or both of R
6
and R
7
represent hydrogen, methyl, ethyl, propyl, butyl, dimethylaminoethyl, dimethylaminopropyl, or taken together, represent 4-morpholinyl, 4-methylpiperazinyl, 4-phenylpiperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1,2,3,6-tetrahydropyridinyl;
R
3
is selected from:
hydrogen and
hydroxy;
R
4
is a 2-substituted thiazolyl or imidazolyl system as above defined.
Compounds of formula 1 as defined above can be prepared by
(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 a compound of formula 3 or 7,
wherein R
6
and R
7
are as defined above, and if necessary, hydrolysing the resultant compound and
(b) converting the resultant compound of formula 1 into a different compound of formula 1 by appropriate chemical reactions, such as alkylation, reduction, condensation/substitution.
In particular, the compounds of formula 1 wherein Z represents sulfur may be obtained by reacting a compound of formula 2 with a compound of formula 3 as above defined, analogously to the procedure described in the literature (see, for instance,
The Chemistry of Heterocyclic Compounds
, A. Weissberger Ed., John Wiley & Sons, 1979, vol. 34/1, p. 165; or Houben-Weyl,
Methoden der Organischen Chemie
, vol. E 8b, Georg Thieme, 1995).
The solvent is a proper organic solvent such as methanol, ethanol, dioxane or dimethylformamide. The reaction is carried out for a period of 1 to 24 hours at a temperature ranging from room temperature to 100° C. Preferably the solvent is a 1:1 mixture of ethanol and dioxane.
Compounds of formula 1 in which Z represents nitrogen can be prepared by reacting a compound of formula 2 with a compound of formula 7 as above defined, as described in the literature (see: T. L. Little and S. E. Webber
J. Org. Chem
. 1994, vol. 59, p. 7299).
The solvent is a proper organic solvent such as methanol, ethanol, acetonitrile, dioxane or dimethylformamide. The reaction is carried out for a period of 1 to 24 hours at a temperature ranging from room temperature to 100° C. Preferably the solvent is dimethylformamide and the reaction is carried out at room temperature. The resulting intermediate 2-acetylamino-imidazoles of formula 8
wherein R
1
, R
2
and R
3
are as defined above are then hydrolized and the resultant compound of the formula 1 wherein R
6
and R
7
are hydrogens can be converted into different compounds of the formula 1 by alkylation. According to other conversion reactions of step b), a compound of formula 1, wherein R
1
, R
2
, R
3
and R
4
are as defined above, can also be converted into a different compound of formula 1 by appropriate chemical reactions described for the anthracyclines and anthracyclinones(see: F. Arcamone,
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). Compounds of formula 1 in which R
1
, R
3
and R
4
are as described above and R
2
is hydrogen are prepared by reacting the corresponding compounds where R
2
is an hydroxyl group with a reducing agent such as sodium dithionite in a proper solvent at room temperature. Preferably, the solvent is a 1:1 mixture of water and dimethylformamide.
Compounds of formula 1 in which R
1
, R
2
and R
4
are as defined above and R
2
is NR
4
R
7
, wherein R
6
and R
7
are as defined above, are prepared by reacting compounds of formula 1, wherein R
1
, R
3
and R
4
are as defined above and R
2
is a hydroxyl group, with an excess of ethylchlorofo
Bandiera Tiziano
Lansen Jacqueline
Mantegani Sergio
Traquandi Gabriella
Varasi Mario
D'Souza Andrea M.
Lambkin Deborah C.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Pharmacia & Upjohn S.p.A.
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