Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-12
2001-04-03
Huang, Evelyn Mei (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S063000, C546S014000, C546S048000
Reexamination Certificate
active
06211192
ABSTRACT:
The present invention relates to new substituted camptothecin derivatives possessing antitumor activity, to process for their preparation, and to pharmaceutic compositions containing them.
Camptothecin and some of its analogs display potent antitumor activity by the inhibition of Topoisomerase I, that is an enzyme involved in some important cellular functions and cellular growth (see, for instance, Wani et al., J. Med. Chem. 1987, 30, 1774; Hsiang et al., Cancer Res. 1989, 49, 4385; Cancer Res. 1989, 49, 1465). Anticancer activity of Camptothecin both in vitro and in vivo is significantly greater for the lactone versus the carboxylate form (as disclosed, for instance, by W. J. Slichenmyer et al., in “The Current Status of Camptothecin Analogues as Antitumor Agents”, J. Natl. Cancer Inst. 1993, 85, 271-291, and references therein), since a closed &agr;-hydroxy lactone ring is an important structural requirement for both passive diffusion of drug into cancer cells, as well as for successful drug interaction with the pharmacological target.
It has recently been pointed out that, in the presence of biologically relevant levels of human albumin, the biologically active form of camptothecin has a very short half-life (about 12 min.), and 2 hours after drug addition to human plasma, a percentage greater than 99% of the drug has converted to camptothecin carboxylate, the biologically inactive and potentially toxic form of the drug (see Burke, G. T.; Mi, Z. “The Structural Basis of Camptothecin Interactions with Human Serum Albumin: Impact on Drug Stability”, J. Med. Chem. 1994, 37, 40-46). The same authors disclose also the importance of the substitution in 9 and 7 positions on the camptothecin nucleus in order to improve drug stability in the presence of albumin.
There is therefore a need to find new camptothecin derivatives that have high intrinsic potency, and may gain, at the same time, stability in the presence of serum albumin.
Accordingly, the present invention relates to alkynyl-substituted camptothecins of formula (I)
wherein:
R
1
is selected from:
hydrogen;
an optionally substituted C
1
-C
6
alkyl;
C
3
-C
7
cycloalkyl;
C
3
-C7 cycloalkyl C
1
-C
6
alkyl;
phenyl C1-C6 alkyl;
an optionally substituted phenyl;
an optionally substitued naphthyl;
—R, —NR
3
R
4
, wherein R
x
is C
1
-C
4
alkylene, R
3
and R
4
are, each independently, hydrogen, C
1
-C
6
alkyl, phenyl, or benzyl;
—(R
y
)
m
—COOR
5
, wherein m is zero or 1, R
y
is C
1
-C
4
alkylene, R
5
is hydrogen, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, or phenyl C
1
-C6 alkyl;
—(R
z
)
n
—COR
6
, wherein n is zero or 1, R
z
is C
1
-C
4
alkylene, R
6
is C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl C
1
-C
6
alkyl, an optionally substituted phenyl, or —NR
7
R
8
, wherein R
7
and R
8
are, each independently, hydrogen or C
1
-C
6
alkyl; and
—SiR
9
R
10
R
11
, wherein R
9
, R
10
and R
11
are, each independently, C
1
-C
4
alkyl;
R
2
is selected from:
hydrogen; C
1
-C
6
alkyl; C
3
-C
7
cycloalkyl; and phenyl C
1
-C
6
alkyl;
X is selected from:
hydrogen; C
1
-C
6
alkyl; C
3
-C
7
cycloalkyl; C
1
-C
6
alkoxy; C
3
-C
7
cycloalkoxy; C
1
-C
6
alkanoyloxy; benzoyloxy; amino; hydroxy; nitro; chlorine; and a methylene- or ethylene-dioxy group linked to positions 10 and 11 of the molecule; and the pharmaceutically acceptable salts thereof.
In the formulae of the present specification, a dotted line
indicates a substituent below the plane of the ring, while a wedged line
indicates a substituent above the plane of the ring.
Pharmaceutically acceptable salts according to the present invention are the salts with pharmaceutically acceptable acids, both inorganic acids such as, e.g. hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acid, and organic acids such as, e.g., citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, trifluoroacetic, methanesulfonic, ethanesulfonic, benzenesulfonic, or p-toluensulfonic acid.
Pharmaceutically acceptable salts of the compounds of formula (I) containing an acid group, i.e. carboxy, with pharmaceutically acceptable bases are also included in the scope of the present invention. Pharmaceutically acceptable bases may be both inorganic bases such as, for instance, alkali metal, e.g. sodium or potassium, or alkaline earth metal, e.g. calcium or magnesium, hydroxides, and organic bases such as, for instance, alkyl amines, e.g. methylamine or triethylamine, aralkylamines, e.g. benzylamine, dibenzylamine, &agr;- or &bgr;-phenyl-ethylamine, or heterocyclic amines such as, e.g., piperidine, 1-methyl-piperidine, piperazine or morpholine.
An optionally substituted phenyl may be represented by a group
wherein Q, linked to ortho, meta or para position of the phenyl ring, represents hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkanoyloxy, nitro, amino, mono- or di-alkylamino with from 1 to 6 carbon atoms in the alkyl moiety, tolylsulfonylamino or chlorine, or Q represents a 5 or 6 membered aromatic heterocycle with one or two heteroatoms selected among nitrogen, oxygen or sulphur, optionally mono- or di-substituted by C
1
-C
6
alkyl groups. Examples of the said heterocycles are, for instance, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, furan, thiophene, pyridine, pyrazine, pyrimidine and the like.
Preferably, Q is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, amino, tolylsulfonylamino, chlorine, or Q represents an optionally substituted pyrrole. Particularly preferred values of Q are hydrogen, methoxy, amino, tosylamino, 2,5-dimethylpyrrol-1-yl and chlorine.
An optionally substituted naphthyl is a naphth-1-yl or naphth-2-yl group optionally substituted by C
1
-C
6
alkyl or alkoxy groups.
In the present specification, the hydrocarbon chain of the alkyl, alkylene, alkoxy, and alkanoyloxy groups may be a straight or branched chain. Preferably, C
1
-C
6
alkyl is C
1
-C
4
alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl. More preferably, C
1
-C
4
alkyl is methyl, ethyl or propyl. The C
1
-C
6
alkyl may be substituted, e.g., by hydroxy, alkoxy, phenoxy, thioalkyl, amino, or alkylamino groups. Preferably, C
3
-C
7
cycloalkyl is C
4
-C
6
cycloalkyl, e.g. cyclobutyl, cyclopentyl or cyclohexyl. Preferably, C
3
-C
7
cycloalkyl C
1
-C
6
alkyl is cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopentylpropyl or 3-cyclohexylpropyl. Preferably, C
1
-C
4
alkylene is, e.g., methylene, ethylene, n-propylene, 1-methyl-ethylene, n-butylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, or 1-methyl-propylene. Preferably, C
1
-C
6
alkoxy is C
1
-C
4
alkoxy, e.g. methoxy, ethoxy or propoxy. Preferably, C
1
-C
6
alkanoyloxy is C
1
-C
4
alkanoyloxy, e.g. methanoyloxy, ethanoyloxy or propanoyloxy. A preferred class of compounds according to this invention is represented by compounds of the above formula (I) wherein;
R
1
is selected from:
hydrogen; C
1
-C
4
alkyl; phenyl C
1
-C
6
alkyl; phenyl;
—R
x
—NR
3
R
4
, wherein R
x
is a C
1
-C
4
alkylene, R
3
and R
4
are, each independently, C
1
-C
4
alkyl; —(R
y
)
m
—COOR
5
, wherein m is zero or 1, R
y
, is a C
1
-C
4
alkylene, R
5
is hydrogen or C
1
-C
4
alkyl; and —(R
z
)
n
—COR
6
, wherein n is zero or 1, R
z
is a C
1
-C
4
alkylene, R
6
is C
1
-C
6
alkyl, phenyl, or —NR
7
R
8
, wherein R
7
and R
8
are hydrogen; and —SiR
9
R
10
R
11
, wherein R
9
, R
10
and R
11
are methyl or ethyl;
R
2
is hydrogen or C
1
-C
4
alkyl;
X is selected from:
hydrogen; amino; hydroxy; C
1
-C
6
alkoxy; or a methylene- or ethylene-dioxy group linked to positions 10 and 11 of the molecule; and the pharmaceutically acceptable salts thereof
Examples of specific compounds according to the present invention are the following:
9-ethynyl-camptothecin (1);
9-phenylethynyl-camptothecin (2);
9-(dimethylaminopropyn-1-yl)-camptothecin (3);
9-hydroxypropyn-1-yl-camptothecin (4);
9-trimethylsilylethynyl-camptothecin (5);
9-cyclopentylethynyl-camptothecin (6);
9-cyclohexylpropyn-1-yl-camptothecin (7);
9-hexyn-1-yl-camptothecin (8);
7-ethyl-9-ethynyl
Bedeschi Angelo
Candiani Ilaria
Capolongo Laura
Fagnola Maria Chiara
Visentin Giuseppina
Huang Evelyn Mei
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Pharmacia & Upjohn S.p.A.
LandOfFree
Alkynyl-substituted camptothecins and process for their... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Alkynyl-substituted camptothecins and process for their..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Alkynyl-substituted camptothecins and process for their... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2452874