Polymeric derivatives of camptothecins

Details Polymeric derivatives of camptothecins Polymeric derivatives of camptothecins

2000-03-31

2001-12-11

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Solid synthetic organic polymer as designated organic active...

Aftertreated polymer

C424S078320, C546S048000, C525S329400, C514S081000

Reexamination Certificate

active

06328953

ABSTRACT:

The invention relates to polymeric conjugates of 20-O-[glycyl-aminoacyl-glycyl]camptothecins. Our WO-95/10304 describes and claims conjugates of camptothecins linked to a polymer through a peptidyl spacer. We have now found that the conjugates in which the spacer is a glycyl-aminoacyl-glycyl are of exceptional value as antitumor agent and are endowed with remarkable antitumor activity and reduced toxicity in comparison with the free drug.
Particularly the present invention provides polymeric conjugates of the formula (1) consisting of:
(i) from 85 to 97 mol % of N-(2-hydroxypropyl)methacryloylamide units represented by formula (3)
(ii) from 3 to 15 mol % of 20-O-(N-methacryloyl-glycyl-aminoacyl-glycyl)-camptothecin units represented by formula (4).
 wherein n is from 2 to 8, —[O-CPT] represents the residue of a camptothecin of formula (2)
which is linked at the C-20 position and in which each of R
1
, R
2
, R
3
, R
4
and R
5
which are the same or different, is hydrogen, C
1
-C
12
linear or branched alkyl, nitro, amino, (CH
2
)
a
NR
6
R
7
in which a is from 0 to 4 and R
6
and R
7
are hydrogen or one of R
6
or R
7
is hydrogen and the other of R
6
or R
7
is C
1
-C
6
alkyl, or NR
6
R
7
represents a piperazino or N-alkyl-piperazino ring optionally substituted with C
1
-C
6
linear or branched alkyl or piperidino ring, (CH
2
)
a
NHCOR
8
in which a is as above defined and R
8
is C
1
-C
8
linear or branched alkyl or a group NR
6
R
7
as above, hydroxy or O-CO-R
8
in which R
8
is as above defined or represents a 1-piperidino ring or 1,4′-bipiperidine, or R
2
and R
3
taken together represent the residue O—(CH
2
)
b
—O, in which b is 1 or 2, or R
4
and R
5
represent the residue (CH
2
)
m
, in which m is from 2 to 4, or the residue CH
2
—O—CH
2
or CH
2
NHCH
2
and (iii) from 0 to 12 mol % of N-methacryloyl-glycine or N-(2-hydroxy-propyl)methacryloyl-glycinamide units represented by formula (5)
 wherein [Z] represents a hydroxy group or a residue of formula —NH—CH
2
—CH(OH)—CH
3
.
The polymeric conjugates of the formula (1) may be indicated as MAG-CPT(s) and may also be represented as follows:
[(3)]
x
; [(4)]
y
; [(5)]
z
wherein (3), (4) and (5) are units of the formula as above defined, and x is from 85 to 97 mol %, y is from 3 to 15 mol % and z is from 0 to 12 mol %.
A preferred embodiment of compounds of the present invention are those in which —[O-CPT] in formula (4) is a residue of a camptothecin of formula (2) selected from:
camptothecin [2a: R
1
=R
2
=R
3
=R
4
=R
5
=H];
9-aminocamptothecin [2b: R
1
=R
2
=R
3
=R
5
=H, R
4
=NH
2
];
9-nitrocamptothecin [2c: R
1
=R
2
=R
3
=R
5
=H, R
4
=NO
2
];
7-ethyl-10-hydroxycamptothecin [2d: R
1
=R
2
=R
4
=H, R
3
=OH, R
5
=CH
2
CH
3
];
7-ethyl-10-[1,4′-bipiperidinyl]carbonyloxycamptothecin [2e: R
1
=R
2
=R
4
=H, R
3
=OCO-[1,4′-bipiperidinyl], R
5
=CH
2
CH
3
],
7-methylendimethylamino-10-hydroxycamptothecin [2f: R
1
=R
2
=R
4
=H, R
3
=OH, R
5
=CH
2
N(CH
3
)
2
] and
7-[methylen-(4′-methylpiperazino)]-9,10-ethylendioxycamptothecin [2g: R
1
=R
4
=H, R
2
,R
3
=O—CH
2
CH
2
—O, R
5
=methylen-(4′-methylpiperazino)].
Preferably, the polymeric conjugates of the formula (1) contain the N-(2-hydroxypropyl) methacryloyl amide units represented by the formula (3) in a proportion of 90% or more; more preferably 90%. The conjugate may also contain from 3 to 10 mol % of the units represented by the formula (4), more preferably 10 mol % of such units. Preferably the conjugate of formula (1) does not contain residues of formula (5), i.e. z is 0. Content of active camptothecin derivative of formula (2) in the conjugate of formula (1) may be from 2 to 15% (weight/weight), more preferably 10% (w/w). The preparation of the compounds of the present invention may be carried out by a process (herein named Route I) which comprises reacting 20-O-(aminoacyl-glycyl) camptothecin derivative of formula (6)
NH
2
—(CH
2
)
n
—CO-Gly-[OCPT]  (6)
wherein n and [OCPT] are as above defined, with a polymer (B) consisting essentially of:
from 85 to 97 mol % of N-(2-hydroxypropyl)methacryloylamide units represented by formula (3) as above defined,
and from 3 to 15 mol % of N-methacryloyl-glycyl derivative units represented by formula (7)
wherein [Y] is the residue of an active ester, preferably p-nitrophenyl ester, or a hydroxy group; and optionally displacing the remaining active ester groups with 1-amino-2-propanol. The condensation of derivative of formula (6) with the polymer of formula (B), is carried out in conditions capable of preserving the nature of linkage between camptothecin and the aminoacyl-glycyl spacer as well as that of the conjugate.
Polymers of formula (B), consisting of N-(2-hydroxypropyl)-methacryloylamide units of formula (3) and of N-methacryloyl-glycine units of formula (7), are prepared by copolymerization of N-(2-hydroxypropyl)methacrylamide with N-methacryloyl-glycine or N-methacryloyl-glycine active-ester derivatives, as described in Makromol.Chem. 178, 2159 (1977). The residue [Y] may represent a phenoxy group which is substituted on the phenyl ring by one ore more electron-withdrawing groups, such as nitro or halogen. Preferably the residue [Y] represents p-nitro phenoxy.
Reaction between (6) and (B) to form polymeric-drug-conjugate of formula (1) of the present invention can typically carried out at temperature from 15 to 30° C., preferably at room temperature for 15 hours; then the aminolysis of the remaining active ester groups can be performed in the presence of 1-amino-2-propanol at room temperature, from 0.5 to 1 hour. The conjugate suitably is precipitate with ethyl acetate dissolved in ethanol and reprecipitated with ethyl acetate.
For example, the polymer (B) in which [Y] represents the residue of an active ester, provided at a concentration of 15% (weight/volume) in dry dimethylsulfoxide, is treated with 20-O-(aminoacyl-glycyl)camptothecin derivative (6), 3% (w/v), at room temperature for 15 hours. Then 1-amino-2-propanol, 0.1% (w/v) is added and the reaction mixture is kept at room temperature for 1 hour. The polymeric-drug-conjugate. MAG-CPTs, can be precipitated with ethyl acetate, collected, washed with ethyl acetate, then dissolved with absolute ethanol at a concentration of 10% (weight/volume) and precipitated again with ethyl acetate to give the conjugates of formula (1) according to the invention. The content of camptothecin in the polymeric conjugate of the invention is determined by HPLC or absorbance spectroscopy analysis.
The compounds of the formula (1) c an be also prepared by a process (herein named Route II) which comprises the polymerization between N-(2-hydroxypropyl) methacrylamide of the formula (8)
and 20-O-[methacryloyl-glycyl-(aminoacyl )-glycyl]camptothecin derivatives of the formula (9)
wherein n and [OCPT] are as above defined, in conditions capable of preserving the nature of linkage between camptothecin and spacer glycyl-aminoacyl-glycyl as well as that of the conjugate.
Reaction between (8) and (9) can typically carried out at temperature from 50 to 70° C., preferably at 60° C., from 6 to 24 hours, preferably for 15 hours, in aprotic solvent such as dimethylsulfoxide and in presence of catalyst, such as 2,2′-azobisisobutyronitrile. The conjugate is precipitate with ethyl acetate dissolved in ethanol and reprecipitated with ethyl acetate.
For example N-(2-hydroxypropyl)methacrylamide (8), provided at a concentration of 22% (w/v) and 20-O-[methacryloyl-glycyl-(
6
-aminohexanoyl)-glycyl]camptothecin derivative (9) at concentration of 6% (w/v) in dry d

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