Compounds useful in preparing camptothecin derivatives

Details Compounds useful in preparing camptothecin derivatives Compounds useful in preparing camptothecin derivatives

2003-04-16

2004-04-20

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S316000, C546S048000, C546S191000

Reexamination Certificate

active

06723729

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to manufacture of camptothecin derivatives therapeutically useful as anti-cancer drugs, in particular the camptothecin derivative irinotecan and salts thereof. More particularly, the invention relates to a novel intermediate and to a process for preparing a camptothecin derivative via that intermediate.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 6,121,451 to Henegar & Sih, incorporated herein by reference, discloses a process for preparing the antineoplastic drug irinotecan, also known as 7-ethyl-10-hydroxycamptothecin 10-[1,4′-bipiperidine]-1′-carboxylate or CPT-11 free base. In the disclosed process, a compound therein identified as 14CPT (I) is first reacted with 1-(4-hydroxy-2-aminophenyl)-1-propanone (II) to form an intermediate compound (III), which is then reacted with 4-piperidinopiperidinecarbamyl chloride (IV) to produce CPT-11 free base (V), as shown schematically below.
Alternative materials and methods for preparing irinotecan and other therapeutically useful camptothecin derivatives are desired in the art.
SUMMARY OF THE INVENTION
Novel compounds are now provided, having the formula (VI)
where R
1
is hydrogen, an alkyl aralkyl, hydroxymethyl, carboxymethyl, acyloxymethyl or trialklsilyl group, or a group —CH
2
NR
3
R
4
where N is a linking nitrogen atom and where R
3
and R
4
are as defined hereinbelow. Also provided are salts of the compounds of formula (VI) with pharmaceutically acceptable anions.
Options for R
3
and R
4
are:
(a) R
3
and R
4
are independently selected from hydrogen and alkyl, alkenyl, hydroxyalkyl and alkoxyalkyl groups;
(b) R
3
is hydrogen or an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group, and R
4
is —COR
5
where R
5
is hydrogen or an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group; or
(c) R
3
and R
4
taken together with the linking nitrogen atom form a saturated 3- to 7-member heterocyclic group.
Compounds of the invention are useful intermediates in a process to prepare camptothecin derivatives of formula (VII)
where R
1
is as defined above and R
2
is hydrogen or an alkyl group, preferably hydrogen.
In a preferred embodiment R
1
is an ethyl group and R
2
is hydrogen. According to this embodiment, the novel compound of formula (VI) is 4-amino-3-propionylphenyl-1,4′-bipiperidine-1′-carboxylate, which is a useful intermediate in a process to prepare irinotecan (V) and salts thereof, for example the hydrochloride salt CPT-11. Thus, according to another embodiment of the invention, a process is provided comprising a step of reacting 4-amino-3-propionylphenyl-1,4′-bipiperidine-1′-carboxylate with the compound of formula (I) above to form irinotecan.
In yet another embodiment of the invention, a process is provided for preparing a compound of formula (VI). This process can be illustrated with respect to the compound of formula (VI) where R
1
is an ethyl group, i.e., 4-amino-3-propionylphenyl-1,4′-bipiperidine-1′-carboxylate. In this case the process comprises a step of reacting 1-(4-hydroxy-2-aminophenyl)-1-propanone (II) with 4-piperidinopiperidinecarbamyl chloride (IV) to form 4-amino-3-propionylphenyl-1,4′-bipiperidine-1′-carboxylate. By appropriate modification of compound (II) one of skill in the art will be able to make other compounds of formula (VI) of the invention.
Typically, an irinotecan or CPT-11 product prepared by a process using 4-amino-3-propionylphenyl-1,4′-bipiperidine-1′-carboxylate will contain at least a detectable amount of that compound. Thus, in yet another embodiment of the invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of irinotecan and/or a salt thereof and at least a detectable amount of 4-amino-3-propionylphenyl-1,4′-bipiperidine-1′-carboxylate and/or a salt thereof. By its presence in a detectable amount, 4-amino-3-propionylphenyl-1,4′-bipiperidine-1′-carboxylate is useful as an analytical marker for a product of (a) a process involving that compound as a reagent or (b) a process involving as reagents 1-(4-hydroxy-2-aminophenyl)-1-propanone and 4-piperidinopiperidinecarbamyl chloride under circumstances permitting these reagents to react to form 4-amino-3-propionylphenyl-1,4′-bipiperidine-1′-carboxylate.
DETAILED DESCRIPTION OF THE INVENTION
R
1
in a compound of formula (VI) of the present invention is hydrogen, an alkyl, aralkyl, hydroxymethyl, carboxymethyl, acyloxymethyl or trialkylsilyl, e.g., trimethylsilyl, group, or a group —CH
2
NR
3
R
4
where N is a linking nitrogen atom and where (a) R
3
and R
4
are independently selected from hydrogen and alkyl alkenyl, hydroxyalkyl and alkoxyalkyl groups; (b) R
3
is hydrogen or an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group, and R
4
is —COR
5
where R
5
is hydrogen or an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group; or (c) R
3
and R
4
taken together with the linking nitrogen atom form a saturated 3- to 7-member heterocyclic group. Also provided are salts of the compounds of formula (VI) with pharmaceutically acceptable anions.
Alkyl, alkenyl, aralkyl, acyl and alkoxy groups herein, unless otherwise defined, have 1-30, preferably 1-18, more preferably 1-6, carbon atoms. In particularly preferred compounds of formula (VI), R
1
is a C
1-4
alkyl, most preferably an ethyl, group.
Compounds of formula (VI) above exist in free base form and in various pharmaceutically acceptable salt forms, which are embodiments of the present invention.
Pharmaceutically acceptable salts of compounds of formula (VI) include without restriction salts of the following acids: hydrochloric, hydrobromic, sulfuric, methanesulfonic, phosphoric, nitric, benzoic, citric, tartaric, fumaric and maleic acids, and mono- and dicarboxylic acids of formula CH
3
—(CH
2
)
n
—COOH and HOOC—(CH
2
)
n
—COOH where n is 0 to 4, for example malonic acid. The hydrochloride salt is particularly preferred.
In another embodiment of the invention a process is provided comprising a step of reacting 4-amino-3-propionylphenyl-1,4′-bipiperidine-1′-carboxylate (the compound of formula (VI) where R
1
is ethyl) or a salt thereof with 14CPT ((4S)-4-ethyl-7,8-dihydro-4-hydroxy-(1H)-pyrano[3,4-f]indolizine-3,6,10(4H)-trione), the compound of formula (I) above, to form irinotecan or the corresponding salt thereof.
This reaction can illustratively be carried out by beating 4-amino-3-propionylphenyl-1,4′-bipiperidine-1′-carboxylate and 14CPT together in a suitable solvent, for example acetic acid. The product of the reaction can then be purified by a suitable chromatographic method and isolated, for example by crystallization from a suitable solvent medium. An illustrative example of a process of this embodiment of the invention is provided below in @Example 2.
Accordingly, the novel compound 4-amino-3-propionylphenyl-1,4′-bipiperidine-1′-carboxylate or a salt thereof is a useful intermediate in a manufacturing process for irinotecan or a salt thereof.
Optionally, irinotecan or a salt thereof prepared by a process of the invention can be further processed to yield other camptothecin derivatives by methods known in the art. For example, irinotecan prepared as described herein can be subjected to hydrolysis in an acid medium, for example in presence of hydrochloric acid, to yield 7-ethyl-10-hydroxycamptothecin.
In yet another embodiment of the invention a process for preparing 4-amino-3-propionylphenyl-1,4′-bipiperidine-1′-carboxylate is provided, comprising a step of reacting 1-(4-hydroxy-2-aminophenyl)-1-propanone (II) with 4-piperidinopiperidinecarbamyl chloride (IV).
This reaction can illustratively be carried out by mixing known compounds (II) and (IV) together in a suitable solvent, for example pyridine. Alternatively, a solvent system comprising methylene chloride, tetrahydrofuran, acetonitrile or the like together with a suitable base such as triethylamine or diisopropylethylamine can be used as a me

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