AU749692B2 - Antineoplastic cyclolignan derivatives - Google Patents

Description

S&FRef: 318967D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

a.

Name and Address of Applicant: Actual Inventor(s): Address for Service: Universidad de Salamanca E-37007 Salamanca Spain Marina Gordaliza, Maria Angeles Castro, Arturo San Feliciano, Jose Maria Miguel del Corral, Maria Luisa Lopez Dolores G. Gravalos Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Invention Title: Antineoplastic Cyclolignan Derivatives The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c Antineoplastic Cyclolignan Derivatives This invention is concerned with antineoplastic cyclolignan derivatives, the preparation of such derivatives, and pharmaceutical compositions containing them.

It has now been found, in accordance with the present invention, that certain new cyclolignan derivatives, as hereinafter defined, possess good selectivity as cytotoxic agents against in vitro cultured human solid tumour cell lines as compared with other lignans.

According to a first embodiment of the invention there is provided a compound of formula 7 9 08' 8'Z Ar (I) in which Ar is a 3,4,5-trialkoxyphenyl or a 4-hydroxy-3,5-dialkoxyphenyl; X is a nitrogen atom; Y is a hydrogen atom or an alkyl, alkenyl, (poly)haloalkyl, aryl, hydroxy, alkoxy, 15 amino, monoalkylamino, dialkylamino, arylamino, acyl or acetamido group; Z is an alkyl, hydroxyalkyl, acyl, carboxy, alkoxycarbonyl or aryloxycarbonyl group; and the dotted lines indicate one double bond located at position 8 or as-8' With reference to formula the alkyl groups preferably have from 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl and other alkyl groups.

The aryl group of Y is preferably a phenyl or substituted phenyl group. Suitable substituents include the groups given for Y.

The alkoxycarbonyl groups preferably have from 1 to 6 carbon atoms in the alkoxy 25 part, more preferably 1 to 4 carbon atoms. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and other alkoxycarbonyl groups.

The alkenyl groups preferably have from 3 to 6 carbon atoms, more preferably 3 to 4 carbon atoms. Examples include allyl or crotonyl groups.

The (poly)haloalkyl groups preferably have from 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and preferably have one or more fluoro, chloro or bromo atoms. The (poly)haloalkyl groups are suitably monohalo or perhalo groups. Examples include chloroethyl or trifluoroethyl groups.

[I:\DayLib\LIBH]01310.doc:LJG 2 The alkoxy groups preferably have from 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and other alkoxy groups.

The substituent groups in the substituted amino groups are suitably as described above.

The acyl groups preferably have from 1 to 20 carbon atoms, and more preferably are either short-chain acyl groups with 1 to 3 carbon atoms, or long chain acyl groups with 12 to 18 carbon atoms. The long chain acyl groups may be saturated or unsaturated, preferably of the kind occurring in natural fatty acids. Examples of acyl groups include formyl, acetyl or stearyl.

The aryl group of the arylamino group is suitably as described above.

The hydroxyalkyl groups are preferably 1-hydroxyalkyl groups, having from 1 o 6 carbon atoms, more preferably 1 to 4 carbon atoms. Examples include hydroxymethyl, 1hydroxylethyl, 1-hydroxypropyl and other hydroxyalkyl groups.

The aryloxycarbonyl groups preferably have a phenyl or substituted phenyl group.

The present compounds can exist as optical isomers and the invention embraces the individual isomers and mixtures thereof, including the diasteriomeric or racemic mix. The stereochemistry of the substituents may be selected as desired and, for example, the Z group can be a or P.

20 More generally, the preferred compounds of this invention include compounds of formula wherein one double bond is located at position 7-8 and the function at S* position 9 is a hydrazone.

Individual preferred compounds of this invention include LL-16, which is the phenylhydrazone of methyl 9-deoxy-9-oxo-a-apopicropodophyllate.

The compounds of formula as noted above, have cytotoxic activity.

Accordingly, in a second embodiment of the invention there is provided a pharmaceutical composition which comprises a compound of formula 9 Ar (1 0 8' Ar

(I)

30 in which Ar is a 3,4,5-trialkoxyphenyl or a 4-hydroxy-3,5-dialkoxyphenyl; X is a nitrogen atom; Y is a hydrogen atom or an alkyl, alkenyl, (poly)haloalkyl, aryl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, arylamino, acyl or acetamido group; Z is an alkyl, hydroxyalkyl, acyl, carboxy, alkoxycarbonyl or aryloxycarbonyl Sgroup; and [I:\DayLib\LIBH]01310.doc:UG the dotted lines indicate one double bond located at position a7-8 or a8-8', together with a pharmaceutically acceptable carrier or diluent. Such compositions may, for example, be intended for oral, parenteral or rectal administration in association with suitable appropriate adjuvants. Also disclosed herein is a method for the preparation of a cytotoxic composition which comprises using, as cytotoxic ingredient, a compound of formula According to a third embodiment of the invention there is provided a method for the treatment or prophylaxis of tumours in a mammal requiring said treatment or prophylaxis, which method comprises administering to said mammal an effective amount of at least one compound according to the first embodiment of the invention, or a composition according to the second embodiment of the invention.

According to a fourth embodiment of the invention there is provided a compound according to the first embodiment of the invention or a composition according to the second embodiment of the invention when used for the treatment or prophylaxis of tumours in a mammal requiring said treatment or prophylaxis.

According to a fifth embodiment of the invention there is provided the use of a compound according to the first embodiment of the invention in the manufacture of a medicament for the treatment or prophylaxis of tumours in a mammal requiring said treatment or prophylaxis.

20 The antineoplastic activity of compounds in accordance with this invention is illustrated by the following table, which shows the IC 5 0 values for several cyclolignan derivatives against different tuour cell lines.

cyclolignan derivatives against different tumour cell lines.

o

C"

,°oo P-388 A-549 HT-29 *LL-16 1 0.5 0.02 Podophyllotoxin 0.005 0.005 0.01 Epipodophyllotoxin 0.5 0.1 0.1 Compounds of the invention may be prepared from podophyllotoxin and related compounds of the formula

R

CH

3 0 OCH 3

OCH

3

(A)

[I:\DayLib\LIBH]01310.doc:UG For example, see Hartwell and Schrecker, Fortschrite Chem. Org. Naturstoff 15, 83 (1953), which describes podophyllotoxin where R is hydroxy and 8'-H is P; deoxypodophyllotoxin where R is hydrogen and 8'-H is P; and deoxypicropodophyllin where R is hydrogen and 8'-H is ct. See also J. Med. Chem. 29, 1547-1550 (1986) and Chem. Pharm. Bull. 40, 2720-2727 (1992).

The following reaction scheme illustrates the preparation of representative compounds: a)b) cy d) a) b)

OH

COOR

Ar d) C S

C

9* C C Ar 0 -Ar ArCOOR Ar

C

*5 'C C

C,

CC 0

S

a) KOH/MeOH; b) CH 2

N

2 c) BC1 3

/C

6

H

6 heating; d) Swem oxidation; e) Y-NH 2 Other equivalent reaction conditions can be employed, and as appropriate other known starting compounds can be used.

Examples In order that the invention may be further understood, the following Examples are 15 given by way of illustration only.

[I:\DayLib\LIBH]01310.doc:UG Comparative Example 1 Preparation of *r p..

S.

0 0O S

S

55.* 400 mg of podophyllotoxin were dissolved in 30 mL of KOH/MeOH 10% and stirred at room temperature for 30 minutes. After removing the methanol, water was added and the solution was neutralised by 2N HC1 until the pH was 7, and then extracted with EtOAc. The reaction product was treated with an ethereal solution of CH 2

N

2 to afford 430 mg of methyl picropodophyllate.

To a precooled (-60 0 C) and stirred solution of oxalyl chloride (0.24 mL) in dry 0o CH 2 C2 (5 mL) was added dropwise 0.4 mL ofDMSO in CH 2 C1 2 (2 mL). After 5 minutes at -60 0 C, a solution of 430 mg of methyl picropodophyllate in 3 mL of CH 2 Cl 2 was slowly added. The reaction mixture was kept at the same temperature for 30 min, then triethylamine (1.27 mL) was added. The mixture was warmed to 0 C over 1 h, quenched with water and extracted with CH 2 C1 2 The reaction product gave 220 mg of LL-15 after 15 flash chromatography.

m.p: 72-74 C [ao]D (CHC13): -160.90 UV kmax (EtOH) 215 (34500), 250 (30000), 358 (26300) IR (CHC13) 3020, 2840, 1740, 1680, 1510, 1240, 1140, 1050 Example 2 Preparation of LL-16 0 S

S.

S

5555 S 0.00 1.000 6060 60#0 [I:\DayLib\LIBH]01310.doc:UG 6 0.1 mL of phenylhydrazine was added to a solution of 180 mg of (obtained in Comparative Example 1) in 5 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 7 days, then water was added and 150 mg of LL-16 were collected.

515 m.p: 172-174 0

C

[a]D (CHC13): -309.1° UV kmax (EtOH) 209 (28600), 377 (24100) IR (CHCl 3 cm- 1 3020, 2950, 1740, 1610, 1510, 1260, 1140, 1050 Comparative Example 3 Preparation of LL-34, LL-35 and LL-36 0.15 mL of 1,2-ethanedithiol and 3 mL of SiMe 3 Cl were added to 100 mg of in 3 mL of CH 2 C1 2 After 20 hours at room temperature with stirring under N 2 and washing with diluted aq. NaOH, 112 mg of LL-34 were obtained.

To 40 mg of LL-34 in 3mL of dry ether a suspension of 50 mg of LiA1H 4 in dry ether was added. After 3 hours at room temperature and usual working, 37 mg of were obtained.

STo a solution of 40 mg of HgO and 0.2 5mL of BF 3 Et20 in 5 mL of THF/H 2 0 20 15) were added 40 mg of LL-35. The mixture was stirred under N 2 for 3 hours. Then diluted with CH 2 C1 2 and the precipitate discarded. The solution after evaporation yielded 30 mg of LL-36.

[a]D (CHC1 3 -85.1° UVmax (EtOH) 215 (16500), 245(14300), 356 (8200) IR (CHCl 3 cm- 1 3600-3100, 2940, 2860, 1670, 1600, 1510, 1240, 1135, 1045 SCOOCH3

H

3

CH

3

OCH

3 LL-34 [I:\DayLib\LIBH]01310.doc:UG

KKW)

CH

3 Oj -OCH 3 00H 3

H

CH

2 0H

CH

3 Oj -OCH 3

OCH

3 LL-36 [I:\DayLib\LIBH]OI 310.doc:UG

Claims (6)

1. A compound of formula 7 9 Ar (I) in which Ar is a 3,4,5-trialkoxyphenyl or a 4-hydroxy-3,5-dialkoxyphenyl; X is a nitrogen atom; Y is a hydrogen atom or an alkyl, alkenyl, (poly)haloalkyl, aryl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, arylamino, acyl or acetamido group; Z is an alkyl, hydroxyalkyl, acyl, carboxy, alkoxycarbonyl or aryloxycarbonyl group; and the dotted lines indicate one double bond located at position 67-8 or 688'

2. The compound LL-16, which is the phenylhydrazone of methyl 9-deoxy-9- oxo-a-apopicropodophyllate.

3. An antineoplastic cyclolignan derivative, substantially as hereinbefore 15 described with reference to Example 2.

4. A pharmaceutical composition which comprises a compound of formula 7 9 0X 8^-Y \8I o-8' z Ar (I) in which Ar is a 3,4,5-trialkoxyphenyl or a 4-hydroxy-3,5-dialkoxyphenyl; X is a nitrogen atom; Y is a hydrogen atom or an alkyl, alkenyl, (poly)haloalkyl, aryl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, arylamino, acyl or acetamido group; Z is an alkyl, hydroxyalkyl, acyl, carboxy, alkoxycarbonyl or aryloxycarbonyl group; and 25 the dotted lines indicate one double bond located at position 7 8 or A88'; together with a pharmaceutically acceptable carrier A pharmaceutical composition according to claim 7, wherein said compound of formula is the compound LL-16, which is the phenylhydrazone of methyl 9-deoxy-

9-oxo-a-apopicropodophyllate. 6. A method for the treatment or prophylaxis of tumours in a mammal requiring S kaid treatment or prophylaxis, which method comprises administering to said mammal an [i:\DayLib\LIBH]013 effective amount of at least one compound according to any one of claims 1 to 3, or of a composition according to claim 4 or A compound according to any one of claims 1 to 3 or a composition of claim 7 or 8 when used for the treatment or prophylaxis of tumours in a mammal requiring said treatment or prophylaxis.

11. The use of a compound according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment or prophylaxis of tumours in a mammal requiring said treatment or prophylaxis. Dated 6 May, 2002 Universidad de Salamanca Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON S.. S.. [I:\DayLib\LIBH]01310.doc:UG