MXPA00008646A - Anti-tumour agents - Google Patents

Abstract

The invention concerns anti-tumour agents of formula (I) wherein each of R1, R2 and R3 has the meanings defined in the specification including hydrogen, (1-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, amino, (1-4C)alkylamino and (1-4C)alkoxy;each of R4 and R5 is (1-4C)alkyl;each of R6 and R7 is hydrogen or (1-4C)alkyl;X is oxygen;m is 1 or 2 and each R8 is as defined in the specification;each of Y1 and Y2 is halogeno, (1-4C)alkanesulphonyloxy, benzenesulphonyloxy or phenyl-(1-4C)alkanesulphonyloxy;or a pharmaceutically-acceptable salt thereof;provided that at least one of R1, R2 and R3 is other than hydrogen;a process for their preparation, pharmaceutical compositions containing them and their use in the production of an anti-proliferative effect.

Description

ANTI-TUMOR AGENTS DESCRIPTION OF THE INVENTION The invention relates to cytotoxic anti-tumor agents. More particularly, the invention relates to novel (1,4-benzoquinonyl) alkanoic acid derivatives which support a substituent comprising a cytotoxic portion of mustard nitrogen. The invention also relates to processes for the preparation of (1,4-benzoquinonyl) alkanoic acid derivatives, for pharmaceutical compositions containing them and their use in the production of an anti-tumor effect in a warm-blooded animal. just like man. Many of the current treatments for cell proliferation diseases such as cancer and psoriasis use cytotoxic agents which inhibit DNA synthesis or cell division. Such compounds tend to lack specificity and can be toxic to cells generally since the neoplastic cells are usually only slightly different from normal cells. The toxic effect of the cytotoxic agent on rapidly dividing tumor cells may be beneficial although normal cells in which continuous cell division occurs such as in cells of the spinal cord and in epithelial cells of the intestine may also be adversely affected.

There are particular difficulties in obtaining an effective treatment of solid tumors using chemotherapy with cytotoxic agents or radiotherapy since, within the hypoxic internal regions of the tumor mass where the network of blood capillaries is deficient, cell division is slow or absent. Such hypoxic regions exist in most of the major classes of solid tumors, for example in bladder, breast, cervical, colorectal, head and neck, lung, ovarian, pancreatic, prostate and stomach tumors. In particular it has been shown by the analyzes of the clinical samples that a significant proportion of the majority of head and neck, breast and cervical tumors, for example between 10% and 30% of the tumor mass, is severely hypoxic with a oxygen tension below 5mm Hg (0.0066 bar). It has been recognized that the presence of such hypoxic regions within solid tumors may present an opportunity to allow more selective cytotoxic drug therapy based on an approach of either prodrug or double prodrug. For example, a prodrug approach is described by B.D. Palmer et al., J. Med. Chem., 1992, 35, 3214-3222, and in an International Patent Application WO 93/11099 which relates to a nitro-substituted anilino-mustard compound which may be capable of reducing to a more potent amino-substituted anilino-mustard. One problem with this proposal was that those additional substituents which were necessary to allow rapid enzymatic reduction of the nitro group tended to decrease the cytotoxic potency of the resulting substituted amino compound. The dual prodrug approach was collected to address this problem. For example, it is described by G. J. Atwell et al. , J. Med. Chem., 1994, 37, 371-380, and B. M. Sykes et al., J ^ Chem. Soc. Perkin Transact. II, 1995, 337-342, that certain N- derivatives. { - [bis (2-chloroethyl) amino] phenyl} -2-Nitrophenylacetamide could be reduced to the corresponding 2-aminophenylacetamide derivatives which could be cyclized to liberate the aniline mustard 4- [bis (2-chloroethyl) amino] aniline. An alternative dual-proforma approach involves interconversion in biological systems of quinone and hydroquinone portions. For example, it is described by L. A. Carpino et al., J. Org. Chem., 1989, 54, 3303-3310, that a certain (1,4-benzoquinonyl) alkanoic acid derivative can provide a feasible approach for the delivery of a cytotoxic agent. The model compounds that were prepared included N, N-di- (2-chloroethyl) -3- (2-methoxy-3,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyramide and N, N-di- (2-chloroethyl) -3- (2, 3-dimethoxy-5-methyl-1,4-benzoquinonyl) -3-methylbutyramide which were designed to release the simple mustard bis (2-chloroethyl) amine . It is further known from Proceedings of the American Association for Cancer Research, 1997, 3_8, 433-434 (Extract No. 2894) that the cytotoxic melphalan mustard drug can be linked to a (1,4-benzoquinonyl) alkanoic acid. It was noted that the fastest in vitro bioreductive activation was of the order of 25% per hour that is to say about 2.5 hours and this was linked to the reduction potentials in the range of -480 to -520 mV. In contrast, a slower in vitro bioreductive activation of other prodrugs of the order of 10% per hour, that is to say at about 6 hours, was associated with a reduction potential of the order of -730 mV. It is an object of the present invention to provide dual prodrug quinone compounds which upon reduction to hydroquinone are rapidly broken to release the cytotoxic agent. The present invention provides an antitumor agent of the formula I wherein R 1 is hydrogen, Cl-4 alkyl, C 3-4 alkenyl, C 3-4 alkynyl, hydroxy-Cl-4 alkyl, Cl-4 alkyloxy Cl-4 alkyl, Cl-4 amino-alkyl 4, Cl-4 alkylamino of Cl-4, di- [Cl-4 alkyl] amino-alkyl of Cl-4, pyrrolidin-1-yl-alkyl of Cl-4, piperidin-alkyl of Cl-4 , Cl-4-morpholine-alkyl, Cl-4-piperazin-1-yl-alkyl, Cl-4-alkyl-Cl-4-alkyl-alkyl, Cl-4-carboxy-alkyl, Cl-alkoxycarbonyl -4-Cl-4 alkyl, carbamoyl-Cl-4 alkyl, N-alkylcarbamoyl Cl-4-Cl-4 alkyl, N, N-di- [Cl-4 alkyl] carbamoyl-Cl- alkyl 4, amino, Cl-4 alkylamino, C3-4 alkenylamino, C3-4 alkynylamino, di- [Cl-4] amino alkyl, di- [C3-4 alkenyl] amino, di- [C3 alkynyl] -4] amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-alkylpiperazine of Cl-4-l-yl, hydroxy-alkylamino of C2-4, alkoxy of Cl-4-alkylamino of C2 -4, aminoalkylamino of C2-4, alkylamino of Cl-4-alkylamino of C2-4, di- [alqu ilo of Cl-4] amino-alkylamino of C2-4, pyrrolidin-1-yl-alkylamino of C2-4, piperidin-alkylamino of C2-4, morpholin-alkylamino of C2-4, piperazin-1-yl-alkylamino of C2-4, 4-alkylpiperazine of Cl-4-l-yl-alkylamino of C2-4, alkanoylamino of C2-4, alkanoylamino of C2-4-alkylamino of C2-4, carboxyalkylamino of Cl-4, alkoxy of Cl- 4-carbonyl-alkylamino of Cl-4, carbamoylalkylamino of Cl-4, N-alkylcarbamoyl of Cl-4-alkylamino Cl-4, N, N-di- [Cl-4 alkyl] carbamoyl-alkylamino of Cl-4, hydroxy, Cl-4 alkoxy, C2-4 hydroxyalkoxy, Cl-4-alkoxy C2-4 alkoxy, C2-4 aminoalkoxy, Cl-4 alkylamino C2-4 alkoxy, di- [alkyl] of Cl-4] amino-alkoxy of C2-4, pyrrolidin-1-yl-alkoxy of C2-4, piperidinalcoxy of C2-4, morpholino-alkoxy of C2-4, piperazin-1-yl-alkoxy of C2-4 or 4-alkylpiperazine of Cl-4-1-yl-C2-4 alkoxy; R2 is hydrogen, Cl-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, Cl-4 hydroxyalkyl, Cl-4 alkyloxy Cl-4 alkyl, Cl-4 aminoalkyl, Cl-4 alkylamino 4-Cl-4 alkyl, di- [Cl-4] alkyl aminoalkyl of Cl-4, pyrrolidin-1-yl-alkyl of Cl-4, piperidinoalkyl of Cl-4, morpholinoalkyl of Cl-4, piperazin-1 -Cl-4-alkyl, 4-alkylpiperazine of Cl-4-l-yl-Cl-4 alkyl, carboxyalkyl of Cl-4, Cl-4-alkoxycarbonyl of Cl-4 alkyl, carbamoylalkyl of Cl-4 , N-alkylcarbamoyl of Cl-4-alkyl of Cl-4, N, N-di- [Cl-4 alkyl] carbamoyl-Cl-4 alkyl, amino, alkylamino of Cl-4, alkenylamino of C3-4, C 3-4 alkynylamino, di- [C 1-4 alkyl] amino, di- [C 3-4 alkenyl] amino, di- [C 3-4 alkynyl] amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin -1-yl, 4-alkylpiperazione of Cl-4-l-yl, hydroxy-alkylamino of C2-4, alkoxy of Cl-4-alkylamino of C2-4, aminoalkylamino of C2-4, alkylamino of Cl-4-alkylamino of C2 -4, di- [Cl-4 alkyl] amin o-C2-4 alkylamino, pyrrolidin-1-yl-alkylamino of C2-4, piperidino-alkylamino of C2-4, morpholinoalkylamino of C2-4, piperazin-1-yl-alkylamino of C2-4, 4-alkylpiperazine of Cl-4-l-yl-alkylamino of C2-4, alkanoylamino of C2-4, alkanoylamino of C2-4-alkylamino of C2-4, carboxyalkylamino of Cl-4, alkoxycarbonyl of Cl-4-alkylamino of Cl-4, carbamoylalkyl of Cl-4, N-alkylcarbamoyl of Cl-4-alkylamino of Cl-4, N, N-di- [Cl-4 alkyl] carbamoyl-alkylamino of Cl-4, hydroxy, alkoxy of Cl-4 , C2-4 -hydroxy-alkoxy, Cl-4-alkoxy-C2-4-alkoxy, C2-4-aminoalkoxy, Cl-4-alkylamino of C2-4-alkoxy, di- [Cl-4 alkyl] amino- C 2-4 alkoxy, pyrrolidin-1-yl-C 2-4 alkoxy, piperidino-C 2-4 alkoxy, C 2-4 morpholinoalkoxy, C 2-4 piperazin-1-yl-alkoxy or Cl-4-alkylpiperazine 4-l-yl-C2-4 alkoxy; 'R3 is hydrogen, Cl-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, Cl-4 hydroxyalkyl, Cl-4 alkyloxy Cl-4 alkyl, Cl-4 aminoalkyl, Cl-alkylamino -4-Cl-4 alkyl, di- [Cl-4 alkyl] amino-alkyl of Cl-4, pyrrolidin-1-yl-alkyl of Cl-4, piperidinalkyl of Cl-4, morpholinoalkyl of Cl-4, piperazin-1-yl-Cl-4 alkyl, 4-alkylpiperazine of Cl-4-l-yl-alkyl of Cl-4, carboxyalkyl of Cl-4, alkoxycarbonyl of Cl-4-alkyl of Cl-4, carbamoylalkyl of Cl-4, N-alkylcarbamoyl of Cl-4 -alkyl Cl-4, N, -di- [Cl-4 alkyl] carbamoyl-Cl-4 alkyl, amino, Cl-4 alkylamino, C 3-4 alkenylamino, C 3-4 alkynylamino, di- [ Cl-4] amino] amino, .di- [C3-4 alkenyl] amino, di- [C3-4 alkynyl] amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-alkylpiperazine of Cl-4-l-yl, hydroxy-alkylamino of C 2-4, alkoxy of Cl-4-alkylamino of C 2-4, aminoalkylamino of C 2-4, alkylamino of Cl-4-alkylamino of C 2-4, di- [ Cl-4] amino-alkylamino of C2-4, pyrrolidin-1-yl-alkylamino of C2-4, piperidinoalkylamino of C2-4, morpholinoalkylamino of C2-4, piperazin-1-yl-alkylamino of C2-4, 4- C2-4 Cl-4-l-yl-alkylamino alkyl-cyperazine, C2-4-alkanoylamino, C2-4-alkanoylamino-C2-4-alkylamino, Cl-4-carboxyalkylamino, Cl-4-alkylamino-Cl-alkylamino 4, Cl-4 carbamoylalkylamino, N-alkylcarbamoyl of Cl-4-alkylamino of Cl-4,, N, N-di- [Cl-4 alkyl] carbamoylalkylamino of Cl-4, hydroxy, alkoxy of Cl-4, C2-4 hydroxyalkoxy, Cl-4 alkoxy C2-4 alkoxy, C2-4 aminoalkoxy, Cl-4 alkylamino of C2-4 alkoxy, di- [Cl-4 alkyl] amino-alkoxy of C2 -4, pyrrolidin-1-yl-alkoxy of C2-4, piperidinoalkoxy of C2-4, morpholinoalkoxy of C2-4, piperazin-1-yl-alkoxy of C2-4 or 4-alkylpiperazine of Cl-4-l-il -alcoxy of C2-4; R 4 is Cl 4 alkyl; R5 is Cl4 alkyl; R6 is hydrogen or Cl4 alkyl; R7 is hydrogen or Cl4 alkyl; X is oxygen; m is 1 or 2 and each R is independently hydrogen, halogen, hydroxy, Cl-4 alkoxy, C 2-4 alkenyloxy, C 2-4 alkynyloxy, Cl 4 alkyl, C 3-4 alkenyl, C 3 alkynyl -4, amino, alkylamino of Cl-4, di- [Cl-4 alkyl] amino, cyano, C 2-4 alkanoylamino, carboxy, Cl-4 alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl of Cl-4 or N, N-di- [Cl-4 alkyl] carbamoyl; Y1 is halogen, Cl-4 alkanesulfonyloxy, benzenesulfonyloxy or phenyl-alkanesulfonyloxy of Cl-4; and Y2 is halogen, Cl-4 alkanesulfonyloxy, benzenesulfonyloxy or phenyl-alkanesulfonyloxy of Cl-4; and wherein any heterocyclic group in R1, R2 or R3 is optionally substituted with 1, 2 or 3 alkyl substituents of Cl-4, and wherein any phenyl group in Y1 or Y2 when Y1 and Y2 are benzenesulfonyloxy or phenyl-alkanesulfonyloxy Cl-4 optionally substituted with 1, 2 or 3 substituents selected from halogen, nitro, cyano, trifluoromethyl, hydroxy, amino, Cl-4 alkyl, Cl-4 alkoxy, Cl-4 alkylamino and di- [Cl -4] amino; or a pharmaceutically acceptable salt thereof; provided that at least one of R1, R2 and R3 is other than hydrogen. Within the present invention it will be appreciated that an anti-tumor agent of the invention may possess one or more asymmetric carbon atoms and may therefore exist in the diastereomeric, racemic and optically active forms. It is to be understood that the invention encompasses any such forms, which possess anti-tumor activity, with a common general knowledge being that various diastereomeric forms can be separated and how a racemic compound can be separated from its optically active forms. It should also be understood that the compounds of the invention can exist in solvated as well as unsolvated forms, as well as, for example, hydrated forms. It should be understood that the invention encompasses all such solvated forms which possess anti-tumor activity. The appropriate values for the generic groups mentioned above are subsequently established. The term "alkyl" includes straight and branched chain alkyl groups, but references to individual alkyl groups such as "propyl" are specific to the linear chain version only. A similar convention applies to other generic terms. A suitable value for each of R1, R2, R3, R4, R5, R6, R7 and R8 when it is C1-4 alkyl or for an alkyl substituent of Cl4 on a phenyl or heterocyclic group is, for example, methyl, ethyl, propyl, isopropyl, butyl or isobutyl. A suitable value for each of R 1, R 2, R 3 and R 8 when it is Cl 4 alkoxy or for a Cl 4 alkoxy substituent on a phenyl group is, for example, methoxy, ethoxy, propoxy, butoxy or isobutoxy. A suitable value for each of R, R, R and R when it is alkylamino of Cl-4 or for an alkylamino substituent of Cl-4 on a phenyl group is, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino or isobutylamino. A suitable value for each of R 1, R 2, R 3 and R 8 when it is di- [Cl 4 alkyl] amino or for a substituent of di- [Cl 4 alkyl] amino on a phenyl group is, for example, dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino or di-isopropylamino. Suitable values for each group R1, R2 or R3 include, for example: for C3-4 alkenyl: allyl, methylallyl, 2-butenyl and 3-butenyl; for C3-4 alkynyl: 2-propynyl and 2-butynyl; for hydroxyalkyl of Cl-4: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; for Cl-4 alkoxy-Cl-4 alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl; for aminoalkyl of Cl-4: aminomethyl, 1-aminoethyl, 2-aminoethyl and 3-aminopropyl; for Cl-4 alkylamino of Cl-4 alkyl: methylaminomethyl, ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl; for di- [Cl-4 alkyl] aminoalkyl of Cl-4: dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylaminopropyl; for pyrrolidin-1-yl-alkyl of Cl-4: pyrrolidin-1-ylmethyl and 2- (pyrrolidin-1-yl) ethyl; for piperidinalkyl Cl-4:. piperidinomethyl and 2-piperidinoethyl; for morpholinalkyl of Cl-4: morpholinomethyl and 2-morpholinoethyl; for piperazin-1-yl-alkyl of Cl-4: piperazin-1-ylmethyl and 2- (piperazin-1-yl) ethyl; 4-alquilpiperacina Cl-4-l-yl-alkyl Cl-4: 4-methylpiperazin-l-ylmethyl, 4-ethylpiperazin-l-ylmethyl, 2- (4-methylpiperazin-l-yl) ethyl and 2- (4-ethylpiperazin-1-yl) ethyl; for carboxyalkyl of Cl-4: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and 3-carboxypropyl; for Cl-4 alkoxy-carbonyl-Cl-4: I methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl and 3-ethoxycarbonylpropyl; for carbamoylalkyl Cl-4: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl, and 3- carbamoylpropyl; for N-alkylcarbamoyl Cl-4-alk? I Cl-4 N-methylcarbamoylmethyl, N-ethylcarbamoylmethyl, N-propilcarbamoilmetilo, 1- (N-methylcarbamoyl) ethyl, 1- (ethylcarbamoyl) ethyl, 2- (N-methylcarbamoyl ethyl), 2- (N-ethylcarbamoyl) ethyl and 3- (N-methylcarbamoyl) propyl; for N, N-di- [Cl- alkyl] carbamoyl Cl-4: N, N-dimethylcarbamoylmethyl, N-ethyl-N-methylcarbamoylmethyl, N, N-diethylcarbamoylmethyl, 1- (N, N-dimethylcarbamoyl) ethyl, 1- (N, N-diethylcarbamoyl) ethyl, 2- (N, N-dimethylcarbamoyl) ethyl, 2- (NN-diethylcarbamoyl) ethyl and 3- (N, N-dimethylcarbamoyl) propyl; for C3-4 alkenylamino: allylamino and methylalylamino; for C3-4 alkynylamino: 2-propynylamino and 3-propynylamino; for di- [C3-4 alkenyl] amino: diallylamino for C3-4 di-alkynyl-amino: di- (2-propynyl) amino; for 4-alipiperazine of Cl-4-l-yl: 4-methylpiperazin-1-yl and 4-ethylpiperazin-1-yl; for C2-4 hydroxyalkylamino: 2-hydroxyethylamino, 3-hydroxypropylamino and -hydroxybutylamino; for Cl-4-alkylamino of C2-4 alkoxy: 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino and 3-ethoxypropylamino; for C2-4 aminoalkylamino: 2-aminoethylamino, 3-aminopropylamino and 4-aminobutylamino; for alkylamino Cl-4-alkylamino C2-4: 2-methylaminoethylamino, 2-ethylaminoethylamino, 2-propilaminoetilamino, 3-methylaminopropylamino, 3-ethylaminopropylamino and 4-methylaminobutylamino; for di- [alkyl Cl-4] aminoalkylamino of C2-: 2-dimethylaminoethylamino, 2- (N-ethyl-N-methylamino) ethylamino, 2-diethylaminoethylamino, 2-dipropilaminoetilamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino and 4- dimethylaminobutylamino; for the pyrrolidin-1-yl-alkylamino of C 2-4: 2- (pyrrolidin-1-yl) ethylamino and 3- (pyrrolidin-1-yl) propylamino; for C2-4 piperidinalkylamino: 2-piperidinoethylamino and 3-piperidinopropylamino; for C2-4 morpholyalkylamino: 2-morpholinoethylamino and 3-morpholinopropylamino; for piperazin-1-yl-alkylamino of C 2-4: 2- (piperazin-1-yl) ethylamino and 3- (piperazin-1-yl) propylamino; for 4-alkylpiperazine of Cl-4-l-yl-alkylamino of C 2-4: 2- (4-methylpiperazin-1-yl) ethylamino and 3- (4-methylpiperazin-1-yl) propylamino; for C2-4 alkanoylamino: acetamido, propionamido and butyramido; for C2-4 alkanoylamino-C2-4 alkylamino: 2-acetamidoethylamino, 3-acetamidopropylamino and 2-propionamidoethylamino; for Cl-4 carboxyalkylamino: carboxymethylamino, 1-carboxyethylamino, 2-carboxyethylamino and 3-carboxypropylamino; for Cl-4-carbonyl-alkylamino of Cl-4: methoxycarbonylmethylamino, ethoxycarbonylmethylamino, 1-methoxycarbonylethylamino, 2-methoxycarbonylethylamino, 2-ethoxycarbonylethylamino, 2- (tert-butoxycarbonyl) ethylamino and 3-methoxycarbonylpropylamino; for carbamoylalkylamino of Cl-4: carbamoylmethylamino, 1-carbamoylethylamino, 2-carbamoylethylamino and 3-carbamoylpropylamino; for N-alkylcarbamoyl of Cl-4-alkylamino of Cl-4: N-methylcarbamoylmethylamino, N-ethylcarbamoylmethylamino, 2- (N-methylcarbamoyl) ethylamino, 2- (N-ethylcarbamoyl) ethylamino y. 3- (N-methylcarbamoyl) propylamino; for N, N-di- [Cl-] alkylcarbamazyl-alkylamino of Cl-4: N, N-dimethylcarbamoylmethylamino, N-ethyl-N-methylcarbamoylmethylamino, N, N-diethylcarbamoylmethylamino, 2- (N, N-dimethylcarbamoyl) ethylamino, 2- (N, N-diethylcarbamoyl) ethylamino and 3- (N, N-dimethylcarbamoyl) propylamino; for C2-4 hydroxyalkoxy: 2-hydroxyethoxy, 3-hydroxypropoxy and 4-hydroxybutoxy; for Cl-4-alkoxy of C 2-4 alkoxy: 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, and 3-ethoxypropoxy; for C2-4 aminoalkoxy: 2-aminoethoxy and 3-aminopropoxy; for C 2-4 alkylamino of Cl 2 -alkoxy: 2-methylaminoethoxy, 2-ethylaminoethoxy, 2-propylaminoethoxy, 3-methylaminopropoxy and 3-ethylaminopropoxy; for di- [Cl-] alkylC2-4 aminoalkoxy: 2-dimethylaminoethoxy, 2- (N-ethyl-N-methylamino) ethoxy, 2-diethylaminoethoxy, 2-dipropylaminoethoxy, 3-dimethylaminopropoxy and 3-diethylaminopropoxy; for pyrrolidin-1-yl-alkoxy of C2-: 2- (pyrrolidin-1-yl) ethoxy and 3- (pyrrolidin-1-yl) propoxy; for C2-4 piperidinolcoxy: 2-piperidinoethoxy and 3-piperidinopropoxy; for C2-4 morpholinoalkoxy: 2-morpholinoethoxy and 3-morpholinopropoxy; for piperazin-1-yl-C2-4 alkoxy: 2- (piperazin-1-yl) ethoxy and 3- (piperazin-1-yl) propoxy; for 4-alkylpiperazine of Cl-4-l-yl-alkoxy of C2-: 2- (4-methylpiperazin-1-yl) ethoxy and 3- (4-methylpiperazin-1-yl) propoxy, A suitable value for R8, Y1 or Y2 when it is halogen or for a halogen substituent on a phenyl group is, for example, fluoro, chloro, bromo or iodo. Suitable values for each R8 group include, for example: for C2-4 alkenyloxy: vinyloxy, allyloxy, methylalkyloxy and 2-butenyloxy; for C2-4 alkynyloxy: ethynyloxy and 2-propynyloxy; for C3-4 alkenyl: allyl, methylallyl, 2-butenyl and 3-butenyl; for C3-4 alkynyl: 2-propynyl and 2-butynyl; for C2-4 alkanoyl: acetyl, propionyl and butyryl; for Cl-4 alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl; for N-alkylcarbamoyl of Cl-4: N-methylcarbamoyl and N-ethylcarbamoyl; para-N, N-di- [Cl-4 alkyl] carbamoyl: N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl. A suitable value for Y1 or Y2 when it is alkanesulfonyloxy of Cl-4 is, for example, methanesulfonyloxy, ethanesulfonyloxy or propanesulfonyloxy; when it is, for example, phenyl-alkanesulfonyloxy of Cl-4 is, for example, phenylmethanesulfonyloxy or 2-phenylethanesulfonyloxy. It will be appreciated that, when it is stated that a heterocyclic group in R1, R2 or R3 can be optionally substituted, heterocyclic groups include those specified in the definitions of R1, R2 and R3 such as, for example, a pyrrolidin-1-yl group, morpholino, piperidine-Cl-4 alkyl, piperazin-1-yl-alkylamino of C2-4 or 4-alkylpiperazin of Cl-4-1-yl-alkoxy of C2-4. A suitable pharmaceutically acceptable salt of an anti-tumor agent of the invention is, for example, an acid addition salt of an anti-tumor agent of the invention which is sufficiently basic, for example, an acid addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition to a suitable pharmaceutically acceptable salt of an anti-tumor of the invention which is sufficiently acidicis an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which allows a physiologically acceptable cation , for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine. Particular novel anti-tumor agents of the invention include, for example, compounds of formula I, or pharmaceutically acceptable salts thereof, wherein: (a) R, R or R is independently hydrogen, Cl-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, Cl-4 hydroxyalkyl, Cl-4 alkyloxy Cl-4 alkyl, Cl-4 aminoalkyl, Cl-4 alkylamino Cl-4 alkyl, di- [Cl-4 alkyl] amino-alkyl of Cl-4, pyrrolidin-1-yl-alkyl of Cl-4, piperidinoalkyl of Cl-4, morpholinoalkyl of Cl-4, piperazin-1-yl-alkyl of Cl-4 , 4-alkylpiperazine of Cl-4-1-yl-alkyl of Cl-4, carboxy-alkyl of Cl-4, alkoxycarbonyl of Cl-4-alkyl of Cl-4, carbamoylalkyl of Cl-4, N-alkylcarbamoyl of Cl -4-Cl-4 alkyl or N, N-di- [Cl-4 alkyl] carbamoyl-Cl-4 alkyl, with the proviso that at least one of R1, R2 or R3 is different from hydrogen; and each of R 4, R 5, R 6, R 7, R 8, m, X, Y 1 and Y 2 have any of the meanings defined above or in this section in relation to the particular novel anti-tumor agents of the invention; (b) R1, R2 or R3 is independently amino, C1-4 alkylamino, C3-4 alkenylamino, C3-4 alkynylamino, di- [Cl4] amino alkyl, di- [C3-4 alkenyl] amino, di- [C 3-4 alkynyl] amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-alkylpiperazine of Cl-4-l-yl, hydroxy-alkylamino of C 2-4, alkoxy of Cl-4-alkylamino of C2-4, aminoalkylamino of C2-4, alkylamino of Cl-4-alkylamino of C2-4, di- [Cl-4 alkyl] amino-alkylamino of C2-4, pyrrolidin-1- C2-4 -alkylamino of C2-4, piperidinoalkylamino of C2-4, morpholinoalkylamino of C2-4, piperazin-1-yl-alkylamino of C2-4, 4-alkylpiperazine of Cl-4-1-yl-alkylamino of C2-4, C2-4 alkanoylamino, C2-4 alkanoylamino-C2-4 alkylamino, carboxyalkylamino of Cl-4, "Cl-4-alkylamino alkylamino of Cl-4, carbamoyl-alkylamino of Cl-4, N-alkocarbamoyl of Cl -4-alkylamino of Cl-4 or N, -di- [Cl-4 alkyl] carbamoyl-alkylamino of Cl-4, and each of R4, R5, R6, R7, R8, m, X, Y1 and Y2 have which any of the meanings defined above or in this section in relation to the particular novel anti-tumor agents of the invention; (c) R1, R2 or R3 is independently Cl-4 alkoxy, C2-4 hydroxyalkoxy, Cl-4 alkoxy C2-4 alkoxy, C2-4 aminoalkoxy, Cl-4 alkylamino-C2- alkoxy 4, di- [Cl-4 alkyl] amino-C2-4 alkoxy, pyrrolidin-1-yl- (2-C) alkoxy ,. C2-4 piperidinoalkoxy, C2-4 morpholinoalkoxy, C2-4 piperazin-1-yl-alkoxy or 4-alkylpiperazine of Cl-4-1-yl- (2-C) alkoxy; and each of R 4, R 5, R 6, R 7, R 8, m, X, Y 1 and Y 2 have any of the meanings defined above or in this section in relation to the particular anti-tumor agents of the invention; (d) not more than two of R1, R2 and R3 have any of the meanings defined in paragraph (b) above; and each of R 4 -, R 5, R 6, R 7, R 8, m, X, Y 1 and Y 2 have any of the meanings defined above or in this section in relation to the particular novel anti-tumor agents of the invention; (e) not more than one of R1, R2 and R3 have any of the meanings defined in paragraph (b) above; and each of R 4, R 5, R 6, R 7, R 8, m, X, Y 1 and Y 2 have any of the meanings defined above or in this section in relation to the particular novel anti-tumor agents of the invention; (f) each of R4 and R5 is independently methyl, ethyl, propyl or isopropyl and each of R1, R2, R3, R6, R7, R8, m, X, Y1 and Y2 have any of the meanings defined above or in this section in relation to the particular novel anti-tumor agents of the invention; (g) R6 is hydrogen, methyl, ethyl, propyl or isopropyl and R7 is hydrogen or methyl; and each of R1, R2, R3, R4, R5, R8, m, X, Y1 and Y2 have any of the meanings defined above or in this section in relation to the particular novel anti-tumor agents of the invention; (h) m is 1 or 2 and each R is independently hydrogen, halogen, hydroxy, Cl-4 alkoxy, Cl-4 alkyl, amino, Cl-4 alkylamino, di- [Cl-4 alkyl] amino or cyano; and each of R1, R2, R3, R4, R5, R6, R7, X, Y1 and Y2 have any of the meanings defined above or in this section in relation to the particular novel anti-tumor agents of the invention; (i) m is 1 and R8 is hydrogen, halogen, hydroxy, Cl-4 alkoxy, Cl-4 alkyl, amino, Cl-4 alkylamino, di- [Cl-4 alkyl] amino or cyano; and each of R1, R2, R3, R4, R5, R6, R7, X, Y1 and Y2 have any of the meanings defined above or in this section in relation to the particular novel anti-tumor agents of the invention; (j) each of Y1 and Y2 is halogen or each of Y1 and Y2 is Cl-4 alkanesulfonyloxy, benzenesulfonyloxy or phenyl-alkanesulfonyloxy of Cl-4; and each of R1, R2, R3, R4, R5, R6, R7, R8, m and X, have any of the meanings defined above or in this section in relation to the particular novel anti-tumor agents of the invention. A preferred compound of the invention is an anti-tumor agent of the formula I wherein each of R1, R and R is independently hydrogen, methyl, ethyl, propyl, allyl, methylallyl, 2-hydroxyethyl, 3-hydroxypropyl, 2- methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 2-carboxyethyl, 3-carboxypropyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl, 3-ethoxycarbonylpropyl, 2- (N-methylcarbamoyl) -ethyl, 3- (N-methylcarbamoyl) propyl, 2- (N, N-dimethylcarbamoyl) ethyl, 3- (N, N-dimethylcarbamoyl) propyl, methylamino, ethylamino, propylamino, isopropylamino, allylamino, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino , 3-methoxypropylamino, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 3-methylaminopropylamino, 2-ethylaminoethylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, 2- (pyrrolidin- 1-yl) ethylamino, 3- (pyrrolidin-1-yl) propylamino, 2-piper idinoethylamino, 3-piperidinopropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 2- (piperazin-1-yl) ethylamino, 3- (piperazin-1-yl) propylamino, 2- (4-methylpiperazin-1-yl) ethylamino, - (4-methylpiperazin-1-yl) propylamino, 2-acetamidoethylamino, 2-propionamidoethylamino, 3-acetamidopropylamino, 3-propionamidopropylamino, 2-carboxyethylamino, 3-carboxypropylamino, 2-methoxycarbonylethylamino, 2-ethoxycarbonylethylamino, 2- (tert-butoxycarbonyl) ethylamino, 3-methoxycarbonylpropylamino, 3-ethoxycarbonylpropylamino, 3- (tert-butoxycarbonyl) propylamino, methoxy or ethoxy; each of R 4 and R 5 is independently hydrogen, methyl, ethyl, propyl or isopropyl; R6 is hydrogen, methyl, ethyl, propyl or isopropyl; R7 is hydrogen or methyl; X is oxygen; m is 1 or 2 and each R 8 is independently hydrogen, fluoro, chloro, bromo, methoxy, ethoxy, methyl, ethyl, propyl, isopropyl or cyano; and 'each of Y1 and Y2 is independently chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy or phenylmethanesulfonyloxy; or a pharmaceutically acceptable salt thereof; with the proviso that at least one of R1, R2 and R3 is different from hydrogen and with the proviso that not more than two of R1, R2 and R3 is a substituted amino group (such as methylamino, 2-morpholinoethylamino or 2- acetamidoethylamino). A further preferred compound of the invention is an anti-tumor agent of the formula I wherein R 1 is hydrogen, Methyl, ethyl, propyl, allyl, methylallyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl, 3-ethoxycarbonylpropyl, 2- ( N-methylcarbamoyl) ethyl, 3- (N-methylcarbamoyl) propyl, 2- (N, N-dimethylcarbamoyl) ethyl, 3- (N, N-dimethylcarbamoyl) propyl, methylamino, ethylamino, propylamino, isopropylamino, allylamino, 2-hydroxyethylamino , 3-hydroxypropylamino, 2-methoxyethylamino, 3-methoxypropylamino, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 3-methylaminopropylamino, 2-ethylaminoethylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3 -dietilaminopropilamino, 2- (pyrrolidin-1-yl) ethylamino, 3- (pyrrolidin-1-yl) propylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 2- (piperazin-1-yl) ethylamino, 3- (piperazin-1-yl) propylamino, 2- (4-methylpiperazin-1-yl) -ethylamino, 3- (4 -metilpiperacin-l-yl) propylamino, 2-acetamidoetilamino, 2-propionamidoetilamino, 3-acetamidopropilamino, 3-propionamidopropilamino, 2-metoxicarboniletilamino, 2-etoxicarboniletilamino, 2- (tert -butoxycarbonyl) ethylamino, 3-metoxicarbonilpropilamino, 3-etoxicarbonilpropilamino, 3- (tert-butoxycarbonyl) propylamino, methoxy or ethoxy; R is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, allyl, methylallyl, methoxy or ethoxy; RJ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, allyl, methylallyl, methoxy or ethoxy; R 4 is methyl, ethyl, propyl or isopropyl; R5 is methyl, ethyl, propyl or isopropyl; R6 is hydrogen, methyl, ethyl, propyl or isopropyl; R7 is hydrogen or methyl; X is oxygen; m is 1 or 2 and each R 8 is independently hydrogen, fluoro, chloro, bromo, methoxy, ethoxy, methyl, ethyl, propyl or isopropyl; Y1 is chlorine, bromine, iodine or methanesulfonyloxy; and Y2 is chloro, bromo, iodo or methanesulfonyloxy; or a pharmaceutically acceptable salt thereof; with the proviso that at least one of R1, R4- and R3 is different from hydrogen. A further preferred compound of the invention is an anti-tumor agent of the formula I wherein R 1 is hydrogen, methyl, ethyl, propyl, allyl, 2-methoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, allylamino, 2-dimethylaminoethylamino, -diethylaminoethylamino, 2- (pyrrolidin-1-yl) ethylamino, 2-piperidinoethylamino, 2-morpholinoethylamino, 2- (piperazin-1-yl) ethylamino, 2- (4-methylpiperazin-1-yl) ethylamino, 2-acetamidoethylamino, methoxy or ethoxy; R2 is hydrogen, methyl, ethyl, propyl, allyl, methoxy or ethoxy; R3 is hydrogen, methyl, ethyl, propyl, isopropyl, allyl, methoxy or ethoxy; R 4 is methyl or ethyl; R5 is methyl or ethyl; R is hydrogen, methyl or ethyl; R is hydrogen; X is oxygen; m is 1 and R8 is located in meta for X and R8 is hydrogen, fluoro, chloro, methyl, ethyl, propyl or isopropyl; and each of Y1 and Y2 is chlorine, bromine or iodine; or a pharmaceutically acceptable salt thereof; with the proviso that at least one of R1, R "and R is different from hydrogen.An additional preferred compound of the invention is an anti-tumor agent of the formula I wherein R1 is hydrogen, methyl, 2-methoxyethyl, isopropylamino 2-morpholinoethylamino, 2-acetamidoethylamino or methoxy, R 2 is hydrogen, methyl, allyl or methoxy, R 3 is methyl, ethyl, propyl or allyl, each of R 4 and R 5 is methyl, R 6 is hydrogen or methyl, R 7 is hydrogen; X is oxygen, m is 1 and R is hydrogen, and each of Y1 and Y2 is chlorine; or a pharmaceutically acceptable salt thereof. A preferred specific compound of the invention is the following anti-tumor agent of the formula I: 4- [bis (2-chloroethyl) amino] phenyl 3- [2- (2-acetamidoethylamino) -3-methoxy-5-methyl- 1, 4-benzoquinonyl] -3-methylbutyrate, 4- [bis (2-chloroethyl) amino] phenyl 3- [2- (2-methoxyethyl) -3,5-dimethyl-1,4-benzoquinonyl] -3-methylbutyrate 4- [bis (2-chloroethyl) amino] phenyl 3- (3-allyl-2,5-dimethyl-l, -benzoquinonyl) -3-methylbutyrate, 4- [bis (2-chloroethyl) amino] phenyl 3- methy1-3- (2,3,5-trimethyl-l, -benzoquinonyl) butyrate, 4- [bis (2-chloroethyl) amino] phenyl 3- (2,5-dimethyl-1,4-benzoquinonyl) -3- methylbutyrate, 4- [bis (2-chloroethyl) amino] phenyl 3- [3-methoxy-5-methyl-2- (2-morpholinoethylamino) -1,4-benzoquinonyl] -3-methylbutyrate or 4- [bis (2-chloroethyl) amino] -phenyl-2,3-dimethyl-3- (2,3,5-trimethyl-1,4-benzoquinonyl) butyrate; or a pharmaceutically acceptable salt thereof. It is an object of a further aspect of the present invention to provide a group of novel (1, -benzoquinonyl) alkanoic acid derivatives which have balanced reduction potentials ie reduction potentials which are not too low in such a way that the Reduction rate of the 1,4-benzoquinonyl group is substantially decreased and not too high so that a significant amount of reduction occurs outside the hypoxic region of the tumor mass. According to this aspect of the present invention, there is provided an anti-tumor agent of the formula I, or a pharmaceutically acceptable salt thereof, as defined above wherein the reduction potential of the compound is in the range, for example, -200 to -500 mV, preferably in the range, for example, -200 to -475 mV, more preferably in the range of, for example, -250 to -450 mV. The methodology used to measure the reduction potentials of the compounds of the invention is described in detail below. An anti-tumor agent of the formula I, or a pharmaceutically acceptable salt thereof, it can be prepared by any known process or be applicable to the preparation of the chemically related compounds. According to a further feature of the invention, the processes defined below are provided for the preparation of an anti-tumor agent of the formula I, or a pharmaceutically acceptable salt thereof, in which unless otherwise stated, each one of R1, R2, R3, R4, R5, R6, R7, R8, m, X, Y1 and Y2 have any of the meanings defined above. The necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described below within the accompanying Examples. Alternative necessary starting materials are obtained by procedures analogous to those illustrated and such analogous procedures are achieved using the common capacity of an organic chemical. In accordance with this aspect of the invention there is provided a process for the preparation of an antitumor agent of the formula I, or a pharmaceutically acceptable salt thereof, as defined above which comprises: the reaction of an acid of the formula II wherein each of R1, R2, R3, R4, R5, Rd and R7 has any of the meanings defined above, or a reactive derivative thereof, with a compound of formula III wherein each of X, R8, m, Y1 and Y2 have any of the meanings defined above. A suitable reactive derivative of an acid of the formula II is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester such as pentafluorophenyl trifluoroacetate, an alcohol such as 1-hydroxybenzotriazole or a uranium salt such as 2- (1-hexafluorophosphate) benzotriazolyl) -1, 1, 3, 3-tetramethyluronium (V); an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as N, N'-dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. The reaction is preferably carried out in the presence of a suitable base such as, for example, a metal carbonate, alkaline or alkaline earth metal, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium hydride or hydride of potassium, or an organometallic base such as an alkyl lithium, for example lithium di-isopropylamide, or, for example, an organic base of amine such as, for example, pyridine, 2,6-lutidine, collidine, 4- dimethylaminopyridine, triethylamine, morpholine or diazobicyclo- [5.4.0] undec-7-ene. The reaction is also preferably carried out in a suitable inert solvent or diluent, for example methylene chloride, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethisulfoxide or acetone, and at a temperature in the range of, for example, -78 ° to 150 ° C, conveniently at or near room temperature. Optionally, when there is an amino, alkylamino, hydroxy or carboxy group in R1, R2, R3 or R8, any such group can be protected by a conventional protecting group which can be removed when desired by conventional means. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl group, ethoxycarbonyl or tert-butoxycarbonyl, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the selection of the protecting groups. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as the tert-butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be removed, for example, by hydrogenation on a catalyst such as palladium on carbon or by treatment with a Lewis acid, for example boron tris (trifluoroacetate). An alternative protecting group suitable for a primary amino group is, for example, a phthaloyl group which can be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protective group for a hydroxy group is, for example, an acyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the selection of the protecting group. Thus, for example, an acyl group such as an alkanoyl group or an aroyl can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a group ter butyl which can be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example, a benzyl group which can be removed, for example, by hydrogenation on a catalyst such as palladium on carbon. The starting materials of formula II and III are either commercially available or can be prepared by standard procedures of organic chemistry. For example, the starting material of formula II can be prepared by the hydrolysis of a 3,4-dihydrocoumarin of formula IV. wherein each of R1, R2, R3, R4, R5, R6 and R7 have any of the meanings defined above, and the subsequent oxidation of the hydroquinone thus formed. Suitable conditions for hydrolysis and subsequent oxidation reactions for use in the preparation of the starting material of formula II of a 3,4-dihydrocoumarin of formula IV include, for example, any agents known in the art for such conversions. . For example, the hydrolysis step can be carried out using a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. If the hydrolysis step is carried out under an atmosphere of air or oxygen, the oxidation of hydroquinone occurs spontaneously. Alternatively, 3,4-dihydrocoumarin can be hydrolyzed with water in the presence of an oxidizing agent such as an iron halide, for example ferric chloride. In general, the reaction was carried out in a suitable inert solvent or diluent, for example water, acetonitrile, N, N-dimethylformamide, methanol or ethanol, and at a temperature in the range, for example, from 15 ° to 100 ° C, conveniently in the range of, for example, 20 ° to 80 ° C. When a pharmaceutically acceptable salt of a compound of the formula I is required, it can be obtained, for example, by the reaction of the compound with a suitable acid or base using a conventional procedure. When an optically active form of a compound of formula I is required, it can be obtained by carrying out the above process using an optically active starting material, or by resolution of a racemic form of the compound using a conventional procedure. As stated above, the compounds of formula I of the present invention possess antitumor activity, in particular activity by virtue of the release of a cytotoxic agent in a hypoxic region of a tumor mass. The cytotoxic and anti-tumor activities of the compounds of the invention can be assessed using, for example, one or more of the methods subsequently undertaken (a) An in vitro assay which determines the lacunacy of a test compound to cause cross-linking of a piece of DNA using a procedure adapted from the work of Sunter et. a_l, Biochemical Pharmacology, 1992,? _, 59-64. The effects of the test compounds were assessed by their ability to crosslink the DNA strands of a plasmid: marked P32 linearized. Cross-linking was detected by denaturing the DNA and measuring its mobility by gel electrophoresis on a neutral agarose gel. Pieces of double and single strand DNA were separated by molecular size. The detailed methodology was as follows: A circular PBR322 DNA plasmid was linearized (Pharmacia Biotech., St. Albans, Hertfordshire, UK) using a restriction endonuclease Hind III and after terminal dephosphorylation with alkaline phosphatase, T4 polynucleotide kinase was used ( Biolabs, Hitchin, Hertfordshire, UK) to add ATP [? - 32P] to the 5 'ends of the DNA. Each test compound was dissolved in DMSO and added to a mixture of the DNA plasmid (12.5 ng per assay) and a pH 7.2 regulator comprising 25 mM of triethanolamine buffer and 1 mM of EDTA. The treatments were carried out under aerobic conditions (the solutions were gassed with air) or hypoxic conditions (the solutions were degassed by bubbling overnight with nitrogen and then maintained in an anaerobic chamber with the addition of a 3 to 10 fold excess of the sodium dithionite reducing agent) up to 3 hours at a temperature in the range of 30 ° to 37 ° C. The reaction was stopped by the addition of an ice-cooled mixture of 0.6 M sodium acetate, 20 mM EDTA and 100 μg / mg tRNA (Sigma, Poole, Dorset, UK). The DNA was precipitated by the addition of 95% ethanol, isolated and stored at -20 ° C overnight. Each DNA plasmid sample was re-suspended in a mixture of 30% aqueous DMSO and 1 M EDTA and denatured by heating at 90 ° C for 2 minutes. The denatured DNA sample was mixed with a pH 8.0 regulator comprising 20% Ficoll 400 (Sigma, Poole, Dorset, UK), 0.1 M EDTA and 0.25% bromophenol blue and applied to an electrophoresis gel (0.8% agarose in buffer pH 8.2 tris-borate-EDTA). Each gel was polarized at 30 volts (3 v / cm) for 3 hours or until the bromophenol dye reached the gel end. The gel was dried and the single and double stranded DNA was quantified using an image-forming phospho (Molecular Dynamics Lymited, Kemsing, England). Standard samples of double-stranded and single-stranded DNA were run on each gel and the percentage of double-stranded DNA in the test sample was calculated. Dose response curves were constructed using various concentrations of each test compound to allow determination of the test dose yielding 50% double-stranded DNA. (b) An in vi tro test which determines the ability of a test compound to inhibit the growth of T18 murine breast cancer cells in cell culture under toxic conditions. The cells were cultured in monolayer in 96-well plates and treated with compounds for two hours under an atmosphere of 90% air and 10% C02. The cells were then cultured for 6 days, at which time the extent of proliferation was assessed using a bromide endpoint of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium (MTT). The test is similar to that described in J. Immunological Methods, 1983, 65, 55-63. The detailed methodology was as follows: Murine T18 breast cells (derived from a spontaneous mammary tumor in the colony of Balb / c mice Zeneca Pharmaceuticals, Mereside, Macclesfield, UK) were harvested from an exponentially growing monolayer culture. Cells were counted, diluted in RPMl 1640 culture medium (Gibco BRL, Life Technologies, Paisley, UK; supplemented with 15% fetal calf serum, glutamine, pyruvate, penicillin and streptomycin), and transferred to 96-well plates at 500 cells per 50μl per well. The cells were incubated at 37 ° C in a C02 incubator (i.e. under an atmosphere of 90% air and 10% C02) for 2 days. An additional fresh culture medium (125 μl) was added to each well. Each test compound was dissolved in DMSO and diluted to the required test concentration in water. A 25 μl portion of each test solution was added to each well. The plates were then returned to the incubator for 2 hours. At the end of this time, the supernatant was removed from the culture medium containing the test compound. The residual cells in each well were washed once with 200 μl of phosphate-buffered saline (PBSA) and fresh culture medium (200 μl) was added. The plates were then returned to the C02 incubator and cultured for 6 days. A 50 μl portion of MTT (5 mg / ml) was added to each well and the plates were incubated for an additional 4 hours, during which time the viable cells converted the MTT into an insoluble intracellular deposit of formazan blue, the extension of the conversion proportional to the number of viable cells in the well. The supernatant of the culture medium containing excess MTT was removed and DMSO (100 μl) was added to solubilize the formazan, the concentration of which was measured by determining the optical density at 540 nM. Various concentrations of each test compound were tested to allow determination of the concentration causing 50% inhibition (IC50) • (c) An in vitro test which determines the ability of a test compound to inhibit growth in a Oxygenated culture medium of spheroidal aggregates (~ 400 microns in diameter) of murine breast cancer cells EMT6. Since the distance of diffusion of oxygen through the tegido is approximately 120-150 microns, such spheroids have a central population of chronically hypoxic cells and an outer layer of well oxygenated cells. The multicellular spheroids were treated with test compounds for 2 hours as well as a well oxygenated suspension culture. The spheroids were subsequently washed from the test compound and the selected spheroids were transferred to a static culture so that the effect of the treatment on the volume of growth could be measured. The detailed methodology was as follows: EMT6 murine breast cells (obtained from PR Twentyman, MRC Oncology and Radiotherapeutics Units, Cambridge, UK) were harvested from individual growth monolayer cultures and approximately 1x10 cells were used to inoculate a rotary culture vessel 500 ml containing Eagles minimum essential medium (200 ml, supplemented with 10% fetal calf serum, glutamate, non-essential amino acids, penicillin and streptomycin). The rotating vessel was gassed with a mixture of 90% air and 10% C02, sealed and incubated at 37 ° C for 4-5 days with stirring (50 rpm for the first 24 hours and subsequently 40 rpm). The cells were added in clusters which grew in tight spheroids with an average diameter of approximately 400 microns. Aliquots (5 ml) of culture medium containing spheroids were transferred to conical flasks (siliconized, 25 ml) which were gassed with a mixture of 90% air and 10% C02 and sealed with a rubber stopper. The flasks were placed in an orbital shaker in a C02 incubator at 37 ° C and shaken gently for at least 15 minutes. Each test compound was dissolved in DMSO and diluted to the required test concentration in water. A 200 μl portion of each test solution was added by syringe to each sealed flask. The resulting mixtures were incubated for 2 hours, each transferred to a centrifuge tube and allowed to settle. The supernatant of the culture medium containing the test compound was decanted and the fresh culture medium (5 ml) was added to each tube. The contents of each tube were then transferred to plastic petri dishes (35 mm diameter) and observed under a dissecting microscope with a grid eyepiece. From each treatment group, 6 spheroids were selected uniformly and approximately 400 microns in diameter and transferred to separate wells in a 24-well plate, to each well of which 1% agar would be added (0.3 ml; to create a base layer that prevents the union of the spheroids) and 1 ml of culture medium. The area of each spheroid was measured using an image analyzer and the 24-well plates were transferred to a C02 incubator at 37 ° C. The spheroids are then re-measured every 2-3 days for up to 21 days, with fresh culture medium (250 μl) added to each well every 3 days. The volumes of the spheroids were calculated from the area measurements (assuming spherical shape) and volume growth curves were constructed from which the effect of the treatment could be assessed. The test dose that caused the balance (without growth or spheroid size regression) for a period of 2-3 weeks was recorded. (d) An in vivo assay in a group of Balb / c mice which determines the ability of a test compound to delay the growth of T18 murine breast tumors. The detailed methody was as follows: T18 murine breast tumor tissue was routinely maintained by an animal-to-animal passage. To prepare a batch of tumors for an experiment, tumor tissue was removed from various Balb / c donor mice and placed in saline. The outer tissue was removed and the regions of tumor that looked healthy were cut into pieces of approximately 1 mm 3 and were implanted subcutaneously by trocar into the left flanks of female Balb / c mice anesthetized. After '2-3 weeks, most implants have grown to approximately 8 mm in diameter. The animals were placed randomly in groups of 6-7, rejecting any with very large tumors, or small ones. Each test compound was dissolved in DMSO and diluted with Cremofor EL followed by saline to give a 1: 1: 3 mixture of DMSO, Cremophor EL and saline. Each test compound was administered by the intraperitoneal route as a single bolus dose (0.1 ml per 10 g of body weight of each animal). The control animals received vehicle alone. All mice were weighed daily and the dimensions (length and width) of each tumor were measured every 2-3 days using vernier calipers. The measurements were used to estimate the volume of each tumor assuming an elongated ellipsoid shape towards the pores (volume = p / 6 x Length x Width2). The growth curves were constructed and the effect of the treatment was assessed using an endpoint of growth retardation. Although the pharmacical properties of the compounds of the formula I vary with a structural change as expected, in general the activity possessed by the compounds of the formula I in the following concentrations or doses in one or more of the above test procedures can be shown. : Test (a): under hypoxic conditions, IC50 in the range, for example 1-20 μM; under oxic conditions, IC50 generally greater than three times the highest; Test (b-): IC50 in the range, for example, 1-30 μM; Test (c): for stasis; ED50 in the range, for example, 1-16 μM; and Test (d): a dose in the range, for example, 30-100 mg / kg intraperitoneally gives a growth retardation of, for example, 4 to 15 days.

Thus, by way of example, the compound of example 2 below has an IC50 of 4.8 μM in test (b), a dose of ED50 stasis of about 6 μM in test (c) and a growth retardation of about 12 days of a single bolus dose of approximately 50 mg / kg intraperitoneally in the test (d). As stated above it is an object of one aspect of the present invention to provide dual prodrug compounds which rapidly release a cytotoxic drug when they encounter a region of low oxygen tension such as in the hypoxic region of a solid tumor. This property can be assessed, for example, using the following test procedure:. Each test compound was dissolved in acetonitrile (approximately 2 mg / ml) and diluted in a phosphate buffer pH 7.4 (if solubility difficulties are encountered, the minimum additional amount of acetonitrile is added) to give a test concentration of approximately 5 x 10 ~ 5M. Each test solution was completely degassed with helium and heated to a thermostatically controlled reaction temperature of 37 ° C. A solution of sodium dithionite (Na2S204) (100 μl of a 100 mg / ml solution in degassed water) was added to one portion (1.4 ml) of each test solution. Aliquots of the reaction solution were taken at regular intervals and analyzed by high performance liquid chromatography (HPLC) for the release of the cytotoxic drug portion and the formation of the appropriate 3,4-dihydrocoumarin. Typical HPLC conditions involve the use of a S50DS1 reverse phase column (250 x 4.6 mm, packed with Spherisorb particles with 5 micron octadecylsilane coating from Jones Chromatography, Hengoed, Glamorgan, UK) using a 75: 25: 0.1 mixture of acetonitrile, water and trifluoroacetic acid as eluent and a flow rate of 1.5 ml per minute. In general, it was found that, under reductive conditions, the compounds of the invention of the formula I rapidly release the cytotoxic portion of the drug with a tvs of less than 2 hours, preferably less than 1 hour, more preferably less than 20 minutes and especially less than 10 minutes. In general, it was found that the reductive conditions caused the release of the cytotoxic portion of the drug so rapidly that the hydroquinone product of the reduction step could not be detected. In such cases, the release rate of the cytotoxic drug was substantially less than 10 minutes. As stated above it is a further object of another aspect of the present invention to provide double prodrug compounds which possess a balanced reduction potential, i.e. a reduction potential that is not so high that a significant portion of the reduction occurs outside of the areas of low oxygen tension and not so low that a significant proportion of the reduction does not occur in an area of low oxygen tension. The reduction potential of the compounds of the present invention can be assessed, for example, using the following test procedure: Each test compound (2 mg) is dissolved in DMF and a cyclic voltammetry is carried out using a Luggin Cell coupled with platinum working and secondary electrodes and a reference electrode of standard saturated calomel (SCE) and tetra-butylammonium bromide (0.1 mole per liter in DMF) as electrolyte (see, for example, GA Mabbott, 'J Chem. Ed. , 1983, 60_, 697 and JG Dick et al., Metrohm Monographs, Electrode Reaction Kinetics determined by Cyclic Sweep Triangular Wave Voltammetry, 1983). In a typical experiment, for example, the potential of the working electrode, controlled relative to the reference electrode, was measured at 100 mV per second of the initial potential at the interruption potential and back to the initial potential. The current produced was plotted as a function of the potential and the potential of the cathodic peak (Epc) was taken as a measure of the reduction potential in the DMF solution. A value of Eaq was determined for each test compound in the aqueous solution by means of a calibration graph based on the measured Epc values of the DMF solutions of a group of standard quinone compounds for which the values of Eaq pH 7 in aqueous solutions (P. Wardman, J., Phys. Chem. Ref. Data, 1989 18, 1637). The calibration graph allowed to determine the following equation: Eaq (V) = 1.23 Epc (V) + 0.62 'In general, the compounds of the invention of the formula I have a calculated value of Eaq in the range, for example, of - 200 to -500 mV, preferably in the range, for example, from -200 to -475 mV, more preferably in the range, for example, from -250 to -450 mV. According to a further aspect of the invention there is provided a pharmaceutical composition which comprises an anti-tumor agent of the formula I, or a pharmaceutically acceptable salt thereof, as defined above in association with a pharmaceutically acceptable diluent or carrier. . The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for local administration as an ointment or cream or for rectal administration as a suppository.

In general, the above compositions can be prepared in a conventional manner using conventional excipients. The anti-tumor agent will normally be administered to a warm-blooded animal at a unit dose within the range of 50-10,000 mg per square meter of body area, ie approximately 1-200 mg / kg, and this normally provides a therapeutically dose effective A unit dosage form such as a tablet or capsule will usually contain, for example, 1-250 mg of the active ingredient. Preferably a daily dose in the range of 1-50 mg / kg is used. However, the daily dose will necessarily vary depending on the host treated, the particular route of administration, and the severity of the disease being treated. Accordingly, the optimal dosage can be determined by the practitioner who is treating any particular patient. According to a further aspect of the present invention there is provided an anti-tumor agent of the formula I as defined above for use in a method of treating the human or animal body by therapy. It has been found that the compounds of the present invention possess anti-poliferative properties such as anti-tumor properties which are believed to arise from the selective hypoxia release of a cytotoxic agent of the double prodrug of the formula I. Accordingly, the compounds of the present invention invention is expected to be useful in the treatment of tumors of sufficient size to possess hypoxic regions in such a way that the reduction of the 1,4-benzoquinonyl portion occurs and the cytotoxic portion is subsequently released rapidly. It will be appreciated by the person skilled in the art that the aforementioned anti-proliferative activity of the compounds of the present invention against spheroidal aggregates of murine breast cancer cells EMT6 demonstrate not only that the compounds of the present invention are hypoxia prodrugs selective of a cytotoxic agent but also the cytotoxic agent, once it is released, can diffuse into the nearby oxic regions of the cell aggregate to continue the destruction of the cancer cells. As a result, sufficient cytotoxic amount can be released to cause stasis of the growth of the spheroidal aggregate of cancer cells. Thus according to this aspect of the invention there is provided the use of an anti-tumor agent of the formula I, or a pharmaceutically acceptable salt thereof, as defined above in the manufacture of a medicament for use in the production of an effect anti-proliferative in a warm-blooded animal such as man. According to an additional feature of this aspect of the invention a method is provided for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to the animal an amount effective of an anti-tumor agent of the formula I, or a pharmaceutically acceptable salt thereof, as defined above. As stated above, the size of the dose required for the therapeutic or prophylactic treatment of a particular proliferative disease will necessarily vary depending on the host treated, the route of administration and the severity of the disease being treated. A unit dose in the range, for example, of 1-200 mg / kg, preferably 1-100 mg / kg, more preferably 1-10 mg / kg is contemplated. The anti-tumor effect of the compounds of the present invention may be applied as a therapy alone or may also involve one or more other substances and / or treatments. Such co-treatment can be achieved by the simultaneous, sequential or separate administration of the individual compounds of the treatment. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each cancer patient such as a combination of surgery, radiotherapy and / or chemotherapy. In particular, it is known that irradiation or treatment with anti-angiogenic agents and / or reducing vascular permeability can increase the amount of hypoxic tissue within a tumor. Therefore the effectiveness of the compounds of the present invention is expected to be improved by co-treatment with radiotherapy and / or with an anti-angiogenic agent. In general such chemotherapy can cover three main categories of therapeutic agent: (i) anti-angiogenic agents including those that are believed to act as inhibition of vascular endothelial growth factor (VEGF) such as the compounds described in International Patent Applications WO 97/22596, WO 97/30035 and WO 97/32856 and antiangiogenic agents that work by different mechanisms, for example linomide, inhibitors of the integrin avß3 function, angiostatin, razoxin and thalidomide; (ii) cytostatic agents such as antiestrogens (e.g. tamoxifen, toremifene, raloxifene, droloxifene and iodoxifene), progestogens (e.g. megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrazole, vorazole and exe tin), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bicalutamide and cyproterone acetate), agonists and antagonists of LHRH (for example goserelin acetate, luprolide and buserelin), testosterone 5a-dihydroreductase inhibitors (for example finasteride), anti-invasion agents (for example inhibitors of metalloproteinase such as marimastat and inhibitors of the plasminogen activator receptor function urokinase) and inhibitors of growth factors (eg, epidermal growth factor inhibitors (EGF), fibroblast growth factor (FGF), platelet-derived growth factor and hepatocyte growth factor such as inhibitors of the EGF receptor of tir osine kinase and serine / threonine kinase inhibitors); and (iii) anti-proliferative drugs, antineoplastic drugs and combinations thereof, as used in medical oncology, such as antimetabolites (for example antifolates such as methotrexate and raltitrexed, fluoropyrimidines such as 5-fluorouracil, purine analogs and adenosine and arabinoside). cytosine); anti-tumor antibiotics (for example bleomycins and anthracyclines such as doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin and mithramycin); platinum derivative (for example cisplatin and carboplatin); alkylating agents (for example mustard nitrogen, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosoureas and thiotepa); antimitotic agents (for example vinca alkaloids such as vincrisitine and taxoids such as taxol and taxotere); topoisomerase inhibitors (for example epipodophyllotoxins such as etoposide and teniposide, amsacrine and topotecan). The invention will now be illustrated in the following non-limiting Examples in which, unless stated otherwise: (i) the evaporations were carried out by rotary evaporation in vacuo and the working procedures were carried out after the elimination of solid waste such as drying agents by filtration; (ii) unless otherwise stated, the operations were carried out at room temperature, that is in the range of 18-25 ° C and under an atmosphere of an inert gas such as argon; (iii) column chromatography (by the instantaneous process) and medium pressure liquid chromatography (MPLC) were performed on silica Merck Kieselgel (Art. 9385) or reverse phase silica Merck Lichroprep RP-18 (Art. 9303) obtained from E. Merck, Darmstadt, Germany; (iv) the returns are given only for illustration and are not necessarily the maximum obtainable; (v) the melting points were determined using a Mettler SP62 automatic melting point apparatus, an oil bath apparatus or a hot plate apparatus Koffler (vi) the structures of the final products of formula I were confirmed by (generally proton) nuclear magnetic resonance (NMR) and mass spectrum techniques; Chemical change values of proton magnetic resonance were measured on the delta scale and the peak multiplicities are shown as follows: s, single; d, double; . t, triple; m, multiple, unless otherwise stated the final products of formula I were dissolved in CD3SOCD3 for determination of NMR values; (vii) the intermediates were generally not completely characterized and the purity was assessed by thin layer chromatography (TLC), infra-red (IR) or NMR analysis; (viii) the following abbreviations are used: DMF N, N-dimethylformamide; DMA N, N-dimethylacetamide; DMSO Dimethisulfoxide; EDTA Ethylenediaminetetraacetic acid. Example 1 A solution of l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.208 g) in methylene chloride (2 ml) was added to a stirred mixture of 3- (5-allyl-2. dimethyl-1,4-benzoquinonyl) -3-methylbutyric acid (0.2 g), 4- [bis (2-chloroethyl) -amino] phenol hydrochloride (J. Chem. Soc. Perkin Trans. I, 1973, 2397-2402; 0.2 g), 4-dimethylaminopyridine (0.186 g) and methylene chloride (8 ml).

The resulting mixture was stirred at room temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9: 1 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. The resulting material was further purified by HPLC using a 92.5: 7.5 mixture of cyclohexane and ethyl acetate as eluent. Thus, 4- [bis (2-chloroethyl) amino] phenyl 3- (5-allyl-2,3-dimethyl-l, -benzoquinonyl) -3-methylbutyrate was obtained as an oil (0.127 g), - NMR spectrum: (CDC13) 1.52 (s, 3H), 1.55 (s, 3H), 1.9 (s, 3H), 1.96 (s, 3H), 3.19 (s, 2H), 3.47 (d, 2H), 3.58 (t, 4H) ), 3.67 (t, 4H), 5.0 (m, 2H), 5.82 (m, 1H), 6.6 (d, 2H), 6.85 (d, 2H); Mass spectrum: (M + Na +) 518, 516, 514. The 3- (5-allyl-2,3-dimethyl-l, -benzoquinonyl) -3-methylbutyric acid used as starting material was obtained as follows: mixture of 6-hydroxy-4,4,7,8-tetramethyl-3,4-dihydrocoumarin (J. Amer. Chem. Soc, 1983, 105, 2752-2760, 5 g), allyl bromide (5.9 ml), Potassium carbonate (9.4 g) and DMF (50 ml) was stirred at room temperature for 2.5 hours. The mixture was partitioned between diethyl ether and water. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. Thus, 6-allyloxy-4,7,7,8-tetramethyl-3, -dihydrocoumarin (6 g) was obtained which was used without further purification; NMR spectrum: (CDCI3) 1.32 (s, 6H), 2.16 (s, 3H), 2.22 (s, 3H), 2.56 (s, 2H), 4.53 (d, 2H), 5.35 (m, 2H), 6.08 (m, 1H), 6.64 (s, 1H). A mixture of the material thus obtained (6 g) and N, N-dimethylaniline (95 ml) was stirred and heated at 200 ° C for 4.5 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 4: 1 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, 5-allyl-6-hydroxy-4,7,7,8-tetramethyl-3,4-dihydrocoumarin (4.4 g), melting point 152-154 ° C, was obtained.; NMR spectrum: (CDCI3) 1-43 (s, 6H), 2.18 (s, 3H), 2.23 (s, 3H), 2.54 (s, 2H), 3.57 (d, 2H), 4.93 (s, 2H) , 5.22 (m, 2H), 6.1 (m, 1H). A solution of a portion (2.2 g) of the material thus obtained in acetonitrile (22 ml) was stirred and heated to reflux. A solution of ferric chloride hexahydrate (10.8 g) in a mixture of acetonitrile (22 ml) and water (22 ml) was added in portions and the mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature and partitioned between diethyl ether and a 5% aqueous sodium bicarbonate solution. The aqueous phase was acidified by the addition of 2N aqueous hydrochloric acid and extracted with diethyl ether. The resulting organic phase was dried (MgSO 4) and evaporated. Thus, 3- (5-allyl-2,3-dimethyl-1,4-benzoquinonyl) -3-methylbutyric acid (0.43 g) was obtained; NMR spectrum: (CDC13) 1.45 (s, 6H), 1.94 (s, 3H), 1.95 (s, 3H), 3.01 (s, 2H), 3.45 (d, 2H), 5.0 (m, 2H), 5.8 (m, 1H). Example 2 • Using a procedure analogous to that described in Example 1, 3- [2- (2-methoxyethyl) -3,5-dimethyl-1,4-benzoquinonyl] -3-methylbutyric acid was reacted with 4-hydrochloride. - [bis (2-chloroethyl) amino] phenol to give 4- [bis (2-chloroethyl) amino] phenyl 3- [2- (2-methoxyethyl) -3,5-dimethyl-1,4-benzoquinonyl] -3 -methylbutyrate as an oil in a 55% yield. NMR spectrum: (CDC13) 1.52 (s, 6H), 1.97 (s, 3H), 2.15 (s, 3H), 2.7 (t, 2H), 3.2 (s, 2H), 3.22 (s, 3H), 3.35 (t, 2H), 3.6 (t, 4H), 3.68 (t, 4H), 6.6 (d, 2H), 6.86 (d, 2H); Mass spectrum: (M + Na +) 536, 534, 532. 3- [2- (2-Methoxyethyl) -3,5-dimethyl-1,4-benzoquinonyl] -3-methylbutyric acid used as starting material obtained as follows: A solution of 6-hydroxy-4,4,5,7-tetramethyl-3,4-dihydrocoumarin (J. Org. Chem., 1989, 54_, 3303, 10.6 g) in acetonitrile (125 ml) was it stirred and heated to reflux. A solution of ferric chloride hexahydrate (25 g) in a mixture of acetonitrile (115 ml) and water (115 ml) was added in portions for 2 hours. The resulting mixture was cooled to room temperature and partitioned between diethyl ether and water. The organic phase was extracted with 5% aqueous sodium bicarbonate solution. The aqueous phase was acidified by the addition of 2N aqueous hydrochloric acid and extracted with diethyl ether. The organic phase was dried (MgSO 4) and evaporated. The residue was purified by column chromatography on silica using a 1: 1: 0.02 mixture of petroleum ether (boiling point 40 to 60 ° C), diethyl ether and acetic acid as eluent. Thus, 3-methyl-3- (3,5-dimethyl-1,4-benzoquinonyl) butyric acid (3.08 g) was obtained; NMR spectrum (CDC13) 1.44 (s, 6H), 1.99 (s, 3H), 2.17 (s, 3H), 3.05 (s, 2H), 6.45 (s, 1H). A mixture of 3-methyl-3- (3,5-dimethyl-1,4-benzoquinonyl) butyric acid (6g), 2-tert-butyl-1,3-diisopropyl-isourea (20 g) and methylene chloride ( 100 ml) was stirred at room temperature for 16 hours. The mixture was evaporated. Diethyl ether was added and the mixture was filtered. The filtrate was evaporated and the residue was purified by column chromatography on silica using a 6: 1 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, tert-butyl 3-methyl-3- (3,5-dimethyl-1,4-benzoquinonyl) butyrate was obtained as an oil (5.97 g); NMR spectrum: (CDCl 3) 1-35 (s, 9H), 1.43 (s, 6H), 1.99 (s, 3H), 2.17 (s, 3H), 2.90 (s, 2H). A mixture of tert-butyl 3-methyl-3- (3,5-dimethyl-1,4-benzoquinonyl) butyrate (1.5 g), 3-methoxypropionic acid (1.07 g) and silver nitrate (0.873 g) was dissolved in a mixture of acetonitrile (20 ml) and water (20 ml). The mixture was stirred and heated to 75 ° C and a solution of sodium persulfate (Na2S208; 2.57 g) in water (20 ml) was added over a period of 30 minutes. The resulting mixture was stirred at 75 ° C for an additional 30 minutes and then cooled to room temperature. The mixture was partitioned between diethyl ether and water. The organic phase was washed with water and with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. The residue was purified by column chromatography on silica using a 9: 1 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, tert-butyl 3- [2- (2-methoxyethyl) -3,5-dimethyl-1,4-benzoquinonyl] -3-methylbutyrate was obtained as an oil (0.279 g); NMR spectrum: (CDC13) 1.37 (s, 9H), 1.41 (s, 6H), 2.0 (s, 3H), 2.13 '(s, 3H), 2.73 (t, 2H), 2.9 (s, 2H), 3.3 (s, 3H), 3.43 (t, 2H). A mixture of the material thus obtained, trifluoroacetic acid (0.6 ml), water (1 drop) and methylene chloride (1.8 ml) was stirred at room temperature for 2.5 hours. The mixture was evaporated to give the required starting material in quantitative yield; NMR spectrum: (CDCI3) 1.43 (s, 6H), 2.0 (s, 3H), 2.15 (s, 3H), 2.72 (s, 2H), 3.1 (s, 2H), 3.32 (s, 3H), 3.42 (t, 2H). Example 3 Using a procedure analogous to that described in Example 1, the acid 3-. { 2- [2- (N, N-dimethylcarbamoyl) ethyl] -3,5-dimethyl-1,4-benzoquinonyl} 3-methylbutyric was reacted with 4- [bis (2-chloroethyl) amino] phenol hydrochloride to give 4- [bis (2-chloroethyl) amino] phenyl3-. { 2- [2- (N, N-dimethylcarbamoyl) -ethyl] -3,5-dimethyl-1,4-benzoquinonyl} -3-methylbutyrate as an oil in a yield of 24%; NMR spectrum: (CDC13) 1.51 (s, 6H), 1.97 (s, 3H), 2.16 (s, 3H), 2.35 (t, 2H), 2.72 (t, 2H), 2.8 (s, 3H), 2.9 (s, 3H), 3.21 (s, -2H), 3.57 (t, 4H), 3.67 (t, 4H), 6.61 (d, 2H), 6.84 (d, 2H); Mass spectrum: (M + Na +) 577, 575, 573. The acid 3-. { 2- [2- (N, N-dimethylcarbamoyl) ethyl] -3,5-dimethyl-1,4-benzoquinonyl} -3-methylbutyric used as a starting material was obtained as follows: A mixture of tert-butyl 3-methyl-3- (3,5-dimethyl-1,4-benzoquinonyl) butyrate (1 g), succinic acid (0.809 g) ) and silver nitrate (0.582 g) was dissolved in a mixture of acetonitrile (13 ml) and water (13 ml). The mixture was stirred and heated to 70 ° C and a solution of sodium persulfate (1.71 g) in water (.13 ml) was added dropwise. The resulting mixture was heated at 70 ° C for an additional 10 minutes and then cooled to room temperature. The mixture was divided between diethyl ether and a saturated aqueous sodium bicarbonate solution. The aqueous phase was acidified to pH 2 with 2N aqueous hydrochloric acid and extracted with diethyl ether. The organic extract was washed with water, dried (MgSO 4) and evaporated. Thus, tert-butyl 3- [2- (2-carboxyethyl) -3,5-dimethyl-l > 4-benzoquinonyl] -3-methylbutyrate as a foam (0.544 g); NMR spectrum: (CDC13) 1.37 (s, 9H), 1.4 (s, 6H), 2.01 (s, 3H), 2.14 (s, 3H), 2.5 (t, 2H), 2.76 (t, 2H), 2.91 (s, 2H). A solution of l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.577 g) in methylene chloride (2 ml) was added to a stirred mixture of tert-butyl 3- [2- (2-carboxyethyl) -3 , 5-dimethyl-1,4-benzoquinonyl] -3-methylbutyrate (0.73 g), a solution of dimethylamine (4 mmol) in chloroform (1.1 ml), and methylene chloride (10 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 3: 2 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, tert-butyl 3- was obtained. { 2- [2- (N, N-dimethylcarbamoyl) ethyl] -3,5-dimethyl-1,4-benzoquinonyl} -3-methylbutyrate as an oil (0.23 g); NMR spectrum: (CDCI3) 1.35 (s, 9H), 1.41 (s, 6H), 2.01 (s, 3H), 2.14 (s, 3H), 2.45 (t, 2H), 2.75 (t, 2H), 2.88 (s, 2H), 2.94 (s, 3H), 2.98 (s, 3H). A mixture of a portion (0.2 g) of the material thus obtained, trifluoroacetic acid (0.45 ml), water (1 drop) and methylene chloride (2 ml) was stirred at room temperature for 4 hours. The mixture was evaporated to give the required starting material in quantitative yield; NMR spectrum: (CDCI3) 1.43 (s, 6H), 1.96 (s, 3H), 2.14 (s, 3H), 2.48 (m, 2H), 2.72 (m, 2H), 3.0 (m, 8H). Example 4 Using a procedure analogous to that described in Example 1, 3- (5-allyl-2,3-dimethoxy-1,4-benzoquinonyl) -3-methylbutyric acid was reacted with 4- [bis (2-chloroethyl) ) amino] phenol to give 4- [bis (2-chloroethyl) amino] phenyl 3- (5-allyl-2,3-dimethoxy-1,4-benzoquinonyl) -3-methylbutyrate as an oil in a yield of 20%; NMR spectrum: (CDC13) 1.53 (s, 6H), 3.21 (s, 2H), 3.47 (s, 2H), 3.6 (s, 4H), 3.68 (t, 4H), 3.89 (s, 3H), 3.9 (s, 3H), 5.02 (m, 2H), 5.82 (m, 1H), 6.63 (d, 2H), 6.85 (d, 2H); Mass spectrum: (M + Na +) 550, 548, 546. 3- (5-Allyl-2,3-dimethoxy-1,4-benzoquinonyl) -3-methylbutyric acid used as starting material was obtained as follows: Sodium hydrosulfite (Na2S204, 26 g) was added as a portion to a stirred solution of 2,3-dimethoxy-1,4-benzoquinone (J. Med. Chem., 1971, L4, 45, 5 g) in a mixture of methanol (50 ml) and water (100 ml). The resulting mixture was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO 4) and evaporated to give 2,3-dimethoxyhydroquinone (2 g); NMR spectrum: (CD3S0CD3) 3.71 (s, 6H), 6.37 (s, 2H), 8.47 (s, 2H). A mixture of 2,3-dimethoxyhydroquinone (3.6 g), methyl 3, 3-dimethylacrylate (3.2 ml) and methanesulfonic acid (36 ml) was stirred and heated at 70 ° C for 2 hours. The mixture was poured onto a mixture of ice and water and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with a 5% aqueous sodium bicarbonate solution, dried (MgSO) and evaporated. The residue was purified by column chromatography on silica using a 3: 2 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, 6-hydroxy-7,8-dimethoxy-4,4-dimethyl-3,4-dihydrocoumarin (2.3 g) was obtained; NMR spectrum: (CDCl 3) 1.3 (s, 6H), 2.59 (s, 2H), 3.95 (s, 6H), 5.58 (s, 1H), 6.64 (s, 1H). A mixture of 6-hydroxy-7,8-dimethoxy-4,4-dimethyl-3,4-dihydrocoumarin (1.6 g), allyl bromide (1.65 ml), potassium carbonate (2.63 g) and DMF (15 ml) it was stirred and heated at 70 ° C for 1 hour. The mixture was partitioned between diethyl ether and water. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. The residue was purified by column chromatography on silica using a 3: 2 mixture of petroleum ether (boiling point 40 to 60 ° C) and diethyl ether as eluent. Thus, 6-allyloxy-7,8-dimethoxy-4,4-dimethyl-3,4-dihydrocoumarin (1.51 g) was obtained; NMR spectrum: (CDC13) 1.31 (s, 6H), 2.59 (s, 2H), 3.9 (s, 3H), 3.95 (s, 3H), 4.57 (d, 2H), 5.37 (m, 2H), 6.08 (m, 1H), 6.58 (s, 1H). A mixture of the material thus obtained and N, N-dimethylaniline (20 ml) was stirred and heated at 200 ° C for 4 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 1: 1 mixture of petroleum ether (boiling point 40 to 60 ° C) and diethyl ether as eluent. Thus, 5-allyl-6-hydroxy-7,8-dimethoxy-4,4-dimethyl-3,4-dihydrocoumarin (1.4 g) was obtained; NMR spectrum: (CDCI3) 1.44 (s, 6H), 2.56 (s, 2H), 3.58 (m, 2H), 3.91 (s, 3H), 3.97 (s, 3H), 5.02 (m, 2H), 5.73 (s, 1H), 6.02 (m, 1H). A mixture of a portion (0.65 g) of the material thus obtained, 2N aqueous sodium hydroxide solution (1 ml) and water (25 ml) was stirred at room temperature in air for 1.5 hours. The mixture was extracted with diethyl ether. The organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. The residue was purified by column chromatography on silica using a 50: 50: 0.1 mixture of petroleum ether (boiling point 40 to 60 ° C), diethyl ether and acetic acid as eluent. Thus, the required starting material (0.112 g) was obtained; NMR spectrum: (CDC13) 1 46 (s, 6H), 3.03 (s, 2H), 3.44 (s, 2H), 3.9 (s, 3H), 3.95 (s, 3H), 5.02 (m, 2H), 5.83 (m, 1H).

Example 5 • A mixture of 3- (2-methylamino-3,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyric acid (unpurified, 3.73 g), 4- [bis (2-chloroethyl) amino hydrochloride ] phenol (3.96 g), 2- (1-benzotriazolyl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (V) (5.55 g), triethylamine (4.22 g) and acetonitrile (115 ml) was stirred at room temperature for 22 hours. The mixture was evaporated and the residue was purified by chromatography on silica colony using a 4: 1 mixture of hexane and ethyl acetate as eluent. Thus, 4- [bis (2-chloroethyl) amino] phenyl 3- (2-methylamino-3,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyrate was obtained as a gum (1.95 g); NMR spectrum: (CDC13) 1.5 (s, 6H), 2.0 (s, 3H), 2.2 (s, 3H), 3.05 (d, 3H), 3.15 (s, 2H), 3.55-3.7 (m, 8H) , 5.15 (broad s, 1H), 6.6 (d, 2H), 6.9 (d, 2H); Mass spectrum: (M + H +) 484, 482, 480. The 3- (2-methylamino-3,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyric acid used as starting material was obtained as follows: An ethanolic solution of methylamine (8.03 M, 40 ml) was added to a stirred solution of 3- (2-bromo-3,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyric acid (J. Org. Chem. , 1989, 54, 3303-3310; 10.03 g) in methanol (400 ml) and the resulting mixture was stirred at room temperature in the dark for 18 hours. The mixture was poured into water (3 L) and acidified to pH 2 by the addition of 5N aqueous hydrochloric acid. The mixture was extracted with diethyl ether. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. Thus, an unpurified sample of the required starting material was obtained as a gum (6.14 g); Mass Spectrum: (MH ~) 264. EXAMPLE 6 A mixture of l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.271 g) in methylene chloride (3 ml) was added to a stirred mixture of 3- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.271 g) in methylene chloride (3 ml). [3,5-dimethyl-2- (2-morpholinoethylamino) -1,4-benzoquinonyl] -3-methylbutyric acid (unpurified, 0.413 g), 4- [bis (2-chloroethyl) amino] phenol hydrochloride (0.322 g) ), 4-dimethylamino-pyridine (0.327 g) and methylene chloride (12 ml). The resulting mixture was stirred at room temperature for 4 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using progressively polar mixtures of hexane and ethyl acetate as eluent. Thus, 4- [bis (2-chloroethyl) amino] phenyl 3- [3,5-dimethyl- (2-morpholinoethylamino) -1, -benzoquinonyl] -3-methylbutyrate was obtained as a gum (0.061 g); NMR spectrum: (CDC13) 1.5 (s, 6H), 1.95 (s, 3H), 2.2 (s, 3H), 2.4 (t, 4H), 2.55 (t, 2H), 3.15, 2H), 3.45 (m , 2H), 3.7 (m, 12H), 5.65 (t, 1H), 6.6 (d, 2H), 6.85 (d, 2H); Mass Spectrum: (M + H +) 583, 581, 579.

The 3- [3,5-dimethyl-2- (2-morpholinoethylamino) -1,4-benzoquinonyl] -3-methylbutyric acid used as starting material was obtained as follows: A mixture of 3- (2-bromo- 3, 5-dimethyl-1,4-benzoquinonyl) -3-methylbutyric acid (1.14 g), 2-morpholinoethylamine (2.35 g) and DMA (10 ml) was stirred for 20 hours in the dark. The mixture was evaporated and the residue was partitioned between ethyl acetate and an aqueous sodium chloride solution. The aqueous solution was acidified to pH 2 by the addition of dilute aqueous hydrochloric acid and the resulting solution was passed down through an HP20 resin column (a crosslinked styrene-divinylbenzene resin from Biotage UK Ltd., Hertford, UK) using initially water and then acetonitrile as eluent. Thus, an unpurified sample of the required starting material was obtained as a gum (0.436 g); Mass Spectrum: (MH ") 363. EXAMPLE 7 Using a procedure analogous to that described in Example 5, 3- [2- (2-acetamidoethylamino) -3-methoxy-5-methyl-1,4-benzoquinonyl] 3-methylbutyric was reacted with 4- [bis (2-chloroethyl) amino] phenol to give a product which was further purified by reverse phase HPLC using a 39:11 mixture of methanol and water as eluent. 'had 4- [bis (2-chloroethyl) amino] phenyl 3- [2- (2-acetamidoethylamino) -3-methoxy-5-methyl-1,4-benzoquinonyl] -3-methylbutyrate as a gum in a yield of 13%; NMR spectrum: (CDC13) 1.55 (s, 6H), 1.85 (s, 3H), 2.2 (s, 3H), 3.2 (s, 2H), 3.4 (t, 2H), 3.5-3.8 (m, 13H) , 5.95 (broad s, 1H), 6.6 (d, 2H), 6.85 (d, 2H); Mass Spectrum (M + H +) 571, 569, 567. 3- [2- (2-Acetamidoethylamino) -3-methoxy-5-methyl-1,4-benzoquinonyl] -3-methylbutyric acid used as starting material was obtained as follows: a mixture of 3- (2,3-dimethoxy-5-methyl-1,4-benzoquinonyl) -3-methylbutyric acid (J. Org. Chem., 1989, 5_4, 3303-3310; 1.2 g ), N-acetylethylenediamine (1.43 g) and methanol (20 ml) was stirred at room temperature for 20 days in the dark. The mixture was evaporated and the residue was dissolved in dilute aqueous hydrochloric acid and purified by chromatography on an HP20 resin column using initially water and then a 4: 1 mixture of water and acetonitrile as eluent. Thus an unpurified sample was obtained from the required starting material as a rubber (1.19 g); Mass Spectrum: (MH ") 351. Example 8 Using an analogous procedure to that described in Example 5, 3- (3-allyl-2,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyric acid was made react with 4- [bis (2-chloroethyl) aminogoldhenol to give 4- [bis (2-chloroethyl) amino] phenyl 3- (3-allyl-2,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyrate as an oil 'in a yield of 26%; NMR spectrum: (CDC13) 1.52 (s, 6H), 1.96 (s, 3H), 2.17 (s, 3H), 3.15 (d, 2H), 3.2 (s, 2H ), 3.56-3.72 (m, 8H), 4.99 (m, 2H), 5.72 (m, 1H), 6.58-6.88 (m, 4H); Mass Spectrum: (M + H +) 496, 494, 492. The 3- (3-Allyl-2,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyric acid used as a starting material was obtained as follows: Allyl bromide (8.45 g) was added to a mixture of hydroxy-4, 4, 5, 8-tetramethyl-3,4-dihydrocoumarin (J. Org. Chem., 1989, 5_4, 3303-3310; 5 g), potassium carbonate (9.4 g) and DMF. (50 ml. The resulting mixture was stirred at room temperature for 2 hours. a was divided between diethyl ether and water. The organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. Thus, 6-allyloxy-4,4,5,8,8-tetramethyl-3,4-dihydrocoumarin (5.2 g) was obtained; NMR spectrum: (CDCI3) 1.48 (s, 6H), 2.28 (s, 3H), 2.34 (s, 3H), 2.57 (s, 2H), 4.5 (m, 2H), 5.36 (m, 2H), 6.07 (m, 1H), 6.63 (s, 1H). A mixture of a portion (3 g) of the material thus obtained and N, N-diethylaniline (40 ml) was stirred and heated at 180 ° C for 18 hours. The mixture was cooled to room temperature, acidified by the addition of 5N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. Thus, 7-allyl-6-hydroxy-4,4,5,8-tetramethyl-3,4-dihydrocoumarin (2.9 g) was obtained; NMR spectrum: (CDC13) 1.48 (s, 6H), 2.24 (s, 3H), 2.37 (s, 3H), 2.58 (s, 2H), 3.44 (d, 2H), 4.84 (s broad, 1H), 5.12 (m, 2H), 5.98 (m, 1H). A mixture of a portion (2.6 g) of the thus obtained material, aqueous sodium hydroxide solution IN (17.5 ml) and acetonitrile (50 ml) was stirred at room temperature in air for 4 days. The mixture was acidified by the addition of 5N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and evaporated. Thus, 3- (3-allyl-2,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyric acid was obtained as an oil (2.7 g); NMR spectrum: (CDCI3) 1-44 (s, 6H), 1.95 (s, 3H), 2.14 (s, 3H), 3.0 (s, 2H), 3.19 (d, 2H), 5.0 (m, 2H) , 5.77 (m, 1H). Example 9 Using an analogous procedure to that described in Example 5, 5-, 2- (2,5-dimethyl-3-propyl-1,4-benzoquinonyl) -3-methylbutyric acid was reacted with 4- [bis (2 -chloroethyl) amino] phenol to give 4- [bis (2-chloroethyl) amino] phenyl 3- (2,5-dimethyl-3-propyl, 4-benzoquin-nyl-3-methylbutyrate in a yield of 32%; NMR spectrum: (CDC13) 0.91 (t, 3H), 1.39 (m, 2H), 1.52 (s, 6H), 1.95 (s, 3H), 2.18 (s, 3H), 2.35 (t, 2H), 3.2 (s, 2H), 3.55-3.73 (m, 8H), 6.6 (d, 2H), 6.84 (d, 2H), Mass Spectrum: (M + H +) 498, 496, 494. The acid 3- ( 2,5-dimethyl-3-propyl-1,4-benzoquinonyl) -3-methylbutyric used as starting material was obtained as follows: A mixture of 7-allyl-6-hydroxy-4,4,5,8-tetramethyl 3,4-dihydrocoumarin (3 g), 10% 10% palladium on carbon catalyst (0.5 g) and methanol (75 ml) was stirred under a hydrogen atmosphere for one hour, the mixture was filtered and the filtrate was filtered. evaporated, thus obtaining 6-hydroxy-4, 4, 5, 8-tetr amethyl-7-propyl-3,4-dihydrocoumarin (1.06 g); NMR spectrum: (CDC13) 1.03 (t, 3H), 1.46 (s, 6H), 1.57 (s, 2H), 2.23 (s, 3H), 2.36 (s, 3H), 2.6 (m, 4H), 4.58 (s, 1H). A mixture of the material thus obtained, aqueous sodium hydroxide solution IN (4.5 ml) and acetonitrile (15 ml) was stirred at room temperature in air for 4 days. The mixture was acidified by the addition of 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. Thus, 3-2,5-dimethyl-3-propyl-1,4-benzoquinonyl) -3-methylbutyric acid was obtained as an oil (1.12 g); NMR spectrum: (CDC13) 0.93 (t, 3H), 1.38-1.5 (m, 8H), 1.95 (s, 3H), 2.14 (s, 3H), 2.39 (m, 2H), 3.0 (s, 2H) .

Example 10 N, N'-dicyclohexylcarbodiimide (0.33 g) was added to a stirred mixture of 3- (2,3-dimethoxy-5-methyl-1,4-benzoquinonyl) -3-methylbutyric acid (0.45 g), N- hydroxybenzotriazole (0.01 g) and methylene chloride (20 ml) which had been cooled in a bath with ice and the resulting mixture was stirred for 5 minutes. A solution of 4- [bis (2-chloroethyl) amino] phenol hydrochloride (0.43 g) and triethylamine (0.45 ml) in methylene chloride (5 ml) was added and the reaction mixture was stirred at room temperature for 1.5 hours . The mixture was evaporated and the residue was purified by column chromatography on silica using progressively polar mixtures of hexane and ethyl acetate as eluent. The material thus obtained was further purified by reverse phase column chromatography on silica using decreasingly polar mixtures of water and methanol as eluent. Thus, 4- [bis (2-chloroethyl) amino] phenyl 3- (2,3-dimethoxy-5-methyl-1,4-benzoquinonyl) -3-methylbutyrate was obtained as an oil (0.19 g); NMR spectrum: (CDC13) 1.52 (s, 6H), 2.18 (s, 3H), 3.23 (s, 2H), 3.57-3.76 (m, 8H), 3.89 (s, 3H), 3.95 (s, 3H) , 6.62 (d, 2H), 6.87 (d, 2H); Mass spectrum: (M + H +) 498. EXAMPLE 11 Using an analogous procedure to that described in Example 5, 3- (2,3,5-trimethyl-1,4-benzoquinonyl) -3-methylbutyric acid was reacted with 4- [bis (2-chloroethyl) amino] phenol to give 4- [bis (2-chloroethyl) amino] phenyl 3- (2,3,5-trimethyl-1,4-benzoquinonyl) -3-methylbutyrate as a solid in a yield of 40%; NMR spectrum: (CDC13) 1.52 (s, 6H), 1.9 (s, 3H), 1.92 (s, 3H), 2.18 (s, 3H), 3.2 (s, 2H), 3.55-3.72 (m, 8H) , 6.6-6.9 (m, 4H); Mass Spectrum: (M + H +) 466. 3- (2,3,5-Trimethyl-1,4-benzoquinonyl) -3-methylbutyric acid used as a starting material was obtained as follows: Methyl 3, 3-dimethylacrylate (6 g) to a stirred mixture of 2, 3, 5-trimethylhydroquinone (7.6 g) and methanesulfonic acid (40 ml) which had been heated to 75 ° C and the mixture was stirred at 75 ° C for 1 hour. hour. The mixture was poured onto a mixture of ice and water and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with a 5% aqueous sodium bicarbonate solution, dried (MgSO 4) and evaporated. Thus, 6-hydroxy-4, 4, 5, 7, 8-pentamethyl-3,4-dihydrocoumarin (10.7 g) was obtained; NMR spectrum: (CDC13) 1.48 (s, 6H), 2.18 (s, 3H), 2.22 (s, 3H), 2.37 (s, 3H), 2.55 (s, 2H), 4.6 (s, 1H). A mixture of a portion (5.85 g) of the material so obtained, aqueous sodium hydroxide solution 0.5N (50 ml) and acetonitrile (100 ml) was stirred at room temperature in air for 18 hours. The mixture was acidified by the addition of 5N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. Thus the required starting material (4.1 g) was obtained which was used without further purification; NMR spectrum: (CDC13) 1.46 (s, 6H), 1.93 (s, 3H), 1.96 (s, 3H), 2.15 (s, 3H), 3.02 (s, 2H). Example 12 Using a procedure analogous to that described in Example 5, 3- (2,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyric acid was reacted with 4- [bis (2-chloroethyl) amino] phenol to give 4- [bis (2-chloroethyl) amino] phenyl 3- (2,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyrate as a solid in a yield of 9%; NMR spectrum: (CDCI3) 1-52 (s, 6H), 1.98 (m, 3H), 2.16 (s, 3H), 3.2 (s, 2H), 3.55-3.73 (m, 8H), 6.42 (m, 1H), 6.6-6.9 (m, 4H); Mass Spectrum: (M + H +) 452. The 3- (2,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyric acid used as starting material was obtained as follows: A mixture of 6-hydroxy-4 , 4, 5, 8-tetramethyl-3,4-dihydrocoumarin (J. Org. Chem., 1989, 5_4, 3303-3310; 2.2 g), aqueous sodium hydroxide solution IN (10 ml) and acetonitrile (20 ml) ) was stirred at room temperature in air for 2 days. The mixture was acidified by the addition of 5N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. Thus the required starting material (1.8 g) was obtained which was used without further purification; NMR spectrum: (CDC13) 1.44 (s, 6H), 2.12 (s, 3H), 2.4 (s, 3H), 3.02 (d, 2H), .7.25 (s, 1H). Example 13 Using an analogous procedure to that described in Example 1, 3- (5-isopropylamino-2-methyl-1,4-benzoquinon-3-yl) -3-methylbutyric acid was reacted with 4- [bis (2 -chloroethyl) amino] phenol and the product was purified by reverse phase column chromatography on silica using decreasingly polar mixtures of water and methanol as eluent. Thus, 4- [bis (2-chloroethyl) amino] phenyl 3- (5-isopropylamino-2-methyl-1,4-benzoquinon-3-yl) -3-methylbutyrate was obtained as a gum in a yield of 6%; NMR spectrum: (CDC13) 1.2 (d, 6H), 1.55 (s, 6H), 2.22 (s, 3H), 3.15 (s, 2H), 3.45 (m, 1H), 3.5-3.75 (m, 8H) , 5.35 (d, 1H), 5.4 (s, 1H), 6.6 (d, 2H), 6.85 (d, 2H); Mass spectrum: (M + H +) 495. The 3- (5-isopropylamino-2-methyl-1,4-benzoquinon-3-yl) -3-methylbutyric acid used as starting material was obtained as follows: A mixture of 6-hydroxy-4,4,5,8-tetramethyl-3,4-dihydrocoumarin (17.5 g), N-bromosuccinimide (15.2 g) and chloroform (2.5 L) was stirred at room temperature for 2.5 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 5: 1 mixture of hexane and ethyl acetate as eluent. Thus, 7-bromo-6-hydroxy-4, 4, 5, 8-tetramethyl-3,4-dihydrocoumarin (6 g) was obtained; NMR spectrum: (CDC13) 1.45 (s, 6H), 2.39 (s, 3H), 2.45 (s, 3H), 2.6 (s, 2H), 5.6 (s, 1H). A mixture of the material thus obtained, pyridinium chlorochromate (34 g) and DMA (150 ml) was stirred at room temperature for 5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO 4) and evaporated. Thus, 3- (3-bromo-2,5-dimethyl-1,4-benzoquinonyl) -3-methylbutyric acid was obtained as an oil (5.3 g); NMR spectrum: (CDC13) 1.4 (s, 6H), 2.15 (s, 3H), 2.2 (s, 3H), 3.0 (s, 2H). A mixture of a portion (3.9 g) of the thus obtained material, isopropylamine (15 ml) and methanol (150 ml) was stirred at room temperature for 2 days. The mixture was evaporated and the residue was partitioned between diethyl ether and a saturated aqueous sodium chloride solution. The organic phase was dried (MgSO) and evaporated. Thus the required starting material was obtained as a gum (2.25 g); Mass Spectrum: (M + HT + X 280. Example 14 4- [Bis (2-chloroethyl) amino] phenol hydrochloride (0.537 g) was added to a stirred mixture of 3- [3-methoxy-5-methyl-2- (2-morpholinoethylamino) -1, 4 -benzoquinonyl] -3-methylbutyric acid (0.7 g), l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.42 g), N-hydroxybenzotriazole (0.295 g), N-methylmorpholine (1.09 ml) and methylene chloride ( 70 ml) which had been cooled in a bath with ice. The resulting mixture was stirred at room temperature for 20 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using progressively polar mixtures of hexane and ethyl acetate as eluent. Thus 4- [bis (2-chloroethyl) amino] phenyl 3- [3-dimethoxy-5-methyl-2- (2-morpholinoethylamino) -1,4-benzoquinonyl] -3-methylbutyrate was obtained as a gum (0.246 g ); NMR spectrum: (CDC13) 1.5 (s, 6H), 2.1 (s, 3H), 2.55 (t, 2H), 3.18 (s, 2H), 3.5-3.7 (m, 4H), 3.75 (s, 3H) , 5.65 (t, 1H), 6.6 '(d, 2H), 6.85 (d, 2H); Mass Spectrum: (M + H +) 596. 3- [3-Methoxy-5-methyl-2- (2-morpholinoethylamino) -1,4-benzoquinonyl] -3-methylbutyric acid used as starting material was obtained as follow: A mixture of 3- (2,3-dimethoxy-5-methyl-1,4-benzoquinonyl) -3-methylbutyric acid (0.524 g), 2-morpholinoethylamine (1.21 g) and methanol (25 ml) was stirred at room temperature in the dark for 10 hours. The mixture was evaporated and the residue was dissolved in dilute aqueous hydrochloric acid (10 ml). The solution was applied to an HP20 resin column and diluted initially with water and then with a 4: 1 mixture of water and acetonitrile. Thus, an unpurified sample of the required starting material was obtained as a gum (0.462 g); Mass Spectrum: (MH ") 379. EXAMPLE 15 Using a procedure analogous to that described in Example 5, 3- [2- (2-tert-butoxycarbonylethylamino) -3-methoxy-5-methyl-1, 4- benzoquinonyl] -3-methylbutyric was reacted with 4- [bis (2-chloroethyl) amino] phenol The mixture was evaporated and the residue was purified by column chromatography on silica using progressively polar mixtures of hexane and ethyl acetate as eluent The product thus obtained was further purified by reverse phase silica column chromatography using decreasingly polar mixtures of water and methanol as eluent, thus obtaining 4- [bis (2-chloroethyl) amino] phenyl 3- [2- (2 -ter-butoxycarbonylethylamino) -3-methoxy-5-methyl-1,4-benzoquinonyl] -3-methylbutyrate as a gum in a yield of 1.5%; NMR spectrum: (CDC13) 1.45 (s, 9H), 1.5 (s, 6H), 2.2 (s, 3H), 2.45 (s, 3H), 3.15 (s, 2H), 3.6 (m, 4H), 3.7 (m, 6H), 3.75 (2, 3H), 5.4 (t, 1H), 6.6 (d, 2H), 6.85 (d, 2H); Mass Spectrum: (M + H +) 613. 3- [2- (2-tert-Butoxycarbonylethylamino) -3-methoxy-5-methyl-1,4-benzoquinonyl] -3-methylbutyric acid used as starting material obtained as follows: A mixture of 3- (2, 3-dimethoxy-5-methyl-1,4-benzoquinonyl) -3-methylbutyric acid (1.23 g), 2- (tert-butoxycarbonyl) ethylamine hydrochloride (2.38 g) , triethylamine (1.76 g) and methanol (25 ml) was stirred at room temperature in the dark for 20 days. The mixture was evaporated and the residue was partitioned between diethyl ether and dilute aqueous hydrochloric acid solution. The organic phase was dried (MgSO 4) and evaporated. Thus the required starting material was obtained as a gum (1.26 g); Mass spectrum: (M + H +) 396. Example 16 Using a procedure analogous to that described in Example 1, the acid 3- (2-pyrrolidin-1-yl-1,4-benzoquinone-6-yl) -3- methylbutyric was reacted with 4- [bis (2-chloroethyl) amino] phenol and the product was purified by column chromatography on silica using a 1: 1 mixture of petroleum ether (boiling point 40 to 60 ° C) and acetate of ethyl as eluent. Thus, 4- [bis (2-chloroethyl) amino] phenyl 3- (2-pyrrolidin-1-yl-1,4-benzoquinonyl) -3-methylbutyrate was obtained in a yield of 60%; NMR spectrum: (CDC13) 1.42 (s, 6H), 1.9 (m, 4H), 3.04 (s, 2H), 3.0-3.8 (broad m, 4H), 3.57 (t, 4H), 3.68 (t, 4H) ), 5.4 (s, 1H), 6.48 (s, 1H), 6.6 (d, 2H), 6.81 (d, 2H); Mass spectrum: (M + H +) 493, 495 & 497. The 3- (2-pyrrolidin-1-yl-1,4-benzoquinon-6-yl) -3-methylbutyric acid used as starting material was obtained as follows: A solution of sodium periodate (1 g) in Water (1 ml) was added to a stirred solution of 3- (1,4-benzoquinonyl) -3-methylbutyric acid (1 g) in chloroform (30 ml). Pyrrolidine (0.8 ml) was added dropwise and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was dried (MgSO4) and evaporated and the residue was purified by reverse phase HPLC using decreasingly polar mixtures of water, methanol and acetic acid as eluent. Thus the required starting material was obtained (0.52 g); NMR spectrum: (CDCI3) 1-33 (s, 6H), 1.95 (m, 4H), 2.86 (s, 2H), 3 * .1-3.9 (s broad, 4H), 5.42 (d, 1H), 6.45 (d, 1H). Example 17 Using an analogous procedure to that described in Example 10 except that the reaction mixture was heated to reflux for 3 hours instead of stirring at room temperature for 1.5 hours, 3-methyl-3- (3,5-dimethyl) acid -1,4-benzoquinonyl) butyric was reacted with 4- [bis (2-chloroethyl) amino] phenol and the product was purified by column chromatography on silica using a 9: 1 mixture of hexane and ethyl acetate as eluent. Thus, 4- [bis (2-chloroethyl) amino] phenyl-3-methyl-3- (3,5-dimethyl-l, -benzoquinonyl) butyrate was obtained in a yield of 8%; NMR spectrum: (CDC13) 1.5 (s, 6H), 1.95 (s, 3H), 2.2 (s, 3H), 3.24 '(s, 2H), 3.54-3.75 (m, 8H), 6.46 (m, 1H ), 6.62 (d, 2H), 6.87 (m, 2H); Mass spectrum: (M + H +) 452. EXAMPLE 18 Using an analogous procedure to that described in Example 1, 3- (5-methyl-3-propyl-1,4-benzoquinon-2-yl) -3- acid methylbutyric was reacted with 4- [bis (2-chloroethyl) amino] phenol and the product was purified by column chromatography on silica using a 4: 1 mixture of petroleum ether (boiling point 40 to 60 ° C) and acetate of ethyl as eluent. Thus, 4- [bis (2-chloroethyl) amino] phenyl 3- (5-methyl-3-propyl-1,4-benzoquinon-2-yl) -3-methylbutyrate was obtained in a yield of 53%; NMR spectrum: (CDCl 3) 1.0 (t, 3H), 1.44 (m, 2H), 1.54 (s, 6H), 1.94 (s, 3H), 2.61 (m, 2H), 3.23 (s, 2H), 3.59 (t, 4H) ), 3.68 (t, 4H), 6.46 (s, 1H), 6.61 (d, 2H), 6.86 (d, 2H); Mass spectrum: (M + H +) 502, 504 &506. The acid 3- (5-Methyl-3-propyl-1, -benzoquinon-2-yl) -3-methylbutyric used as a starting material was obtained as follows: A mixture of 6-hydroxy-4,4,7-trimethyl-3, 4 -dihydrocoumarin (J. Amer. Chem. Soc. 1983, 105. 2752-2760; 10 g), allyl bromide (12.6 ml), potassium carbonate (20 g) and DMF (100 ml) was stirred at room temperature for 2 hours The mixture was partitioned between diethyl ether and water The organic phase was washed with a saturated aqueous chloride solution, dried (MgSO¿) and evaporated to give 6-allyloxy-4, 7-7. trimethyl 3, 4-dihydrocoumarin (12 g); NMR spectrum: (CDC13) 1.32 (s, 6H) , 2.22 (s, 3H), 2.58 (s, 2H) 4.53 (m, 2H), 5.35 (m, 2H), 6.05 (m, 2H), 6.71 (s, 1H), 6.85 (s, 1H). A mixture of a portion (6 g) of the material thus obtained and N, N-dimethylaniline (96 ml) was stirred and heated at 200 ° C for 5 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 4: 1 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, 5-allyl-6-hydroxy-4,4,7-trimethyl-3,4-dihydrocoumarin (3.7 g) was obtained; NMR spectrum: (CDCI3) 1.42 (s, 6H), 2.22 (s, 3H), 2.56 (s, 2H), 3.58 (m, 2H), 4.87 (s, 1H), 5.2 (m, 2H), 6.08 (m, 1H), 6.8 (s, 1H). A mixture of a portion (1 g) of the material thus obtained, 10% palladium on carbon catalyst (0.15 g) and ethanol (60 ml) was stirred under 3 atmospheres of hydrogen pressure for 3 * 0 minutes. The mixture was filtered and the filtrate was evaporated to give 6-hydroxy-5-propyl-4, 4, 7-trimethyl-3,4-dihydrocoumarin (1 g); NMR spectrum: (CDC13) 1.06 (t, 3H), 1.46 (s, 6H), 1.66 (m, 2H), 2.21 (s, 3H), 2.56 (s, 2H), 2.72 (m, 2H), 4.57 (s, 1H), 6.72 (s, 1H). A solution of the material thus obtained in acetonitrile (12 ml) was stirred and heated to reflux. A solution of ferric chloride hexahydrate (2.18 g) in a mixture of acetonitrile (10 ml) and water (10 ml) was added in portions for 2 hours. The mixture was cooled to room temperature and partitioned between diethyl ether and a 5% aqueous sodium bicarbonate solution. The aqueous phase was acidified with the addition of 2N aqueous hydrochloric acid and extracted with diethyl ether. The resulting organic phase was dried (MgSO 4) and evaporated. Thus, 3- (5-methyl-3-propyl-1,4-benzoquinon-2-yl) -3-methylbutyric acid was obtained as an oil (0.335 g); NMR spectrum: (CDC13) 0.99 (t, 3H), 1.42 (m, 2H), 1.46 (s, 6H), '1.97 (s, 3H), 2.6 (m, 2H), 3.03 (s, 2H), 6. 45 (s, 1H). Example 19 Using a procedure analogous to that described in Example 1, 3- [3- (2-ethoxycarbonylethyl) -5-methyl-1,4-benzoquinon-2-yl] -3-methylbutyric acid was reacted with 4- [bis (2-chloroethyl) amino] phenol and the product was purified by column chromatography on silica using a 4: 1 mixture of petroleum ether (40 to 60 ° C boiling point) and ethyl acetate as eluent. Thus, 4- [bis (2-chloroethyl) amino] phenyl 3- [3- (2-ethoxycarbonylethyl) -5-methyl-1,4-benzoquinon-2-yl] -3-methylbutyrate was obtained in a yield of 60%; NMR spectrum: (CDC13) 1.26 (t, 3H), 1.54 (s, 3H), 1.55 (s, 3H), 1.94 (s, 3H), 2-.46 (m, 2H), 2.96 (m, 2H) ), 3.25 (s, 2H), 3.59 (t, 4H), 3.68 (t, 4H), 4.15 (m, 2H), 6.48 (s, 1H), 6.61 (d, 2H), 6.86 (d, 2H); Mass spectrum: (M + Na +) 560 & 562. 3- [3- (2-Ethoxycarbonylethyl) -5-methyl-1, -benzoquinon-2-yl] -3-methylbutyric acid used as a starting material was obtained as follows: A mixture of 6-hydroxy- 4, 4, 7-trimethyl-3,4-dihydrocoumarin (J. Amer. Chem. Soc, 1983, 105, 2752-2760, 6.7 g), hexamethylenetetramine (4.56 g) and trifluoroacetic acid (70 ml) was stirred and dried. heated at 60 ° C for 16 hours. Water (50 ml) was added and the mixture was stirred at room temperature for 3 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 5: 1 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, 5-formyl-6-hydroxy-4,4,7-trimethyl-3,4-dihydrocoumarin (6 g, 80%) was obtained; NMR spectrum: (CDC13) 1.71 (s, 6H), 2.38 '(s, 3H), 2.74 (s, 2H), 7.24 (s, 1H), 10.63 (s, 1H). A mixture of a portion (5 g) of the thus obtained material, benzyl bromide (3 ml), potassium carbonate (3.25 g) and DMF (100 ml) was stirred and heated at 80 ° C for 1 hour. The mixture was poured into water (200 ml) and extracted with diethyl ether. The organic extract was washed with a saturated aqueous solution of sodium chloride, dried (MgSO 4) and evaporated to give 6-benzyloxy-5-formyl-4,7,7-trimethyl-3,4-hydrocoumarin (6.9 g); NMR spectrum: (CDC13) 1.38 (s, 6H); 2.32 (s, 3H); 2.55 (s, 2H); 4.83 (s, 2H); 7.05 (s, 1H); 7.39 (m, 5H); 10.53 (s, 1H). A mixture of 6-benzyloxy-5-formyl-4,7,7-trimethyl-3,4-hydrocoumarin (7.4 g), (ethoxycarbonylmethylene) triphenyl-phosphorane (8 g) and toluene (100 ml) was stirred and heated to a reflux for 16 hours. The resulting mixture was cooled to room temperature and poured into a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the extract was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and? It vanished. The residue was purified by column chromatography on silica using a 3: 2 mixture of petroleum ether (boiling point 40 to 60 ° C) and diethyl ether as eluent. Thus ethyl 3- (6-benzyloxy-4,4,7-trimethyl-3,4-dihydrocoumarin-5-yl) acrylate was obtained as a white solid (7.9 g); NMR spectrum: (CDCI3) 1.3 (t, 3H), 1.41 (s, 6H), 2.31 (s, 3H), 2.56 (s, 2H), 2.23 (m, 2H), 2.63 (s, 2H), 6.26 (d, 1H), 7.9 (s, 1H), 7.35 (m, 5H), 7.82 (d, 1H).

A mixture of the material thus obtained, 10% palladium on carbon catalyst (1 g) and ethanol (500 ml) was stirred under an atmosphere of hydrogen pressure for 1.5 hours. The catalyst was removed by filtration and the solvent was evaporated to give. ethyl 3- (6-benzyloxy-4,4,7-trimethyl-3,4-dihydrocoumarin-5-yl) propionate as a white solid (6.1 g); NMR spectrum: (CDC13) 1.29 (t, 3H), 1.46 (s, 6H), 2.22 (s, 3H), 2.56 (s, 2H), 2.74 (t, 2H), 3.13 (t, 2H), 4.2 (m, 2H), 6.78 (s, 1H), 6.81 (s, 1H). A solution of ferric chloride hexahydrate (21 g) in a mixture of acetonitrile (50 ml) and water (50 ml) was added in small portions for 45 minutes to a stirred solution of a portion. (5 g) of the ethylpropionate thus obtained in acetonitrile (50 ml). The resulting mixture was heated at 90 ° C for 45 minutes. The mixture was cooled to room temperature and partitioned between diethyl ether and a 5% aqueous sodium bicarbonate solution. The aqueous phase was acidified to pH 2 by the addition of 2N aqueous hydrochloric acid and extracted with diethyl ether. The resulting organic phase was dried (MgSO 4) and evaporated. The residue was purified by column chromatography on silica using a 50: 50: 0.1 mixture of petroleum ether (boiling point 40 to 60 ° C), - diethyl ether and acetic acid as eluent. Thus, 3- [3- (2-ethoxycarbonylethyl) -5-methyl-1,4-benzoquinon-2-yl] -3-methylbutyric acid (0.48 g) was obtained.; NMR spectrum: (CDC13) 1.26 (t, 3H), 1.47 (s, 6H), 1.98 (s, 3H), 2.45 (m, 2H), 2.97 (m, 2H), 3.06 (s, 2H), 4.15 (m, 2H), 6.48 (s, 1H). • EXAMPLE 20 Using a procedure analogous to that described in Example 1, 3- [2- (2-methoxycarbonylethyl) -3,5-dimethyl-1,4-benzoquinoline] -3-methylbutyric acid was reacted with sodium. - [bis (2-chloroethyl) amino] phenol and the product was purified by column chromatography on silica using a 6: 1 mixture of petroleum ether (40 to 60 ° C boiling point) and ethyl acetate as eluent. The product thus obtained was further purified by reverse phase column chromatography on silica using an 80: 20: 1 mixture of methanol, water and acetic acid as eluent. Thus, 4- [bis (2-chloroethyl) amino] phenyl 3- [2- (2-methoxycarbonylethyl-3,5-dimethyl-1, -benzoquinonyl] -3-methylbutyrate was obtained in a yield of 21%; NMR spectrum : (CDC13) 1.5 (s, 6H), 1.97 (s, 3H), 2.16 (s, 3H), 2.4 (m, 1H), 2.72 (m, 1H), 3.2 (s, 2H), 3.58 (m , 4H), 3.65 (s, 3H), 3.67 (m, 4H), 6.61 (d, 2H), 6.86 (d, 2H), Mass Spectrum: (M + Na +) 560, 562 &564. The acid 3- [2- (2-methoxycarbonylethyl) -3,5-dimethyl-1,4-benzoquinonyl] -3-methylbutyric used as a starting material was obtained as follows: A mixture of tert-butyl 3-methyl-3- ( 3, 5-dimethyl-1,4-benzoquinonyl) butyrate (0.5 g), succinic momomethyl ester (0.45 g) and silver nitrate (0.085 g) was dissolved in a mixture of acetonitrile (6.5 ml) and water (6.5 ml) The mixture was stirred and heated to 75 ° C and a solution of sodium persulfate (Na2S208, 0.265 g) in water (2 ml) was added by dripping over a period of 20 minutes.The resulting mixture was stirred at 75 ° C. for 10 minutes add and then cooled to room temperature. The mixture was partitioned between diethyl ether and water. The organic phase was washed with water and with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. The residue was purified by column chromatography on silica using a 21: 4 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, tert-butyl 3- [2- (2-methoxycarbonylethyl) -3,5-dimethyl-1,4-benzoquinonyl] -3-methylbutyrate (0.075 g) was obtained; NMR spectrum: (CDC13) 1.36 (s, 9H), 1.4 (s, 6H), 2.01 (s, 3H), 2.14 (s, 3H), 2.44 (t, 2H), 2.73 (t, 2H), 2.9 (s, 2H), 3.67 (s, 3H). A mixture of the material thus obtained, trifluoroacetic acid (2.5 ml), water (0.1 ml) and methylene chloride (2.5 ml) was stirred at room temperature for 2 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and a dilute aqueous solution of sodium bicarbonate. The aqueous phase was acidified to pH 2 by the addition of dilute aqueous hydrochloric acid and extracted with diethyl ether. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried (MgSO 4) and evaporated. Thus, the required starting material (0.51 g) was obtained; NMR spectrum: (CDCI3) 1.36 (s, 6H), 1.93 (s, 3H), 2.07 (s, 3H), 2.32 (s, 2H), 2.67 (t, 2H), 2.95 (s, 2H), 3.61 (s, 3H). Example 21 'Using a procedure analogous to that described in Example 1, 3- (5-allyl-2,3-dimethyl-1,4-benzoquinonyl) -3-ethylpentanoic acid was reacted with 4- [bis (2-chloroethyl) amino] phenol and the product was purified by column chromatography on silica using an 8.5: 1.5 mixture of petroleum ether - (boiling point 40 to 60 ° C) and ethyl acetate as eluent. The product thus obtained was further purified by reverse phase column chromatography on silica using an 80: 20: 1 mixture of methanol, water and acetic acid as eluent. Thus, 4- [bis (2-chloroethyl) amino] phenyl 3- (5-allyl-2,3-dimethyl-1,4-benzoquin-nyl) -3-ethylpentanoate was obtained in a yield of 79%; NMR spectrum: (CDCI3) 0.92 (t, 6H), 1.91 (s, 3H), 1.92 (s, 3H), 1.97 (m, 4H), 3.24 (s, 2H), 3.44 (m, 2H), 3.59 (t, 4H), 3.68 (t, 4H), 5.01 (m, 2H), 5.78 (, 1H), 6.61 (d, 2H), 6.87 (d, 2H); Mass spectrum: (M + Na +) 542, 544 & 546. 3- (5-Allyl-2,3-dimethyl-1,4-benzoquinonyl) -3-ethylpentanoic acid used as starting material was obtained as follows: A solution of a mixture of 2,3-dimethyl-1 , 4-benzoquinone (J. Qrg. Chem., 1983, 4_8, 2932, 0.65 g) and ethyl 3-oxalooxy-3-ethylpentanoate (2.21 g) in methylene chloride (20 ml) was added to a stirred solution of persulfate of sodium (Na2S20s; 2.27 g) in water (20 ml) and the mixture was stirred at room temperature for 10 minutes. Silver nitrate (0.081 g) was added and the mixture was stirred and heated to reflux for 2 hours. The mixture was cooled to room temperature and extracted with methylene chloride. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. The residue was purified by reverse phase column chromatography on silica using an 80: 20: 1 mixture of methanol, water and acetic acid as eluent. Thus, ethyl 3- (2,3-dimethyl-l, 4-benzoquinonyl) -3-ethylpentanoate (0.146 g) was obtained; NMR spectrum: (CDC13) 0.78 (t, 6H), 1.15 (-t, 3H), 1.62 (m, 2H), 1.82 (m, 2H), 1.88 (s, 2H), 2.0 (s, 3H), 2.01 (s, 3H), 4.0 (m, 2H), 6.44 (s, 1H). After scaling the previous reaction, a solution of sodium dithionite (Na2S204; 15.2 g) in water (185 ml) was added to a solution of ethyl 3- (2,3-dimethyl-1,4-benzoquinonyl) -3- ethyl pentanoate (10.2 g) in methanol (370 ml).

Then concentrated hydrochloric acid was slowly added (10 ml) and the resulting mixture was stirred at room temperature for 90 minutes. The mixture was evaporated and the residue was extracted with diethyl ether, dried (MgSO 4) and evaporated. The residue was purified by column chromatography on silica using methylene chloride as eluent. Thus, 4,4-diethyl-6-hydroxy-7,8-dimethyl-3,4-dihydrocoumarin (8.5 g) was obtained; NMR spectrum: (CDC13) 0.82 (t, 6H), 1.6 (m, 4H), 2.18 (s, 3H), 2.25 (s, 3H), 2.56 (s, 2H), 4.86 (s, 1H), 6.48 (s, 1H). A mixture of a portion (4 g) of the material thus obtained, allyl bromide (5.85 g), potassium carbonate (6.7 g) and DMF (50 ml) was stirred at room temperature for 90 minutes. The solvent was evaporated and the residue was partitioned between diethyl ether and dilute aqueous hydrochloric acid solution. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. The residue was purified by column chromatography on silica using a 4: 1 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, 6-allyloxy-4,4-diethyl-7,8-dimethyl-3,4-dihydrocoumarin (4.1 g) was obtained; NMR spectrum: (CDC13) 0.83 (t, 6H), 1.62 (m, 4H), 2.19 (s, 3H), 2.23 (s, 3H), 2.58 (s, 2H), 4.51 (m, 2H), 5.27 (d, 1H), 5.42 (d, 1H), 6.06 (m, 1H), 6.51 (s, 1H). A mixture of the material thus obtained and N, N-dimethylaniline (50 ml) was stirred and heated at 200 ° C for 4.5 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9: 1 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, 5-allyl-4,4-diethyl-6-hydroxy-7,8-dimethyl-3,4-dihydrocoumarin (1.36 g) was obtained.; NMR spectrum: (CDC13) 0.83 (t, 6H), 1.63 (m, 2H), 1.98 (m, 2H), 2.19 (s, 3H), 2.25 (s, 3H), 2.58 (s, 2H), 3.59 (m, 2H), 5.2 (d, 1H), 5.25 (d, 1H), 6.0 (m, H). A solution of the material thus obtained in acetonitrile (20 ml) was stirred and heated to reflux. A solution of ferric chloride hexahydrate (2.56 g) in a mixture of acetonitrile (25 ml) and water (25 ml) was added in portions and the mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature and the organic solvent was evaporated. The residue was extracted with diethyl ether. The organic extract was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. The residue was purified by column chromatography on silica using progressively polar mixtures of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, 3- (5-allyl-2,3-dimethyl-1,4-benzoquinonyl) -3-ethylpentanoic acid (0.1 g) was obtained; NMR spectrum: (CDCl 3) 0.86 (t, 6H), 1.9 (m, 4H), 1.94 (s, 6H), 3.07 (s, 2H), 3.43 (m, 2H), 5.02 (m, 2H) ), 5.78 (m, 1H). The ethyl 3-oxaloxy-3-ethylpentanoate used as the starting material was obtained as follows: A solution of ethyl 3-ethyl-3-hydroxypentanoate (J. Med. Chem., 1988, 3_1, 431; 7g) in chloride of methylene (32 ml) was added over 1 hour to a solution of oxalyl chloride (6.38 g) in methylene chloride (8 ml). The resulting mixture was stirred at room temperature for 2 days. The solvent was evaporated, the residue was dissolved in dioxane (20 ml) and added in cold water (150 ml). The mixture was stirred for 1 hour. The mixture was extracted with diethyl ether, dried (MgSO4) and evaporated to give the required starting material as an oil (11.6 g); NMR spectrum: (CDC13) 0.95 (t, 6H), 1.27 (t, 3H), 2.05 (m, 4H), 2.98 (s, 2H), 4.17 (m, 2H). Example 22 Using a procedure analogous to that described in Example 1, 3- (5-allyl-2,3-dimethyl-1,4-benzoquinonyl) -3,4-dimethylpentanoic acid was reacted with 4- [bis (2 chloroethyl) amino) phenol and the product was purified by column chromatography on silica using an 8.5: 1.5 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, 4- [bis (2-chloroethyl) amino] phenyl-3- (5-allyl-2,3-dimethyl-1,4-benzoquin-nyl) -3,4-dimethylpentanoate was obtained in a yield of 48%; NMR spectrum: (CDC13) 0.96 (d, 3H), 0.98 (d, 3H), 1.5 (s, 3H), 1.9 (s, 3H), 1.92 (s, 3H), 2.45 (m, 1H), 2.55 (d, 1H), 3.37 (m, 1H), 3.57 (m, 5H), 3.67 (m, 4H), 3.77 (d, 1H), 4.96 (d, 1H), 5.02 (d, 1H), 5.7 ( m, 1H), 6.62 (d, 2H), 6.84 (d, 2H); Mass spectrum: (M + Na +) 542, 544 and 546. 3- (5-Allyl-2,3-dimethyl-1,4-benzoquinonyl-3,4-dimethylpentanoic acid used as starting material was obtained as follows : Using a procedure analogous to that described in the first paragraph of the portion of Example 21 which has to do with the preparation of starting materials, 2,3-dimethyl-1,4-benzoquinone was reacted with 3-oxaloxy- 3, 4-dimethylpentanoate methyl to give methyl 3- (2,3-dimethyl-1,4-benzoquinonyl) -3,4-dimethylpentanoate in a yield of 36%; NMR spectrum: (CDC13) 0.6 (d, 3H), 0.86 (d, 3H), 1.02 (s, 3H), 1.93 (s, 3H), 1.94 (s, 3H), 2.32 (m, 1H), 2.45 (d, 1H), 3.31 (d, 1H) ), 3.45 (s, 3H), 6.38 (s, 1H) The material thus obtained was carried through the sequence of reactions described in the additional paragraphs of the portion of Example 21 which has to do with the preparation of materials This was obtained in turn: 6-hydroxy-4-isopropyl-4,7,8-trimethyl-3, 4- dihydrocoumarin in a yield of 97%; NMR spectrum: (CDC13) 0.81 (d, 3H), 0.91 (d, 3H), 1.22 (s, 3H), 1.81 (m, 1H), 2.17 (s, 3H), 2.23 (s, 3H), 2.41 (d, 1H), 2.81 (d, 1H), 4.7 (s, 1H), 6.54 (s, 1H); 6-allyloxy-4-isopropyl-4,7,8-trimethyl-3,4-dihydrocoumarin in a yield of 85%; NMR spectrum: (CDC13) 0.81 (d, 3H), 0.91 (d, 3H), 1.24 (s, 3H), 1.82 (m, 1H), 2.18 (s, 3H), 2.23 (s, 3H), 2.43 (d, 1H), 2.79 (d, 1H), 4.52 (d, 2H), 5.28 (m, 1H), 5.41 (m, 1H), 6.08 (m, 2H), 6.56 (s, 1H); 5-allyl-6-hydroxy-4-isopropyl-4,7,8-trimethyl-3,4-dihydrocouma-fight in a yield of 37%; NMR spectrum: (CDC13) 0.88 (d, 3H), 0.96 (d, 3H), 1.42 (s, 3H), 2.03 (m, 1H), 2.19 (s, 3H), 2.23 (s, 3H), 2.4 (d, 1H), 2.72 (d, 1H), 3.41 (m, 1H), 3.75 (m, 1H), 4.98 (s, 1H), 5.13 (m, 1H), 5.26 (m, 1H), 6.05 ( m, 1H); and 3- (5-Allyl-2,3-dimethyl-1,4-benzoquinonyl) -3,4-dimethylpentanoic acid in a 28% yield; NMR spectrum: (CDCI3) 0.9 (d, 3H), 0.92 (d, 3H), 1.93 (s, 3H), 1.95 (s, 3H), 2.32 (d, 1H), 2.39 (m, 1H), 3.32 (m, 1H), 3.52 (m, 1H), 3.6 (d, 1H), 4.94 (m, 1H), 5.0 (m, 1H), 5.8 (m, 1H). The methyl 3-oxaloxy-3,4-dimethylpentanoate used as a starting material was obtained as follows: A solution of methyl 3-hydroxy-3,4-dimethylpentanoate (J. Amer. Chem. Soc, 1980, 102, 3614 18.2 g) in methylene chloride (85 ml) was added over 1 hour to a solution of oxalyl chloride (18.05 g) in methylene chloride (18 ml). The resulting mixture was stirred at room temperature for 2 days. The solvent was evaporated, the residue was dissolved in acetone (50 ml) and added in cold water (450 ml). The mixture was stirred for 1 hour. The mixture was extracted with diethyl ether, dried (MgSO 4) and evaporated to give the required starting material (21.8 g); NMR spectrum: (CDCI3) 0.97 (d, 3H), 1.0 (d, 3H), 1.54 (s, 3H), 2.47 (m, lh), 2.96 (d, 1H), 3.07 (d, 1H), 3.7 (s, 3H). Example 23 Using a procedure analogous to that described in Example 1, 2,3-dimethyl-3- (2,3,5-trimethyl-1,4-benzoquinonyl) butyric acid was reacted with 4- [bis (2-chloroethyl) amino] phenol and the product was purified by column chromatography on silica using an 8.5: 1.5 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus it was obtained to give 4- [bis (2-chloroethyl) amino] phenyl-2,3-dimethyl-3- (2,3,5-trimethyl-1,4-benzoquinonyl) butyrate as an oil in a yield of twenty%; NMR spectrum: (CDCI3) 1.25 (d, 3H), 1.45 (s, 3H), 1.50 (s, 3H), 1.95 (s, 3H), 1.97 (s, 3H), 2.21 (s, 3H), 3.60 (t, 4H), 3.67 (t, 4H), 3.85 (c, 1H), 6.61 (d, 2H), 6.82 (d, 2H); Mass Spectrum: (M + Na +) 502, 504 and 506. The 2,3-dimethyl-3- (2,3,5-trimethyl-1,4-benzoquinonyl) butyric acid used as starting material was obtained as follows : Ethyl 2, 3-dimethylbut-2-enoate (4.49 g) was added to a stirred mixture of 2, 3, 5-trimethylhydroquinone (4.58 g) and methanesulfonic acid (38 ml) which had been heated to 80 ° C. and the mixture was stirred at 80 ° C for 2 hours. The mixture was poured onto a mixture of ice and water and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using a 4: 1 mixture of petroleum ether (boiling point 40 to 60 ° C) and ethyl acetate as eluent. Thus, 6-hydroxy-3, 4, 4, 5, 7, 8-hexamethyl-3,4-dihydrocoumarin (3.99 g) was obtained.; NMR spectrum: (CDC13) 1.13 (d, 3H), 1.39 (s, 3H), 1.4 (s, 3H), 2.18 (s, 3H), 2.21 (s, 3H), 2.34 (s, 3H), 2.45 (m, 1H), 4.55 (s, 1H). A solution of N-bromosuccinimide (1.3 g) in acetonitrile (39 ml) was added dropwise over 15 minutes to a stirred mixture of a portion (1.5 g) of the 3,4-dihydrocuitiarin thus obtained, water (12 ml) and acetonitrile (108 ml). The mixture was stirred at room temperature for 30 minutes. The resulting mixture was partitioned between diethyl ether and water. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and evaporated. Thus, the required starting material (1.7 g) was obtained; NMR spectrum: (CDC13) 1.15 (d, 3H), 1.35 (s, 3H), 1.42 (s, 3H), 1.99 (s, 6H), 2.16 (s, 3H), 3.67 (m, 1H). Example 24 Pharmaceutical Compositions The following illustrates the representative pharmaceutical dosage forms of the invention as defined herein (the active ingredient is called "Compound").

X "), for therapeutic or prophylactic use in humans: (a) Tablet I mg / tablet Compound X 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Corn starch paste (5% weight / volume paste) 2.25 Magnesium stearate 3.0 (b) Tablet II mg / tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Corn starch 15.0 Polyvinylpyrrolidone (5% weight / volume pulp) 2.25 Magnesium stearate 3.0 (c) Tablet III mg / tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0 Corn starch paste (5% weight / volume paste) 0.75 Magnesium stearate 1.0 (d) Capsule mg / capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium 1.5 (e) Injection I (50 mg / ml) Compound X ....- 5.0% w / v Sodium hydroxide solution 15.0% v / v 0.1 M hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w / v Water for injection up 100% (f) Injection II (10 mg / ml) Compound X 1.0% w / v Sodium phosphate BP 3.6% w / v Sodium hydroxide solution 15.0% v / v Water for injection up to 100% (g) Injection III (1 mg / ml, regulated at pH6) Compound X 1.0% w / v Sodium phosphate BP 2.26% w / v Citric acid 0.38% w / v Polyethylene glycol 400 3.5% w / v Water for injection up to 100% h) Aerosol I mg / ml Compound X 10.0 Sorbitan trioleate 13.5 Trichlorofluoromethane 910.0 Dichlorodifluoromethane 490.0 i) Aerosol II mg / ml Compound X 0.2 Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0 Dichlorodifluoromethane 280.0 Dichlorotetradifluoroethane 1094.0 j) Aerosol III mg / ml Compound X 2.5 Sorbitan trioleate 3.38 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetradifluoroethane 191.6 k) Aerosol IV mg / ml Compound X 2.5 Soy lecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetradifluoroethane 191.6 (1) Ointment ml Compound X 40 mg Ethanol 300 μl Water 300 μl l-Dodecylazacycloheptan-2-one 50 μl Propylene glycol up to 1 ml Note The above formulations can be obtained by conventional procedures well known in the pharmaceutical art. Tablets (a) - (c) can be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. The aerosol formulations (h) - (k) can be used in conjunction with standard aerosol metered dose dispensers, and the sorbitan trioleate and soy lecithin suspension agents can be replaced by an alternative suspending agent such as sorbitan monooleate, sesquioleate of sorbitan, polysorbate 80, polyglycerol oleate or oleic acid.

Claims (5)

CLAIMS 1. An anti-tumor agent of the formula I characterized in that R1 is hydrogen, Cl-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, Cl-4 hydroxyalkyl, Cl-4 alkyloxy Cl-4 alkyl, Cl-4 aminoalkyl, alkylamino Cl-4-Cl-4 alkyl, di- [Cl-4 alkyl] amino-Cl-4 alkyl, pyrrolidin-1-yl-Cl-4 alkyl, Cl-4 piperidinalkyl, Cl-4 morpholinalkylp , Cl-4-piperazin-1-yl-alkyl, 4-alkylpiperazine of Cl-4-l-yl-Cl-4 alkyl, carboxyalkyl of Cl-4, Cl-4-alkoxycarbonyl of Cl-4 alkyl, carbamoylalkyl of Cl-4, N-alkylcarbamoyl of Cl-4-alkyl of Cl-4, N, N-di- [Cl-4 alkyl] carbamoylalkyl of Cl-4, amino, alkylamino of Cl-4, alkenylamino of C3- 4, C 3-4 alkynylamino, di- [C 1-4 alkyl] amino, di- [C 3-4 alkenyl] amino, di- [C 3-4 alkynyl] amino, pyrrolidin-1-yl, piperidino, morpholino , piperazin-1-yl, 4-alkylpiperazine of Cl-4-l-yl, hydroxy-alkylamino of C2-4, alkoxy of Cl-4-alkylamino of C2-4, aminoalkylamino of C2-4, alkylamino of Cl-4-alkylamino of C2-4, di- [Cl-4 alkyl] amino-alkylamino of C2-4, pyrrolidin-1-yl-alkylamino of C2-4, piperidinalkylamino of C2-4, morpholinalkylamino of C2-4, piperazin-1-yl-alkylamino of C2-4 , 4-alkylpiperazine of Cl-4-l-yl-alkylamino of C2-4, alkanoylamino of C2-4, alkanoylamino of C2-4-alkylamino of C2-4, carboxyalkylamino of Cl-4, alkoxycarbonyl of Cl-4-alkylamino of Cl-4, carbamoylalkylamino of Cl-4, N-alkylcarbamoyl of Cl-4-alkylamino of Cl-4, N, -di- [Cl-4 alkyl] carbamoyl-alkylamino of Cl-4, hydroxy, alkoxy of Cl -4, C2-4 hydroxy-lkoxy, Cl-4-alkoxy of C2-4 alkoxy, C2-4 aminoalkoxy, Cl-4 alkylamino of C2-4 alkoxy, di- [Cl-4 alkyl] amino-C2-4 alkoxy, pyrrolidin-1-yl-C2-4 alkoxy, C2-4 piperidinoalkoxy, C2-4 morpholinoalkoxy, C2-4 piperazin-1-yl-alkoxy or Cl-4-alkylpiperazine 4-l-yl-C2-4 alkoxy; R2 is hydrogen, Cl-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, Cl-4 hydroxyalkyl, Cl-4 alkyloxy Cl-4 alkyl, Cl-4 aminoalkyl, Cl-4 alkylamino 4-Cl-4 alkyl, di- [Cl-4 alkyl] amino-alkyl of Cl-4, pyrrolidin-1-yl-alkyl of Cl-4, piperidinalkyl of Cl-4, morpholinoalkyl of Cl-4, piperazin -1-yl-Cl-4-alkyl, 4-alkylpiperazine of Cl-4-l-yl-Cl-4 alkyl, carboxyalkyl of Cl-4, Cl-4-alkoxycarbonyl of Cl-4 alkyl, carbamoylalkyl Cl-4. N-alkylcarbamoyl Cl-4-alkyl Cl-4, N, N-di- [Cl-4 alkyl] carbamoyl-Cl-4 alkyl, amino, Cl-4 alkylamino, C3-4 alkenylamino, alkynylamino of C3-4, di- [Cl-4 alkyl] amino, di- [C 3-4 alkenyl] amino, di- [C 3-4 alkynyl] amino, pyrrolidin-1-yl, piperidino, morpholino, piperazine- 1-yl, 4-alkylpiperazione of Cl-4-l-yl, hydroxy-alkylamino of C2-4, alkoxy of Cl-4-alkylamino of C2-4, amino-alkylamino of C2-4, alkylamino of Cl-4-alkylamino of C2-4, di- [Cl-4 alkyl] amino-alkylamino of C2-4, pyrrolidin-1-yl-alkylamino of C2-4, piperidinoalkylamino of C2-4, morpholinoalkylamino of C2-4, piperazin-1-yl -alkylamino of C2-4, 4-alkylpiperazine of Cl-4-l-yl-alkylamino of C2-4, alkanoylamino of C2-4, alkanoylamino of C2-4-alkylamino of C2-4, carboxyalkylamino of Cl-4, alkoxycarbonyl of Cl-4-alkylamino of Cl-4, carbamoylalkylamino of Cl-4, N-alkylcarbamoyl of Cl-4-alkylamino of Cl-4, N, N-di- [Cl-4 alkyl] carbamoyl-alkylamino of Cl- 4, hid Roxy, Cl-4-alkoxy, C2-4-hydroxyalkoxy, Cl-4-alkoxy-C2-4-alkoxy, C2-4-aminoalkoxy, Cl-4-alkylamino of C2-4-alkoxy, di- [Cl-alkyl] -4] C2-4 amino-alkoxy, pyrrolidin-1-yl-C2-4 alkoxy, C2-4 piperidinoalkoxy, C2-4 morpholinoalkoxy, piperazin-1-yl-C2-4 alkoxy or 4-alkylpiperazine of Cl-4-l-yl-C2-4 alkoxy; R3 is hydrogen, Cl-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, Cl-4 hydroxyalkyl, Cl-4 alkyloxy Cl-4 alkyl, Cl-4 aminoalkyl, Cl-4 alkylamino 4-Cl-4 alkyl, di- [Cl-4 alkyl] amino-alkyl of Cl-4, pyrrolidin-1-yl-alkyl of Cl-4, Cl-4 piperidinoalkyl, Cl-4 morpholyalkyl, Cl-4-piperazin-1-yl-alkyl, 4-alkylpiperazine from Cl-4-l-yl-Cl-4 alkyl, Cl-4 carboxyalkyl, alkoxycarbonyl of Cl-4-Cl-4 alkyl, Cl-4 carbamoylalkyl, N-alkylcarbamoyl of Cl-4-Cl-4 alkyl, N, N-di- [Cl-4 alkyl] carbamoyl-Cl- alkyl 4, amino, Cl-4 alkylamino, C3-4 alkenylamino, C3-4 alkynylamino, di- [Cl-4] amino alkyl, di- [C3-4 alkenyl] amino, di- [C3 alkynyl] -4] amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-alkylpiperazine of Cl-4-l-yl, hydroxyalkylamino of C 2-4, alkoxy of Cl-4-alkylamino of C 2-4 , C2-4 aminoalkylamino, Cl-4-alkylamino of C2-4 alkylamino, di- [Cl4] alkyl] amino-alkylamino of C2-4, pyrrolidin-1-yl-alkylamino of C2-4, piperidinoalkylamino of C2-4, C2-4 morpholinoalkylamino, piperazin-1-yl-alkylamino of C2-4, 4-alkylpiperazine of Cl-4-l-yl-alkylamino of C2-4, alkanoylamino of C2-4, alkanoylamino of C2- 4-alqui C2-4 lamino, Cl-4 carboxyalkylamino, Cl-4 alkylaminocarbonyl of Cl-4, Carbamoylalkylamino of Cl-4, N-alkylcarbamoyl of Cl-4-alkylamino of Cl-4, N, N-di- [Cl-4 alkyl] carbamoyl-alkylamino of Cl-4, hydroxy, alkoxy of Cl-4, hydroxyalkoxy of C 2-4, alkoxy of Cl-4-alkoxy of C 2-4, aminoalkoxy of C 2-4, alkylamino of Cl -4-C2-4 alkoxy, di- [Cl-4 alkyl] amino-C2-4 alkoxy, pyrrolidin-1-yl-C2-4 alkoxy, C2-4 piperidinoalkoxy, C2-4 morpholinoalkoxy, piperazin-1-yl-alkoxy of C2-4 or 4-alkylpiperazine of Cl-4-l-yl-alkoxy of C2-4; R 4 is Cl 4 alkyl; R5 is Cl4 alkyl; R6 is hydrogen or Cl4 alkyl; R is hydrogen or Cl-4 alkyl; X is oxygen; m is 1 or 2 and each R 8 is independently hydrogen, halogen, hydroxy, Cl-4 alkoxy, C 2-4 alkenyloxy, C 2-4 alkynyloxy, Cl 4 alkyl, C 3-4 alkenyl, C 3 alkynyl 4, amino, alkylamino of Cl-4, di- [Cl-4 alkyl] amino, cyano, C2-4 alkanoylamino, carboxy, Cl-4 alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl of Cl-4 or N, N -di- [Cl-4 alkyl] carbamoyl; Y1 is halogen, Cl-4 alkanesulfonyloxy, benzenesulfonyloxy or phenyl-alkanesulfonyloxy of Cl-4; and Y2 is halogen, Cl-4 alkanesulfonyloxy, benzenesulfonyloxy or phenyl-alkanesulfonyloxy of Cl-4; and where any heterocyclic group in R1, R2 or R3 is optionally substituted with 1, 2 or 3 alkyl substituents of Cl-4, and wherein any phenyl group on Y1 or Y2 when Y1 and Y2 are benzenesulfonyloxy or phenyl-alkanesulfonyloxy of Cl-4 optionally substituted with 1, 2, < _ 3 selected entities of halogen, nitro, cyano, cifluorcn < = • cu-hydroxy, amino, Cl-4 alkyl, d-oxy of \ -? , Isminc h-Cl-4 aiqtj and di- | Cl-4] amino alkyl, '> or a pharmaceutically acceptable salt thereof; with the proviso that at least one of P1, P P is different from hydrogen. 2. The anti-tumor agent of I formulate I in accordance with claim i, characterized by qi f J i1 each of R ", R and I is ndepndly hydrogen, methyl, ethyl, propyl, acetyl, methylallyl, 2- ndroxyethyl, 3-hydroxypropyl, 2-? Neox ethanol, 2-ethoxylated 3-methoxypropyl, 3-ethoxypropyl, 2-cabobo-ethyl, 3-carboxypropyl, 2-methoxycarbon, 2 -et_? carbon _ = Only, Ib 3-methoxylcarbonyl, 3-ethoxycarbonyl, ropyl, 1- (N-ethylcarbamoyl) -ethyl, 3- (N-methyl-dihydro-bamoyl, pioxy, dimethylcarbamoyl) ethyl, 3- (N, N-dimethylcurbamoyl) iopyl, methylamino, ethylamino, propylammon, isopropyl amino, lammo, 2-hydroxy ethamolamine, hydroxy-2-methoxyethylamine, 3-methoxy ? prop? lammo, 2-an inoetilami? < "3-aminopropylamine, 2-methamphetamine, 5-methylaminopiopilamino, 2-etuiminoeplamino, 3-ethylammopropylamino, 2-d? Met? Lammoet lammo, 2-di-ethylaminoethylamine, 3-d? Met ? lam? noprc? lam? no, 3-25 diethylaminopropilammo, 2- (p? rroi? d? n-1-? l) et lamino, 3- (p? rrol? d? n-1-? l) propylamino, 2-p? per? d? noet? lammo, 3-piperidinopropylamine, 2-morpholinoethylamine, 3-morpholinopropylamino, 2- (p? peracm-1-? l) ethylamino, 3- (p? perac? n- 1-a 1) propylamino, 2- (4-met? Lp? Peru in-li]) ethylamm, 3- (4-met? Lp? Perate? N-1-? L) p upilammo, 2-acetamidoethylamino, 2 -prop? onam? doet? lam? no, 3-acetamidopropylamino, 3-prop? onam? doprop? lam? no, 2-carboxyethylamino, 3-carbo /? prop? lam? no, 2-methoxycarbonylethylammo, 2-ethoxy? carbon? let_lam? no, 2 - (e-butoxycarboni 1) ethylammon, 3-methoxycarbonylpropylamino, 3-ethoxycarbonylpropylamino, 3- (ter-bu cocaric) -nil) propylamino, methoxy or etho> each; R and R5 is independently hydrogen, methyl, ethyl, propyl or isopropyl; R1"is hydrogen, methyl, ethyl, propyl or isopropyl; R e hydrogen or methyl; X is oxygen; m is 1 or 2 and each R is independently hydrogen, fluoro, chloro, bromo, methoxy, ethoi, methyl, ethyl, propyl, isopropyl or cyano; and each of Y1 and Y2 is independently chloro Dromo, iodo, methanesulfonyloxy, benzenesulfonyl or femmethanesulfonyloxy; or a pharmaceutically acceptable salt of ios 1] 3 same; with the proviso that at least one of F1, I < > It is different from hydrogen and with the condition that < * or more Je two of R, R ~ "and RJ is a substituted amino group (L ^ i as methylamino, 2-morfolmoethylammo or.-acetamidoe tilammo) b 3. The anti-tumoral agent of Formule I in accordance with claim 1 characterized by -R is hydrogen, methyl, ethyl, propyl, < lyl, methylallyl, 2-hydroxyl, 3-hydropropyl, 2-methoxy, < 3 > It is 3-ethoxy-propylene, 2-methoxycarbon, lethal, 2-0-butylcarbonyleryl, 3-methoxycarbon-

1-pyridyl, 3-carboxypropyl 2- ( N-methyl arbamoyl) ethyl, 5- (methylcarbamoyl) propyl, 2- (N, N-dimethylcarbamoyl) ethylamine, 3- (N, N-dimethylcarbamoyl) propyl, nonylamino, eLi lamino, propylammon, isopropylamine, allylamino , 2-n? Drox? Et? Lan? No, b 3-h? Drox? Prop? Lam? No, 2-methox? Et? La? N? No, 3-meto / iprop? Lam no,

2 - . 2-aminoethylamino,

3-ammopropyl lamine, 2-melaminoerylamino, j-methylammopropylamino, 2-e-Lilaminoethylamine, 3-ethylammopropylammon, 2-d? Methalaminoethane, 2-diethylaminoinamino, 3- d? met? iam? noprrp? lam? no, 3-0 diethylaminopropilammo, 2- (p? rrol? d? n-1-? i) eti lamine, 3- (p? rrol? dm-1-? l) propylamm, 2-mper? d? noet? lam? no, 3- pipepdinop opylamm, 2-morpholmoethylamm, 3- morpholinopropylamm, 2- (p? pera?? n-1-? l) et ylamino, 3- (p? peracin-1-? l) propylammon, 1 - (

4-met? lp? perac? n-1-? 1) -5 erylamino, 3- (-met? lp? perac? nl-? l) propylamm 2 -acetamidoethylamino, 2-prop? onam? doet? lammo, 3-acetamidopropylammo, 3-prop? onam? doprop? lammo, 2-enecarbonylethylamino, 2-ethoxy? carbon? let? lamino, 2- (er-butoxycarbonyl) ethylammon, 3-met? '' rcarbon? lp? op? lamrno, 3-ethoxycarbonylpropylammo, 3- (tert-butoxycarbonyl) prop: lamino, methoxy or ethoxy; R "is hydrogen, methyl, ethyl, propyl, isopropyl, bucyl, halo, methylallyl, methoxy, R is hydrogen, methyl, thio, propyl, isopropyl, butyl, halo, methyalyl, ethoxy. ethoxy, R 4 is methyl, ethyl, propyl or isopropyl, R 5 is methyl, ethyl, propyl or isopropyl, Rc is hydrogen, methyl, ethyl, propyl or isopropyl, P 'is hydrogen or methyl, X is oxygen, m is 1 or 2. and each RJ is independently hydrogen, fluoro, chloro, bromo, methoxy, ethoxy, methyl, ethyl, propyl or isopropyl, and Y is chloro, bromo, iodo or methanesulfonyl.i; x is chloro, bromo, iodo or methanesulfonyl. ., - or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R1, R and RJ is different from hydrogen 4. The anti-tumor agent of d formula i in accordance with claim 1 caracered where P is hydrogen, methyl, ethyl, propyl, allyl, 2-methoxy, methylamino, ethylamino, propylamino, isopropyl, amino, allylamino, 2-dimethylammoetylamino no, 2-da e? ilammoetii-uarno, j 2- (p? rrol? d? n-1-? l) ethylamino, 2- j peridmoe ilamino, 2- morpholinoethylamm, 2- (p? peraz? n-1 -? l) eci lamino, 2- (4- met? lp? perac? n-1- l) ethylamm, 2-acrtam? doet? lam? no, m-to'i or ethoxy; R ~ is hydrogen, methyl, ethyl, propyl, illo, methoxy or etho-i; R "is hydrogen, methyl, ethyl, pr-g, isopropyl, halo, methoxy or eto.i; R" is methyl or ethyl; RJ is methyl or ethyl; R is hydrogen, methyl or ethyl; R is hydrogen; X is oxygen; m is 1 and R8 is located in metr for A and R is hydrogen, chlorine, chlorine, methyl, ethyl, propyl? or isopropyl; and each of Y and Y "is chlorine, bromine or iodine, or a pharmaceutically acceptable salt" we Masmos; with the proviso that at least one of R, i and R "is different from hydrogen." "J 5. The antitumor agent of the formula I according to claim 1, characterized in that R ~ is hydrogen, methyl, 2-methoxyethyl , isopropylamino, 2-morpholinoethylamino, 2-acetamidoethylamino or methoxy; R '"is hydrogen, methyl, allyl or methoxy; R 'is methyl, ethyl, propyl or allyl; each of RJ and R5 is methyl; R '"is hydrogen or methyl, R is hydrogen, X is oxygenate is 1 and R ° is hydrogen, and each of Y1 and Y" is chlorine; or a pharmaceutically acceptable salt thereof. 6. The anti-tumor agent of formula I according to claim 1, characterized in that it is selected from: 4- [bis (2-chloroethyl) amino] phenyl 3- [2- (2-acetamidoethylamino) -3-methoxy -

5-methyl-l, 4-benzoquinonyl] -3-methylbutyrate, 4- [bis (2-chloroethyl) amino] phenyl 3- [2- (2-methoxyethyl) -3,5-dimethyl-1, -benzoquinonyl] -3-methylbutyrate, 4- [bis (2-chloroethyl) amino] phenyl 3- (3-ali 1-2, 5-dimethyl-1,4-benzoquinonyl) -3-methylbutyrate, 4- [bis (2-chloroethyl) ) amino] phenyl 3-methyl-3- (2,3,5-trimethyl-l, -benzoquinonyl) butyrate, 4- [bis (2-chloroethyl) amino] phenyl 3- (2,5-dimethyl-1,4) -benzoquinonyl) -3-methylbutyrate, 4- [bis (2-chloroethyl) amino] phenyl 3- [3-methoxy-5-methyl-2- (2-morpholinoethylamino) -1,4-benzoquinone] -3- methylbutyrate and 4- [bis (2-chloroethyl) amino] -phenyl-2,3-imethyl-3- (2,3,5-tr-methyl-1, -benzoquinonyl) butyrate; or a pharmaceutically acceptable salt thereof. 7. An anti-tumor agent of the formula I, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 6 characterized in that the reduction potential of the compound is in the range of -200 to -475 mV. 8. The process for the preparation of an anti-tumor agent of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1, characterized in that it comprises: the reaction of an acid of the formula II wherein each of RJ, R2, R ', R ", R", P, and R7 have any of the defined meanings -in claim 1, or a reactive derivative thereof, with a compound of formula III wherein each of > Rd, m, Y, and Y have any of the meanings defined in claim 1, and when a pharmaceutically acceptable salt of a compound of formula I is required, it can be obtained by reaction of the compound with a base or Suitable acid using a conventional procedure and when an optically active form of a compound of the formula I sc requires, can be obtained by carrying out the above process using an optically active starting material, or by resolution of a racemic form of the compound using a process conventional composition 9. The pharmaceutical composition which comprises an anti-tumor agent of the formula I, or a pharmaceutically acceptable salt thereof, in accordance with the indication 1, characterized by which is in association with a pharmaceutically acceptable diluent or carrier. 10. The use of a nti-tumor agent of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1, in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal.