Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention concerns aromatic oxidation/hydroxylation activated prodrugs, particularly anti-tumour prodrugs and those which are specifically activated by the oxidation/hydroxylation activities of the cytochrome P450 family of enzymes.
• cytotoxic drugs are known that can be used for therapeutic purposes. However, they typically suffer from the problem that they are generally cytotoxic and therefore may affect cells other than those that are required to be destroyed. This can be alleviated to some extent by the use of targeted drug delivery systems, for example direct injection to a site of tumourous tissue or, e.g. binding the cytotoxic agent to an antibody that specifically recognises an antigen displayed only on the cancer cell surface. Alternatively, electromagnetic radiation may be used to cause chemical alteration in an agent at a desired site such that it becomes cytotoxic. However, all of these techniques have, to a greater or lesser extent, certain limitations and disadvantages.
• the compound (+)-CC-1065 and the duocarmycins are naturally occurring representatives of a class of DNA alkylating agents.
• the naturally occurring compounds consist of a DNA alkylating unit based upon a pyrrolo[3,2-e]indole core, with one or two sub units, conferring DNA binding capabilities.
• CC-1065 and duocarmycin A comprise a spirocyclic cyclopropane group responsible for the DNA alkylation properties.
• Duocarmycin B 2 , C 2 and D 2 are believed to be precursors for cyclopropane actives, and comprise a substituted (by a leaving group) methyl group at the eight position on the dihydro pyrrole ring.
• CC-1065 has been synthesised by various routes, summarised by Boger et al in Chem. Rev. 1997, 97, 787-828.
• OMOM is an alkoxy alkoxy group.
• the compound is proposed as a precursor of a mitomycin hybrid, ie the cyclopropane-ring-closed indoline form.
• the present invention relates to precursors of analogues of CC-1065 which are indole derivatives, which do not have the hydroxyl group in the benzene ring of indole alkylating sub unit, and which are hence substantially inactive as DNA alkylating agents themselves.
• cytochrome P450 isoforms in tumour cells provides a molecular target for the development of new antitumour drugs that could be selectively activated by the CYP enzymes in tumour cells, although no drug examples were given.
• a number of other CYP isoforms have been shown to be over expressed in various tumours. Many of the CYP's expressed in tumours are mentioned in Patterson,
• prodrugs of styrene- and chalcone-derivatives are described.
• the respective hydroxylated forms of the prodrugs, formed in situ, are potent tyrosine kinase (TK) inhibitors. Inhibition of TK activity contributes to tumour inhibition and cell destruction.
• the prodrugs were shown to be activated by microsomal preparations expressing CYP1 B1 enzyme, and to have cytotoxic activity against cell lines expressing the same enzyme, whilst having much lower cytotoxic activity against cell lines not expressing the enzyme.
• the present invention is directed to a new class of prodrugs which are expected to be hydroxylated in situ by CYP enzymes, in particular enzymes expressed at high levels in tumours as described by Patterson LH, et al, op. cit.
• the prodrugs are believed to be metabolisable by CYP1 B1 enzyme.
• Some of the compounds are new.
• the present invention relates to the first therapeutic use of a broad range of compounds.
• Y is a leaving group; (preferably selected from OCOOR 5 , OCONHR 6 , Cl, Br, I and OSO 2 R 7 in which R 5 , R 6 , and R 7 are each selected from C 4 alkyl, optionally substituted phenyl, C,. 12 aralkyl and optionally substituted heteroaryl);
• R 1 is -Ar, NH 2 , R 8 or OR 8 ;
• R 2 and R 3 are each independently selected from H, C 1-4 alkyl, -OH, C, .4 alkoxy, -CN, Cl, Br, I, -NO 2 , -NH 2 , -NHCOR 9 , -COOH, -CONHR 10 , - NHCOOR 10 and -COOR 10 ;
• R 4 is selected from H, C M alkyl, CN, Cl, Br, I, NO 2 , NH 2 , -NHCOR 9 , -COOH, -CONHR 10 , -NHCOOR 10 and -COOR 10 ;
• R 8 , R 9 and R 10 are independently selected from C ⁇ alkyl, optionally substituted phenyl, C 7 . 12 -aralkyl and optionally substituted heteroaryl and ligands;
• Ar is selected from
• B is N or CR 14 ;
• R 12 is H, -COAr 1 , -CONH 2 -COOH, -COR 16 or -COOR 16 ; the or each R 13 is selected from OH, C ⁇ alkoxy, C ⁇ alkyl, -NO 2 , - NH 2 , -NHR 17 , -NR 17 2 , -N + R 17 3 , -CN, Cl, Br, I, -NHCOR 15 , -COOH, -CONHR 16 , - NHCOOR 16 and -COOR 16 ; m is O, 1 or 2;
• R 14 is selected from OH, C ⁇ alkoxy, C 1-4 alkyl, -NO 2 , -NH 2 , -CN, Cl, Br, I, -NHCOR 15 , -COOH, -CONHR 16 , -COOR 16 , -NHCOOR 16 and H;
• R 15 is selected from C ⁇ alkyl, optionally substituted phenyl, optionally substituted heteroaryl, C 7 . 12 aralkyl, a ligand and Ar 1 ;
• R 16 is selected from C ⁇ alkyl, optionally substituted phenyl, C 7 . 12 - aralkyl and optionally substituted heteroaryl and a ligand; each R 17 is selected from C ⁇ alkyl, optionally substituted phenyl, optionally substituted heteroaryl and C 7.12 -aralkyl; and
• Ar 1 is selected from the same groups as Ar, provided that no more than one group R 11 or R 13 in any one ring includes a group Ar 1 .
• the animal which is treated is generally a human, although the compounds may also have veternary use.
• the indication treated is generally cancer including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus.
• the tumour may, for instance, be defined as a tumour expressing high levels of CYP1 B1.
• the leaving group Y is, for instance, a leaving group which has utility in nucleophilic substitution reactions. Suitable examples of such groups are -OCOOR 5 , -OCONHR 6 , Cl, Br, I, or -OSOOR 7 , in which R 5 , R 6 and R 7 are each selected from C ⁇ alkyl, optionally substituted phenyl, C 7 _ 12 -aralkyl and optionally substituted heteroaryl. Most preferably the leaving group is a halogen atom, preferably chlorine.
• Optional substituents in phenyl, aralkyl and heteroaryl groups are, for instance, C,. 4 -alkyl, halogen, hydroxyl, C.,. 4 -alkoxy, -NH 2 , -NHR 17 -, -NR 17 2 , -N + R 17 3 , -NO 2 -, -CN, -COOH, -NHCOR 15 , -CONHR 16 , -NHCOOR 16 , -COOR 16 etc.
• the term ligand includes a group having specific targeting characteristics, useful for instance in antibody or gene- directed enzyme prodrug-type environments.
• a ligand may be an oligopeptide, biotin, avidin or streptavidin, a polymeric group, an oligonucleotide or a protein. Preferably it has specific binding characteristics such as an antibody or fragment, an antigen, a sense or anti- sense oligo-nucleotide, or one of avidin, streptavidin and biotin, that is it is one component of a specific binding pair. Alternatively it may be a group designed for passive targeting, such as a polymeric group, or a group designed to prolong the stability or reduce immunogenicity such as a hydrophilic group. US-A-5843937 discloses suitable ligands for conjugating to these types of actives and methods for carrying out the conjugation.
• the group Ar 1 is preferably
• R 1 is other than -OR 8 in a pharmaceutically active compound.
• the group R 1 in a compound of the general formula I or IA is a group Ar.
• the compound may include two aromatic groups joined to one another.
• one of the groups R 11 of the Ar group, or the group R 12 is a group Ar 1 .
• the group R 12 should be other than a group
• the substituent Ar is a group
• B is preferably CR 14 .
• R 14 is preferably H.
• the groups B and Z are selected amongst the same preferable groups.
• n is at least 1 and one of the groups R 11 is -NHCOAr 1 .
• Ar 1 is preferably a group
• R 12 in such a group Ar is other than COOR 16 , more preferably it is a group -COAr 1 , in which Ar 1 preferably is the same type of group.
• m in the indole type group is preferably zero.
• R 11 there may be several substituents R 11 . Most preferably such substituents are selected amongst C ⁇ -alkoxy groups.
• the core benzene ring of the DNA alkylating sub-unit is preferably unsubstituted (R 3 and R 4 are both hydrogen).
• X is H. It is believed that, hydroxylation of the compound will occur in situ at the carbon atom to which X is attached, thereby activating the compound enabling it to act as a DNA alkylating agent.
• compositions comprising compounds of the formula I and IA or salts and a pharmaceutically acceptable excipient.
• Pharmaceutical compositions may be suitable for intramuscular, intraperitoneal, intrapulmonary, oral or, most preferably, intravenous administration.
• the compositions contain suitable matrixes, for example for controlled or delayed release.
• the compositions may be in the form of solutions, solids, for instance powders, tablets or implants, and may comprise the compound of the formula I in solid or dissolved form.
• the compound may be incorporated in a particulate drug delivery system, for instance in a liquid formulation.
• excipients include lactose, sucrose, mannitol, and sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose, such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; gums, including arabic and tragacanth; and proteins, such as gelatin and collagen.
• disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, and alginic acid or a salt thereof, such as sodium alginate.
• Solid compositions may take the form of powders and gels but are more conveniently of a formed type, for example as tablets, cachets or capsules (including spansules). Alternative, more specialised types of formulation including liposomes, nanosomes and nanoparticles.
• the compounds of the formula I and IA may be synthesised in a method in which a compound of the formula II or IIA, as the case may be,
• Y 1 is a leaving group or is hydroxyl; is reacted with a compound of the general formula III R 18 COY 2 III in which R 18 is selected from C 1 . 4 -alkyl, optionally substituted phenyl, C 7 . 12 -aralkyl, optionally substituted heteroaryl and Ar 2 ;
• Ar 2 is selected from
• B 1 is N or CR 23 ;
• R 20 is an amine protecting group
• R 21 is an amine protecting group, -CONH 2 , -COOH, -COR 27 or -COAr 3 ; the or each R 20 is selected from C,. 4 -alkoxy, C ⁇ -alkyl, NO 2 , CN, Cl, Br, I, -NHR 24 , -NR 25 2 , -N + R 25 3 -, NHCOR 26 , -COOH, -CONHR 27 and -COOR 27 ; q is O, 1 or 2;
• R 23 is selected from H, C ⁇ -alkoxy, C ⁇ -alkyl, NO 2 , CN, Cl, Br, I, -NHR 24 , -NR 25 2 , -N + R 25 3 -, NHCOR 26 , COOH, -CONHR 27 and COOR 27 ;
• R 24 is an amine protecting group
• R 26 is selected from Ar 3 , C ⁇ -alkyl, optionally substituted phenyl, C 7 . 12 - aralkyl, optionally substituted heteroaryl and a ligand
• each R 25 is selected from H, C ⁇ -alkyl, optionally substituted phenyl, C 7.12 -aralkyl and optionally substituted heteroaryl;
• R 26 is selected from C ⁇ -alkyl, optionally substituted phenyl, C 7 . 12 - aralkyl optionally substituted heteroaryl and a ligand;
• Ar 3 is selected from the same groups as Ar 2 ; and Y 2 is a leaving group, provided that no more than one R 19 or R 22 in any one ring includes a group Ar 3 .
• a group Ar 3 is
• Y 2 is, for instance, selected amongst the preferred leaving groups listed above for Y. Most suitably the definition of Y 2 is Cl. Alternatively, the group Y 2 may be OH. In this case, it may be necessary to include a coupling agent to assist in the coupling reaction. Y 1 may be the same as Y or may be another leaving group, or hydroxyl, which may be converted to Y in a subsequent step.
• reaction between the compound of the general formula II or A, as the case may be, and the carboxylic acid or derivative of the general formula II is carried out under conditions allowing such coupling to take place.
• Such conditions are similar to those generally used for formation of peptide bonds, for instance as used in peptide synthetic methods.
• any protected amine groups After the coupling process, it may be desirable to deprotect one or more of any protected amine groups. If further reaction, for instance with other derivatising agents such as glycosyl compounds, peptides, polymers etc is desired through any such amine groups, it may be desirable to deprotect only those to which subsequent reaction to to take place, whilst retaining the other amine groups in a protected form. Selection of suitable amine protecting groups and protection and deprotection protocols may be made using techniques commonly utilised in peptide chemistry.
• the starting compound for such a cyclisation reaction may be represented by the general formula IV
• R 28 is an amine protecting group, one of Z 1 and Z 2 is Y 4 and the other is H;
• Y 4 is H, or is a leaving group which is different from or the same as Y 1 ; and Y 3 is a radical leaving group.
• Y 3 is preferably a halogen atom, more preferably Br or I.
• the group Z 1 is Y 4
• Y 4 is either H or a leaving group, preferably the same group as Y 1 .
• Y 4 is not active as a leaving group but may be so in subsequent steps of the synthesis.
• the reaction is conducted in the presence of a suitable catalyst, optionally in the presence of a free radical trap.
• a group Y 4 is preferably I.
• Y 4 is a leaving group the cyclisation may be carried out in the presence of radical derived from azoisobutyronitrile.
• Suitable catalysts for such a radical cyclisation step are tin hydride compounds such as tributyl tin hydride. Such a synthetic route is illustrated in Example 1.
• Suitable radicals for carrying out the cyclisation reaction using a compound IV in which Y 4 is H are nitroxy compounds such as 2,2,6,6- tetramethylpiperidinyloxy (TEMPO) radical.
• TEMPO 2,2,6,6- tetramethylpiperidinyloxy
• Z 2 is Y 4 and Y 4 is a leaving group, preferably a trialkyl stannyl group, and to carry out the reaction in the presence of a suitable catalyst palladium complexes such as tetrakis (triphenylphosphine) palladium (0), bis(triphenyl phosphine) palladium (II) chloride or palladium (II) acetate.
• a suitable catalyst palladium complexes such as tetrakis (triphenylphosphine) palladium (0), bis(triphenyl phosphine) palladium (II) chloride or palladium (II) acetate.
• Y 4 is active as a leaving group.
• the dihydroquinoline intermediate is oxidised to form a further intermediate which is an epoxide, for instance using a peroxide reagent.
• the epoxide intermediate is reduced using a suitable selective reducing agent such as a dialkyl aluminium hydride to produce the corresponding tetrahydroquinoline alcohol which is subsequently halogenated, for instance using carbon tetrachloride/triphenyl phosphine.
• a suitable selective reducing agent such as a dialkyl aluminium hydride
• This reaction is illustrated in Example 2.
• the compound of the general formula IV may be produced by alkylation of the sodium salt of the corresponding amiline derivative with a trans-1 ,3-dihaloprop-2-ene compound.
• the carboxylic acid derivative of the general formula III may be synthesised using the methods generally described in Boger et al, 1997 op.cit, for instance PDE-I and PDE-II may be synthesised using the
• the present invention relates to the creation of a range of prodrugs that have little or no cytotoxic effects when in their normal state, but are highly cytotoxic (i.e. have a substantially increased cytotoxicity) when activated by oxidation or hydroxylation by CYP enzymes.
• This provides for a self-targeting drug delivery system in which a non cytotoxic (or negligibly cytotoxic) compound can be administered to a patient, for example in a systemic manner, the compound then being activated at the site of the tumour cells (intratumoural activation) to form a highly cytotoxic compound which acts to kill the tumour cells.
• cytotoxic or negligibly cytotoxic
• the fact that the CYP isoforms are not expressed by normal cells mean that the activation of the compound only occurs at the site of the tumour cells and therefore only tumour cells are affected, thus providing a self-targeting system.
• the prodrugs of the present invention have the distinct advantage of being useful in the treatment of tumours at any site in the body, meaning that even tumours that have undergone metastasis (which are normally not susceptible to site specific therapies) may be treated.
• the prodrug may be an antitumour prodrug.
• tumours include cancers (malignant neoplasms) as well as other neoplasms e.g. innocent tumours.
• the prodrug may be activated by hydroxylation by isoforms of cytochrome P450's.
• the selectivity between tumour tissue and normal tissue can be enhanced in a two part procedure.
• intratumoural hydroxylation of the prodrugs of the present invention provides them with a surprising and unexpected efficacy.
• Hydroxylated forms of the prodrugs are potent DNA alkylating agents that bind in the minor groove of DNA and alkylate the purine bases at the N3 position. As such, they are potent cytotoxic agents whose exact biological mechanism of action is unknown but involves the disruption of template and other functions of DNA. General inhibition of template function of DNA will affect and be generally cytotoxic to all dividing cells in the body and lead to unacceptable side effects in a therapeutic setting. However, the targetted production of hydroxylated forms only in tumour cells that overexpress particular isoforms of cytochrome P450's will lead to a specific cytotoxic effect only in those cells. The non-hydroxylated forms are essentially non- toxic to all cells.
• Example 1 The synthesis of one compound of the general formula I is carried out according to the following reaction scheme.
• test compound activation by CYP enzymes was carried out using NADPH supplemented rat liver microsomes.
• Incubation mixtures comprised microsomal protein (1 mg/ml), reduced-nicotinamide adenine dinucleotide phosphate (NADPH, 10mM) and phosphate buffer (pH7.4, 100mM).
• Test compound (0.01 - 100 ⁇ M final concentration) in DMSO (20 ⁇ l) was added to the microsomal incubation mixtures (0.5ml) and incubated for 60 min at 37C. Control incubates contained test compound and microsomal incubation mixture terminated at 0 time.
• MTT 50 ⁇ l; 2mg/ml stock solution
• a hydrogen acceptor tetrazolium salt is reduced to formazan dye by mitochondrial dehydrogenase of viable cells.
• the media was aspirated from cells and DMSO (100 ⁇ l/well) added to solubilise the coloured formazan dye.
• Absorbance of the formazan dye in the 96-well- plates was then determined at 550nm. The effect of microsomal activation by the test compound on the arrest of CHO cell growth could be determined by comparing the IC 50 (concentration that inhibited cell growth by 50%) with and without microsomal incubation.
• * represents significance at p>0.05.

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