HK1066216B - Novel pyridyl cyanoguanidine compounds - Google Patents

Description

Novel pyridyl cyanoguanidine compounds

Technical Field

The present invention relates to novel pyridyl cyanoguanidines, pharmaceutical compositions thereof, and their use in the manufacture of medicaments.

Background

Pyridyl cyanoguanidines such as pinadil (N-1, 2, 2-trimethylpropyl-N' -cyano-N "- (4-pyridyl) guanidine), originally found for the opening of potassium channels, were subsequently developed as antihypertensive agents. Replacement of the side chain of pinadil with a longer side chain-containing aryl group resulted in disappearance of the antihypertensive activity, but on the other hand, oral administration to rats was found to show the antitumor activity in a rat model with Yoshida ascites tumor.

Different classes of pyridyl cyanoguanidines having antiproliferative activity are disclosed, for example, in EP 660823, WO 98/54141, WO 98/54143, WO 98/54144, WO 98/54145, WO00/61559 and WO 00/61561. Schou et al, Bioorganic and medicinal chemistry Letters 7(24), 1997, pp.3095-3100, which examined the antiproliferative effect of a fraction of pyridyl cyanoguanidine in vitro using different human lung and breast cancer cell lines and normal human fibroblasts, discuss the structure-activity relationship (SAR) of these compounds.

Further results from in vivo and in vitro testing of a particular cyanoguanidine compound, N- (6- (4-chlorophenoxy) hexyl) -N' -cyano-N "- (4-pyridyl) guanidine, have been reported in P-J V Hjarnaa et al, Cancer Res.59, 1999, pp.5751-5757. The compound shows comparable potency in vitro compared to the reference cytostatic agents daunomycin and paclitaxel, while showing a rather low anti-proliferative activity against normal human endothelial cells. In vivo test in athymic mice transplanted with human tumor cells, the compound shows substantial antitumor activity, and also has antagonistic effect on tumor cells resistant to conventional antitumor drugs such as paclitaxel.

The ideal drug requires a delicate balance between factors such as activity, bioavailability, toxicity, level of side effects, solubility, etc., which improves the cyanoguanidine-based drug.

Summary of The Invention

The present inventors have found that novel pyridyl cyanoguanidine compounds containing a heterocyclic group have surprisingly high antiproliferative activity. Accordingly, the present invention is directed to compounds of formula I and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and prodrugs thereof:

wherein R1 is hydrogen, halogen, or one or more straight or branched, saturated or unsaturated C_1-6A hydrocarbyl group optionally substituted with: halogen, hydroxy, cyano, nitro, carboxy, alkoxy, alkoxycarbonyl, alkylcarbonyl, formyl, amino, aminoalkyl, aminocarbonyl, alkylcarbonylamino, thio, aminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, dihydroxyphosphonoxy or phosphono; x is a linear or branched, saturated or unsaturated C_1-12A hydrocarbondiyl group, and optionally substituted with: halogen, hydroxy, cyano, nitro, carboxy, alkoxy, alkoxycarbonyl, alkylcarbonyl, formyl, amino, aminoalkyl, aminocarbonyl, alkylcarbonylamino, thio, aminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, dihydroxyphosphonooxy or phosphono;

y is a bond, O, C (O), S, S (O), S (O)₂C (O) O, NH, C (O) NH, OC (O) or NHC (O);

z is an aromatic or non-aromatic heterocyclic group having 5 to 12 ring atoms, optionally substituted with: halogen, hydroxy, cyano, nitro, alkoxy, alkoxycarbonyl, alkylcarbonyl, formyl, aminoalkyl, or a straight-chain or branched, saturated or unsaturated C_1-4A hydrocarbyl group optionally substituted with: halogen, hydroxy, cyano, nitro, alkoxy, alkoxycarbonyl, alkylcarbonyl, formyl or aminoalkyl;

provided that R1 is not attached to a nitrogen atom in the pyridine ring.

The invention also relates to the use of compounds of formula I in therapy and to pharmaceutical compositions containing compounds of formula I.

The invention also relates to a method of treating or preventing a disease comprising administering to a patient an effective amount of a compound of formula I.

Furthermore, the invention relates to the use of compounds of formula I for the preparation of medicaments.

Detailed Description

In this context, the word "hydrocarbon" means a moiety comprising only hydrogen and carbon, preferably having from 1 to 18, such as from 1 to 12 (e.g. 1 to 6), carbon atoms. Examples of said hydrocarbons include methane, ethane, ethylene, acetylene, butane, butene, butyne, isobutane, tert-butane, hexane, 1, 3-dimethyl-hexane, octane, octene, nonyne, dodecane, dodecene, and the like. Removal of one or two hydrogen atoms from a hydrocarbon, respectively, results in the corresponding hydrocarbyl and hydrocarbadiyl radicals.

The term "heterocyclyl" means a monocyclic ring having 1 to 3 heteroatoms selected from N, O and S, and a fused bicyclic ring having 1 to 4 heteroatoms selected from N, O and S. Examples include thienyl, furyl, pyranyl, isobenzofuryl, benzopyranyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, indolinyl, purinyl, quinolinyl, 1, 5-naphthyridinyl, 1, 2-naphthyridinyl (cinnonilyl), chromanyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, oxazinyl, tetrahydrofuranyl, oxazolidinyl, tetrahydropyranyl, tetrazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, benzimidazolyl, and benzofuryl.

The term "halogen" means fluorine, chlorine, bromine and iodine.

The term "pharmaceutically acceptable salt" means a salt of a compound of formula I having an acid or basic group prepared by reaction with an appropriate base or acid. Examples of such acids are hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, acetic, phosphoric, lactic, maleic, phthalic, citric, propionic, benzoic, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, toluenesulfonic, sulfamic and fumaric acid. Examples of such bases are potassium hydroxide, sodium hydroxide, ammonia and amines.

The term "solvate" means a substance formed by the interaction of a compound, in particular a compound of formula I, with a solvent such as ethanol, glycerol or water, wherein the substance is in solid form. When water is the solvent, the solvate means a hydrate.

The term "N-oxide" means a pyridyl N-oxide derivative of the compounds of the present invention. These compounds can be prepared by oxidizing pyridyl nitrogen with a suitable oxidizing agent, such as 3-chloro-perbenzoic acid dissolved in an inert solvent, such as methylene chloride.

The term "alkyl" means a monovalent group derived from an alkane (preferably an alkane having 1 to 8 carbon atoms), such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and cyclohexyl.

The term "alkoxy" means a group of the formula-OR, wherein R is alkyl as described above.

The term "alkoxycarbonyl" means a group of formula-C (O) -OR, wherein R is alkyl as described above.

The term "alkylcarbonyl" means a group of formula-c (o) -R, wherein R is alkyl as described above.

The term "aminoalkyl" means of formula-R-NR'₂A group wherein R is an alkyl group as described above, each R' independently represents an alkyl group as described above or hydrogen.

The term "aminocarbonyl" means a compound of formula-C (O) -NR'₂Wherein each R' independently represents an alkyl group as described above or hydrogen.

The term "sulfamoyl" means a compound of the formula-S (O)₂-NR’₂Wherein each R' independently represents an alkyl group as described above or hydrogen.

The term "alkylsulfonylamino" means a compound of the formula N (R') -S (O)₂-R, wherein R is an alkyl group as indicated above, and R' each independently represents an alkyl group as indicated above or hydrogen.

The term "amino" means of formula-NR'₂Wherein each R' independently represents an alkyl group as indicated above or hydrogen.

The term "prodrug" means a derivative of an active compound that does not or does not necessarily possess the physiological activity of the active compound, but that can be cleaved by an enzyme (e.g., in vivo hydrolysis) so that the active compound can be released upon administration of the prodrug. Methods for the preparation of prodrugs of the compounds of the invention are disclosed in International Patent Application PCT/DK 01/00750.

In a preferred embodiment of the invention, R1 represents hydrogen, halogen, or represents one or more linear or branched, saturated or unsaturated C_1-6A hydrocarbyl group; x represents a linear or branched saturated or unsaturated C_1-12A hydrocarbon diradical;

y represents O or C (O);

z represents an aromatic or non-aromatic heterocyclic group having 5 to 10 ring atoms.

In a more preferred embodiment of the invention, R1 represents hydrogen; x represents a straight chain C_5-10A hydrocarbon diradical;

y represents O;

z represents an aromatic or non-aromatic heterocyclic group having 5 to 10 ring atoms;

in another preferred embodiment, Z is selected from: pyridyl, imidazolyl, quinolyl and pyrimidyl.

Specific examples of compounds of formula I include

N- [6- (3-pyridyl-oxy) -1-hexyl ] -N' -cyano-N "- (4-pyridyl) -guanidine;

n- [6- (1-imidazolyl) -1-hexyl ] -N' -cyano-N "- (4-pyridyl) -guanidine;

n- [6- (2-quinolyl-oxy) -1-hexyl ] -N' -cyano-N "- (4-pyridyl) -guanidine;

n- [6- (3-pyridyl) -1-hexyl ] -N' -cyano-N "- (4-pyridyl) -guanidine;

n- [6- (3-quinolinyl) -1-hexyl ] -N' -cyano-N "- (4-pyridyl) -guanidine; and

n- [6- (5-pyrimidinyl) -1-hexyl ] -N' -cyano-N "- (4-pyridyl) -guanidine.

Furthermore, the applicant has found that the following compounds are particularly suitable for use in the preparation of the compounds of formula I:

3- [6- (N-tert-butoxycarbonylamino) -1-hexyl-oxy ] -pyridine;

3- [ 6-amino-1-hexyl-oxy ] -pyridine hydrochloride;

3- [ 6-amino-1-hexyl-oxy ] -pyridine;

1- [6- (N-tert-butoxycarbonylamino) -1-hexyl ] -imidazole;

1- (6-amino-1-hexyl) -imidazole hydrochloride;

1- (6-amino-1-hexyl) -imidazole;

2- [6- (N-tert-butoxycarbonylamino) -1-hexyl-oxy ] -quinoline; and

2- (6-amino-1-hexyl-oxy) -quinoline.

General preparation method

As shown in the scheme, the compound of formula I is prepared by reacting a compound of formula II (wherein R1 is the same as in formula I) with a compound of formula III (wherein X, Y and Z are the same as in formula I).

The reaction may be carried out in a suitable solvent such as pyridine, optionally in the presence of a tertiary amine such as triethylamine and a catalyst such as 4- (N, N-dimethylamino) -pyridine at between room temperature and 100 ℃. In this reaction, R1, X, Y and Z may temporarily contain suitable protective functional groups.

The compounds of the formulae II and III are known from the literature or are prepared by methods known to the person skilled in the art.

As shown in the scheme, in another embodiment, a thiourea of formula IV, wherein the substituents are as defined in (I) and are temporarily protected if necessary, is reacted with one or more equivalents of N, N-dicyclohexylcarbodiimide (DCCD) and cyanamide in an inert solvent, such as acetonitrile, at or above room temperature to produce the compound of formula I. The compounds of formula IV can be prepared by methods well known to those skilled in the art.

Pharmaceutical preparation

In another aspect, the invention also relates to pharmaceutical formulations of the compounds of formula I. The formulations of the invention, which can be used in both veterinary and human therapy, contain the active ingredient in association with a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Generally, the formulations contain 0.1 to 100% by weight of active ingredient. Typically, one dosage unit of the formulation comprises 0.07mg to 1g of a compound of formula I.

The term "dosage unit" means a unit that is a single dose of a drug capable of being administered to a patient and that is easy to handle and package, or a physically and chemically stable unit dose containing the active substance alone or in admixture with a solid or liquid pharmaceutical diluent or carrier.

Formulations include, for example, those suitable for oral (including sustained release and timed release formulations), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intraarticular and intraarterial), transdermal, ocular, topical, nasal or buccal administration.

The formulations may be conveniently stored in unit dosage form and may be prepared by any of the methods known in the pharmaceutical industry, for example as described in Remington,The Science and Practice of Pharmacy，20^thed., 2000. All methods include the step of bringing into association the active ingredient with a carrier, which may contain one or more accessory ingredients. Generally, the active ingredient is incorporated into the dosage form by uniformly mixing it with a liquid carrier or a finely divided solid carrier or bothIntimately mixed and then, if necessary, processed into the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in powder or granular form; solutions or suspensions in aqueous or non-aqueous liquids (e.g., ethanol or glycerol); or an oil-in-water emulsion or a water-in-oil emulsion. Such oils may be edible oils, such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginates, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomers and polyvinylpyrrolidone. The active ingredient may also be administered in the form of a bolus, electuary or paste.

The active ingredient is optionally mixed with one or more accessory ingredients, compressed or formed into tablets. Compressed tablets are prepared in a suitable machine by compressing, in a free-flowing active ingredient form (e.g. powder or granules), optionally mixed with: binders such as lactose, glucose, starch, gelatin, acacia gum, tragacanth gum, sodium alginate, carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycol, paraffin, and the like; lubricant: such as sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like; disintegrating agents, such as starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium starch glycolate, polyvinylpyrrolidone, etc.; or a dispersant such as polysorbate 80. In a suitable machine, a mixture of the active ingredient in powder form and a suitable carrier moistened with an inert liquid diluent is shaped into moulded tablets by moulding.

Formulations for rectal administration may be presented as a suppository in which the compound of the invention is combined with a low melting point, water or non-water soluble solid such as cocoa butter, hydrogenated vegetable oil, polyethylene glycol or fatty acid esters of polyethylene glycol, and elixirs may be prepared with myristyl palmitate.

Formulations suitable for parenteral administration will ultimately include sterile oily or aqueous preparations of the active ingredient, preferably isotonic with the blood of the recipient, e.g., isotonic saline, isotonic dextrose solution or buffers. The formulation may conveniently be sterilized, for example by filtration through a bacterial-retaining filter, addition of a sterilising agent to the formulation, irradiation of the formulation or heating. Liposomal formulations are also suitable for parenteral administration, see, e.g.Encyclopedia of Pharmaceutical Technology，vol.9，1994。

Alternatively, the compounds of formula I may be presented as sterile solid preparations, such as lyophilized powders, which may be readily dissolved in a sterile solvent prior to use.

The transdermal preparation may be in the form of a paste or patch.

Formulations suitable for ocular administration may be presented as sterile aqueous preparations of the active ingredient in microcrystalline form, e.g., as an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems have also been used to deliver active ingredients for ocular administration, e.g., inEncyclopedia of Pharmaceutical Technology，vol.2, 1989.

Formulations suitable for topical or ocular administration include liquid or semi-liquid formulations such as liniments, lotions, gels, dressings, oil-in-water or water-in-oil emulsions, such as creams, ointments or pastes; or as a solution or suspension, such as drops.

Formulations suitable for oral or nasal administration include powders, self-propelling and aerosol formulations such as aerosols and sprays.

In addition to the aforementioned ingredients, the formulation of the compounds of formula I may also include one or more other ingredients such as diluents, buffers, flavoring agents, colorants, surfactants, thickeners, preservatives such as methyl hydroxybenzoate (including antioxidants), emulsifiers and the like.

In systemic treatment using the present invention, a daily dose of 0.001-500mg, preferably 0.002-100mg (e.g., 0.003-20mg/kg or 0.003-5mg/kg) of a compound of formula I per kg of body weight of the mammal corresponds to a daily dose of 0.01-37000mg for an adult. However, the invention also provides compounds and compositions having longer dosing intervals (e.g., weekly, every three weeks, or monthly). In the topical treatment of skin diseases, the ointments, creams or lotions contain 0.1 to 750mg/g, preferably 0.1 to 500mg/g (e.g. 0.1 to 200mg/g) of a compound of formula I. In topical application to the eye, ointments, drops or gels contain 0.1 to 750mg/g, preferably 0.1 to 500mg/g (e.g. 0.1 to 200mg/g) of a compound of formula I. The oral composition preparation is preferably a tablet, capsule or drop, containing 0.07-1000mg, preferably 0.1-500mg of the compound of formula I per dosage unit.

Cyanoguanidine derivatives have been found to modulate I_κActivity of B kinase (hereinafter abbreviated as IKK). Intracellular active NF can be controlled by modulating IKK activity_κB level. Thus, it is believed that cyanoguanidines may be used in proliferative diseases and others by modulating active NF_κB levels in the treatment of diseases to be treated (e.g. inflammation).

NF_κB is a member of the Rel family of transcription factors, which are ubiquitous in animal cells. Rel proteins are able to form dimers, the most prevalent of which is called NF_κB。NF_κB is a p50/p65 heterodimer capable of activating the appropriate ligand_κB transcription of the gene of the binding site. In unstimulated cells, NF_κB through NF with_κB inhibiting protein I_κB_sThe interaction of (a), is maintained in the cytoplasm. In response to cellular stimuli, e.g. antiproliferative drugs or ionizing radiation, I_κThe B kinase complex (IKK) is rapidly activated and is shown at I_κNF of B_κIn the B binding domain, two serine residues are phosphorylated. Then the phosphorylated I_κB is degraded by 26S proteasome, and NF_κB is not degraded but transferred into the nucleus [ Wang,Science，274，784-787，1996，Cusak， Cancer Research，60，2323-2330，2000；Karin， Immunology，12，2000，85-98]. Thus, in the cell, NF_κB is always present, but in inactive form. NF following transfer into the nucleus_κB is especially inducible anti-apoptosis gene c-IAP1, c-IAP2, TRAF1, TRAF2, Bfi-1/A1, Bcl-X_LAnd Mn-SOD [ Platel,Oncogene，19，2000，4159-41699]rendering the cells anti-apoptotic. This effect is called NF_κAnti-apoptotic effects of B. Thus, antiproliferative drugs and ionizing radiation induce resistance of cells to treatments, rendering these treatments ineffective. Thus, active NF in inducing resistance, such as resistance of cancer cells to anti-proliferative drugs and/or ionizing radiation_κB is a key factor. Constitutive active NF_κThe fact that B is found in cancer tumor resistant cells further supports the above theory [ Patel,Oncogene，19，4159-4169，2000]. Regardless of the treatment to which the resistance is reduced, such as by controlling the activity of IKK, intracellular active NF_κA decrease in B levels will decrease the intracellular expression level of the gene encoding the anti-apoptotic factor Schwartz,Surgical Oncology，8，1999，143-153]。

active NF_κThe role of B is not limited to preventing apoptosis. At the same time, NF_κB is also an important inflammatory and immune gene activator. Active NF_κB induces a gene encoding cyclooxygenase 2(COX2), COX2 catalyzes the synthesis of proinflammatory prostaglandins. Furthermore, in the late phase of the inflammatory attack, COX2 catalyzes the synthesis of the anti-inflammatory cyclopentenone prostaglandins. COX2 is also known to have antiviral effects, suggesting NF in the treatment of inflammation and viral diseases_κB may also be an object [ Rossi,Nature，403，2000，103-108]。NF_κb is also responsible for the regulation of genes that play a central role in many other cellular life processes. Such as NF_κB regulates genes encoding cytokines and growth factors, adhesion molecules, acute phase reactants, receptors and chemoattractants [ Schwartz,Surgical Oncology，8，1999，143.153]. From Rossi atNatureThe reduction in 403, 103-108, 2000 further supports the idea that compounds of another type (i.e. cyclopentenone prostaglandins) are said to inhibit I_κB kinase, indicating that cyclopentenone prostaglandins have potential therapeutic effects in cancer, inflammation and viral infections.

I_κB and NF_κB is non-covalently bound, masking its nuclear localization signal, and thus preventing its transfer into the nucleus. A variety of different I's have now been identified_κBs, e.g. I expressed in most cells_κB alpha and I_κB β, they bind to p65 Rel protein in cells, i.e. NF_κB. In different stimulatory responses, different factors leading to NF-. kappa.B activation make different I_κAnd B phosphorylates.

I_κThe B kinase complex consists of three subunits, IKK α, IKK β and IKK γ, with a total molecular weight of 900 kDa. IKK alpha and IKK beta are both represented as I_κB kinase activity, and_κb is phosphorylated, while IKK γ is a regulatory subunit. IKK α is an 85kDa protein and IKK β is an 87kDa protein, both subunits showing a large degree of homology. Although both IKK α and IKK β are catalytically active, it has been surprisingly found that IKK provides I_κDuring B phosphorylation, only IKK β is necessary.

As described above, active NF can be controlled by controlling the activity of IKK_κB levels, for use as a therapeutic intervention in the treatment of proliferative diseases such as cancer, particularly resistant cancer. Control of IKK activity is also used in the treatment of inflammatory or viral diseases. Control of IKK activity can be used either as a sole therapy or as part of a combination therapy in combination with other therapeutic approaches.

Apoptosis is a genetically encoded cell death program characterized by a "positive determination" of death that a cell makes based on its own environment, its internal metabolism, developmental history, etc. Unlike necrosis, cells that have been stimulated into apoptosisOften capable of revival, but death is selected in order to benefit the whole organism. Necrosis is usually associated with traumatic tissue and cell lysis, while during apoptosis cells condense and degrade within the cell in a controlled manner, at which point apoptosis and necrosis are also distinct [ Tran,Science and Medicine，6，18-27，1999；Williams， Trends Cell Biol.，2，263-267，1992]。

in a preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I in combination with one or more other pharmacologically active compounds for the treatment of a proliferative disease. Examples of compounds that may be used in conjunction with the compounds of the present invention in the treatment of proliferative diseases include S-triazine derivatives, such as altretamine; enzymes, such as aspartase; antibiotics, such as bleomycin, actinomycin, daunorubicin, doxorubicin, demethoxydaunorubicin, mitomycin, epidaunorubicin, and plicamycin; alkylates such as busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, levo-sarcolysin, procarbazine and thiotepa; antimetabolites such as cladribine, cytarabine, floxuridine, fludarabine phosphate, fluorouracil, hydroxyurea, mercaptopurine, methotrexate, zalcitabine, pentostatin, and thioguanine; antimitotic agents such as etoposide, paclitaxel, teniposide, vinblastine, vinorelbine and vincristine; hormonal substances, such as aromatase inhibitors, e.g. aminophenylpiperidine ketone, corticosteroids, such as dexamethasone and prednisone, and luteinizing hormone-releasing hormone (LH-RH); antiestrogens such as tamoxifen, formestane and letrozole; antiandrogens, such as flutamide; biological response modifiers, for example lymphokines, such as atrazine and other interleukins; interferons, such as interferon alpha; growth factors such as erythropoietin, filgrastim and sargramostim; differentiating agents, for example vitamin D derivatives such as seocalcitol and all-trans retinoic acid; immunomodulators such as levamisole; and monoclonal antibodies, tumor necrosis factor alpha and angiogenesis inhibitors. Finally, although ionizing radiation is not readily defined as a compound, it is still widely used in the treatment of neoplastic diseases and may be combined with the compounds of the present invention. Since patients receiving antitumor therapy are often associated with severe side effects, it is also necessary to administer drugs that are not themselves antitumor, but are used to help alleviate the side effects. Such compounds include amifostine, leucovorin and mesna.

In particular, in the combined compositions of the invention, antiproliferative compounds such as paclitaxel, fluorouracil, etoposide, cyclophosphamide, cisplatin, carboplatin, vincristine, zalcitabine, vinorelbine, chlorambucil, doxorubicin, levo-sarcolysin and seocalcitol are effective.

It will be appreciated that in simultaneous or sequential administration, the combination compositions of the invention may be a mixture of compounds or may be separate compounds. The time interval in the continuous dosing regimen is determined by a medical professional or veterinarian within the skill of the art.

In particular, proliferative diseases or disorders that can be treated by the methods of the invention include various cancer and neoplastic diseases or disorders, including leukemia, acute myeloid leukemia; chronic myelogenous leukemia; chronic lymphocytic leukemia; myelodysplasia, multiple myeloma; hodgkin lymphoma or non-hodgkin lymphoma; small cell lung cancer or non-small cell lung cancer; gastric, intestinal or colorectal cancer; prostate, ovarian, or breast cancer; head, brain, or neck cancer; cancer of the urethra, kidney or bladder; malignant melanoma; liver cancer; uterine cancer or pancreatic cancer.

The invention also relates to the use of a compound of formula I, optionally in combination with other anti-tumor compounds as described above, in the preparation of a medicament, and. In particular, the medicament is used to treat proliferative diseases, such as the above-mentioned cancers.

Preparation method

Chemical shiftChloroform (d) as a relative to an internal standard tetramethylsilane (d 0.00) or chloroform (d 7.25) or deuterium¹³C NMR, δ 76.81) via¹Nuclear Magnetic Resonance (NMR) spectrum (300MHz) of H and¹³NMR (75.6MHz) measurement of C. Unless an interval is provided, multiple peaks are represented by approximate mid-point values, either defined as (singlet(s), doublet (d), triplet (t), quartet (q)) or indeterminate (broadpeak (br)). The organic solvent used is an anhydrous solvent.

Preparation 1

3- [6- (N-tert-Butoxycarbonylamino) -1-hexyl-oxy]-pyridine

3-hydroxypyridine (262mg) was added to a suspension of 60% sodium hydride (128mg) in N, N-dimethylformamide (5ml), and the mixture was stirred at 60 ℃ for 30 minutes. After cooling in ice, a solution of N- (tert-butoxyhydroxy) -6-bromo-hexylamine (770mg) (helv, chim. acta 76891 (1993)) dissolved in N, N-dimethylformamide (3ml) was added dropwise and stirred at room temperature overnight. Ice and water were added and the mixture was extracted three times with diethyl ether. The organic phase is washed with saturated sodium chloride, dried and evaporated, leaving a yellow oil which is purified by silica gel chromatography using diethyl ether as eluent to give the desired colorless oil.

¹H NMR(CDCl₃)δ＝8.29(bs，1H)，8.20(m，1H)，7.18(m，2H)，4.53(bs，1H)，4.00(t，2H)，3.13(q，2H)，1.80(m，2H)，1.44(s，9H)，1.60-1.30(m，6H)

Preparation 2

3- [ 6-amino-1-hexyl-oxy]-pyridine hydrochloride

3- [6- (N-tert-Butoxycarbonylamino) -1-hexyl-oxy ] -pyridine (180mg) was treated with excess hydrogen chloride in diethyl ether, stirred for 45 min and evaporated in vacuo. Trituration with ether, decantation and evaporation gave the title compound as a colorless powder.

¹H NMR(DMSO)δ＝8.64(d，1H)，8.46(d，1H)，8.08(m，1H)，8.08(bs，3H)，7.88(dd，1H)，4.20(t，2H)，2.74(m，2H)，1.76(m，2H)，1.59(m，2H)，1.41(m，4H)

Preparation 3

3- [ 6-amino-1-hexyl-oxy]-pyridine

The 3- [ 6-amino-1-hexyl-oxy ] -pyridine hydrochloride aqueous solution was made strongly basic with sodium hydroxide and extracted twice with chloroform. The organic phase was dried in vacuo and evaporated to give a yellow oil which was used in the next step without further purification.

Preparation 4

1- [6- (N-tert-Butoxycarbonylamino) -1-hexyl radical]-imidazoles

Imidazole (70mg) and 1.4M sodium salt of methanol (1ml) were added to N, N-dimethylformamide (3ml), and the mixture was stirred at room temperature for 30 minutes. A solution of N-tert-butoxycarbonyl-6-bromo-hexylamine (280mg) in N, N-dimethylformamide (1ml) was added thereto, and the mixture was heated at 80 to 90 ℃ for 30 minutes and then stirred at room temperature overnight. After evaporation in vacuo, stirring with acetone and filtration to give a filtrate, which after evaporation is purified by chromatography on silica gel using ethyl acetate/methanol (4: 1) as eluent to give the title compound as a colourless oil.

¹H NMR(CDCl₃)δ＝7.46(t，1H)，7.05(t，1H)，6.90(t，1H)，4.60(bs，1H)，3.92(t，2H)，3.08(q，2H)，1.76(m，2H)，1.44(s，9H)，1.44(m，2H)，1.32(m，4H)

Preparation 5

1- (6-amino-1-hexyl) -imidazole hydrochloride

The preparation is as described in preparation 2, with the only difference that 1- [6- (N-tert-butoxycarbonylamino) -1-hexyl ] -imidazole is used instead of 3- [6- (N-tert-butoxycarbonylamino) -1-hexyl-oxy ] -pyridine. Colorless crystals.

¹H NMR(DMSO)δ＝14.99(bs，1H)，9.31(t，1H)，8.23(bs，3H)，7.86(t，1H)，7.71(t，1H)，4.22(t，2H)，2.73(m，2H)，1.81(m，2H)，1.58(m，2H)，1.36(m，2H)，1.23(m，2H)

Preparation 6

1- (6-amino-1-hexyl) -imidazole;

the preparation is as described in preparation 3, with the only difference that 3- [ 6-amino-1-hexyl-oxy ] -pyridine hydrochloride is replaced by 1- (6-amino-1-hexyl) -imidazole hydrochloride. A colorless oil.

Preparation 7

2- [6- (N-tert-Butoxycarbonylamino) -1-hexyl-oxy]-quinolines

The compound was prepared as described in preparation 1, with the only difference that 2-hydroxyquinoline was substituted for 3-hydroxypyridine. The crude product was purified by silica gel chromatography using ethyl acetate as eluent to afford the desired compound as a colorless oil.

¹H NMR(CDCl₃)δ＝7.66(d，1H)，7.56(m，2H)，7.35(bd，1H)，7.22(m，1H)，6.70(d，1H)，4.57(bs，1H)，4.28(m，2H)，3.12(m，2H)，1.75(m，2H)，1.44(s，9H)，1.55-1.35(m，6H)

Preparation 8

2- (6-amino-1-hexyl-oxy) -quinoline

2- [6- (N-tert-Butoxycarbonylamino) -1-hexyl-oxy ] -quinoline (480mg) was treated with excess hydrogen chloride in diethyl ether and stirred at room temperature for 1 hour. The crystals were separated by filtration, redissolved in water, made to be strongly basic with sodium hydroxide, and extracted twice with chloroform. The organic phase was dried over potassium carbonate, filtered and evaporated to give the title compound as a colorless oil.

¹H NMR(CDCl₃)δ＝7.66(d，1H)，7.56(m，2H)，7.36(m，1H)，7.22(m，1H)，6，69(d，1H)，4.29(m，2H)，2.70(t，2H)，1.76(m，2H)，1.65(bs，2H)，1.45(m，6H)

Example 1

N- [6- (3-pyridyl) -1-hexyl]-N '-cyano-N' - (4-pyridyl) -guanidine

A mixture of 3- [ 6-amino-1-hexyl-oxy ] -pyridine (150mg), S-methyl-N-cyano-N' -4-pyridyl-isothiourea (123mg), triethylamine (0.18ml), 4- (N, N-dimethylamino) -pyridine (3.5mg) and pyridine (5ml) was stirred at 60 ℃ overnight. After cooling to room temperature, it was evaporated twice with toluene in vacuo to remove pyridine and the residue was distributed between water and ethyl acetate. The organic phase is dried and evaporated and the crude product obtained is purified by chromatography on silica gel using ethyl acetate/methanol/aqueous ammonia (40: 10: 2.5) as eluent. The pure fractions were collected and evaporated, and the title compound was crystallized from ethyl acetate.

¹H NMR(DMSO)δ＝9.40(bs，1H)，8.38(bd，2H)，8.28(d，1H)，8.15(dd，1H)，7.86(bt，1H)，7.37(m，1H)，7.31(dd，1H)，7.22(bs，2H)，4.04(t，2H)，3.28(q，2H)，1.74(m，2H)，1.56(m，2H)，1.40(m，4H)

Example 2

N- [6- (1-imidazolyl) -1-hexyl]-N' -cyano-N "- (4-pyridyl) -guanidine;

the compound was prepared as described in example 1, the only difference being the substitution of 1- (6-amino-1-hexyl) -imidazole for 3- [ 6-amino-1-hexyl ] -pyridine.

¹H NMR(DMSO)δ＝9.35(bs，1H)，8.39(m，2H)，7.86(bt，1H)，7.61(t，1H)，7.22(m，2H)，7.14(t，1H)，6.88(t，1H)，3.94(t，2H)，3.26(q，2H)，1.70(m，2H)，1.52(m，2H)，1.27(m，4H)

Example 3

N- [6- (2-quinolyl-oxy) -1-hexyl]-N, -cyano-N "- (4-pyridyl) -guanidine;

the preparation is as described in example 1, with the only difference that 2- (6-amino-1-hexyl-oxy) -quinoline is substituted for 3- [ 6-amino-1-hexyl-oxy ] -pyridine.

¹H NMR(DMSO)δ＝9.39(bs，1H)，8.38(m，2H)，7.90(d，1H)，7.87(bt，1H)，7.73(m，1H)，7.62(m，1H)，7.55(bd，1H)，7.30-7.10(m，3H)，6.61(d，1H)，4.23(m，2H)，3.27(q，2H)，1.61(m，2H)，1.54(m，2H)，1.39(m，4H)

Example 4

N- [6- (3-pyridyl) -1-hexyl]-N' -cyano-N "- (4-pyridyl) -guanidine;

the preparation is as described in example 1, with the only difference that 3- [ 6-amino-1-hexyl-oxy ] -pyridine is replaced by 3- (6-amino-1-hexyl) -pyridine.

¹³C NMR(DMSO)δ＝157.0，150.1，149.5，146.9，145.8，137.4，135.6，123.3，116.4，114.5，41.7，31.9，30.4，28.5，28.1，25.8

Example 5

N- [6- (3-quinolyl) -1-hexyl]-N' -cyano-N "- (4-pyridyl) -guanidine;

the preparation is as described in example 1, with the only difference that 3- [ 6-amino-1-hexyl-oxy ] -pyridine is replaced by 3- (6-amino-1-hexyl) -quinoline.

¹³C NMR(DMSO)δ＝157.0，151.9，150.1，146.2，145.7，135.0，133.7，128.5，128.4，127.7，127.5，126.4，116.4，114.5，41.7，32.1，30.3，28.5，28.1，25.8

Example 6

N- [6- (5-pyrimidinyl) -1-hexyl]-N' -cyano-N "- (4-pyridyl) -guanidine;

the preparation is as described in example 1, with the only difference that 5- [ 6-amino-1-hexyl ] -pyrimidine is substituted for 3- [ 6-amino-1-hexyl-oxy ] -pyridine.

¹³C NMR(DMSO)δ＝157.1，156.6，156.2，149.9，145.5，135.3，116.3，114.4，41.7，29.9，29.2，28.4，28.0，25.7

Claims (10)

1. A compound of formula I:

wherein R1 is hydrogen;

x is C_4-12A hydrocarbon diradical;

y is a bond or O;

z is an aromatic or non-aromatic heterocyclic group having 5 to 12 ring atoms, optionally substituted with hydroxy;

provided that R1 is not attached to a nitrogen atom in the pyridine ring and Z is not tetrahydropyranyl.

2. A compound according to claim 1, wherein R1 is hydrogen; x is saturated C_4-12A hydrocarbon diradical;

y is a bond or O;

z is an aromatic or non-aromatic heterocyclic group having 5 to 10 ring atoms.

3. A compound according to claim 1, wherein R1 is hydrogen;

x is straight-chain saturated C_5-10A hydrocarbon diradical;

y is a bond or O;

z is an aromatic heterocyclic group having 5 to 10 ring atoms.

4. A compound according to claim 2 or 3 wherein Z is pyridyl, imidazolyl, quinolinyl or pyrimidinyl.

5. A compound according to claim 1, selected from:

n- [6- (3-pyridyl-oxy) -1-hexyl ] -N' -cyano-N "- (4-pyridyl) -guanidine;

n- [6- (1-imidazolyl) -1-hexyl ] -N' -cyano-N "- (4-pyridyl) -guanidine;

n- [6- (2-quinolyl-oxy) -1-hexyl ] -N' -cyano-N "- (4-pyridyl) -guanidine;

n- [6- (3-pyridyl) -1-hexyl ] -N' -cyano-N "- (4-pyridyl) -guanidine;

n- [6- (3-quinolinyl) -1-hexyl ] -N' -cyano-N "- (4-pyridyl) -guanidine; and

n- [6- (5-pyrimidinyl) -1-hexyl ] -N' -cyano-N "- (4-pyridyl) -guanidine;

6. a pharmaceutical composition comprising a compound according to any one of claims 1 to 5, and further comprising a pharmaceutically acceptable excipient.

7. A composition according to claim 6 in dosage unit form.

8. Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of an inflammatory disease.

9. Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of a proliferative disease.

10. Use according to claim 9, wherein said proliferative disease is selected from: leukemia; acute myeloid leukemia; chronic myelogenous leukemia; chronic lymphocytic leukemia; myelodysplasia; multiple myeloma; hodgkin lymphoma or non-hodgkin lymphoma; small cell lung cancer or non-small cell lung cancer; gastric, intestinal, or colorectal cancer; the prostate; ovarian or breast cancer; head, brain, or neck cancer; cancer of the urethra, kidney or bladder; malignant melanoma; liver cancer, uterine cancer or pancreatic cancer.