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  • A61K31/4164—1,3-Diazoles
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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  • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
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  • C07D401/14—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 three or more hetero rings
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  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• This invention relates to novel compounds that posses antineoplastic activity.
• the present invention relates to novel derivatives of 2-aminoimidazoline having various sulfonyl substituents at position 1 and alkyl or aryl substituents at position 4, their tautomers, pharmaceutically acceptable salts, hydrates, solvates, and prodrugs, processes for their preparation, their use as antitumor drugs and pharmaceutical compositions containing them as active ingredients.
• the cell cycle is an ordered set of events, culminating in cell growth and division into two daughter cells. It consists of four distinct stages: gap number 1 (Gl); synthesis (S); gap number 2 (G2) and mitosis or cell division (M). Control of the cell cycle is very complex and involves regulation at a number of levels. Cell cycle checkpoints are regulatory pathways that control the order and timing of cell cycle transitions and ensure that critical events such as DNA replication and chromosome segregation are completed correctly before letting the cell progress further through the cycle.
• G2/M checkpoint In cancerous cells, the normal regulatory processes are disrupted and cell growth is uncontrolled.
• One of the main abnormalities in human cancer cells is the loss of the Gl phase checkpoint, primarily due to mutations in p53. Consequently, enforcement of the G2/M checkpoint represents an attractive mode of action for new antineoplastic agents, as sustained arrest of cancer cells in G2/M phase triggers cell death by apoptosis.
• G2/M progression is tightly regulated by several cellular macromolecules, including tubulins, microtubule-associated proteins and motor proteins, such as kinesins and dynesins.
• Targeting the G2/M checkpoint has been clinically validated with drugs that either stabilize (taxanes) or disrupt (vinca alkaloids) microtubule formation.
• the importance of G2/M arrest was also validated in the clinic with drugs that have different molecular targets, e.g., Velcade (proteasome inhibitor).
• arylsulfonylimidazolone derivatives were disclosed as antineoplastic agents, with activity superior to the known antitumor sulfonylureas (U.S. Patent No. 5,932,742).
• those compounds are not soluble in water, which is a serious disadvantage for cytotoxic anticancer agents that commonly are administered in highly controlled manner as slow iv injections.
• This invention provides a new class of 2-aminoimidazoline derivatives containing substituted sulfonyl moiety attached to the nitrogen at position 1 and aliphatic or aromatic substituent attached to the carbon at position 4, and their use as antineoplastic agents.
• the compounds of the invention have a general structure presented in Formula (I),
• a heterocyclic moiety having more than 6 carbon atoms and one or more nitrogen, sulfur and/or oxygen atoms.
• the moieties may contain the atoms in a single ring or in fused rings and can be saturated or unsaturated and additionally substituted with amino or carboxy groups.
• heterocyclic moieties include indolyl, quinolyl, chromanyl, benzimidazolyl, benzoxazolyl, benzothienyl, benzofuranyl, and quinolinyl.
• X is a hydrogen atom, carbonyl, thiocarbonyl or imine.
• R 3 is null.
• R 3 is:
• R' is hydrogen or alkyl
• n 0-3
• R" is unsubstituted or substituted alkyl, cycloalkyl, phenyl, benzyl, a 5- or 6-membered, optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, and
• R' and R" can be connected or not;
• the invention also encompasses tautomers, pharmaceutically acceptable salts, hydrates, solvates, and prodrugs of the above-defined compounds of Formula (I).
• halo as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
• alkyl as used herein is intended to include straight chain, branched and cyclic alkyl groups, being saturated monovalent hydrocarbon radicals.
• the straight alkyl may have 1-20, preferably 1-10, more preferably 1-7 carbon atoms.
• the branched and cyclic alkyls may have 3-20, preferably 3-10, more preferably 3-7 carbon atoms.
• Lower alkyl denotes alkyl having up to 7 carbon atoms.
• alkenyl as used herein, unless otherwise indicated, includes monovalent hydrocarbon radicals having at least one carbon-carbon double bond and also having straight, cyclic or branched moieties as provided above in the definition of "alkyl". As used herein, alkenyl may have 2-20, preferably 2-10, more preferably 2-7, carbon atoms.
• alkynyl as used herein, unless otherwise indicated, includes monovalent hydrocarbon radicals having at least one carbon-carbon triple bond and also having straight, cyclic or branched moieties as provided above in the definition of "alkyl". As used herein, alkynyl may have 2-20, preferably 2-10, more preferably 2-6, carbon atoms.
• alkoxy as used herein, unless otherwise indicated, includes (9-alkyl groups wherein “alkyl” is as defined above.
• aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl. As used herein, aryl may have 6-18, preferably 6-12, more preferably 6-10, ring carbon atoms.
• 4-10 membered heterocyclic includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system.
• Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
• An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine).
• An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl.
• non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl,
• tetrahydrothienyl tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, 2- pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imid
• aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
• a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached).
• heterocyclic groups may have up to 20 atoms in their ring systems.
• phrases "pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups, which may be present in the compounds of Formula (I).
• the compounds of Formula (I) that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• the acids that may be used to prepare pharmaceutical acceptable acid addition salts of such basic compounds of Formula (I) are those that form non-toxic acid addition salts, i.e.
• salts containing pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate (4,4'-methylenebis(3-hydroxy-2-naphthoate)) salts.
• pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisul
• Those compounds of the Formula (I) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
• Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the sodium and potassium salts, and also organic amine as well as ammonium salts.
• Certain compounds of Formula (I) may have asymmetric centers and therefore exist in different enantiomeric forms.
• This invention relates to the use of all optical isomers and stereoisomers of the compounds of Formula (I) and mixtures thereof.
• the compounds of Formula (I) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
• the subject invention also includes isotopically-labelled compounds, and the pharmaceutically acceptable salts thereof, which are identical to those recited in Formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, and 36 C1, respectively.
• Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
• Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon- 14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
• Isotopically labelled compounds of Formula (I) of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
• Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more ⁇ e.g. , two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of Formula (I).
• the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine,
• prodrugs can be derivatized as amides or alkyl esters.
• the amide and ester moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
• Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and
• phosphoryloxymethyloxycarbonyls as outlined in D. Fleisher, R. Bong, B. H. Stewart, Advanced Drug Delivery Reviews (1996) 19, 115.
• Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs and sulfate esters of hydroxy groups.
• Derivatization of hydroxy groups as (acyloxy) methyl and (acyloxy) ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in R. P. Robinson et al., . Medicinal Chemistry (1996) 39, 10.
• the compounds of this invention may be prepared from the appropriate starting materials. It is intended that where optical isomers are available, the pure isomers and diastereoisomers, and any and all mixtures thereof, be within the scope of the claims.
• the exemplified compounds, and the methods for their preparation, are presented merely by way of example, and the presentation of selected examples is not intended to limit the scope of the invention.
• Compounds 3 can also be converted in one-step into 5 by treatment with trifluoroacetic acid in DCM.
• R 2 in Formula (I) represents a heterocyclic system, especially indoline, to which additional substituent R 3 is connected through the carbonyl group.
• R 3 is connected through the carbonyl group.
• a mild hydrolysis of compound 6 provides deprotected intermediate 10, which is than transformed into 11 by reaction with carbonyl diimidazole.
• the activated intermediate 10 undergoes reaction with a variety of nucleophiles, for example amines, alcohols, thiols, etc. which, following removal of the Boc protection, lead to compounds 8 (Formula I).
• Another object of this invention is to provide a method of treating a mammal suffering from cancer or another disease characterized by undesirable cell proliferation, with the compounds of the invention.
• the method of the invention comprises
• a preferred use of compounds of this invention is to treat disorders selected from breast, colorectal, lung, prostate, bladder, brain, head and neck, renal, kidney, squamous cell, esophageal, gastric, thyroid, pancreatic, skin, bone, liver, ovarian and gynecological cancer, sarcomas, melanoma and hematological malignancies (acute and chronic lymphocytic and myelogenous lekemias, Hodgkin and non-Hodgkin lymphomas, mycosis fungoides, Sezary syndrome), and pre-malignant diseases (lymphoproliferative disorders).
• Another areas of use of compounds of this invention are disorders associated with lymphocyte proliferation in organ transplantation, inflammatory, allergic or autoimmune disease selected from the group of asthma, psoriasis, rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythromatosus, vasculitis, vascular hyperproliferation, diabetic retinopathy, liver cirrhosis, and gout.
• the dose of the compound used in the treatment of such disease will vary in the usual way with the weight and metabolic health of the patient, the severity of any side effects, and the relative efficacy of the compound employed when used against the type of tumor involved.
• the preferred initial dose for the general patient population will be determined by routine dose-ranging studies, as is conducted for example during clinical studies.
• Therapeutically effective doses for individual patients may be determined by titrating the amount of drug given to the individual to arrive at the desired therapeutic effect without incurring an unacceptable level of side effects, as is currently and routinely done with other forms of chemotherapy.
• Administration of the compounds of this invention may be by any method used for administering therapeutics, such as for example oral, intravenous, intramuscular, subcutaneous, or rectal administration.
• compositions useful for providing anti-proliferative including anti-tumor activity which comprise at least one compound of the invention.
• the pharmaceutical composition may also comprise additives such as preservatives, excipients, fillers, wetting agents, binders, disintegrants, buffers, and/or carriers.
• additives such as preservatives, excipients, fillers, wetting agents, binders, disintegrants, buffers, and/or carriers.
• compositions or formulations according to the invention may be dissolved or suspended as known in the art in a vehicle suitable for injection or infusion.
• vehicles include isotonic saline, buffered or unbuffered, D5W, and the like. They also may contain other ingredients, including other active ingredients.
• compositions may also be in the form of controlled release or sustained release compositions as known in the art, for instance, in matrices of biodegradable or non- biodegradable injectable polymeric microspheres or microcapsules, in liposomes, in emulsions, and the like.
• novel compounds of this invention may be used per se (free base), or in the form of their pharmaceutically acceptable, water-soluble addition salts, such as hydrochlorides, hydrobromides, acetates, sulfates, methanesulfonates, citrates, and the like.
• Example 1 The present invention is illustrated by the following Examples.
• Example 1 The present invention is illustrated by the following Examples.
• the water layer was adjusted to pH ⁇ 7 by the addition of 10% citric acid and shaken well.
• the organic layer was separated, dried with MgS04 and condensed.
• a jellylike product was formed after the addition of ether.
• the product was filtered, washed with ether and dried.
• Cell growth inhibitory activity of compounds of this invention was determined using a standard MTT assay.
• Adherent cells of colon human tumor (HT-29) sourced from ATCC (cells number: HTB-38) were treated with DMSO solutions of tested compounds with the ultimate concentration of DMSO in the test solution being 0.1%.
• MTT was added, and after a brief incubation the resulting formazan was dissolved in addional DMSO and the solutions were scanned using 570 nm wavelength.
• MTT assay after 72 hr exposure to a tested compound Ranges of cell growth inhibitory activities are defined as follows: A: ⁇ 100 nM, B: 100-500 nM, C: >500 nM.

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