OA16304A - Cyclic N, N'-diarylthioureas and N, N'diarylureas as androgen receptor antagonists, anti-cancer agent, method for producing and using same. - Google Patents
Cyclic N, N'-diarylthioureas and N, N'diarylureas as androgen receptor antagonists, anti-cancer agent, method for producing and using same. Download PDFInfo
- Publication number
- OA16304A OA16304A OA1201300026 OA16304A OA 16304 A OA16304 A OA 16304A OA 1201300026 OA1201300026 OA 1201300026 OA 16304 A OA16304 A OA 16304A
- Authority
- OA
- OAPI
- Prior art keywords
- methyl
- cyclic
- isomers
- androgen receptor
- group
- Prior art date
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- 125000004122 cyclic group Chemical group 0.000 title claims abstract description 28
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- 238000004519 manufacturing process Methods 0.000 title description 2
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- IQPQWNKOIGAROB-UHFFFAOYSA-N [N-]=C=O Chemical compound [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000000844 anti-bacterial Effects 0.000 description 1
- 230000000843 anti-fungal Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000038129 antigens Human genes 0.000 description 1
- 108091007172 antigens Proteins 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000000477 aza group Chemical group 0.000 description 1
- 244000052616 bacterial pathogens Species 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium(0) Chemical class [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical class [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000007374 clinical diagnostic method Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 101700038865 dec-1 Proteins 0.000 description 1
- 101710015544 decr-1.2 Proteins 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical class CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical class OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005368 heteroarylthio group Chemical group 0.000 description 1
- 125000005842 heteroatoms Chemical group 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M laurate Chemical class CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical class [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical class CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical class [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000069 prophylaxis Effects 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical class CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical class NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
Abstract
The invention relates to novel cyclic N,N'diarylureas and N,N'-diarylthioureas as androgen receptor antagonists, an anti-cancer agent, a pharmaceutical composition, a drug and a method for treating cancerous diseases, including prostate cancer. Cyclic N,N'-diarylthioureas or N,N'-diarylureas of general formula 1, the optical (R)- and (S)isomers thereof and pharmaceutically acceptable salts thereof having androgen receptor antagonist properties are proposed,
Description
The invention relates to novel cyclic Ν,Ν’-diarylthioureas and Ν,Ν’-diaryIureas androgen receptor antagonists, anti cancer agent, pharmaceutical composition, médicament and method for treatment of cancer including prostate cancer.
Prior art
There are known androgen receptor antagonists which are -l,3-diaryl-5,5-dimethyl-2thioxoiniidazolidin-4-ones I, 5,7-diaryl-6-thioxo-5,7-diazaspiro[3,4]octan-8-ones II and 1,3diaryL2-thioxo-l,3-diazaspiro[4,4]nonan-4-ones III exhibiting anticancer activity [W02006124118, W02007127010], Amongst these compounds the most promoted is 4-[3-[4cyano-3-(trifluoromethyl)phenyl]-5,5-diniethyl-4-oxo-2-thioxoimidazolidin-l-yl]-2-fluoro-N' methylbenzamide MDV3100 (androgen receptor antagonist with ICjq = 36 nM), which is now in the III phase of clinical trials as médicament for prostate cancer treatment [Drug Data Rep., 2009, 31(6), 609].
I II III MDV3100
Searching for highly effective anticancer médicaments exhibiting enhanced activity and reduced toxicity, is still one of the main directions in the development of novel pharmacological remédies for cancer treatment, including prostate cancer. In this context the development of
I
I novel anticancer active agents, pharmaceutical compositions and médicaments, and also methods for their préparation and use is of essential importance.
Disclosure of the invention
In the context of the invention, the tenns are generally defined as follows:
“Azaheterocycle” means an aromatic or non aromatic mono- or poly- cyclic System, comprising at least one nitrogen atom in the cycle. Azaheterocycle may hâve one or more “cyclic System” substituents.
“Active composent” (drug-substance) means a physiologically active compound of synthetic or other origin (biotechnological, vegetable, animal, microbe and so on), exhibiting phaimacological activîty and being an active component of pharmaceutical composition, employing in production and préparation of médicaments.
“Alkyl” means an aliphatic hydrocarbon straight or branched chain with 1-12 carbon atoms. Branched means an alkyl chain wîth one or more “lower alkyl” substituents. Alkyl group may hâve one or more substituents of the same or different structure (“alkyl substituent”) including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylihio, arylsulfonyl, alkylsulfonylheteroaralkyloxy and so on.
“Antagonists” mean ligands which being bound to definite receptors not cause active cellular responses. Antagonists prevent linkage between agonists and receptors and by that block spécifie receptor signal transmission.
“Aryl” means aromatic mono- or poly- cyclic System with 6-14 carbon atoms, predominantly 6-10 carbon atoms. Aryl may hâve one or more “cyclic System substituents” of the same or different structure. Phenyl, substituted phenyl, naphthyl, or substituted naphthyl are the représentatives of aryl groups. Aryl could be annelated with nonaromatic cyclic System or heterocycle.
“Heterocyclyl” means aromatic or saturated mono- or polycyclic System with 3 - 10 carbon atoms, preferably from 5 to 6, wherein one or more carbon atoms are substituted by one or more heteroatoms, such as N, S or O. Prefïx “aza”, “oxa” or “thia” before “heterocyclyl” means that N, O or S atoms are introduced in the cycle, respectively. Heterocyclyl may hâve one or more “cyclic system sustituents” of the same or different structure. N- and S- atoms of heterocyclyl cycle could be oxidized to N-oxide, S-oxide or S-dioxide. Piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, fhiazolidinyl, 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiophenyl and others are examples of heterocyclyl.
“Hydrate” means stoichiometric or nonstoichiometric compositions of compounds or their salts with water.
“Substituent” means a chemical radical attached to scaffold (fragment), for example, “alkyl substituent”, “amino group substituent”, “carbamoyl substituent”, and “cyclic System 5 substituent”, the meanings of which are defined in this section.
“Médicament” - is a compound (or mixture of compounds in the form of pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other ready forms intended for restoration, improvement or modification of physiological functions at humans and animais, and also for treatment and prophylaxis of diseases, diagnostics, 10 anesthésia, contraception, cosmetology and others.
“Lower alkyl” means a straight or branched alkyl with 1-4 carbon atoms.
“Pharmaceutical composition” means a composition comprising a compound of general formula 1 and at least one of components selected from the group consisting of pharmaceutically acceptable and pharmacologicaly compatible Allers, solvents, diluents, 15 auxilîary, distributing and sensing agents, delivery agents, such as preservatives, stabilizers, disintegrators, moîsteners, emulsifîers, suspending agents, thickeners, sweeteners, flavouring agents, aromatizing agents, antibacterial agents, fongicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which dépend on the nature and way of administration and dosage. Examples of suitable suspending agents are ethoxylated isostearyl 20 alcohol, polyoxyethene, sorbîtol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacant and their mixtures as well. Protection against the action of microorganisms can be provided by various antibacterial and antifungal agents, such as, for example, parabens, chlorobutanole, sorbic acid, and similar compounds. Composition may also contain isotonie agents, such as, for example, sugar, sodium chloride, 25 and similar compounds. Prolonged effect of composition may be achîeved by agents slowing down absorption of active ingrédient, for example, aluminum monostearate and 'gélatine. Examples of suitable carriers, solvents, diluents and delivery agents include water, éthanol, polyalcohols and their mixtures, natural oils (such as olive oil) and organic esters (such as ethyl oleate) for injections. Examples of Allers are lactose, milk-sugar, sodium citrate, calcium 30 carbonate, calcium phosphate and the like. Examples of disintegrators and distributors are starch, alginic acid and its salts, and silicates. Examples of suitable lubricants are magnésium stéarate, sodium lauryl sulfate, talc and polyethylene glycol of high molecular weight. Pharmaceutical composition for pérorai, sublingval, transdermal, întramuscular, intravenous, subcutaneous, local or rectal administration of active ingrédient, alone or in combination with another active compound may be administered to hum ans and animais in standard administration form, or in mixture with traditional pharmaceutical carriers. Suitable standard administration forms include pérorai forms such as tablets, gelatin capsules, pills, powders, granules, chewing-gums and pérorai solutions or suspensions, sublingval and transbuccal administration forms; aérosols; implants; local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of introduction and rectal administration forms. Pharmaceutical compositions are usually prepared by means of standard procedures by mixing an active compound with liquid or overgrounded solid carrier.
“Pharmaceutically acceptable sait” means a relatively nontoxic both organic and inorganic salts of acids and bases disclosed in this invention. Salts could be prepared in situ in processes of synthesîs, isolation or purification of compounds or be prepared specially. In particular, bases salts could be prepared starting from purified base of disclosed compound and suitable organic or minerai acid. Examples of salts prepared in this manner include hydroch!ondes, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acétates, oxalates, valeriates, oleates, palmitates, stéarates, laurates, borates, benzoates, lactates, ptoluenesulfonates, citrates, maleates, fumarates, succinates, tartrates, methane sulphonates, malonates, salicylates, propionates, ethane sulphonates, benzene sulfonates, sulfamates and the like (Detailed description of properties of such salts is given in: Berge S.M., et al., “Pharmaceutical Salts” J.Pharm.Sci., 1977, 66: 1-19). Salts of disclosed acids may be also prepared by reaction of purified acids specifically with suitable base; moreover, métal salts and amine salts may be synthesized too. Métal salts are salts of sodium, potassium, calcium, barium, magnésium, zink, lithium and aluminum, sodium and potassium salts being preferred. Suitable inorganic bases from which métal salts can be prepared are sodium hydroxide, carbonate, bicarbonate and hydride; potassium hydroxide, carbonate and bicarbonate, lithium hydroxide, calcium hydroxide, magnésium hydroxide, zinc hydroxide. Organic bases suitable for préparation of disclosed acid salts are amines and amino acids of sufficient basicity to produce stable sait suitable for medical purposes use (in particular, they are to hâve low toxîcity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris(hydroxymethyl)aminomethane and the like. Besides, salts can be prepared using some tetraalkylammonium hydroxides, such as holine, tétraméthylammonium, tetraethylammonîum, and the like. Aminoacids may be selected among main aminoacids - lysine, omithine and agrinine.
The authors hâve disclosed novel cyclic Ν,Ν’-diarylthioureas and Ν,Ν’-diarylureas of the general formula 1, optical (R)- and (S)- isomers and pharmaceutically acceptable salts thereof which are androgen receptor antagonîsts:
wherein:
X represents oxygen or sulfur;
m = 0 or 1 ;
RI represents C]-C3aikyl;
R2 and R3 represent hydrogen; or
R2 and R3 together with the C-atom they are attached to fonn C = O group;
R4 and R5 represent hydrogen; or
R4 represents hydrogen, R5 represents methyl; or
R4 represents methyl, R5 represents CH2R6 group in which R6 îs C1-C3 alkoxycarbonyl; cafboxyl; hydroxyl group optionally substituted with methyl or benzyl; or
R5 and R4 together with the C-atom they are attached to form 5- or 6- membered heterocycle comprising at least one oxygen atom or nitrogen atom optionally substituted with methyl; or R4 and R5 together with the C-atom they are attached to represent NH group.
The preferred compounds are Ν,Ν’-diarylthioureas and Ν,Ν’-dîarylureas, their optical (R)- and (S)- isomers and pharmaceutically acceptable salts of the general formulas 1.2,1.3 or 1.4:
1.2 1.3 1.4 wherein:
X, RI, R2, R3, R4 and R5 hâve the above meanings,
The more préférable compounds are cyclic Ν,Ν’-diarylthioureas of formulas 1.2(1), 1.2(2), 1.2.2 and 1.2.3, their optical (R)-isomers - (R)-1.2(2), (R)-1.2.2, (R)-1.2.3 and (S)isomers - (S)~1.2(2), (S)-1.2.2 and (5)-1.2.3:
1-2(1) 1.2(2)
1.2.2 1.2.3
R5 (R}-1.2(2) (RJ-1.2.2 (R)-1.2.3
(S)-1.2{2) (SJ-1.2.2 (S)-1.2.3 wherein:
R5 and R4 together with the C-atom they are attached to form 5- or 6- membered heterocycle comprising at least one oxygen atom or nitrogen atom optionally substituted with methyl, R6 has the meaning mentioned above.
The more préférable compounds are also compounds of formulas 1.2.2(1), 1.2.2(2), 1.2.2(3), 1.2.3(1), 1.2.3(2) and 1.2.3(3), their optical (R)-isomers - (R)-1.2.2(l), (R)-1.2.2(2), (R)-1.2.2(3), (R)-1.2.3(l), and (S)-isomers - (S)-I.2.2(l), (S)-1.2.2(2), (S)-1.2.2(3), (S)-1.2.3(l), or a pharmaceutically acceptable sait thereof,
1.2.2(1): R6 =OCH3;
1.2.2(2): R6 =OCH2Ph;
1.2.2(3): R6 = OH;
(R}-1.2.2(1): R6=OCH3;
(R}-1.2.2(2): R6=OCH2Ph;
(R}-1.2.2(3): R6=OH;
(S)-1.2.2(1 ):R6 =OCH3;
(S)-1.2.2(2): R6 = OCH2Ph;
(S)-1.2.2(3): R6 = 0H;
cf3
1.2.3(1) (R)-1.2.3(1) (S)-1.2.3(1)
O.F CF.
CH3
1.2.3(2) 1.2.3(3) wherein R6 represents hydroxyl group optionally substituted with methyl or benzyl,
The subject of the présent invention is a method for préparation of compounds of the
10. general formula 1.2 and optical (R)- and (S)- isomers thereof.
1,3-DiaryIhydantoines of the general formula 1.2 are prepared by interaction of isothiocyanate 3.2 with the corresponding 4-(cyanomethyl)aminobenzamides 4.1 or (4carbamoylphenylamino) acetic acids 4.2 according to scheme 1.
s
CONHR1
4.1: W = CN
4.2: W =CO2H wherein:
RI, R4 and R5 hâve the above meanings.
Scheme 1.
Optically active cyclic Ν,Ν’-diarylthioureas, (R)-1.2 and (S)-1.2 isomers, are prepared either trom the corresponding optically active (R)-4.1, (R)-4.2, (S)-4.1 and (S)-4.2 starting materials, or by resolution of racemic mixtures of cyclic Ν,Ν’-diarylthioureas 1.2 to enantiom ers.
CONHR1 (RH-2
C0NHR1 (S)-1.2
wherein:
RI, R4 and R5 hâve the above meanings.
l,3-Diaryltetrahydropyrimidin-2-ones of the general formula 1.3.1 are prepared by interaction of the corresponding N,N '-diarylureas of the general formula 2 with 1,3dibromopropane according to scheme 2.
wherein:
RI has the above meaning.
Scheme 2.
Compounds of the general formula 13.2 are prepared by interaction of isocyanate 3.1 or isothiocyanate 3.2 with the corresponding ethyl β-alaninates of the general formula 5 with subséquent cyclization of obtained ureas of the general formula 6 according to scheme 3.
wherein:
X and RI hâve the above meanings.
Scheme 3.
l,4-Diaryl[l,2,4]triazolidin-3,5-diones of the general formula 1.4 are prepared by interaction of the corresponding hydrazine 7 with isocyante 3.1 and subséquent condensation of the prepared semicarbazide 8 with diphosgene according to scheme 4.
ίο
1.4 wherein:
RI has the above meaning.
Scheme 4.
Novel androgen receptor antagonists are also suîtable for investigation of molecular mechanism of inhibition and activation of androgen receptors.
Novel cyclic Ν,Ν’-diarylthioureas and Ν,Ν’-diarylureas of the general formula 1 are androgen receptor antagonists, at that their actîvity exceeds the actîvity of known androgen receptor antagonists, published in patent application W02006124118, W02007127010, and in Drug Data Rep., 2009, 31(6), 609.
Besides, novel antagonist 1.2.2(1) is more than three times as less toxical as MDV3100 antagonist, because its maximum tolerated dose (MTD), determined in experiments with male mice of CD1 line is equel to MTD >100 mg/kg, whilst MTD for MDV3100 is about ~ 30 mg/kg.
The subject of the présent invention is novel antïcancer agent representing at least one cyclic Ν,Ν’-diarylthioureas or N,N’- diarylureas of the general formula 1.
The subject of the présent invention is also novel pharmaceutical composition comprising as an active component at least one cyclic N,N’-diarylthîourea or Ν,Ν’-diarylurea of the general formula 1, its optically active isomer or pharmaceutically acceptable sait exhibiting anticancer actîvity in effective amount.
The more préférable composition is the pharmaceutical composition exhibiting actîvity towards prostate cancer comprising as active component at least one cyclic N,N’-diarylthiourea
or Ν,Ν’-diarylurea of the general formula 1, its optical isomer or phaimaceutically acceptable sait.
Pharmaceutical compositions may include pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients mean diluents, auxilîary agents and/or carriers 5 employing in the sphere of phannaceutics. According to the invention the pharmaceutical composition in addition to the cyclic Ν,Ν’-diarylthiourea or Ν,Ν’-diarylurea of the general formula 1, its optically active isomer or pharmaceutically acceptable sait may include other active components, among other things exhibiting anti-cancer activity, provided that they do not give rise to undesirable side-effects.
According to the présent invention, if it is necessary to use the pharmaceutical composition in clinical practice it can be mixed up with various traditional pharmaceutical cames.
According to the présent invention the carriers used in pharmaceutical compositions represent carriers which are applied in the sphere of phannaceutics for préparation of 15 commonly used forms including: bînding agents, greasing agents, disintegrators, solvents, diluents, stabilîzers, suspending agents, colorless agents, taste flavors are used for pérorai forms; antiseptie agents, solubilizers, stabilîzers are used in the forms for injections; base materials, diluents, greasing agents, antiseptie agents are used in local forms.
The purpose of the présent invention is also the method for préparation of 20 pharmaceutical compositions.
The object in view is achieved by mixing novel anti-cancer agent with an inert exicipient and/or solvent, the distinctive feature of which consists in utilization as anticancer agent, at least, one cyclic Ν,Ν’-diaryltliiourea or Ν,Ν’-diarylurea of the general formula 1, its optically active isomer or pharmaceutically acceptable sait.
The subject of the présent invention is also a médicament in the form of tablets, sheaths or injections including novel anticancer agent or novel pharmaceutical composition intended for cancer treatment.
The preferred médicament including novel anticancer agent or novel pharmaceutical composition is a médicament in tend ed for treatment of prostate cancer.
The subject of the présent invention is also therapeutic cocktails for treatment of cancer diseases, among them prostate cancer, includuing as one of the components novel médicament or novel pharmaceutical composition, comprising as active component at least one cyclic Ν,Ν’diarylthiourea or Ν,Ν’-diarylurea of the general formula 1, its optically active isomer or pharmaceutically acceptable sait.
Therapeutîc cocktails for treatment of prostate cancer, along with the médicament disclosed in the invention, may include other known drug substances intended for treatment cancer diseases,
According to the présent invention the method for treatment of oncologie diseases, among them, prostate cancer, at humans and warm-blooded animais consists in introduction to human or warm-blooded animal of novel médicament, novel pharmaceutical composition or novel therapeutîc cocktail.
Médicaments could be administered perorally or parenterally, for example, întravenously, subcutaneously, intraperitoneally or locally. The clinical dosage of the active 10 component of the general formula 1 could be corrected depending on: therapeutîc efficiency and bîoavailability of the active ingrédients in organism, rate of their exchange and deducing from organism, and also depending on the âge, sex and the severity of the patient’s symptoms; the daily dosage for adults falls within the range of about 10 to about 500 mg of the active ingrédient, preferably of about 50 to about 300 mg. Therefore, according to the présent 15 invention in the process of préparation of a médicament from the pharmaceutical composition as units of dosage ît is necessary to keep in mind the above effective dosage, so that each unit of dosage should contain of about 10 to about 500 mg of the compound of the general formula 1, preferably 50 ~ 300 mg. In accordance with the recommendation of physician or pharmacist the above dosage can be taken several times during the definite time intervals (preferably — from 20 one to six times).
Best Embodiment of the invention
The invention is illustrated by the following drawings.
Fig.l, Weîght change of male mice at pérorai introduction of compound 1.2.2(1).
Fig.2. Weight change of male mice ai pérorai introduction of compound MDV3100.
The examples given below describe synthesis of Ν,Ν’-diarylthioureas and N,N’diarylureas and data of their biological investigation, which illustrate but not limit the scope of the invention.
Example 1. Synthesis of W-methyl-4-{4-oxo-2-thioxo-3-[3-(trifluoromethyI)-430 cyanophenyl]iniidazolidin-l-yl}-2-fluorobenzamide 1-2(1). Glycine (80 mg, 1.07 mmol) and K2CO3 (207 mg, 1.5 mmol) were added to solution of 4-iodo-N-methyl-2-fluorobenzamide (279 mg, 1 mmol) in DMF (3 ml). The reaction mixture was stirred at 140°C for 18 min. in microwave oven, cooled, diluted with AcOEt (10 ml) and water (10 ml), neutralized with HCl to pH 2-3, organic layer was separated, water layer was extracted with AcOEt (5 x 20 ml), The combined extracts were washed with brine, dried over Na^SCfi and evaporated in vacuo. The product was isolated by colomn chromatography on SiO2. It gave JV-(4-methylcarbamoyl-2fluorophenyl)glycine 4.2(1) (R1=CH3, R4=R5=H,). A solution of V-(4-methylcarbamoyl-25 fluorophenyl)glycine 4.2(1) (113 mg, 0.5 mmol) and 4-isothiocyanato-2(trifluo rom ethyl )benzonirile 3.2 (174 mg, 1.0 mmol) in DMF (2 ml) was stirred at 90°C for 12 h. The reaction mixture was evaporated in vacuo, and jV-methyl-4-{4-oxo-2-thioxo-3-[3(trifluoromethyl)-4“Cyanophenyl]-imidazolidin-l-yl}-2-fluorobenzamide 1-2(1), was isolated by HPLC method, LCMS (M+H)+ 437.
Example 2. General method for synthesis ofÀLmethyl-4-(5-methyl-4-oxo-2-thîoxo-3[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-l-yl}-2-fluorobenzamide 1.2(2), Mmefhyl-4{(S)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidm-l-yl}-2fluorobenzamide (S)-1.2(2) and jV-methyI-4-{(R)-5-methyl-4-oxo-2-thioxo-3-[3(trifluoromethyl)-4-cyanophenyl]imidazolidin-l-yl}-2-fiuorobenzamide (R)-1.2(2).
(D,L)-, (D)- or (L)-AIanine (347 mg, 7.8 mmol) and Cs2CO3 (2.54 g, 7.8 mmol) were added to the solution of jV-methyl-2J4-difluorobenzamide (667 mg, 3.9 mmol) in DMSO (3 ml). The reaction mixture was stirred in closed vial at 90°C for 18 h. Cooled mixture was diluted with isopropanol, neutralized with HCl (1.36 ml, 15.6 mmol), filtered, evaporated in vacuo, and by HPLC method M-(4-methylcarbamoyI-3-fluorophenyl)alanine 4.2(2) (R1=CH3, R4=H,
R5=CH3), (S)-N-(4-mcthylcarbamoyl- 3-fluorophenyl) alanine (S)-4,2(2) or (R)-N-(4methylcarbamoyl-3-fluorophenyl)alanine (R)-4.2(2) were isolated. LCMS (M+H)+ 241. ’H NMR (DMSO-rie, 400 MHz): 12.66 (br. s, IH), 7.62 (m, IH), 7.45 (t, 8.8 Hz, IH), 6.67 (br.
d, 7.2 Hz, IH), 6.42 (dd, = 8.4 Hz, J2 = 2.0 Hz, IH), 6.29 (dd, Λ = 14.8 Hz, J2 = 2.0 Hz, IH), 4.03 (m, IH), 2.73 (d, J= 4.4 Hz, 3H), 1.37 (d, J= 7.2 Hz, 3H). Solution of amine 4.2(2), (S)-4.2(2) or (R)-4.2(2) (110 mg, 0.46 mmol) and 4-isothiocyanato-2-(trifluoromethyI)benzonitrile 3.2 (144 mg, 0.55 mmol) in DMF (2 ml) was stirred at 90°C for 12 h in microwave oven, then additional portion of 4-isothiocyanato-2-(trifluoromethyI)-benzonitrile 3.2 (50 mg, 0.19 mmol) was added and stirring was continued for another 12 h. The reaction mixture was evaporated in vacuo, and by HPLC method #-methyl-4-{5-methyl-4-oxo-2-thioxo-3-[330 (trifluoromeÎhyl)-4-cyanophenyl]imidazolidin-l-yl}-2-fluorobenzamide 1.2(2), or N-methyl-4{(S)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyI)-4-cyanophenyl]imidazolidin-l-yl}-2fluorobenzamide (S)-1.2(2) or 2V-methyl-4-[(R)-5-methyl-4-oxo-2-thioxo-3-[3(trifluoromethyl)-4-cyanophenyl]imidazolidin-l-yl}-2-fluorobenzarrtide (R)-1.2(2) were isolated, respectively. The apparent inhibition constant of androgen receptors (KJ for these compounds are; KiL2(2) = 140.2 ηΜ, ΚΑ^21 = 106.7 ηΜ π κΑ’1*2*2* = 73.6 ηΜ, respectively. LCMS (Μ+Η)+ 451. ’Η NMR (CDC13, 400 MHz): 8.28 (t,J= 8.6 Hz, IH), 8.01 (d, J= 8.0 Hz, IH), 7.94 (d, J = 1.2 Hz, IH), 7.81 (dd, J/ = 8.0 Hz, J2 = 1.2 Hz, IH), 7.48 (dd, Jj = 12.4 Hz, J2 = 1.6 Hz, IH), 7.36 (dd, J2 = 8.4 Hz, J2 = 1.6 Hz, IH), 6.72 (br. m, IH), 4.83 (q, J =7.2 Hz, IH), 3.08 (d,J=4.8Hz, 3H), 1.60 (d,J=7.2 Hz, 3H).
Example 3. Synthesis of N-methyL4-{2-thio-3-[3-(trifluoromethyl)-4-cyanophenyl]hydantoin-l-yl)-2-fluorobenzamides 1.2.2 and 1.2.3 (general method). Solution of the corresponding jV-methyl-2-fluoro-4-[(l-cyanomethyl)amino]benzamide 4.1 (0.75 mmol) and 4isoÎhiocyanato-2-(trifluoromethyl)benzonitriIe 3.2 (342 mg, 1.5 mmol) in DMF (3 ml) was stirred at 110 °C for 12 h in microwave oven. The reaction mixture was dissolved in MeOH (30 ml), IN HCl (7.5 ml) was added and the résultant mixture was boiled for 1.5 h. The solution was evaporated in vacuo, treated with water, the solid was filtered off, washed with water and dried în vacuo. The product was isolated by HPLC method. It gave: 7V-methyl-4-[5-methyl-5(methoxymethyI)-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]-imidazolÎdin-l-yI]-2fluorobenzamide 1.2.2(1), κ/·2’2(1) = 115.9 nM, which was separated to enantiomers by means of high pressure liquid chromatography on Chiralpak HD-H 25x1 cm (Chiral Technologies Inc., USA). Mixture of 80% n-hexane, 20% 2-propanoI and 0.02% triethylamine was used as eluent. Flowrate was 4 ml/min. It gave optîcally pure isomers (R)-l.2.2(1) and (S)-1.2.2(l), = 53.3 ηΜ, Κ/®-1·2·2^ = 721.5 nM. LCMS (M+H)+ 495. ’H NMR (CDC13, 400 MHz): 8.28 (t, J= 8.4 Hz, IH), 7.99 (d, J= 8.0 Hz, IH), 7.92 (s, IH), 7.80 (d, J = 8.0 Hz, IH), 7.29 (dd, J2 = 8.8 Hz, J2 = 1.2 Hz, IH), 7.21 (dd, Λ = 11.6 Hz, J2 = 1.2 Hz, IH), 6.72 (q, 4.4 Hz, IH), 3.71 (d, J = 10.0 Hz, IH), 3.43 (s, 3H), 3.35 (d, J = 10.0 Hz, IH), 3.09 (d, J= 4.4 Hz, 3H), 1.52 (s, 3H);
A-methyl-4-{5-[(benzyloxy)methyl]-5-methyL4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4cyanophenyl]imidazolîdin-l-yl}-2-fluorobenzamide 1.2.2(2). LCMS (M+H)+ 571. ’H NMR (CDC13, 400 MHz): 8.22 (t, J= 8.4 Hz, IH), 7.96 (d, J= 8.0 Hz, IH), 7.86. (s, IH), 7.70 (dd, Λ = 8.0 Hz, J2 = 1.2 Hz, IH), 7.39 (m, 3H), 7.29 (m, 2H), 7.25 (dd, f = 8.4 Hz, J2 = 1.6 Hz, IH), 7.18 (dd, J} = 8.4 Hz, Λ = 1.6 Hz, IH), 6.71 (q, J= 4.8 Hz, IH), 4.59 (m, 2H), 3.79 (d, J= 10.2 Hz, IH), 3.45 (d, J= 10.2 Hz, IH), 3.08 (d, J= 4,8 Hz, 3H), 1.51 (s, 3H);
ethyl [4-methyl-3-(4-methylcarbamoyl-3-fluorophenyl)-5-oxo~2-thioxo-1 ~[3(trifïuorom ethyl)-4-cyanophenyI]imidazolidin-4-yl} acetate 1.2.2(4) (R1=CH3, R4=CH3s R5=CH2COOC2H5). LCMS (M+Hf 536. JH NMR (CDC13,400 MHz): 8.26 (t, J= 8.4 Hz, IH), 8.01 (d, J= 8.0 Hz, IH), 8.00 (s, IH), 7.90 (dd, Jt = 8.0 Hz, J2 = 1.6 Hz, IH), 7.18 (dd, J, = 8.0 Hz, Λ = 1.6 Hz, IH), 7.10 (dd, Λ = 8.0 Hz, J2 = 1.6 Hz, IH), 6.78 (q, J=4.8 Hz, IH), 4.26 (m,
IH), 3.13 (d, J= 18.0 Hz, 1 H), 3.09 (d, J =4.8 Hz, 3H), 2.64 (d,7 = 18.0 Hz, IH), 1.67 (s, 3H), 1.31 (t, 7= 7.0 Hz, 3H);
jV-methyL4-{4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanopheiiyl]-7-oxa-l,3diazaspiro[4.4]non-l-yl}-2-fluorobenzamide 1.2.3(1), Ki1’2’3^5 = 33,9 nM. LCMS (M+H)+ 493. lH NMR (CDC13, 400 MHz): 8.30 (t, 7= 8.4 Hz, IH), 8.02 (d, 7= 8.4 Hz, IH), 7.98 (d, 7= 1.6 Hz, IH), 7.85 (dd, 7/ = 8.4 Hz, J2 = 1.6 Hz, IH), 7.34 (dd, 7, = 8.4 Hz, 72 = 1.6 Hz, IH), 7.25 (dd, 7/=11.8 Hz, 7.2= 1.6 Hz, 1 H), 6.78 (q,7=4.4 Hz, IH), 4.43 (d,7= 10.0 Hz, IH), 4.16 (d, 7= 10,0 Hz, IH), 3.96 (m, IH), 3.75 (m, IH), 3.09 (d,7= 4.4 Hz, 3H), 2.74 (m, IH), 2.48 (m, IH);
N-methyL4-{4-oxo-2-thioxo-3-[3-(trifluorometbyl)-4Cyanopbenyl]-8-oxa-l,3diazaspiro[4.5]dec-l-yl}-2-fluorobenzamide 1.2.3(2). LCMS (M+H)* 507. *H NMR (CDC13, 400 MHz): 8.32 (t, 7= 8.4 Hz, IH), 8.01 (d, 7= 8.0 Hz, IH), 7.95 (s, IH), 7.83 (d, 7= 8.0 Hz, IH), 7.20 (d, 7= 8.4 Hz, IH), 7.10 (d,7= 8.0 Hz, IH), 6.73 (br. m, IH), 4.18 (m, 2H), 3.94 (m, 2H), 3.09 (d, 7= 4.4 Hz, 3H), 2.07 (m, 4H);
N-methyl-4- {8-niethyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyI]-1,3,8triazaspiro[4.5]dec-l-yl}-2-fluorobenzamide 1.2.3(3). Kj1'2’3^ = 39.2 nM, IC50=170nM. LCMS (M+H)* 520. ’H NMR (DMSO-76, 400 MHz): 10.09 (br. s, IH), 8.48 (q, 7= 4.4 Hz, IH), 8.43 (d, 7=8.4 Hz, IH), 8.29 (s, 1 H), 8.11 (d, 7= 8.4 Hz, 1 H), 7.84 (t, 7= 8.0 Hz, IH), 7.42 (d, 7 = 10.4 Hz, IH), 7.30 (d, 7= 8.0 Hz, IH), 3.50 (m, 4H), 2.80 (d, 7 = 4.4 Hz, 3H), 2.78 (s, 3H), 2.72 (d,7= 14.0 Hz, IH), 2.16 (m, 2H).
Such salts of the compounds of general formula 1.2.3 of the présent invention as hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulfate, acetate could be formed by methods well known in the art. For example, the compound 1.2.3(3) was dissolved in dichloromethane and a saturated solution of HCl in dioxane was added. The N-methyl-4-{8m ethyl-4-oxo-2-thioxo-3-[3-(trifluoroinethyl)-4-cyanophenyl]-1,3,8-triazaspiro[4.5]dec-1 -yl} 2-fluorobenzamide hydrochloride sait 1.2.3(3)*HC1 obtained in the precipitate was washed with dioxane, evaporated and dried. LCMS (M+H)* 520.
Example 4. Synthesis of 2V-mefhyl-4-[5-(hydroxymethyl)-5-inethyl-4-oxo-2-thioxo-3[3-(trifluoroniethyI)-4-cyanopbenyl]imidazolidin-l-yl]-2-fluorobenzamide 1.2.2(3). BBr3 (53 mkl, 0.55 mmol) was added dropwise to solution of2V-methyl-4-[5-methyl-5-(methox>'methyl)4~oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-l-yl]-2-fluorobenzamide (55 mg, 0.11 mmol) in CH2C12 (1.5 ml) in argon atmosphère at -78°C. The reaction mixture was stirred at -78 °C for 3 h and then for another 3 h at room température. After the reaction was completed the excess of BBr3 was neutralized by addition of 5% Na2CO3 solution (10 ml), the
CY product was extracted with AcOEt, dried over NasSCU, evaporated in vacuo, and by HPLC method 77-methyl-4^5-(hydroxymethyl)-5-methyl-4-oxo-2-Îhioxo-3-[3-(trifluoromethyl)-4cyanophenyl]imidazolidin-l-yl]-2-f!uorobenzainide 1.2.2(3) was isolated, Kj1·2·2^ = 46.3 nM, ]H NMR (DMSO-d6, 400 MHz): 8.43 (br. m, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 7.98 (d, J= 8.4 Hz, 1H), 7.78 (t, /= 8.0 Hz, 1H), 7.42 (d, 10.8 Hz, 1H), 7.37 (d, J= 8.0 Hz, 1H),
5.93 (t, .7=4.4 Hz, 1H), 3.81 (dd, Λ = 11.6 Hz, Λ = 4.4 Hz, 1H), 3.45 (dd, Λ = 11.6 Hz, J2 = 5.0 Hz, 1 H), 2.79 (d, J= 4.0 Hz, 3H), 1.38 (s, 3H).
Example 5. Synthesis of {4-methyl-3-(4-methyIcai’bamoyl-3-fiuorophenyl)-5-oxo-2thioxo-l-[3-(trifluoromethyl)-4-cyanophenyI]imidazoIidin-4-yl}acetic acid 1.2.2(5) (R1=CH3, R4=CH3, R5=CH2COOH). Solution ofNaOH (7 mg, 0.172 mmol) in water (0. 5 ml) was added to the solution of ester (46 mg, 0.086 mmol) 1.2.2(4) în alcohol (2 ml), and the reaction mixture was stirred for 12 h (LCMS control). The solvent was evaporated, isopropanol (2 ml) and HCl (15 mkl, 0.172 mmol) were added, fîltered and evaporated again in vacuo. (4-Meth yl-3-(4methylcarbarnoyl-3-fluoiOphenyl)-5-oxo-2-thioxo-l-[3-(trifluoromethyl)-4cyanophenyl]imidazolidin-4-yl}acetic acid 1.2.2(5) was isolated by HPLC method. LCMS (M+H)+ 469. ‘H NMR (DMSO-ri6, 400 MHz): 13.31 (br. s, 1H), 8.44 (m, 2H), 8.10 (s, 1H), 7.95 (d, J= 7.6 Hz, 1H), 7.81 (t, J= 8.0 Hz, 1H), 7.25 (d, J = 10.8 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 3.16 (d, J= 17.6 Hz, 1H), 2.79 (d, J= 3.6 Hz, 3H), 2.70 (d, 17.6 Hz, 1H), 1.59 (s, 3H).
Example 6. Synthesis of 4-[3-[3-(trifluoromethyl)-4-cyanophenyl]-2-oxo-tetrahydropyrimidin-I(2/ï)-yl]-N-methyl-2-fluorobenzamide 1.3.1. K2CO3 (109 mg, 0.79 mmol) and 1,3dibromopropane (32 mkl, 0.32 mmol) were added to a solution of 4-[4-cyano-3(trifïuoromethyl)-phenylcarbamoylamino]-77-methyl-2-fluorobenzamide (100 mg, 0.26 mmol) 2 in DMF (2 ml). Mixture was stirred at 90°C. In 18 h another portion of K2CO3 (109 mg) and 1,3-dibromopropane (32 mkl) were added and stirring was continued at the same température. Addition was repeated by 2 more times. After the réaction was completed the mixture was
I evaporated in vacuo, the residue was dissolved in chloroform, washed with water, dried over Na2SO4, the solvent was evaporated. The product was isolated by colomn chromatography on SiO2 (eluent - AcOEt). LCMS (M+H)'*’421. ’HNMR (DMSO-ri6, 400 MHz): 8.17 (br. m, 1H), 8.13 (d, J= 8.4 Hz, 1H), 8.07 (d, J= 2.0 Hz, 1H), 7.83 (dd, Λ = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.62 (t, J= 8.4 Hz, 1H), 7.38 (dd, J} = 12.4 Hz, J2 = 2.0 Hz, 1H), 7.29 (dd, Js = 8.4 Hz, J2 = 2.0 Hz, 1H), 3.90 (t, J= 5.8 Hz, 2H), 3.81 (t, J= 5.8 Hz, 2H), 2.77 (d, 4.8 Hz, 3H), 2.21 (m, 2H).
Example 7. Synthesis of Ar-methyl-4-{[3-(trifluoromethy])-4-cyanophenyl]-2,4-dioxotetrahydropyrimidin-l(2/7)-yl}benzarnide 1.3.2(1), (X=O, R1=CH3). Ethyl acrylate (8 g, 80 mmol) and DBU (0.81 g, 5.4 mmol) were added to a solution of 4-amino-77-methyl-2-
fluorobenzamide (9 g, 53.6 mmol) in DMSO (90 ml) and stirring was continued for 24 h at 70°C (LCMS control). The reaction mixture was subjected to lyophilization, the residue was recrystallized from aqueous alcohol. It gave ethyl N-[4-(methyl carbamoyl)-3-fluorophenylj-βalaninate 5. LCMS (M+H)+ 269. ]H NMR (DMSOX6, 400 MHz) d 7.57 (br. s, IH), 7.48 (t,J = 5 8.8 Hz, IH), 6.47 (br. s, IH), 6.42 (d, J = 8.8 Hz, IH), 6.33 (d, J = 14.8 Hz, IH), 4.07 (q, J =
7.2 Hz, 2H), 3.32 (br. m, 2H), 2.73 (d, J= 4.4 Hz, 3H), 2.55 (t, J= 6A Hz, 2H), 1.18 (t, J = 7.2 Hz, 3 H). The solution of 4-isocyanato-2-(trifluoromethyl)benzonitrile (425 mg, 1.87 mmol) 3.1 and ethyl jV-[4-(methylcarbamoyl)-3-fluorophenylj-β-alaninate (500 mg, 1.87 mmol) 5 (R1=CH3) in CH2C12 (10 ml) was stirred for 5 h. The réaction mixture was evaporated in vacuo, 10 and the product was isolated by colomn chromatography on SiO2 (eluent — rz-hexane : AcOEt :
Et3N = 1:1:0.03). It gave ethyl 7V-[4-(methylcabanioyl)-3-f]uoroplienyl]-M-{[3(trifluorometliyl)-4-cyanophenyl]-carbamoylA-alaninate 6(1) (R1=CH3, X=O). LCMS (M+H)+ 481. HCl (2.5 ml) was added to the solution of ethyl V-[4-(methylcabamoyl)-3fluorophenyl]-?/-{[3-(trifluoromethyl)-4-cyanophenyl]-carbamoyl}-P-alaninate (500 mg, 1.04 15 mmol) 6(1) in AcOH (5 ml) and the résultant mixture was stirred for 15 h. The reaction mixture was poured into water, the product was extracted with EtOAc. Organic layer was dried over Na2SO4, evaporated in vacuo and by means of colomn chromatography on SiO2 (eluent - nhexane : AcOEt = 1:1) :V-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyi]-2,4-dioxotetrahydropyrimidin-I(27/)-yl}benzainide 1.3.2, (X=O, R1=CH3) was isolated; KiI3‘2(I) = 85.6 20 nM, LCMS (M+H)+ 435. ’H NMR (DMSO-èZ6, 400 MHz): d 8.29 (d, J = 7.6 Hz, IH), 8.23 (br.
m, IH), 8.11 (s, IH), 7.89 (d, J= 2.0 Hz, 1 H), 7.67 (t, J= 8.4 Hz, IH), 7.39 (d, J = 12.4 Hz, IH), 7.33 (d, J= 8.4 Hz, IH), 4.02 (t, 6.4 Hz, 2H), 3.03 (t, J= 6.4 Hz, 2H), 2.77 (d, J= 4.4
Hz, 3H).
Example 8. Synthesis of N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-4-oxo-225 thioxo-tetrahydropyrimidin-l(2H)-yl)benzamide 1.3.2(2), (X=S, RÎ=CH3). A solution of 4isoihiocyanato-2-(trifluoromethyl)benzonitrile (320 mg, 1.51 mmol) 3.2 and ethyl JV-[4(methyIcarbamoyl)-3-fluorophenyl]-P-alaninate (404 mg, 1.51 mmol) 5 (R1=CH3) in DMF (8 ml) was heated at 60°C in microwave stove for 8 h. The reaction mixture was evaporated in vacuo, and by means of colomn chromatography on SiO2 (eluent - n-hexane : AcOEt =1:2) 30 ethyl W-[4-(methylcarbamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyI)-4cyanophenyljthiocarbamoylj-p-alaninate 6(2) (R1=CH3, X=S) was isolated. LCMS (M+H)+ 497. A solution of NaOH (32 mg, 0.8 mmol) în water (0.25 ml) was added to a solution of ester (200 mg, 0.4 mmol) 6(2) in alcohol (1 ml), and the résultant mixture was stirred at 80°C for 2 h
(LCMS control), cooled and neutralized with HCl (69 mkl, 0.8 mmol), evaporated in vacuo, the residue was extracted with hot isopropanol and evaporated in vacuo again. It gave 2V-[4(methyIcarbamoyl)-3-fluorophenyl]-jV-{[3-(trifluoromethyl)-4-cyanophenyl]thiocarbamoyl}-3alanine 6(3) (Rl=CH3, X=S). LCMS (M+H)+ 469. TBTU (86 mg, 0.36 mmol) and diisopropylethylamine (llO mg, 0.84 mmol) were added to the solution of the prepared acid (l 14 mg, 0.24 mmol) 6(3) in DMF (1.5 ml). The reaction mixture was stirred at 45°C for 15 h. When the reaction was completed (LCMS control) the solution was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4, evaporated in vacuo and by HPLC method jV-methyl-4- {[3-(trifluoromethyl)-4-cyanophenyl]-4-oxo-2-thioxo10 tetrahydropyrimidin-l(27/)-yl}-2-fluorobenzamide 13.2(2) (R1=CH3) X=S) was isolated; K.i.3.2(2) = 95 2 nM. LCMS (M+H)+ 45] iH NMR (DMSO-e/ô, 400 MHz): 8.35 (q, J = 4.4 Hz, IH), 8.27 (d, J= 8.0 Hz, IH), 8.06 (d, J= 1.6 Hz, IH), 7.83 (dd, Jj = 8.0 Hz, J2 = 1.6 Hz, IH), 7.71 (t, 7=8.2 Hz, IH), 7.42 (dd, Λ = 11.0 Hz, Λ = 1.8 Hz, IH), 7.33 (dd, 7/ = 8.2 Hz, J2 = 1.8 Hz, IH), 4.13 (t, 6.8 Hz, 2H), 3.17 (t, 7= 6.8 Hz, 2H), 2.78 (d, J= 4.4 Hz, 3H).
Example 9. Synthesis of V-metiiyl-2-fluoro-4-[4-[3-(trifluoromethyl)-4-cyanophenyl]3,5-dioxo-l,2,4-triazolidin-l-yl]benzamide 1.4 (R1=CH3). 2.5M Solution of NaNO2 (2.38 ml) was added dropwise to a solution of 4-amÎno-Ar-methyl-2-fluorobenzamide (1 g, 5.95 mmol) in b 5N HCl (3.1 ml), so that the température of the reaction mixture did not exceed 5°C. The mixture was stirred for additional 30 min at the same température, after that the prepared solution was added drop by drop to a suspension of 3η€12*2Η2Ο (4.03 g, 17.9 mmol) in HCl (4.2 ml) at 0°C, and stimng was continued for 2 h at the same température. Precipitated solid was filtered off, dissolved in water (40 ml) and NaOH was added to strongly basic reaction. The mixture was extracted with ether (3*100 ml), dried over MgSO4 and evaporated în vacuo. It gave 4-hydrazino-Ar-methyl-2-fiuorobenzamide 7 (R1=CH3). LCMS (M+H)+ 184. ’H NMR (CDC13, 400 MHz): 7.96 (t, J= 8.4 Hz, IH), 6.64 (br. m, IH), 6.60 (t, 7= 1.6 Hz, IH), 6.57 (dd,
Ji = 7.2 Hz, J2 = 2.0 Hz, IH), 5.60 (br. s, IH), 3.66 (br. s, 2H), 3.00 (dd, J} = 4.8 Hz, J2 = 1.2 Hz, IH). The solution of 4-isocyanato-2-(tnfluoromethyl)benzonitrile (59 mg, 0.27 mmol) 3.1 in dioxane (2 ml) was added to a solution of 4-hydrazino-jV-methyl-2-fluorobenzamide (54 mg, 0.29 mmol) 7 in dioxane (3 ml), and the résultant mixture was stirred for 2 h. Then dioxane was distilled in vacuo, the residue was crambled with ether, filtered off and dried în vacuo. It gave 2-[(4-methylcarbamoyl)-3~fluorophenyl]W-[3-(trifluoromethyl)-4-cyanophenyl]-hydrazine carboxamide 8(1) (R1=CH3). LCMS (M+H)+ 405. lH NMR (DMSO-76, 400 MHz): 9.65 (br. s, IH), 8.72 (br. s, IH), 8.37 (s, IH), 8.25 (br. s, IH), 8.03 (br. m, IH), 7.88 (d, J= 8.8 Hz, IH),
7.58 (ni, 2H), 6.63 (d, J= 8.4 Hz, IH), 6.48 (d, J = 14.0 Hz, IH), 2.77 (d, 4.4 Hz, 3H).
Triethylamine (56 mkl, 0,4 mmol) and diphosgene (27 mkl, 0.22 mmol) were added one after another to 2-[ (4-m ethyl carbamoyl)-3 - fluorophenyl] -X-[3-(trifluoromethyl)-4-cyanophenyl] hydrazine carboxamide (80 mg, 0.2 mmol) 8(1) in dichloroethane (2 ml). The reaction mixture 5 was stirred in a closed vial at 80 °C for 15 h. The solvent was evaporated in vacuo and the residue was subjected to chromatography on SiO2 (eluent - CH2C12: MeOH, gradient from 100:1 till 20:1). It gave jV-methyI-2-fluoro-4-[4-[3-(trifluoromethyl)-4-cyanophenyl]-3,5-dioxol,2,4-triazolidin-l-yl]benzamide 1.4 (R1=CH3). K;1'4 = 55.2 nM, LCMS (M+H)+ 422. ]H NMR (DMSO-^ê, 400 MHz): 11.53 (s, IH), 8.22 (br. m, IH), 8.16 (d, 8.8 Hz, IH), 7.99 (dd, J} =
8.8 Hz, Λ = 1.6 Hz, IH), 7.95 (d, J= 1.6 Hz, IH), 7.81 (t, J = 8,4 Hz, IH), 7.69 (dd, Λ = 8.8
Hz, J2 = 2.0 Hz, IH), 7.62 (dd, Js = 12.0 Hz, J2 = 2.0 Hz, IH), 2.79 (d, J= 4.4 Hz, 3H).
Example 10. Détermination of antagoniste activity of cyclic Ν,Ν’-diarylthioureas and
Ν,Ν’-diarylureas of the general formula l and their analog MDV3100 towards androgen receptors. The ability of novel cyclic Ν,Ν’-diarylthioureas and Ν,Ν’-diarylureas ofthe general 15 formula 1 and MDV3100 agent to block androgen receptors was determined by their effectiveness of inhibition of dihydrotestosterone stimulated expression of prostate spécifie antigen (PSA) in cancer cells of human prostrate LNCap, derived from the American Tissue Culture Collection (ATCC, USA). These cells are sensitive towards 5-a-dihydro testosterone (DHT) and în its presence produce cancer mark ers (PSA). The cells were cultured in RPMI 20 1640 medium (Invitrogen, USA) containing 10% calf sérum (Hyclone, USA), 1% antibacterial/antifungal mixture (Sigma, USA) and 4,5% glucose. Before the experiment the cells were washed and suspended în the same medium in which, however, instead of calf sérum the sérum which had been treated with charcoal for removal of hormone traces was used, The cells were embedded into wells of 96-weIl plates by 100 μΐ per cell (10 000 cells) and left for 4 25 days in încubator at 37°C (100% humidity) in atmosphère of 95% air/5% CO2. After incubation cyclic Ν,Ν’-diarylthioureas or Ν,Ν’-diaryIureas'of the general formula 1 were added to the cells in various concentrations, and then - 20nM DHT (concentration corresponding to 80-90% of maximum stimulation). The cells were left for 5 days for additional incubation under the same conditions. After that the samples of supracellular medium were taken on analysis for 30 PSA content. The test was carried out according to the protocol, recommended by manufacturer of the kit for détermination of PSA (Alpha Diagnostic International, USA). After wetting the wells containing PSA antibodies attached to their bottom to each well 25 μΐ of the tested compounds and 100 μΐ of PSA antibodies conjugated previously with horseradish peroxidase were added successively.
After incubation at room température for 30 minutes, the contents of the wells were removed, the wells were washed several times, and then 100 μΐ of chromogemc substrate of 5 peroxidase was added to each well. Plates were held for 15 min. at room température, after that μΐ of stop solution was added to every well; at that a dye is formed the absorption intensity of which was mesured at 450 nM; the value obtained is proportîonal to PSA concentration in the sample. Based on the dependence of lowering of PSA synthesis, caused by dihydrotestosterone (DHT), on the concentration of the tested compounds, dose-response 10 curves were plotted, from which IC50 values were determined. They were used for calculation of the values of apparent inhibition constants (KJ for the compounds of the general formula I according to Cheng-Prusoff équation. [Cheng, Y., Prusoff, W. H. Relationship between the inhibition constant (K,) and the concentration of inhibitor which causes 50 per cent inhibition (IC5o) of an enzymatic reaction. Biochem Pharmacol. (1973) 22,3099-3108]:
K, = IC50/(HL/Ko), wherein L - agonist concentration (DHT), Ko - receptor activation constant, numerically equal to EC50 value, which is determined in every experiment according to dependence of stimulation of PSA synthesis on DHT concentration.
The data obtained given in the corresponding examples testify that novel androgen 20 receptor antagonîsts, in some cases, are more active than MDV3100, tested under the same conditions as a compound for comparison, for which KiMDVÎ10° = 79.5 nM.
Example 11. Détermination of maximum tolerated dose of novel antagonîsts 1.2.2(1), and 1.2.3(3) and its analog MDV3100. Maximum tolerated dose (MTD) of novel antagonîsts 1.2.2(1) and 1.2.3(3) and its analog MDV3100 were determined in experiments on male mice 25 of CD1 line at pérorai administration 1 time a day within 5 days in doses 10, 30 and 100 mg/kg.
The compound was dissolved in stérile water with addition of Twin-80. Stérile water with Twin-80 was introduced to control animais (Placebo group). Body weight was appreciated, and also animais’ mortality rate. Statistical comparison of groups was carried out according to nonparametric test ANOVA, with the use of Statistica programme.
At the introduction of compounds 1.2.2(1) or 1.2.3(3) in dose up to 100 mg/kg mice death was not observed. On the 3rd - 4th day body weight of mice in the group, received the tested compound in dose 100 mg/kg was less in comparison with the body weight of control animais, however, statistical signîfïcance at this was not observed (fig.l). The data show that compound 1.2.2(1) and 1.2.3(3) has MTD >100 mg/kg.
(Y
I
At the introduction of MDV3100 in doses 10 and 30 mg/kg rnice death was not observed. In the group of mice to which the tested compound was întroduced in dose 100 mg/kg, the body weight began to lower on the 3rd day. On the 5* day body weight of this group of animais statistically differed from body weight of animais from Placebo group (p=0,002, fig. 2). One animal died. The data show that compound MDV3100 has MTD ~ 30 mg/kg.).
Example 12. Préparation of médicament in the form of tablets. Starch (1600 mg), grained lactose (1600 mg), talcum (400 mg) and N-niethyl-4-[5-methyl-5-(methoxyrnethyI)-4oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]-imidazolidin-l-yl]-2-fluorobenzamide (R)-l.2.2(1) (1000 mg) mixed together and pressed in a brick. Prepared brick was crushed to granules and riddled through sieves, gathering granules of 14-16 mesh size. The obtained granules were pelletised in tablets of suitable form of 560 mg by weight each.
Example 13. Préparation of médicament in the form of capsules. N-Methyl-4-[5methyl-5-(methoxymethyl)-4~oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-l-yl]-2-fluorobenzamide (R)-1.2.2(l) was carefully mixed with lactose powder in ratio 2 : 1. The prepared pharmaceutical composition was packed on 300 mg into gelatinous capsules of suitable size.
Example 16. Préparation of médicament in the form of compositions for intramuscular, intraperitoneal or hypodermic injections. N-Methyl-4-[5-methyl-5-(methoxymethyl)-4-oxo-2thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]-iinidazolidin-l-yl]-2-fluorobenzamide (R)1.2.2(1) (500 mg) was dissolved in the mixture of chlorobutanole (300 mg), propylene glycol (2 ml), and water for injections (100 ml). The prepared solution was filtered and placed in 1 ml ampoules which were sealed up and sterilized in an autoclave.
Industrial appiicability
The présent invention could be used in medicîne, veterinary, biochemistry.
Claims (12)
- l. A cyclic XZ-diarylthioureas and ΛζΛΓ-diarylurea compound of general formula 1, or optical (R)- or (S)- isomer, or a pharmaceutically acceptable sait thereof, exhîbiting properties of androgen receptor antagonists, wherein:X represents oxygen or sulfur;m = 0 or 1 ;RI represents C1-C3alkyl;R2 and R3 represent hydrogen; orR2 and R3 together with the carbon atom they are attached to form C = O group;R4 and R5 represent hydrogen; orR4 represents hydrogen, R5 represents methyl; orR4 represents methyl, R5 represents CH2R6 group in which R6 is C1-C3 alkoxycarbonyl, carboxyl, hydroxyl group optionally substituted with methyl or benzyi; orR4 and R5 together with the carbon atom they are attached to form 5- or 6- membered saturated heterocycle including at least one oxygen atom or nitrogen atom optionally substituted with methyl, or tR4 and R5 together with the carbon atom they are attached to represent NH-group.
- 2. The compound of claim 1 selected from cyclic AÇA’-diarylthioureas and Ν,Ν1diarylureas of general formulas 1.2, 1.
- 3 or 1.4, or optical (R)- and (S)- isomers, or a pharmaceutically acceptable sait thereof, wherein:X, RI, R2, R3, R4 and R5 are ail as mentioned above.5 3. The compound of daim 2 selected from the group consisting of cyclic Ν,Ν’diarylthioureas of formulas 1-2(1), 1.2(2), 1.2.2, and 1.2.3, or optical (R)-isomers (R)-1.2(2), (R)-1.2.2, (R)-1.2.3, or (S)-isomers - (S)-1.2(2), (S)-1.2.2 and (3)-1.2.3, or a pharmaceutically acceptable sait thereof,1.2(1) 1.2(2) (R)-1.2(2) (RM .2.2 (RJ-1.2.3 (S)-1.2(2) (SJ-1.2.2 (S)-1.2.3 wherein:R4 and R5 together with the carbon atom they are attached to form 5- or 6- membered saturated5 heterocycle comprising at least one oxygen atom or nitrogen atom optionally substituted with methyl,R6 has the above meanings.
- 4. The compound of claim 2 selected from the group consisting of compounds of formulas 1.2.2(1), 1.2.2(2), 1.2.2(3), 1.2.3(1), 1.2.3(2) and 1.2.3(3), or optical (R)-isomers 10 (R)-1.2.2(1), (R)-1.2.2(2), (R)-1.2.2(3), (R)-1.2.3(l), or (S)-isomers - (S)-1.2.2(l), (S)-1.2.2(2), (S)-1.2.2(3), (S)-1.2.3(l), or a pharmaceutically acceptable sait thereof,1.2.2(1): R6 =OCH3;1.2.2(2): R6 =OCH2Ph;1.2.2(3): R6 = OH;(R)-1.2.2(1): R6 = OCH3;(R)-1.2.2(2): R6 =OCH2Ph;(R)-1.2.2(3): R6 = OH;(S)-1.2.2(1): R6 =OCH3;(S)-1.2.2(2): R6 = OCH2Ph;(S)-1.2.2(3): R6 = OH;1.2.3(1) (R)-1.2.3(1) (S)-1.2.3(1)CH,1.2.3(2) 1.2.3(3) wherein:R6 is hydroxyl group optionally substituted with methyl or benzyl.
- 5. Method for préparation of compounds of the general formula 1.2 and their optical (R)- and (S)- isomers according to claims 1-4 by interaction of the corresponding 4( cyanom ethyl) amino-benzami des 4.1 or (4-carbamoyl-phenylamino)-acetic acids 4.2 or their optical (R)- and (S)-isomers with isothiocyanate 3.2.4.1: W = CN4.2: W =CO2H
- 6. Anticancer agent representing at least one cyclic Ν,Ν’-diarylthiourea or N,N’diarylurea of the general formula 1 according to any of claims 1 - 4 exhibiting properties of androgen receptor antagoniste.
- 7. Pharmaceutical composition exhibiting properties of androgen receptor antagonist comprising as active component anticancer agent according to claim 6.
- 8. Method for préparation of pharmaceutical composition according to claim 7 by mixing anticancer agent according to claim 6 with inert Aller and/or solvent.
- 9. A médicament in the form of tablets, sheaths or injections for treatment of cancerous diseases comprising anticancer agent according to claim 6 or pharmaceutical composition according to claim 7.
- 10. The médicament according to claim 9 intended for prostate cancer treatment.
- 11. Use of an anticancer agent representing at least one cyclic Ν,Ν’-diarylthiourea or N,N’- diarylurea of the general formula 1 according to any of claims 1 - 4 exhibiting properties of androgen receptor antagonists in the préparation of a médicament in the form of tablets, sheaths or injections or a pharmaceutical composition for the treatment of cancerous diseases, among them prostate cancer.
- 12. Androgen receptor antagonists according to claim mechanism of inhibition and activation of androgen receptors.
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