GB2461167A - N-substituted amidoxime derivatives for the prophylaxis and/or treatment of tropical diseases - Google Patents
N-substituted amidoxime derivatives for the prophylaxis and/or treatment of tropical diseases Download PDFInfo
- Publication number
- GB2461167A GB2461167A GB0910622A GB0910622A GB2461167A GB 2461167 A GB2461167 A GB 2461167A GB 0910622 A GB0910622 A GB 0910622A GB 0910622 A GB0910622 A GB 0910622A GB 2461167 A GB2461167 A GB 2461167A
- Authority
- GB
- United Kingdom
- Prior art keywords
- alkyl
- hydroxy
- acid
- cyclohexyl
- nicotinamidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical class C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 title abstract description 14
- 238000011282 treatment Methods 0.000 title abstract description 14
- 238000011321 prophylaxis Methods 0.000 title abstract description 6
- 208000037972 tropical disease Diseases 0.000 title abstract description 6
- 125000000217 alkyl group Chemical group 0.000 abstract description 51
- 239000000203 mixture Substances 0.000 abstract description 40
- 229910052736 halogen Inorganic materials 0.000 abstract description 23
- 150000002367 halogens Chemical class 0.000 abstract description 23
- 125000001424 substituent group Chemical group 0.000 abstract description 23
- 238000000034 method Methods 0.000 abstract description 14
- 238000002360 preparation method Methods 0.000 abstract description 14
- 206010011668 Cutaneous leishmaniasis Diseases 0.000 abstract description 12
- 239000001257 hydrogen Substances 0.000 abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 12
- 239000013543 active substance Substances 0.000 abstract description 10
- 125000003118 aryl group Chemical group 0.000 abstract description 10
- 201000000626 mucocutaneous leishmaniasis Diseases 0.000 abstract description 10
- 206010047505 Visceral leishmaniasis Diseases 0.000 abstract description 9
- 208000000230 African Trypanosomiasis Diseases 0.000 abstract description 8
- 206010001935 American trypanosomiasis Diseases 0.000 abstract description 8
- 208000029080 human African trypanosomiasis Diseases 0.000 abstract description 8
- 201000002612 sleeping sickness Diseases 0.000 abstract description 8
- 208000009846 Central Nervous System Protozoal Infections Diseases 0.000 abstract description 7
- 201000010672 primary amebic meningoencephalitis Diseases 0.000 abstract description 7
- 241000223109 Trypanosoma cruzi Species 0.000 abstract description 6
- 208000001848 dysentery Diseases 0.000 abstract description 6
- 208000024699 Chagas disease Diseases 0.000 abstract description 5
- 201000004792 malaria Diseases 0.000 abstract description 5
- 208000004881 Amebiasis Diseases 0.000 abstract description 4
- 206010001980 Amoebiasis Diseases 0.000 abstract description 4
- 241001235574 Balantidium Species 0.000 abstract description 4
- 208000003495 Coccidiosis Diseases 0.000 abstract description 4
- 206010023076 Isosporiasis Diseases 0.000 abstract description 4
- 208000005448 Trichomonas Infections Diseases 0.000 abstract description 4
- 206010044620 Trichomoniasis Diseases 0.000 abstract description 4
- 241000223105 Trypanosoma brucei Species 0.000 abstract description 4
- 201000006592 giardiasis Diseases 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- 201000009906 Meningitis Diseases 0.000 abstract description 3
- 206010035501 Plasmodium malariae infection Diseases 0.000 abstract description 3
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 abstract description 3
- 241000233872 Pneumocystis carinii Species 0.000 abstract description 3
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 abstract description 3
- 206010035664 Pneumonia Diseases 0.000 abstract description 3
- 201000005485 Toxoplasmosis Diseases 0.000 abstract description 3
- 206010023332 keratitis Diseases 0.000 abstract description 3
- 201000000317 pneumocystosis Diseases 0.000 abstract description 3
- 241000222722 Leishmania <genus> Species 0.000 abstract description 2
- 241000223960 Plasmodium falciparum Species 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 44
- -1 allcylthio Chemical group 0.000 description 35
- 125000003342 alkenyl group Chemical group 0.000 description 22
- 125000003545 alkoxy group Chemical group 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 125000001589 carboacyl group Chemical group 0.000 description 21
- 125000001188 haloalkyl group Chemical group 0.000 description 21
- 125000000304 alkynyl group Chemical group 0.000 description 20
- 125000001072 heteroaryl group Chemical group 0.000 description 20
- 125000003107 substituted aryl group Chemical group 0.000 description 20
- 125000004423 acyloxy group Chemical group 0.000 description 19
- 125000005236 alkanoylamino group Chemical group 0.000 description 19
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 19
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 19
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 19
- 125000004414 alkyl thio group Chemical group 0.000 description 19
- 125000003435 aroyl group Chemical group 0.000 description 19
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 19
- 125000004093 cyano group Chemical group *C#N 0.000 description 19
- 125000000753 cycloalkyl group Chemical group 0.000 description 19
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 125000005110 aryl thio group Chemical group 0.000 description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 18
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 244000045947 parasite Species 0.000 description 10
- 239000004530 micro-emulsion Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 7
- 125000004103 aminoalkyl group Chemical group 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000004064 cosurfactant Substances 0.000 description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 7
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- 239000004094 surface-active agent Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
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- 150000002148 esters Chemical class 0.000 description 5
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- 235000013355 food flavoring agent Nutrition 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 239000003765 sweetening agent Substances 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
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- WBVMIQAMORKYIV-UHFFFAOYSA-N n'-cyclohexyl-n-hydroxy-2-phenoxybenzenecarboximidamide Chemical compound C=1C=CC=C(OC=2C=CC=CC=2)C=1C(=N/O)/NC1CCCCC1 WBVMIQAMORKYIV-UHFFFAOYSA-N 0.000 description 4
- BCVBAZKOQPOXCJ-UHFFFAOYSA-N n'-cyclopentyl-n-hydroxy-2-phenylbenzenecarboximidamide Chemical compound C=1C=CC=C(C=2C=CC=CC=2)C=1C(=N/O)/NC1CCCC1 BCVBAZKOQPOXCJ-UHFFFAOYSA-N 0.000 description 4
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
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- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
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- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
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- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000004304 potassium nitrite Substances 0.000 description 1
- 235000010289 potassium nitrite Nutrition 0.000 description 1
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
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- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
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- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
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- 235000011803 sesame oil Nutrition 0.000 description 1
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- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- YQDGWZZYGYKDLR-UZVLBLASSA-K sodium stibogluconate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].O1[C@H]([C@H](O)CO)[C@H](O2)[C@H](C([O-])=O)O[Sb]21([O-])O[Sb]1(O)(O[C@H]2C([O-])=O)O[C@H]([C@H](O)CO)[C@@H]2O1 YQDGWZZYGYKDLR-UZVLBLASSA-K 0.000 description 1
- 229960001567 sodium stibogluconate Drugs 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- 238000003239 susceptibility assay Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 description 1
- 125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/04—Amoebicides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/58—Amidines
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
N-substituted amidoxime derivatives for the prophylaxis and/or treatment of tropical diseases N-substituted amidoxime derivatives of formula (I) wherein R1is a substituent ; V, W and X are independently C-R2or N, with the proviso that at least one of V, W and X is C-R2; R2is independently hydrogen, alkyl, halogen, -CH2R3, -OR4, -SR4or aryl; and R3and R4are substitutents. Compositions comprising N-substituted amidoxime derivatives, processes for their preparation and their use as pharmaceutically active agents in the prophylaxis and/or treatment of tropical diseases caused by leishmania, trypanosome, protozoa and plasmodium falciparum such as South American trypanosomiasis, African trypanosomiasis, sleeping sickness, Kala-Azar, visceral leishmaniasis, Bagdad boil or Aleppo boil, cutaneous leishmaniasis, espundia, Chagas disease, mucocutaneous leishmaniasis, trichomoniasis, urogential trichomonosis, giardiasis, lamblia dysentery, amoebiasis, primary amebic meningoencephalitis, keratitis or meningitis, coccidiosis, sarcosporidosis, toxoplasmosis, malaria tropica, malaria tertian, malaria quartana, pneumocystis carinii, pneumonia, pneumocystosis, Balantidium dystentery and oriental sore are also outlined.
Description
Novel Amidoxime Derivatives
FIELD OF THE INVENTION
[0001] The present invention relates to novel N-substituted amidoxime derivatives, compositions containing them, processes for their preparation and their use as pharmaceutically active agents.
BACKGROUND OF THE INVENTION
[0002] Human or non-human mammalian diseases attributable to infection of the individual by a parasite, especially those prevalent in developing countries in regions of the world such as sub-Saharan Africa, India, Southeast Asia, Central and Southern America, are poorly treated with existing medicaments. For example, treatment of African sleeping sickness, a disease caused by infection of an individual with Trypansoma brucei parasites, is currently compromised by the poor efficacy, high toxicity and difficult administration requirements of existing drugs such as eflornithine, melarsoprol and suramin. Similarly, treatment of Chagas disease, a disease caused by infection of an individual with Trypanosoma cruzi parasites, is compromised by the ineffectiveness of current drugs such as nifurtimox and benznidazole. Existing therapies for diseases caused by Leishmania sp. parasites, visceral and cutaneous leishmaniasis, including treatment by drugs such as meglumine antimonite, sodium stibogluconate and amphotericin B also suffer from potential toxicity and limited efficacy of these agents. Therefore, there exists a need for new pharmaceutical agents for the effective and safe treatment of these tropical diseases.
[0003] The present invention seeks to provide new compounds of the N-substituted amidoxime family together with processes for their preparation.
[0004] The present invention also seeks to provide compounds, stereoisomeric forms and/or pharmaceutically acceptable salts of the N-substituted amidoxime family which can be used as pharmaceutically active agents, especially for prophylaxis and/or treatment of tropical diseases caused by leishmania, trypanosome, protozoa, and plasmodium falciparum such as South American trypanosomiasis, African trypanosomiasis, sleeping sickness, Kala-Azar, visceral leishmaniasis, Baghdad boil or Aleppo boil, cutaneous leishmaniasis (CL), espundia, Chagas disease, mucocutaneous leishmaniasis (MCL), trichomoniasis, urogenital trichomonosis, giardiasis, lamblia dysentery, amoebiasis, primary amebic meningoencephalitis (PAM), keratitis or meningitis, coccidiosis, sarcosporidosis, toxoplasmosis, Malaria tropica, Malaria tertiana, Malaria quartana, pneumocystis carinii, pneumonia, pneumocystosis, Balantidium dysentery, and oriental sore.
SUMMARY OF THE INVENTION
[0005] The invention provides novel N-substituted amidoxime derivatives of formula (I): N'' R' x-..w*v (I) [0006] wherein R1 is alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl, or unsubstituted or substituted aryl or heteroaryl, whereby the substituents may each be independent of one another and are selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl, alkylsulfoxyl and alkylsulfonyl; 10007] V, W and X are independently C-R2 or N; with the proviso that at least one of V, W and X is C-R2; [0008] R2 is independently hydrogen, alkyl, halogen, -CH2R3, -OR4, -SR4 or aryl; [0009] R3 is cycloalkyl, alkenyl or, alkynyl, each of which is unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl; 100101 R4 is alkyl, cycloalkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, allcylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl; [0011] or a pharmaceutically acceptable salt or solvate thereof.
[0012] These compounds are useful as pharmaceutically active agents, especially for prophylaxis and/or treatment of tropical diseases caused by Trypanosoma sp., Leishmania sp., Balantidiuin coli, Eimeria sp., Entamoeba histolytica, Giardia intestinalis, Isospira sp. Naegleriafowleri, Plasmodiuin sp. and Trichomonas vaginalis such as African trypanosomiasis, Chagas disease, visceral leishmaniasis (VL), cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), diffuse cutaneous leishmaniasis, Balantidium dysentery, coccidiosis, amoebiasis, giardiasis, primary amebic meningoencephalitis (PAM), malaria and trichomoniasis.
DETAILED DESCRIPTION
Definitions [0013] "Alkyl" refers to both straight and branched carbon chains; references to individual alkyl groups are specific for the straight chain (e.g. butyl = n-butyl). In one embodiment of alkyl, the number of carbons atoms is 1-20, in another embodiment of alkyl, the number of carbon atoms is 1-8 carbon atoms and in yet another embodiment of alkyl, the number of carbon atoms is 1-4 carbon atoms. Other ranges of carbon numbers are also contemplated depending on the location of the alkyl moiety on the molecule; [0014] "Alkenyl" refers to both straight and branched carbon chains which have at least one carbon-carbon double bond. In one embodiment of alkenyl, the number of double bonds is 1-3, in another embodiment of alkenyl, the number of double bonds is one. In one embodiment of alkenyl, the number of carbons atoms is 2-20, in another embodiment of alkenyl, the number of carbon atoms is 2-8 and in yet another embodiment of alkenyl, the number of carbon atoms is 2-4. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule; [0015] "Alkynyl" refers to both straight and branched carbon chains which have at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is 1-3; in another embodiment of alkynyl, the number of triple bonds is one. In one embodiment of alkynyl, the number of carbons atoms is 2-20, in another embodiment of alkynyl, the number of carbon atoms is 2-8 and in yet another embodiment of alkynyl, the number of carbon atoms is 2-4. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule; [0016] "Aryl" refers to a C6-Cio aromatic ring structure. In one embodiment of aryl, the moiety is phenyl, naphthyl, tetrahydronapthyl, phenylcyclopropyl and indanyl; in another embodiment of aryl, the moiety is phenyl.
10017] "Alkoxy" refers to -0-alkyl, wherein alkyl is as defined above; 100181 "Alkanoyl" refers to formyl (-C(=O)H) and -C(=O)-alkyl, wherein alkyl is as defined above; [0019] "Alkanoyloxy" refers to OC(=rO)a1ky1, wherein alkanoyl is as defined above; [0020] "Alkanoylamino" refers to -NH2-C(=O)-alkyl, wherein alkanoyl is as defined above and the amino (NH2) moiety can be substituted by alkyl as defined above; 100211 "Aminocarbonyl" refers to -NH2-C(=O), wherein the amino (NH2) moiety can be substituted by alkyl as defined above; 100221 "Alkoxycarbonyl" refers to C(==O)Oa1kyl, wherein alkoxy is as defined above; [0023] "Alkenoyl" refers to -C(=O)-alkenyl, wherein alkenyl is as defined above; [0024] "Alkynoyl" refers to -C(=O)-a[kynyl, wherein alkynyl is as defined above; [0025] "Aroyl" refers to -C(=O)-aryl, wherein aryl is as defined above; [0026] "Alkylsulfinyl" refers to -S(=O)-alkyl, wherein alkyl is as defined above; [0027] "Alkylsulfonyl" refers to -S02-alkyl, wherein alkyl is as defined above; [0028] "Cyclo" as a prefix (e.g. cycloalkyl, cycloalkenyl, cycloalkynyl) refers to a saturated or unsaturated cyclic ring structure having from three to eight carbon atoms in the ring the scope of which is intended to be separate and distinct from the definition of aryl above. Tn one embodiment of cyclo, the range of ring sizes is 4-7 carbon atoms; in another embodiment of cyclo the range of ring sizes is 3-4. Other ranges of carbon numbers are also contemplated depending on the location of the cyclo-moiety on the molecule; [0029] "Halogen" means the atoms fluorine, chlorine, bromine and iodine. The designation of "halo" (e.g. as illustrated in the term haloalkyl) refers to all degrees of substitutions from a single substitution to a perhalo substitution (e.g. as illustrated with methyl as chloromethyl (-CH2CI), dichloromethyl (-CHCI2), trichloromethyl (-CCh)); 100301 "Heterocycle", "heterocyclic" or "heterocyclo" refer to fully saturated or unsaturated, including aromatic (i.e. hetaryl') cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3 -dioxolane and tetrahydro-1,1 -dioxothienyl, triazolyl, triazinyl, and the like. Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2,3 -c]pyridinyl, furo [3,2-b]pyridinyl]or furo [2,3 -b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
[0031] "Pharmaceutically acceptable salt" refers to any salt of a compound of this invention which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. The compounds of the present invention may be basic and may form salts with organic or inorganic acids.
Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfuric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, mandelic acid, o methylmandelic acid, benzenesulfonic acid, adipic acid, d-o-tolyltartaric acid, tartaric acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. In case, the compound bear acidic substituents, the formation of salts with inorganic or organic bases may be possible. Examples of such bases are sodium or potassium hydroxide, ammonium hydroxide, tetraalkylammonium hydroxide, lysine or arginine and the like. Salts may be prepared in a conventional manner using methods well known in the art, for example, by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above.
[00321 Some of the compounds of the present invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. n such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
[0033] In the case of chiral substituents, compounds of the general formula (I) may exist in the form of optical isomers, e.g. enantiomers, diastereomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. Where a compound according to the general formula (I) contains an alkene moiety, the alkene can be presented as a cis or trans isomer or mixture thereof When an isomeric form of a compound of the invention is provided substantially free of other isomers, it will preferably contain less than 5% w/w, more preferably less than 2% w/w and especially less than 1% w/w of the other isomer(s).
[0034] In a first embodiment of the first aspect of the invention there are provided compounds of formula (I) wherein: [0035] R' is C11o alkyl or cycloalkyl, C11o hydroxyalkyl, C110 alkoxyalkyl, or C110 aminoalkyl; [0036] R2 is hydrogen, -CH2R3, -OR4, -SR4 or aryl; [00371 R4 is alkyl, cycloalkyl, alkenyl or alkynyl, unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl.
[0038j In a second embodiment of the first aspect of the invention, there are provided compounds of formula (I) wherein: [0039] R' is unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl, alkylsulfoxyl and alkylsulfonyl; [0040] R2 is independently hydrogen, -CH2R3, -OR4 or -SR4; 100411 R4 is alkyl or cycloalkyl, alkenyl, alkynyl, unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl; [0042] In a third embodiment of the first aspect of the invention, there are provided compounds of formula (I) wherein: [0043] R' is alkyl or cycloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl, alkylsulfoxyl, alkylsulfonyl; [0044] V and X are independently C-R2; [0045] W is N; [0046] R2 is independently hydrogen, alkyl, -CH2R', -OR4 or [0047] R4 is alkyl or cycloalkyl, alkenyl, alkynyl, unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl; [0048] In a fourth embodiment of the first aspect of the invention, there are provided compounds of formula (I) wherein: [0049] R' is alkyl or cycloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl, alkylsulfoxyl and alkylsulfonyl; [0050] V and X are independently C-R2; 100511 WisN; 100521 R2 is independently hydrogen or -OR4; [0053] R4 is alkyl or cycloalkyl, alkenyl, alkynyl, unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl; [0054] In a fifth embodiment of the first aspect of the invention, there are provided compounds of formula (I) wherein: 100551 R' is alkyl or cycloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl, alkylsulfoxyl and alkylsulfonyl; [0056] V and X are independently C-R2; [0057] W is N; [0058] R2 is independently hydrogen or -OR4; 100591 R4 is alkyl or cycloalkyl, alkenyl, alkynyl, unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl.
[0060] In a sixth embodiment of the first aspect of the invention, there are provided compounds of formula (I) wherein: [0061] R' is C110 alkyl or cycloalkyl, Ciio hydroxyalkyl, C11o alkoxyalkyl, or C110 aminoalkyl; 100621 V and X are independently C-R; -10 - [0063] WisN; 100641 R2 is independently hydrogen or -OR4; 100651 R4 is alkyl or cycloalkyl, alkenyl, alkynyl, unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl.
[00661 In a seventh embodiment of the first aspect of the invention, there are provided compounds of formula (I) wherein: [0067] R' is unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl, alkylsulfoxyl and alkylsulfonyl; [0068] V and X are independently C-R2; [00691 W is N; [00701 R2 is independently hydrogen or -OR4; [00711 R4 is alkyl or cycloalkyl, alkenyl, alkynyl, unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independent of one another and are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl.
[0072] In an eighth embodiment of the first aspect of the invention, there are provided compounds of formula (I) wherein: [00731 R' is Ciio alkyl, cycloalkyl, C11o hydroxyalkyl, C11o alkoxyalkyl or Ciio aminoalkyl; [0074] V and X are independently C-R2; 100751 W is N; [0076] R2 is independently hydrogen or -OR4; 100771 R4 is unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl.
[0078] In a ninth embodiment of the first aspect of the invention, there are provided compounds of formula (I) wherein: [0079] R' is unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl, alkylsulfoxyl and alkylsulfonyl; [0080] V and X are independently C-R; [0081] WisN; [0082] R2 is independently hydrogen or -OR4; [0083] R4 is unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl.
10084] In a tenth embodiment of the first aspect of the invention, there are provided compounds of formula (I) wherein R' is Ciio alkyl or cycloalkyl, unsubstituted or substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of, halogen, alkyl, haloalkyl, alkylthio and alkoxy; V and W are independently C-R2; W is N; R2 is hydrogen, -OR4 or phenyl; and R4 is unsubstituted or substituted aryl, whereby the substituents are independently selected from the group consisting of cyano, halogen, alkyl, haloalkyl, alkylthio and alkoxy.
-12 - [0085] In a further embodiment of the first aspect of the invention in formula (I) above W is N and/or V and X are independently C-R2.
100861 In a further embodiment of the first aspect of the invention, the compound of formula (I) is selected from: [0087] 1. 2-(4-tert-Butylphenoxy)-N-cyclohexyl-N'-hydroxy-nicotinamidine [0088] 2. 2-(4-tert-Butylphenoxy)-N-(3 -fluorophenyl)-N'-hydroxy-nicotinamidine [0089] 3. 2-(2-Chlorophenoxy)-N-cyclohexyl-N'-hydroxy-nicotinamidine [0090] 4. N-Cyclohexyl-2-(2-fluorophenoxy)-N'-hydroxy-nicotinamidine 100911 5. N-Cyclohexyl-N'-hydroxy-4-methoxy-benzamidine 100921 6. N-Cyclohexyl-N'-hydroxy-2-phenoxy-benzamidine [0093] 7. N-Cyclopentyl-N'-hydroxy-biphenyl-2-carboxamidine [0094] 8. N-(3 -Ethylphenyl)-N'-hydroxy-biphenyl-2-carboxamidine [0095] 9. N-Cyclohexyl-N'-hydroxy-2-phenoxy-nicotinamidine [0096] 10. N-Cyclohexyl-2-(2-methoxy-4-methylphenoxy)-N'-hydroxy-nicotinamidine [0097] 11. 2-(2-Bromophenoxy)-N-cyclohexyl-N'-hydroxy-nicotinamidine 100981 12. N-Cyclohexyl-2-(2-methoxyphenoxy)-N'-hydroxy-nicotinamidine 100991 13. N-Cyclohexyl-2-(2-methylthiophenoxy)-N'-hydroxy-nicotinamidine 100100] 14. N-Cyclohexyl-2-(2-ethylphenoxy)-N'-hydroxy-nicotinamidine [00101] 15. 2-(2-Chlorophenoxy)-N-hydroxy-N'-(4-methylcyclohexyl)-nicotinamidine [00102] 16. N-Cyclohexyl-2-(4-methylphenoxy)-N'-hydroxy-nicotinamidine [00103] 17. 2-(4-ethylphenoxy)-N-cyclohexyl-N'-hydroxy-nicotinamidine [00104] 18. N-Cyclohexyl-2-(4-isopropylphenoxy)-N'-hydroxy-nicotinamidine 1001 05J 19. N-Cyctohexyl-2-(4-fluorophenoxy)-N'-hydroxy-nicotinamidine -13 - [001061 20. 2-(4-Chlorophenoxy)-N-cyclohexyl-N'-hydroxy-nicotinamidine 1001071 21. N-Cyclohexyl-2-(4-methoxyphenoxy)-N'-hydroxy-nicotinamidine 1001081 22. 2-(4-tert-Butylphenoxy)-N-(3 -fluorophenyl)-N'-hydroxy-6-methyl-nicotinamidine [001091 23. 2-(4-tert-Butylphenoxy)-N-cyclohexyl-N'-hydroxy-6-methyl-nicotinamidine [001101 24. N-Cyclohexyl-2-(2,6-difluorophenoxy)-N'-hydroxy-6-methyl-nicotinamidine [00111] 25. N-Cyclohexyl-2-(2,6-difluorophenoxy)-N'-hydroxy-nicotinamidine 1001121 26. N-Cyclohexyl-2-(2,5 -dichlorophenoxy)-N'-hydroxy-nicotinamidine 1001131 27. 2-(2,6-Difluorophenoxy)-N-(3 -fluorophenyl)-N'-hydroxy-6-methyl-nicotinamidine [001141 28. 2-(2,6-Difluorophenoxy)-N-(3 -fluorophenyl)-N'-hydroxy-nicotinamidine [001151 29. 2-(2,5 -Dichlorophenoxy)-N-(3 -fluorophenyl)-N'-hydroxy-nicotinamidine [001161 30. N-Cyclohexyl-2-(2, 5 -dichlorophenoxy)-N'-hydroxy-nicotinamidine [001171 31. 2-(4-Chlorophenoxy)-N-cyclohexyl-N'-hydroxy-6-methyl-nicotinamidine 1001181 32. N-Cyclohexyl-N'-hydroxy-2-methoxy-benzamidine [001191 33. N-Cyclohexyl-N'-hydroxy-3 -methoxy-benzamidine [00120] 34. N-Cyclohexyl-2-ethyl-N'-hydroxy-benzamidine [001211 35. N-Cyclohexyl-4-ethyl-N'-hydroxy-benzamidine [00122] 36. N-Cyclohexyl-N'-hydroxy-benzamidine [00123] 37. N-Cyclohexyl-N'-hydroxy-2-(p-tolyloxy)-benzamidine [001241 38. N-Cyclohexylmethyl-N'-hydroxy-4-methoxy-benzamidine 1001251 39. N-Hydroxy-4-methoxy-N'-phenyl-benzamidine -14 - [001261 40. N-(4-Ethylphenyl)-N'-hydroxy-4-methoxy-benzamidine 100127] 41. N-(3 -Ethylphenyl)-N'-hydroxy-4-methoxy-benzamidine 100128] 42. N-(2-Ethylphenyl)-N'-hydroxy-4-methoxy-benzamidine [00129] 43. N-Hydroxy-4-methoxy-N'-m-tolyl-benzamidine 100130] 44. N-Biphenyl-3 -yl-N'-hydroxy-4-methoxy-benzamidine 1001311 45. N-(3 -Fluorophenyl)-N'-hydroxy-4-methoxy-benzamidine 1001321 46. 2-Benzyl-N-cyclohexyl-N'-hydroxy-benzamidine and 1001331 47. 2-p-Tolyl-N-cyclohexyl-N'-hydroxy-benzamidine.
The numbers 1 to 47 are assigned to these compounds for reference and identification hereafter.
1001341 The compounds of the invention can be prepared, isolated or obtained by any method apparent to those of skill in the art. Exemplary methods of preparation are described in detail in the examples below.
[00135] According to a feature of the present invention compounds of formula (I) can be obtained by treatment of an unsubstituted amidoxime of formula (II), wherein V, W, and X are as defined above, with a mixture of a nitrite (e.g. sodium nitrite) and an acid (e.g. hydrochloric acid) followed by reaction with an amine of formula R'NH2, optionally in the presence of a solvent, wherein R' is defined above, for example, as illustrated in the reaction scheme below: OH 1) NaNO2, HCI, H20,OH 2) Ri NH2, solvent J,R1 w w_ (II) (I) [00136] It will be appreciated by those skilled in the art that alternatives to both the nitrite salt (e.g. potassium nitrite) and/or acid (e.g. acetic acid, sulfuric acid) may be employed in the first stage of this transformation, and that a variety of solvents (e.g. methanol, ethanol, tetrahydrofuran) may be used in the second stage of this transformation (or by using an excess of R'NH2, this may act as the solvent), and that the choice of exact reaction conditions will be dictated by the properties of the -15 -individual components of the reaction, for example, solubility of the either the unsubstituted amidoxime and/or amine in the solvent to be employed.
Pharmaceutical Compositions and Methods of Administration [00137] According to a further feature of the invention there are provided compositions which comprise an N-substituted amidoxime derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient, carrier or diluent. The composition of the invention can also be in a variety of forms which include, but are not limited to, oral formulations, injectable formulations, and topical, dermal or subdermal formulations.
[00138] The composition of the invention may be in a form suitable for oral use, for example, as dietary supplements, troches, lozenges, chewables, tablets, hard or soft capsules, emulsions, aqueous or oily suspensions, aqueous or oily solutions, dispersible powders or granules, syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, bittering agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
[00139] Tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
[00140] Formulations for oral use may be hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. Capsules may also be soft gelatin capsules, wherein the active ingredient is mixed with water or miscible solvents such as -16-propylene glycol, PEGs and ethanol, or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
1001411 The compositions of the invention may also be in the form of oil-in-water or water-in-oil emulsions. The oily phase maybe a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these.
Suitable emulsifying agents may be naturally-occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
The emulsions may also contain sweetening agents, bittering agents, flavoring agents, and/or preservatives.
1001421 In one embodiment of the formulation, the composition of the invention is in the form of a microemulsion. Microemulsions are well suited as the liquid carrier vehicle. Microemulsions are quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a cosurfactant. They are translucent and isotropic liquids.
[001431 Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase. The size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions). The interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously.
1001441 In one embodiment of the oily phase, the oily phase can be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of such compounds. In one embodiment of the oily phase, the oily phase comprises of triglycerides; in another embodiment of the oily phase, the triglycerides are medium-chain triglycerides, for example, C8-Cio caprylic/capric triglyceride. In another embodiment of the oily phase will represent a % v/v range selected from the group consisting of about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v of the microemulsion.
[00145] The aqueous phase includes, for example, water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. In one -17 -embodiment of the glycol derivatives, the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof. Generally, the aqueous phase will represent a proportion from about 1 to about 4% v/v in the microemulsion.
[00146] Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropyelene glycol monomethyl ether, polyglycolyzed C8-C10 glycerides or polyglyceryl-6 dioleate. In addition to these surfactants, the cosurfactants include short-chain alcohols, such as ethanol and propanol.
[00147] Some compounds are common to the three components discussed above, for example, aqueous phase, surfactant and cosurfactant. However, it is well within the skill level of the practitioner to use different compounds for each component of the same formulation. Tn one embodiment for the amount of surfactant/cosurfactant, the cosurfactant to surfactant ratio will be from about 1/7 to about 1/2. In another embodiment for the amount of cosurfactant, there will be from about 25 to about 75% v/v of surfactant and from about 10 to about 55% v/v of cosurfactant in the microemulsion.
[00148] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, atachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as sucrose, saccharin or aspartame, bittering agents, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid, or other known preservatives.
[00149] Aqueous suspensions may contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occuring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, -18 -heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and/or bittering agents, such as those set forth above.
[00150] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, bittering, flavoring and coloring agents, may also be present.
[00151] Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring agent(s) and/or coloring agent(s).
[00152] The compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-aceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. Preservatives, such as phenol or benzyl alcohol, may be used.
[00153] In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
-19 - [00154] Topical, dermal and subdermal formulations can include emulsions, creams, ointments, gels or pastes.
1001551 Organic solvents that can be used in the invention include but are not limited to: acetyltributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g. N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.
1001561 As vehicle or diluent, mention may be made of plant oils such as, but not limited to soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils such as, but not limited to, petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium-chain (such as C8-C12) triglycerides.
[00157] Dosage forms may contain from about 0.5 mg to about 5 g of an active agent. In one embodiment of the dosage form, the dosage is from about 1 mg to about 500 mg of an active agent, typically about 25 mg, about 50 mg, about 100 mg, about mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1000 mg.
1001581 In one embodiment of the invention, the active agent is present in the formulation at a concentration of about 0.05 to 10% weight/volume. In another embodiment of the invention, the active agent is present in the formulation as a concentration from about 0.1 to 2% weight'volume. In yet another embodiment of the invention, the active agent is present in the formulation as a concentration from about 0.25 to about 1.5% weight/volume. In still another embodiment of the invention, the active agent is present in the formulation as a concentration about 1% weight/volume.
[001591 According to a further feature of the invention there is provided a method of treating or preventing infection in a subject, the method comprising administering -20 -to the subject a therapeutically effective amount of N-substituted amidoxime derivative of formula (T) or a pharmaceutically acceptable salt or solvate thereof 1001601 The compounds of the invention are especially useful for the prophylaxis and/or treatment of South American trypanosomiasis, African trypanosomiasis, sleeping sickness, Kala-Azar, visceral leishmaniasis, Baghdad boil or Aleppo boil, cutaneous leishmaniasis (CL), espundia, Chagas disease, mucocutaneous leishmaniasis (MCL), trichomoniasis, urogenital trichomonosis, giardiasis, lamblia dysentery, amoebiasis, primary amebic meningoencephalitis (PAM), keratitis or meningitis, coccidiosis, sarcosporidosis, toxoplasmosis, Malaria tropica, Malaria tertiana, Malaria quartana, pneumocystis carinii, pneumonia, pneumocystosis, Balantidium dysentery, and oriental sore.
1001611 The pharmaceutical preparation comprising the N-substituted amidoxime derivatives of the invention, for delivery to a human or other mammal, is preferably in unit dosage form, in which the preparation is subdivided into unit doses containing an appropriate quantity of the active component. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet or lozenge itself, or it can be an appropriate number of any of these in packaged form.
[001621 The quantity of active component in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 1000 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
[001631 In therapeutic use for the treatment of a parasitic infection in a human or other mammal, the compounds utilized in the pharmaceutical method of the invention are administered at an initial dosage of about 0.00 1 mg/kg to about 100 mg/kg daily.
The dosages may be varied depending on the requirements of the patient, for example, the size of the human or mammal being treated, the severity of the condition being treated, the route of administration, and the potency of the compound being used.
Determination of the proper dosage and route of administration for a particular situation is within the skill of the practitioner. Generally, the treatment will be -21 -initiated with smaller dosages which are less than the optimum dose of the compound, which can be increased in small increments until the optimum effect under the particular circumstances of the infection is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
[00164] The following Examples illustrate the synthesis of representative compounds used in the present invention and the following Reference Examples illustrate the synthesis of intermediates in their preparation. These examples are not intended, nor are they to be construed, as limiting the scope of the invention. It will be clear that the invention may be practiced otherwise than as particularly described herein. Numerous modifications and variations of the present invention are possible in view of the teachings herein and, therefore, are within the scope of the invention.
1001651 All temperatures are given in degrees Centigrade; room temperature means to 25°C. Reagents were purchased from commercial sources or prepared following literature procedures.
DMF = dimethylformamide TEA = triethylamine [00166] Proton and fluorine magnetic resonance (respectively H NMR and 9F NMR) spectra were recorded on a Varian INOVA NMR spectrometer [400 MHz (H) or 500 MHz (H) and 377 MHz (9F)]. All spectra were determined in the solvents indicated. Chemical shifts are reported in ppm downfield of tetramethylsilane (TMS), referenced to the residual proton peak of the respective solvent peak for H NMR.
1001671 LC-MS spectra were either obtained using a Thermofinnigan AQA MS ESI instrument, using a Phenomenex Aqua 5 micron C18 125A 50 x 4.60 mm column and a linear gradient from 55% methanol: 1% acetonitrile in water to 100% methanol over 3 minutes. 100% methanol was maintained for 2 minutes. Alternatively, LCMS spectra were obtained using an Agilent 12005L HPLC equipped with a 6130 mass spectrometer operating with electrospray ionization.
-22 -
Example 1
1001681 To a cooled (0°C) solution of 2-(4-tert-butylphenoxy)-N-hydroxy-nicotinamidine (340 mg), prepared according to Reference Example 1, in 2 N aqueous hydrochloric acid (6.1 rnL) was added sodium nitrite (92 mg). The reaction was maintained at 0°C for about 3 hours, then the mixture was filtered. The isolated solids were added to a solution of cyclohexylamine (0.54 mL) in tetrahydrofuran and allowed to stir at room temperature for about 16 hours. The reaction was diluted into water and extracted with ethyl acetate. The combined organic fractions were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, concentrated and chromatographed over silica gel to give 2-(4-tert-butylphenoxy)-N-cyclohexyl-N'-hydroxy-nicotinamidine (Compound 1) as an off white solid (70 mg); H NMR (DMSO-d6) ppm 0.99 -1.15 (m,3H) 1.25 (d,2H) 1.30 (s,9H) 1.46 (d,1H) 1.54-1.71 (m,4H) 2.83 (t,1H) 5.66 (d,1H) 6.97 (d,2H) 7.15 (dd,1H) 7.43 (d,2H) 7.78 (d,1H) 8.15 (d,1H) 9.61 (s,1H); LCMS (electrospray) 368 (M+H).
[00169] By proceeding in a similar manner the following compounds were prepared: [00170] 2-(4-tert-butylphenoxy)-N-(3 -fluorophenyl)-N'-hydroxy-6-methyl-nicotinamidine (Compound 2); H NMR (acetonitrile-d) ppm 1.29 (s,9H) 2.26 (s,3H) 6.39 -6.49 (m,3H) 6.53 (dd,1H) 6.69 (td,1H) 6.99 (d,1H) 7.02 -7.13 (m,1H), 7.28 (d,2H) 7.68 (hr. s,1H) 7.81 (d,1H) 8.32 (s,1H); LCMS (electrospray) 394 (M+H); 1001711 2-(4-chlorophenoxy)-N-cyclohexyl-N'-hydroxy-nicotinamidine (Compound 3) as a white solid, H NMR (DMSO-d6) S ppm 0.99 -1.13 (m,3H) 1.23 (dd,2H) 1.46 (d,1H) 1.53 -1.69 (m,4H) 2.73 -2.84 (m,1H) 5.67 (d,1H) 7.07 -7.13 (m,2H) 7.20 (dd,1H) 7.45 -7.51 (m,2H) 7.83 (dd,1H) 8.18 (dd,1H) 9.65 (s,1H); LCMS (electrospray) 346 (M+H); [00172] N-cyclohexyl-2-(2-fluorophenoxy)-N'-hydroxy-nicotinamidine (Compound 4) as a white solid H NMR (DMSO-d6) ppm 0.98 -1.11 (m,3H) 1.18 - 1.32 (m,2H) 1.46 (d,1H) 1.53 -1.71 (m,4H) 2.78 -2.93 (m,1H) 5.68 (d,1H) 7.14 - 7.41 (m,5H) 7.83 (dd,1H) 8.13 (dd,1H) 9.68 (s,1H); LCMS (electrospray) 330 (M+H).
-23 -
Example 2
1001731 To a mixture ofpara-anisaldehyde (0.500 rnL) and sodium acetate trihydrate (671 mg,) in methanol (4 mL) was added hydroxylamine hydrochloride (314 mg). The reaction was allowed to stir for 30 minutes and then diluted into water.
The mixture was extracted with ether three times and the combined organic fractions were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under a stream of nitrogen gas. The residue was dissolved in dimethyl formamide (2 mL) and N-chlorosuccinimide (549 mg) was added. The reaction was allowed to stir for 30 minutes and then diluted into water.
The mixture was extracted with ether three times and the combined organic fractions were washed with water, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under a stream of nitrogen gas. The residue was dissolved in tetrahydrofuran and added to a solution of cyclohexylamine (1.40 mL) in tetrahydrofuran. The reaction was allowed to stir for 16 hours before pouring into aqueous sodium hydroxide solution. The mixture was extracted three times with ethyl acetate and the combined fractions were washed with water, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to give a brown oil. The oil was chromatographed on silica gel to give N-cyclohexyl-N'-hydroxy-4-methoxy-benzamidine (Compound 5) as an off white solid (808 mg); HNMR(DMSO-d6)� ppm 0.97-1.24 (m,5H) 1.40-1.50 (m,1H) 1.54- 1.72 (m,4H) 2.87-3.01 (m,1H) 3.78 (s,3H) 5.26 (d,1H) 6.93 -6.99 (m,2H) 7.31 - 7.37 (m,2H), 9.68 (s,1H); LCMS (electrospray) 249 (M+H).
1001741 By proceeding in a similar manner the following compounds were prepared: [00175] N-cyclohexyl-N'-hydroxy-2-phenoxy-benzamidine (Compound 6) as a white solid, 1H NMR (DMSO-d6) 6 ppm 1.01 (d,3H) 1.09 -1.25 (m,2H) 1.43 (d, 1H) 1.56 (dd,4H) 2.71 -2.85 (m,1H) 5.51 (d,1H) 6.87 -6.99 (m,3H) 7.08 -7.21 (m,2H) 7.34-7.44 (m,4H) 9.45 (s,1H); LCMS (electrospray) 311 (M+H); [001761 N-cyclopentyl-N'-hydroxy-biphenyl-2-carboxamidine (Compound 7) as a white solid, H NMR (400 MHz, DMSO-d6) ppm 0.98 -1.52 (m,8H) 2.94 -3.08 -24 - (m,, 1H) 5.38 (d,1H) 7.29 -7.44 (m,6H) 7.44 -7.54 (m,3H) 9.36 (s,1H); LCMS (electrospray) 281 (M+H); 100177] N-(3 -ethylphenyl)-N'-hydroxy-biphenyl-2-carboxamidine (Compound 8) as a white solid, H NMR (400 MHz, DMSO-d6) ppm 0.88 (t, 3H) 2.23 (q, ,2 H) 5.97 (s,1H) 6.01 (d,1H) 6.53 (d,1H) 6.72 (t,1H) 6.99 (dd,2H) 7.17 -7.25 (m,4H) 7.39 -7.53 (m,3H) 7.85 (s,IH) 10.13 (s,IH); LCMS (electrospray) 317 (M+H).
[00178] By proceeding in a similar manner to the reactions described in Example 1 or 2 above, Compounds 9 to 47 were also prepared.
Reference Example 1
100179] 2-(4-tert-butyl-phenoxy)-nicotinonitril. To a solution of 2-chloro-3 -cyano pyridine (0.500 g and 4-tert-butyl phenol (0.895 g) in DMF (4.3 mL) was added potassium carbonate (1.80 g). The mixture was heated to 100°C for 16 hours before cooling to room temperature and diluting into water. The pH was adjusted to 13 with IM aqueous sodium hydroxide and the aqueous mixture was extracted four times with ether. The combined organic fractions were washed twice with aqueous sodium hydroxide solution, water, saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give 2-(4-tert-butyl-phenoxy)-nicotinonitrile as an off white solid (517 mg) H NMR (DMSO-d6) ppm 1.31 (s,9H) 7.12-7.17 (m,2H) 7.30 (dd,1H) 7.43 -7.49 (m,2H) 8.38 (1.95,2H).
Reference Example 2
[00180] 2-(4-tert-butyl-phenoxy)-N-hydroxy-nicotinamidine. To a mixture of 2- (4-tert-butyl-phenoxy)-nicotinonitrile (514 mg) and hydroxylamine hydrochloride (283 mg) in methanol (6.8 mL) was added sodium hydrogen carbonate (605 mg). The mixture was heated to 68 °C for 16 hours. The reaction was cooled to room temperature, filtered through celite, concentrated in vacuo and the residue was chromatographed over silica gel to give 2-(4-tert-butyl-phenoxy)-N-hydroxy-nicotinamidine as a white solid (347 mg); H NMR (DMSO-d6) � ppm 1.30 (s,9H) -25 - 5.85 (br. s.,2H) 7.03 -7.08 (m,2H) 7.13 (dd,1H) 7.38 -7.46 (m,2H) 7.89 (dd,1H) 8.10 (dd,1H) 9.62 (s,1H).
Trypanosome Strain and Cultivation [00181] All experiments were conducted with the bloodstream-form trypanosome T. brucei brucei 427 strain. Parasites were cultured in T-25 vented cap flasks and kept in humidified incubators at 37°C and 5% CO2. The parasite culture media was complete HMI-9 medium (c.f. Hirumi, Journal of Parasitology 1989, Volume 75, page 985 et seq) containing 10% FBS, 10% Serum Plus medium and penicillinlstreptomycin. To ensure log growth phase, trypanosomes were sub-cultured at appropriate dilutions every 2-3 days.
In Vitro Drug Sensitivity Assays [00182] Log phase cultures were diluted 1:10 in HMT-9 and 10 uL was counted using hemocytometer to determine parasite concentration. Parasites were diluted to 2 x I /niL in HMI-9 to generate a 2-fold working concentration for assay. Compounds to be tested were serially diluted in DMSO and 0.5 uL added to 49.5 uL HMI-9 in triplicate 96-well plates using a Biomek NX liquid handler. Parasites from the diluted stock were added to each well (50 uL) using a Multidrop 384 dispenser to give a final concentration of 1.0x105/mI parasites in 0.4% for DMSO. Trypanosomes were incubated with compounds for 72 hrs at 37°C with 5% CO2. Resazurin (20 uL of 12.5 mg/mi stock) from Sigma-Aldrich was added to each well and plates were incubated for an additional 2-4 hrs. Assay plates were read using an EnVision plate reader at an excitation wavelength of 544 nm and emission of 590 nm. Triplicate data points were averaged to generate sigmoidal dose response curve and determine IC50 values using XLfit curve fitting software from IDBS (Guildford, UK).
[00183] Under these assay conditions, Compounds 1 to 47 of the invention gave an IC50 value in the range of 0.1 to lOug/ml.
[00184] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. While the invention has been described in terms of various embodiments, the skilled artisan -26 -will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims, including equivalents thereof.
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JPH01215994A (en) * | 1988-02-24 | 1989-08-29 | Hokko Chem Ind Co Ltd | Production of benzenecarboxyimidamido derivative by electrolytic reaction |
WO2001051456A2 (en) * | 2000-01-13 | 2001-07-19 | Tularik Inc. | Antibacterial agents |
WO2005033065A1 (en) * | 2003-09-05 | 2005-04-14 | University Of North Carolina At Chapel Hill | Novel amidine compounds for treating microbial infections |
EP1561463A2 (en) * | 1995-11-16 | 2005-08-10 | The University Of North Carolina At Chapel Hill | Benzamidoxime prodrugs as antipneumocystic agents |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01215994A (en) * | 1988-02-24 | 1989-08-29 | Hokko Chem Ind Co Ltd | Production of benzenecarboxyimidamido derivative by electrolytic reaction |
EP1561463A2 (en) * | 1995-11-16 | 2005-08-10 | The University Of North Carolina At Chapel Hill | Benzamidoxime prodrugs as antipneumocystic agents |
WO2001051456A2 (en) * | 2000-01-13 | 2001-07-19 | Tularik Inc. | Antibacterial agents |
WO2005033065A1 (en) * | 2003-09-05 | 2005-04-14 | University Of North Carolina At Chapel Hill | Novel amidine compounds for treating microbial infections |
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Title |
---|
Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), vol 6, 1974, pages 567-571 * |
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US10538497B2 (en) | 2015-12-15 | 2020-01-21 | Merck Sharp & Dohme Corp. | Compounds as indoleamine 2,3-dioxygenase inhibitors |
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