HRP960168A2 - Novel aryl glycinamide derivatives, processes for their preparation and pharmaceutical compounds containing these substances - Google Patents
Novel aryl glycinamide derivatives, processes for their preparation and pharmaceutical compounds containing these substances Download PDFInfo
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- HRP960168A2 HRP960168A2 HR19519245.1A HRP960168A HRP960168A2 HR P960168 A2 HRP960168 A2 HR P960168A2 HR P960168 A HRP960168 A HR P960168A HR P960168 A2 HRP960168 A2 HR P960168A2
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- phenyl
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- alkyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 81
- 238000000034 method Methods 0.000 title claims description 14
- -1 aryl glycinamide derivatives Chemical class 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title abstract description 3
- 239000000126 substance Substances 0.000 title description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 239000001301 oxygen Substances 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 52
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 23
- 229910052794 bromium Inorganic materials 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 14
- 150000001412 amines Chemical class 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 8
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 230000006806 disease prevention Effects 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
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- 239000005557 antagonist Substances 0.000 abstract description 8
- 102000003141 Tachykinin Human genes 0.000 abstract description 5
- 108060008037 tachykinin Proteins 0.000 abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
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- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000007819 coupling partner Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
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- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 201000004614 iritis Diseases 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 208000017830 lymphoblastoma Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- AEWBGTYXABSUNA-UHFFFAOYSA-N n-piperidin-4-ylpropanamide;hydrochloride Chemical compound Cl.CCC(=O)NC1CCNCC1 AEWBGTYXABSUNA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 108010091700 substance P (4-11) Proteins 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000002462 tachykinin receptor antagonist Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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- C07—ORGANIC CHEMISTRY
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
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- C07—ORGANIC CHEMISTRY
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Description
Izum se odnosi na nove derivate arilglicinamida opće formule I
[image]
i njihove farmaceutski prihvatljive soli, postupke za njihovu proizvodnju i farmaceutske sastave koji sadrže te spojeve. Ovi spojevi su dragocjeni (tahikinin)-antagonisti neurokinina.
Kratice koje se koriste u ovom opisu i patentnim zahtjevima imaju slijedeća značenja:
CDI = karbonildiimidazol,
DCCI = dicikloheksilkarbodiimid,
HOBt = 1-hidroksibenztriazol,
THF = tetrahidrofuran,
DMF = dimetilformamid,
RT = sobna temperatura,
DMAP = 4-dimetilaminopiridin,
TBTU = O-benzotriaz-olil-tetrametiluronij-tetrafluorborat.
Za prikaz formula koristit će se pojednostavljen prikaz. Pri tome u prikazu spojeva svi CH3-supstituenti su prikazani sa spojnom crticom, tako na primjer
[image]
Izum se odnosi na nove derivate arilglicinamida opće formule I
[image]
ili njihove farmaceutski prihvatljive soli, u kojima
Ar predstavlja jednostruko do peterostruko supstituirani fenil, ili nesupstituirani ili jednostruko ili dvostruko supstituirani naftil, [pri čemu supstituenti fenila i naftila jesu međusobno neovisno halogen (F, Cl, Br, J), OH,
(C1-C4)alkil, O- (C1-C4) alkil, CF3, OCF3 ili NR9R10 (gdje R9 i R10 međusobno neovisno jesu H, metil ili acetil)]
ili Ar je fenil supstituiran s -OCH2O- ili -O(CH2)2O-;
R1 i R2 zajedno s N, na kojeg su vezani, tvore prsten formule
[image]
u kojoj
p je 2 ili 3,
X predstavlja kisik, N(CH2)nR6 ili CR7R8,
gdje
n je 0, 1 ili 2,
R6 je (C3-C7) cikloalkil, fenil ili naftil, pri čemu fenil može biti jednostruko do trostruko supstituiran s halogenim (F, Cl, Br, J),
(C1-C4)alkil O-(C1-C4)alkil, CF3, OCF3 ili NR15R16 (gdje gdje R15 i R16 međusobno neovisno jesu H, metil ili acetil) ;
R7 i R8 imaju jedno od slijedećih značenja:
a) R7 i R8 su H ako je R3 nesupstituirani ili supstituirani fenil,
b) R7 je fenil, fenil supstituiran s 1 do 3 supstituenta [gdje supstituenti međusobno neovisno jesu halogen (F, Cl, Br, J), (C1C4)alkil, O-(C1-C4)alkil, CF3 ili OCF3], piperidinil, 1-metilpiperidinil,
[image]
[image]
c) R7 i R8 zajedno tvore ostatak
[image]
R3 je H, (C1-C4) alkil, nesupstituirani ili 1-3-struko supstituirani fenil, gdje su supstituenti međusobno neovisno halogen (F, Cl, Br, J), (C1-C4) alkil, O-( C1-C4) alkil, CF3, OCF3 ili NR17R18 (gdje R17 i R18 međusobno neovisno jesu H, metil ili acetil);
R4 je fenil (C1-C4) alkil ili naftil (C1-C4) alkil, gdje fenil može biti supstituiran s 1 do 3 supstituenta, pri čemu su supstituenti međusobno neovisno halogen (F, Cl, Br, J), (C1-C4) alkil, O-( C1-C4)alkil, CF3, OCF3 ili NR19R20 (gdje R19 i R20 međusobno neovisno jesu H, metil ili acetil); i
R5 predstavlja H, (C1-C4) alkil, (C3-C6) cikloalkil, -CH2COOH, -CH2C(O)NH2, -OH ili fenil (C1-C4) alkil.
Spojevi prema izumu dragocjeni su (tahikinin) -antagonisti neurokinina, koji imaju kako antagonizam prema tvari P, tako također i antagonistička svojstva prema neurokininu A, odnosno neurokininu B. Oni se mogu koristiti za liječenje i za preventivu od bolesti kod kojih posreduje neurokinin.
Spojevi opće formule I mogu imati kiselinske skupine, uglavnom ciklokarboksilne skupine, i/ili bazične skupine kao.npr. amino funkcije. Spojevi opće formule I mogu stoga postojati kao unutarnje soli, kao soli s farmaceutski upotrebljivim anorganskim kiselinama, kao što je solna kiselina, sumporna kiselina, fosforna kiselina, sulfonska kiselina ili organske kiseline (kao primjerice maleinska kiselina), fumarna kiselina, limunska kiselina, vinska kiselina ili octena kiselina) ili kao soli s farmaceutski upotrebljivim bazama, kao što su hidroksidi alkalnih ili zemno alklanih metala ili karbonati/ hidroksidi cinka ili aminija ili organskih amina, kao npr. dietilamina, trietilamina, trietanolamina i drugih.
Spojevi prema izumu mogu postojati kao racemati, ali se oni također mogu dobiti i kao čisti enantiomeri,
tj. u (R)- ili (S)-obliku.
Prednost se daje spojevima opće formule I, u kojoj R1 i R2 zajedno s N, na kojeg su vezani, tvore prsten formule
[image]
u kojoj
X predstavalj N(CH2)nR6 ili CR7R8, u kojoj
n, R6, R7 i R8 su kao što je definirano u zahtjevu 1.
Ističu se spojevi formule I, u kojima
X je N(CH2)nR6, gdje n je 0, 1 ili 2, a R6 je (C3-C7)-cikloalkil ili fenil, naročito oni u kojima n je 0, a
R6 je (C3-C7) cikloalkil, posebno oni u kojima R6 je ciklobutil ili cikloheksil.
Ističu se, nadalje, spojevi formule I, u kojima R7 i R8 imaju jedno od slijedećih značenja:
a) R7 i R8 su H ako je R3 nesupstituirani ili supstituirani fenil,
b) R7 je fenil, piperidinil,
[image]
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ako R8 je H, -CHNH2, -NHC(O)CH3, -N (CH3) C (O) CH3 ili CN, ili
c) R7 i R8 zajedno tvore ostatak
[image]
R7 i R8 imaju jedno od slijedećih značenja:
a) R7 i R8 su H ako je R3 nesupstituirani ili supstituirani fenil,
b) R7 je fenil,
[image]
ako R8 je H, -CONH2 ili CN, ili
c) R7 i R8 zajedno tvore ostatak
[image]
Prednost se daje spojevima u kojima R7 je fenil,
[image]
i R8 je H ili CN, naročito onima u kojima R7 je piridino, a R8 je H.
Od gore definiranih spojeva prednost se daje onima u kojima
Ar je nesupstituirani ili jednostruko ili dvostruko supstituirani fenil, ili nesupstituirani naftil, [pri čemu supstituenti fenila međusobno neovisno jesu halogen (F, Cl, Br, J), OH, metil, metoksi, CF3, OCF3 ili dimetilaminj ili Ar je fenil supstituiran s -OCH2O-, pri čemu ta skupina povezuje položaje 2 i 3 ili 3 i 4 fenila, naročito oni u kojima
Ar je nesupstituirani ili jednostruko ili dvostruko supstituirani fenil, ili nesupstituirani naftil, [pri čemu supstituenti fenila međusobno neovisno jesu halogen (F, Cl, Br,) metoksi ili CF3] ili
Ar je fenil supstituiran s -OCH2O-, pri čemu ta skupina povezuje položaje 2 i 3 ili 3 i 4 fenila.
Od prednosti su spojevi u kojima Ar je fenil, 3,4-diklorfenil, 3,4-dimetoksifenil ili 3,4-metilendioksifenil.
Od gore definiranih spojeva ističu se oni i kojima R3 je fenil ili ponajprije H.
Od gore definiranih spojeva ističu se oni i kojima
R4 predstavlja fenil (C1-C3) alkil, gdje fenil može biti supstituiran s l ili 2 supstituenta, pri čemu su supstituenti međusobno neovisno halogen (F, Cl, Br, J), metil, metoksi, CF3 ili OCF3; i
R5 predstavlja H, (C1-C3) alkil, -CH2COOH, -CH2C(O)NH2 ili fenetil, naročito oni spojevi u kojima
R4 je
[image]
i R5 je H ili CH3.
Prednost se daje slijedećim spojevima:
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Gore upotrijebljena oznaka naftila obuhvaća 1-naftil kao također i 2-naftil.
Rezultati istraživanja za spojeve prema izumu:
Receptorski afinitet prema NK1-receptoru (tvar P-receptor) određuje se na humanim stanicama limfoblastoma (IM-9) s kloniranim NK1-receptorima, pri čemu se mjeri 125 prodiranje tvari P markirane sa 125J. Tako dobivene K1-vrijednosti pokazuju učinkovitost spojeva:
Ki
spoj primjer 3: 1, 4 nM
spoj primjer 4: 1,0 nM
spoj primjer 5: 1,3 nM
spoj primjer 33: 1,3 nM
spoj primjer 45: 1,6 nM
spoj primjer 46: 1,4 nM
spoj primjer 52: 1,1 nM
spoj primjer 53: 2,3 nM
spoj primjer 58: 6,4 nM
spoj primjer 59: 4,2 nM
spoj primjer 65: 9,2 nM
spoj primjer 66: 1, 4 nM
spoj primjer 68: 1,5 nM
spoj primjer 70: 2, 8 nM
spoj primjer 71: 2, 1 nM
spoj primjer 72: 6,8 nM
spoj primjer 73: 1,7 nM
spoj primjer 74: 11,8 nM
spoj primjer 75: 180 nM
spoj primjer 76: 7,0 nM
Spojevi prema izumu su dragocjeni (tahikinin)-antagonisti neurokinina, koji imaju naročito NK1-antagonizara, ali također i NK2- i NK3-antagonistička svojstva.
Spojevi prema izumu dragocjeni su (tahikinin)-antagonisti neurokinina, koji imaju kako antagonizam prema tvari P, tako također i antagonistička svojstva prema neurokininu A, odnosno neurokininu B. Oni se mogu iskoristiti za liječenje i preventivu od bolesti kod kojih posreduje neurokininom: liječenje ili sprečavanje upalnih i alergijskih bolesti dišnih puteva, kao astme, kroničnog bronhitisa, erafizema, rinitisa, kašlja, očiju, kao konjuktivitisa ili iritisa, kože, kao dermatitisa kod ekcema na dodir, urtikarije, psorijaze, opeklina od sunca, uboda insekata, neuro-dermitisa, svrbeži, postherpesnih bolova, želučano crijevnog trakta, kao želučanog i čira na dvanaestercu, colitis ulcerosa, Crohnove bolesti, colon irritabile, Hirschsprungove bolesti, zglobova, kao reumatskog artritisa, reaktivni artritisa i Reiterovog sindroma; za liječenje bolesti središnjeg živčanog sistema, kao demencije, Alzheimerove bolesti, šizofrenije, psihoza, depresije, glavobolja (npr. migrene ili glavobolje zbog napetosti), epilepsije; liječenje tumora, kolagenoza, disfunkcije odvodnih mokraćnih puteva, hemoroida, mučnine i povraćanja, izazvanih npr. zračenjem ili terapijom sa citostaticima ili kretanjem i bolesnim stanjima svih vrsta.
Izum se stoga odnosi također na upotrebu spojeva prema izumu kao pomoćnih sredstava i farmaceutskih pripremaka, koji sadrže te spojeve. Primjenjuju se ponajprije na ljudima. Aplikacija spojeva prema izumu može se izvršiti intravenozno, subkutano, intramuskularno, intraperito-nealno, intranazalno, inhalacijski, transdermalno, po želji iontoforezom ili transportiran sa sredstvom za pojačanje poznatim iz literature, i oralno.
Za parenteralnu aplikaciju slojevi formule I ili njihove fiziološki podnošljive soli prevode se u otopine, suspenzije ili emulzije sa za to uobičajenim tvarima, kao sredstvima za poboljšanje topivosti, emulgatorima ili daljnjim pomoćnim tvarima. Kao otapala u obzir dolaze npr. voda, fiziološke otopine natrijevog klorida ili alkoholi, npr. etanol, propandiol ili glicerin, otopine šećera kao otopine glukoze ili manita, ili također mješavine različitih otapala.
Osim toga spojevi se mogu aplicirati pomoću implantata, npr. od polilaktida, poliglikolida ili polihidroksimašlačne kiseline, odnosno inatranazalnih pripremaka.
Oralna učinkovitost spojeva opće formule I može se pokazati slijedećim standardnim ispitivanjem.
Suzbijanje opadanja krvnog tlaka izazvano s NK1 na anesteziranim zamorcima
Zamorci (300-500 grama) bili su anestezirani s pentobarbitalom (50 mg/kg i.p.), intubirani i mehanički su udisali po 10 ml sobnog zraka po kg tjelesne težine s frekvencijom od 60 udisaja po minuti. Mjerenje krvnog tlaka vršeno je preko vratne žile kucavice. Za -intravenozno dovođenje tvari bila je kanilirana vratna vena.
Intravenoznim davanjem NK1-agonista [βAla4, Sar 9, Met (O2)11]SP(4-11) (0,2 μmola/kg) bio je izazvan kratkotrajni pad krvnog tlaka, koji je bio ponavljan ponovnim davanjem NK1-agonista u razmacima od 10 minuta. Na kraju je intraduodenalno dat antagonist neurokinina i u 10 minutnim intervalima induciran je pad krvnog tlaka s NK1-antagonistima.
Suzbijanje pada tlaka uzrokovano navedenim NK1-antagonistima bilo je izmjereno prije i poslije obrade s antagonistima neurokinina.
[image]
Spoj primjera 5 dao je ID50 = 1,4 mg/kg. (ID50 je doza koja pad krvnog tlaka uzrokovan s NK1-agonistima suzbije za 50%.).
Spojevi prema izumu mogu se proizvesti po opće poznatim metodama.
Proizvodnja spojeve može se izvršiti na različite načine. Oba upotrebljiva postupka prikazana su u slijedećoj shemi:
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Postupak A.
Povezivanje karbonske kiseline s aminom HN(R5)R4 može se provesti na različite načine. Uobičajene metode su postupci spajanja koji se primjenjuju u kemiji peptida. Pri tome se upotrebljavaju reagensi spajanja kao TBTU, DCCI/HOBt, CDI, itd. u otprilike ekvivalentnoj količini prema partnerima spajanja. Prikladna otapala su DMF, THF, CH2Cl2, CHCl3, acetonitril ili druga inertna otapala ili njihove mješavine. .Prikladno temperaturne područje je između -50°C i +120°C, ponajprije između 0°C i 40°C.
Karbonska kiselina može se najprije prevesti u odgovarajući kiselinski halogenid pomoću SOCl2, SO2Cl2, PCl3, PCl5 ili PBr3 ili njihove mješavine po poznatim postupcima i konačno se kemijski pretvara s aminom NH(R5) R4 u inertnom otapalu kao npr. CH2Cl2, THF ili dioksanu pri temperaturama između 50°C i +100°C, tipično pri 0°C do 20°C.
Daljnja mogićnost je u tome da se karbonsku kiselinu po poznatim metodama najprije prevede u alkilni ester, obično metilester, koji se tada u inertnom otapalu, kao npr. DMF, dioksanu ili THFr dovodi u reakciju s aminom NH(R5)R4. Reakcijska temperatura je između 20°C i +150°C, tipično između 50°C i 120°C. Reakcija se također može provesti u tlačnoj posudi.
Postupak B.
Ovdje se α-halogen-arilacetamidni derivat dobiven na prethodni poznati način dovodi u reakciju s aminom R1(R2)NH uz odcjepljenje halogenovodika. Za hvatanje odcijepljenog (ili također prekomjernog) halogenovodika upotrebljavaju se anorganske baze, kao npr. K2CO3, NaHCO3 ili CaCO3, ili organske baze, kao npr. trietilamin, Hünigova baza, piridin ili DMAP, ili se upotrebljava amin R1(R2)NH u suvišku. Pri tome se upotrebljava DMF, THF, dioksan ili drugo inertno otapalo. Temperaturne područje reakcije je od 0°C do 100°C, tipično između 10°C i 80°C.
Postupak C.
Spojevi prema izumu u kojima R5 nije H, mogu se proizvesti kako slijedi. Najprije se postupkom A ili B sintetizira odgovarajući spoj u kojem R5 je H. Na kraju se, kako slijedi, provodi N-alkiliranje, da se tako uvede alkil, cikloalkil ili CH2COOH. Spoj prema izumu, u kojem R5 je H, deprotonira se s ekvivalentnom količinom NaH, NaNH2, KOH, NaOCO3 ili nekom drugom jakom bazom. Pri tome se upotrebljava bezvodno, ineretno otapalo, kao npr. THF, dioksan ili dietileter. Na kraju se polako doda odgovarajuće sredstvo za alkiliranje u obliku odgovarajućeg halogenida, tosilata ili mesilata. Kemijska pretvorba provodi se u temperaturnom području od -50°C do +100°C, tipično između 0°C i +50°C. Postupak je opisan u pojedinostima u primjeru 33.
Primjer 1:
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1. stupanj:
2.2 g 1-cikloheksilpiperazina otopi se u 150 ml bezvodnog DMF-a, pomiješa se s 2 g K2CO3, miješa se 20 min pri sobnoj temperaturi i zatim se ohladi na 5°C. Doda se 2,7 g metilestera (R, S) -a-brornfeniloctene kiseline i suspenziju se miješa preko noći pri sobnoj temperaturi. Talog se odfiltrira i filtrat se zgusne. Ostatak se preuzme u octeni ester, ekstrahira se 2 puta s 10%-tnom otopinom KHCO3 i jednom sa zasićenom otopinom NaCl. Organsku fazu se osuši preko Na2SO4, filtrira i zgusne, pri čemu se dobije 3,7 g (R, S)-1-cikloheksil-4-(2-feniloctena kiselina-metilester)-piperazina kao žutog ulja. Iskorištenje: pribl. 100%.
2. stupanj;
2.3 g proizvoda iz 1. stupnja otopi se u 10 ml metanola, pomiješa se s 14 N NaOH i nastalu emulziju miješa se preko noći pri sobnoj temperaturi. Bistru reakcijsku otopinu neutralizira se dodatkom 14 ml 1N HCl, zgusne se do suhog, ostatak se obradi s izopropariolom i čvrstu tvar se odsisa. Filtrat se zgusne i ostatak se ponovno protrlja s izopropanolom, čvrstu tvar se odsisa i sjedini s prethodno dobivenom čvrstom tvari. Tako se dobije 1,6 g (R,S)-1-cikloheksil-4-(2-feniloctena kiselina)-piperazina kao bijelu čvrstu tvar. Iskorištenje: 75%.
3. stupanj:
0,6 g proizvoda iz drugog stupnja, 0,48 g 3,5-bis-(trifluormetil)-benzilamina i 0,32 g HOBT-a suspendira se u 60 ral THF/CH2C12 (1:1) i dodatkom pribl. 0,7 ml Hunigove baze namjesti se na pH 8,5. Pomiješa se s 0,77 g TBTU i miješa se preko noći pri sobnoj temperaturi. Bistru reakcijsku otopinu se zgusne u vakuumu, ostatak se preuzme u CH2Cl2 i izmućka se dva puta s 10%-tnom otopinom KHSO4, jednom sa zasićenom otopinom NaCl, dva puta s 10%-tnom otopinom KHCO3 i jednom sa zasićenom otopinom NaCl. Organsku fazu osuši se preko Na2SO4, odfiltrira i zgusne, pri čemu dolazi do kristalizacije. Dobije se 0,685 g (R,S)-1-cikloheksil-piperazinil-4-[2-feniloctena kiselina-N-(3,5-bis-trifluormetilbenzil)amida] kao žućkaste čvrste tvari.
Iskorištenje: 64%.
Talište: 124-129°C; FAB-MS: (M+H)+ = 528,2.
Primjer 2:
[image]
l. stupanj:
0,49 g 3, 5-bis-(trifluormetil)-benzilamina otopi se u 30 ml bezvodnog CH2Cl2, pomiješa se s 0,3 ml trietilamina, smjesu se ohladi u ledenoj kupelji i u roku od 20 minuta dokaplje se otopinu od 0,46 g klorida (R,S)-α-bromfenil-octene kiseline u 10 ml CH2Cl2. Pusti se stajati preko vikedna pri sobnoj temperaturi, zatim se otapalo izvuče i čvrsti ostatak se protrlja s dietileterom, odsisa i filtrat se zgusne. Pri tome se dobije 0,6 g α-bromfeniloctena kiselina-N-(bis-trifluormetil-benzil)-amida kao čvrste tvari svjelo bež boje. Iskorištenje: 43,5%.
2. stupanj:
0,21 g 4-propionilamino-piperidin-hidroklorida otopi se u 30 ml bezvodnog DMF-a, pomiješa se s 0,33 g K2CO3 i miješa se 30 minuta pri sobnoj temperaturi. K toj smjesi u roku od 20 minuta dokaplje se otopinu od 0,68 g proizvoda iz 1. stupnja u 10 ml DMF-a i miješa se preko noći pri sobnoj temperaturi. Suspenziju se filtrira, filtrat se zgusne, dobiveni uljasti ostatak se preuzme u octeni ester, ekstrahira se dva puta s 10%-tnom otopinom KHCO3 i jednom sa zasićenom otopinom NaCl. Organsku fazu osuši se preko Na2SO4, filtrira, filtrat se zgusne i dobiveni čvrsti ostatak se protrlja s dietileterom i odsisa. Pri tome se dobije 0,33 g (R, S)-4-propicnilamino-1-[2-feniloctena kiselina-N-(3,5-bis-trifluormetilbenzil)amid]-piperidina kao bijele čvrste tvari.
Iskorištenje: 64%.
Talište: 189-191°C; FAB-MS: (M+H)+ = 516,4.
Primjer 33
[image]
Talište: >240°C; FAB-MS: (M+H)+ = 556,4.
0,3 g spoja iz primjera 25 prevede se obradom s KHCO3 u odgovarajuću bazu i osuši. To se otopi u 5 ml bezvodnog THF-a, pomiješa se sa 34 mg NaH (60%-tni u ulju) i miješa se 1,5 sata pri sobnoj temperaturi. Zatim se doda 0,1 g metiljodida i miješa se preko noći. Reakcijsku smjesu pomiješa se s 2 ml THF/vodom (1:1), zatim s 25 ml vode i 3 puta se ispere s eterom. Sjedinjeni eterski ekstrakti osuše se preko Na2SO4 i zgusnu u vakuumu, čime se dobije 170 mg željenog spoja kao slobodne baze (ulje). On se dodatkom eterske solne kiseline u suvišku prevede u dihidroklorid, koji se taloži u obliku žutih kristala. Iskorištenje: 113 mg (36%).
Analogno se mogu proizvesti ostali spojevi izuma, na primjer slijedeći:
Primjer 3
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Farmaceutski pripremci
Injekcijska otopina
200 mg aktivne tvari*
1,2 mg monokalijevog hidrogenfosfata = KH2PO4)
0,2 mg dinatrijevog hidrogenfosfata = ) (pufer)
NaH2P04·2H2O )
94 mg natrijevog klorida (izotonans)
ili
520 mg glukoze )
4 mg albumina (zaštita proteaze)
q.s. natrijeve lužine )
q.s. solne kiseline ) ad pH 6
ad 10 ml vode za injekcijsku namjenu.
Injekcijska otopina
200 mg aktivne tvari*
94 mg natrijevog klorida
ili
520 mg glukoze
4 mg albumina
q.s. natrijeve lužine )
q.s. solne kiseline ) ad pH 9 a
d 10 ml vode za injekcijsku namjenu.
Liofilizat
200 mg aktivne tvari*
520 mg manita (izotonans/tvorac kostura)
4 mg albumina
Otapalo l za liofilizat:
10 ml vode za injekcijske namjene.
Otapalo 2 za liofilizat:
20 mg Polysorbata®80 = Tween®80
(površinski aktivna tvar)
10 ml vode za injekcijske namjene.
*Aktivna tvar: spoj prema izumu, npr. jedan iz primjera 1 do 78.
Doza za čovjeka od 67 kg: 1 do 500 mg.
Claims (21)
1. Derivati arilglicinamida opće formule I
[image]
ili njihove farmaceutski prihvatljive soli, naznačeni time, da
Ar je nesupstituirani ili jednostruko do peterostruko supstituirani fenil, ili jednostruko ili dvostruko supstituirani naftil, [pri čemu supstituenti fenila i naftila međusobno neovisno jesu halogen (F, Cl, Br, J), OH, (C1-C4)alkil, O-( C1-C4)alkil, CF3, OCF3 ili NR9R10 (gdje R9 i R10 međusobno neovisno jesu H, metil ili acetil)] ili Ar je fenil supstituiran s -OCH2O- ili -O(CH2)2O-;
R1 i R2 zajedno s N, na kojeg su vezani, tvore prsten formule
[image]
u kojoj
p je 2 ili 3,
X je kisik, N(CH2)nR6 ili CR7R8, gdje
n je 0, 1 ili 2,
R6 je (C3-C7) cikloalkil, fenil ili naftil, pri čemu fenil može biti jednostruko do trostruko supstituiran s halogenim (F, Cl, Br, J),
(C1-C4)alkil, o-(C3-C4)alkil, CF3, OCF3 ili NR15R16 (gdje gdje R15 i R16 međusobno neovisno jesu H, metil ili acetil) ;
R7 i R8 imaju jedno od slijedećih značenja:
a) R7 i R8 su H ako je R3 nesupstituirani ili supstituirani fenil,
b) R7 je fenil, fenil supstituiran s 1 do 3 supstituenta [gdje supstituenti međusobno neovisno jesu halogen (F, Cl, Br, J), (C1-C4)alkil, O-( C1-C4) alkil, CF3 ili OCF3], piperidinil, 1-metilpiperidinil,
[image]
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R3 je H, (C1-C4) alkil, nesupstituirani ili 1-3-struko supstituirani fenil, gdje supstituenti međusobno neovisno jesu halogen (F, Cl, Br, J), (C1-C4)alkil, O- (C1-C4)alkil, CF3, OCF3 ili NR17R18 (gdje R17 i R18 međusobno neovisno jesu H, metil ili acetil);
R4 predstavlja fenil (C1-C4) alkil ili naftil (C1-C4) alkil, gdje fenil može biti supstituiran s 1 do 3 supstituenta, pri čemu supstituenti međusobno neovisno jesu halogen (F, Cl, Br, J), (C1-C4) alkil, O-( C1-C4) alkil, CF3, OCF3 ili NR19 R20
(gdje R19 i R20 međusobno neovisno jesu H, metil ili acetil); i
R5 predstavlja H, (C1-C4) alkil, (C3-C6) cikloalkil, -CH2COOH, -CH2C(O)NH2, -OH ili fenil (C1-C4) alkil.
2. Spoj prema zahtjevu 1, naznačen time, da
R1 i R2 zajedno s N, na kojeg su vezani, tvore šesteročlani prsten formule
[image]
u kojoj
X predstavlja N(CH2)nR6 ili CR7R8,
gdje n, ,R9, R7 i R8 su definirani kao u zahtjevu 1.
3. Spoj prema zahtjevu 2, naznačen time, da
X je N(CH2)nR6, gdje n je 0, 1 ili 2, a R6 je (C3-C7)cikloalkil ili fenil.
4. Spoj prema zahtjevu 3, naznačen time, da n je 0, a R6 je (C3-C7) cikloalkil.
5. Spoj prema zahtjevu 4, naznačen time, da R6 je ciklobutil ili cikloheksil.
6. Spojevi prema zahtjevu 2, naznačen time, da X je CR7R8, gdje R7 i R8 imaju jedno od slijedećih značenja:
a) R7 i R8 su H ako je R3 nesupstituirani ili supstituirani fenil,
b) R7 je fenil, piperidinil,
[image]
[image]
ako R8 je H, -CHNH2, -NHC(O)CH3, -N(CH3) C(O) CH3 ili CN, ili
c) R7 i R8 zajedno tvore ostatak
[image]
7. Spoj prema zahtjevu 6, naznačen time, da
R7 i R8 imaju jedno od slijedećih značenja:
a) R7 i R8 su H ako je R3 nesupstituirani ili supstituirani fenil,
b) R7 je fenil,
[image]
ako R8 je H, -CONH2 ili CN, ili
c) R7 i R8 zajedno tvore ostatak
[image]
8. Spoj prema zahtjevu 1, naznačen time, da R7 je fenil,
[image]
i R8 je H ili CN.
9. Spoj prema zahtjevu 8, naznačen time, da R7 je piridino, a R8 je H.
10. Spoj prema zahtjevima 1 do 9, naznačen time, da Ar je nesupstituirani ili jednostruko ili dvostruko supstituirani fenil, ili nesupstituirani naftil, [pri čemu supstituenti fenila međusobno neovisno jesu halogen (F, Cl, Br, J), OH, metil, metoksi, CF3, OCF3 ili dimetilamin] ili Ar je fenil supstituiran s -OCH2O-, pri čemu ta skupina povezuje položaje 2 i 3 ili 3 i 4 fenila.
11. Spoj prema zahtjevu 10, naznačen time, da Ar je nesupstituirani ili jednostruko ili dvostruko supstituirani fenil, ili nesupstituirani naftil, [pri čemu supstituenti fenila međusobno neovisno jesu halogen (F, Cl, Br, ) metoksi ili CF3] ili Ar je fenil supstituiran s -OCH2O-, pri čemu ta skupina povezuje položaje 2 i 3 ili 3 i 4 fenila.
12. Spoj prema zahtjevu 11, naznačen time, da Ar je fenil, 3, 4-diklorfenil, 3, 4-dimetoksifenil ili 3,4-metilen-dioksifenil.
13. Spoj prema jednom od zahtjeva l do 12, naznačen time, da R3 je H.
14. Spoj prema jednom od zahtjeva l do 12, naznačen time, da R3 je fenil.
15. Spoj prema jednom od zahtjeva l do 14, naznačen time, da
R4 predstavlja fenil (C1-C3) alkil, gdje fenil može biti supstituiran s l ili 2 supstituenta, pri čemu supstituenti međusobno neovisno jesu halogen (F, Cl, Br, J), metil, metoksi, CF3 ili OCF3; i
R5 predstavlja H, (C1-C3)alkil, -CH2COOH, -CH2C(O)NH2 ili fenetil.
16. Spoj prema zahtjevu 15, naznačen time, da
R4 je
[image]
i R5 je H ili CH3.
17. Spoj prema zahtjevu 1, naznačen time, da je
[image]
18. Postupak za proizvodnju spoja opće formule I prema jednom od zahtjeva l do 17, naznačen time, da se
a) kiselinu
[image]
ili njen halogenid ili alkilni ester kemijski pretvara s aminom
[image]
b) a-halogenarilacetamid
[image]
kemijski se pretvara s aminom
[image]
ili
c) spoj I, u kojem R5 je H, se N-alkilira;
i tako dobiven spoj izolira se kao slobodan spoj ili kao njegova farmaceutski prihvatljiva sol.
19. Farmaceutski pripravak, naznačen time, da sadrži spoj prema jednom od zahtjeva l do 17.
20. Upotreba spoja prema jednom od zahtjeva l do 17, naznačena time, da se koristi za proizvodnju farmaceutskog pripremka za terapiju i preventivu od bolesti kod kojih posreduje neurokinin.
21. Upotreba spoja prema jednom od zahtjeva l do 17, naznačena time, da se koristi za terapiju i preventivu protiv bolesti kod kojih posreduje neurokinin.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE19514112 | 1995-04-14 | ||
DE19519245A DE19519245C2 (de) | 1995-04-14 | 1995-05-25 | Neue Arylglycinamidderivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen |
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Publication Number | Publication Date |
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HRP960168A2 true HRP960168A2 (en) | 1997-08-31 |
HRP960168B1 HRP960168B1 (en) | 2002-04-30 |
Family
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HR960168A HRP960168B1 (en) | 1995-04-14 | 1996-04-12 | Novel aryl glycinamide derivatives, processes for their preparation and pharmaceutical compounds containing these substances |
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US (4) | US6124296A (hr) |
EP (1) | EP0824530B1 (hr) |
JP (1) | JP4035163B2 (hr) |
CN (1) | CN1071329C (hr) |
AT (1) | ATE289996T1 (hr) |
AU (1) | AU706209B2 (hr) |
BG (1) | BG62138B1 (hr) |
BR (1) | BR9604821A (hr) |
CA (1) | CA2218096C (hr) |
CZ (1) | CZ296778B6 (hr) |
EE (1) | EE03872B1 (hr) |
ES (1) | ES2238691T3 (hr) |
HR (1) | HRP960168B1 (hr) |
HU (1) | HU227277B1 (hr) |
IL (1) | IL117888A (hr) |
MX (1) | MX9707053A (hr) |
NO (1) | NO309476B1 (hr) |
NZ (1) | NZ307505A (hr) |
PL (1) | PL190602B1 (hr) |
PT (1) | PT824530E (hr) |
RO (1) | RO120259B1 (hr) |
RU (1) | RU2167866C2 (hr) |
SK (1) | SK282158B6 (hr) |
TR (1) | TR199701173T1 (hr) |
TW (1) | TW449590B (hr) |
WO (1) | WO1996032386A1 (hr) |
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US6413959B1 (en) | 1995-04-14 | 2002-07-02 | Boehringer Ingelheim Kg | Method of treating depression with arylglycinamide derivatives |
TW449590B (en) | 1995-04-14 | 2001-08-11 | Boehringer Ingelheim Kg | New arylglycinamide derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds |
EP0796855B1 (de) * | 1996-03-20 | 2002-02-06 | Hoechst Aktiengesellschaft | Inhibitoren der Knochenresorption und Vitronectinrezeptor-Antagonisten |
US5703237A (en) * | 1996-04-18 | 1997-12-30 | Neurogen Corporation | N-Aminoalkyl-2-anthraquinonecarboxamides; new dopamine receptor subtype specific ligands |
US6284794B1 (en) | 1996-11-05 | 2001-09-04 | Head Explorer Aps | Method for treating tension-type headache with inhibitors of nitric oxide and nitric oxide synthase |
DE19824470A1 (de) * | 1998-05-30 | 1999-12-02 | Boehringer Ingelheim Pharma | Neue Neurokininantagonisten, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen |
EP1110958A1 (en) | 1999-12-20 | 2001-06-27 | Ucb, S.A. | Alpha-arylethylpiperazine derivatives as neurokinin antagonists |
AUPR237301A0 (en) * | 2001-01-02 | 2001-01-25 | Fujisawa Pharmaceutical Co., Ltd. | Benzhydryl derivatives |
US6664253B2 (en) | 2000-10-17 | 2003-12-16 | Boehringer Ingelheim Pharma Kg | Neurokinin antagonists |
DE10051320A1 (de) * | 2000-10-17 | 2002-04-25 | Boehringer Ingelheim Pharma | Neue Neurokininantagonisten, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen |
US6747044B2 (en) | 2000-10-17 | 2004-06-08 | Boehringer Ingelheim Pharma Kg | Neurokinin antagonists |
DE10051321A1 (de) * | 2000-10-17 | 2002-04-25 | Boehringer Ingelheim Pharma | Neue Neurokininantagonisten, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen |
US6620438B2 (en) * | 2001-03-08 | 2003-09-16 | Boehringer Ingelheim Pharma Kg | Pharmaceutical compositions based on anticholinergics and NK1-receptor antagonists |
US7776315B2 (en) | 2000-10-31 | 2010-08-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and additional active ingredients |
EP1295599A1 (en) * | 2001-09-21 | 2003-03-26 | Boehringer Ingelheim International GmbH | Method for the treatment of prevention of atopic dermatitis |
TW200300757A (en) * | 2001-11-16 | 2003-06-16 | Schering Corp | Azetidinyl diamines useful as ligands of the nociceptin receptor orl-1 |
DE10230750A1 (de) * | 2002-07-09 | 2004-01-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Arzneimittelkompositionen auf der Basis neuer Anticholonergika und NK1-Rezeptor-Antagonisten |
US20040048886A1 (en) * | 2002-07-09 | 2004-03-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on new anticholinergics and NK1 receptor antagonists |
US20060275253A1 (en) * | 2003-09-01 | 2006-12-07 | Kazunari Ushida | Beta hydroxy short to medium chain fatty acid polymer |
JP2007532638A (ja) * | 2004-04-14 | 2007-11-15 | アストラゼネカ・アクチエボラーグ | Nk1アンタゴニスト及びセロトニン再取り込み阻害剤としてのアリールグリシンアミド誘導体及びその使用 |
US20060035893A1 (en) | 2004-08-07 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders |
PE20060777A1 (es) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
WO2008090114A1 (en) | 2007-01-24 | 2008-07-31 | Glaxo Group Limited | Pharmaceutical compositions comprising 2-methoxy-5- (5-trifluoromethyl-tetrazol-i-yl-benzyl) - (2s-phenyl-piperidin-3s-yl-) |
WO2011000945A2 (en) * | 2009-07-03 | 2011-01-06 | Nensius Research A/S | Aminoalkamides for use in the treatment of inflammatory, degenerative or demyelinating diseases of the cns |
RU2465273C2 (ru) | 2010-08-31 | 2012-10-27 | Общество С Ограниченной Ответственностью "Биофарм-Меморейн" | ГЕТЕРОЦИКЛИЧЕСКИЕ НИЗКОМОЛЕКУЛЯРНЫЕ sAPP-МИМЕТИКИ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СПОСОБЫ ПОЛУЧЕНИЯ И ПРИМЕНЕНИЯ |
RU2457205C2 (ru) * | 2010-09-07 | 2012-07-27 | Общество С Ограниченной Ответственностью "Биофарм-Меморейн" | Способ, соединение и фармацевтическая композиция и лекарственное средство для восстановления утраченной памяти в норме и патологии |
CN102351733B (zh) * | 2011-07-21 | 2014-03-19 | 凯莱英医药化学(阜新)技术有限公司 | 一种制备2-氨基-n,n-二甲基乙酰胺盐酸盐的方法 |
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US3518274A (en) * | 1967-10-09 | 1970-06-30 | Miles Lab | Phenyl substituted n-(2-aminoethyl)-n-benzylamides |
US3862946A (en) * | 1973-05-24 | 1975-01-28 | Miles Lab | N-benzyl-N-{8 2-phenyl-2-(4-phenyl-1-piperidyl)ethyl{9 {0 propionamide para-chlorobenzene sulfonate |
US3906100A (en) * | 1973-05-24 | 1975-09-16 | Miles Lab | N-benzyl-N-{8 2-phenyl-2-(4-phenyl-1-piperidyl)-ethyl{9 -propionamide para-chlorobenzene sulfonate |
US5612336A (en) * | 1992-07-13 | 1997-03-18 | Merck, Sharp & Dohme Ltd. | Heterocyclic amide derivatives as tachykinin antagonists |
GB9321557D0 (en) * | 1992-11-03 | 1993-12-08 | Zeneca Ltd | Carboxamide derivatives |
FR2717802B1 (fr) * | 1994-03-25 | 1996-06-21 | Sanofi Sa | Nouveaux composés aromatiques, procédé pour leur préparation et compositions pharmaceutiques en contenant. |
US5696123A (en) * | 1994-09-17 | 1997-12-09 | Boehringer Ingelheim Kg | Neurokinin antagonists |
TW449590B (en) | 1995-04-14 | 2001-08-11 | Boehringer Ingelheim Kg | New arylglycinamide derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds |
DE19519245C2 (de) | 1995-04-14 | 2003-04-30 | Boehringer Ingelheim Kg | Neue Arylglycinamidderivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen |
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