JP4187650B2 - 5−ht6レセプター親和性を有するアリールスルホニル誘導体 - Google Patents
5−ht6レセプター親和性を有するアリールスルホニル誘導体 Download PDFInfo
- Publication number
- JP4187650B2 JP4187650B2 JP2003519047A JP2003519047A JP4187650B2 JP 4187650 B2 JP4187650 B2 JP 4187650B2 JP 2003519047 A JP2003519047 A JP 2003519047A JP 2003519047 A JP2003519047 A JP 2003519047A JP 4187650 B2 JP4187650 B2 JP 4187650B2
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- JP
- Japan
- Prior art keywords
- methoxy
- compound
- phenyl
- piperazine
- benzenesulfonyl
- 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.)
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- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 229940060367 inert ingredients Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- RBWRWAUAVRMBAC-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=[C-]C=C1 RBWRWAUAVRMBAC-UHFFFAOYSA-M 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 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
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000003751 serotonin 6 antagonist Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D295/08—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 singly bound oxygen or sulfur atoms
- C07D295/096—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 singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D295/10—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 doubly bound oxygen or sulphur atoms
- C07D295/112—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 doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
Arは、場合によりハロゲンまたは(C1〜C6)アルコキシにより置換された、ナフチルまたはフェニルであり;
R1は、(C1〜C6)アルキルであり;
R2は、水素または(C1〜C6)アルキルである)
で示される(アリールスルホニル−フェニル)−ピペラジン誘導体またはその薬学的に許容され得る塩もしくは溶媒化合物に関する。
−無機酸、例えば塩化水素酸、臭化水素酸、硫酸、硝酸、リン酸等で形成される酸付加塩;または有機酸、例えば酢酸、ベンゼンスルホン酸、安息香酸、ショウノウスルホン酸、クエン酸、エタンスルホン酸、フマル酸、グルコヘプトン酸、グルコン酸、グルタミン酸、グリコール酸、ヒドロキシナフトエ酸、2−ヒドロキシエタンスルホン酸、乳酸、マレイン酸、リンゴ酸、マロン酸、マンデル酸、メタンスルホン酸、ムコン酸、2−ナフタレンスルホン酸、プロピオン酸、サリチル酸、コハク酸、酒石酸、p−トルエンスルホン酸、トリメチル酢酸等で形成される酸付加塩、あるいは
−親化合物中に存在する酸性プロトンが、金属イオン、例えばアルカリ金属イオン、アルカリ土類イオンもしくはアルミニウムイオンにより置き換えられるか、または有機もしくは無機塩基と配位する場合に形成される塩。使用可能な有機塩基は、ジエタノールアミン、エタノールアミン、N−メチルグルカミン、トリエタノールアミン、トロメタミン(tromethamine)等を含む。使用可能な無機塩基は、水酸化アルミニウム、水酸化カルシウム、水酸化カリウム、炭酸ナトリウムおよび水酸化ナトリウムを含む。
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
Hal ハロゲンまたはハロゲン化物
opt. 任意に
P 保護基
TFA トリフルオロ酢酸
TFAA トリフルオロ酢酸無水物
THF テトラヒドロフラン
1−〔2−メトキシ−5−(ナフタレン−1−スルホニル)−フェニル〕−ピペラジン、または
1−〔2−メトキシ−5−(ナフタレン−2−スルホニル)−フェニル〕−ピペラジン。
1−〔5−(4−フルオロ−ナフタレン−1−スルホニル)−2−メトキシフェニル〕−ピペラジン、または
1−〔2−メトキシ−5−(4−メトキシ−ナフタレン−1−スルホニル)−フェニル〕−ピペラジン。
1−(5−ベンゼンスルホニル)−2−メトキシ−フェニル)−ピペラジン。
1−〔5−(4−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン、
1−〔2−メトキシ−5−(4−メトキシ−ベンゼンスルホニル)−フェニル〕−ピペラジン、
1−〔5−(3−フルオロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン、
1−〔5−(3−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン、
1−〔5−(4−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−4−メチル−ピペラジン、
1−〔5−(3,4−ジクロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン、
1−〔5−(3,5−ジクロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン、または
4−〔5−(4−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−4−メチル−ピペリジン。
ai)式(b)
の化合物を、式
の化合物と反応させること、
aii)脱保護すること、および
aiii)場合によりアルキル化して、式(I)
の化合物を得ることか、または
bi)式(b)
の化合物を、式
bii)さらに、式
のグリニャール試薬と反応させること、
biii)脱保護すること、および
biv)場合によりアルキル化して、式(I)
の化合物を得ること、ならびに所望の場合、得られた化合物を薬学的に許容され得る酸付加塩に変換することにより製造してもよい。
当業者が本発明をより深く理解し、実行できるようにするために、下記の製造および例を記載する。これらの例は、本発明の範囲を制限するものではなく、本発明を例示するだけである。
1−〔2−メトキシ−4−(ナフタレン−1−スルホニル)−フェニル〕−ピペラジン
2,2,2−トリフルオロ−1−〔4−(2−メトキシ−フェニル)−ピペラジン−1−イル〕−エタノン
4−メトキシ−3−〔4−(2,2,2−トリフルオロ−アセチル)−ピペラジン−1−イル〕−ベンゼンスルホニルクロリド
2,2,2−トリフルオロ−1−{4−〔2−メトキシ−5−(ナフタレン−1−スルホニル)−フェニル〕−ピペラジン−1−イル}−エタノン
2,2,2−トリフルオロ−1−{4−〔2−メトキシ−5−(ナフタレン−2−スルホニル)−フェニル〕−ピペラジン−1−イル}−エタノン(2)、白色の固体として、MS,MH+ 479;
1−{4−〔5−(4−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(3)、白色の固体として、MS,MH+ 463;
1−{4−〔5−(4−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−4−メチル−ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(3a);
1−{4−〔5−(3−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(4)、白色の固体として、MS,MH+ 463;
1−{4−〔5−(3,5−ジクロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(5)、白色の固体として、MS,MH+ 497,498;
1−{4−〔5−(4−メトキシ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(6)、白色の固体として、MS,MH+ 459;または
1−{4−〔5−(3−フルオロ−ベンゼンスルホニル)−2−メトキシフェニル〕ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(7)、白色の固体として、MS,MH+ 447。
1−{4−〔5−(3−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−4−メチル−ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(8);
1−〔2−メトキシ−5−(ナフタレン−1−スルホニル)−フェニル〕−ピペラジン
2,2,2−トリフルオロ−1−{4−〔2−メトキシ−5−(ナフタレン−2−スルホニル)−フェニル〕−ピペラジン−1−イル}エタノン(2)から1−〔2−メトキシ−5−(ナフタレン−2−スルホニル)−フェニル〕−ピペラジン(102)を得た、MS,MH+ 383、融点279.9〜283.3℃。
1−{4−〔5−(4−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−4−メチル−ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(3a)から1−〔5−(4−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−4−メチル−ピペラジン(103a)を得た、MS,MH+ 367、融点263.4〜272.1℃。
1−{4−〔5−(4−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(3)から1−〔5−(4−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン(103)を得た、MS,MH+ 367、融点263.4〜272.1℃。
1−{4−〔5−(3−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(4)から1−〔5−(3−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン(104)を得た、MS,MH+ 367、融点265〜266.3℃。
1−{4−〔5−(3,5−ジクロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(5)から1−〔5−(3,5−ジクロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕ピペラジン(105)を得た、MS,MH+ 402、融点245.9〜246.2℃。
1−{4−〔5−(4−メトキシ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(6)から1−〔5−(4−メトキシ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン(106)を得た、MS,MH+ 363、融点260.1〜260.6℃。
1−{4−〔5−(3−フルオロ−ベンゼンスルホニル)2−メトキシフェニル〕ピペラジン−1−イル}2,2,2−トリフルオロ−エタノン(7)から1−〔5−(3−フルオロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン(107)を得た、MS,MH+ 351、融点246.0〜250.1℃。
1−{4−〔5−(3−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−4−メチル−ピペラジン−1−イル}−2,2,2−トリフルオロ−エタノン(8)から1−〔5−(3−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−4−メチル−ピペラジン(108)を得た。
1−〔5−(4−メトキシ−ベンゼンスルホニル)2−メトキシフェニル〕−ピペラジン
1−〔5−(4−フルオロ−ナフタレン−1−スルホニル)2−メトキシフェニル〕−ピペラジン
1−〔2−メトキシ−5−(4−メトキシ−ナフタレン−1−スルホニル)フェニル〕ピペラジン
経口投与用組成物
経口投与用組成物
経口投与用組成物
非経口製剤(IV)
坐剤
局所製剤
鼻噴用スプレー製剤
約0.025〜0.5%の活性化合物を含む幾つかの水性懸濁液を鼻噴用スプレー製剤として製造した。これらの製剤は、場合により、不活性成分、例えば結晶セルロース、カルボキシメチルセルロースナトリウム、デキストロース等を含有した。塩酸を加えてpHを調節してもよい。鼻噴用スプレー製剤は、1回操作する毎に典型的には約50〜100マイクロリットルの製剤を送達する鼻噴用スプレー計量供給ポンプにより送達することができる。典型的な投薬スケジュールは4〜12時間毎に2〜4回のスプレーである。
ラジオリガンド結合研究
本発明の化合物のインビトロ結合活性を下記のようにして測定した。
Claims (15)
- Arが置換されていないナフチルである、請求項1記載の化合物。
- 化合物が
1−〔2−メトキシ−5−(ナフタレン−1−スルホニル)−フェニル〕−ピペラジン、または
1−〔2−メトキシ−5−(ナフタレン−2−スルホニル)−フェニル〕−ピペラジン
である、請求項2記載の化合物。 - Arが、フルオロまたはメトキシにより置換されたナフチルである、請求項1記載の化合物。
- 化合物が
1−〔5−(4−フルオロ−ナフタレン−1−スルホニル)−2−メトキシフェニル〕−ピペラジン、または
1−〔2−メトキシ−5−(4−メトキシ−ナフタレン−1−スルホニル)−フェニル〕−ピペラジン
である、請求項2記載の化合物。 - Arが置換されていないフェニルである、請求項1記載の化合物。
- 化合物が
1−(5−ベンゼンスルホニル−2−メトキシ−フェニル)−ピペラジン
である、請求項6記載の化合物。 - Arが、メトキシ、フルオロまたはクロロにより置換されたフェニルである、請求項1記載の化合物。
- 化合物が
1−〔5−(4−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン、
1−〔2−メトキシ−5−(4−メトキシ−ベンゼンスルホニル)−フェニル〕−ピペラジン、
1−〔5−(3−フルオロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン、
1−〔5−(3−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン、
1−〔5−(4−クロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−4−メチル−ピペラジン、
1−〔5−(3,4−ジクロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン、または
1−〔5−(3,5−ジクロロ−ベンゼンスルホニル)−2−メトキシ−フェニル〕−ピペラジン
である、請求項8記載の化合物。 - 請求項1記載の少なくとも1種の化合物の治療的に有効な量を、少なくとも1種の薬学的に許容され得る担体との混合物で含む医薬。
- パーキンソン病、ハンチントン病、不安、うつ病、躁うつ病、精神病、てんかん、強迫障害、偏頭痛、アルツハイマー病、睡眠障害、食欲不振症、過食症、パニック攻撃、注意欠陥過活動性障害、注意欠陥障害、薬物乱用による禁断症、精神***病、水頭症、または機能性腸障害の処置のための、請求項10記載の医薬。
- 請求項1記載の式Iの化合物の製造方法であって、
ai)式(b)
の化合物を、一般式
の化合物と反応させること、
aii)脱保護すること、および
aiii)場合によりアルキル化して、式(I)
の化合物を得ること、または
bi)式(b)
の化合物を、式
bii)さらに、式
のグリニャール試薬と反応させること、
biii)脱保護すること、および
biv)場合によりアルキル化して、式(I)
の化合物を得ること、ならびに所望の場合、得られた化合物を薬学的に許容され得る酸付加塩に変換することを含む方法。 - 請求項12記載の方法により製造される、請求項1〜9のいずれか一項記載の式Iの化合物。
- 病気の処置用医薬を製造するための、請求項1〜9のいずれか一項記載の化合物の使用。
- パーキンソン病、ハンチントン病、不安、うつ病、躁うつ病、精神病、てんかん、強迫障害、偏頭痛、アルツハイマー病、睡眠障害、食欲不振症、過食症、パニック攻撃、注意欠陥過活動性障害、注意欠陥障害、薬物乱用による禁断症、精神***病、水頭症、または機能性腸障害の処置用医薬を製造するための、請求項1〜9のいずれか一項記載の化合物の使用。
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JP4455064B2 (ja) | 2002-03-27 | 2010-04-21 | グラクソ グループ リミテッド | キノリン誘導体および5−ht6リガンドとしてのその使用 |
MXPA05004758A (es) * | 2002-11-08 | 2005-08-02 | Hoffmann La Roche | Benzoxazinonas sustituidas y uso de las mismas. |
TWI289141B (en) * | 2003-03-11 | 2007-11-01 | Hoffmann La Roche F. Ag. | Quinolinone derivatives and uses thereof |
GB0305575D0 (en) * | 2003-03-11 | 2003-04-16 | Glaxo Group Ltd | Novel compounds |
EA009732B1 (ru) | 2003-07-22 | 2008-02-28 | Арена Фармасьютикалз, Инк. | Диарильные и арилгетероарильные производные мочевины в качестве модуляторов 5-ht-рецептора серотонина, пригодные для профилактики и лечения связанных с ним заболеваний |
WO2006062481A1 (en) * | 2004-12-09 | 2006-06-15 | Biovitrum Ab | New benzofuran derivatives and their use in the treatment of obesity, type ii diabetes and cns disorders . |
CA2591937C (en) * | 2004-12-21 | 2013-08-06 | F. Hoffmann-La Roche Ag | Tetralin and indane derivatives and uses thereof |
EP1695971A1 (en) * | 2004-12-30 | 2006-08-30 | Laboratorios Del Dr. Esteve, S.A. | Substituted phenyl-piperazine compounds, their preparation and use in medicaments |
WO2009074607A1 (en) | 2007-12-12 | 2009-06-18 | Glaxo Group Limited | Combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline |
WO2009123714A2 (en) | 2008-04-02 | 2009-10-08 | Arena Pharmaceuticals, Inc. | Processes for the preparation of pyrazole derivatives useful as modulators of the 5-ht2a serotonin receptor |
US9126946B2 (en) | 2008-10-28 | 2015-09-08 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea and crystalline forms related thereto |
SG175187A1 (en) * | 2009-04-30 | 2011-11-28 | Abbott Gmbh & Co Kg | N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-ht6 receptor |
CA2759491A1 (en) | 2009-04-30 | 2010-11-04 | Abbott Gmbh & Co. Kg. | Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-ht6 receptor |
US8343959B2 (en) | 2009-04-30 | 2013-01-01 | Abbott Gmbh & Co. Kg | N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor |
WO2012059432A1 (en) | 2010-11-01 | 2012-05-10 | Abbott Gmbh & Co. Kg | N-phenyl-(homo)piperazinyl-benzenesulfonyl or benzenesulfonamide compounds suitable for treating disorders that respond to the modulation of the 5-ht6 receptor |
WO2012059431A1 (en) | 2010-11-01 | 2012-05-10 | Abbott Gmbh & Co. Kg | Benzenesulfonyl or sulfonamide compounds suitable for treating disorders that respond to the modulation of the serotonin 5-ht6 receptor |
US9663498B2 (en) | 2013-12-20 | 2017-05-30 | Sunshine Lake Pharma Co., Ltd. | Aromatic heterocyclic compounds and their application in pharmaceuticals |
WO2015158313A1 (en) | 2014-04-19 | 2015-10-22 | Sunshine Lake Pharma Co., Ltd. | Sulfonamide derivatives and pharmaceutical applications thereof |
EP4119141A1 (en) | 2015-06-12 | 2023-01-18 | Axovant Sciences GmbH | Nelotanserin for the prophylaxis and treatment of rem sleep behavior disorder |
BR112018000728A2 (pt) | 2015-07-15 | 2018-09-04 | Axovant Sciences Gmbh | resumo método para a profilaxia e/ou tratamento de alucinações visuais em um sujeito com necessidade do mesmo |
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JP2002511097A (ja) * | 1997-07-11 | 2002-04-09 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | 5−ht▲下6▼レセプターアンタゴニストであるスルホンアミド誘導体およびその製造方法 |
ATE236136T1 (de) | 1998-01-16 | 2003-04-15 | Hoffmann La Roche | Benzosulfonderivate |
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PE20020063A1 (es) * | 2000-06-20 | 2002-01-30 | Upjohn Co | Bis-arilsulfonas como ligandos del receptor de 5-ht |
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2002
- 2002-08-05 AU AU2002340804A patent/AU2002340804B2/en not_active Ceased
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- 2002-08-05 WO PCT/EP2002/008696 patent/WO2003014097A1/en active Application Filing
- 2002-08-05 MX MXPA04001250A patent/MXPA04001250A/es active IP Right Grant
- 2002-08-05 RU RU2004107261/04A patent/RU2268884C2/ru not_active IP Right Cessation
- 2002-08-05 NZ NZ530742A patent/NZ530742A/en unknown
- 2002-08-05 DE DE60230424T patent/DE60230424D1/de not_active Expired - Lifetime
- 2002-08-05 ES ES02774499T patent/ES2316619T3/es not_active Expired - Lifetime
- 2002-08-05 JP JP2003519047A patent/JP4187650B2/ja not_active Expired - Fee Related
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- 2002-08-05 CN CNB02815679XA patent/CN1254469C/zh not_active Expired - Fee Related
- 2002-08-05 CA CA002456250A patent/CA2456250A1/en not_active Abandoned
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2004
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Also Published As
Publication number | Publication date |
---|---|
MXPA04001250A (es) | 2004-05-27 |
JP2005502649A (ja) | 2005-01-27 |
KR100608417B1 (ko) | 2006-08-02 |
EP1423106A1 (en) | 2004-06-02 |
HK1070054A1 (en) | 2005-06-10 |
NO20040589L (no) | 2004-03-19 |
US6825202B2 (en) | 2004-11-30 |
CA2456250A1 (en) | 2003-02-20 |
NZ530742A (en) | 2007-07-27 |
WO2003014097A1 (en) | 2003-02-20 |
ES2316619T3 (es) | 2009-04-16 |
NO326497B1 (no) | 2008-12-15 |
PL373397A1 (en) | 2005-08-22 |
CN1254469C (zh) | 2006-05-03 |
US20030069254A1 (en) | 2003-04-10 |
CO5550439A2 (es) | 2005-08-31 |
EP1423106B1 (en) | 2008-12-17 |
RU2268884C2 (ru) | 2006-01-27 |
DE60230424D1 (en) | 2009-01-29 |
AU2002340804B2 (en) | 2008-04-03 |
IL159880A0 (en) | 2004-06-20 |
HRP20040090A2 (en) | 2004-12-31 |
HUP0401235A2 (hu) | 2004-10-28 |
CN1541210A (zh) | 2004-10-27 |
KR20040023738A (ko) | 2004-03-18 |
RU2004107261A (ru) | 2005-09-10 |
ATE417838T1 (de) | 2009-01-15 |
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