WO1999015527A1 - PROCEDE D'OBTENTION DU 2-[4-[4-(m- ETHYLSULFONAMIDOPHENYL) PIPERAZINE-1-YL] BUTYL]-1,3- DIOXOPERHYDROPYRROLO [1,2-c]IMIDAZOL - Google Patents
PROCEDE D'OBTENTION DU 2-[4-[4-(m- ETHYLSULFONAMIDOPHENYL) PIPERAZINE-1-YL] BUTYL]-1,3- DIOXOPERHYDROPYRROLO [1,2-c]IMIDAZOL Download PDFInfo
- Publication number
- WO1999015527A1 WO1999015527A1 PCT/ES1998/000250 ES9800250W WO9915527A1 WO 1999015527 A1 WO1999015527 A1 WO 1999015527A1 ES 9800250 W ES9800250 W ES 9800250W WO 9915527 A1 WO9915527 A1 WO 9915527A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dioxoperhydropyrrolo
- imidazole
- butyl
- piperazin
- obtaining
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 21
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title claims description 53
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 16
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- -1 m-Ethylsulfonamidophenyl Chemical group 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 claims description 4
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 4
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- 239000005557 antagonist Substances 0.000 abstract description 3
- APHPLOYRLDEZMD-UHFFFAOYSA-N n-[3-[4-[4-(1,3-dioxo-5,6,7,7a-tetrahydropyrrolo[1,2-c]imidazol-2-yl)butyl]piperazin-1-yl]phenyl]ethanesulfonamide Chemical compound CCS(=O)(=O)NC1=CC=CC(N2CCN(CCCCN3C(N4CCCC4C3=O)=O)CC2)=C1 APHPLOYRLDEZMD-UHFFFAOYSA-N 0.000 abstract description 3
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 abstract 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 4
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 3
- 229940091173 hydantoin Drugs 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- NIDSRGCVYOEDFW-UHFFFAOYSA-N 1-bromo-4-chlorobutane Chemical compound ClCCCCBr NIDSRGCVYOEDFW-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 230000000862 serotonergic effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RNHALYZIVRYWJY-UHFFFAOYSA-N 3-bromo-1-chlorobutane Chemical compound CC(Br)CCCl RNHALYZIVRYWJY-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010011953 Decreased activity Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000000848 glutamatergic effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002102 hyperpolarization Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- 210000001176 projection neuron Anatomy 0.000 description 1
- JVXZJEUVAOVXIX-UHFFFAOYSA-N propan-2-one;pyridine Chemical compound CC(C)=O.C1=CC=NC=C1 JVXZJEUVAOVXIX-UHFFFAOYSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000003727 serotonin 1A antagonist Substances 0.000 description 1
- 230000000697 serotonin reuptake Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- a subject of the present invention is a new process for obtaining 2- [4- [4- (m-ethyl sulfonamidophenyl) piperazin-1-yljbutyl] -1,3-dioxoperhydropyrrolo [1,2-c] imidazole (1, EF- 7412), a synthetic compound with therapeutic interest due to its antagonistic character of the 5-HT 1A receptor.
- Selective serotonin reuptake inhibitors constitute a group of antidepressant drugs (WF Boyer and JP Feighner, Selective Serotonin Re-Uptake Inhibitors; JP Feighner and WF Boyer, Eds .; Wiley, 1991; pp 89-108) , which exert their action by increasing serotonergic transmission in the brain. These agents have a latency period of three to six weeks (Y. Lecrubier, New Pharmacological Approaches to the Therapy or / Depressive Disorders. Int. Acad Biomed Drugs Res.; J. Mendlewics et al., Eds .; Karger: Basel, 1993; Vol. 5, pp 83-91).
- a subject of the present invention is a new process for obtaining 2- [4- [4- (m-ethyl sulfonamidophenyl) piperazin-l-yl] butyl] -l, 3-dioxoperhydropyrrolo [1, 2-c] imidazole (1, EF-7412), a synthetic compound with therapeutic interest due to its antagonistic character of the 5-HT IA receptor.
- Reagents (a) HNa, DMF; (b) Et 3 N, l- (-ethylsulfonamidophenyl) piperazine (4).
- Reagents (a) KaCC ⁇ , diglyme / ⁇ ; (b) HNa / DMF; (c) EtjN, acetonitrile / ⁇ ; (d) H 2> Pd (C) / MeOH; (e) EtSO ⁇ Cl, pyridine acetone.
- reaction mixture is diluted in water, the solvents are removed under reduced pressure and the solid residue is purified by silica gel column chromatography (ethyl acetate / ethanol 9: 1), isolating 17.1 g (82%) of 1 as a solid that is transformed into the hydrochloride and crystallized from methanol / ethyl ether: mp 187-190 ° C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
L'invention concerne un nouveau procédé d'obtention du 2-[4-[4-( m-éthylsulfonamidophényl) pipérazine-1-yl] butyl]-1,3- dioxoperhydropyrrolo [1,2-c]imidazol (1, EF-7412), composé de synthèse présentant un intérêt thérapeutique lié à son caractère antagoniste du récepteur 5-HT1A. Ce nouveau procédé permet de surmonter les difficultés rencontrées auparavant lors de la préparation, car ce procédé permet d'obtenir le produit souhaité en une séquence synthétique de plus grande simplicité et avec des rendements supérieurs.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU90730/98A AU9073098A (en) | 1997-09-23 | 1998-09-15 | Process for obtaining 2-(4-(4-(m- ethylsulfonamido-phenyl) piperazine-1-yl) butyl)-1,3- dioxoperhydroyrrolo (1,2-c)imidazol |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ESP9701987 | 1997-09-23 | ||
| ES9701987A ES2129370B1 (es) | 1997-09-23 | 1997-09-23 | Procedimiento para la obtencion del 2-(4-(4-(m-etilsulfonamidofenil)p iperazin-1-il(butil)-1,3-dioxoperhidropirrolo)1,2-c(imidazol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999015527A1 true WO1999015527A1 (fr) | 1999-04-01 |
Family
ID=8300663
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/ES1998/000250 WO1999015527A1 (fr) | 1997-09-23 | 1998-09-15 | PROCEDE D'OBTENTION DU 2-[4-[4-(m- ETHYLSULFONAMIDOPHENYL) PIPERAZINE-1-YL] BUTYL]-1,3- DIOXOPERHYDROPYRROLO [1,2-c]IMIDAZOL |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU9073098A (fr) |
| ES (1) | ES2129370B1 (fr) |
| WO (1) | WO1999015527A1 (fr) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7351732B2 (en) | 2002-07-31 | 2008-04-01 | Schwarz Pharma S.L. | Cycloalkanedione derivatives, method for the production thereof and their pharmacological applications |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996006846A1 (fr) * | 1994-09-01 | 1996-03-07 | Universidad Complutense De Madrid | Nouveaux derives d'aryle piperazines |
-
1997
- 1997-09-23 ES ES9701987A patent/ES2129370B1/es not_active Expired - Fee Related
-
1998
- 1998-09-15 AU AU90730/98A patent/AU9073098A/en not_active Abandoned
- 1998-09-15 WO PCT/ES1998/000250 patent/WO1999015527A1/fr active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996006846A1 (fr) * | 1994-09-01 | 1996-03-07 | Universidad Complutense De Madrid | Nouveaux derives d'aryle piperazines |
Non-Patent Citations (2)
| Title |
|---|
| JOURNAL MEDICINAL CHEMISTRY, Vol. 32, 1989, G.E. MARTIN et al., "Activity of Aromatic Substituted Phenylpiperazines Lacking Affinity for Dopamine Binding Sites in a Preclinical Test of Antipsychotic Efficacy", pp. 1052-1056. * |
| JOURNAL MEDICINAL CHEMISTRY, Vol. 39, 1996, M.L. LOPEZ-RODRIGUEZ et al., "Synthesis and Structure-Activity Relationships of a New Model of Arylpiperazines", pp. 4439-4450. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7351732B2 (en) | 2002-07-31 | 2008-04-01 | Schwarz Pharma S.L. | Cycloalkanedione derivatives, method for the production thereof and their pharmacological applications |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2129370A1 (es) | 1999-06-01 |
| ES2129370B1 (es) | 2000-03-01 |
| AU9073098A (en) | 1999-04-12 |
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