EP1140831A1 - Derives d'uree arylpiperidine et aryl-1,2,5,6-tetrahydropyridine presentant une activite de recepteur de 5ht1a - Google Patents
Derives d'uree arylpiperidine et aryl-1,2,5,6-tetrahydropyridine presentant une activite de recepteur de 5ht1aInfo
- Publication number
- EP1140831A1 EP1140831A1 EP99965286A EP99965286A EP1140831A1 EP 1140831 A1 EP1140831 A1 EP 1140831A1 EP 99965286 A EP99965286 A EP 99965286A EP 99965286 A EP99965286 A EP 99965286A EP 1140831 A1 EP1140831 A1 EP 1140831A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- disorder
- hydrogen
- phenyl
- alkyl
- 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.)
- Withdrawn
Links
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- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 title description 11
- 230000000694 effects Effects 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
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- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- -1 perhaloalkyl Chemical group 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 150000002367 halogens Chemical group 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
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- 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 3
- STUHQDIOZQUPGP-UHFFFAOYSA-N morpholin-4-ium-4-carboxylate Chemical compound OC(=O)N1CCOCC1 STUHQDIOZQUPGP-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
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- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 2
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- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims description 2
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- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 claims description 2
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- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 claims description 2
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 claims description 2
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 12
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
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- 125000001424 substituent group Chemical group 0.000 description 8
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
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- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
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- VSOZYVHMRRLERD-UHFFFAOYSA-N 4-(5-fluoro-2-methoxyphenyl)piperidine Chemical compound COC1=CC=C(F)C=C1C1CCNCC1 VSOZYVHMRRLERD-UHFFFAOYSA-N 0.000 description 3
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- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
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- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
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- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Definitions
- US 4,882,432 teaches adamantyl and noradamantyl piperazine carbamates and ureas with high 5-HT1A receptor affinities. These compounds, as well as those disclosed in U.S. patent number 4,797.489 are useful for the treatment of CNS disorders.
- EP 661266- A 1 describes piperidino and piperazino 5-HT2 receptor antagonists and blood platelet aggregation inhibitors.
- WO 9504042 describes 4-phenyl-4-phenylpropyl(enyl) piperidine tachykinin antagonists for treating pain or inflammation or emesis.
- This invention relates to novel arylpiperidine urea and aryl- 1,2, 5,6- tetrahydropyridine urea derivatives.
- novel arylpiperidine urea and aryl- 1,2,5,6 tetrahydropyridine urea derivatives which are antagonists of the 5HT1A receptor subtype.
- compounds of the present invention are useful for the treatment of central nervous system (CNS) disorders such as depression, anxiety, panic, obsessive- compulsive disorder (OCD), sleep disorders, sexual dysfunction, alcohol and drug addiction, cognition enhancement, Alzheimer's disease, Parkinson's disease, obesity and migraine.
- CNS central nervous system
- R 0 and Ri are independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl alkylcycloalkyl, alkylheterocycloalkyl, aryl or heteroaryl, or taken together R 0 and Rj form a heterocycloalkyl, provided that R Q and Ri are not both hydrogen;
- R2 is hydrogen, alkyl or R3 is hydrogen or alkyl;
- R4 is aryl or heteroaryl;
- R5 is alkyl, alkenyl or alkynyl;
- X is hydrogen, halogen, perhaloalkyl, hydroxy, alkoxy, perhaloalkoxy; n is an integer from 1 to 3; and the dotted line is an optional double bond, or a pharmaceutical salt thereof.
- X is preferably halogen substituted at positions 4- or 5-, more preferably is 4-fluoro or 5-fluoro and most preferably is 5-fluoro-.
- R2 is an alkyl group
- R2 is preferably a straight chain alkyl of 1 to 5 carbon atoms
- R3 is preferably a straight chain alkyl of 1 to 4 carbon atoms.
- R 0 and Ri are independently hydrogen or cycloalkyl or taken together are heterocycloalkyl. More preferably R Q and Rj are independently hydrogen or cyclohexyl or taken together are morpholino.
- R 0 and Ri are independently hydrogen or cyclohexyl, or taken together are morpholino, X is 5-fluoro, and R4 is phenyl.
- Alkyl as used herein means a branched or straight chain having from 1 to 6 carbon atoms and more preferably from 1 to 5 carbon atoms.
- exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
- alkenyl as used herein means a branched or straight chain alkyl having from 2 to 6 carbon atoms.
- exemplary alkenyl groups include ethylene and propylene. In some embodiments of the present invention the alkenyl group may be substituted.
- Alkynyl as used herein means a branched or straight chain alkyl of 2 to 6 carbon atoms and at least one carbon-carbon triple bond.
- exemplary alkynyl groups include ethynyl and propynyl.
- the alkynyl group may be substituted with one or more substituents.
- Alkoxy as used herein means an alkyl-O group in which the alkyl group is as previously described.
- exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
- Aryl as used herein means mono or bicyclic aromatic ring having from 6 to 10 carbon atoms. Monocyclic rings preferably have 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures.
- Exemplary aryl groups include phenyl and naphthyl In some preferred embodiments aryl is phenyl, 1-naphthyl or 2-naphthyl. In still more preferred embodiments aryl is phenyl.
- the aryl group may be substituted with one or more substituents. Substituted aryl groups preferably have one to three substituents.
- Cycloalkyl as used herein means a monocyclic alkyl group having from 3 to 8 carbon atoms. In some preferred embodiments cycloalkyl may be substituted with from 1 to 3 substituents.
- Heterocycloalkyl as used herein means a monocyclic alkyl group having from
- heterocycloalkyl groups include piperidinyl, piperazinyl and morpholino.
- heterocycloalkyl groups may be substituted with from 1 to 3 substituents.
- Halogen as used herein means fluorine, chlorine, iodine and bromine.
- Heteroaryl means 5 to 10 membered mono or bicyclic aromatic ring having from 1 to 3 heteroatoms selected from N, O and S. Monocyclic rings preferably have 5 or 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures. Exemplary heteroaryls include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl and benzodioxanyl.
- Preferred heteroaryl groups include thienyl, pyridyl, and furyl. More preferred are heteroaryl groups including 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, and 3-furyl.
- the heteroaryl group may be substituted with one or more substituents. Suitable substituents, unless otherwise noted, include halogen, alkyl, hydroxy, alkoxy, amino, amido, nitro, alkylamino, alkylamido, perhaloalkyl, carboxyalkyl, carboxy, carbamide, dialkylamino and aryl.
- Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents such as an alkyl or alkoxy substituents.
- alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described.
- Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
- a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
- the compounds of this invention contain a chiral center, providing for various seteroisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers.
- the individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture.
- the compounds A and intermediate 4-(halo-2-methoxy-phenyl)-piperidines F or 4-(halo-2-methoxy-phenyl)-l,2,5,6-tetrahydropyridines H of the present invention can be prepared by conventional methods by those skilled in the organic synthesis.
- metal-halogen exchange of an appropriately substituted aryl halide B with a base, such as butyllithium forms a carboanion, and treatment of the resulting mixture with an N-protected-4-piperidone C affords a tertiary alcohol D.
- An example of the nitrogen protecting group Rx of the 4-piperidone C is benzyl, which can be removed by hydrogenation of D to afford amine G.
- Dehydration of G with an acid, such as sulfuric acid can provide the desired 4-(halo-2-methoxy-phenyl)- 1,2,5,6- tetrahydropyridine H.
- Dehydration of the tertiary alcohol D, removal of the nitrogen protecting group, Rx and hydrogenation of the double bond can afford 4-(halo-2- methoxy-phenyl)-piperidine F.
- the protecting group R is of the urethane type, preferably tert-butyloxycarbonyl which may be removed by the action of an acid. After deprotection, the amide may be reduced to an amine M with a reducing reagent such as lithium aluminum hydride (LAH) or diborane, and subsequently acylated to afford the urea A.
- LAH lithium aluminum hydride
- diborane a reducing reagent
- the reaction mixture was diluted with water (50 mL) and EtOAc (50 mL) and the layers separated.
- the aqueous layer was washed with HCl (IN), saturated NaHCO 3 , and the combined aqueous layers were extracted three times with EtOAc.
- the combined organic layers were dried over Na 2 SO 4 and concentrated.
- Compounds of the present invention bind with very high affinity to the 5-HT1 A receptor and consequently, they are useful for the treatment of primary disorders of the central nervous system such as depression, anxiety and panic, as well as secondary attending problems such as sleep disorders and sexual dysfunction. Compounds of the present invention are also useful for other disorders of the central nervous system including alcohol and drug addiction, obesity and migraine. Cognition enhancement may be achieved by use of compounds of the present invention and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease may be treated.
- High affinity for the serotonin 5-HTIA receptor was established by testing a compound's ability to displace [ 3 H] 8-OH-DPAT binding in CHO cells stably transfected with human 5HT1A receptor.
- Stably transfected CHO cells are grown in DMEM containing 10% heat inactivated FBS and non-essential amino acids. Cells are scraped off the plate, transferred to centrifuge tubes, and washed twice by centrifugation (2000 rpm for 10 min., 4°C) in buffer (50 mM Tris pH 7.5). The resulting pellets are aliquoted and placed at -80°C. On the day of assay, the cells are thawed on ice and resuspended in buffer.
- the binding assay is performed in a 96 well microtiter plate in a total volume of 250 ⁇ L. Non-specific binding is determined in the presence of 10 mM 5-HT, final ligand concentration is 1.5 nM. Following a 30 minute incubation at room temperature, the reaction is terminated by the addition of ice cold buffer and rapid filtration through a GF/B filter presoaked for 30 minutes in 0.5% PEL Compounds are initially tested in a single point assay to determine percent inhibition at 1, 0.1, and 0.01 mM, and Ki values are determined for the active compounds.
- the intrinsic activity of compounds of the present invention was established by testing the claimed compounds ability to reverse the stimulation of cyclic adenosinemonophosphate (cAMP) in CHO cells stably transfected with the human 5-HT 1 A receptor.
- cAMP cyclic adenosinemonophosphate
- Stably transfected CHO cells were grown in DMEM containing 10% heat inactivated FBS and non-essential amino acids. The cells are plated at a density of ? xlO 6 cells per well in a 24 well plate and incubated for 2 days in a CO 2 incubator. On the second day, the media is replaced with 0.5 mL treatment buffer (DMEM + 25 mM HEPES, 5 mM theophylline, 10 ⁇ M pargyline) and incubated for 10 minutes at 37°C. Wells are treated with forskolin (1 ⁇ M final concentration) followed immediately by the test compound (0.1 and 1 ⁇ M for initial screen) and incubated for an additional 10 minutes at 37°C.
- DMEM + 25 mM HEPES 5 mM theophylline, 10 ⁇ M pargyline
- compounds of the present invention exhibit high affinity for the 5HT1 A receptor subtype and exhibit intrinsic activity as evidenced by their ability to reverse stimulation of cyclic adenosinemonophosphate (cAMP). Accordingly, compounds of the present invention are useful for treatment of disorders of the central nervous system and may be administered to a patient suffering from one or more of said disorders. Treatment, as used herein, refers to alleviation or amelioration of symptoms of a particular disorder in a patient. In addition, compounds of the present invention may be administered as part of a treatment regime that includes other agents which act on the central nervous system. In some preferred embodiments, compounds of the present invention are part of a combination therapy including a serotonin reuptake inhibitor.
- Serotonin reuptake inhibitors useful in combination therapies of the present invention fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine. Said agents may be administered at the same time, where they may be combined into a single dosage form, or at a different time, as compounds of the present invention, while still being part of the regime of the combination therapy.
- Compounds of the invention may be administered to a patient either neat or with a convention pharmaceutical carrier.
- Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
- the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain up to 99% of the active ingredient.
- Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
- the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
- the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g.
- cellulose derivatives preferably sodium carboxymethyl cellulose solution
- alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
- oils e.g. fractionated coconut oil and arachis oil
- the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
- Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
- the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
- the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
- the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
- the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
- the therapeutically effective dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician.
- the variables involved include the specific psychosis or state of anxiety and the size, age and response pattern of the patient.
- the novel method of the invention for treating conditions related to or are affected by the 5-HT 1 A receptor comprise administering to warm-blooded animals, including humans, an effective amount of at least one compound of Formula A and its non-toxic, pharmaceutically acceptable addition salts.
- the compounds may be administered orally, rectally, parenterally or topically to the skin and mucosa.
- the usual daily dose is depending on the specific compound, method of treatment and condition treated.
- the usual daily dose is 0.01 - 1000 mg/Kg for oral application, preferably 0.5 - 500 mg/Kg, and 0.1 - 100 mg/Kg for parenteral application, preferably 0.5 - 50 mg/Kg.
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- Reproductive Health (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US21334098A | 1998-12-17 | 1998-12-17 | |
US213340 | 1998-12-17 | ||
PCT/US1999/029907 WO2000035875A1 (fr) | 1998-12-17 | 1999-12-16 | Derives d'uree arylpiperidine et aryl-1,2,5,6-tetrahydropyridine presentant une activite de recepteur de 5ht1a |
Publications (1)
Publication Number | Publication Date |
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EP1140831A1 true EP1140831A1 (fr) | 2001-10-10 |
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ID=22794731
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP99965286A Withdrawn EP1140831A1 (fr) | 1998-12-17 | 1999-12-16 | Derives d'uree arylpiperidine et aryl-1,2,5,6-tetrahydropyridine presentant une activite de recepteur de 5ht1a |
Country Status (7)
Country | Link |
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EP (1) | EP1140831A1 (fr) |
JP (1) | JP2002532472A (fr) |
CN (1) | CN1335835A (fr) |
AU (1) | AU3123500A (fr) |
BR (1) | BR9916220A (fr) |
CA (1) | CA2351400A1 (fr) |
WO (1) | WO2000035875A1 (fr) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
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US8106074B2 (en) | 2001-07-13 | 2012-01-31 | Pierre Fabre Medicament | Pyridin-2-yl-methylamine derivatives for treating opiate dependence |
US7115607B2 (en) | 2001-07-25 | 2006-10-03 | Amgen Inc. | Substituted piperazinyl amides and methods of use |
KR101078098B1 (ko) | 2003-01-14 | 2011-10-28 | 아레나 파마슈티칼스, 인크. | 대사 조절제로서의 1,2,3-삼치환된 아릴 및 헤테로아릴유도체, 및 당뇨병 및 고혈당증을 비롯한 이에 관련된장애의 예방 및 치료 |
PT1606282E (pt) * | 2003-02-24 | 2009-02-10 | Arena Pharm Inc | Derivados de fenilo e piridilpiperidina como moduladores do metabolismo da glucose |
WO2005063699A1 (fr) * | 2003-12-31 | 2005-07-14 | Council Of Scientific & Industrial Research | N-aryloxypropanolyl-n'-phenethyl-uree |
US6962945B2 (en) | 2004-03-26 | 2005-11-08 | Council Of Scientific And Industrial Research | N-aryloxypropanolyl-N′-phenethyl-urea |
EP3323818A1 (fr) | 2010-09-22 | 2018-05-23 | Arena Pharmaceuticals, Inc. | Modulateurs du récepteur gpr119 et traitement de troubles associés |
CN107405332A (zh) | 2015-01-06 | 2017-11-28 | 艾尼纳制药公司 | 治疗与s1p1受体有关的病症的方法 |
KR102603199B1 (ko) | 2015-06-22 | 2023-11-16 | 아레나 파마슈티칼스, 인크. | S1p1 수용체-관련 장애에서의 사용을 위한 (r)-2-(7-(4-시클로펜틸-3-(트리플루오로메틸)벤질옥시)-1,2,3,4-테트라히드로시클로-펜타[b]인돌-3-일)아세트산 (화합물 1)의 결정성 l-아르기닌 염 |
Family Cites Families (4)
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US4882432A (en) * | 1989-01-09 | 1989-11-21 | American Home Products Corporation | Polycyclic-carbamic acid piperazinoalkyl esters and amides |
FR2664592B1 (fr) * | 1990-07-10 | 1994-09-02 | Adir | Nouveaux derives de la piperidine, de la tetrahydropyridine et de la pyrrolidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
GB9314758D0 (en) * | 1993-07-16 | 1993-08-25 | Wyeth John & Brother Ltd | Heterocyclic derivatives |
DE19615232A1 (de) * | 1996-04-18 | 1997-10-23 | Merck Patent Gmbh | Neue Carbamoylderivate und deren Verwendung als 5-HT ¶1¶¶A¶-Antagonisten |
-
1999
- 1999-12-16 EP EP99965286A patent/EP1140831A1/fr not_active Withdrawn
- 1999-12-16 AU AU31235/00A patent/AU3123500A/en not_active Abandoned
- 1999-12-16 JP JP2000588137A patent/JP2002532472A/ja active Pending
- 1999-12-16 WO PCT/US1999/029907 patent/WO2000035875A1/fr not_active Application Discontinuation
- 1999-12-16 CA CA002351400A patent/CA2351400A1/fr not_active Abandoned
- 1999-12-16 BR BR9916220-2A patent/BR9916220A/pt not_active IP Right Cessation
- 1999-12-16 CN CN99814560A patent/CN1335835A/zh active Pending
Non-Patent Citations (1)
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See references of WO0035875A1 * |
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BR9916220A (pt) | 2001-09-11 |
AU3123500A (en) | 2000-07-03 |
CN1335835A (zh) | 2002-02-13 |
WO2000035875A1 (fr) | 2000-06-22 |
CA2351400A1 (fr) | 2000-06-22 |
JP2002532472A (ja) | 2002-10-02 |
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