EP1070050A1 - N-aryloxyethyl-indoly-alkylamines for the treatment of depression (5-ht1a receptor active agents) - Google Patents
N-aryloxyethyl-indoly-alkylamines for the treatment of depression (5-ht1a receptor active agents)Info
- Publication number
- EP1070050A1 EP1070050A1 EP99915317A EP99915317A EP1070050A1 EP 1070050 A1 EP1070050 A1 EP 1070050A1 EP 99915317 A EP99915317 A EP 99915317A EP 99915317 A EP99915317 A EP 99915317A EP 1070050 A1 EP1070050 A1 EP 1070050A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- indol
- ethyl
- yloxy
- amine
- fluoro
- 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- Withdrawn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
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 title abstract description 6
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 title abstract description 6
- 239000013543 active substance Substances 0.000 title abstract description 3
- 208000020401 Depressive disease Diseases 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 35
- 239000001257 hydrogen Substances 0.000 claims abstract description 35
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 35
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 25
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 24
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 23
- 150000002367 halogens Chemical class 0.000 claims abstract description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 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 abstract description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 7
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 claims abstract description 7
- 125000000532 dioxanyl group Chemical group 0.000 claims abstract description 7
- 125000002541 furyl group Chemical group 0.000 claims abstract description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims abstract description 7
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims abstract description 5
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims abstract description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 5
- 208000024891 symptom Diseases 0.000 claims abstract description 3
- -1 [3-(lH-Indol-3-yl)-propyl]-[2-(naphthalen- l-yloxy)-ethyl] amine Chemical class 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 230000001430 anti-depressive effect Effects 0.000 claims description 5
- YTQZSTCAJCVZBR-UHFFFAOYSA-N n-[2-(2,3-dihydro-1h-inden-4-yloxy)ethyl]-3-(5-fluoro-1h-indol-3-yl)propan-1-amine Chemical compound C12=CC(F)=CC=C2NC=C1CCCNCCOC1=CC=CC2=C1CCC2 YTQZSTCAJCVZBR-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- PFSLDEREWKLRLJ-UHFFFAOYSA-N 3-(5-fluoro-1h-indol-3-yl)-n-[2-(1h-indol-4-yloxy)ethyl]propan-1-amine Chemical compound C12=CC(F)=CC=C2NC=C1CCCNCCOC1=CC=CC2=C1C=CN2 PFSLDEREWKLRLJ-UHFFFAOYSA-N 0.000 claims description 3
- CXAQUOUMCYXZLS-UHFFFAOYSA-N 3-(5-fluoro-1h-indol-3-yl)-n-[2-(2-methoxyphenoxy)-2-phenylethyl]propan-1-amine Chemical compound COC1=CC=CC=C1OC(C=1C=CC=CC=1)CNCCCC1=CNC2=CC=C(F)C=C12 CXAQUOUMCYXZLS-UHFFFAOYSA-N 0.000 claims description 3
- ISBIUGFQLVFPNK-UHFFFAOYSA-N n-[2-[(6-fluoro-3,4-dihydro-2h-chromen-8-yl)oxy]ethyl]-2-(1h-indol-3-yl)ethanamine Chemical compound C1=CC=C2C(CCNCCOC=3C=4OCCCC=4C=C(C=3)F)=CNC2=C1 ISBIUGFQLVFPNK-UHFFFAOYSA-N 0.000 claims description 3
- IRZUEVZANGAMPR-UHFFFAOYSA-N 3-(1h-indol-3-yl)-n-(2-quinolin-8-yloxyethyl)propan-1-amine Chemical compound C1=CC=C2C(CCCNCCOC=3C4=NC=CC=C4C=CC=3)=CNC2=C1 IRZUEVZANGAMPR-UHFFFAOYSA-N 0.000 claims description 2
- CARASVXDRPSJIU-UHFFFAOYSA-N 3-(1h-indol-3-yl)-n-[2-(1h-indol-4-yloxy)ethyl]butan-1-amine Chemical compound C1=CC=C2C(C(CCNCCOC=3C=4C=CNC=4C=CC=3)C)=CNC2=C1 CARASVXDRPSJIU-UHFFFAOYSA-N 0.000 claims description 2
- FJYSNFYXXFBCDC-UHFFFAOYSA-N 3-(1h-indol-3-yl)-n-[2-(1h-indol-4-yloxy)ethyl]propan-1-amine Chemical compound C1=CC=C2C(CCCNCCOC=3C=4C=CNC=4C=CC=3)=CNC2=C1 FJYSNFYXXFBCDC-UHFFFAOYSA-N 0.000 claims description 2
- WEVQBZNODPTEIQ-UHFFFAOYSA-N 3-(5-fluoro-1h-indol-3-yl)-n-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]propan-1-amine Chemical compound C1CCCC2=C1C=CC=C2OCCNCCCC1=CNC2=CC=C(F)C=C21 WEVQBZNODPTEIQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000935 antidepressant agent Substances 0.000 claims description 2
- 229940005513 antidepressants Drugs 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- WNRBGXHMJJCVAE-UHFFFAOYSA-N n-[2-(1-benzofuran-7-yloxy)ethyl]-3-(5-fluoro-1h-indol-3-yl)propan-1-amine Chemical compound C12=CC(F)=CC=C2NC=C1CCCNCCOC1=CC=CC2=C1OC=C2 WNRBGXHMJJCVAE-UHFFFAOYSA-N 0.000 claims description 2
- ITQRLHNJJPKGJL-UHFFFAOYSA-N n-[2-(2,3-dihydro-1h-inden-5-yloxy)ethyl]-3-[(5-fluoro-1h-indol-3-yl)oxy]propan-1-amine Chemical compound C1=C2CCCC2=CC(OCCNCCCOC2=CNC3=CC=C(C=C32)F)=C1 ITQRLHNJJPKGJL-UHFFFAOYSA-N 0.000 claims description 2
- DUTGEQMBAUMVEL-UHFFFAOYSA-N n-[2-[(6-fluoro-3,4-dihydro-2h-chromen-8-yl)oxy]ethyl]-2-(5-fluoro-1h-indol-3-yl)ethanamine Chemical compound C1CCOC2=C1C=C(F)C=C2OCCNCCC1=CNC2=CC=C(F)C=C21 DUTGEQMBAUMVEL-UHFFFAOYSA-N 0.000 claims description 2
- OCQNJCBHBVWXAS-UHFFFAOYSA-N n-[3-(5-fluoro-1h-indol-3-yl)propyl]-2-(2-methoxyphenoxy)propan-1-amine Chemical compound COC1=CC=CC=C1OC(C)CNCCCC1=CNC2=CC=C(F)C=C12 OCQNJCBHBVWXAS-UHFFFAOYSA-N 0.000 claims description 2
- NYFAEGAHZKBLIJ-UHFFFAOYSA-N 3-(1h-indol-3-yl)-n-(2-phenoxyethyl)propan-1-amine Chemical compound C=1NC2=CC=CC=C2C=1CCCNCCOC1=CC=CC=C1 NYFAEGAHZKBLIJ-UHFFFAOYSA-N 0.000 claims 1
- VRHDCZABKKGHEU-UHFFFAOYSA-N n-[2-[(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)oxy]ethyl]-2-(5-fluoro-1h-indol-3-yl)ethanamine Chemical compound C12=CC(F)=CC=C2NC=C1CCNCCOC1=CC(F)=CC2=C1OCC2 VRHDCZABKKGHEU-UHFFFAOYSA-N 0.000 claims 1
- REHCIQBRDJQQIG-UHFFFAOYSA-N n-[2-[(6-fluoro-3,4-dihydro-2h-chromen-8-yl)oxy]ethyl]-3-(5-fluoro-1h-indol-3-yl)propan-1-amine Chemical compound C1=C(F)C=C2C(CCCNCCOC=3C=4OCCCC=4C=C(C=3)F)=CNC2=C1 REHCIQBRDJQQIG-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 174
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
- 229910001868 water Inorganic materials 0.000 description 83
- 239000000243 solution Substances 0.000 description 73
- 239000002904 solvent Substances 0.000 description 70
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 66
- 239000000047 product Substances 0.000 description 66
- 238000004587 chromatography analysis Methods 0.000 description 60
- 239000003921 oil Substances 0.000 description 56
- 235000019198 oils Nutrition 0.000 description 56
- 239000000203 mixture Substances 0.000 description 48
- 238000000921 elemental analysis Methods 0.000 description 47
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 46
- 239000012044 organic layer Substances 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- 238000003756 stirring Methods 0.000 description 42
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 42
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 239000007787 solid Substances 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 22
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- 150000003891 oxalate salts Chemical class 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 16
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 12
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- 239000012267 brine Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- DPHNJPUOMLRELT-UHFFFAOYSA-N 2,3-dihydro-1h-inden-4-ol Chemical compound OC1=CC=CC2=C1CCC2 DPHNJPUOMLRELT-UHFFFAOYSA-N 0.000 description 10
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- JBFFCANWDYAYFN-UHFFFAOYSA-N 3-(5-fluoro-1h-indol-3-yl)propan-1-amine Chemical compound C1=C(F)C=C2C(CCCN)=CNC2=C1 JBFFCANWDYAYFN-UHFFFAOYSA-N 0.000 description 8
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 6
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- 239000002552 dosage form Substances 0.000 description 3
- UCSVJZQSZZAKLD-UHFFFAOYSA-N ethyl azide Chemical compound CCN=[N+]=[N-] UCSVJZQSZZAKLD-UHFFFAOYSA-N 0.000 description 3
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- 239000000706 filtrate Substances 0.000 description 3
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
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Classifications
-
- 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
- C07D401/12—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to compounds useful for the treatment of diseases affected by disorders of the serotonin-affected neurological systems. More specifically, the present invention is directed to aryloxyethyl-indoly-alkylamine derivatives useful for the treatment of such diseases.
- compositions which enhance neurotransmission of serotonin are useful for the treatment of many psychiatric disorders, including depression and anxiety.
- the first generation of non-selective serotonin-affecting compounds operated
- SSRIs selective serotonin reuptake inhibitors
- the present invention relates to a new class of molecules which have the ability 35 to act concommitantly at the 5-HT1A autoreceptors and with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of anxiety or depression, as well as other serotonin disorders.
- U.S. Patent No. 3,371,098 discloses sec. and tert. indolylethylamines useful as sedatives, anticonvulsants and analegesics.
- U.S. Patent No. 5,436,264 discloses N-aryloxyalkyl-tryptamine-like compounds of the following formula as alpha- 1-adrenergic receptor antagonists for the treatment of cardiovascular disorders.
- EP 0722 941 A2 discloses the preparation of a series of hetero-oxy alkanamines of the following formula for the treatment of depression and other disorders for which serotonin uptake inhibitors are normally used. x I
- Japanese Patents 05255302 and 09040648 disclose the following compounds which are reported to be useful for the treatment of central nervous system-related diseases, such as anxiety and depression.
- the compounds of the present invention invention are aminomethyl benzoxezine indoles represented by Formula I:
- R j is hydrogen, lower alkyl, or aryl
- R 2 is hydrogen, lower alkyl, phenyl, or substituted phenyl
- X and Y are each, independently, hydrogen, lower alkyl, lower alkoxy, or halogen, or together combine with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl, dihydrofuranyl, furanyl, dioxanyl, oxazolyl, or isoxazolyl group;
- Z is hydrogen, halogen, or lower alkoxy; with the proviso that when X, Y or Z represent lower alkoxy, they are not present at the ortho position; W is hydrogen, halogen, lower alkoxy, lower alkyl, cyano, or a trifluoromethyl group; and n is 2-5; or pharmaceutically acceptable salts thereof.
- the present invention is further derived to pharmaceutical compounds containing such compounds, as well as methods for alleviating symptoms of depression comprising administering the present compounds to a patient in need thereof.
- the compounds of the present invention are those represented by
- R j is hydrogen, methyl or aryl
- R 2 is hydrogen
- X and Y are each, independently, hydrogen, halogen or lower alkoxy, or together combine with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyridinyl, dioxanyl, oxazolyl, furanyl or dihydrofuranyl group; - 4 -
- Z is hydrogen, halogen or lower alkoxy; with the proviso that when X, Y or Z are lower alkoxy they are not present at the ortho position; W is hydrogen or halogen; and n is 2-4; or pharmaceutically acceptable salts thereof.
- the compounds of the present invention are selected from the following:
- lower alkyl and “lower alkoxy” are meant to include both straight and branched carbon chains containing 1 to 6 carbon atoms.
- halogen is meant to include fluorine, chlorine, bromine, and iodine.
- substituted phenyl is meant to include a phenyl moiety substituted with an alkyl, halogen, or alkoxy group.
- aryl is meant to include aromatic radicals containing 6-12 carbon atoms.
- the compounds of Formula I may advantageously be used in the form of the pharmaceutically acceptable acid addition salts thereof.
- Such salts may be formed with both inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
- inorganic or organic acids for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedis
- the compounds of the present invention may be prepared by any suitable method known to those skilled in the art. However, the present compounds may be advantageously prepared according to any one of Schemes 1 to 10 set forth below. In the Schemes, the intermediate compounds discussed hereinafter are identified in parenthesis. The compound produced in each of Schemes 1 to 10 is identified with reference to the appropriate, corresponding Example.
- the fumarate salt was prepared in ethanol: mp 121.5 -122°C: Elemental analysis for C I6 H 19 NO 2 » C 4 H 4 O 4
- triphenylphosphine 2.6 g, 9.9 mmol
- 2-chloroethanol 2-chloroethanol
- DIAD diisopropyl azidodicarbimide
- 6-Fluorochroman-8-carbaldehyde To a solution of 6-fluorochroman (0.7 g, 4.6 mmol) in anhydrous methylene chloride (20 ml) was added TiCl 4 (1.57 g, 8.3 mmol) and ⁇ , ⁇ '-dichloromethyl methyl ether (0.53 g, 4.6 mmol) slowly at 0°C. The reaction was allowed to reach room temperature slowly and stirred for 16 hours. The reaction mixture was poured into ice- water, extracted with methylene chloride (3 x 100 ml), washed with saturated sodium carbonate (5 x 150 ml) and brine (3 x 100ml).
- This compound was prepared in the manner described for 45(a) above by replacing 4-indanol with 5,6,7,8-tetrahydro-l-naphthol (4 g, 0.027 mol) ) in 46% yield (2.57 g) as a clear oil.
- This compound was prepared in the manner described for 45(a) above by replacing 4-indanol with 1-naphthol (5 g, 0.035 mol) ) in 82% yield (6.34 g) as a clear oil.
- the oxalate salt was prepared in ethanol: mp 185-188°C Elemental analysis for C 19 H 20 F 2 N 2 O 2 » C 2 H 2 O 4
- the oxalate salt was prepared in ethanol: mp 188-189°C Elemental analysis for C 19 H 21 FN 2 O 2 « C 2 H 2 O 4 « 0.25H 2 O Calc'd C, 59.04; H, 5.63; N, 6.62
- the oxalate salt was prepared in ethanol: mp 197.5-198.5°C Elemental analysis for C 20 H 22 N 2 O 3 »C 2 H 2 O 4
- the fumarate salt was prepared in isopropanol: mp 189.5-190.5°C
- the oxalate salt was prepared in ethanol: mp 213-214°C
- the oxalate salt was prepared in isopropanol: mp 214-215°C
- the oxalate salt was prepared in ethanol: mp 201-203°C
- the oxalate salt was prepared in THF: mp 181-183 °C
- the fumarate salt was prepared in ethanol: mp 203-205°C Elemental analysis for C 23 H 24 N 2 O » 0.5C 4 H 4 O 4 «0.25H 2 O Calc'd: C, 73.78; H,6.56; N, 6.88
- the PCR cloning of the human 5-HT 1A receptor subtype from a human genomic library has been described previously Chanda et al., Mol. Pharmacol.. 43:516 (1993).
- a stable Chinese hamster ovary cell line expressing the human 5-HT 1A receptor subtype (5-HT 1A .CHO cells) was employed throughout this study. Cells were maintained in DMEM supplemented with 10% fetal calf serum, non-essential amino acids and penicillin/ streptomycin.
- Cells were grown to 95-100% confluency as a monolayer before membranes were harvested for binding studies. Cells were gently scraped from the culture plates, 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 were aliquoted and placed at -80°C. On the day of assay, the cells were thawed on ice, and resuspended in buffer. Studies were conducted using [ 3 H]8-OH-DPAT as the radioligand. The binding assay was performed in 96 well microtiter plates in a final total volume of 250 ⁇ L of buffer.
- the [ 35 S]-GTP ⁇ S binding assay was similar to that disclosed by Lazareno and Birdsall, Br. J. Pharmacol.. 109: 1120, (1993). Briefly, 5-HT 1A cloned receptor membrane fragments (as used for 5-HT 1A receptor binding assays) were stored at -70 °C until needed. When needed, membranes were rapidly thawed, centrifuged at 40,000 x g for 10 minutes and resuspended at 4 °C for 10 minutes in assay buffer (25 mM HEPES, 3 mM MgCl 2 , 100 mM NaCI, 1 mM EDTA, 10 uM GDP, 500 mM DTT, pH 8.0).
- assay buffer 25 mM HEPES, 3 mM MgCl 2 , 100 mM NaCI, 1 mM EDTA, 10 uM GDP, 500 mM DTT, pH 8.0.
- the following assays were performed by incubating the cells with DMEM containing 25 mM HEPES, 5 mM theophylline and 10 ⁇ M pargyline for a period of 20 minutes at 37°C. Functional activity was assessed by treating the cells with forskolin (1 uM final concentration) followed immediately by test compound (6 concentrations) for an additional 10 min at 37°C. In separate experiments, 6 concentrations of antagonist were preincubated for 20 min prior to the addition of 10 nM 8-OH-DPAT and forskolin. The reaction was terminated by removal of the media and addition of 0.5 ml -42- ice cold assay buffer. Plates were stored at -20°C prior to assessment of cAMP formation by a cAMP SPA assay (Amersham).
- the compounds of the present invention are active towards 5HT1 A receptors and generally elevate serotonin levels by inhibiting 5-HT transport. Accordingly, the present compounds should be useful in treating disorders related to defects in serotonin concentration.
- the compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
- 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. Any of the solid carriers known to those skilled in the art may be used with the compounds of this invention.
- Particularly suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.
- Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs of the compounds of this invention.
- the compounds 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.
- 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) and their derivatives and 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 to prepare compositions for parenteral administration. - 44 -
- 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.
- Compositions for oral administration may be either in liquid or solid composition form.
- the pharmaceutical compositions containing the compounds of this invention are in unit dosage form, e.g., tablets or capsules.
- the compositions may be sub-divided in unit doses containing appropriate quantities of the present compounds.
- 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 amount of the compounds of this invention that is administered and the dosage regimen depends on a variety of factors, including the weight, age, sex, and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the specific compound employed, and thus may vary widely.
- the pharmaceutical compositions may contain the compounds of this invention in the range of about 0.1 to about 2000 mg, preferably in the range of about 0.5 to about 500 mg and more preferably between about 1 and about 100 mg.
- Projected daily dosages of active compound are about 0.01 to about 100 mg/kg body weight. The daily dose can be conveniently administered two to four times per day.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- General Chemical & Material Sciences (AREA)
- Psychiatry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5725298A | 1998-04-08 | 1998-04-08 | |
US57252 | 1998-04-08 | ||
PCT/US1999/007621 WO1999051575A1 (en) | 1998-04-08 | 1999-04-07 | N-aryloxyethyl-indoly-alkylamines for the treatment of depression (5-ht1a receptor active agents) |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1070050A1 true EP1070050A1 (en) | 2001-01-24 |
Family
ID=22009457
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99915317A Withdrawn EP1070050A1 (en) | 1998-04-08 | 1999-04-07 | N-aryloxyethyl-indoly-alkylamines for the treatment of depression (5-ht1a receptor active agents) |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1070050A1 (en) |
JP (1) | JP2002510675A (en) |
CN (1) | CN1304403A (en) |
AU (1) | AU3386199A (en) |
CA (1) | CA2327359A1 (en) |
WO (1) | WO1999051575A1 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10006139A1 (en) * | 2000-02-11 | 2001-08-16 | Merck Patent Gmbh | Indol-3-yl derivatives |
SE0102640D0 (en) * | 2001-07-31 | 2001-07-31 | Astrazeneca Ab | Novel compounds |
FR2845992B1 (en) * | 2002-10-16 | 2005-02-04 | Pf Medicament | 3- (CYCLOPENTEN-1YL) -BENZYL-OU3- (CYCLOPENTEN-1YL) -HETEROARYLMETHYL-AMINE DERIVATIVES AND THEIR USE AS MEDICAMENTS FOR THE TREATMENT OF SCHIZOPHRENIA |
DE10305739A1 (en) * | 2003-02-11 | 2004-08-19 | Merck Patent Gmbh | New indolyl-substituted benzofuran derivatives, are 5-HT(1A) agonists and 5-HT reuptake inhibitors useful e.g. as anxiolytic, antidepressant, neuroleptic and/or antihypertensive agents |
DE10306941A1 (en) * | 2003-02-18 | 2004-08-26 | Merck Patent Gmbh | New indolyl-substituted benzofuranyloxy-alkylamine derivatives, are 5-hydroxytryptamine reuptake inhibitors useful e.g. as anxiolytic, antidepressant, neuroleptic and/or antihypertensive agents |
US7371769B2 (en) | 2004-12-07 | 2008-05-13 | Solvay Pharmaceuticals B.V. | Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-D2 receptors and serotonin reuptake sites |
US8101619B2 (en) | 2004-12-08 | 2012-01-24 | Solvay Pharmaceuticals B.V. | Phenylpiperazine derivatives with a combination of partial dopamine-D2 receptor agonism and serotonin reuptake inhibition |
RU2007125659A (en) * | 2004-12-08 | 2009-01-20 | Солвей Фармасьютикалс Б.В. (Nl) | Phenylpiperazine derivatives combining the properties of incomplete agonism to dopamine-D2 receptors and inhibition of reuptake of serotonin |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3371098A (en) * | 1966-11-29 | 1968-02-27 | Philips Corp | 5- and 6-methoxy-3-(phenoxyethyl-aminoethyl)-indoles |
FR2463765A1 (en) * | 1979-08-17 | 1981-02-27 | Clin Midy | NEW ACTIVE INDOLE DERIVATIVES ON THE CARDIOVASCULAR SYSTEM |
US5189179A (en) * | 1990-08-29 | 1993-02-23 | Merrell Dow Pharmaceuticals Inc. | Serotonin 5ht1a agonists |
US5436264A (en) * | 1993-08-19 | 1995-07-25 | Syntex (U.S.A.) Inc. | N-aryloxyalkyl tryptamine α1 -adrenergic receptor antagonists |
FR2731223A1 (en) * | 1995-03-02 | 1996-09-06 | Pf Medicament | NOVEL BI-TRYPTAMINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
-
1999
- 1999-04-07 EP EP99915317A patent/EP1070050A1/en not_active Withdrawn
- 1999-04-07 CA CA002327359A patent/CA2327359A1/en not_active Abandoned
- 1999-04-07 JP JP2000542296A patent/JP2002510675A/en active Pending
- 1999-04-07 WO PCT/US1999/007621 patent/WO1999051575A1/en not_active Application Discontinuation
- 1999-04-07 AU AU33861/99A patent/AU3386199A/en not_active Abandoned
- 1999-04-07 CN CN99807013A patent/CN1304403A/en active Pending
Non-Patent Citations (1)
Title |
---|
See references of WO9951575A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2327359A1 (en) | 1999-10-14 |
WO1999051575A1 (en) | 1999-10-14 |
JP2002510675A (en) | 2002-04-09 |
CN1304403A (en) | 2001-07-18 |
AU3386199A (en) | 1999-10-25 |
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