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2 substances in Reaxys
2016-06-15 14h:28m:46s (EST)
O
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N
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Reaxys ID 10342703 View in Reaxys
1/2 Chemical Name: α-PVP; PVP; 1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one; α-pyrrolidinovalerophenone; α-pyrrolidinopentiophenone Linear Structure Formula: C15H21NO Molecular Formula: C15H21NO Molecular Weight: 231.338 Type of Substance: heterocyclic InChI Key: YDIIDRWHPFMLGR-UHFFFAOYSA-N Note:
O N
Substance Label (4) Label References 3bc
Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409, View in Reaxys
7
Kolanos; Sakloth; Jain; Partilla; Baumann; Glennon; ACS Chemical Neuroscience; vol. 6; nb. 10; (2015); p. 1726 - 1731, View in Reaxys
α-PVP
Marusich, Julie A.; Antonazzo, Kateland R.; Wiley, Jenny L.; Blough, Bruce E.; Partilla, John S.; Baumann, Michael H.; Neuropharmacology; vol. 87; (2014); p. 206 - 213, View in Reaxys
4d (free base)
Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys
Derivative (1) Derivative O-2387
References Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys
Chromatographic Data (1) Chromatographic Location data
References
TLC (Thin layer chromatography)
Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409, View in Reaxys
supporting information
Crystal Property Description (1) Colour & Other Location Properties yellow
supporting information
References Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409, View in Reaxys
NMR Spectroscopy (2) 1 of 2
Description (NMR Spec- Chemical shifts; Spectrum troscopy) Nucleus (NMR Spectroscopy)
1H
Solvents (NMR Spectro- chloroform-d1 scopy) Frequency (NMR Spectroscopy) [MHz]
400
Location
supporting information
Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409, View in Reaxys 2 of 2
Description (NMR Spec- Chemical shifts; Spectrum troscopy) Nucleus (NMR Spectroscopy)
13C
Solvents (NMR Spectro- chloroform-d1 scopy) Frequency (NMR Spectroscopy) [MHz]
100
Location
supporting information
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Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409, View in Reaxys IR Spectroscopy (1) 1 of 1
Description (IR Spectroscopy)
Bands
Solvent (IR Spectroscopy)
neat liquid
Location
supporting information
Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409, View in Reaxys Mass Spectrometry (3) Description (Mass Location Spectrometry)
References
high resolution supporting informass spectrome- mation try (HRMS); spectrum
Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409, View in Reaxys
EI (Electron impact); GCMS (Gas chromatography mass spectrometry); Spectrum
Sauer, Christoph; Peters, Frank T.; Haas, Claudia; Meyer, Markus R.; Fritschi, Giselher; Maurera, Hans H.; Journal of Mass Spectrometry; vol. 44; nb. 6; (2009); p. 952 964, View in Reaxys
CI (Chemical ionization); Spectrum
Sauer, Christoph; Peters, Frank T.; Haas, Claudia; Meyer, Markus R.; Fritschi, Giselher; Maurera, Hans H.; Journal of Mass Spectrometry; vol. 44; nb. 6; (2009); p. 952 964, View in Reaxys
Pharmacological Data (5) 1 of 5
Comment (Pharmacological Data)
Bioactivities present
Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys; Sauer, Christoph; Peters, Frank T.; Haas, Claudia; Meyer, Markus R.; Fritschi, Giselher; Maurera, Hans H.; Journal of Mass Spectrometry; vol. 44; nb. 6; (2009); p. 952 - 964, View in Reaxys; Runyon, Scott P.; Carroll, F. Ivy; Current Topics in Medicinal Chemistry; vol. 6; nb. 17; (2006); p. 1825 - 1843, View in Reaxys; Marusich, Julie A.; Antonazzo, Kateland R.; Wiley, Jenny L.; Blough, Bruce E.; Partilla, John S.; Baumann, Michael H.; Neuropharmacology; vol. 87; (2014); p. 206 - 213, View in Reaxys; Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409, View in Reaxys; Gatch, Michael B.; Dolan, Sean B.; Forster, Michael J.; Journal of Pharmacology and Experimental Therapeutics; vol. 354; nb. 2; (2015); p. 103 - 110, View in Reaxys; Kolanos; Sakloth; Jain; Partilla; Baumann; Glennon; ACS Chemical Neuroscience; vol. 6; nb. 10; (2015); p. 1726 - 1731, View in Reaxys 2 of 5
Comment (Pharmacological Data)
physiological behaviour discussed
Gatch, Michael B.; Dolan, Sean B.; Forster, Michael J.; Journal of Pharmacology and Experimental Therapeutics; vol. 354; nb. 2; (2015); p. 103 - 110, View in Reaxys 3 of 5
Comment (Pharmacological Data)
physiological behaviour discussed
Kolanos; Sakloth; Jain; Partilla; Baumann; Glennon; ACS Chemical Neuroscience; vol. 6; nb. 10; (2015); p. 1726 - 1731, View in Reaxys 4 of 5
Comment (Pharmacological Data)
physiological behaviour discussed
Marusich, Julie A.; Antonazzo, Kateland R.; Wiley, Jenny L.; Blough, Bruce E.; Partilla, John S.; Baumann, Michael H.; Neuropharmacology; vol. 87; (2014); p. 206 - 213, View in Reaxys 5 of 5
Effect (Pharmacological Data)
biotransformation
Species or Test-System (Pharmacological Data)
Wistar rat
Sex
male
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Route of Application
gavage (p.o.)
Concentration (Pharmacological Data)
20 mg/kg
Kind of Dosing (Pharmacological Data)
title comp. used as HNO3 salt
Metabolite XRN (Pharmacological Data)
20313968; 2830646; 20313969; 20313970; 20313972
Metabolite (Pharmacological Data)
C15H19NO2; α-Amino-valerophenon; C15H21NO2; C15H19NO3; C15H19NO4
Sauer, Christoph; Peters, Frank T.; Haas, Claudia; Meyer, Markus R.; Fritschi, Giselher; Maurera, Hans H.; Journal of Mass Spectrometry; vol. 44; nb. 6; (2009); p. 952 - 964, View in Reaxys
Reaxys ID 10382946 View in Reaxys
2/2 Chemical Name: O-2387; 2-pyrrolidin-1-yl-phenyl-pentan-1one hydrochloride Linear Structure Formula: C15H21NO*ClH Molecular Formula: C15H21NO*ClH Molecular Weight: 267.799 Type of Substance: heterocyclic InChI Key: ROMXVSMENBAYRM-UHFFFAOYSA-N Note:
O N Cl
H
Substance Label (2) Label References 8; α-PVP
Kolanos, Renata; Solis, Ernesto; Sakloth, Farhana; De Felice, Louis J.; Glennon, Richard A.; ACS Chemical Neuroscience; vol. 4; nb. 12; (2013); p. 1524 - 1529, View in Reaxys
4d
Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys
Patent-Specific Data (1) References Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English, View in Reaxys Melting Point (2) 1 of 2
Melting Point [°C]
173
Solvent (Melting Point)
ethanol; diethyl ether
Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys 2 of 2
Melting Point [°C]
137
Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English, View in Reaxys NMR Spectroscopy (4) 1 of 4
Description (NMR Spec- Chemical shifts troscopy) Nucleus (NMR Spectroscopy)
1H
Solvents (NMR Spectro- dimethylsulfoxide-d6 scopy) Frequency (NMR Spectroscopy) [MHz]
300.53
Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys
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2 of 4
Description (NMR Spec- Chemical shifts troscopy) Nucleus (NMR Spectroscopy)
13C
Solvents (NMR Spectro- dimethylsulfoxide-d6 scopy) Frequency (NMR Spectroscopy) [MHz]
75.58
Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys 3 of 4
Nucleus (NMR Spectroscopy)
1H
Original Text (NMR Spectroscopy)
H NMR 6 10.85-10. 65 (br, 1H), 8. 11 (d, 2H), 7.78 (t, 1H), 7.64 (t, 2H), 5.62 (m, 1H), 3.7-3. 55 (br, 1H), 3. 55-3. 4 (br, m, 1H), 3. 35-3. 2 (br, m, 1H), 3.15 - 3. 0 (br, m, 1H), 2.15-1. 85 (br, m, 6H), 1.4-1. 2 (m, 1H), 1.15-0. 95 (m, 1H), 0.78 (t, J= 7 Hz, 3H)
Comment (NMR Spectroscopy)
Signals given
Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English, View in Reaxys 4 of 4
Nucleus (NMR Spectroscopy)
13C
Original Text (NMR Spectroscopy)
C NMR, 5 196. 7,134. 9,134. 5, 129. 2, 128. 8, 67.3, 53.6, 51.9, 31.7, 22.9, 17.4, 13.7
Comment (NMR Spectroscopy)
Signals given
Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English, View in Reaxys Mass Spectrometry (1) Description (Mass Comment (Mass Spectrometry) Spectrometry)
References
CI (Chemical ioni- Molecular peak zation)
Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English, View in Reaxys
Pharmacological Data (11) 1 of 11
Comment (Pharmacological Data)
Bioactivities present
Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys; Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English, View in Reaxys; Kolanos, Renata; Solis, Ernesto; Sakloth, Farhana; De Felice, Louis J.; Glennon, Richard A.; ACS Chemical Neuroscience; vol. 4; nb. 12; (2013); p. 1524 - 1529, View in Reaxys 2 of 11
Comment (Pharmacological Data)
physiological behaviour discussed
Kolanos, Renata; Solis, Ernesto; Sakloth, Farhana; De Felice, Louis J.; Glennon, Richard A.; ACS Chemical Neuroscience; vol. 4; nb. 12; (2013); p. 1524 - 1529, View in Reaxys 3 of 11
Effect (Pharmacological Data)
transport
Species or Test-System (Pharmacological Data)
HEK293 cells expressing human norepinephrine transporter
Kind of Dosing (Pharmacological Data)
DMSO solution
Method (Pharmacological Data)
<3H>norepinephrine uptake assayed; cells preincubated with title comp. for 10 min in Krebs-HEPES at 25 deg C; after addition of <3H>norepinephrine incubated for 10 min; nonspecific uptake defined with 5 μmol/L mazindol
Type (Pharmacological Data)
IC50
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Value of Type (Pharmacological Data)
56.0 nmol/l
Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys 4 of 11
Effect (Pharmacological Data)
transporter; inhibition of
Species or Test-System (Pharmacological Data)
membranes of HEK293 cells expressing human NET
Kind of Dosing (Pharmacological Data)
DMSO solution
Method (Pharmacological Data)
membranes preincubated with title comp. in assay buffer, pH 7.4 for 10 min; after addition of <125I>RTI-55 (40-80 pmol/L) incubated at 25 deg C for 90 min; nonspecific binding defined with 5 μmol/L mazindol; quantified by scintillation counting
Further Details (Pharmacological Data)
NET: norepinephrine transporter
Type (Pharmacological Data)
Ki
Value of Type (Pharmacological Data)
199 nmol/l
Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys 5 of 11
Effect (Pharmacological Data)
transporter; inhibition of
Species or Test-System (Pharmacological Data)
membranes of HEK293 cells expressing human SERT
Kind of Dosing (Pharmacological Data)
DMSO solution
Method (Pharmacological Data)
membranes preincubated with title comp. in assay buffer, pH 7.4 for 10 min; after addition of <125I>RTI-55 (40-80 pmol/L) incubated at 25 deg C for 90 min; nonspecific binding defined with 5 μmol/L imipramine; quantified by scintillation counting
Further Details (Pharmacological Data)
SERT: serotonin transporter
Type (Pharmacological Data)
Ki
Value of Type (Pharmacological Data)
> 10 μmol/l
Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys 6 of 11
Effect (Pharmacological Data)
transport
Species or Test-System (Pharmacological Data)
HEK293 cells expressing human dopamine transporter
Kind of Dosing (Pharmacological Data)
DMSO solution
Method (Pharmacological Data)
<3H>dopamine uptake assayed; cells preincubated with title comp. for 10 min in KrebsHEPES at 25 deg C; after addition of <3H>dopamine incubated for 10 min; nonspecific uptake defined with 5 μmol/L mazindol
Type (Pharmacological Data)
IC50
Value of Type (Pharmacological Data)
52.3 nmol/l
Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys
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7 of 11
Effect (Pharmacological Data)
transporter; inhibition of
Species or Test-System (Pharmacological Data)
membranes of HEK293 cells expressing human DAT
Kind of Dosing (Pharmacological Data)
DMSO solution
Method (Pharmacological Data)
membranes preincubated with title comp. in assay buffer, pH 7.4 for 10 min; after addition of <125I>RTI-55 (40-80 pmol/L) incubated at 25 deg C for 90 min; nonspecific binding defined with 5 μmol/L mazindol; quantified by scintillation counting
Further Details (Pharmacological Data)
DAT: dopamine transporter
Type (Pharmacological Data)
Ki
Value of Type (Pharmacological Data)
33.7 nmol/l
Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432, View in Reaxys 8 of 11
Effect (Pharmacological Data)
dopamine transporter; binding to
Species or Test-System (Pharmacological Data)
Rhesus monkey
Route of Application
intravenous
Method (Pharmacological Data)
Example 70 Dopamine transporter occupancy of pyrovalerone analogs Entry of compounds into brain is an important criterion for assessing the diagnostic and therapeutic potential of compounds targeted to the central nervous system. Access of compounds into brain targets may be attenuated by rapid peripheral metabolism, by sequestration by proteins or organs in peripheral tissues, or by the blood brain barrier. Brain imaging is an efficient method for determining the biological potential of a novel compound designed to affect brain function or to image the brain. As the compounds of the invention are high affinity ligands for the dopamine transporter, we determined whether they occupy the dopamine transporter in living brain within 1 hour of administration. To monitor occupancy of the dopamine transporter, PET imaging was conducted with the high affinity dopamine transporter probe [11C] CFT ( [11C] WIN 35, 428}. Rhesus monkeys were anesthetized with ketamine and xylazine and an indwelling intravenous catheter was placed in a leg vein. DAT density (binding potential) was acquired with [11 C] CFT to obtain baseline levels. Immediately following completion of the imaging session, monkeys were administered the test compound intravenously via the indwelling catheter and PET imaging was conducted one hour after administration. Imaging data from the pre-and post-drug session were compared and occupancy was calculated on the basis of reduced [11 C] CFT binding potential one hour or longer after administration of the compound. The following table (Table 1) summarizes pilot data from this study.
Results
title compound occupancy of dopamine transporter was 64percent
Location
Page/Page column 47-48
Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English, View in Reaxys 9 of 11
Effect (Pharmacological Data)
dopamine transporter; binding to
Species or Test-System (Pharmacological Data)
dopamine transporter (DAT) cells
Method (Pharmacological Data)
The present invention relates to compounds that bind and/or inhibit monoamine transporters such as the dopamine, serotonin and norepinephrine transporters of mammalian systems. More specifically, the invention relates to compounds, such as pyrovalerone analogs, that are active (as racemates or purified enantiomers) in monoamine uptake systems and are selective for different monoamine uptake systems such as DAT, NET, and SERT. For example, an enantiomer, 2S-pyrovalerone (see Scheme 1) is potent at DAT, (ICso = 3nM) and selective at SERT (ICso > 4 X Compounds of the invention are represented by the following general formulae: wherein, Ri = one to four substituents independently selected from the group consisting of H, halogen (preferably F, Br, Cl, or 1), substituted or unsubstituted alkyl (preferably methyl, ethyl, isopropropyl, isobutyl, or t-butyl), substituted or
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unsubstituted alkoxy (preferably methoxy), substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynyloxy, (CH2) n-Ar, OH, OC (O)-alkyl (preferably methyl); CF3 ; N02 ; NH2 ; CN; NHCOCH3 ; CO-alkyl (more preferably COCH3), CH20H, (CH2) nOR2 (in which n is 1 to 4) and (CH2) nOCOR2 ; (in which n is 1 to 4); R2 = H, substituted or unsubstituted alkyl (preferably methyl, ethyl, isopropropyl, isobutyl, or t-butyl), substituted or unsubstituted alkoxy (preferably methoxy), substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynyloxy, or CH2ArRI ; R3 = one or two substituents independently selected from the group consisting of H, halogen (preferably F, Br, Cl, or I), substituted or unsubstituted alkyl (preferably methyl, ethyl, isopropropyl, isobutyl, or t-butyl), substituted or unsubstituted alkoxy (preferably methoxy), substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynyloxy, OH, (CH2) nArR1 ; CF3; N02 ; NH2 ; CN; NHCOCH3, CO-alkyl (preferably COCH3), CH20H, (CH2) nOR2 (in which n is 1 to 4) and (CH2) nOCOR2 ; (in which n is 1 to 4); R4 = H, halogen (preferably F, Br, Cl, or 1), substituted or unsubstituted alkyl (preferably methyl), substituted or unsubstituted alkoxy (preferably methoxy), substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynyloxy, OH, OC (O)-alkyl (preferably methyl) ; CF3 ; N02 ; NH2 ; CN; NHCO-alkyl (preferably NHCOCH3), COCH3, CH20H, (CH2) nOR2 (in which n is 1 to 4) and (CH2) nOCOR2; (in which n is 1 to 4); Ar is an aromatic group (preferably phenyl or naphthyl); n= 0-4; m, p = 0-2; and X = O, CH2, S, SO2, or SO; or a pharmaceutically acceptable salt of the compound; with the proviso that, when the compound is a racemic mixture, the compound is not a- pyrrolidino-valerophenone, l-(p-methyl-phenyl)-2pyrrolidino-pentan-1-one (also known as pyrovalerone), 1-phenyl-2-pyrrolidino-3-methylbutan-1-one, 1- (p-methoxy-phenyl)-2- pyrrolidino-pentan-1-one, 1- (p-hydroxy-phenyl)-2pyrrolidino-pentan-1-one, 1-phenyl-2- pyrrolidino-butan-1-one, 1-phenyl-2-pyrrolidino-heptan-1-one, 1- (p-chloro-phenyl)-2- pyrrolidino-pentan-1-one, 1- (m-methyl-phenyl)-2-pyrrolidino-pentan-1-one, 1-phenyl-2- pyrrolidino-nonan-1-one, l- (p-methoxy-phenyl)-2-pyrrolidino-hexan-1-one, or a- (2'-methyl- pyrrolidino)-valerophenone. In preferred embodiments, Ri represents F (at the 2,3 or 4 position); Cl (at the 2,3 or 4 position); I (at the 2,3 or 4 position) 3,4-diCl ; 3-C1, 4-C (CH2) CH3; 3-Br, 4-isopropyl; 3-1, 4- C (CH2) CH3; 4-C1, 3C (CH2) CH3; 4-Br, 3-isopropyl; 4-1, 3-isopropyl; 3,4-diOH ; 3,4-diOAc ; 3,4- diOCH3 ; 3OH, 4-C1 ; 3-OH, 4-F; 3-OAc, 4-C1 ; 3-OAc, 4-F; 3-C1, 4-OH; 3-F, 4-OH; 3-Cl, 4-OAc; or 3-F, 4-OAc. In certain preferred embodiments, Ri is an aromatic group. The invention also p Results
title compound Ki with respect to dopamine transporter (DAT) was 33.7 (no unit); uptake was 52.3 (no unit)
Location
Page/Page column 3-4; sheet 1
Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English, View in Reaxys 10 of 11
Effect (Pharmacological Data)
serotonin transporter (SERT); binding to
Species or Test-System (Pharmacological Data)
serotonin transporter (SERT) cells
Method (Pharmacological Data)
The present invention relates to compounds that bind and/or inhibit monoamine transporters such as the dopamine, serotonin and norepinephrine transporters of mammalian systems. More specifically, the invention relates to compounds, such as pyrovalerone analogs, that are active (as racemates or purified enantiomers) in monoamine uptake systems and are selective for different monoamine uptake systems such as DAT, NET, and SERT. For example, an enantiomer, 2S-pyrovalerone (see Scheme 1) is potent at DAT, (ICso = 3nM) and selective at SERT (ICso > 4 X Compounds of the invention are represented by the following general formulae: wherein, Ri = one to four substituents independently selected from the group consisting of H, halogen (preferably F, Br, Cl, or 1), substituted or unsubstituted alkyl (preferably methyl, ethyl, isopropropyl, isobutyl, or t-butyl), substituted or unsubstituted alkoxy (preferably methoxy), substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynyloxy, (CH2) n-Ar, OH, OC (O)-alkyl (preferably methyl); CF3 ; N02 ; NH2 ; CN; NHCOCH3 ; CO-alkyl (more preferably COCH3), CH20H, (CH2) nOR2 (in which n is 1 to 4) and (CH2) nOCOR2 ; (in which n is 1 to 4); R2 = H, substituted or unsubstituted alkyl (preferably methyl, ethyl, isopropropyl, isobutyl, or t-butyl), substituted or unsubstituted alkoxy (preferably methoxy), substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynyloxy, or CH2ArRI ; R3 = one or two substituents independently selected from the group consisting of H, halogen (preferably F, Br, Cl, or I), substituted or unsubstituted alkyl (preferably methyl, ethyl, isopropropyl, isobutyl, or t-butyl), substituted or unsubstituted al-
Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
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koxy (preferably methoxy), substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynyloxy, OH, (CH2) nArR1 ; CF3; N02 ; NH2 ; CN; NHCOCH3, CO-alkyl (preferably COCH3), CH20H, (CH2) nOR2 (in which n is 1 to 4) and (CH2) nOCOR2 ; (in which n is 1 to 4); R4 = H, halogen (preferably F, Br, Cl, or 1), substituted or unsubstituted alkyl (preferably methyl), substituted or unsubstituted alkoxy (preferably methoxy), substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynyloxy, OH, OC (O)-alkyl (preferably methyl) ; CF3 ; N02 ; NH2 ; CN; NHCO-alkyl (preferably NHCOCH3), COCH3, CH20H, (CH2) nOR2 (in which n is 1 to 4) and (CH2) nOCOR2; (in which n is 1 to 4); Ar is an aromatic group (preferably phenyl or naphthyl); n= 0-4; m, p = 0-2; and X = O, CH2, S, SO2, or SO; or a pharmaceutically acceptable salt of the compound; with the proviso that, when the compound is a racemic mixture, the compound is not a- pyrrolidino-valerophenone, l-(p-methyl-phenyl)-2pyrrolidino-pentan-1-one (also known as pyrovalerone), 1-phenyl-2-pyrrolidino-3-methylbutan-1-one, 1- (p-methoxy-phenyl)-2- pyrrolidino-pentan-1-one, 1- (p-hydroxy-phenyl)-2pyrrolidino-pentan-1-one, 1-phenyl-2- pyrrolidino-butan-1-one, 1-phenyl-2-pyrrolidino-heptan-1-one, 1- (p-chloro-phenyl)-2- pyrrolidino-pentan-1-one, 1- (m-methyl-phenyl)-2-pyrrolidino-pentan-1-one, 1-phenyl-2- pyrrolidino-nonan-1-one, l- (p-methoxy-phenyl)-2-pyrrolidino-hexan-1-one, or a- (2'-methyl- pyrrolidino)-valerophenone. In preferred embodiments, Ri represents F (at the 2,3 or 4 position); Cl (at the 2,3 or 4 position); I (at the 2,3 or 4 position) 3,4-diCl ; 3-C1, 4-C (CH2) CH3; 3-Br, 4-isopropyl; 3-1, 4- C (CH2) CH3; 4-C1, 3C (CH2) CH3; 4-Br, 3-isopropyl; 4-1, 3-isopropyl; 3,4-diOH ; 3,4-diOAc ; 3,4- diOCH3 ; 3OH, 4-C1 ; 3-OH, 4-F; 3-OAc, 4-C1 ; 3-OAc, 4-F; 3-C1, 4-OH; 3-F, 4-OH; 3-Cl, 4-OAc; or 3-F, 4-OAc. In certain preferred embodiments, Ri is an aromatic group. The invention also p Results
title compound Ki with respect to serotonin transporter (SERT) was >10,000 (no unit)
Location
Page/Page column 3-4; sheet 1
Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English, View in Reaxys 11 of 11
Effect (Pharmacological Data)
norepinephrine transporter (NET); binding to
Species or Test-System (Pharmacological Data)
norepinephrine transporter (NET) cells
Method (Pharmacological Data)
The present invention relates to compounds that bind and/or inhibit monoamine transporters such as the dopamine, serotonin and norepinephrine transporters of mammalian systems. More specifically, the invention relates to compounds, such as pyrovalerone analogs, that are active (as racemates or purified enantiomers) in monoamine uptake systems and are selective for different monoamine uptake systems such as DAT, NET, and SERT. For example, an enantiomer, 2S-pyrovalerone (see Scheme 1) is potent at DAT, (ICso = 3nM) and selective at SERT (ICso > 4 X Compounds of the invention are represented by the following general formulae: wherein, Ri = one to four substituents independently selected from the group consisting of H, halogen (preferably F, Br, Cl, or 1), substituted or unsubstituted alkyl (preferably methyl, ethyl, isopropropyl, isobutyl, or t-butyl), substituted or unsubstituted alkoxy (preferably methoxy), substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynyloxy, (CH2) n-Ar, OH, OC (O)-alkyl (preferably methyl); CF3 ; N02 ; NH2 ; CN; NHCOCH3 ; CO-alkyl (more preferably COCH3), CH20H, (CH2) nOR2 (in which n is 1 to 4) and (CH2) nOCOR2 ; (in which n is 1 to 4); R2 = H, substituted or unsubstituted alkyl (preferably methyl, ethyl, isopropropyl, isobutyl, or t-butyl), substituted or unsubstituted alkoxy (preferably methoxy), substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynyloxy, or CH2ArRI ; R3 = one or two substituents independently selected from the group consisting of H, halogen (preferably F, Br, Cl, or I), substituted or unsubstituted alkyl (preferably methyl, ethyl, isopropropyl, isobutyl, or t-butyl), substituted or unsubstituted alkoxy (preferably methoxy), substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynyloxy, OH, (CH2) nArR1 ; CF3; N02 ; NH2 ; CN; NHCOCH3, CO-alkyl (preferably COCH3), CH20H, (CH2) nOR2 (in which n is 1 to 4) and (CH2) nOCOR2 ; (in which n is 1 to 4); R4 = H, halogen (preferably F, Br, Cl, or 1), substituted or unsubstituted alkyl (preferably methyl), substituted or unsubstituted alkoxy (preferably methoxy), substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynyloxy, OH, OC (O)-alkyl (preferably methyl) ; CF3 ; N02 ; NH2 ; CN; NHCO-alkyl (preferably NHCOCH3), COCH3, CH20H, (CH2) nOR2 (in which n is 1 to 4) and (CH2) nOCOR2; (in which n is 1 to 4); Ar is an aromatic group (preferably phenyl or naphthyl); n= 0-4; m, p = 0-2; and X = O, CH2, S, SO2, or SO; or a pharmaceutically acceptable salt of the compound; with the proviso that, when the compound is a rac-
Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
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emic mixture, the compound is not a- pyrrolidino-valerophenone, l-(p-methyl-phenyl)-2pyrrolidino-pentan-1-one (also known as pyrovalerone), 1-phenyl-2-pyrrolidino-3-methylbutan-1-one, 1- (p-methoxy-phenyl)-2- pyrrolidino-pentan-1-one, 1- (p-hydroxy-phenyl)-2pyrrolidino-pentan-1-one, 1-phenyl-2- pyrrolidino-butan-1-one, 1-phenyl-2-pyrrolidino-heptan-1-one, 1- (p-chloro-phenyl)-2- pyrrolidino-pentan-1-one, 1- (m-methyl-phenyl)-2-pyrrolidino-pentan-1-one, 1-phenyl-2- pyrrolidino-nonan-1-one, l- (p-methoxy-phenyl)-2-pyrrolidino-hexan-1-one, or a- (2'-methyl- pyrrolidino)-valerophenone. In preferred embodiments, Ri represents F (at the 2,3 or 4 position); Cl (at the 2,3 or 4 position); I (at the 2,3 or 4 position) 3,4-diCl ; 3-C1, 4-C (CH2) CH3; 3-Br, 4-isopropyl; 3-1, 4- C (CH2) CH3; 4-C1, 3C (CH2) CH3; 4-Br, 3-isopropyl; 4-1, 3-isopropyl; 3,4-diOH ; 3,4-diOAc ; 3,4- diOCH3 ; 3OH, 4-C1 ; 3-OH, 4-F; 3-OAc, 4-C1 ; 3-OAc, 4-F; 3-C1, 4-OH; 3-F, 4-OH; 3-Cl, 4-OAc; or 3-F, 4-OAc. In certain preferred embodiments, Ri is an aromatic group. The invention also p Results
title compound Ki with respect to norepinephrine transporter (NET) was 199 (no unit); uptake was 56 (no unit)
Location
Page/Page column 3-4; sheet 1
Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English, View in Reaxys
Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
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