- Novel 5-hydroxytryptamine and norepinephrine dual reuptake inhibitor and medical application thereof
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The invention belongs to the field of medicinal chemistry, particularly relates to a novel serotonin and norepinephrine dual reuptake inhibitor and medical application thereof, and discloses a compound as represented by a formula I and a pharmaceutically acceptable salt thereof, and application of the compound and the pharmaceutically acceptable salt in preparation of antidepressant drugs.
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Paragraph 0058; 0060-0061
(2020/07/06)
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- COMPOUNDS HAVING MULTIMODAL ACTIVITY AGAINST PAIN
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The present invention relates to a compound of formula (I): wherein the meanings for the various substituents are as disclosed in the description, having dual pharmacological activity towards both the α2δ subunit, in particular the α2δ- 1 subunit, of the voltage-gated calcium channel and the NET receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.
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Page/Page column 59
(2019/01/17)
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- Chemoenzymatic synthesis of (S)-duloxetine using carbonyl reductase from Rhodosporidium toruloides
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A chemoenzymatic strategy was developed for (S)-duloxetine production employing carbonyl reductases from newly isolated Rhodosporidium toruloides into the enantiodetermining step. Amongst the ten most permissive enzymes identified, cloned, and overexpressed in Escherichia coli, RtSCR9 exhibited excellent activity and enantioselectivity. Using co-expressed E. coli harboring both RtSCR9 and glucose dehydrogenase, (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol 3a was fabricated with so far the highest substrate loading (1000 mM) in a space-time yield per gram of biomass (DCW) of 22.9 mmol L-1 h-1 g DCW-1 at a 200-g scale. The subsequent synthetic steps from RtSCR9-catalyzed (S)-3a were further performed, affording (S)-duloxetine with 60.2% overall yield from 2-acethylthiophene in >98.5% ee.
- Chen, Xiang,Liu, Zhi-Qiang,Lin, Chao-Ping,Zheng, Yu-Guo
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supporting information
p. 82 - 89
(2016/02/23)
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- OLIGOMER-ARYLOXY-SUBSTITUTED PROPANAMINE CONJUGATES
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The invention relates to (among other things) oligomer- aryloxy-substituted propanamine conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over un-conjugated aryloxy-substituted propanamine compounds.
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Paragraph 0255; 0257
(2016/11/17)
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- A method for preparing optically active 3-amino-1-propanol derivatives as an intermediate and a method for preparing (S)-duloxetine using the same
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The present invention relates to a method for preparing optically active 3-AMNO1-propanol derivatives as an intermediate and a method for preparing (s)-duloxetine using the same. This method can obtain optically active 3-AMNO1-propanol with higher yield and optical purity (ee) than any other conventional methods. Using this as an intermediate compound, it is possible to manufacture duloxetine which is enantiomerically pure and has high optical purity (ee).(DD) Nisoxetine(EE) Duloxetine(CC) 3-amino-1-propanol(BB) Fluoxetine(AA) TomoxetineCOPYRIGHT KIPO 2015
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Paragraph 0118-0121
(2016/12/01)
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- Pharmaceutical compounds wiht angiogenesis inbhibitory activity
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Compounds of formula (I): wherein: A, R, T, Q, L, Z, G, X and A' are as defined in the description. B and D, equal to or different from each other, are selected between heteroaryl and aryl, wherein at least one of the hydrogen atoms of said heteroaryl and aryl are substituted with groups selected from SO3-, SO3H, COO-, COOH, and one or more of the other hydrogen atoms of said heteroaryl and aryl are optionally substituted as reported in the description.
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Paragraph 0095
(2014/10/28)
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- PHARMACEUTICAL COMPOUNDS
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Compounds of formula (I): wherein: A, R, T, Q, L, Z, G, X and A′ are as defined in the description.B and D, equal to or different from each other, are selected between heteroaryl and aryl, wherein at least one of the hydrogen atoms of said heteroaryl and aryl are substituted with groups selected from SO3?, SO3H, COO?, COOH, and one or more of the other hydrogen atoms of said heteroaryl and aryl are optionally substituted as reported in the description.
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Paragraph 0249; 0250
(2014/12/09)
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- PERMANENTLY POSITIVELY CHARGED ANTIDEPRESSANTS
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The present invention provides compounds comprising a substructure of below formula 3: or a salt or prodrug thereof and the use of such compounds in treatment of e.g. CNS disorders.
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Page/Page column 67; 68
(2013/03/26)
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- Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depression
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Compounds possessing more than one functional activity incorporated into the same molecule may have advantages in treating complex disease states. Balanced serotonin/norepinephrine reuptake inhibitors (SNRIs) (i.e., (R)- and (S)-norduloxetine) were chemically linked to a PDE4 inhibitor via a five carbon bridge. The new dual SNRI/PDE4 inhibitors (i.e., (R)-15 and (S)-15) showed moderately potent serotonin reuptake inhibition (IC50 values of 442 and 404 nM, respectively) but low reuptake inhibition of norepinephrine (IC50 values of 2097 and 2190 nM, respectively) in vitro. The dual SNRI/PDE4 inhibitors (i.e., (R)-15 and (S)-15) also inhibited PDE4D2 (i.e., Ki values of 23 and 45 nM, respectively). Due to their synergistic functional activity, SNRI/PDE4 inhibitors may be effective in treating diseases such as depression.
- Cashman, John R.,Ghirmai, Senait
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experimental part
p. 6890 - 6897
(2010/01/06)
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- PROCESS FOR PREPARING DULOXETINE HYDROCHLORIDE
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Enantiomerically pure S-(+)-duloxetine hydrochloride with high purity as determined by area percentage of HPLC are disclosed. Also disclosed are improved process for preparing duloxetine hydrochloride of formula (I).
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Page/Page column 36-37; 38-39
(2008/12/07)
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- Synthesis of enantiomerically pure γ-azidoalcohols by lipase-catalyzed transesterification
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An enantioselective synthesis of chiral γ-azidoalcohols via lipase-catalyzed resolution is described. The efficiency of various lipases and the effect of different solvents have been studied. Pseudomonas cepacia immobilized on diatomaceous earth (PS-D) in n-hexane catalyzed the transesterification process in an efficient manner providing γ-azidoalcohols in high enantiomeric excess.
- Kamal, Ahmed,Malik, M. Shaheer,Shaik, Ahmad Ali,Azeeza, Shaik
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p. 1078 - 1083
(2008/09/19)
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- METHODS FOR THE PRODUCTION OF 3-METHYLAMINO-1-(THIENE-2-YL)-PROPANE-1-OL
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The invention relates to enzymatic and non-enzymatic methods for the production of 3-methylamino-1-(thiene-2-yl)-propane-1-ol; in addition to enzymes for carrying out said method; nucleic acid sequences coding for said enzymes, expression cassettes containing them, vectors and recombinant hosts.
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Page/Page column 32
(2008/06/13)
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- PROPANAMINE DERIVATIVES AS SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS
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There is provided a heretoaryloxy/thio 3-substituted propanamine compound of formula (I) wherein A is selected from -O- and -S-; X is selected from phenyl optionally substituted with up to 5 substituents each independently selected from halo, C1-C4 alkyl and C1-C4 alkoxy, thienyl optionally substituted with up to 3 substituents each independently selected from halo and C1-C4 alkyl, and C2-C8 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl and C4-C8 cycloalkylalkyl, each of which may be optionally substituted with up to 3 substituents each independently selected from halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl-S(O)n- where n is 0, 1 or 2, -CF3, -CN and -CONH2; Y is selected from dihydrobenzothienyl, benzothiazolyl, benzoisothiazolyl, quinolyl, isoquinolyl, naphthyridyl, and thienopyridyl, each of which may be optionally substituted with up to 4 or, where possible, up to 5 substituents each independently selected from halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl-S(O)n- where n is 0, 1 or 2, nitro, acetyl, -CF3, -SCF3 and cyano; Z is selected from H, OR3 or F, wherein R3 is selected from H, C1-C6 alkyl and phenyl C1-C6 alkyl; R1 and R2 are each independently H or C1-C4 alkyl; and pharmaceutically acceptable salts thereof.
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- 3-METHYLAMINO-1-(2-THIENYL)-1-PROPANONE, PRODUCTION AND USE THEREOF
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The invention relates to the production of 3-methylamino-1-(2-thienyl)-1-propanone and the use thereof for producing the pharmaceutical (+)-(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine oxalate (trade name Duloxetine?).
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Page/Page column 6
(2008/06/13)
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- An asymmetric synthesis of duloxetine hydrochloride, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled isotopomers
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Two 14C-isotopomers of duloxetine HCl (S-(+)-N-methyl-3(1-naphthalenyloxy)-3(2-thiophene)propanamine hydrochloride), a potent mixed serotonin/norepinephrine Uptake inhibitor have been prepared by an asymmetric synthesis. The palladium catalyzed cross-coupling of 2-thienoyl chloride (3c) (or its [carbonyl-14C] isotopomer 3d) with vinyl tri-n-butylstannane, followed by addition of HCl afforded the key pro-chiral intermediate chloroketone (5a,b). Chiral reduction with borane in the presence of the appropriate oxazaborolidine catalyst (14a or b) provided the S-chloroalcohol (7a) and its 14C-labeled counterpart 7b or the analogous R-chloroalcohol (6). Activation of 7a,b by reaction with NaI/acetone, followed by reaction of the corresponding iodoalcohol with methylamine yielded the penultimate aminoalcohols (8a,b). Formation of the alkoxide with NaH, followed by reaction with 1-fluoronaphthalene yielded duloxetine or its 14C-labeled isotopomer 9. Alternatively, reaction of 6 with 1-naphthol-[1-14C] under Mitsunobu conditions afforded aryl-ether 10a,b, which was in turn activated by reaction with NaI/acetone Subsequent reaction of 10c,d with methylamine followed by salt formation yielded duloxetine or its naphthalene-labeled isotopomer (13) as their HCl salts.
- Wheeler,Kuo
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p. 213 - 223
(2007/10/02)
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- MODERN FRIEDEL-CRAFTS CHEMISTRY XVI. REACTION OF THIOPHENE WITH BIFUNCTIONAL MOLECULES UNDER DIFFERENT FRIEDEL-CRAFTS CATALYSTS: ATTEMPTED SYNTHESIS OF CYCLOPENTA THIOPHENES AND DIHYDROBENZO THIOPHENES
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The reaction of thiophene (1) with 3-chloropropionyl chloride (2), 4-chlorobutyryl chloride (3), crotonyl chloride (4) and cinnamoyl chloride (5) under different Friedel-Crafts catalysts (AlCl3/CH3NO2, FeCl3, and AlCl3/CS2) was investigated.The cyclic products 4,5-dihydro-6H-4-methylcyclopenta-thiophen-6-one, 5,6-dihydrobenzothiophen-7(4H)one and 4-phenyl-6H-cyclopentathiophen-6-one were formed.The different behaviors of compounds (2-5) towards thiophene were discussed.
- El-Khagawa, Ahmed M.,El-Zohry, Maher F.,Ismail, Mohamed T.
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