DOCSLIB.ORG

United States Patent Office

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
United States Patent Office Patented Feb. 11, 1947 2,415,786 UNITED STATES PATENT OFFICE UNSYMMETRICALLY SUBSTITUTED PPERAZINES Johannes S. Buck, East Greenbush, and Richard Baltzly, New York, N. Y., assignors to Bur roughs Welcome & Co. (U. S. A.) Inc., New York, N.Y., a corporation of New York No Drawing. Application January 6, 1944, serial No. 517,224 9 Claims. (C. 260-268) 2 This invention relates to N-monosubstituted According to the present invention, these diffi and N-N'-unsymmetrically disubstituted piper culties are overcome by treating piperazine with azines and has for an object to provide new com a halide of benzyl or of a substituted benzyl to positions of the above type and a novel and im form a reaction mixture containing, in addition proved method of making the same. to unreacted piperazine and di-N-N'- Substituted Another object is to provide a method of mak piperazine, a substantial amount of N-mono sub ing and isolating the above substances which is stituted piperazine separating the mono-N-sub Suitable for commercial Operation. stituted piperazine from the unreacted piperazine In our copending application Serial No. 476,914, and the disubstituted piperazine, introducing the filed February 24, 1943, of which the present ap O desired substituent on to the second N' nitrogen plication is a continuation in part and in our atom of the mono-N-substituted piperazine, then Copending application Serial No. 517,225, filed removing the benzyl or substituted benzyl group January 6, 1944, which is also a continuation in by catalytic hydrogenation. part, We have described certain methods for mak As catalysts for this hydrogenation, platinum, ing and isolating substituted piperazines of the palladium and nickel are all suitable, but We pre type fer in general to use palladium since, while CEI-CI equally or perhaps more effective in removing a benzyl group, it is practically devoid of any N /N-R tendency to reduce aromatic rings. CH-CH 20 The term benzyl derivatives as used in the where R is an aralkyl, or a higher alkyl, and R' present specification and claims, includes the is either hydrogen or a second radical different halogen derivatives such as p-chlorobenzyl and from R. organic derivatives such as anisyl The present invention refers to a new and dif ferent process for making any of the above com 25 pounds, which new process can also be used for 4-phenyl-benzyl or alpha-menaphthyl (alpha the production of numerous mono-N-substituted naphthyl-methyl). and unsymmetrically N,N'-disubstituted piper The method according to the present invention azines, many of which are not obtainable at all permits the preparation of numerous mono by any of the processes described in our above 30 alkyl, mono-acyl and other monosubstituted mentioned copending applications, nor by any piperazines with a very high yield. of the methods known in the art. A particular advantages of the process accord The main difficulty involved in preparing mono ing to the invention is that it is possible to obtain Substituted piperazines, from which unsym monosubstituted piperazines of the type metrically disubstituted derivatives can also be 35 CH-CH2 obtained, resides in the isolation of the substance H-N NR from the unreacted piperazine and the disubsti / tuted piperazine which are present and which CH-CH in many cases have similar boiling points. in which R" is a radical, such as a lower alkyl Amines are extremely hard to separate by frac 40 having less than 8 carbon atoms, which when in tional distillation unless their boiling points are troduced into unreacted piperazine will not pro Widely separated. Furthermore, the classical duce a separable mixture of mono- and di methods of separating secondary from tertiary substituted compounds, or a radical Such as an amines are of no avail in this case, since a mono acyl, an aryl sulfonyl or a substituted aryl Sul substituted piperazine reacts as both a secondary 45 fonyl, which will produce such separable mixtures and a tertiary amine. Even where a mixture con only under certain conditions, or a radical of taining mono- and symmetrically disubstituted relatively small inherent stability such as piperazines of widely different boiling points or acyloxyalkyl, hydroxyphenaikyl, carbamido, Sub Solubilities is formed, the separation of the mono stituted carbamido and carbamidino. Substituted compounds from the disubstituted 50 From the mono-N substituted piperazines ob reaction products and the unreacted piperazine tained in this manner, unsymmetrically disub is frequently difficult or even impossible if the stituted piperazines of any desired type may be stability of the introduced substituent is insuff obtained by introducing on to the first N nitrogen cient to Withstand the conventional separation atom made available by the preceding catalytic methods such as fractional distillation. SS hydrogenation, the desired substituent which is 2,415,786 3 4 different from the substituent present in the (equals alpha naphthyl-methyl) piperazine was monosubstituted compound but may be selected Separated as in Example i. from the Same group. Subsequently the monosubstituted compound Thus, it is possible to produce unsymmetrically was reacted with butyl chloride to yield N-alpha N-R, N'-R'-disubstituted piperazines where R. naphthyl-methylene-N'-butyl piperazine hydro represents a radical selected from the group con chloride. On addition of 1 equivalent of hydro sisting of the lower alkyls having less than 8 chloric acid and removal of the alpha-menaph carbon atoms, acyl, aryl sulfonyl, substituted thyl group by catalytic hydrogenation, mono-N'- aryl sulfonyl, acyloxyalkyl and hydroxyphenialkyl butyl piperazine dihydrochloride was crystallized and R' represents a radical Selected from the 10 from alcohol ether. group consisting of the lower alkyls having less than 8 carbon atoms, acyl, aryl Sulfonyl, Substi Eacample 5 tuted aryl sulfonyl, acyloxyalkyl, phenacyl, sub Anisyl chloride (CH3O C6H4CH2C1) (1 mol) stituted phenacyl, hydroxyphen alkyl, carbamido, (from anisyl alcohol (CH3OC6H4CH2OH) and hy substituted carbamido, thiocarbamido, substi 15 drogen chloride) was reacted with piperazine (1. tuted thiocarbamido and carbamidino. mol) in absolute alcohol solution. The bulk of The following examples may serve to illustrate, the dianisyl piperazine formed as a by-product without limiting the invention. Separated towards the end of the reaction as its Eacample 1 dihydrochloride and was filtered off. The solvent was evaporated from the filtrate, the residue Piperazine hexahydrate was dissolved in ab 20 diluted with water, basified and the anisyl piper Solute ethanol and benzyl chloride added with azine extracted with ether. The Small amount stirring. After standing overnight the alcohol of impurities remaining was separated by vac was distilled off and the residue partitioned be uum distillation. tween ether and sodium hydroxide solution, The 25 The mono-N-anisyl piperazine so produced was greater part of the unreacted piperazine re reacted in benzene with p-nitrobenzoyl chloride. mained in the aqueous layer. The ethereal layer The resulting compound, N-anisyl-N'-p-nitro was dried over K2CO3 and distilled in vacuo to benzoyl piperazine hydrochloride separated and separate pure monobenzyl piperazine from the was recrystallized from alcohol. On drastic cat dibenzylpiperazine. 30 alytic hydrogenation in alcoholic solution at room The monobenzyl piperazine was methylated by temperature With a platinum catalyst, first the the procedure of Clarke, Gillespie and Weiss nitro group was reduced to an amino group and hauss (J. Amber. Chem. Soc., 55, 4571 (1933)), thereafter the anisyl group was split off to yield and the product, after liberation of the base was the mono-N'-p-amino-benzoyl piperazine dihy treated with benzoyl chloride to remove any 35 drochloride. monobenzyl piperazine that had remained un Eacample 6 reacted. Basic material Was again liberated with Fourteen parts by weight of mono-N-benzy pi alkali and distilled in vacuo. The product, N perazine (Example 1) were reacted in alcoholic benzyl-N'-methyl piperazine, was crystallized as Solution With five parts by weight of ethylene the dihydrochloride from absolute alcohol-ether 40 oxide yielding 17 parts of crude N-benzyl-N'- mixture and this dihydrochloride was hydrogen hydroxyethyl piperazine. This was then ben ated catalytically in glacial acetic acid with the ZOylated by the Schotten Baumann method and aid of palladized-charcoal. After filtration from the product purified by crystallization as the di the catalyst and evaporation of the solution in hydrochloride. This material, N-benzyl-N'-ben vacuo, the product, mono-N-methyl piperazine 45 zoyloxyethyl piperazine dihydrochloride was hy dihydrochloride was crystallized from methanol drogenated with hydrogen and palladized char ether. coal in 80% acetic acid solution yielding toluene Eacample 2 and mono-N'-benzoyloxyethyl piperazine dihy Piperazine hexahydrate was treated in abso drochloride. lute alcohol with p-chlorobenzyl chloride and the Eacample 7 mono-N-p-chlorobenzylpiperazine was separated Mono-N-p-chlorobenzyl piperazine as ob from the unreacted piperazine and from disub tained according to Example 2, was treated with stituted piperazine by fractional distillation. a slight excess of phenacyl bromide to yield N-p- The mono-p-chloro-benzyl piperazine was re chloro-benzyl-N'-phenacyl piperazine. This was acted with ethyl bromide to yield N-p-chloro catalytically hydrogenated to mono-N'-(beta benzyl-N'-ethyl piperazine hydrobromide. An phenyl-beta-hydroxyethyl) piperazine. other equivalent of hydrobromic acid was added to give the dihydrobromide and this product was Eacample 8 catalytically hydrogenated. After filtration from Anisyl chloride (CH3O C6H4 CH2Cl (1 mol) the catalyst and evaporation of the solution in 60 (from anisy alcohol (CH3OC6H4CH2OH) and hy vacuo, mono-N'-ethyl piperazine dihydrobromide drogen chloride) was reacted with piperazine (1 was crystallized from alcohol ether. mol) in absolute alcohol solution. The bulk of the dianisyl piperazine formed as a by-product Eacample 3 separated towards the end of the reaction as its 85 dihydrochloride and was filtered off.
Load more

Recommended publications
  • Recent Progress Toward the Asymmetric Synthesis of Carbon-Substituted Piperazine Pharmacophores and Oxidative Related Heterocycles RSC Medicinal Chemistry
    Volume 11 Number 7 July 2020 RSC Pages 735–850 Medicinal Chemistry rsc.li/medchem ISSN 2632-8682 REVIEW ARTICLE Plato A. Magriotis Recent progress toward the asymmetric synthesis of carbon-substituted piperazine pharmacophores and oxidative related heterocycles RSC Medicinal Chemistry View Article Online REVIEW View Journal | View Issue Recent progress toward the asymmetric synthesis Cite this: RSC Med. Chem.,2020,11, of carbon-substituted piperazine pharmacophores 745 and oxidative related heterocycles Plato A. Magriotis † The important requirement for approval of a new drug, in case it happens to be chiral, is that both enantiomers of the drug should be studied in detail, which has led synthetic organic and medicinal chemists to focus their attention on the development of new methods for asymmetric synthesis especially of relevant saturated N-heterocycles. On the other hand, the piperazine ring, besides defining a major class of saturated N-heterocycles, has been classified as a privileged structure in medicinal chemistry, since it is more than frequently found in biologically active compounds including several marketed blockbuster drugs such as Glivec (imatinib) and Viagra (sildenafil). Indeed, 13 of the 200 best-selling small molecule drugs in 2012 contained a piperazine ring. Nevertheless, analysis of the piperazine substitution pattern reveals a lack Creative Commons Attribution 3.0 Unported Licence. of structural diversity, with almost every single drug in this category (83%) containing a substituent at both Received 16th February 2020, the N1- and N4-positions compared to a few drugs having a substituent at any other position (C2, C3, C5, Accepted 27th April 2020 and C6). Significant chemical space that is closely related to that known to be biologically relevant, therefore, remains unexplored.
    [Show full text]
  • Piperazine (MDBZP)
    1-(3-4- methylendioxybenzyl)piperazine (MDBZP) Pre-Review Report Expert Committee on Drug Dependence Thirty-fifth Meeting Hammamet, Tunisia, 4-8 June 2012 35th ECDD (2012) Agenda item 5.3e 1-(3-4-methylendioxybenzyl)piperazine (MDBZP) - 2 - 35th ECDD (2012) Agenda item 5.3e 1-(3-4-methylendioxybenzyl)piperazine (MDBZP) Acknowledgements This report has been drafted under the responsibility of the WHO Secretariat, Essential Medicines and Health Products, Medicines Access and Rational Use Unit. The WHO Secretariat would like to thank the following people for their contribution in producing this pre-review report: Dr Simon Elliott, United Kingdom (literature review and drafting), Dr Caroline Bodenschatz (editing) and Mr Kamber Celebi, France (questionnaire report). - 3 - 35th ECDD (2012) Agenda item 5.3e 1-(3-4-methylendioxybenzyl)piperazine (MDBZP) - 4 - 35th ECDD (2012) Agenda item 5.3e 1-(3-4-methylendioxybenzyl)piperazine (MDBZP) Contents SUMMARY ............................................................................................................................... 7 1. Substance identification .................................................................................................... 8 A. International Nonproprietary Name (INN) ................................................................ 8 B. Chemical Abstract Service (CAS) Registry Number ................................................. 8 C. Other Names ..............................................................................................................
    [Show full text]
  • Adrenoceptor Antagonistic Properties of Some 1,4-Substituted Piperazine Derivatives
    ORIGINAL ARTICLES Department of Bioorganic Chemistry, Chair of Organic Chemistry1; Department of Pharmacodynamics2; Department of Cytobiology and Histochemistry, Laboratory of Pharmacobiology3, Faculty of Pharmacy Medical College; Faculty of Chemistry4, Jagiellonian University Krakow, Poland Synthesis, ␣-adrenoceptors affinity and ␣1-adrenoceptor antagonistic properties of some 1,4-substituted piperazine derivatives H. Marona 1, M. Kubacka 2, B. Filipek 2, A. Siwek 3, M. Dybała 3, E. Szneler 4, T. Pociecha 1, A. Gunia 1, A. M. Waszkielewicz 1 Received March 24, 2011, accepted April 25, 2011 Dr. Anna M. Waszkielewicz, Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland [email protected] Pharmazie 66: 733–739 (2011) doi: 10.1691/ph.2011.1543 A series of different 1,4-substituted piperazine derivatives (1–11) was synthesized. It comprised 1- (substituted-phenoxyalkyl)-4-(2-methoxyphenyl)piperazine derivatives (1–5); 1,4-bis(substituted-phenoxy- ethyl)piperazine derivatives (6–8) and 1-(substituted-phenoxy)-3-(substituted-phenoxyalkylpiperazin-1- yl)propan-2-ol derivatives (9–11). All compounds were evaluated for affinity toward ␣1- and ␣2-receptors by radioligand binding assays on rat cerebral cortex using [3H]prazosin and [3H]clonidine as specific radioli- gand, respectively. Furthermore ␣1-antagonistic properties were checked for most promising compounds (1–5 and 10) by means of inhibition of phenylephrine induced contraction in isolated rat aorta. Antago- nistic potency stayed in agreement with radioligand binding results. The most active compounds (1–5) 3 displaced [ H]prazosin from cortical binding sites in low nanomolar range (Ki = 2.1−13.1 nM).
    [Show full text]
  • Mass Spectral, Infrared and Chromatographic Studies on Designer Drugs of the Piperazine Class by Karim M. Hafiz Abdel-Hay a Diss
    Mass Spectral, Infrared and Chromatographic Studies on Designer Drugs of the Piperazine Class by Karim M. Hafiz Abdel-Hay A dissertation submitted to the Graduate Faculty of Auburn University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Auburn, Alabama May 7, 2012 Approved by C. Randall Clark, Chair, Professor of Pharmacal Sciences Jack DeRuiter, Professor of Pharmacal Sciences Forrest Smith, Associate Professor of Pharmacal Sciences Angela Calderon, Assistant Professor of Pharmacal Sciences Abstract The controlled drug 3,4-methylenedioxybenzylpiperazine (3,4-MDBP) has regioisomeric and isobaric substances of mass equivalence, which have similar analytical properties and thus the potential for misidentification. The direct regioisomers of 3,4-MDBP include the 2,3- methylenedioxy substitution pattern and the indirect regioisomers include the three ring substituted methoxybenzoylpiperazines. The ethoxy and methoxymethyl ring substituted benzylpiperazines constitute the major category of isobaric substances evaluated in this study. The direct and indirect regioisomers of 3,4-MDBP and also isobaric substances related to MDBP were synthesized and compared to 3,4-MDBP by using gas chromatographic and spectrophotometric techniques. The GC-MS studies of the direct regioisomers and isobaric substances of 3,4-MDBP indicated that they can not be easily differentiated by mass spectrometry. The synthesized compounds were converted to their perfluoroacyl derivatives, trifluoroacetyl (TFA), pentafluoropropionyl amides (PFPA) and heptafluorobutryl amides (HFBA), in an effort to individualize their mass spectra and to improve chromatographic resolution. Derivatized 3,4-MDBP was not distingushed from its derivatized regioisomers or isobars using mass spectrometry. No unique fragment ions were observed for the various regioisomeric and the isobaric compounds.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2002/0102215 A1 100 Ol
    US 2002O102215A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0102215 A1 Klaveness et al. (43) Pub. Date: Aug. 1, 2002 (54) DIAGNOSTIC/THERAPEUTICAGENTS (60) Provisional application No. 60/049.264, filed on Jun. 6, 1997. Provisional application No. 60/049,265, filed (75) Inventors: Jo Klaveness, Oslo (NO); Pal on Jun. 6, 1997. Provisional application No. 60/049, Rongved, Oslo (NO); Anders Hogset, 268, filed on Jun. 7, 1997. Oslo (NO); Helge Tolleshaug, Oslo (NO); Anne Naevestad, Oslo (NO); (30) Foreign Application Priority Data Halldis Hellebust, Oslo (NO); Lars Hoff, Oslo (NO); Alan Cuthbertson, Oct. 28, 1996 (GB)......................................... 9622.366.4 Oslo (NO); Dagfinn Lovhaug, Oslo Oct. 28, 1996 (GB). ... 96223672 (NO); Magne Solbakken, Oslo (NO) Oct. 28, 1996 (GB). 9622368.0 Jan. 15, 1997 (GB). ... 97OO699.3 Correspondence Address: Apr. 24, 1997 (GB). ... 9708265.5 BACON & THOMAS, PLLC Jun. 6, 1997 (GB). ... 9711842.6 4th Floor Jun. 6, 1997 (GB)......................................... 97.11846.7 625 Slaters Lane Alexandria, VA 22314-1176 (US) Publication Classification (73) Assignee: NYCOMED IMAGING AS (51) Int. Cl." .......................... A61K 49/00; A61K 48/00 (52) U.S. Cl. ............................................. 424/9.52; 514/44 (21) Appl. No.: 09/765,614 (22) Filed: Jan. 22, 2001 (57) ABSTRACT Related U.S. Application Data Targetable diagnostic and/or therapeutically active agents, (63) Continuation of application No. 08/960,054, filed on e.g. ultrasound contrast agents, having reporters comprising Oct. 29, 1997, now patented, which is a continuation gas-filled microbubbles stabilized by monolayers of film in-part of application No. 08/958,993, filed on Oct.
    [Show full text]
  • The Design and Synthesis of 1,4-Substituted Piperazine Derivatives Bull
    The Design and Synthesis of 1,4-Substituted Piperazine Derivatives Bull. Korean Chem. Soc. 2012, Vol. 33, No. 8 2597 http://dx.doi.org/10.5012/bkcs.2012.33.8.2597 The Design and Synthesis of 1,4-Substituted Piperazine Derivatives as Triple Reuptake Inhibitors Minsoo Han,†,‡ Younghue Han,† Chiman Song,† and Hoh-Gyu Hahn†,* †Organic Chemistry Laboratory, Korea Institute of Science and Technology, Seoul 136-791, Korea. *E-mail: [email protected] ‡Department of Chemistry, Korea University, Seoul 136-701, Korea Received April 12, 2012, Accepted May 7, 2012 Novel 1,4-substituted piperazine derivatives 5, Series A and B were designed by fragment analysis and molecular modification of 4 selected piperazine-containing compounds which possess antidepressant activity. We synthesized new 39 analogues of Series A and 10 compounds of Series B, respectively. The antidepressant screening against DA, NE, and serotonin neurotransmitter uptake inhibition was carried out using the Neurotransmitter Transporter Uptake Assay Kit. The compounds in Series B showed relatively higher reuptake inhibitory activity for SERT, NET, and DAT than those in Series A. The length of spacer between the central piperazine core and the terminal phenyl ring substituted at the piperazine ring in Series B seems to exert an important role in the activity. Key Words : Major depressive disorder, Antidepressants, Triple reuptake inhibitor, Piperazine, CNS drug Introduction pharmacokinetics. Therefore, TRIs as a single molecule are expected to be the next generation of antidepressant and Major depressive disorder (MDD) is a common and seri- remain desirable. ous illness with the potential to become the leading cause of Among the broad range of templates, heterocyclic scaffolds disability worldwide.
    [Show full text]
  • Annexure-1 Patents Granted for Drugs (Products and Processes)
    ANNEXURE‐1‐ Patents Granted for Drugs/Medicines (Products and Processes) related to fields of Chemicals and Biotechnology during last 3 years and current year . Application_number Patent_date_Of_G TITLE_OF_INVENTION PATENT_NUMBER rant 1432/MUMNP/2010 01‐04‐2016 A METHOD OF ADAPTING THE PROCEDURE FOR EPICUTANEOUS 272455 DESENSITIZATION 1844/KOLNP/2008 01‐04‐2016 [4‐(6‐HALO‐7‐SUBSTITUTED ‐2,4‐DIOXO‐1,4‐DIHYDRO‐2H‐ 272457 QUINAZOLIN‐3‐YL)‐PHENYL]‐5‐CHLORO‐THIOPHEN‐2‐YL‐ SULFONYLUREAS AND FORMS AND METHODS RELATED THERETO 2284/CHE/2007 05‐04‐2016 STILBENE BASED COMPOUNDS AS HDAC INHIBITORS 272490 306/DELNP/2009 05‐04‐2016 "A COMPOSITION FOR ENHANCING EXECUTIVE COGNITIVE 272500 FUNCTION IN A HEALTHY HUMAN SUBJECT" 3512/KOLNP/2008 05‐04‐2016 BIFUNCTIONAL HISTONE DEACETYLASE INHIBITORS 272514 3451/DELNP/2006 07‐04‐2016 "VINFLUNINE PHARMACEUTICAL COMPOSITION AND PROCESS FOR 273980 PREPARING THE SAME." 2481/MUM/2008 10‐04‐2016 PREPARATION OF PHENYLACETIC ACID DERIVATIVE 276185 2019/MUM/2008 12‐04‐2016 STABLE ORAL ATORVASTATIN FORMULATION AND PROCESS OF ITS 272594 PREPARATION 4334/DELNP/2008 12‐04‐2016 “A LENTIVIRAL VECTOR‐BASED VACCINE” 272595 118/DELNP/2009 12‐04‐2016 “STABLE LAQUINIMOD PREPARATIONS” 272596 4129/KOLNP/2009 12‐04‐2016 RECONSTITUTED SURFACTANTS HAVING IMPROVED PROPERTIES 272602 2218/CHE/2007 13/04/2016 CARBON NANOSPHERE‐N‐(4‐CHLORO‐3‐TRIFLUOROMETHYL‐ 272637 PHENYL)‐2‐ETHOXY‐6‐PENTADECYLBENZAMIDE COMPOSITION AND A PROCESS THEREOF 1876/KOLNP/2010 13‐04‐2016 COMPOSITIONS AND METHODS FOR TREATING DISEASES OF THE 272623 NAIL 3140/CHENP/2006
    [Show full text]
  • United States Patent Office Patented Feb
    3,562,278 United States Patent Office Patented Feb. 9, 1971 2 3,562,278 enumerated above, the substituents can be the same or 1-2-(2-SUBSTITUTED-3-INDOLYL)ETHYL-4-SUB different and can occupy any available carbon atom of the STITUTED.PPERAZINES phenyl ring. Sydney Archer, Bethlehem, N.Y., assignior to Sterling The compounds of Formula I where R2 is carbo-lower Drug inc., New York, N.Y., a corporation of Dela 5 alkoxy are prepared by reacting a 2-carbo-lower-alkoxy Ware 3-(2-haloethyl)indole of Formula II with an appropriate No Drawing. Continuation-in-part of application Ser. No. 1-substituted-piperazine of Formula III according to the 733,250, May 31, 1968, which is a continuation-in-part reaction: of application Ser. No. 634,899, May 1, 1967. This application Sept. 16, 1969, Ser. No. 858,499 R Claims priority, applicity Canada, Apr. 16, 1968, 10 XY-n-CHCH-x 17,589 - H-N N-R1 - I int. C. C07d 51/70 y-COO Alk N-/ U.S. C. 260-268 17 Claims N R H 5) ABSTRACT OF THE DISCLOSURE I III where R1, R3, and R4 have the meanings given above, Alk Novel 1-2-(2-substituted - 3 - indolyl)ethyl-4-substi represents lower-alkyl, and X represents halogen. The re tuted-piperazines having psychomotor depressant activity. action can be carried out either in the absence of a sol 20 vent or in an organic solvent inert under the conditions of the reaction, for example methanol, ethanol, isopropanol, This application is a continuation-in-part of my prior and the like, and in the presence of an acid-acceptor, the co-pending application S.N.
    [Show full text]
  • 1-(4-Methoxyphenyl) Piperazine (Meopp) Pre-Review Report
    1-(4-methoxyphenyl) piperazine (MeOPP) Pre-Review Report Expert Committee on Drug Dependence Thirty-fifth Meeting Hammamet, Tunisia, 4-8 June 2012 35th ECDD (2012) Agenda Item 5.3d 1-(4-methoxyphenyl)piperazine (MeOPP) - 2 - 35th ECDD (2012) Agenda Item 5.3d 1-(4-methoxyphenyl)piperazine (MeOPP) Acknowledgements This report has been drafted under the responsibility of the WHO Secretariat, Essential Medicines and Health Products, Medicines Access and Rational Use Unit. The WHO Secretariat would like to thank the following people for their contribution in producing this pre-review report: Dr Simon Elliott, United Kingdom (literature review and drafting), Dr Caroline Bodenschatz (editing) and Mr Kamber Celebi, France (questionnaire report). - 3 - 35th ECDD (2012) Agenda Item 5.3d 1-(4-methoxyphenyl)piperazine (MeOPP) - 4 - 35th ECDD (2012) Agenda Item 5.3d 1-(4-methoxyphenyl)piperazine (MeOPP) Contents SUMMARY ............................................................................................................................... 7 1. Substance identification .................................................................................................... 8 A. International Nonproprietary Name (INN: ................................................................. 8 B. Chemical Abstract Service (CAS) Registry Number ................................................. 8 C. Other Names ............................................................................................................... 8 D. Trade Names .............................................................................................................
    [Show full text]
  • A Review on Analgesic and Anti-Inflammatory Activities of Various Piperazinyl Containing Pyridazine Derivatives
    Progress in Chemical and Biochemical Research 2020, 3(2), 81-92 Progress in Chemical and Biochemical Research Journal homepage: www.pcbiochemres.com Review Article A Review on Analgesic and Anti-Inflammatory Activities of Various Piperazinyl Containing Pyridazine Derivatives Md. Tauqir Alam1, Abida1, and Mohammad Asif2* 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha 91911, PO Box 840, Saudi Arabia 2Department of Pharmacy, Himalayan Institute of Pharmacy and Research, Dehradun, (Uttarakhand), 248007, India G R A P H I C A L A B S T R A C T A B S T R A C T Most currently used nonsteroidal anti-inflammatory drugs (NSAIDs) have some restrictions for therapeutic use since they may cause gastrointestinal and renal side effects that are undividable from their pharmacological activities. In this review various piperazinyl containing pyridazine derivatives were studied for their analgesic and anti-inflammatory activities and their side effects. Synthesis of new A R T I C L E I N F O compounds devoid of such side effects has become an important goal K E Y W O R D S Pyridazine; for medicinal chemistry. ---Analgesic; Anti-inflammatory; Piperazinylpyridazines © 2020 by SPC (Sami Publishing Company) Introduction dual inhibition of COX and 5-lypoxygenase enzymes has beenused for treatment of inflammation and Although various nonsteroidal anti-inflammatory pain, introduced as a novel therapeutic target. One drugs (NSAIDs) are available for the treatment of of the examples of dual acting analgesic and anti- pain, their chronic use for treatment of pain inflammatory molecules was tepoxalin (figure 1), is associated with inflammation limits their a diarylpyrazole derivative [2].
    [Show full text]
  • Marrakesh Agreement Establishing the World Trade Organization
    No. 31874 Multilateral Marrakesh Agreement establishing the World Trade Organ ization (with final act, annexes and protocol). Concluded at Marrakesh on 15 April 1994 Authentic texts: English, French and Spanish. Registered by the Director-General of the World Trade Organization, acting on behalf of the Parties, on 1 June 1995. Multilat ral Accord de Marrakech instituant l©Organisation mondiale du commerce (avec acte final, annexes et protocole). Conclu Marrakech le 15 avril 1994 Textes authentiques : anglais, français et espagnol. Enregistré par le Directeur général de l'Organisation mondiale du com merce, agissant au nom des Parties, le 1er juin 1995. Vol. 1867, 1-31874 4_________United Nations — Treaty Series • Nations Unies — Recueil des Traités 1995 Table of contents Table des matières Indice [Volume 1867] FINAL ACT EMBODYING THE RESULTS OF THE URUGUAY ROUND OF MULTILATERAL TRADE NEGOTIATIONS ACTE FINAL REPRENANT LES RESULTATS DES NEGOCIATIONS COMMERCIALES MULTILATERALES DU CYCLE D©URUGUAY ACTA FINAL EN QUE SE INCORPOR N LOS RESULTADOS DE LA RONDA URUGUAY DE NEGOCIACIONES COMERCIALES MULTILATERALES SIGNATURES - SIGNATURES - FIRMAS MINISTERIAL DECISIONS, DECLARATIONS AND UNDERSTANDING DECISIONS, DECLARATIONS ET MEMORANDUM D©ACCORD MINISTERIELS DECISIONES, DECLARACIONES Y ENTEND MIENTO MINISTERIALES MARRAKESH AGREEMENT ESTABLISHING THE WORLD TRADE ORGANIZATION ACCORD DE MARRAKECH INSTITUANT L©ORGANISATION MONDIALE DU COMMERCE ACUERDO DE MARRAKECH POR EL QUE SE ESTABLECE LA ORGANIZACI N MUND1AL DEL COMERCIO ANNEX 1 ANNEXE 1 ANEXO 1 ANNEX
    [Show full text]
  • Butler. K ...99 Juby. P . F ...208 Kaiser. C ...6. 18
    CONTRI BUTORS Bach. M . K ........ 238 Lienhard. G . E ........ 249 Benet. L . Z ....... 259 Morrow. D . F ......... 182 Blohm. T . R ....... 169 Nagasawa. H . T ........ 269 Bundy. G . L ....... 157 Pachter. 1 . J ........ 157 Burgus. R ........ 194 Rachlin. A . I ........ 145 Butler. K ........ 99 Robinson. F . M ........ 31 Cheng. C . C ....... 129 Roe. A . M .......... 59 Colten. H . R ....... 228 Rudzik. A . D ......... 39 Cronin. T . H ....... 119 Sciavolino. F . C ....... 99 Czuba. L . J ....... 78 Schowen. R . L ........ 279 Davies. J ........ 217 Schwender. C . F ....... 69 Drube. C . G ....... 109 Stewart. J . M ........ 289 Engelhardt. E . L ..... 6 Thomas. R . C ......... 296 Friis. W ......... 39 Thompson. J . A ........ 269 Gallo. D ......... 182 Topliss. J . G ........ 59 Gandour. R . D ...... 279 Tozzi. S ........... 89 Harbert. C . A ...... 47 Waitz. J . A ......... 109 Hitchings. G . H ..... 1 Wechter. W . J ........ 217 Hoffer. M ........ 145 Weissman. A ......... 47 Hudyma. T . W ....... 208 Wiley. R . A ......... 259 Juby. P . F ........ 208 Zirkle. C . L ......... 6. 18 Kaiser. C ........6. 18 ANNUAL REPORTS IN MEDICINAL CHEMISTRY Volume 7 Sponsored by the Division of Medicinal Chemistry of the American Chemical Society Editor-in- Chief: RICHARD V. HEINZELMAN THE UPJOHN COMPANY KAUMAZOO, MICHIGAN SECTION EDITORS EDWARD ENGELHARDT 0 JOHN TOPLISS 0 KENNETH BUTLER IRWIN PACHTER 0 WILLIAM WECHTER 0 ROBERT WILEY @ACADEMIC PRESS New York and London 1972 COPYRIGHT 0 1972, BY ACADEMICPRESS, INC. ALL RIGHTS RESERVED NO PART OF THIS BOOK MAY BE REPRODUCED IN ANY FORM, BY PHOTOSTAT, MICROFILM, RETRIEVAL SYSTEM, OR ANY OTHER MEANS, WITHOUT WRITTEN PERMISSION FROM THE PUBLISHERS. ACADEMIC PRESS, INC.
    [Show full text]