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(12) Patent Application Publication (10) Pub. No.: US 2006/00094.65 A1 Edgar Et Al

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US 2006OOO9465A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/00094.65 A1 Edgar et al. (43) Pub. Date: Jan. 12, 2006 (54) TREATMENT OF SLEEP DSORDERS USING Related U.S. Application Data SLEEPTARGET MODULATORS (60) Provisional application No. 60/349,912, filed on Jan. 18, 2002. Provisional application No. 60/357,320, (76) Inventors: Dale Edgar, Wayland, MA (US); David filed on Feb. 15, 2002. G. Hangauer, East Amherst, NY (US); Harry Jefferson Leighton, Rockport, Publication Classification ME (US) (51) Int. Cl. A61K 31/496 (2006.01) Correspondence Address: C07D 471/04 (2006.01) MINTZ, LEVIN, COHN, FERRIS, GLOWSKY (52) U.S. Cl. ...................................... 514/253.04; 544/362 AND POPEO, PC. ONE FINANCIAL CENTER (57) ABSTRACT BOSTON, MA 02111 (US) The invention is directed to compositions used for treating Sleep disorders. In addition, the invention provides conve Appl. No.: 10/501,855 nient methods of treatment of a sleep disorder. Furthermore, (21) the invention provides methods of treating Sleep disorders using compositions that remain active for a discrete period (22) PCT Fed: Jan. 21, 2003 of time to reduce side effects. More specifically, the inven tion is directed to the compositions and use of ester deriva tized traZOdone compounds for the treatment of Sleep dis (86) PCT No.: PCT/US03/01845 orders. Patent Application Publication Jan. 12, 2006 Sheet 1 of 8 US 2006/00094.65 A1 IGHRIQ?INH Patent Application Publication Jan. 12, 2006 Sheet 2 of 8 US 2006/00094.65 A1 ZCHRI[10][H Patent Application Publication Jan. 12, 2006 Sheet 3 of 8 US 2006/00094.65 A1 $GIRI[10IH cHEETSWERIN N nOH ad W&N (%) Patent Application Publication Jan. 12, 2006 Sheet 4 of 8 US 2006/00094.65 A1 #7GIRLÍTÐIH (Z=u)di6x/6u101ddO-uuuu(g)- ÆETSWEHTºº & no did Wa(%) Patent Application Publication Jan. 12, 2006 Sheet 5 of 8 US 2006/00094.65 A1 FIGURES NREMSLEEP 120 180 MINUTES AFTER TREAMENT - (A) Methylcellulose vehicle 1 ml/kg PO (n=10) P CO.025 -- (B) HY2725:30mg/kg PO CT-18 (n=8) NREM SLEEP 120 MNUTSAFER TREATMENT - (A) Methylcellulose vehicle 1 ml/kg PO (n=10) * P & O.O25 - (B) Trazodone: 30mg/kg PO CT-18 (n=9) Patent Application Publication Jan. 12, 2006 Sheet 6 of 8 US 2006/00094.65 A1 FIGURE 6 REMSLEEP 12:00 O:00 CRC NTIME - (A) Methylcellulose vehicle 1 ml/kg PO (n=10) * P & O.025 - (B) HY2725; 30mg/kg PO CT-18 (n=8) 2. REMSLEEP 0:00 12:DO CRC NTIME - (A) Methylcellulose vehicle 1 ml/kg PO (n=10) P a 0.025 - (B) Trazodone: 30mg/kg PO CT-18 (n=9) Patent Application Publication Jan. 12, 2006 Sheet 7 of 8 US 2006/00094.65 A1 LGIRI[15)IH Patent Application Publication Jan. 12, 2006 Sheet 8 of 8 US 2006/00094.65 A1 8CHRIQ?INH US 2006/0009465 A1 Jan. 12, 2006 TREATMENT OF SLEEP DSORDERS USING Such that the disorder is treated. Accordingly, the therapeutic SLEEPTARGET MODULATORS compound can have the formula: REFERENCE TO RELATED APPLICATION wherein SR is a Serotonin receptor antagonist, MR is a 0001. This application claims priority to pending U.S. metabolite reducing moiety that reduces the formation of Provisional Patent Application Attorney Docket Number wake promoting metabolites, EG is an ester group that HPZ-010-1 (Application No.60/349,912) filed on Jan. 18, modifies the half-life of the therapeutic compound, SP and 2002, and pending U.S. Provisional Patent Application SP are spacer molecules, n, q, and rare independently 0 or Attorney Docket Number HPZ-010-2 (Application No.60/ 1, and r and q are 0 when MR is the ester group. 357,320) filed on Feb. 15, 2002. This application is also 0009. Another aspect of the invention is a method of related to pending U.S. Provisional Patent Application Serial treating a Serotonin receptor associated disorder, comprising No. 60/ (Attorney Docket Number HPZ-010-3), filed administering to a Subject an effective amount of a thera on even date herewith, entitled “Treatment of Sleep Disor ders Using Sleep Target Modulators'. The entire content of peutic compound, Such that the disorder is treated. Accord each of the above-identified applications is hereby incorpo ingly, the therapeutic compound can have the formula: rated herein by reference. wherein SR is a Serotonin receptor antagonist, EG is an ester BACKGROUND OF THE INVENTION group that modifies the half-life of the therapeutic com 0002 Difficulties in falling asleep, remaining asleep, pound, SP is a Spacer molecule, and n is 0 or 1. Sleeping for adequate lengths of time, or abnormal Sleep 0010. In another aspect of the invention, the invention is behavior are common Symptoms for those Suffering with a a method of treating a sleep disorder. The method comprises Sleep disorder. A number of Sleep disorders, e.g., insomnia administering an effective amount of a therapeutic com or sleep apnea, are described in the online Merck Manual of pound, Such that the sleep disorder is treated, wherein the Medicinal Information. compound has a favorable biological property (FBP). 0.003 Current treatment of many sleep disorders include 0011. An additional aspect of the invention is a method of the use of prescription hypnotics, e.g., benzodiazapines, that treating a sleep disorder. The method comprises administer may be habit-forming, lose their effectiveness after extended ing an effective amount of a therapeutic compound to a use, and metabolize more slowly for certain designated Subject, Such that the Sleep disorder is treated. Accordingly, groups, e.g., elderly perSons, resulting in persisting medica the therapeutic compound is traZodone compound that con tive effects. tains a moiety Selected and positioned, Such that a wake promoting metabolite is not formed. The therapeutic com 0004) Other, more mild manners of treatment include pound can have the formula: over-the-counter antihistamines, e.g., diphenhydramine or dimenhydrinate, which are not designed to be strictly Seda tive in their activity. This method of treatment is also wherein TZ is a trazodone compound, MR is a metabolite asSociated with a number of adverse side effects, e.g., reducing moiety that reduces the formation of wake pro persistence of the Sedating medication after the prescribed moting metabolites, EG is an ester group that modifies the time of treatment, or the so-called “hangover effect”. Many half-life of the therapeutic compound, SP and SP are of these side effects result from nonspecific activity in both Spacer molecules, n, q, and r are independently 0 or 1, and the periphery as well as the Central Nervous System (CNS) r and q are 0 when MR is the ester group that modifies the during this period of extended medication. half-life of the therapeutic compound. 0012 Another aspect of the invention is directed to a SUMMARY OF THE INVENTION method of treating a sleep disorder. The method comprises 0005. A need exists for the development of new compo administering an effective amount of a therapeutic com Sitions used for the improved treatment of Sleep disorders pound to a Subject, Such that the Sleep disorder is treated. that remain active for a discrete period of time to reduce side Accordingly, the therapeutic compound can have the for effects, such as the “hangover effect.” mula: 0006 Therefore, the invention is directed to composi tions used for treating sleep disorders. In addition, the wherein TZ is a traZOdone compound, EG is an ester group invention provides convenient methods of treatment of a that modifies the half-life of the therapeutic compound, SP Sleep disorder. Furthermore, the invention provides methods is a Spacer molecule, and n is 0 or 1. of treating sleep disorders using compositions that remain 0013 Another aspect of the invention is a method of active for a discrete period of time to reduce Side effects. modulating a Serotonin receptor associated disorder target. 0007 More specifically, the invention is directed to the The method comprises administering an effective amount of compositions and use of ester derivatized traZodone com a therapeutic compound to a Subject, Such that the disorder pounds for the treatment of Sleep disorders. target is modulated, wherein the therapeutic compound comprises the formula: 0008 Thus, in one aspect of the invention, the invention is directed to a method of treating a Serotonin receptor EG-(SP)-ISR-(SP)-IMR) asSociated disorder. The method comprises administering an wherein SR is a Serotonin receptor antagonist, MR is a effective amount of a therapeutic compound to a Subject, metabolite reducing moiety that reduces the formation of US 2006/0009465 A1 Jan. 12, 2006 wake promoting metabolites, EG is an ester group that wherein TZ is a trazodone compound, MR is a metabolite modifies the half-life of the therapeutic compound, SP, and reducing moiety that reduces the formation of wake pro SP are spacer molecules, n, q, and rare independently 0 or moting metabolites, EG is an ester group that modifies the 1, and r and q are 0 when MR is the ester group. half-life of the therapeutic compound, SP, and SP are 0.014) Another aspect of the invention is a method of Spacer molecules, n, q, and r are independently 0 or 1, and modulating a Serotonin receptor associated disorder target. r and q are 0 when MR is the ester group that modifies the The method comprises administering an effective amount of half-life of the therapeutic compound. a therapeutic compound to a Subject, Such that the disorder 0021. A further aspect of the invention is a compound target is modulated, wherein the therapeutic compound comprising the formula: comprises the formula: wherein TZ is a traZOdone compound, EG is an ester group wherein SR is a Serotonin receptor antagonist, EG is an ester that modifies the half-life of the therapeutic compound, SP group that modifies the half-life of the therapeutic com is a Spacer molecule, and n is 0 or 1.
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    ANDHRA PRADESH POLLUTION CONTROL BOARD D.No. 33-26-14 D/2, Near Sunrise Hospital, Pushpa Hotel Centre, Chalamalavari Street, Kasturibaipet, Vijayawada 520010. Website :www.appcb.ap.nic.in CONSENT ORDER FOR ESTABLISHMENT AND OPERATION Order No. 135 /APPCB/CFE/RO-VSP/HO/2014 Dt: 26.04.2018 Sub: APPCB CFE - M/s. Torrent Pharmaceuticals Ltd., (Formerly M/s. Glochem Industries Ltd.,) Plot No: 77, JN Pharmacity, Thanam (V), Parawada (M), Visakhapatnam District Consent for Establishment (CFE) and Consent for Operation (CFO) for Change of Product Mix under Sec. 25 / 26 of Water (P & C of P) Act, 1974 and Under Sec. 21 of Air (P&C of P) Act, 1981 - Issued - Reg. Ref: 1) CFE expansion order dt. 10.06.2016. 2) received through A.P. Single Desk Portal on 27.03.2018. 3) 10.04.2018. 4) CFE Committee meeting held on 24.04.2018. 5) 25.04.2018. 1. In the reference 2nd cited, an application was submitted to the Board seeking Consent for Establishment (CFE) and Consent for Operation order (CFO) for Change of Product Mix within the existing premises to produce the products with installed capacities as mentioned below, with an additional investment of Rs. 0.34 Crore. As per CFE (expansion) order dt. 10.06.2016: S. Quantity Name of the Product No (kg/day) 1 RALOXIFINE HYDROCHLORIDE 16.66 2 AMLODIPINE BESILATE 27.77 3 CETIRIZINE DIHYDROCHLORIDE 1.389 4 CLOPIDOGREL BESILATE 2.22 5 RABEPRAZOLE SODIUM 4.166 6 OLANZAPINE 3.333 7 TRIENTINE DI HYDROCHLORIDE 0.277 8 ALFUZOSIN HYDROCHLORIDE 2.777 9 AMISULPRIDE 1.389 10 LEVOCETIRIZINE DIHYDROCHLORIDE 8.333 11 TERBINAFINE