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(12) United States Patent (10) Patent No.: US 6,887,866 B2 Jenkins Et Al

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(12) United States Patent (10) Patent No.: US 6,887,866 B2 Jenkins Et Al USOO6887866B2 (12) United States Patent (10) Patent No.: US 6,887,866 B2 Jenkins et al. (45) Date of Patent: May 3, 2005 (54) SHORT-ACTING SEDATIVE HYPNOTIC DE 27 31 460 A1 1/1978 AGENTS FOR ANESTHESIA AND SEDATION EP O 236 280 B1 6/1991 GB 1032872 6/1956 (75) Inventors: Thomas E. Jenkins, La Honda, CA SE g ''E. ESSESS 1571 395 7/1980 (US) s s WO WO 96/32135 10/1996 OTHER PUBLICATIONS (73) Assignee: Theravance, Inc., South San Francisco, CA (US) “SUBLIMAZE (E 2ml injection, 10ml injection' 4 pages. South African Electronic Package Inserts. Published by (*) Notice: Subject to any disclaimer, the term of this Malahyde Information Systems. Publication date Apr. 19, patent is extended or adjusted under 35 1984, Jan. 21, 1983.* U.S.C. 154(b) by 20 days. Strazzolini et al., “Nitrolysis of t-Butyl and 1-Adamantyl Esters' Tetrahedron Letters, vol. 39, pp. 9255–9258 (21) Appl. No.: 10/350,624 (1998).* Clarke, “The Eugends’, Intravenous Anaesthesia, Chapter 8, (22) Filed: Jan. 24, 2003 pp. 162–192 (1974). (65) Prior Publication Data MacKenzie et al., “Formulation and evaluation of a pro panidid hydroxypropryl-3-cyclodextrin Solution for intra US 2003/0153554 A1 Aug. 14, 2003 venous anesthesia”, Int. Journ. of Pharmaceutics. Vol. 59, pp Related U.S. Application Data 191-196 (1997). (60) Provisional application No. 60/351,385, filed on Jan. 25, Swerdlow, “A Trial of Propanidid (FBA. 1420): A New 2002, and provisional application No. 60/379,219, filed on Ultrashort-Acting Anaesthetic', Brit J. Anaesth. Vol. 37, pp May 9, 2002. 785–789 (1985). Wynands et al., “A Clinical Study of Propanidid (FBA (51) Int. Cl." ........................ A01N 43/00; AO1N 43/40; 1420), Can. Anaes. Soc. J., vol. 12, No. 6, pp 587-594 AO1N 43/36; A61K 31/55; A61K 31/44 (1985). (52) U.S. Cl. .................. 514/217.11; 514/354; 514/423; Zipf et al., “Local and endoanesthetic side effects of the 514/534; 540/607; 546/226; 548/540; 560/37 Short-term narcotic, propanidid and Some homologs. Effects (58) Field of Search ............................ 514/217.11, 354, of a Solubilizer on the degree of activity”, Arzneim 514/423, 534; 546/226; 540/607: 548/540; Forsch... vol. 17, No. 8, pp 1021–1026 (1967) (In German 560/37, 75 with English abstract). (56) References Cited * cited by examiner U.S. PATENT DOCUMENTS Primary Examiner Mukund J. Shah 3,086,976 A 4/1963 Hitman et al. Assistant Examiner Zachary C. Tucker 3,484,527 A 12/1969 Arnold et al. (74) Attorney, Agent, or Firm-Robert P. Saxon; Jeffrey A. 3,510,559 A 5/1970 Arnold et al. Hagenah; David E. Boone 3,511877 A 5/1970 Arnold et al. 4,401,830 A 8/1983 Umumura et al. (57) ABSTRACT 4,711902 A 12/1987 Serno 4,918,092 A * 4/1990 Frenette et al. ............. 514/382 The invention provides compounds compositions and meth 5,242.944. A 9/1993 Park et al. .................. 514/466 ods useful for inducing or maintaining general anesthesia or Sedation in mammals. FOREIGN PATENT DOCUMENTS DE 1134981 8/1962 33 Claims, 1 Drawing Sheet 5 O O O 2 O 10 O U.S. Patent May 3, 2005 US 6,887,866 B2 FIG. I. 5 O Number of Carbons 2 O 1 O O FIG. 2 A Propofol (20 min) B Propofol (3 h) C Propofol (5 h) D Compound 1 (20 min) E Compound 1 (3 h) F Compound 1 (5h) G Propanidid (20 min) H Propanidid (3h) F G W US 6,887,866 B2 1 SHORTACTING SEDATIVE HYPNOTIC (I) AGENTS FOR ANESTHESIA AND SEDATION R2 CROSS REFERENCE TO RELATED O N APPLICATIONS n R3 This application claims the benefit of U.S. Provisional O Application Nos. 60/351,385, filed Jan. 25, 2002, and O-R 60/379,219, filed May 9, 2002, the disclosures of which are 1O incorporated herein by reference. BACKGROUND OF THE INVENTION O 15 NR4 1. Field of the Invention O This invention is directed to novel substituted phenylace tic acid ester compounds which are useful as short-acting wherein: Sedative hypnotic agents for anesthesia and Sedation. This R" is selected from the group consisting of (C-C)alkyl, invention is also directed to pharmaceutical compositions (C-C)alkenyl, (C-C) alkynyl, (C-C)cycloalkyl comprising Such compounds, methods for using Such com (C-C)alkyl, phenyl, and benzyl; pounds for inducing or maintaining anesthesia or Sedation; R° and Rare each independently selected from the group consisting of (C.C)alkyl, (C-C)alkenyl, and (C-C) and intermediates for preparing Such compounds. alkynyl, or R and R, together with the nitrogen atom to 2. State of the Art 25 which they are attached, form a heterocyclic ring having from 5 to 7 atoms; and Propofol, 2,6-diisopropylphenol, (Diprivan(R) Injectable R" is selected from the group consisting of (C-C)alkyl, Emulsion, AstraZeneca) is an injectable anesthetic that has (C-C)alkenyl, and (C-C)alkynyl, hypnotic properties. It can be used to induce and maintain provided that the sum of the carbon atoms in R', R, R, general anesthesia and for Sedation. Although propofol is a and R' is greater than 7. widely-used anesthetic, its usefulness is Somewhat limited The invention is also directed to intermediates useful for due to its long and unpredictable post infusion duration of preparing compounds of formula (I). Accordingly, the inven action. This unpredictable duration of action leads to irregu tion provides a compound of formula (II): lar and often long patient recovery times that are undesir 35 (II) able. OH Propanidid 4-(N,N-diethylcarbamoyl)methoxy-3- methoxyphenyl)acetic acid propyl ester), is another inject able anesthetic that has been approved for use in Several 40 countries outside the United States. Although propanidid provides a much shorter and predictable recovery time than propofol, it is not as potent an anesthetic. Additionally, Epontolof), an injectable emulsion formulation of propanidid, provided by Bayer, was withdrawn from the 45 market in Great Britain in 1983 because of concern over anaphylactoid reactions. Thus, in Spite of the fact that wherein R and R" are as defined herein and R is hydrogen propanidid provides Shorter and more predictable recovery or hydroxyl. times than propofol, it has not been accepted widely as an The invention further provides a pharmaceutical compo injectable anesthetic. 50 Sition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula Currently there is a need for novel injectable anesthetic (I). agents. Preferred agents will have a shorter and more The compounds of the invention are highly effective predictable duration of action than propofol. Preferred Short-acting Sedative hypnotic agents for use in the induction agents will also be more potent than propanidid. 55 and maintenance of anesthesia and Sedation. Accordingly, the invention also provides a method for inducing or main taining anesthesia or Sedation in a mammal, comprising SUMMARY OF THE INVENTION administering to the mammal an effective amount of a compound of the invention. The invention also provides a Applicants have discovered novel Substituted phenylace 60 method for inducing or maintaining anesthesia or Sedation in tic acid ester compounds which are useful as short-acting a mammal, comprising administering to the mammal an Sedative hypnotic agents. The agents have a shorter and effective amount of a pharmaceutical composition of the more predictable duration of action than propofol and are invention. also more potent than propanidid. 65 BRIEF DESCRIPTION OF THE DRAWINGS Accordingly, this invention provides a compound of for FIG. 1 compares the dose in mg/kg of compounds of the mula (I): invention to produce a mean loSS of righting refleX of 2 US 6,887,866 B2 3 4 minutes in rats with the dose required of the prior art The term “opioid” refers to synthetic narcotics that have compound, propanidid. opiate-like activities (e.g., analgesia), but are not derived FIG. 2 compares the total recovery time in minutes from opium. following termination of infusions of 20 minutes, 3 hours, The term "short-acting as used herein refers to agents and 5 hours in rats of compound 1 of the present invention that are pharmacokinetically responsive. When short-acting with the recovery time following termination of infusion of agents are administered by infusion, the effects of the agents the prior art compounds propanidid and propofol. cease promptly upon termination of the infusion. DETAILED DESCRIPTION OF THE While a broad definition of the invention is set forth in the INVENTION Summary of the Invention, certain agents or compositions When describing the compounds, compositions and meth may be preferred. Specific and preferred values listed herein ods of the invention, the following terms have the following for radicals, Substituents, and ranges are for illustration only; meanings, unless otherwise indicated. they do not exclude other defined values or other values The term “(C-C) alkyl” refers to a monoradical within defined ranges for the radicals and Substituents. branched or unbranched Saturated hydrocarbon chain having 15 A preferred agent that can be incorporated into the com from 1 to 6 carbon atoms. This term is exemplified by groups positions of the invention and that can be administered Such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso according to the methods of the invention is a compound of butyl, n-hexyl, and the like. As used herein, “Me” represents formula (I) as described above, wherein the sum of the methyl, “Et” represents ethyl, “propyl and “Pr” represent number of carbon atoms in R', R, R, and R" ranges from n-propyl, and "iPr' represents iso-propyl.
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