WO1994000432A1 - Derives d'epinephrine anorexiques - Google Patents

Derives d'epinephrine anorexiques Download PDF

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Publication number
WO1994000432A1
WO1994000432A1 PCT/US1993/006250 US9306250W WO9400432A1 WO 1994000432 A1 WO1994000432 A1 WO 1994000432A1 US 9306250 W US9306250 W US 9306250W WO 9400432 A1 WO9400432 A1 WO 9400432A1
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Prior art keywords
rats
alkyl
acetyl
methylepinephrine
hydroxy
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PCT/US1993/006250
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English (en)
Inventor
Shu Yuan Yeh
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The United States Of America, Represented By The Secretary, Department Of Health And Human Services
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Priority to AU46597/93A priority Critical patent/AU4659793A/en
Publication of WO1994000432A1 publication Critical patent/WO1994000432A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

  • This invention relates to certain novel and valuable chemical products, namely certain substituted hydroxybenzylalcohols, such as metaraminol-derivatives and their phar aceutically-acceptable salts.
  • the invention further relates to pharmaceutical compositions useful for weight reduction in mammals that include as their active ingredient certain substituted hydroxybenzylalcohols, such as metaraminol, metaraminol derivatives, ⁇ - methylnorepinephrine, o-methyl-epinephrine, or N- substituted ⁇ -methylepinephrine-related compounds.
  • the invention further relates to the use of these chemical products and pharmaceutical compositions as anorectic agents for mammals.
  • Metaraminol a potent sympathomimetic amine that increases both systolic and diastolic blood pressure, is the active ingredient of the prescription drug Aramine®.
  • the d: g is used by the medical profession to elevate or maintain blood pressure in patients.
  • Aramine® is for prevention and treatment of the acute hypotensive state occurring with spinal anesthesia.
  • Aramine® is also indicated as. adjunctive treatment of hypotension due to hemorrhage, reactions to medications, surgical complications, and shock associated with brain damage due to trauma or tumor. 1992 Physicians' Desk Reference at 1424.
  • U.S. Patent No. 1,995,709 relates to certain monohydroxyphenylpropanolamines and their synthesis, including metaraminol, which were noted later to be valuable therapeutic agents for increasing blood pressure and in reducing viral- or hay fever-induced congestion in such tissues as the nasal mucosa.
  • U.S. Patent No. 4,988,710 relates to compounds and methods to protect against cholinergic neurotoxins, said compounds including certain arylalkanolamines.
  • U.S. Patent No. 5,059,422 relates to compositions for the parenteral administration of certain phenylethanolamine derivatives.
  • U.S. Patent No. 3,313,687 discloses certain aminoalkanones as appetite-suppressing agents (wherein the compounds are distinct from those disclosed in the present invention)
  • a number of references disclose compounds that act to encourage an animal to eat more, increase the growth rate, or to alter the ratio of lean to fat ratios in an animal's muscles.
  • U.S. Patent No. 4,404,222 relates to a method of administration of certain arylethanola ines for enhancing the growth rate of meat-producing animals and improving the efficiency of feed utilization in animals so treated.
  • 4,407,819 relates to a method for increasing deposition of lean meat and/or improving lean meat to fat ratios in warm-blooded animals by administration of certain phenylethanolamine derivatives and acid addition salts thereof.
  • U.S. Patent No. 3,818,101 discloses a compound related to applicants* compound that creates a pathologic desire to eat.
  • Ary1-4-piperidinyl-methanols ha e also been reported in the patent literature.
  • U.S. Patent No. 2,833,775 relates to substituted piperidines having antihistaminic, antispasmodic, antiacetylcholine, and analgesic activity, to intermediates, and to methods of preparation.
  • 2,928,835 relates to esters of 2-piperidylphenyl-substituted methanols and ethanols, useful for their stimulatory effect on the central nervous system, such as antibarbituric and locomotor activities.
  • U.S. Patent No. 3,632,767 relates to certain 4-substituted piperidines used as antidepressants in mammals.
  • U.S. Patent No. 3,705,169 relates to hydroxyphenyl-2- piperidinylcarbonols that have ⁇ -adrenergic stimulant and selective bronchodilating activities.
  • 4,783,471 relates to N-aralkyl piperidinemethanol derivatives that inhibit the binding of serotonin to the 5HT 2 receptor site, methods of preparation, and methods of use.
  • the '471 compounds are noted for use as an antifibrillatory agent (used to determine antiarrhythmic properties) and as a topical anesthetic.
  • U.S. Patent No. 4,877,798 relates to a new use of compounds disclosed in the '471 patent, that being for treatment of fibromyalgia.
  • U.S. Patent No. 4,912,117 relates to another new use for compounds disclosed in the '471 patent, that being for treatment of certain cardiac disorders, such as variant angina, fibrillation and other sorts of arrhythmia.
  • U.S. Patent No. 5,021,428 relates to yet another new use for compounds disclosed in the '471 patent, that being the prophylactic treatment of migraine headache.
  • hydroxybenzylalcohols have been noted in the technical literature, however, it has neither been noted nor suggested that such compounds have anorectic activity.
  • MDA 4-methylenedioxyamphetamine
  • MDMA 3,4- methylenedioxymethamphetamine
  • 3-Hydroxy-4-methoxymethamphetamine, 4- hydroxy-3-methoxymethamphetamine, ⁇ -methyl-N- methyldopamine (3,4-dihydroxymethamphetamine) , 4-hydroxy- 3-methoxyamphetamine, and MDA have been identified as metabolites of MDMA in rats both in vivo and in vitro and in the urine of humans. See M. Hiramatsu, et al., J. Pharmacol. Exp. Ther. 254; 521-527 (1990) ; H.K. Lim, et al., Chem. Res. Toxicol. .1: 370-378 (1988); M.Y.
  • o-Methyl-N-methyldopamine and ⁇ - methyldopamine may undergo beta- hydroxylation in the body to form ⁇ -methylepinephrine and ⁇ -methylnorepinephrine, respectively.
  • U.S. Patent No. 5,055,460 shows the use of ephedrine in conjunction with caffeine and aspirin and U.S. Patent No. 4,843,071 discloses the treatment of obesity with tyrosine and a norepinephrine re-uptake inhibitor.
  • U.S. Patent No. 3,357,885 discloses an appetite-inhibiting composition containing a phenethylamine together with an aminoalkylpolycyclic compound. More remotely related compounds which are diaromatic secondary amines for obesity treatment and weight loss control are disclosed in U.S. Patent Nos. 4,478,849, 4,396,627, 4,602,044 and 4,391,826.
  • the principal object of the present invention is to provide certain hydroxybenzylalcohol compounds, pharmaceutical compositions and methods of effecting weight reduction in mammals which do not have a CNS stimulatory effect.
  • the present invention is predicated on the discovery that hyroxybenzylalcohol derivatives comprised of epinephrine-derivatives, metaraminol, and metaraminol derivatives are useful for body-weight reduction in mammals without CNS stimulatory effect observed with other compounds previously known and used in the art.
  • amphetamine and N-substituted amphetamine-related compounds such as methamphetamine, benzphetamine and phentermine, etc.
  • amphetamine and N-substituted amphetamine-related compounds such as methamphetamine, benzphetamine and phentermine, etc.
  • all of the compounds of the present invention and especially ⁇ -methylnorepinephrine ( ⁇ -MeNorEpi) and ⁇ - methylepinephrine ( ⁇ -MeEpi) which are analogues of amphetamine and methamphetamine, are potent anorectic agents without the CNS stimulatory effect.
  • novel hyroxybenzylalcohols pharmaceutical compositions which include as the active ingredient the novel hyroxybenzylalcohol and method of using the novel hyroxybenzylalcohols for effecting weight reduction of a mammal are provided.
  • the present invention provides novel pharmaceutical compositions and methods for effecting body-weight reduction in mammals with certain hydroxybenzylalcohols, particularly epinephrine derivatives, metaraminol, and metaraminol derivatives.
  • Figure 1 shows body weight reduction of rats treated with MDA, MDMA and their putative metabolites, 4-hydroxy- 3-methoxy-amphetamine, ⁇ -methyldopamine, ⁇ - methylnorepinephrine, ⁇ -methylepinephrine and saline.
  • Figures 2A-2C show the food intake of rats treated with ⁇ -methylepinephrine at 8:00 hours for three consecutive days.
  • Figure 3 shows a comparison of the body weights of saline control rats with the body weights of ⁇ - methylepinephrine-treated rats at 8:00 hours for three consecutive days.
  • Figure 4 shows the body weight of rats after food deprivation for three consecutive days.
  • Figure 5 shows current horizontal activity of rats where treatment started in the morning with ⁇ - ethylepinephrine in comparison to treatment with saline.
  • Figure 6 shows cumulative locomotor activity of rats treated with ⁇ -methylepinephrine in comparison to treatment with saline.
  • Figures 7A-7C show the water intake of rats administered ⁇ -methylepinephrine compared to the rats administered saline.
  • Figures 8A-8L show the food intake of rats administered ⁇ -methylepinephrine at 18:00 hours daily over a 3-day period.
  • Figure 9 shows the change in body weight of rats administered ⁇ -methylepinephrine at 18:00 hours daily for three consecutive days compared to rats administered saline.
  • Figure 10 shows current horizontal activity of rats treated with ⁇ -methylepinephrine compared to rats treated with saline following dosing at 18:00 hours.
  • Figure 11 shows cumulative horizontal activity of rats treated with ⁇ -methylepinephrine compared to rats treated with saline following dosing at 18:00 hours.
  • Figures 12A-12L show the food intake of rats administered ⁇ -methylepinephrine at 8:00 and 18:00 hours daily.
  • Figure 13 shows the body weight change in rats with varying dosages of subcutaneously injected ⁇ - methylepinephrine at 8:00 and 18:00 hours.
  • Figure 14 shows the rate of growth for rats injected subcutaneously with varying dosages of ⁇ - methylepinephrine.
  • Figure 15 shows the current horizontal activity of rats treated with injections of ⁇ -methylepinephrine at 8:00 and 18:00 hours.
  • Figure 16 shows the cumulative horizontal activity of rats treated with injections of ⁇ -methylepinephrine at 8:00 and 18:00 hours.
  • Figure 17 shows the dose-response curve of ⁇ - methylepinephrine for the inhibition of food intake.
  • Figures 18A-18L show the food intake of rats administered ⁇ -methylnorepinepherine at 18:00 hours over a 3-day period.
  • Figures 19A-19L show the inhibition of food intake after administration of ⁇ -methylnorepinepherine at 8:00 and 18:00 hours over a 3-day period.
  • Figure 20 shows the change in body weight of rats treated with ⁇ -methylnorepinepherine at 18:00 hours daily for three consecutive days.
  • Figure 21 shows the change in the body weight of rats treated with 0.1 to 2.5 mg/kg of ⁇ -methylnorepinepherine at 8:00 and 18:00 hours daily for three consecutive days.
  • Figure 22 shows the rate of growth of rats treated with 0.1 to 2.5 mg/kg of ⁇ -methylnorepinepherine at 8:00 and 18:00 hours daily for three consecutive days.
  • Figure 23 shows the current locomotor activity of rats treated at 8:00 and 18:00 hours with ⁇ - methyInorepinepherine.
  • Figure 24 shows the cumulative locomotor activity of rats treated at 8:00 and 18:00 hours with ⁇ - methylnorepinepherine.
  • Figure 25 shows the dose-response curve of ⁇ - ethyInorepinepherine on the inhibition of food intake.
  • Figures 26A-26L show the effect of metaraminol on food intake in rats administered the drug at 18:00 hours over a 3-day period.
  • Figure 27 shows the dose-response curve of metaraminol for suppression of food intake in non-food deprived rats.
  • Figures 28A-28D show the effect of metaraminol on food intake in fasted rats.
  • Figure 29 shows the dose-response curve of metaraminol for suppression of food intake in fasted-rats.
  • Figures 30A and 30B show the effect of metaraminol on body weight (30A) and growth rate (30B) in rats.
  • Figures 31A and 3IB show the effect of metaraminol on locomotor activity.
  • Figures 32A-32C show the effect of metaraminol on water intake in rats.
  • the following detailed description of the invention is provided to aid those skilled in the art in practicing the present invention, which generally relates to certain novel and valuable chemical products, namely certain piperidine-containing, substituted hydroxybenzylalcohols and their pharmaceutically-acceptable salts.
  • the invention further relates to pharmaceutical compositions useful for weight reduction that alternatively contain as the active ingredient one of these chemical products or other substituted hydroxybenzylalcohols, such as metaraminol, ⁇ -methylepinephrine, ⁇ -methylnorepinephrine, and N-substituted ⁇ -methylnorepinephrine related compounds.
  • the invention also relates to the use of these pharmaceutical compositions as anorectic agents for mammals.
  • the present invention provides novel hydroxybenzylalcohol derivatives, which are useful for body weight reduction in mammals without CNS stimulatory effect.
  • the novel hydroxybenzylalcohol derivatives are of the formula:
  • R lf R 2 , R 3 , and R 5 are each independently H, F, Cl, Br, or halogenated alkyl ( ⁇ -C ⁇ ) ;
  • R 4 is H, acetyl, propionyl, benzoyl, alkyl (C- L -C 3 ) , or hydroxyalkyl ( € 2 -0 3 ) ;
  • R 10 is acetyl, propionyl, butyryl, benzyl, N- methylenecyclopropane, or N-methylenecyclobutane.
  • These derivatives may also be in the form of pharmaceutically acceptable salts.
  • compositions comprising hydroxybenzyl ⁇ alcohol derivatives comprised of epinephrine derivatives, metaraminol, and metaraminol derivatives are provided.
  • the pharmaceutical compositions include as their active ingredient an anorectic-effective amount of a substituted hydroxybenzylalcohol of the formula:
  • R lf R 2 , and R 5 are each independently H, hydroxy, F, Cl, Br, or halogenated alkyl ( 0 2 -0 3 ) > R 3 i s H hydroxy, F, Cl, Br, alkoxy (C ⁇ Cs) , benzyloxy, acetyl, propyl, benzoyl, hydroxy lmethyl, methyl, amino, formamido, acetamido, me t hy 1 su 1 f ony 1 am i do , nitro, methy lsulf onylmethy 1 , tr if luoromethy 1 , p- methoxybenzylamino , or an halogenated alkyl (C 1 -C 3 ) ;
  • R 4 is H, F, Cl, hydroxy, acetoxy, propionoxy, benzoyloxy, alkoxy ( ⁇ -0 3 ) , benzyloxy, hydroxyalkoxy
  • R 6 and R 7 are each independently H or alkyl (C ⁇ -
  • R 8 is H, alkyl (C 1 -C 3 ) , acetyl, propionyl, butyryl, benzyl, N-methy lenecyclopr opane , or N- methy lenecyclobutane ;
  • R 9 is H, alkyl ( ⁇ -0 4 ) , acetyl.
  • n is an integer of from 0 to 5 and a pharmaceutically acceptable carrier.
  • anorectic agent defined as above provides a pharmaceutical composition which is suitable for body weight reduction in mammals without CNS stimulatory effect.
  • preferred hydroxybenzylalcohols, including stereoisomers, in accordance with the invention have the formula:
  • ⁇ is R, F, Cl or hydroxy
  • R is hydroxy, alkoxy (0 2 -0 3 ) , benzyloxy, acetyl, propyl, benzoyl, hydroxylmethyl, methyl, amino, formamido, acetamido, methylsulfonylamido, nitro, methylsulfonylmethyl, trifluoromethyl, or p-methoxybenzylamino
  • R 3 is hydroxy, alkoxy (C 1 -C 3 ) , benzyloxy, acetyl, propyl, benzoyl, hydroxylmethyl,, methyl, amino, formamido, acetamido, methylsulfonylamido, nitro, benzyloxy, methylsulfonylmethyl , trifluoromethyl , or p-methoxybenzylamino
  • R 2 and R 3 together may form alkylene dioxyl ( ⁇ -0 3 )
  • R lf R 2 , R 3 and R 5 are each independently H, F, Cl,
  • R 4 is hydroxy, acetoxy, propionoxy, benzoyloxy, alkoxy ( ⁇ -0 3 ) , hydroxyalkoxy (C x -
  • R 6 and R 7 are each independently H or alkyl (C x - C 3 ) ;
  • R 8 and R 9 are each independently H, alkyl ( ⁇ -0 3 ) , acetyl, propionyl, butyryl, benzyl, N- methylenecyclopropane, or N-methylenecyclobutane;
  • R 10 is acetyl, propionyl, butyryl, benzyl, N- methylenecyclopropane, or N-methylenecyclobutane;
  • n is an integer of from 0 to 3.
  • the alkyloxylamine side chain of Formula Ilia may be in cyclic form where n is 5 and R 6 is hydrogen or alkyl resulting in compounds such as 4(3,4-dihydroxyphenyl)- methoxypiperidinyl derivatives.
  • R 2 is hydrogen.
  • R 2 and R 3 are each hydroxy, R is methyl, R 5 is hydrogen, R 6 is methyl or hydrogen, and R 7 is hydrogen.
  • Particularly preferred anti-obesity and anorectic agents are N-substituted catecholamine derivatives having the formula:
  • R 4 is CH 3 or C 2 H 5 ;
  • R 5 is H, CH 3 , or C 2 H 5 ;
  • R 6 is H, CH 3 , C 2 H 5 , or C 3 H 7 ;
  • R 7 is H, CH 3 , C 2 H 5 , C 3 H 7 , or CH 2 C 6 H 5 .
  • the most preferred anti-obesity and anorectic agents are ⁇ -methylepinephrine, ⁇ -methylnorepinephrine, and metaraminol.
  • a method of effecting weight reduction in a mammal in need thereof whereby an anorectic- effective amount of a compound of Formula I, II, Ilia, Illb, or IV.
  • the method comprises the administration to a mammal of a composition which includes the anorectic agent and an acceptable pharmaceutical carrier.
  • the anorectic agents of the present invention can be used in any suitable dosage form, including tablets, powders and capsules, and may be formulated with any suitable carriers, excipients, flavors, etc. , so long as they are pharmaceutically acceptable.
  • the dosage unit is in the form of a tablet or powder, there may be present various pharmaceutically acceptable binders, fillers or other solid diluents.
  • the capsule may be either the hard or soft variety and may be made of any suitable capsule material which will disintegrate in the digestive tract. Examples of such encapsulating materials are gelatin and methylcellulose.
  • the capsule may contain, in addition to the anorectic agent, a liquid carrier such as fatty oil. The following Examples are illustrative of the anorectic effect of the compounds discussed herein.
  • Examples 1-4 illustrate the anorectic effect of epinephrine-type substituted hydroxybenzylalcohols.
  • Examples 5-13 illustrate the anorectic effect of metaraminol-type substituted hydroxybenzylalcohols.
  • Example 14 and Table 4 are directed to methodology whereby the rat-model data disclosed herein can be used for human application.
  • Examples 2, 3, 5, 6 and 11 provide methods and results that demonstrate the absence of CNS activity when the present invention for weight reduction was used.
  • Example 1 This experiment illustrates effective body weight reduction by ⁇ -methylepinephrine, MDA, MDMA and ⁇ - methylnorepinephrine.
  • Materials: ( ⁇ )3,4-Methylenedioxyamphetamine HCl (MDA) and ( ⁇ )3,4-methylenedioxymethamphetamine (MDMA) were obtained from the National Institute on Drug Abuse.
  • MDA Methylenedioxyamphetamine
  • MDMA ⁇ -methylenedioxymethamphetamine
  • ⁇ - Methylnorepinephrine HCl, ⁇ -methylepinephrine HCl and ⁇ - ethyldopamine were provided by Sterling-Winthrop Research Institute (Rensselaer, NY) and Merck Sharp & Doh e Research Institute (West Point, PA) .
  • 4-Hydroxy-3- methoxyamphetamine was synthesized by condensation of vanillin with nitroethane to form ⁇ -nitrostyrene and reduction with lithium aluminum hydride according to the procedure of F.A. Ramirez, et al. (J. Am. Chem. Assoc. 22.:2781-2803 (1988)), which has been described previously by Yeh et al., supra.
  • mice Male Sprague-Dawley rats (Harlan Indianapolis, IN, 200-225 g) were housed 3 per propylene cage in an air-conditioned room (22°C) with 12 hour light- dark cycle with food and water provided ad libitum. Drug dissolved in saline was injected subcutaneously at a consentration 10 mg/kg (as base), twice daily (at 8:00 and 18:00 hours), for either 5 (MDA and its metabolites) or 7 (MDMA and its metabolite and saline) consecutive doses. All animals were housed for one week after arrival before being used for an experiment. Six rats were used for each group and weighed once daily, in the morning.
  • the altered body weight was expressed as per 100 gm of the initial weight since the body weight of rats varied slightly at the beginning of the experiment.
  • the rats lost 8.05%, 6.82%, 6.07% and 9.68% of their initial body weight following the administration of two doses of MDA, ⁇ -methylnorepinephrine, MDMA, and ⁇ -methylepinephrine, respectively, whereas the rats in the saline control group gained 3.34% of the body weight.
  • 4-Hydroxy-3- methoxyamphetamine and ⁇ -methyldopamine had no effect on body weight.
  • This experiment illustrates anorectic and stimulatory effects of ⁇ -methylepinephrine in rats.
  • ⁇ -Methylepinephrine was obtained from Sterling-Winthrop Research Institute (Rensselaer, NY) .
  • Animal treatments Male Sprague-Dawley rats (Harlan Industries, Indianapolis, IN, weighing 300 ⁇ 10 g) , 3 per propylene cage with free access to food (Purina chow) and water, were housed in an air-conditioned room (22°C) with 12/12 hour light dark cycle (light on at 7:00 and off at 19:00). All animals were housed for at least one week after arrival before being used for an experiment.
  • Protocol 1 Rats were transferred from the vivarium to a quiet laboratory, weighed and placed individually in an activity monitor (40X40X30 cm: Digiscan Optical Animal Activity Monitor, model RXY, Omnitech Electronics, Inc., Columbus OH) . Preweighed ground chow (in Hoffman cup) and preweighed water (in Hoffman cup) were provided ad libitum in the monitor.
  • the rats were taken out of the monitor, injected subcutaneously with a dose of ⁇ -methylepinephrine, 0.1 to 10 mg/kg, dissolved in acid-saline (0.9% of NaCl in 0.01 N HCl) in a volume of 2 ml/kg, or saline, and placed back in the monitor.
  • Horizontal (including ambulatory and repetitive movement) and ambulatory activities were monitored immediately in one hour intervals for a period of 24 hours following dosing.
  • Horizontal and ambulatory activity were registered every hour by a Dataloger. No one entered the lab during the experimental period.
  • the rats were transferred to the vivarium, injected subcutaneously daily with a dose of drug and placed individually into a metabolic cage (Nalge Co. , Rochester, NY) provided with preweighed ground chow and preweighed water.
  • the rats were transferred to propylene cages with food and water provided ad libitum.
  • the rats were deprived from food but not water. Food and water intake were quantified every 24 hours for the first 3 days and body weight every 24 hours for the whole experimental period by subtracting the weight of the remaining food, water and body weight from the initial weight. Saline was used for control rats.
  • Protocol 2 The results obtained from protocol 1 indicate that ⁇ -methylepinephrine is a potent anorectic agent without stimulatory effect. In consideration of the behavior of rats that eat at night and rest during daytime, anorectic effect of ⁇ -methylepinephrine may be diminished when it was injected in the morning. Protocol 2 extended the studies of protocol 1 except that ⁇ - methylepinephrine ( ⁇ -MeEpi) was injected subcutaneously at 18:00. On day 2 and 3, the food intake of rats was measured at 1, 3, 14 and 24 hour intervals after dosing. Water intake and body weight of rats were recorded daily.
  • Protocol 3 Rats were injected subcutaneously with various doses of ⁇ -methylepinephrine twice daily at 8:00 and 18:00 hours, starting in the morning. The food intake was measured at 10 hours after the first injection and at 1, 3, 14 and 24 hour intervals after the evening injection. Water intake and body weight were recorded daily.
  • Food intake The food intake of rats treated with ⁇ -methylepinephrine daily in the morning for 3 days is shown in Figures 2A-2C. After drug treatment for one day, the food intake of rats treated with saline, 0.1, 1, 5 and 10 mg/kg of ⁇ -methylepinephrine was 19.75 ⁇ 2.46 g, 25.75 ⁇ 3.38 g, 16.5 g ⁇ 1.15 g, and 3.25 ⁇ 0.75 g, respectively.
  • the food intake of rats treated with 10 mg/kg of ⁇ -methylepinephrine for one day was significantly decreased than that of rats treated with saline or with 0.1, 1.0 and 5 mg/kg of ⁇ -methylepinephrine at levels of p ⁇ 0.01, p ⁇ 0.01, p ⁇ 0.01, and p ⁇ 0.01, respectively.
  • the food intake of rats treated with 5, or 1.0 and 0.1 mg/kg of ⁇ -methylepinephrine was not significantly different from that of saline treated rats.
  • Efficacy of ⁇ -methylepinephrine on inhibition of food intake The ED 50 of ⁇ -methylepinephrine on inhibition of food intake of rats at 1, 3, 6, 14, and 24 hour intervals was estimated to be ⁇ 0.24, 0.30, 0.35, 0.68, and 2.74 mg/kg, respectively.
  • the rats administered a large dose (10 to 20 mg/kg) of ⁇ -methylepinephrine appeared to have respiratory difficulty, laid prone on the floor of the cage and showed piloerection. Five out of 11 rats died after being administered two consecutive doses (8:00 and 18:00 hours) of 20 mg/kg of the drug.
  • the LD 50 value of ⁇ - methylepinephrine estimated to be larger than 20 mg/kg, will be established when drug is available.
  • the efficacy of ⁇ -methylepinephrine, based on the LD 50 value of 20 mg/kg, at 3, 14 and 24 hours was estimated to be 67, 29 and 7.3 respectively.
  • FIG. 17 shows the ED 50 of ⁇ - methylepinephrine on inhibition of food intake.
  • the food intake of rats injected subcutaneously with various doses of ⁇ -methylepinephrine once in the evening (N 4) is shown.
  • the body weight of food-deprived rats decreased 15 g per day, and 47 ⁇ 2.04 g for a three day period (Figure 4) . These data are comparable to the body weight lost after subcutaneous injection of ⁇ -methylepinephrine twice daily for 5 consecutive doses, observed previously.
  • Water intake The water intake (about 40 g/day) of rats administered with 0.1 to 10 mg/kg of ⁇ - methylepinephrine was not significantly different from that of rats treated, with saline ( Figures 7A-7C) .
  • the body weight change of rats injected subcutaneously with 5, or 10 mg/kg of ⁇ - methylepinephrine twice daily for 3 consecutive days was significantly decreased on days 1 to 9.
  • the body weight change of rats injected subcutaneously with 20 mg/kg of ⁇ -methylepinephrine twice daily for one day was significantly decreased on days 1 to 13.
  • the body weight of rats treated with " 20 mg/kg of ⁇ - methylepinephrine twice daily for one day returned to the original weight (Figure 13) .
  • the rate of growth of saline control rats was about 3 g per day and the curve of growth rate was very smooth.
  • the growth rate of rats injected subcutaneously with 1 to 20 mg/kg, especially 5 to 20 mg/kg, of ⁇ -methylepinephrine was up and down which indicates the change of eating behavior ( Figure 14) .
  • Locomotor activity As compared with that of saline controls, the current horizontal activity of rats treated with 5 or 10 mg/kg of ⁇ -methylepinephrine twice daily showed a trend toward decrease from one to 23 hour periods and was significantly decreased at 12, 13, 15, 16, 20, 22 and 23 hour intervals ( Figure 15) . The cumulative horizontal activity of rats treated with 5 or 10 mg/kg of ⁇ -methylepinephrine was significantly decreased from 12 to 23 hour intervals following dosing ( Figure 16) .
  • Water intake of rats administered ⁇ -methylepinephrine twice daily The water intake of rats injected subcutaneously with 1 to 10 mg/kg of ⁇ -methylepinephrine twice daily was not significantly different from that of saline control. The water intake of rats injected SC with 20 mg/kg of ⁇ -methylepinephrine twice daily for one day was significantly decreased on days 1 to 3 from that of saline control.
  • This experiment illustrates anorectic and stimulatory effects of ⁇ -methylnorepinephrine in rats.
  • the rats were injected subcutaneously with a dose of drug once at 18:00 hours or twice at 8:00 and 18:00 hours daily for 3 days, placed individually into a metabolic cage (Nalge Co. Rochester, NY) , and provided with preweighed ground chow and preweighed water following the dosing. On day 4 the rats were transferred to propylene cages with food and water provided ad libitum.
  • rats were transferred from the vivarium to a quiet laboratory, weighed and placed individually in an activity monitor (40X40X30 cm: Digiscan Optical Animal Activity Monitor, model RXY, Omnitech Electronics, Inc., Columbus, OH).
  • Preweighed ground chow (in Hoffman cup) and preweighed water (in Hoffman cup) were provided ad libitum in the monitor. After an exploratory period of about 30 minutes, the rats were taken out from the monitor, injected subcutaneously with a dose of ⁇ -methylnorepinephrine, 0.1 to 10 mg/kg, dissolved in acid-saline (0.9% of NaCl in 0.01 N HCl), or saline, in a volume of 2 ml/kg, and placed back in the monitor. Horizontal (including ambulatory and repetitive movement) and ambulatory activities were monitored immediately in one hour intervals for a period of 23 hours following dosing. Horizontal and ambulatory activity were registered every hour by a Dataloger.
  • ⁇ -methylnorepineprine After subcutaneous injection of 1 to 2.5 mg/kg of ⁇ -methylnorepinephrine twice daily, the food intake of rats was significantly inhibited from 3 to 24 hour intervals from days 1 to 3 ( Figures 19A-19L) .
  • Efficacy of ⁇ -methylnorepineprine ED 50 of ⁇ -methy1- norepineprine for inhibition of food intake at the 1, 3, 14 and 24 hour interval was estimated to be 0.76 mg/kg, 0.79 mg/kg, 1.96 mg/kg and 2.60 mg/kg, respectively.
  • the anorectic effect of ⁇ (-)3,4-dihydroxynorephedrine is comparable to that of ⁇ -methylnorepinephrine.
  • LD 50 of (-)3,4-dihvdroxynorepinephrine The rats administered with 5 to 10 mg/kg of (-)3,4- dihydroxynorephedrine appeared to have respiratory difficulty, laid prone on the floor of the cage and showed piloerection. After subcutaneous injection of 20 mg/kg of (-)3,4-dihydroxynorephedrine, only one rat survived for more than 14 days; one died at 30 hours; two died at about 32 hours; 6 died between 32 and 46 hours following the drug administration.
  • the growth rate of rats treated with various doses of ⁇ -methylnorepinephrine once daily was not significantly different from that of saline control rats (data not shown) .
  • the body weight of rats treated with 2.5 mg/kg of ⁇ -methylnorepinephrine twice daily was significantly decreased from days 1 to 10 (p ⁇ 0.01) ( Figure 21).
  • the body weight of rats treated with 1.0 mg/kg of ⁇ -methylnorepinephrine twice daily showed a trend toward decrease and was significantly decreased at days 3, 6, 7 and 9 after drug administration.
  • the body weight of rats treated with 1.0 mg/kg of ⁇ -methylnorepinephrine twice daily showed a trend toward decrease (Figure 21) .
  • the growth rate of rats treated with 2.5 mg/kg of ⁇ - methyInorepinephrine, twice daily was significantly decreased at days 1, 2, and increased on days 4 and 8 from that of saline control rats ( Figure 22) .
  • the growth rate of saline control rats was about 3g per day and the growth rate curve was very smooth.
  • the growth rate of rats injected subcutaneously with 2.5 mg/kg of ⁇ - methyInorepinephrine was up and down, which may indicate the change in eating behavior.
  • the growth rate of rats treated with 0.25 and 1.0 mg/kg of ⁇ -methylnorepinephrine, twice daily, showed a trend toward decrease.
  • the growth rate of rats treated with various doses of ⁇ - meth Inorepinephrine, once daily, showed a trend toward decrease (data not shown) .
  • Locomotor activity The current locomotor activity of rats treated with 1.0 mg/kg ⁇ -methylnorepinephrine twice daily showed a trend toward decrease and was significantly decreased at hour 12, 14, 16 and 22 following the dosing from that of rats treated with saline ( Figure 23) . Decreasing locomotor activity of rats administered ⁇ -methylnorepinephrine appears due to suppression of eating activity since the time of decreasing locomotor activity coincides with the eating time (at 19 hours which is after the lights were turned off) .
  • Example 4 This experiment demonstrates a method whereby the epinephrine-type substituted hydroxybenzylalcohols can be synthesized. Procedural detail can be added by one of ordinary skill in the art of organic chemical synthesis.
  • 3,4-dihydr ⁇ benzylaldehyde was converted to 3,4- dibenzyloxybenzyladehyde, which was then ⁇ reacted with C 2 H 5 MgI to form 3,4-dibenzyloxyphenylisopropanol.
  • Dehydration of 3,4-dibenzyloxyphenylisopropanol forms 3,4- dibenzyloxyphenylisopropylene.
  • Treat 3,4- dibenzyloxyphenylisopropylene with NBS and water to produce a bromohydrin that was subsequently reacted with ammonia or methylamine and alkylamines (RNH 2 ; R C n H n+2 .
  • n 1 to 4) to form 3,4-dibenzyloxyphenylisopropanol-amine or 3,4-dibenzyloxyphenylisopropanolmethylamine and various 3 , 4-dibenzyloxyphenylisopropanolamine analogs, respectively, and finally hydrolyzed to yield ⁇ - methyInorepinephrine, or ⁇ -methylepinephrine and various ⁇ -methylepinephrine analogs.
  • 3,4- dibenzyloxybenzylaldehyde was treated with ethyl 2- bromopropionate and zinc, and subsequently treated with hydrazine hydrate to yield a hydrazide of 3,4- dibenzyloxyphenylhydra( ⁇ -methy1)acrylic acid. Nitration of the hydrazide yields a 5-(3,4-dibenzyloxyphenyl-4- methyl-2-oxazolidone. N-methylation of 5-(3,4- dibenzyloxyphenyl-4-methyl-2-oxazolidonewithmethylsufate forms 5-(3,4-dibenzyloxyphenyl)-4-methyl-N-methyl-2- oxazolidone.
  • the rats were injected subcutaneously with a dose of 10 mg/kg (as base) for 5 or 7 consecutive doses. ***, and ** indicate significant differences at p ⁇ 0.001, and p ⁇ 0.01, respectively, from the saline control group.
  • mice Male Sprague-Dawley rats (Harlan Industries, Indianapolis, IN, weighing 300 ⁇ 10 g) were housed, 3 per propylene cage with free access to Purina Chow and water, in an air-conditioned room (22 ⁇ 1°C) with 12/12 h light dark cycle (light on at 7:00 and off at 19:00). All animals were housed for at least one week after arrival before being used for an experiment.
  • the rats were transferred to propylene cages with food and water provided ad libitum. Following drug administration, food intake at 1, 3, 14, and 24 h time intervals was quantified by subtracting the weight of the remaining food from the initial weight of food at each time period for 3 days. Water intake every 24 hr for 3 days and body weight alteration every 24 hr for 10 days were also quantified by the same procedure. For studying the anorectic effect of the drug in rats that were fasted for 24 h, the rats were injected with the drug once. The food and water intake and change of body weight were monitored for 24 h.
  • rats were transferred from the vivarium to a quiet laboratory. Once in the quiet laboratory, the subject was weighed and placed individually in an activity monitor (40X40X30 CM: Digiscan Optical Animal Activity Monitor, model RXY, Omnitech electronics. Inc., Columbus, OH) . After an exploratory period of at least 30 min, the rats were taken out from the monitor, injected SC with a dose of metaraminol as stated- below, and placed back in the monitor. Horizontal (including ambulatory and repetitive movement) and ambulatory activities were monitored immediately in 10 min intervals for a period of 180 min following each dose. Horizontal and ambulatory activity were registered every 10 min by a Datalogger. Preweighed ground chow (in Hoffman cup) and preweighed water (in Hoffman cup) were provided ad libitum in the monitor. No one entered the lab during the experimental period. Saline was used for control rats.
  • an activity monitor 40X40X30 CM: Digiscan Optical Animal Activity Monitor, model RXY, Omnitech electronics. Inc.
  • the ED 50 of metaraminol on suppression of food intake was calculated from a linear regression curve according to methods known to those skilled in the art.
  • the linear regression curve was obtained by plotting food intake (as percent of the saline control) of rats treated with various dosed quantities of metaraminol versus the log of the quantities.
  • the linear regression curve was analyzed with a BMDP program according to the methods of Dixon et al. , supra.
  • the growth rate of rats was calculated from the difference of body weight at the conclusion of one day from that of the day before. Stimulatory activity data were analyzed for one-way ANOVA statistical significance and t-test with Bonferroni- adjustment for multiple comparisons using a MBDP program. Id.
  • the ED 50 values of metaraminol on suppression of food intake in fasted-rats at 1 and 3 h intervals were calculated to be 3.01 and 3.59 mg/kg, respectively (data presented in Figure 29, wherein the asterisk symbols, * and **, indicate significant differences from that of saline control rats at p ⁇ 0.05 and p ⁇ 0.01 levels, respectively).
  • metaraminol Following administration of a dose of 10 mg/kg of metaraminol, the subject rats appeared to have respiratory difficulty, laid prone on the floor of the cage and showed piloerection. After subcutaneous injection of 10, 20, 25, 30, 35, 40, 50, and 60 mg/kg of metaraminol, one out of 16, eight out of ten, three out of ten, zero out of ten, eight out of ten, six out of ten, seven out of eight, and eight out of eight rats died, respectively, within one week following drug administration. From this data, and using a method known to one of ordinary skill in the art, the 50% lethal dose (LD 50 ) of metaraminol in rats after subcutaneous injection was calculated to be 26.59 mg/kg.
  • LD 50 50% lethal dose
  • the LD 50 value obtained in Example 8 was 26.59 mg/kg.
  • the ED 50 of metaraminol on suppression of food intake in non-food-deprived rats after periods of 1, 3, 14, and 24 h post-injection was calculated to be 0.75 mg/kg, 1.37 mg/kg, 2.43 mg/kg, and 2.85 mg/kg, respectively.
  • the ED 50 after 1 and 3 h post-injection was calculated to be 3.01 mg/kg and 3.59 mg/kg, respectively.
  • Locomotor activity was correlated inversely with food intake. Decreasing locomotor activity of rats administered metaraminol may be due to the suppression of eating activity because the time of decreasing locomotor activity coincides with the usual eating time (after the lights are turned off) .
  • Metaraminol (alternatively known as: ⁇ -(l- aminoethyl) -3-hydroxybenzenemethanol; m- hydroxynorephedrine; m-hydroxypropadrine; - hydroxyphenylpropanolamine; metaradrine; Aramine, etc.) was prepared from hydroxyisonitrosopropiophenone (British patent #353,361).
  • the (-)form of metarminol was prepared from 1-m-hydroxyphenylacetylcarbinol (British patent #396,951; Swiss Patent #162,367; Hartubg et al. U.S. patents #1,948,162, 1,951,302 and 1,995,709; J.Am Chem. Soc. 52:4149-4960 (1931); The Merck Index at 772 (9th ed. 1976) .
  • Metaraminol analogs can be prepared by modification of the procedure for preparation of ⁇ -methylepinephrine as described by Smissman et al. (J. Med. Chem. 14:702-7 (1971)). Metaraminol analogs can also be prepared by modification of the procedure for preparation of phenylephrine as described by Bergmann and Sulzbacher (J. Org. Chem 16:84-89 (1951)). Briefly, 3- benzyloxyphenylisopropylene was prepared by dehydration of 3-benzyloxyphenylisopropanol.
  • n l to 4) to form 3- benzyloxyphenylisopropanolamine and various 3- benzyloxyphenylisopropanolamine analogs which were hydrolyzed to yield metaraminol and various metaraminol analogs.
  • the saline control rats ate 4.99 ⁇ 0.29, 8.89 ⁇ 0.71, 23.85 ⁇ 0.54 And 26.94 ⁇ 0.56 G of food at 1, 3, 14 and 24 h intervals, respectively.
  • the anorectic dosage of amphetamine for treatment of obesity in humans at 3 hour intervals is 10 - 20 mg, according to the "Physicians' Desk Reference” 1992 edition.
  • the anorectic dosages of amphetamine for treatment of obesity in humans is approximately 8 to 15 times the ED 50 value observed in the rats at 3 hour intervals.
  • the anorectic dosages of ⁇ -methylepinephrine and ⁇ - methylnorepinephrine for treatment of obesity in humans at 3 hour intervals can be about 2.5 to 4.5 mg (ED 50 at 3 hour x (8 - 15) and about 6.0 to 12 mg. (ED 50 at 3 hour x (8 - 15) , respectively.
  • a similar analysis can be performed on the metaraminol-type substituted hydroxybenzylalcohol anorectic agents disclosed herein, using methods known to those of ordinary skill.

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Abstract

L'invention concerne certains nouveaux hydroxybenzylalcools substitués contenant de la piperidine et leurs sels pharmaceutiquement acceptable (I). L'invention concerne également des compositions pharmaceutiques de réduction du poids contenant alternativement, comme ingrédient actif, un de ces produits chimiques ou d'autres hydroxybenzylalcools substitués, tels que métaraminol, α-méthylènepinéphrine, α-méthylnorépinéphrine, et des composés apparentés à la α-méthylnorépinéphrine N-substitués de formule (II) où X représente (a) et (b). L'invention concerne également l'utilisation de ces compositions pharmaceutiques comme agents anoréxiques pour mammifères.
PCT/US1993/006250 1992-06-30 1993-06-30 Derives d'epinephrine anorexiques WO1994000432A1 (fr)

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EP0718286A1 (fr) * 1994-12-22 1996-06-26 Bristol-Myers Squibb Company Dérivé de 3-alkoxybenzylpiperidine utiles comme agents mélatonergique

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0718286A1 (fr) * 1994-12-22 1996-06-26 Bristol-Myers Squibb Company Dérivé de 3-alkoxybenzylpiperidine utiles comme agents mélatonergique

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