WO1994000432A1

WO1994000432A1 - Anorectic epinephrine derivatives

Info

Publication number: WO1994000432A1
Application number: PCT/US1993/006250
Authority: WO
Inventors: Shu Yuan Yeh
Original assignee: US Department of Health and Human Services
Current assignee: US Department of Health and Human Services
Priority date: 1992-06-30
Filing date: 1993-06-30
Publication date: 1994-01-06
Anticipated expiration: 1994-12-30
Also published as: AU4659793A

Abstract

The present invention relates to certain novel piperidine-containing, substituted hydroxybenzyl alcohols and their pharmaceutically-acceptable salts (I). The invention further relates to pharmaceutical compositions useful for weigth reduction that alternatively contain as the active ingredient one of these chemical products or other substituted hydroxybenzyl alcohols, such as metaraminol, α-methylepinephrine, α-methylnorepinephrine, and N-substituted α-methylnorepinephrine related compounds of formula (II) where X = (a) and (b). The invention also relates to the use of these pharmaceutical compositions as anorectic agents for mammals.

Description

ANORECTIC EPINEPHRINE DERIVATIVES

FIELD OF THE INVENTION

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, α- methylnorepinephrine, o-methyl-epinephrine, or N- substituted α-methylepinephrine-related compounds. The invention further relates to the use of these chemical products and pharmaceutical compositions as anorectic agents for mammals.

BACKGROUND OF THE INVENTION

An anorectic effect in pharmacology is considered by those skilled in the art to be a result of activity on the central nervous system (CNS) . It has been reported that metaraminol does not exhibit CNS activity. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 7th ed. , at 170. However, the use of metaraminol as an anorectic agent and the use of certain metaraminol derivatives as anorectic agents has not been reported previously. 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. Accordingly, indications and usage for Aramine® are 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.

Arylalkanolamines have been reported in the patent literature. For example, 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. Another example, 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.

Although there is one reference (U.S. Patent No. 3,313,687) that 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. For example, 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. U.S. Patent No. 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. And 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. For example, 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. U.S. Patent No. 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 β-adrenergic stimulant and selective bronchodilating activities. U.S. Patent No. 4,783,471 relates to N-aralkyl piperidinemethanol derivatives that inhibit the binding of serotonin to the 5HT₂ 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.

Certain of the epinephrine-variety substituted hydroxybenzylalcohols have been noted in the technical literature, however, it has neither been noted nor suggested that such compounds have anorectic activity. The hydroxybenzylalcohols, α-methylepinepherine and α- methylnorepinephrine, for instance, have been shown to be downstream metabolic by-products of certain neurotoxins, as follows: The metabolism of certain ring-substituted derivatives of amphetamine and methamphetamine, such as 3 , 4-methylenedioxyamphetamine (MDA) and 3,4- methylenedioxymethamphetamine (MDMA) , has been studied in rats and humans. 3-Hydroxy-4-methoxymethamphetamine, 4- hydroxy-3-methoxymethamphetamine, α-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. Yousif, et al., Drug and Alcohol Dependence 2j5: 127-135 (1990); K. Verebey, et al., J. Am. Med A. 259: 1649-1650 (1988). 4- Hydroxy-3-methoxyamphetamine and α-methyldopamine have been identified as metabolites of MDA in the brain of rats and in the urine of various animal species. See G.M. Marquardt, et al., Biochemical Pharmacol. .27: 1503-1505 (1978); J.K. Midha, et al., Drug Metab. Disp. J5: 143-148 (1977); Yousif, et al., supra.

These metabolites may undergo further processing in vivo, as follows: o-Methyl-N-methyldopamine and α- methyldopamine, like dopamine, may undergo beta- hydroxylation in the body to form α-methylepinephrine and α-methylnorepinephrine, respectively.

Comparative neurochemical and stimulatory effects of MDA with its metabolites, 4-hydroxy-3-methoxyamphetamine, o-methyldopamine and α-methylnorepinephrine, and of MDMA with its metabolites, MDA and α-methylepinephrine have been studied in rats. S.Y. Yeh, et al., Pharmacol. Biochem. & Behav. 39: 787-790 (1991).

There is no disclosure that α-methylepinephrine or α- methylnorepinephrine have ever been used for anti-obesity or weight reduction purposes. Additionally, compounds related to α-methylepinephrine and α-methylnorepinephrine, also known as 2-methylamino-l-(3,4-dihydroxyphenyl)-1- isopropanol and 2-amino-l-(3,4-dihydroxyphenyl)-1- isopropanol, respectively, have not been disclosed for use as anti-obesity or weight reduction compounds. Literature of interest to this discussion of epinephrine-type substituted hydroxybenzylalcohol anorectic agents follows: Epinephrine and N-substituted-amino-1-(3,4- dihydroxyphenyl)-l-ethanol compounds such as isoproterenol have been disclosed in U.S. Patent 4,525,359 as ingredients in a composition that is applied directly to fatty deposits, as by topical application, for elimination of those fatty deposits. Another compound of interest, a dopamine fatty acid conjugate has been disclosed by U.S. Patent 4,939,174 as an appetite suppressing drug.

Other somewhat related drugs have been used as one ingredient in a multi-ingredient composition for appetite inhibition, weight loss control or obesity treatment. For example, 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.

It has also been reported that MDA, MDMA, 4-hydroxy- 3-methoxyamphetamine and α-methyldopamine, unlike α- methylepinephrine, decreased the concentration of serotonin (5-HT) in the frontal cortex. Yeh et al., supra. MDA and MDMA, but not α-methyldopamine, 4-hydroxy- 3-methoxyamphetamine, and α-methylepinephrine, was also found to decrease the concentration of 5- hydroxyindoleacetic acid (5-HIAA) in the frontal cortex. Yeh et al., supra. MDA and MDMA, but not their metabolites (except α-methylepinephrine which increased activity at 15 and 30 minutes) , increased locomotor activity from 15 to 180 minutes following the drug administration. Yeh et al., supra. Heretofore, hydroxybenzylalcohol compounds which have an anorectic effect in mammals and which do not have a CNS stimulatory effect have not been known. Accordingly, 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.

SUMMARY OF THE INVENTION 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. Thus, unlike amphetamine and N-substituted amphetamine-related compounds such as methamphetamine, benzphetamine and phentermine, etc., which are known anorectic agents having strong CNS stimulatory properties, all of the compounds of the present invention and especially α-methylnorepinephrine (α-MeNorEpi) and α- methylepinephrine (α-MeEpi) , which are analogues of amphetamine and methamphetamine, are potent anorectic agents without the CNS stimulatory effect. A group of substituted phenylisopropanolamine derivatives and particularly α-methylnorepinephrine- related compounds, metaraminol, and derivatives thereof, were also discovered to be effective anti-obesity and anorectic agents. In one aspect of the present invention 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.

In another aspect, 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.

These and other features and advantages of the invention will be more readily apparent upon reading the following description of a preferred exemplified embodiment of the invention and upon reference to the accompanying drawings, all of which are given by way of illustration only, and are not limitative of the present invention, wherein:

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows body weight reduction of rats treated with MDA, MDMA and their putative metabolites, 4-hydroxy- 3-methoxy-amphetamine, α-methyldopamine, α- methylnorepinephrine, α-methylepinephrine and saline.

Figures 2A-2C show the food intake of rats treated with α-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 α- 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 α- ethylepinephrine in comparison to treatment with saline.

Figure 6 shows cumulative locomotor activity of rats treated with α-methylepinephrine in comparison to treatment with saline.

Figures 7A-7C show the water intake of rats administered α-methylepinephrine compared to the rats administered saline. Figures 8A-8L show the food intake of rats administered α-methylepinephrine at 18:00 hours daily over a 3-day period. Figure 9 shows the change in body weight of rats administered α-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 α-methylepinephrine compared to rats treated with saline following dosing at 18:00 hours.

Figure 11 shows cumulative horizontal activity of rats treated with α-methylepinephrine compared to rats treated with saline following dosing at 18:00 hours.

Figures 12A-12L show the food intake of rats administered α-methylepinephrine at 8:00 and 18:00 hours daily.

Figure 13 shows the body weight change in rats with varying dosages of subcutaneously injected α- methylepinephrine at 8:00 and 18:00 hours.

Figure 14 shows the rate of growth for rats injected subcutaneously with varying dosages of α- methylepinephrine. Figure 15 shows the current horizontal activity of rats treated with injections of α-methylepinephrine at 8:00 and 18:00 hours.

Figure 16 shows the cumulative horizontal activity of rats treated with injections of α-methylepinephrine at 8:00 and 18:00 hours.

Figure 17 shows the dose-response curve of α- methylepinephrine for the inhibition of food intake.

Figures 18A-18L show the food intake of rats administered α-methylnorepinepherine at 18:00 hours over a 3-day period.

Figures 19A-19L show the inhibition of food intake after administration of α-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 α-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 α-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 α-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 α- methyInorepinepherine. Figure 24 shows the cumulative locomotor activity of rats treated at 8:00 and 18:00 hours with α- methylnorepinepherine.

Figure 25 shows the dose-response curve of α- 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.

DETAILED DESCRIPTION OF THE INVENTION

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, α-methylepinephrine, α-methylnorepinephrine, and N-substituted α-methylnorepinephrine related compounds. The invention also relates to the use of these pharmaceutical compositions as anorectic agents for mammals.

The following detailed description of the invention should not be construed to limit the present invention, as modifications and variations in the embodiments herein discussed may be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.

The contents of each of the references cited in the present application are herein incorporated by reference in their entirety. In one aspect, 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:

wherein R_lf R₂, R₃, and R₅ are each independently H, F, Cl, Br, or halogenated alkyl (^-C^) ; R₄ is H, acetyl, propionyl, benzoyl, alkyl (C-_L-C₃) , or hydroxyalkyl (€₂-0₃) ; and R₁₀ is acetyl, propionyl, butyryl, benzyl, N- methylenecyclopropane, or N-methylenecyclobutane. These derivatives may also be in the form of pharmaceutically acceptable salts. In another embodiment of the present invention, pharmaceutical 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:

wherein R_lf R₂, and R₅ are each independently H, hydroxy, F, Cl, Br, or halogenated alkyl ( 0₂-0₃) _> ^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 (C₁-C₃) ; R₄ is H, F, Cl, hydroxy, acetoxy, propionoxy, benzoyloxy, alkoxy (^-0₃) , benzyloxy, hydroxyalkoxy (^-0₃) , acetyl, propyl, benzoyl, hydroxy lmethy 1 , methyl, amino, formamido, acetamido, methylsulfonylamido , nitro , methylsulf ony lmethyl, trif luoromethyl, or p- methoxybenzylamino; R₃ and R₄ may form alkylene dioxyl ( ^ C₃) ; and wherein X is selected from the group consisting of

a

wherein R₆ and R₇ are each independently H or alkyl (C_λ-

C₃) ; R₈ is H, alkyl (C₁-C₃) , acetyl, propionyl, butyryl, benzyl, N-methy lenecyclopr opane , or N- methy lenecyclobutane ; R₉ is H, alkyl (^-0₄) , acetyl. propionyl, butyryl, phenyl, phenylalkyl (C^C^) , benzyl, benzoyl, N-methylenecyclopropane , or N- methylenecyclobutane; R₁₀ is acetyl, propionyl, butyryl, benzyl, N-methylenecyclopropane , or N- methylenecyclobutane; n is an integer of from 0 to 5 and a pharmaceutically acceptable carrier. Use of the anorectic agent defined as above provides a pharmaceutical composition which is suitable for body weight reduction in mammals without CNS stimulatory effect. Of the hydroxybenzylalcohols defined by Formula 11(a) and 11(b), preferred hydroxybenzylalcohols, including stereoisomers, in accordance with the invention have the formula:

wherein ^ is R, F, Cl or hydroxy; R is hydroxy, alkoxy (0₂-0₃) , benzyloxy, acetyl, propyl, benzoyl, hydroxylmethyl, methyl, amino, formamido, acetamido, methylsulfonylamido, nitro, methylsulfonylmethyl, trifluoromethyl, or p-methoxybenzylamino; R₃ is hydroxy, alkoxy (C₁-C₃) , benzyloxy, acetyl, propyl, benzoyl, hydroxylmethyl,, methyl, amino, formamido, acetamido, methylsulfonylamido, nitro, benzyloxy, methylsulfonylmethyl , trifluoromethyl , or p-methoxybenzylamino; R₂ and R₃ together may form alkylene dioxyl (^-0₃) ; n is an integer of from 0 to 5; R₄ is alkyl ( y- -C-s) ; R₅ is H or alkyl (0^0₃) ; R₆ is H or alkyl (^-0₃) ; and R₇ is H, alkyl (C^C^ , phenyl, phenylalkyl (C-γ-C^) , benzyl, or benzoyl; or the formula:

(IHb)

wherein R_lf R₂, R₃ and R₅ are each independently H, F, Cl,

Br, or halogenated alkyl (^-0₃) ; R₄ is hydroxy, acetoxy, propionoxy, benzoyloxy, alkoxy (^-0₃) , hydroxyalkoxy (C_x-

C₃) ; and wherein X is

wherein R₆ and R₇ are each independently H or alkyl (C_x- C₃) ; R₈ and R₉ are each independently H, alkyl (^-0₃) , acetyl, propionyl, butyryl, benzyl, N- methylenecyclopropane, or N-methylenecyclobutane; R₁₀ 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 R₆ is hydrogen or alkyl resulting in compounds such as 4(3,4-dihydroxyphenyl)- methoxypiperidinyl derivatives. Preferably in the compounds of Formula Ilia, R₂ is hydrogen. Most preferably in the compounds of Formula Ilia, R₂ and R₃ are each hydroxy, R is methyl, R₅ is hydrogen, R₆ is methyl or hydrogen, and R₇ is hydrogen.

Particularly preferred anti-obesity and anorectic agents are N-substituted catecholamine derivatives having the formula:

HO- XXy, - °C-^{H *}C-⁴ N^*• _(IV)

H R R-.

HO wherein R₄ is CH₃ or C₂H₅; R₅ is H, CH₃, or C₂H₅; R₆ is H, CH₃, C₂H₅, or C₃H₇; and R₇ is H, CH₃, C₂H₅, C₃H₇, or CH₂C₆H₅. The most preferred anti-obesity and anorectic agents are α-methylepinephrine, α-methylnorepinephrine, and metaraminol.

In yet a further aspect of the present invention, there is provided 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. Preferably the method comprises the administration to a mammal of a composition which includes the anorectic agent and an acceptable pharmaceutical carrier.

The preparation of the compounds of formulas I-IV are well known and can be found in the related art noted above as well as other readily available published procedures such as that described in the following references: U.S. Patent No. 2,151,459; Iwamoto, et al., J. Org. Chem. 9_:513-17 (1944); Smissman, et al., J. Med. Chem. 14(8) : 702-7 (1971); Ger. Patent No. 1,048,592 (January 15, 1950) . For example, using the synthesis of α- methylepinephrine and α-methylnorepinephrine as an example (described in detail in Example 4) , all of the compounds embraced by formula Ilia can be synthesized.

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. When 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. Table 1, included immediately after Example 4, presents the data of Examples 1-4. Examples 5-13 illustrate the anorectic effect of metaraminol-type substituted hydroxybenzylalcohols. Tables 2-3, included immediately after Example 13, present the data of Examples 5-13. 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 α-methylepinephrine, MDA, MDMA and α- methylnorepinephrine. Materials: (±)3,4-Methylenedioxyamphetamine HCl (MDA) and (±)3,4-methylenedioxymethamphetamine (MDMA) were obtained from the National Institute on Drug Abuse. α- Methylnorepinephrine HCl, α-methylepinephrine HCl and α- 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 β-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.

Methods: 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.

Data were analyzed for statistical significance using the students' t-test.

Results

Reduction in body weight: The effects of MDA, MDMA and their putative metabolites, injected subcutaneously at a dose of 10 mg/kg (as base) for 4 or 6 consecutive doses, on body weight reduction of rats are shown in Figure 1 and Table 1. The mean (± s.e.m.) body weights at the beginning were 228 (± 13.39), 244 (± 3.64), 210 (± 6.47), 236 (± 2.54), 239 (± 3.62), 249 (± 3.83) and 239 (± 3.46) g for rats treated with MDA, MDMA, 4-hydroxy-3- methoxyamphetamine, α-methyldopamine, α-methylnor- epinephrine, α-methylepinephrine and saline, respectively.

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, α-methylnorepinephrine, MDMA, and α-methylepinephrine, respectively, whereas the rats in the saline control group gained 3.34% of the body weight. 4-Hydroxy-3- methoxyamphetamine and α-methyldopamine had no effect on body weight. Following the administration of 4 doses of MDA, MDMA and α-methylepinephrine, the rats lost 9.20%, 7.16% and 17.57% of their initial body weight, respectively. Rats gained 3.09%, 2.26% and 4.74% of body weight following the administration of 4-hydroxy-3- methoxyamphetamine, α-methylnorepinephrine and saline, respectively. After the administration of 6 doses of MDMA and α-methylepinephrine, the rats lost 2.93% and 24.38%, of their body weight, respectively. The differences in change of the body weight following the administration of MDA, α-methylnorepinephrine, MDMA and α-methylepinephrine were highly significant as compared to that of saline controls.

Another experiment (Yeh et al., supra) has shown that α-methylepinephrine and α-methylnorepinephrine, unlike MDA and MDMA, was without stimulatory and neurotoxic effects.

Example 2

This experiment illustrates anorectic and stimulatory effects of α-methylepinephrine in rats.

Materials: α-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. After an exploratory period of 30 minutes, the rats were taken out of the monitor, injected subcutaneously with a dose of α-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. On day 2, 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. On day 4, the rats were transferred to propylene cages with food and water provided ad libitum. On day 10 to 13, 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 α-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 α-methylepinephrine may be diminished when it was injected in the morning. Protocol 2 extended the studies of protocol 1 except that α- methylepinephrine (α-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 α-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.

Data analysis: Data were analyzed for ANOVA statistical significance and t-test with Bonferroni- adjustment for multiple comparisons using the BMDP program of Dixon et al., BMDP Statistical software Manual (University of California (Berkeley) Press, 1990). Results of Protocol 1:

Food intake: The food intake of rats treated with α-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 α-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 α-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 α-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 α-methylepinephrine was not significantly different from that of saline treated rats. After drug treatment for two days, the food intake of rats treated with 10 mg/kg of α-methylepinephrine was significantly less than that of rats treated with saline or with 0.1, 1.0, and 5 mg/kg of α-methylepinephrine at levels of p < 0.05, p < 0.01, p < 0.05, and p < 0.01, respectively. After drug treatment for three days, the food intake of rats treated with 10 mg/kg of α-methylepinephrine was not significantly different from that of rats treated with saline or with the lower doses of α-methylepinephrine. Efficacy of α-methylepinephrine on inhibition of food intake: The ED₅₀ of α-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 α-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 LD₅₀ value of α- methylepinephrine, estimated to be larger than 20 mg/kg, will be established when drug is available. The efficacy of α-methylepinephrine, based on the LD₅₀ value of 20 mg/kg, at 3, 14 and 24 hours was estimated to be 67, 29 and 7.3 respectively.

See Figure 17 which shows the ED₅₀ of α- methylepinephrine on inhibition of food intake. The food intake of rats injected subcutaneously with various doses of α-methylepinephrine once in the evening (N = 4) is shown. The asterisk symbols, ** and *, indicate significant differences from that of saline control rats, at p < 0.01 and p < 0.05 level, respectively.

Changes of body weight: As compared to the body weight of saline control rats which increased daily, the body weight of rats treated with 10 mg/kg of α- methylepinephrine for 1, or 2 and 3 days was significantly decreased (p < 0.01). See Figure 3. The body weight of rats treated with 10 mg/kg of α-methylepinephrine for three days and withdrawn from the drug for 1 to 7 days was also significantly decreased. The change of body weight of rats administered with 0.1 mg/kg to 5 mg/kg of α- methylepinephrine was not significantly different from that of saline control rats.

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 α-methylepinephrine twice daily for 5 consecutive doses, observed previously.

It is pointed out that on day 4 (10 mg/kg of α-methylepinephrine) and on day 5 (saline control group) the food content in the food holder was low (because it was a Saturday) and on days 6 and 7 (for 0.1 mg/kg, 1.0 mg/kg and 5 mg/kg of α-methylepinephrine) the air conditioning was turned off during day time for installation of additional units. This may have affected the change in body weight. Locomotor activity: As illustrated in Figure 5, the current horizontal activity of rats treated with α- ethylepinephrine was less than that of rats treated with saline. As compared to that of saline controls, the current horizontal activity of rats treated with either 1 or 5 and 10 mg/kg of α-methylepinephrine was significantly decreased (p < 0.01) at 10 to 12 hour intervals following the drug administration in the morning. The current horizontal activity of rats treated with 10 mg/kg, but not 1 and 5 mg/kg, of α-methylepinephrine was significantly decreased (p < 0.05) than that of saline controls at 14, 15, 23 and 24 hours following the drug administration. Locomotor activity of rats decreased proportionally with the dose of α-methylepinephrine administered. Decreasing locomotor activity of rats administered α- methylepinephrine appears to be due to the suppression of eating activity since the time of decreasing locomotor activity coincides with the eating time (at 19 hours which is after the lights are turned off) . The cumulative locomotor activity of rats administered 1.0 or 5 and 10 mg/kg of α-methylepinephrine was significantly decreased at 10 to 14 hours, 10 to 18 hours and 10 to 24 hours following drug administration, respectively, than that of rats injected with saline (p < 0.05) (Figure 6). Similar results were observed for ambulatory activity of rats treated with α-methylepinephrine or saline.

Water intake: The water intake (about 40 g/day) of rats administered with 0.1 to 10 mg/kg of α- methylepinephrine was not significantly different from that of rats treated, with saline (Figures 7A-7C) .

The results confirm previous observation, i.e., α-methylepinephrine is a potent anorectic agent without stimulatory activity.

Results obtained from protocol 2:

Food intake of rats administered α-methylepinephrine at 18:00: As illustrated in Figures 8A-8D, on day 1, the food intake of rats administered 0.1 or 1 mg/kg of α- methylepinephrine was significantly decreased (at p < 0.05 and p < 0.01 level, respectively) at the 3 hour interval than that of saline control rats following the drug administration. The food intake of rats treated with 5 or 10 mg/kg of α-methylepinephrine was significantly decreased at 1 to 24 hour intervals than that of saline control rats.

After drug treatment for 2 and 3 days, the food intake of rats was significantly decreased at the 3 hour interval when treated with 1 or 5 and 10 mg/kg, and at the 14 hour interval when treated with 5 or 10 mg/kg, of α- methylepinephrine than that of saline control rats.

Change of body weight: As illustrated in Figure 9, the body weight of rats administered 1.0 mg/kg to 10 mg/kg of α-methylepinephrine in the evening was not significantly altered as compared to that of saline controls during and after the drug administration.

Water intake of rats administered α-methylepinephrine at 18:00: The water intake of rats treated with 0.1 to 10 mg/kg of α-methylepinephrine was not significantly different from that of saline controls. Locomotor activity: As compared with that of saline controls the current horizontal activity of rats treated with 5 or 10 mg/kg of α-methylepinephrine was significantly decreased from 2 to 5 hour intervals following dosing in the evening (Figure 10) . The cumulative horizontal activity of rats treated with 5 or 10 mg/kg of α-methylepinephrine was significantly decreased from the 2 to 23 hour intervals following dosing in the evening (Figure 11) .

Results obtained from protocol 3:

Food intake of rats administered α-methylepinephrine twice daily: As compared with that of saline controls, the food intake of rats injected subcutaneously with 1 to 20 mg/kg of α-methylepinephrine was significantly inhibited at the 1 to 24 hour intervals following dosing on the first day. On the second day treatment, the food intake of rats injected subcutaneously with 2.5 to 10 mg/kg of α-methylepinephrine was significantly inhibited at the 1 to 24 hour intervals whereas the food intake of those treated with 1 mg/kg of α-methylepinephrine was significantly inhibited at the 1 hour intervals only following dosing. On the third day, the food intake of rats injected subcutaneously with 2.5, 5 and 10 mg/kg of α-methylepinephrine was significantly inhibited at the 3 hours, 3 to 14 hours and 3 to 24 hour intervals, respectively, whereas the rats treated with 1 mg/kg of α- methylepinephrine were not significantly different than that of saline controls. The rats treated with two doses of 20 mg/kg of α-methylepinephrine did not eat any food for more than a 3 day period (Figures 12A-12L) . Change of body weight: As compared to the body weight change of saline control rats which increased daily, the body weight of rats injected subcutaneously with 1 mg/kg of α-methylepinephrine for one day was significantly decreased; on days 2 to 11 the body weight change of rats treated with 1 mg/kg of α-methylepinephrine was not significantly different from that of saline controls. The body weight change of rats injected subcutaneously with 2.5 mg/kg of α-methylepinephrine twice daily for 3 consecutive days showed a trend toward decrease from days 1 to 9 and was significantly decreased on days 1, 2, 4, 7 and 9. The body weight change of rats injected subcutaneously with 5, or 10 mg/kg of α- 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 α-methylepinephrine twice daily for one day was significantly decreased on days 1 to 13. On day 5, 4 days after withdrawal of the drug, the rats lost 117 ± 3.13 g, which is 40% of the original weight. On day 14, the body weight of rats treated with ^"20 mg/kg of α- 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 α-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 α-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 α-methylepinephrine was significantly decreased from 12 to 23 hour intervals following dosing (Figure 16) .

Water intake of rats administered α-methylepinephrine twice daily: The water intake of rats injected subcutaneously with 1 to 10 mg/kg of α-methylepinephrine twice daily was not significantly different from that of saline control. The water intake of rats injected SC with 20 mg/kg of α-methylepinephrine twice daily for one day was significantly decreased on days 1 to 3 from that of saline control.

Example 3

This experiment illustrates anorectic and stimulatory effects of α-methylnorepinephrine in rats.

Materials: (±) α-Methylnorepinephrine HCl was provided by Sterling-Winthrop Research Institute (Rensselaer, NY). (-) 3,4-dihydroxynorepinephrine was purchased from the Aldrich Chemical Company (Milwaukee,

WI) .

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.

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. For stimulatory activity study, 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 α-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. No one entered the lab during the experimental period. 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 of the food, water and body weight, respectively. Saline was used for control rats.

Data analysis: Data were analyzed for ANOVA statistical significance and t-test with Bonferroni- adjustment for multiple comparisons using the BMDP program (Dixon et al., supra) . Results

Food intake: As compared with saline controls, the food intake of rats administered in the evening with 2.5 or 5 mg/kg of α-methylnorepinephrine was significantly decreased on days 1 to 3 (Figures 18A-18L) ; the food intake of rats treated with 1 mg/kg of α-methylnorepinephrine was significantly decreased on day 2 at the 3 hour interval and the food intake of rats treated with 0.25 or 1 mg/kg of α-methylnorepinephrine was significantly decreased on days 2 and 3 at the 1 and 3 hour intervals. After subcutaneous injection of 1 to 2.5 mg/kg of α-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 α-methylnorepineprine: ED₅₀ of α-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 α-methylnorepinephrine. Because the amount of α-methylnorepinephrine on hand was not enough to study the lethality of α-methylnorepinephrine, (-)3,4- dihydroxynorephedrine, which has the same basic chemical structure, was substituted for the α-methylnorepinephrine in the lethality studies.

LD₅₀ 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. After injection of 10 mg/kg of (-) 3,4-dihydroxynorephedrine, 3 died between 30 and 32 hours; 4 died between 32 and 46 hours; two died at about 53 hours; one died after 7 days. After administration of 8 mg/kg of (-)3,4-dihydroxynorephedrine, one died at about 32 hours; another died at about 55 hours, and a third died at about 80 hours; 7 rats survived more than 10 days. After injection of 6 mg/kg of (-)3,4- dihydroxynorephedrine, two rats died at about 32 hours, 8 rats survived after 7 days. The LD₅₀ was estimated to be about 9 mg/kg. The efficacy of α-methylnorepinephrine as an anorectic agent at 1, 3, 14 and 24 hour intervals was estimated to be 11.7, 11.5, 4.59 and 3.5 respectively. See Figure 25. The dose-response curve of α- methylnorepinephrine on the food intake of rats injected subcutaneously with various doses of α- ethyInorepinephrine once in the evening (N = 4) . The asterisks, * and **, indicate significant differences from that of saline control rats at p < 0.05 and p < 0.01 level, respectively.

Change of body weight: As compared to the body weight of saline control rats which increased daily, the body weight of rats treated with 5 mg/kg of α- methyInorepinephrine was significantly decreased from days 1 to 9 (p < 0.01) (Figure 20). The body weight of rats treated with 2.5 mg/kg of α-methylnorepinephrine showed a trend toward decrease and was significantly decreased at days 7 and 8 after drug administration. The body weight of rats treated with 0.25 of 1.0 mg/kg of α- methylnorepinephrine showed a trend toward decrease (Figure 20) . The growth rate of rats treated with various doses of α-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 α-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 α-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 α-methylnorepinephrine twice daily showed a trend toward decrease (Figure 21) . The growth rate of rats treated with 2.5 mg/kg of α- 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 α- 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 α-methylnorepinephrine, twice daily, showed a trend toward decrease. The growth rate of rats treated with various doses of α- 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 α-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 α-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) . The cumulative locomotor activity of rats administered 1.0 mg/kg of α-methylnorepinephrine twice daily was significantly decreased from hour 14 through 23 intervals following dosing from that of rats injected with saline (p < 0.05) (Figure 24). Similar results were observed for ambulatory activity of rats treated with α- methyInorepinephrine. The current and cumulative locomotor activity of rats treated with 1.0 mg/kg α-methylnorepinephrine once showed a trend toward decrease as compared to that of rats treated with saline (data not^~ shown) . Water intake: The water intake (about 40 g/day) of rats administered with 0.1 to 5 mg/kg of α- methyInorepinephrine was not significantly different from that of rats treated with saline (data now shown) . The results confirm previous observations, i.e., α- methylnorepinephrine is a potent anorectic agent without stimulatory activity.

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-dihydrόbenzylaldehyde was converted to 3,4- dibenzyloxybenzyladehyde, which was then_^ reacted with C₂H₅MgI 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 (RNH₂; R=C_nH_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 α- methyInorepinephrine, or α-methylepinephrine and various α-methylepinephrine analogs. Alternatively, 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(α-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. Hydrolysis of 5-(3,4-dibenzyloxyphenyl-4- methyl-2-oxazolidone and 5-(3,4-dibenzyloxyphenyl)-4- methyl-N-methyl-2-oxazolidone with HCl yields α- methylnorepinephrine and α-methylepinephrine , respectively . Another procedure , l- ( 3 , 4 - dibenzyloxylphenyl) -l-alkyne-l-ols were first converted to l- (3 , 4-dibenzyloxylphenyl) -2-oxo-l-alkanols which were subsequently reduced in the presence of ammonia or primary amine to give α-methylepinephrine and α- methylnorepinephrine , respectively .

Table 1. Body weight reduction of rats treated with MDMA,

MDA, 4 -hydroxy- 3 -methoxy amphetamine (4-HO-3-MeOA) , α- methy ldopamine ( α-MeDA) and α-methylepinephrine (α-MeEpi) .

BODY WT.. a BODY WEIGHT CHANGE (α/100. MEAN ÷ s.e.m TREATMENT N DAY 0 DAY 1 DAY 2 DAY 3

SALINE 6 239 ± 3.19 +3.38 ± 0.69 +4.82 ± 1.19

MDA 6 232 ± 11.54 -7.91 ± 1.12*" -9.14 ± 1.62"*

4-HO-3-MeOA 6 210 ± 5.93 -0.19 ± 1.97 +3.26 ± 1.30 α-MeDA 6 236 ± 2.33 +0.49 ± 0.74 +2.29 ± 0.85 MDMA 6 244 ± 3.34 -6.03 ± 0.85" -7.12 ± 1.14*** -2.89 ± 0.93" α-MeEpi 5 250 ± 3.51 -10.03 ± 2.05*" -16.56 ± 2.49*" -23.59 ± 2.23*" α-MeNorEpi 5 239 ± 3.32 -6.76 ± 0.99"

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.

Example 5

This Experiment Illustrates Anorectic and Stimulatory Effects of Metaraminol in Rats

Animals were treated and experiments were conducted in accordance with methods known to workers of ordinary skill in the relevant art. Detailed parameters follow:

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 received subcutaneous injections of a dose of metaraminol bitartrate (purchased from Sigma Chemical Co., St. Louis, MO) dissolved in sterilized 0.9% NaCl solution (saline) . Doses were formulated in a volume of

2 ml/kg. Injections were administered at 18:00 daily for

3 consecutive days. Following metaraminol administration, the rats were placed individually into a metabolic cage (Nalge Co., Rochester, NY) and provided with preweighed ground Purina Chow (#5001) and preweighed water. On day

4 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.

For studying stimulatory activity of experimental subjects, 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.

Example 6 Data Analysis:

The ED₅₀ 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.

Example 7

Anorectic Effect of Metaraminol:

Table 2 and Figures 26A-26L report results on food intake in rats treated with various doses of metaraminol injected subcutaneously once daily at 18:00 h for 3 consecutive days (N=4) . The asterisk symbols, * and **, indicate significant differences from that of saline control rats at p < 0.05 and p < 0.01 levels, respectively.

As early as one hour post-injection of subjects with 3.0 and 5.0 mg/kg of metaraminol, a significant decrease (to 11% and 2%, respectively, of control) in food intake was noted. After 24 h, food intake was still reduced, to 63% and 21%, respectively, of the control values. Similar results were obtained on days 2 and 3 of the experiment as well, as noted in the abovementioned figures and table.

Although the food intake of rats treated with 1 mg/kg of metaraminol decreased to 41% and 88% at 1 and 24 h timepoints, respectively, this result was not significantly different from that of controls. Therefore, a dose concentration of 1 mg/kg of metaraminol is considered to be suboptimal. Rats were administered various dose concentrations of metaraminol to determine an ED₅₀ for suppression of food intake. Linear regression analysis of data generated by measuring food intake in various intervals (reported as a percentage of saline controls) as a function of the log of the dose of metaraminol administered revealed that the ED₅₀ of metaraminol for suppression of food intake at 1, 3, 14 and 24 h intervals were 0.75, 1.37, 2.43 and 2.85 mg/kg, respectively (Figure 27, wherein the asterisk symbols, * and **, indicate significant differences from that of saline control rats at p < 0.05 and p < 0.01 levels, respectively) .

Slightly different results were obtained when the subject rats were fasted prior to administration of metaraminol. Following administration of 5.0 and 10.0 mg/kg of metaraminol at 18:00 hours, the food intake of fasted-rats was significantly decreased from one to 24 h timepoints; after one h, food intake was reduced to 31% and 24%, respectively, of the control values; after 24 hours, food intake was reduced to 86% and 80%, respectively, of the control values (N=4; data presented in Table 3 and Figures 28A-28D, wherein the asterisk symbols, * and **, indicate significant differences from that of saline control rats at p < 0.05 and p < 0.01 levels, respectively). The ED₅₀ 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).

Example 8

Toxicitv Of 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 (LD₅₀) of metaraminol in rats after subcutaneous injection was calculated to be 26.59 mg/kg. A lower confidence limit of 14.86 mg/kg and an upper confidence limit of 47.58 mg/kg was also calculated. (This result varies considerably from a published result, which states that the LD₅₀ is 117 mg/kg. Barnes and Eitherington, Drug Dosage In Laboratory Animals: A Hand Book (1966) at 144.)

Example 9 LD_5Q And ED₅₀ of Metaraminol

The LD₅₀ value obtained in Example 8 was 26.59 mg/kg. The ED₅₀ 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. In fasted rats, the ED₅₀ after 1 and 3 h post-injection was calculated to be 3.01 mg/kg and 3.59 mg/kg, respectively. Example 10 Effect Of Metaraminol On Body Weight And Growth:

As compared to that of saline controls, the change of body weight of rats administered subcutaneous injections of 3.0 or 5.0 mg/kg of metaraminol once daily at 18:00 hours for 3 consecutive days was significantly decreased from days 1 to 9 (data presented in Figures 30A and 30B, wherein the asterisk symbols, * and **, indicate significant differences from that of saline control rats at p < 0.05 and p < 0.01 levels, respectively). The growth of rats administered 5.0 mg/kg of metaraminol was significantly decreased on day 1 only from that of saline control (Figures 30A and 30B) .

Example 11

Stimulatory Effect Of Metaraminol:

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) .

The metaraminol-induced current horizontal locomotor activity of rats treated with a subcutaneous injection of 1, 5, or 10 mg/kg of metaraminol at 18:00 hours was generally less than that of rats injected with saline within 60 to 90 minutes after drug administration; rats treated with 3 mg/kg evidenced significantly less locomotor activity than controls (N=4; data presented in Figures 31A and 3IB, wherein the asterisk symbols, * and **, indicate significant differences from that of saline control rats at p < 0.05 and p < 0.01 levels, respectively) . Example 12 Effect Of Metaraminol On Water Intake:

On day 3, the water intake of rats administered metaraminol was significantly increased over that of rats treated with saline (see Figures 31A and 3IB) . On days 1 and 2, there was no significant differences noted in water intake as between metaraminol- and saline-treated subjects.

Example 13

Method To Synthesize Metaraminol Derivatives:

Metaraminol, (alternatively known as: α-(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 α-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. 3-benzyloxyphenylisopropanol was prepared from the reaction of C₂H₅MgI with 3- benzyloxyphenylaldehyde which was converted from 3- hydroxybenzaldehyde. Accordingly, metaraminol and metaraminol analogs can be prepared by the following procedures: 1) Treat 3-benzyloxyphenylisopropylene with NBS and water to produce a bromohydrin. Subsequent reaction of the bromohydrin with ammonia or alkylamine (RNH₂; R=C_nH_n+2. n=l to 4) to form 3- benzyloxyphenylisopropanolamine and various 3- benzyloxyphenylisopropanolamine analogs which were hydrolyzed to yield metaraminol and various metaraminol analogs.

2) Treat 3-benzyloxyphenylpropylene with a peracid, e.g. m-chlorperoxybenzoic acid, to form an epoxide. Treat the epoxide with LiA(NHBz)₄ to form 3-benzyloxyphenyl(2-benzylamino)propanol. Reduction of 3-benzyloxyphenyl(2-benzylamino)propanol yields metaraminol. Alternatively, treat 3- benzyloxybenzyladehyde with ethyl 2-bromopropionate and zinc, then treat with hydrazine hydrate to yield a hydrazide of 3-benzyloxyphenylhydra(α- methyl)acrylic acid. Subsequent nitration of the hydrazide forms 5-(3-benzyloxyphenyl)-4-methyl-2- oxazolidone, which was hydrolyzed with HCl to yield metarminol.

10

15

MEAN ± S.E.M. MEAN ± S.E.M. MEAN ± S.E.M.

SALINE 2.33 4.72 18.93 22.63 1.65 5.58 20.05 21.77 1.10 6.45 18.88 20.75 0.28 0.58 0.64 0.81 0.49 0.39 0.93 1.01 0.45 1.08 0.59 0.85

20 ^a The actual amounts of food intake (in grams) of saline control rats are set forth in lower portion of table. ^b One out of four rats died between 14H and 24H following drug administration.

25

Table 3. The effect of Metaraminol on food intake in

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.

Example 14 Extension Of Rat-Model Data To Human Application:

While applicants' experiments have been conducted on rats, there is a large volume of data that indicates that such experiments in rats is readily transferrable to humans. See the chapters "Animal Models of Eating Disorders" by A.M.J. Montgomery and "Screening Methods for Anorectic, Antiobesity and Orectic Agents" by J. Sepinwell and A.C. Sullivan in Behavioral Models in Psvchopharmacology. edited by Professor Paul Willner (Cambridge University Press, 1991) . For example, the ED₅₀ of amphetamine, α- methylepinephrine and α-methyl-norepinephrine for suppression of food intake in rats has been experimentally determined as indicated in the above Examples and in the Table 4 below. 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 ED₅₀ value observed in the rats at 3 hour intervals. Based on the ED₅₀ of amphetamine for suppression of food intake in rats and the therapeutic dosage used in humans, the anorectic dosages of α-methylepinephrine and α- methylnorepinephrine for treatment of obesity in humans at 3 hour intervals can be about 2.5 to 4.5 mg (ED₅₀ at 3 hour x (8 - 15) and about 6.0 to 12 mg. (ED₅₀ 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.

Table 4. ED₅₀ Values on Inhibition of Food Intake

ED₅₀ mg/kg, IN RATS, AT DRUG 1H 3H 14H 24H

The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

Claims

What is claimed is:

1. A chemical compound of the formula:

or a pharmaceutically acceptable salt of said compound, wherein R_l R₂, R₃, and R₅ are each independently H, F, Cl, Br, or halogenated alkyl y-^) ; R₄ is H, acetyl, propionyl, benzoyl, alkyl (C^C ) , or hydroxyalkyl (^-0₃) ; and R₁₀ is acetyl, propionyl, butyryl, benzyl, N- methylenecyclopropane, or N-methylenecyclobutane.

2. A pharmaceutical composition comprising an anorectic effective amount of a compound of the formula:

wherein R_x, R₂, and R₅ are each independently H, hydroxy, F, Cl, Br, or halogenated alkyl (^-0₃) ; R₃ is H, hydroxy, F, Cl, Br, alkoxy (^-0₃) , benzyloxy, acetyl, propyl, benzoyl, hydroxylmethy1, methyl, amino, formamido, acetamido, methylsulfonylamido, nitro, methylsulfonylmethyl, trifluoromethyl, p-methoxybenzylamino, or halogenated alkyl (^-0₃) ; R₄ is H, F, Cl, hydroxy, acetoxy, propionoxy, benzoyloxy, alkoxy (^-0₃) , benzyloxy, hydroxyalkoxy (C_x- C₃) , acetyl, propyl, benzoyl, hydroxylmethy1, methyl, amino, formamido, acetamido, methylsulfonylamido, nitro, methylsulfonylmethyl trifluoromethyl, or p- methoxybenzylamino; R₃ and R₄ may form an alkylene dioxyl (C-_L-C₃) ; and wherein X is

N—R 10

wherein R₆ and R₇ are each independently H or alkyl (^-0₃) ; R₈ is H, alkyl (Cy-0₂) , acetyl, propionyl, butyryl, benzyl, N-methylenecyclopropane, or N-methylenecyclobutane; R₉ is H, alkyl (C^C^ , acetyl, propionyl, butyryl, phenyl, phenylalkyl (C₁-C₃) , benzyl, benzoyl, N- methylenecyclopropane, or N-methylenecyclobutane; R₁₀ is acetyl, propionyl, butyryl, benzyl, N- methylenecyclopropane, or N-methylenecyclobutane; n is an integer of from 0 to 5 and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2, wherein said compound is of the formula:

wherein R₂ is H, F, Cl, or hydroxy; R₂ is hydroxy, alkoxy (^-0₃) , benzyloxy, acetyl, propyl, benzoyl, hydroxylmethyl, methyl, amino, formamido, acetamido, methylsulfonylamido, nitro, methylsulfonylmethyl, trifluoromethyl, or p- methoxybenzylamino; R₃ is hydroxy, alkoxy (C₁-C₃) , benzyloxy, acetyl, propyl, benzoyl, hydroxylmethyl, methyl, amino, formamido, acetamido, methylsulfonylamido, nitro, benzyloxy, methylsulfonylmethy1 , trifluoromethyl, or p-methoxybenzylamino group; R₂ and R₃ may form an alkylene dioxyl (C_λ-C₃) ; n is an integer of from 0 to 5; R₄ is alkyl (^-0₃) ; R₅ is H or alkyl (C₁-C₃) ; R₆ is H or alkyl (C₁-C₃) ; and R₇ is H, alkyl (C^-C^) , phenyl, phenylalkyl (C_±-C₃) , benzyl, or benzoyl.

4. The pharmaceutical composition of claim 3, wherein said compound is of the formula:

wherein R₄ is CH₃ or C₂H₅; R₅ is H, CH₃ or C₂H₅; R₆ is H, CH₃, C₂H₅ or C₃H₇; R₇ is H, CH₃, C₂H₅, C₃H₇ or CH₂C₆H₅.

5. The pharmaceutical composition of claim 4, wherein said compound is α-methylepinephrine.

6. The pharmaceutical composition of claim 4, wherein said compound is α-methylnorepinephrine.

7. The pharmaceutical composition of claim 3, wherein Ry is hydrogen.

8. The pharmaceutical composition of claim 3, wherein R and R₃ each are hydroxy; R₄ is methyl; R₅ is H; R₆ is methyl or hydrogen; R₇ is H.

9. The pharmaceutical composition of claim 2, wherein said compound is of the formula:

wherein R_lf R , R₃ and R₅ each are independently H, F, Cl, Br, or halogenated alkyl (0₂-0₃) _> ^R ^^s hydroxy, acetoxy, propionoxy, benzoyloxy, alkoxy (0₂-0₃) • hydroxyalkoxy (C_λ- C₃) ; and wherein X is

wherein R₆ and R₇ are each independently H or alkyl (^-0₃) ; R₈ and R₉ are each independently H, alkyl (0₃^₃) , acetyl, propionyl, butyryl, benzyl, N-methylenecyclopropane, or N- methylenecyclobutane; R₁₀ is acetyl, propionyl, butyryl, benzyl, N-methylenecyclopropane, orN-methylenecyclobutane; n is an integer of from 0 to 3.

10. The pharmaceutical composition of claim 9, wherein said compound is metaraminol.

11. The pharmaceutical composition of claim 2, wherein said composition is in the form of a tablet, a powder or a capsule.

12. The pharmaceutical composition of claim 3, wherein said composition is in the form of a tablet, a powder or a capsule.

13. The pharmaceutical composition of claim 4, wherein said composition is in the form of a tablet, a powder or a capsule.

14. The pharmaceutical composition of claim 5, wherein said composition is in the form of a tablet, a powder or a capsule.

15. The pharmaceutical composition of claim 6, wherein said composition is in the form of a tablet, a powder or a capsule.

16. The pharmaceutical composition of claim 7, wherein said composition is in the form of a tablet, a powder or a capsule.

17. The pharmaceutical composition of claim 8, wherein said composition is in the form of a tablet, a powder or a capsule.

18. The pharmaceutical composition of claim 9, wherein said composition is in the form of a tablet, a powder or a capsule.

19. The pharmaceutical composition of claim 10, wherein said composition is in the form of a tablet, a powder or a capsule.

20. A method of effecting weight reduction in a mammal comprising administering to said mammal an anorectic effective amount of a compound of the formula:

wherein R_x, R , and R₅ are each independently H, hydroxy, F, Cl, Br, or halogenated alkyl (C₂-C₃) ; R₃ is H, hydroxy, F, Cl, Br, alkoxy (0₂-0₃) _* benzyloxy, acetyl, propyl, benzoyl, hydroxylmethyl, methyl, amino, formamido, acetamido, methylsulfonylamido, nitro, methylsulfonylmethyl, trifluoromethyl, p-methoxybenzylamino, or halogenated alkyl ( i~^c ₃) ' ^R ₄ ^^{s H}' ^F' ^cl' hydroxy, acetoxy, propionoxy, benzoyloxy, alkoxy (0 -0₃) ' benzyloxy, hydroxyalkoxy (C_x- C₃) , acetyl, propyl, benzoyl, hydroxylmethyl, methyl, amino, formamido, acetamido, methylsulfonylamido, nitro, methylsulfonylmethyl, trifluoromethyl, or p- methoxybenzylamino; R₃ and R₄ may form alkylene dioxyl (C₂- C₃) ; and wherein X is

N—R 10

wherein R₆ and R₇ are each independently H or alkyl (C₂-C₃) ; R₈ is H, alkyl (C -C₃) , acetyl, propionyl, butyryl, benzyl, N-methylenecyclopropane, or N-methylenecyclobutane; R_g is H, alkyl (C₂~C₄) , acetyl, propionyl, butyryl, phenyl, phenylalkyl (C₂-C₃) , benzyl, benzoyl, N- methylenecyclopropane, or N-methylenecyclobutane; R₂₀ is acetyl, propionyl, butyryl, benzyl, N- methylenecyclopropane, or N-methylenecyclobutane; n is an integer of from 0 to 5 and a pharmaceutically acceptable carrier.

21. The method of claim 20, wherein said compound is of the formula:

wherein R_x is H, F, Cl, or hydroxy; R₂ is hydroxy, alkoxy

(C₂-C₃) , benzyloxy, acetyl, propyl, benzoyl, hydroxylmethy1, methyl, amino, formamido, acetamido, methylsulfonylamido, nitro, methylsulfonylmethy1, trifluoromethyl, or p- methoxybenzylamino; R₃ is hydroxy, alkoxy (C -C₃) , benzyloxy, acetyl, propyl, benzoyl, hydroxylmethyl, methyl, amino, formamido, acetamido, methylsulfonylamido, nitro, methylsulfonylmethy1 , trifluoromethy1 , or p-methoxybenzylamino; R₂ and R₃ may form alkylene dioxyl

(C -C₃) ; n is an integer of from 0 to 5; R is alkyl (C₂- C₃) ; R₅ is H or alkyl (C₂-C₃) ; R₆ is H or alkyl (C -C₃) ; and R₇ is H, alkyl (C₂~C ) , phenyl, phenylalkyl (C₂-C₃) , benzyl, or benzoyl.

22. The method of claim 21, wherein said compound is of the formula:

wherein R₄ is CH₃ or C₂H₅; R₅ is H, CH₃ or C₂H₅; R₆ is H, CH₃, C₂Hc, or C₃H₇; R is H, CH₃, C₂Hc, C₃H , or CH CgHc.

23. The method of claim 22, wherein said compound is α-methylepinephrine.

24. The method of claim 22, wherein said compound is α-methylnorepinephrine.

25. The method of claim 21, wherein R is H.

26. The method of claim 21, wherein R and R₃ are each hydroxy; R is methyl; R₅ is H; R₆ is methyl or H; R₇ is H.

27. The method of claim 20, wherein said compound is of the formula:

wherein R_λ , R₂, R₃ and R₅ are each independently H, F, Cl, Br, or halogenated alkyl (C₂-C₃) ; R₄ is hydroxy, acetoxy, propionoxy, benzoyloxy, alkoxy (C₂-C₃) , or hydroxyalkoxy (C₂-C₃) ; and, wherein X is

wherein R₆ and R₇ are each independently H or alkyl (C -C₃) ; R₈ and R₉ are each independently H, alkyl (C₂-C₃) , acetyl, propionyl, butyryl, benzyl, N-methylenecyclopropane, or N- methylenecyclobutane; R₂₀ is acetyl, propionyl, butyryl, benzyl, N-methylenecyclopropane, or N-methylenecyclobutane; n is an integer of from 0 to 3.

28. The method of claim 27, wherein said compound is metaraminol.