CHAPTER-II a Novel Process for Synthesis of Eprazinone Hydrochloride Which Is a Drug from the Class of Antitussive Agents

Home , Dropropizine, Eprazinone, Levodropropizine, Oxolamine, Zipeprol

CHAPTER-II A novel process for synthesis of Eprazinone hydrochloride which is a drug from the class of antitussive agents.

INTRODUCTION : Antitussive drugs are widely used in the treatment of coughs. They are particularly indicated in nonproductive cough, usually associated with different respiratory diseases varying from mild throat infections to the more serious bronchitis and asthma. Nonproductive cough is often painful and fatiguing to the patient especially during the night when, lying down, relief from this persistent reflex is greatly desired. The main ways used to inhibit the cough reflex involve either suppressing the cough center or anesthetizing the respiratory mucosa. Several drugs are available for the treatment of cough, but the number of safe and effective antitussive agents devoid of central effects or local anesthetic activity is rather limited. Opioid alkaloids still seem to be the most effective compounds available, in spite of their several well-established side effects and the risk of addiction. Morphine is an effective antitussive at doses lower than the doses that produce analgesia and sedation. It is not commonly used for antitussive activity due to side effects and the potential for abuse and addiction. Morphine has poor oral bioavailability due to a significant first-pass effect by the liver. Codeine, the 3-methoxy derivative of (-)-morphine, is the most notable representative of the morphine family, and its major side effects, such as sedation, depression, and constipation, are well known.1 Methylation of morphine significantly improves the oral bioavailability by reducing the first-pass effect. Codeine phosphate and codeine sulfate are found in many preparations, including tablets, liquids, and syrups. Codeine has analgesic effects that are about one-tenth that of morphine, but its antitussive potency is about equal to that of morphine. The side effects of codeine are significantly less than those seen with morphine at antitussive doses. Toxicity (especially in cats) is exhibited as excitement, muscular spasms, convulsions, respiratory depression, sedation, and constipation. Codeine should not be used after GI tract surgery. The potential for addiction and abuse of codeine is considerably lower than that for morphine.

H CH3 CH N N 3 H H HO MeO O O H OH OH

Morphine Codeine

The antitussive effect does not appear to be related to the binding of traditional opiate receptors. For example, dextromethorphan is an opiate derivative with good antitussive activity, but it does not have activity at opiate receptors and is not analgesic or addictive. For many years, novel antitussives have been sought through structures incorporating the essential features of codeine series.2 Dextromethorphan and dimemorphan , which have the same absolute configuration as (+)-morphine, emerged as clinically useful antitussives with fewer side effects than codeine, although they both showed potent central activity.3 Dextromethorphan is technically not considered an opiate because it does not bind to

traditional opiate receptors and is not addictive or analgesic. It is the D-isomer of levorphanol. The L-isomer of levorphanol has addictive and analgesic properties. Dextromethorphan is the safest antitussive to use in cats and is reported to be more efficacious in cats than codeine. In addition, dimemorphan has been reported to have analgesic properties 4.

H CH H CH N 3 N 3 H H

MeO H3C

Dextromethorphan Dimemorphan

Further simplifications of the morphine nucleus provided newer antitussive agents, structural families less closely related to the morphinans. One of the most crowded class is

represented by the phenothiazines among which pipazetate 5 was shown to exhibit antitussive properties, through a central mechanism of action, together with antibronchospastic effects. Clophedianol6 and cloperastine 7 belong to another big class of antitussives which are bis- arylmethane/ethane derivatives provided with lateral chains containing tertiary amines. The former is reported to depress the cough center and stimulate the respiratory center. Besides, it shows antibronchospastic properties. More selectively, cloperastine does not interact with the respiratory center.

O Cl CH3 O O N N CH3 N N OH

S Pipazetate Clophedianol

Cl O N Cloperastine In the group of 1,4-disubstituted-piperazines; eprazinone, zipeprol 8 and dropropizine 9 are the best known representatives.

Zipeprol is a centrally acting cough suppressant which acts as a local anaesthetic and may also have mucolytic, antihistamine-like and anticholinergic properties. 10 It is sold with several brand names such as Zinolta and Respilene. It is not available in the United States or Canada and has been discontinued in Europe. It is still available in some countries in Asia and South America.

Zipeprol has been used recreationally and is heavily abused in Korea, mainly for the hallucinations it produces. Such abuse has become an issue due to the seizures and various neurological side effects it causes at high dosages. Many fatalities have been reported. 11

Dropropizine is a racemic non-opiate antitussive agent which has been used clinically for many years. More recently, Levodropropizine the levo-rotatory (S)-enantiomer of dropropizine 12 showed less sedative properties than the racemate or the dextro isomer, maintaining a considerable analgesic activity. Compared with the racemic drug, levodropropizine exhibits in animal models similar antitussive activity but considerably lower central nervous system (CNS) depressant effects. It is also less likely to cause sedation in treated patients.

CH3 N OH N

NO N OCH 3

O CH3 OCH 3 Eprazinone Ziperol

OH N N OH

Dropropizine

In the class of heterocyclic oxadiazoles, oxolamine 13 emerged as one of the most active representatives. This antitussive agent was suggested to have a predominantly peripheral mechanism of action because of its major activity in tests involving a diffuse stimulation of the bronchial tree.

CH3 H C 3 N N

O N

Oxolamine

PRESENT WORK Eprazinone hydrochloride is an antitussive drug that affects the dissolution of mucus in the respiratory tract. Due to its broncho-secretolytic activity, the drug is used in ailments of respiratory tract and the main active ingredient in several expectorant formulations. Eprazinone, chemically represented by 3-[4-(2-ethoxy-2-phenyl-ethyl) piperazin-1-yl]-2- methyl-1-phenyl-propan-1-one possesses mucolytic and antitussive activity and administered in the form of its hydrochloride salt.

CH3 N NO

O CH3 Eprazinone

There are mainly three synthetic routes available in literature for industrial synthesis of eprazinone which involves Mannich reaction of piperazine moiety and propiophenone in presence of paraformaldehyde/trioxymethylene. One of the literature method for preparation of eprazinone ( 1) as described in scheme- 114 involves reaction of 2-phenyl-2-ethoxy ethyl bromide (6) with excess of anhydrous piperazine to give 1-(2-ethoxy, 2-phenyl)ethyl piperazine (7). Hydrochloride salt of intermidiate-7 on Mannich reaction with propiophenone, trioxymethylene and hydrochloric acid in ethanol gave eprazinone hydrochloride with an overall yield of 30%. The intermediate 2-phenyl 2-ethoxy ethyl bromide (6) has been prepared by the reaction of styrene, ethanol and tert-butylhypobromite.

H CH 3 N CH3

O O NH N CH Br N 2 t-Butyl hypobromite H + H3C OH MDC Ethanol/reflux Styrene 6 7

CH3

CH3 N NO Trioxymethylene EtOH/HCl O . 2HCl CH Reflux 3 Eprazinone hydrochloride (1) Scheme 1

In another synthesis 15 of Eprazinone ( 1) as described in scheme 2, mono CBZ-protected piperazine (8) on Mannich reaction with propiophenone, paraformaldehyde in presence of hydrochloric acid in ethanol gives intermediate 9 which on subsequent CBZ-deprotection followed by N-alkylation with 2-phenyl-2-ethoxyethyl bromide (6) provides the desired target molecule, eprazinone.

O Paraformaldehyde O H N EtOH/HCl CH3 Reflux CH3 N O N + N

CBZ O Propiophenone 8 9 CH3

CH N Deprotection CH3 NH 3 N NO

O O CH3 10 Eprazinone Scheme 2

In yet another approach for the synthesis of eprazinone,16 Grignard reagent of propyl 3-[4-(2-ethoxy-2-phenyl-ethyl) piperazin-1-yl]-2-bromide was reacted with benzonitrile, in diethyl ether. Subsequent hydrolysis with hydrochloric acid yields eprazinone hydrochloride (scheme-3).

CN CH3 N Diethylether CH3 N NO + BrMg Hydrolysis N O

CH3 O CH3 Benzonitrile 11 Eprazinone Scheme 3

There are many drawbacks associated with these literature processes for industrial production of eprazinone: 1) For preparation of key intermediate 6 (scheme 1), tert-butylhypobromite was used which is hazardous and highly flammable. 2) The preparation of Grignard reagent and its further reaction (scheme 3) requires stringent conditions as they are highly sensitive to moisture, thereby requiring an anhydrous environment. Further, the use of highly inflammable solvent such as diethyl ether makes the process unsuitable for commercial purpose. To overcome these problems, we realized the need to develop an alternative, cost effective and safe process for commercial synthesis of eprazinone. Accordingly, a synthetic study was undertaken to develop a safe and economically efficient process for the synthesis of eprazinone. Scheme 4 describes the retrosynthetic analysis of eprazinone.

CH3

ON ONH N O N

CH3 CH3 .2 HCl

Eprazinone hydrochloride (1)

O NH OHNH N N

H N

O O N Br H CH3

Phenacyl bromide Acetophenone Scheme 4

As per proposed synthetic approach, acetophenone can be easily brominated to give phenacyl bromide which on condensation with piperazine and subsequent reduction could give alcohol intermediate. Finally o-alkylation of alcohol intermediate using ethyl bromide followed by Mannich reaction with propiophenone and paraformaldehyde in presence of HCl would afford eprazinone hydrochloride. Accordingly the condensation of phenacyl bromide with piperazine was studied using potassium carbonate in dimethylformamide at 80-85°C. The reaction was monitored by TLC where complete consumption of phenacyl bromide was observed. The product was isolated by pouring the reaction mass into water followed by filtration of the precipitated solid. Unfortunately, the isolated product was confirmed to be the undesired dimeric compound 12 by 1H NMR and mass spectral analysis.

O O N

Br HNHN N O

Phenacyl bromide 12 Scheme 5

The dimeric impurity 12 was formed by reaction of phenacyl bromide at both the nitrogen atoms of piperazine ring. To overcome this problem of dimeric impurity formation, one of the amino group of piperazine ring was protected with boc anhydride to get 1-boc piperazine. Further reaction of phenacyl bromide and 1-boc piperazine was studied using potassium carbonate as a base in DMF. The reaction was monitored by TLC and was completed in 2 hours at 25-30°C temperature. The new compound formed was isolated by addition of water into the reaction mass followed by filtration. The new compound was characterized by NMR and mass analysis and was found to be desired intermediate 3 (scheme 6).

boc O O N

Br HN N boc N

Phenacyl bromide 3 Scheme 6

Further reduction of intermediate 3 was studied by using sodium borohydride as reducing agent in methanol solvent. Sodium borohydride was added in portions to the mixture of 3 and methanol. After addition of sodium borohydride, reaction mixture was refluxed for 4 hours. The reaction was monitored by TLC and formation of new compound was observed. To destroy excess sodium borohydride from the reaction mixture, acetone was added in to the reaction mass and refluxed for 1.0 hour. For isolation of the product methanol was distilled from the reaction mixture and dichloromethane was added to extract the product. Dichloromethane layer was washed with water and concentrated to get new compound

which was characterized by NMR and mass spectroscopy and was found to be desired compound 4 (scheme 7).

boc boc O N OH N N N NaBH 4

Methanol 3 4 Scheme 7

Phenacyl bromide is a powerful lachrymator and it is unsafe to handle it on large scale. To avoid the handling of phenacyl bromide, its insitu condensation with 1-boc piperazine was studied. Accordingly acetophenone was brominated using bromine in dichloromethane. The reaction was monitored by TLC and formation of phenacyl bromide was observed which was confirmed by NMR and mass analysis. For insitu condensation of phenacyl bromide with 1-boc piperazine, potassium carbonate was added into the reaction mass. After stirring the reaction mass for 1.0 hour, 1- boc piperazine was added slowly by dissolving in dichloromethane. The reaction was monitored by TLC and formation of compound 3 was observed. The reaction mass was filtered to remove byproduct and filtrate after water washing directly taken for next step of carbonyl reduction using sodium borohydride. For reduction of carbonyl function to hydroxyl group, compound 3 in dichloromethane was stirred with sodium borohydride and methanol at 25-30°C for 2 to 4 hours where formation of compound 4 was observed. Hence acetophenone was converted to compound 4 without isolation of phenacyl bromide and intermediate 3 (scheme 8).

boc O OH N

N CH3

Insitu Acetophenone 4 Scheme 8

For introduction of ethyl group, o-alkylation of hydroxyl group in compound 4 was studied under basic conditions. Normally alcoholic o-alkylation works only with sodium

hydride or t-BuOK etc. Accordingly, this conversion was studied using potassium tert- butoxide as a strong base, ethyl bromide as an ethylating agent in aprotic polar solvent, N- methylpyrrolidone. To our satisfaction, this reaction conversion afforded the expected product 5 which was confirmed by spectral analysis (scheme 9).

CH3 boc boc OH N O N

N N Ethyl bromide

t-BuOK/NMP 4 5 Scheme 9

The reaction was optimized with respect to reaction temperature, quantity of ethylating agent, base and solvent. Further intermediate 5 was isolated as its hydrochloride salt and its conversion to eprazinone was studied via Mannich condition. As per reported methodologies, eprazinone dihydrochloride has been prepared by refluxing a mixture of 1-(2-phenyl-2-ethoxy) piperazine dihydrochloride, propiophenone and paraformaldehyde (or trioxymethylene), conc. HCl in ethanol solvent (Mannich condition). Accordingly Mannich reaction of HCl salt of intermediate 5 was studied using propiophenone, paraformaldehyde/trioxymethylene, Conc. HCl in different alcoholic solvents like methanol, ethanol and isopropanol. Best results were obtained by carrying the reaction in isopropanol.

CH CH 3 3 O boc N O N NO N Paraformaldehyde CH3 . 2 HCl CH HCl IPA/HCl 3 Reflux

HCl salt of 5 Eprazinone hydrochloride(1) Scheme 10

In the final optimized process, hydrochloride salt of 5 was refluxed with propiophenone (1.1 eq.), paraformaldehyde (2.0 eq.) and Conc. HCl (1.2 eq.) in 3 volumes

of isopropanol for 8 to 10 hours. Product was isolated by cooling the reaction mass at 0-5°C followed by filtration. Crude product was purified by recrystallization from 80:20 mixture of methanol and water. From our study, we concluded that the following synthetic scheme (scheme 11) with optimized condition provided best results for the manufacture of eprazinone hydrochloride with respect to yield and purity.

boc

N boc O O O N N Br N Br H CH3 2 MDC K2CO 3/MDC

Acetophenone Phenacyl bromide 3

CH3 boc boc OH N O N

NaBH N N 4 Ethyl bromide

Methanol t-BuOK/NMP 4 5

CH3 ON N O

Paraformaldehyde CH3 CH3 .2 HCl IPA/HCl Reflux Eprazinone hydrochloride (1)

Scheme 11

Advantages of the newly developed process over the literature processes: • Use of hazardous and highly flammable reagent, tert-butyl hypochlorite/bromite was avoided making the process safe, eco-friendly and industrial feasible. • Most of the steps in the novel process are insitu which helps in handling and to increase the productivity at industrial scale. • Overall yields are higher as compared to literature methods. • The raw materials and reagents used are safe and cheaply available. 76

In conclusion, a new and improved process is developed for synthesis of Eprazinone dihydrochloride starting from cheap raw material acetophenone. This process is currently being evaluated for the commercial manufacturing of eprazinone hydrochloride.

EXPERIMENTAL SECTION 1 The H NMR spectra were recorded in DMSO-d6 on Varian 400 MHz; the chemical shifts were reported in δ ppm relative to TMS. The IR spectra were recorded in the solid state KBr dispersion using Perkins Elmer FT–IR spectrophotometer. The mass spectra were recorded on Applied Biosystems spectrometer. The melting points were determined by using Buchi apparatus. The solvents and reagents were used without purification. The purity by HPLC of all the compounds was checked on Waters make HPLC system using reverse phase C-18 column. Tertiary butyl piperazine 4-(2-phenyl ethan-2-one)-1-carboxylate (3):

O CH3 CH3

O NOCH3 N

Acetophenone (200 g, 1.66 mol) was mixed with dichloromethane (400 mL) and the reaction mixture was cooled at 10°C. Bromine (266 g, 1.66 mol) was dissolved in dichloromethane (200 mL) and added slowly into the reaction mixture by maintaining the reaction temperature at 10 to 20°C. After addition of bromine, the reaction mixture was stirred at 25 to 30°C for 2 to 4 hours till acetophenone becomes absent on TLC. The reaction mixture was directly taken for next step without isolation of phenacyl bromide. Potassium carbonate (344.0g, 2.49 mol) was added to the reaction mixture of phenacyl bromide and stirred at 25-30°C for 1.0 hour. The reaction mixture was cooled at 15 to 20°C and a mixture of 1-boc piperazine (372.0 g, 2.0 mol) in dichloromethane (800 mL) was added slowly with stirring. The reaction mixture was stirred at 15-20°C for 2 to 4 hours till phenacyl bromide becomes absent by TLC. After completion of the reaction, the reaction mixture was filtered, the filtrate washed with water and taken directly for next step. For characterization purpose, small sample of compound 3 was isolated, purified and subjected to spectral analysis.

Molecular Formula : C17 H24 O3N2. MS ( m/z) : 305

1H NMR : δ 1.40 (s, 9 H), 2.46-2.50 (m, 4 H), 3.32 (t, J=4.6 Hz, 4 H), 3.88

(DMSO-d6, 400 MHz) (s, 2 H), 7.51 (t, J=7.8 Hz, 2 H), 7.62 (m, 1 H), 7.97 (d, J=7.1 Hz, 2 H); 13 C NMR : 27.99, 52.27, 63.39, 78.66, 127.94, 128.52, 133.14, 135.80,

(DMSO-d6, 100 MHz) 153.74, 196.67. Elemental analysis : Calcd.: C, 67.10; H, 7.89; N, 9.21. Found: C, 65.85; H, 7.89; N, 10.34%.

Tertiary butyl piperazine (4-(2-phenyl 2-hydroxy ethyl-1-yl))-1-carboxylate (4)

O CH3 CH3

OH NOCH3 N

Sodium borohydride (31.5 g, 0.829 mol) was added to the reaction mixture of 3 in dichloromethane. Methanol (200 mL) was added slowly at 25 to 40°C and the reaction mixture was stirred for 4 to 6 hours at 25 to 30°C temperature. After completion of the reaction, water (2.0 L) was added to the reaction mixture at 25 to 30°C. After stirring the reaction mixture for 30 minutes, the organic layer was separated, washed with water (2×1.0L)) and concentrated to give crude alcohol 4 which was used directly in the next step. A small sample of the compound 4 was purified and characterized.

Molecular Formula : C17 H26 O3N2. MS ( m/z) : 307 1H NMR : δ 1.39 (s, 9 H), 2.36-2.50 (m, 6 H), 3.22-3.32 (m, 4 H), 4.68 (m, 1

(DMSO-d6, 400 MHz) H), 5.00 (s, 1 H), 7.22 (m, 1 H), 7.28-7.35 (m, 4 H); 13 C NMR : 28.01, 52.84, 66.22, 69.76, 78.60, 125.92, 126.72, 127.83, 144.52,

(DMSO-d6, 100 MHz) 153.76. Elemental analysis : Calcd.: C, 66.60; H, 8.49; N, 9.15. Found: C, 65.32; H, 8.74; N, 9.11%.

Tertiary butyl piperazine (4-(2-phenyl 2-ethoxy ethyl-1-yl))-1-carboxylate hydrochloride (5)

CH3 O CH3 CH3

O NOCH3 N

Crude alcohol 4 was dissolved in N-methylpyrrolidone (800 mL) and the solution was cooled at 0 to 5°C. Potassium tert-butoxide (373 g, 3.33 mol) was added to the cold solution followed by addition of ethyl bromide (362 g, 3.32 mol) at 0 to 5°C. The reaction mixture was stirred at 25 to 30°C for 6 to 8 hours. After completion of the reaction, water (2.0 L) was added slowly into the reaction mixture maintaining the temperature below 30°C. After stirring the reaction mixture for 30 minutes, dichloromethane (400 mL) was added and stirring continued for 30 minutes. The organic layer was separated, washed with water and concentrated to give crude 5 (free base) which was dissolved in acetone (800 mL). 25% solution of HCl in IPA (600 g, 4.1 mol) was slowly added to the solution of 5 at 25 to 30°C and the mixture was stirred at 25 to 30°C for 1.0 hour. The reaction mass slurry was filtered, the wet cake was washed with chilled acetone (200 mL) and dried at 50 to 55°C under vacuum to afford 5 as its HCl salt with > 99% purity by HPLC (λmax : 210 nm; Mobile phase- Acetonitrile: Buffer (pH 3.5) in 30:70 ratio). Yield : 320 g, (52% yield on acetophenone)

Molecular formula : C19 H30 O3N2.HCl IR (KBr) : 2978, 2893, 2434, 1693, 1425, 1365, 1271, 1246, 1178, 1151, 1128, 1078, 1064, 1028, 968, 873, 756, 702 cm -1 MS( m/z) : 335 1H NMR : δ 1.14 (t, J=7.0 Hz, 3 H), 1.42 (s, 9 H), 3.07 (brs, 2 H), 3.20-

(DMSO-d6, 400 MHz) 3.33 (m, 4 H), 3.40-3.46 (m, 3 H), 3.65 (d, J=12 Hz, 1 H), 3.98 (d, J=13.8 Hz, 2 H), 4.98 (d, J=9.6 Hz, 1 H), 7.34-7.44 (m, 5 H), 11.08 (brs, 1 H); 13 C NMR : 15.03, 27.89, 50.91, 51.74, 60.37, 63.54, 75.60, 79.76, 126.52,

(DMSO-d6, 100 MHz) 128.41, 128.68, 138.28, 153.41.

Elemental analysis : Calcd.: C, 61.50; H, 8.36; N, 7.55. Found: C, 60.62; H, 8.86; N, 7.60%.

Eprazinone dihydrochloride (1)

ON N O

CH3 CH3 .2 HCl Paraformaldehyde (48.5 g, 1.61 mol)) and propiophenone (119 g, 0.89 mol) were added with stirring to a mixture of compound 5 (300 g, 0.81 mol) and isopropanol (900 mL). Hydrochloric acid (97 mL, 0.97 mol) was then added to the reaction mixture and temperature of the reaction was raised at 75 to 80°C. The reaction mixture was stirred at 75 to 80°C for 8 to 12 hours. For isolation of the product the reaction mixture was cooled at 0 to 5°C and filtered. The wet cake was washed with chilled isopropanol (150 mL)and dried at 50 to 55°C under vacuum (600 to 700 mm of Hg) to give crude product which was further recrystallized from methanol + water mixture to give Eprazinone dihydrochloride with >

99% purity by HPLC (λmax : 210 nm; Mobile phase- Acetonitrile: Buffer (pH 3.5) in 30:70 ratio). Yield : 230 g, (65% yield)

Molecular formula : C24 H32 O2N2.2HCl Melting point : 201-203 °C; IR (KBr) : 2980, 2638, 2548, 2363, 1683, 1596, 1447, 1270, 1224, 1096, 1081, 977, 964, 862, 800, 758, 702 cm -1 MS( m/z) : 381 1H NMR : δ 1.21 (t, J=7.0 Hz, 3 H), 1.37 (d, J=7.2 Hz, 3 H), 3.43-3.53 (m, 4

(DMSO-d6, 400 MHz) H), 3.62 (m, 1 H), 3.81 (brs, 8 H), 3.97 (m, 1 H), 4.27 (m, 1 H), 4.94 (d, J=10.2 Hz, 1 H), 7.48-7.55 (m, 5 H), 7.66 (t, J=7.7 Hz, 2 H), 7.80 (t, J=7.4 Hz, 1 H), 8.11 (d, J=7.6 Hz, 2 H); 13 C NMR : 14.20, 16.48, 37.21, 48.74, 49.35, 58.15, 60.79, 64.48, 74.88,

(DMSO-d6, 100 MHz) 126.99, 128.71, 129.06, 129.11, 129.31, 134.12, 134.69, 136.34, 203.32

Elemental analysis : Calcd.: C, 63.50; H, 7.50; N, 6.17. Found: C, 63.60; H, 7.56; N, 6.35%.

1H NMR spectra of Compound 3

13 C NMR spectra of Compound 3

Mass spectra of Compound 3

1H NMR spectra of Compound 4

13 C NMR spectra of Compound 4

Mass spectra of Compound 4

1H NMR spectra of Compound 5

13 C NMR spectra of Compound 5 86

Mass spectra of Compound 5

IR spectra of Compound 5

HPLC Chromatogram of Compound 5

1H NMR spectra of Compound 1

13 C NMR spectra of Compound 1

Mass spectra of Compound 1

IR spectra of Compound 1

HPLC Chromatogram of Compound 1

REFERENCES 1. Eddy, N. B.; Friebel, H.; Hahn, K. J.; Halbach, H. Codeine and its Alternates for Pain and Cough Relief. Bull. W. H. 0. 1969, 40, 721-730. 2. Miller, D. Antitussives. Burger's Medicinal Chemistry; WileyInterscience: New York, 1981; Part 111, Cap. 53, pp 759-785. 3. (a) Craviso, G. L.; Musacchio, J. M. High-Affinity Dextromethorphan Binding Sites in Guinea Pig Brain I. Initial Characterization. Mol. Pharmacol. 1983, 23, 619-628. (b) Craviso, G. L.; Musacchio, J. M. High-Affinity Dextromethorphan Binding Sites in Guinea Pig Brain 11. Competition Experiments. Mol. Pharmacol. 1983, 23, 629-640. (c) Musacchio, J. M.; Klein, M.; Santiago, L. J. Allosteric Modulation of Dextromethorphan Binding Sites. Neuropharmacology 1987, 26, 997-1001. (d) Tortella, F. C.; Pellicano, M.; Bowery, N. G. Dextromethorphan and neuromodulation: old drug coughs up new activities. Trends Pharmucol. Sci. 1989,10, 501-506. Gandolfi et al. 4. (a) Kase, Y.; Kito, G.; Miyata, T.; Uno, T.; Takahama, K.; Ida, H. Antitussive Activity and other Related Pharmacological Properties of d-3-Methyl-N-methylmorphinan(A T-17). Arzneim.- Forsch. 1976,26,353-360. (b) Kase, Y.; Kito, G.; Miyata,T.; Takahama, K.; Uno, T.; Ida, H. On the Sites of Antitussive Action of d-3-Methyl-N-methylmorphina(nA T-17). Arzneim: Forsch. 1976,26, 361-366. 5. Hahn, K J.; Friebel, H. Wirkungen hustenhemmender Pharmaka im zentralen Anteil der Hustenreflexbahn. (Effects of antitussive agents on the coughing center and in other parts of the central structures of the cough reflex.) Med. Pharmacol. Exp. 6. GMsswald, R. l-Phenyl-l-(o-chlorophenyl)-3-dimethylamino-propanol-(l), ein neuer hustenhemmender Stoff. (1-Phenyl-140-chlorophenyl)-3-imethylamino-propanol-(1)a, n ew antitussive agent.) Arzneim.-Forsch. 1958,8, 550-553. 7. (a) Canti, G.; Franco, P.; Micolin, A. Study on the pharmacological activity of l-[2-(p- chloro-a-phenylbenzyloxy)ethylpiperidine (cloperastine). Boll. Chim. Farm. 1983,122,384- 92, (b) Oldini, C.; Vecchi, E. Double-blind investigation of the antitussive effectiveness of cloperastine. Curr. Ther. Res. Clin. Exp. 1987, 42,99-105. 8. Rispat, G.; Burgi, H.; Cosnier, D.; Duchsne-Marullaz, P.; Streichenberger, G. General Pharmacological Properties of a New Non-opiate Antitussive: Zipeprol (3024 CERM).

Arzneim: Forsch. 1976, 26, 523-530. (b) Constantin, M.; Pognat, J. F. Zipeprol Metabolism in Man and in the Animal. Arzneim.-Forsch. 1978,28, 64-72. 9. (a) Noel, P. R. B. Dropropizine (UCB 1967), an Antitussive: Oral Toxicity Study in Pure- bred Dogs. Arzneim.-Forsch. 1969, 19, 1246-1249. (b) Cartwright, K; Paterson, J. L. Human volunteer studies of the antitussive activity of dropropizine. J. Pharm. Pharmacol. 1971,23 (Suppl.), 2479. (c) Nosalova, G.; Korpas, J.; Strapkova, A. Experimental evaluation of a new Czechoslovak antitussive drug dropropizine (Ditustat). Furmakoter. Zpr. 10. Rispat G, Burgi H, Cosnier D, et al. General pharmacological properties of a new non-opiate antitussive: zipeprol (3024 CERM). I. Action on respiratory function and acute toxicity. Arzneimittelforschung. 1976 Apr; 26(4):523-30. 11. Chung H, Park M, Hahn E, et al. Recent trends of drug abuse and drug-associated deaths in Korea. Ann N Y Acad Sci. 2004 Oct; 1025:458-64. 12. (a) Giani, R.; Marinone, E.; Melillo, G.; Borsa, M.; Tonon, G. C. Synthesis and Pharmacological Screening of New Phenylpiperazinepropane Derivatives and Their Enantiomers. Arzneim.-Forsch. 1988, 38, 1139-114. (b) Malandrino, S.; Melillo, G.; Bestetti, A.; Borsa, M.; Giuliani, P.; Tonon, G. C. Antitussive Properties of Levodropropizine. Arzneim.-Forsch. 1988, 38, 1141-1143. (c) Bosi, R.; Braga, P. C.; Centanni, S.; Legnani, D.; Moavero, N. E.; Allegra, L. Antitussive Activity and Respiratory System Effects of Levodropropizine in Man. Arzneim: Forsch. 1988,38, 1159-1166. 13. Silvestrini, B.; Pozzatti, C. Antitussive Activity and Other Pharmacological Properties of Six Oxadiazoles. Arch. Znt. Pharmmodyn. Ther. 1960,129,249-263. (b) Silvestrini, B.; Pozzatti, C. Pharmacological Properties of 3-Phenyl-5,4-Diethylaminoethyl-1,2,4-Oxadiazole. Br. J. Pharmacol. Chemother. 1961,16, 209-217. 14. Mauvernay, Roland Y (Riom, France) US 3,448,192; 1969 15. Ramon Conde, Juan; Bermejo, Juan; Alcaide Garcia, Antonio. (Laboratorios Liade S. A., Spain). ES 424173; 1976 16. Yoshioka, Yoshiatsu. (Toho Iyaku Kenkyusho Co., Ltd., Japan). JP 51088979; 1976.