Method of treating depression using di-substituted -&#39; -phenethylcarbamic acid esters
[ 1 Apr. 8, 1975 1 METHOD or TREATING DEPRESSION usmc Dl-SUBSTITUTED -B-PHENETHYLCARBAMIC ACID ESTERS [75] Inventors: John Hans Biel, Lake Bluff. Ill.:  
 Irwin L. Klundt, Brookfield. Wis.  
 [73] Assignee: Aldrich Chemical Company,  
 Milwaukee, Wis.  
 [221&#39; Filed: Aug. 2, 1973 [21] Appl. No.: 385,010  
 Related US. Application Data [62] Division at Ser. No. 96.586. Dec. 9, 1970. Pat. No.  
 [52] U.S. Cl. 424/300; 424/244; 424/285; 424/301 [51] Int. Cl...-.. A6lk 27/00 [58] Field of Search 424/300; 260/271 C [56] p 4 References Cited UNITED STATES PATENTS 3.600.427 &#39;8/19&#39;71 Verbiscar 260/471 c Primary Examiner-Stanley Friedman Attorney, Agent, qr FirmR0bert L. Niblack; Joyce R. Krei; Vincent A. Mallare [57] Y ABSTRACT Novel di-substitut&#39;ed B-phenethylcarbamic acid esters. The compounds are useful as antidepressants and anti- Parkinsonism agents.  
 9 Claims, No Drawings METHOD OF TREATING DEPRESSION USING DI-SUBSTITUTED -B-PIIENETI-IYLCARBAMIC ACID ESTERS This is a division of application Ser. No. 96,586 filed Dec. 9, 1970, now U.S. Pat. No. 3,801,624.  
 BACKGROUND OF THE INVENTION Until recently, patients suffering from Parkinsonism were treated with anticonvulsants, antispasmodics, central nervous system stimulants, and the like, in an attempt to produce temporary amelioration of their complaints. In severe cases, surgical procedures were employed with some success. L-Dopa was the first single agent found to be effective in reversing the akinesia and rigidity of Parkinsonism, particularly in severe cases. An increase in mental alertness and wakefulness,  
 relief from depression, and an increase in intellect has also been observed in patients receiving L-Dopa.  
  While L-Dopa has produced some rather promising results in experimental therapy and is being used in a limited number of patients, it is not well tolerated by&#39;a number of patients. The most frequent side effects are nausea, vomiting, postural hypotension, cardiac dysrhythmia and choreiform movements. The abnormal,  
 . involuntary movements pose severe problems to the drugs continued use in approximately 50 percent of the patients. Furthermore, dopamine itself is not orally active and has a very short duration of action. Thus; the search for more effective, orally active, long-acting anti-Parkinson agents continues. It is an object of the present invention to provide such agents.  
 SUMMARY This invention relates to novel B-phenethylcarbamic acid esters represented structural formula: I  
 di-substituted bythe wherein: R and R are hydrogen, benzyl, substituted benzyl, or  
 wherein A is O, NH, or S, and R is lower alkyl, lower alkenyl, or lower alkynyl; and R is lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, c&#39;yclopropylmethyl, B-(Z-furyU-ethyl or azetidinyl; with the limita- Lower alkenyl&#34; refers to both straight and branched chain alkenyl groups containing from 2 to 5 carbon atoms, such as&#39;vinyl, allyl, methallyl, l-pentenyl, and the like.  
  Lower alkynyl refers to C -C alkyl groups as defined above from which two hydrogen atoms have been removed from each of two adjacent carbon atoms to produce acetylenic unsaturation; e.g., propargyl, 2- butynyl, l=pentynyl, and the like.  
  Substituted b&#39;enzyl refers to a mono, di-, or trisubstituted ben zyl moiety substituted in the ortho, meta and/or para positions by a chloro, fluoro, iodo, bromo, or tri-fluoromethyl atom.  
 Halo includes chloro, fluoro, bromo, and iodo.  
  The anti-Parkinson activity of the above compounds was established using the Harmonyl (deserpidine) Antagonism Test. In the Harmony] test, mice are dosed Y orally with 50 mg/kg of deserpidine 24 hours prior to drug evaluationqln mice, deserpidine produces ptosis, hunched posture, sedation, catalepsy and rigidity. L- Dopa produces marked reversal of the above effects in mice. Antagonism of the deserpidine effects in mice are graded slight (1), moderate (2) or marked (3), based on the reversal of the Harmonyl effects. The compounds of the invention produce moderate to marked reversal in dosages of from 10 to 200 mg/kg of body weight.  
  The compounds are generally administered to mammalian Parkinsonism patients in dosages of from 10 to 200 mg/kg of body weight daily, preferably in divided doses. While the compounds exhibit both oral and parenteral activity, the preferred route of administration is the oral route. The oral LD of the compounds of this invention in mice are approximately 6()0l .000 mg/kg.  
  The antidepressant activity of the compounds of this invention was first established in the modified dopa test as described by Everett et al., Fed. Proc., 23 p. 198 (1964). The compounds are useful as antidepressant agents when administered to depressed patients in dosages of from 10 to 200 mg/kg of&#39;body weightdaily, preferably in divided doses.  
 Representative compounds of the present invention include:&#39;  
 3,4-Dibenzyloxy-B-phenethylcarbamic acid, furfu&#39;ryl ester,  
 3,4-DihydroxyB-phenethylcarbamic acid, ethyl ester,  
 3,4-Dihydroxy-B-phenethylcarbamic acid, isopropyl ester,  
 3,4-Dihydroxy-B-phenethylcarba&#39;mic acid, n-butyl ester,  
 3,4-Dibenzyloxy-B-phenethylcarbamic acid, B-trichloroethyl ester, 3,4-Dibenzyloxy-B-phenethylcarbamic acid, isopropyl ester,  
 3,4-Dihydroxy-fi phenethylcarbamic acid, trichloro-- ethyl ester, 3,4-Dihydroxy-B-phenethylcarbamic acid, 3- azetidinyl ester, 3,4-Dibenzyloxy-B-phenethylcarbmic acid, cyclopro pylmethyl ester, 3,4-Dithioethoxycarbonyl-B-phenethylcarbamic acid, ethyl ester 3,4-Dimethoxycarbonyl-B-phenethylcarbamic acid,  
  methyl ester 3,4-Dipropargyloxycarbonyl-B-phenethylcarbamic acid, propargyl ester,  
 3,4-Diallyloxycarbonyl-B-phenethylcarbamic acid, lowed to stand at room temperature overnight, filtered, allyl ester and solvent removed in vacuo and the residue purified The method of synthesis of the compounds of this inby a Kugelrohr distillation to give 14 g (78%) of 3,4- vention is represented by the following reaction dibenzyloxy-fi-phenethylisocyanate as a light yellow scheme. 5 oil, b.p. l80 (0.05 mm).  
  RC1 ca uo no CHO RO@CHO R H GH-N ao R0 R0 I no on -ca maco R&#39; ROCCl 2 2 2 Pd/C/H O 5 no cs ca naco a&#39; o CH -CH -NH I R0 R0 RACC ft.  
  0]. meet m V o ll moi Q CH -CH -NH CO R RACO R0 CH -CH -N C O Generally speaking, protocatechualdehyde. l, (Ald- I Analysis Calcd. for C H NO C, 76.86; H, 5.89; N, rich Chemical Co.) is reacted with RCl (i.e., benzyl 3.90; Found: C, 77.17; H, 5.75; N, 3.90 chloride, etc.) to prepare 2-(wherein R=C H CH B. 3,4-Dibenzyloxy-B-phenethylcarbamic acid, isopro- 2 is converted to the corresponding B-nitrostyrene, 3, pyl ester which is treated with lithium aluminum hydride and the In a 50 ml flask equipped with a magnetic stirrer and resulting amine 4 reacted-with an appropriate chloroa reflux condenser protected by a drying tube were formate to prepare 5 (R=loweralkyl, etc.) or the placed 4.5 g (12.5 mole) of 3,4-dibenzyloxy-B- amine 4 can be converted to the isocyanate 8 and then phenethylisocyanate, 20 ml of benzene, 1.3 ml of dry reacted with an appropriate alcohol to prepare 5. Reisopropanol and a crystal of bicyclo[2,2,2] 1,4- moval of the catechol protecting group produces 6 diazaoctane. The reaction was heated at reflux for 20 which can be converted to 7(A=O, NH or S) by treathours. Removal of the solvent left a residue which coning 6 with either an appropriate chloroformate or an tained the unreacted isocyanate. The residue was redisisocyanate. solved in 25 ml of benzene, 1.3 ml of isopropanol The following examples further illustrate the present added and 2 drops of DBU (Aldrichl,3-diazabicyinvention. clo[5,4,0]undec-5 ene) added. This was heated to reflux for 24 hours. The reaction was cooled, diluted with EXAMPLE 1 25 ml of benzene, filtered and the solvent was removed PREPARATION OF in vacuo. The residue was dissolved in 150 ml of hot cy- 3,4-DlBENZYLOXY B-PHENETHYLCARBAMIC clohexane and set aside to crystallize. The white solid ACID, ISOPROPYL ESTER was filtered off and dried in vacuo to yield 2.1 g of 3,4- dibenzyloxy-B-phenethylcarbamic acid, isopropyl ester, m.p. 83C.  
 55 Analysis Calcd. for C .;H NO C, 74.44; H, 6.97; N,  
 3.34; Found: C, 74.68; H, 6.89; N, 3.41  
 A. 3,4-Dibenzyloxy-B-phenethylisocyanate In a 500 ml three necked flask equipped with a gas inlet tube and a Claisen head for distillation were placed 18.5 g (0.05-mole) of benzyloxydopamine hydrochloride in 350 ml of toluene. This was heated to reflux and ml of toluene distilled off. The Claisen head was replaced with a reflux condenser equipped The following compounds were prepared according with a drying tube and phosgene was bubbled through to the method of Example 1 by replacing isopropanol the refluxing solution for 4 hours. The reaction was alwith the appropriate alcohol.  
 EXAMPLES 2 9 l n 0 ca -ca -mic-oa,  
 Analvsis EX- Empirical (L1 c cl Found it R1 R R 11.1. Formula 0 n N c a N 2 ll 11 (CH3)2CH 91.5-92.5 c n uo 60.25 7.11 5.86 60.13 7.25 5.77 3 a a 001 011 155 157 c a m uo 40.21 3.68 4.12 40.48 3.84 4.14 4 a H A411 118 119 0 11 110 62.07 6.81 5.57 62.20 6.51 5.59 5 H a 9 D 102 -104 0 11 80, 63.42 7.7 5.28 63.40 7.99 5.71 6 ll c a cc a 127 129 C14H19N06 56.64 6.40 4.71 56.71 6.44 4.60 7 0 11 014 C 1-l Cl-I 011 001 127.5-128.5 CZSHZACINOI 59.01 4.75 2.75 59.16 4.63 2.88 8 C H Cll c n ca ca(cn s0 83 0 51 80 74.44 6.97 3.34 74.68 6.89 3.41 9 0 11 011 0 11 611 ca w 71 73 C l-I N0 73.36 6.11 3.06 73.36 5.97 3.1  
 EXAMPLE 1O the compositions, or by heating the compositions. They 3,4-Dll-lYDROXY-B-PHENETHYLCARBAMIC ACID, ETHYL ESTER A solution of 45 g of 3,4-dibenzyloxy-B-phenethylcarbamic acid, ethyl ester, prepared according to the method of Example 1, in 200 ml of ethanol containing 3 g of moist 10% Pd/C was hydrogenated at p.s.i. The reaction was filtered, evaporated to dryness and recrystallized from benzene to yield 18.4 g of product, m.p. 99-l0l.  
 Analysis Calcd. for C l-l NQpC, 58.65; H, 6.71; N,  
 6.22; Found: C 58.63; H, 6.58, N, 5.98  
  The compounds useful in the practice of the present invention are generally formulated into pharmaceutical compositions comprising, as an active ingredient, at least one of the active agents in association with a pharmaceutical carrier or diluent. The compounds useful in the practice of the invention exhibit both oral and parenteral activity and can be formulated in dosage forms for oral or parenteral administration.  
  Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. in such solid dosage forms, the active compound is admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.  
  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Besides inert diluents, such compositions can also include adjuvants,  
 such as wetting agents, emulsifying and suspending agents and sweetening, flavoring and perfuming agents.  
  Preparations according to this invention for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.  
  The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient shall be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect. on the route of administration, and on the duration of the treatment.  
 We claim:  
  1. A method of relieving the systems of depression in a mammalian patient in need of such treatment comprising the administration to said patient of a therapeutically effective amount of a compound of the formula:  
 wherein R and R are the same or different members of the group consisting of hydrogen or benzyl; and R, is loweralkyl, lowerhaloalkyl, cyclopropylmethyl or cyclopentyl.  
  2. A method in accordance withclaim 1 wherein the compound is 3,4-dihydroxy-B-phenethylcarbamic acid, ethyl ester.  
  3. A method in accordance with claim 1 wherein the compound is 3,4-dibenzyloxy-B-phenethyl-carbamic acid, ethyl ester.  
  4. A method in accordance with claim 1 wherein R, is loweralkyl.  
 5. A method in accordance with claim 1 wherein R is ethyl.  
  6. A method in accordance with claim 1 wherein R is iso-propyl.  
  7. A method in accordance with claim 1 wherein R is chloroethyl.  
  8. A method in accordance with claim 1 wherein R is cyclopropylmethyl.  
 9. A method in accordance with claim 1 wherein R is cyclopentyl.