SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF SOME ALKOXY SUBSTITUTED Beta-PHENYLETHYLAMINE DERIVATiVES
Mesis Presented to The AHgarh Muslim University
for the D^ree of Doctor of Philosophy
By SHAHANSHAH HUSAIN, M. SC.
1966 T620 ACKNOWLEDGEMENT
The author acknowledges with gr.atitude the keen interest and valuable guidance of Dr. A.R. Kidwai, M.S. (Illinois), Ph.D. (Cornell), Professor and Head of the Department of Chemistry, Aligarh Muslim University, Aligarh and Dr. G.S. Sidhu, B.Sc. (Hons.), M.Sc., Ph.D. (Lucknow), Director, Regional Research Laboratory, Hyderabad.
The author gratefully acknowledges valuable discussions with Dr. P.B, Sattur, M.Sc., Ph.D. (Karnatak), Scientist, Regional Research Laboratory, Hyderabad through- out the progress of this work.
The author is indebted to Riker Laboratories, Northridge, California, U.S.A. and Prof. U.K. Sheth, Professor of Pharmacology, Seth G.S. Medical College, Bombay for carrying out the pharmacological screening of the compounds.
The work recorded in this thesis is original and has not been submitted for any other degree of this or other universities.
Department of Chemistry (SHAHANSHAH HUSAIN) Aligarh Muslipk .U^vive-rsity ^ ALIGARH.
Dated: y^^^ CONTENTS
Page
CHAPTER
Introduction 1
CHAPTER II
N-Chloroacyl-p-phenyl- ethylamines Experimental 26
CHAPTER III
N-Aminoacyl-p-phenyl- 44 ethylamines
Experimental 69
CHAPTER IV
N-Aminoalkyl-p-phenyl- 112 ethylamines Experimental 129
CHAPTER
Pharmacology 176
APPENDIX 201
SUMMARY 206
--:oOo:— CHAPTER INTRODUCTION
The chemistry and pharmacology of P-phenylethyl- amines has been widely studied after the discovery of their actions on the sjnnpathetic nervous system. Because they mimic the action of the naturally occurring amines of the sympathetic nervous system, they are also known as sympatho- mimetic amines. The observation of 7ulpias in 1856 that the secretion of the adrenal medulla could raise the blood pressure in laboratory animals and in man, led . a number of workers to investigate the chemistry and pharmacology of related amines. Barger and Dale^ in their comprehensive investigation synthesized a number of compounds having in common the P-phenylethylamine grouping (I).
(I)
Interest in the naturally occurring and synthetic P-phenylethyT.amines was further increased when Sp§th^ in 1919 recognised the presence of P-phenylethylamine skeleton in the structure of Mescaline, i.e. P-3,4,5-trimethoxyphenylethyl- amine (II), the active hallucinogenic principle of 2
mescatbuttoa or pellote.
H3C0 NH.
H3C0
(IT)
Some of the naturally occurring P-phenylethylamines with their source are as follows:
S.No, Structure and name Source
1. Putrefactive decom- position products of proteins^, in some species of (ITT) Acacia'^. p-phenylethylamine
2. Chenopodiaceae, Arthrophytum lepto- CH. cladum Popov^»®, flowering tops of (IV) N-methyl-P-phenyliethylamine Acacia prominens*^* 3
S.No. Structure and name Source
OH 3. Halostachys caspica C.A. Mey2»®. NH —CH.
(V) (Halostachine ^ Phenethanolmethylamlne
4. Ergot species^®' in the salivary glands of cephalo- NH. pods^^"^'^, several species of American . mistletoes; (VI) (phorodendron (Tyramine) flavescens Nutt.,), p-hydroxy-p-phenylethylamine Phorodendron californicum Nutt)l^»l®
5. Certain strains of "barley Thermal or putrefactive NH- CH: HO decarboxylation of the natural N-methyl f7II) tjrrosine^'^'^. C^I-methyl tyr amine ) p-p-hydroxyphenylethylmethyl- amine 4
S.No, Structure and name Source
6. Gactaceae, Anhalonium fissuratura HO Engelffll^. CH,
(VIII) (Hordenjne; Anhaline) P-p-hydroxyphenylethyldimethylamlne
7. Argentine cactus, Trichocereus N (CHa)^. OH candicans^^, HO + » T. lamprochlorus^®.
(IX) (Candicine) p-p-OH-phenylethyl trimethyl- ammonlum hydroxide
8. On the pods of common broom, p, Cytisus scoparias NH. and roots of Hermidium alipes S. Wats39. (X) (r?-Hydroxy Tyramine) P-3,4-dihydroxyphenylethylamine 5
S.No. Structure and name Source
9. Bark of prickly ash, Zanthoxylum america- n-co-ch=
(XI) (0-Methyltyramine-N-methylcInnamide) N-(2-anisylethyl)-N-methylclnnainlde
Mescal buttons^^
NHCOCH,
(XII) N-acetylmescaline
11. H3CO Argentine cactus, Trichocereus N-CH, terscheckil3®. H,CO I CH, OCH
(XIII) (Trichocereine) NjN-dimethylmescallne The pharmacological study of P-phenyletl^lamines has been mainly coacerned with their action on the blood pressure and on the bronchodilator properties. Various reviews^^'^'^ have appeared from time to time and hence only the salient features of structure activity relation- ship are highlighted here,
P-phenylethylamine molecule has been studied for the structucpe activity relationship from the following aspects.
cL I / c -c- N o \
1. Effect of substitution on nitrogen 2. Effect of substitution on the c(- and P- carbon atoms 3. Effect of substitution on the benzene nucleus.
1. Effect of Substitution on Nitrogen
It has not been possible to draw overall conclusions 7 regarding the effect of alkyl substitution on the amino nitrogen. But in general it appears that the N-methyl compounds are less active^®'^® than the corresponding primary amines but this generalization has also exceptions, p-3,4-dihydroxyphenethylamine'^^ (XI7) is four times less active than its -N-CH3 derivative'^! (X7).
HO
NH- R HO
(XIV) R=H
(XV) R = CH;
In many cases, the decrease in pressor activity is accompanied by a rise in toxicity of the methylamine derivatives^S, This holds true even for dialkylated compounds. Tertiary amines of this series become less active and more toxic as the size of the alkyl group is increased and many of them no longer possess pressor action.
The effect of N-alkylation of p-phenyletliylamine having alkyl groups such as ethyl, propyl, butyl or benzyl has shown that these N-alkylated compounds are less active than 8 the parent substance, p-phenylethylamine, and N-phenylethyl- ethylene-diamine (XVI) in smaller doses has no effect on blood pressure but at a dose of 20 mgAg produces a transient fall of blood pressure^"^.
NH~ CH2 — CH2 —NH2
(XVI)
2, Effect of substitution on the oc-carbon atom
Amongst the various possible substituents at the o(-carbon atom, the methyl group has received the most atten- tion. The presence of a methyl group on the o(-carbon atom consistently reduces the pressor activity and tends to increase the toxicity but confers greater stability to the molecule against an enzymatic attack and also the compounds can be orally administered, p-phenylethylamine is inactive when taken by mouth but its o(-.methyl derivative, benzedrine (XVII), is active and the duration of action is also longer^^; Benzedrine has been employed in therapy as an analeptic drug. When the alkyl group is larger than methyl, the pressor activity further decreases and toxicity also increases. The N-methyl derivative of benzedrine (Pervitin) (XVIII) has been 9
employed clinically as an antifatigue agent2 9
CH,
(XVII) Benzedrine
CH.
NH-CH3
(XVIII) Pervitin
Replacement of a methyl group by a phenyl group in amphetamine (XIX) gives rise to a depressant effect of 30 the central nervous system
o NH-
(XXIV) 10
The influence of other groups has not been adequately investigated.
3. Effect of Substitution on g-carbon Atom
The effect of alcoholic P-hydroxy group has received much attention as the. naturally occurring alkaloids such as Ephedrine (XX) and Epinephrine (XXI) are well known for their therapeutic use.
OH OH CH, HO
NH-CH. NH-CH, HO (XX) (XXI) Ephedrine Epinephrine
Introduction of a methyl group on the P-carbon atom enhances the pressor activity as compared with the c(-methyl substitu- tion'^*As the size of the alkyl group on p-carbon atom is increased, pressor activity decreases and toxicity increases'^. The effect of an amino group on p-carbon atom leads to bronchodilator action. Thus l-(3;4-dihydroxy- phenyl)-l-amino(2-methylamino)ethane (XXII) has been claimed to posses bronchodilator action^^. 11
NH HO
NH- CH3 HO
(XXII)
4. Effect of substitatloQ In the pheayl aucleus
The effect of a monosubstitoted phenolic hydroscy group such as in Tyramine and the effect of disubstituted hydroxyl groups in epinephrine is well known. It has been well established that the presence of the two hydroxyl groups in catechol structure produces a higher physiological activity. It is, however, interesting to observe that analogous derivatives'with three hydroxyl grou^js exhibit less pressor activity than those compounds having only the catechol structure, Alkylation or acylation of the phenolic hydroxyl group leads to less active compounds. But, however, powerful pressor activity has been exhibited by the compounds of the type (XXIII)
RO
R = OCH, (XXIII) 12
In case of other alkoxy substituted derivatives, oo A, Gee sink and W.A. den Hartog Jager reported that mescaline has no effect on arterial pressure whereas P-3,4-dimethoxy- phenylethylamine at a dose of 100 mgA^g increases the arterial pressure by 20 per cent in cat. The effect of p-alkoxy- substituents having an alkoxy group ranging from methoxy to nonoxy was studied for their inhibiting action on both iso- lated smooth organs and in intact animals. It was observed that the inhibitory action increases as the size of the alkyl group increases upto hexyloxy and thereafter the activity falls^^^ Benington et al investigated the effect of alkyl group particularly of methyl grou?) and reported that N-methyl-3,4-dimethyl and 3,4-trimetl:^l- phenylethylamine causesa rapid increase of blood pressure^^.
The effect of halogen substituted in the nucleus has not been investigated systematically. The effect of chlorine in para position confers more activity on the
Parent P-phenylethylamine, whereas the introduction of fluorine in the nucleus increases the toxicity by 30-40 44 per cent
PRESENT WORK
It is evident from the above literature that the effects of an N-acylamino and N-alkylamino substituents on the N-atom have not been investigated. It was, therefore, thought worthwhile to undertake a systematic investigation of the alkoxy substituted phenylethylamines having an 13 acylamino and alkylamino substitueats on the amino nitrogen. In the present investigation compounds of the following types (A), (B) and (C) have been synthesised and tested for their pharmacological behaviour in experimental animals,
NH- CO-Y — CI
(A)
NH - CO- Y — N Z
(B)
NH — CH,- Y - N Z
(C)
where R^ and Rg represent H; methoxy in p-position; 3,4-di- methoxy; 3-methoxy-4-etho3?y5 3,4-diethoxy and 3,4-methylBne- dioxy groups. 14 y stands for CH2; -CH- and -CH2-CH2- and CHo
-N Z stands for
Et — N. -N O —N Et \ / V
CH, CH.
— N -N —N —N CH- V V V V
Compounds of series 'A' are intermediates for the synthesis of compounds of series where the terminal chlorine of the series 'A' is replaced by a variety of groups such as diethylamine, morpholine, piperidine, pyrrolidine and 2-, 3-, or 4-methylpiperidine. However, the compounds of series 'A' are also of interest because of their structural resemblance to N-ben2yl-p-chloropropionamide (Hibicon) (XXIV)
CH2—NH —CO—CHj— CH2—CI
(XXIV) 15 which was introduced into therapy as an antiepileptic drug and was later on withdrawn from therapeutic use because of its toxicity. Compounds belonging to series 'A' were obtained by reacting chloroacetyl, 2- and 3-ehloropropionylchlorides with various P-phenylethylamines in alkaline medium. These are described in experimental part of Chapter II,
Compounds of series 'C were obtained by reduction of compounds represented by series 'B' with lithium aluminium hydride in tetrahydrofuran and also by the direct condensation of the basic alkylchlorides with p-phenylethylamines.
A glance at structures 'A', 'B' and 'C shows that the compounds of series 'A' are neutral, those of 'B' are basic amides and those of structures 'C are diamines. It is possible that the differences in physiological activity of compounds in these series may be related to the basicity of the compounds and one of the ideas behind the synthesis of these compounds was to find such correlations.
Pharmacology
The compounds synthesised during the course of the present work have been sent for pharmacological screening in experimental animals. Pharmacological screening takes considerable time and the data about all the compounds is not yet available. The data as far as has been received till the time of writing of the thesis, is discussed in Chapter V, 16
BEFERENGES
1. G. Barger and H.H. Dale, J. Physiol., (Lond.), 41, 19 (1910). 2. E. Spath, Monatsh, 40, 129 (l9l9).
3. M. GuggenheimBase, l Di(1951)e biop;ene. n Amine, 4th Ed., S. Karger, 4. E.P. Whi-^e, New Zealand J. Sci. Tech., 2i]B, 139 (1943/ 44).
N,K. Y':irasbevskii, -T. Gen. Chem., (U.S.S.R.), 9, (1939). 6. N.K. Yura?hevskii, Gen. Chem., (U.S.S.R.), JJ, 157 (1941). 7. E.P. '^rhite. New Zealand J. Sci. Tech., 252, 451 (1954); Chem. Abs., 49, 9535 (l955). 8. Yu. I. Syrneva, Farmalsol. i. Toksikol., 4, No. 1, 4- (1941); Chem. Abs., 1029 (1944). 9. G.P. Menshikov and M.M. Rubinstein, J. Gen. Chem., (U.S.S.R.), 13, 801 (1943); Chem. Abs., 39, 1172 (1945). 10. G. Barker, Pharm. -T,, 82, I4l (1909). 11. G. Barger, J. Chem. Soc., 95, 1^23 (1909). 12. M. Henze, physiol. Chem., 87, 51 (l913). 13. M. Henze, ohysiol. Chem., 227 (1929). 14. P. Bottazzi, Arch, intern, physiol., IS, 313 (l92l). 1". Crawford and '-LfC. '''Jatanabe, J. Biol. Chem., 19, 303 (1914). 16. A.C. Crawford and N.K. V/atanabe, J. Biol. Chem., 24, 169 (1916). 17. S. Kirkwood and L. Marion, J. Am. Chem. Soc., 72,
18. A. Heffer, Arch, exptl. Pathol. Pharmakol., 24i 6S (1894). 17
19. L. Heti, Compt. rend, soc. biol., 114, 811 (1933). 20. L. Reti anH R.I. Arnolt, Actas y Trabajos del Congreso Naicional de Medicina, "Rosario, 2, 39 (193.S). 21. H. Schmalfuss and A. Haider, Biochem. Z., 2^6, 226 (l93l) 22. F.B, La For^e an^ '•f.i^'. Barthel, J. Org. Ghem., 9, 250 (1944). 23. W.H, Hartunc, Chem. rev., 9, 389 (l93l). 24. W.H. Hartun", Ind. Ens. Ghem., 126 (1945).
25. F. Hauschild64,7 Arch(1940), e^oDtl. . Pathol. Pharmacol., 195, Alfrc"^ Burner, Medicinal Chemistry, Tnterscience PabTisher?, London, 1960, p. 597.
2^. Daniel Rovfit and Albert TPanke, Conrot. rend. soc. biol., 141, 325 (1947); Chem. Abs., 42, 982 (1948). 28. K.K. Chen, O.K. Wu and. F. Henriksen, .T. Pharmacol., 2f., 363 (1929). 29. ¥.H. Hartunf^ and J.C. Munch., J. Am. Chem. Soc., 53, 187S (1931).
30. J.A. Gunn and M.R. Gurd, J. Physiol.. 98, 424 (l940); Ghem. Abs., M, 8064 (1940).
31. R. Duschinsky, L.A. Dolan, L.O. Randall and G. Lehmamann, J. Am. Ghem. Soc., 69, 3150 (1947). 32. A. Geesink and W.A. den Harto^ Jager, Arch. -Neerland. nhysiol., 24, 79 (1939); Chem. Abs., 7901 (1939). 33. A. BuT-ger, Vgdicinal Chemistry, Vol. I, p. 312 (l95l), Tnterscience Publishers Inc., N.Y, 34. F. Benineton, R.D. Morin, Leland G. Clark, Jr., and R. Phyllis Fox, J. Org. Ghem., 1979 (19'^8). 35. E. Spath and J. Bruck, Ber., 7jl, 1275 (l938). 36. L. Reti and J.A. Castrillon, J. Am. Chem. Soc., 73, 1767 (1951). 18
37. G-.S. WalDOle, J. Ghem. Soc., 97, 94i (iQlO).
38. G. Gol-ischmledt, Monatsh., 659 (1913).
39. D.'''/. •Pmelow and 0. Gisvold, J. Am. Pharm. Assoc., 23, 270 (1944). 40. Gordon A. Alles, J. Pharmacol., 47, 339 (1933).
41. M.L. Tainter, J. Pharmacol., 43 (l930).
42. M.R. Warren, D.G. Marsh, C.R. Thompson, R.S. Shelton and T.J. Becker. J. Pharmacol., TO, 187 (1943). 43. M.L. Tainter, Arch, intern, pharmacodynamie, 46, 192 (1933). ,
44. C.M. Suter and A.^-f. Weston, J. Am. Ghem. Soc., 63^ 602 (1941). CHAPTER II 19
N-CHLOROACYL~p-PHEN¥LETHYLAMINES
N-chloroacyl-p-phenylethylamines were required for the synthesis of N-aminoacyl-p-phenylethylamines and also for pharmacological screening.
Most of the chloroacylaryl amides which have been studied so far are derived from ben2ylamines and were prepared primarily for testing for anticonvulsant activity against electroshock and audiogenic seizures^"One of the compounds viz, N-3-chloropropionylbenzylamine(XXIV) was introduced in therapy under the name of Hibicon® and was later withdrawn on account of its toxic effects.
CHg-NH—CO —CH2—CH2—CI
(XXIV)
Phenacon, N-.(3-chloropropionyl)-.p-phenyletbylamine (XX7)
NH —CO —CH,—CH. CI
(XXIV) 20
is also used as an antispasmodic and has been claimed to be active over a wide range.
The chloroacyl amides derived from P-phenylethyl- amines have not been systematically studied so far excepting for the recent work of Sidhu, Sattur, Ansari, Rao and Zaheer of this laboratory, who synthesised compounds of the follow- ing general structure
NH — CO CI
(XXVI)
where R]^ and Rg represent H, chloro and dichloro in 2:3, 3:4, 2:5 and 3:4 positions and'Y'represents an alkyl chain such as -CHg-, -CH-, -CHg-CHg-. CH3
None of these compounds showed promise as Central Nervous System (CNS) depressants and did not afford any pro- tection against electroshock seizures in mice. The present work was designed to prepare similar compounds with alkoxy substituents in the benzene ring. 21
Present work
Some N-chloroacyl-P-pheaylethylamines described in Table 2, 3 and 4 were prepared by condensation of chloro- acylchlorides such as chloroacetyl chloride, 2-, and 3-chloro- propionyl chlorides with p-phenylethylamines described in Table 1, The p-phenylethylamines were prepared by methods described in literature.
TABLE 1
NH.
S.No. R. b.p. C/mm Reference
1 H H 197/790 18 2 H methoxy 120/2 14,16 3 methoxy methoxy 150-152/5 15 4 methoxy ethoxy 165/15-18 16 5 ethoxy ethoxy 129/2 17 6 methylenedioxy 166/20 4, 18 22
Reaction of chloroacyl chlorides with P-phenylethylamines
The amines described in Table 1 were reacted with chloroacyl chlorides such as chloroacetyl chloride, 2-. and 3-chloropropionyl chloride in aqueous sodium hydroxide suspension to give the corresponding N-chloroacyl-p-phenyl- ethylamines of the general structure (XX7II)
NH — CO—Y CI
(xmi)
where H, methoxy, ethoxy H, methoxy, ethoxy methylenedioxy -CH2-,
-CH2-CH2-, -CH- I CHo
The compounds thus sjrathesised are described
in Table 2, 3 and 4. 23
(D O ®a I Th .2 K
o o H siH # B Oi I ft H CO I u o rH CM I u
o ^ ^ fe*o ^ u Ph m XI CV3 +» -p ® 0) o a •H m s I © C® iH
ffl iH o^ ^ o^ a « XI x; +9 +3 +3 S a fM oc a
® o H o O o o 10 to ^to Eto tBo to J W W 03 03 K
o a O] CO ^ to 1 CO (D H O O iH O o w CO 0> H * ID (3> I 00 6 O Oi o u a iH P) X I u-u ^ ^ ^ ^ «w o o o w si•p X•pI •p -p u (D ffi ffi ffi & B s O •H -®o £3 O H +» o o o ffi m ED x! si Si s +> •p +» ffi ffi ffi a B M cr cr ffi o • o o O00 H UoD ®o C;O: 0O0 a lO lO ic to to to ^ W 03 W 03 o a 03 CO ^ lO o o c (P s> o o § CD • C\3 H H 01 a> lO 00 1 I 1 i u p. H H to CO O TH Oi 0> a H H CM C\] ^o o^ o^ o^ I XJ xi X! m +3 -p •p u ® 0) Q> o a o a •H -o pa o (D u C® EH XJ I iH ^o o^ o^ "Cf o • 00 Oi o H o o iH o H rH o C\3 CO LO to CO 26 EXPERIMENTAL 1. Preparation of p-pheaylethylamlnes Starting from appropriately substituted benzaldehydes, corresponding P-phenylethylamines were obtained through follow- ing sequence of reactions. R-CHO Malonic acid R-CH=:CH-COOH Reduction Na/Hg or Pd/C, H R-CH2-CH2-COOH NH, SOCl, RCH2CH2CONH2 RCH2CH2COCI NaOCl NH4OH or NaOBr RCH2CH2CONH2 NaOCl or NaOBr • RCH2CH2NH2 27 Preparation of Aldehydes Anisaldehyde, vanillin, 3-etho3cy-4-hydroxy- benzaldehyde and piperonal were the commercial samples. 3,4-Dimethoxybenzaldehyde, 3-methoxy-4-ethoxy benzalde- hyde were prepared by methylating and ethylating vanillin with dimethylsulphate and diethylsulphate respectively. 3,4-Diethoxybenzaldehyde was prepared by ethylating 3~ethoxy-4-hydro3{ybenzaldehyde with diethylsulphate. Preparation of substituted Cinnamic acids A mixture of the appropriately substituted benzaldehyde (l mole) malonic acid (1.3 mole) dry pyridine (2 mole) and 3-5 ml. of piperidine per mole was gradually heated to 90-95°C and maintained at this temperature for 3 hours. It was then refluxed gently for another hour, till the evolution of carbondioxide ceased. The hot mixture was poured in 25^ cold HCl, the acid content being 1.5 molar equivalent of pyridine used. The solid cinnamic acid was filtered, washed with water. The product was usually pure enough for further reactions. The substituted cinnamic acids prepared by the above procedure are listed in Table 5. 28 TABLE 5 CH - COOH S.No. R2 m.p. °C Reference 1 H methoxy 174 21 2 methoxy methoxy 181 20 3 methoxy ethoxy 203-205 16 4 ethoxy ethoxy 156 17 5 3,4-methylenedioxy 232 16 29 Reduction of clnnamlc acids to the corresponding P-phenyl- proplonle acids The clnnamlc acids described In Table 5 were reduced to the corresponding P-phenylproplonlc acids by (a) sodium amalgam and (b) by catalytic hydrogenatIon. (a) Sodium amalgam reduction The substituted clnnamlc acid (35 g) was dissolved in aqueous sodium hydroxide solution (lOOO ml; 0.]5 per cent). Freshly prepared sodium amalgam (750 g; 3 per cent) was added in small portions during ten hours with continuous stirring. The supernatant liquid was filtered off and the filtrate after concentrating to half the volume was acidified with cone, hydrochloric acid. The P-phenylpropionic acid which separated out was filtered and dried. The acids were sufficiently pure for the next step, (b) Catalytic hydrogenatlon A suspension of pure substituted clnnamlc acid (300 g) in ethanol (lOOO ml) containing Pd/C catalyst (3 g; 105^) was hydrogenated in a medium pressure hydrogenatlon unit. The contents were stirred at 60-65°, The absorption of one molar equivalent of hydrogen was complete within 30 to 45 minutes (55 kg/cm^). The mixture after cooling was filtered free of catalyst, and after removal of most of the solvent, the residue was poured in excess of water. 30 The white shiny crystalline hydrocinnamic acid was filtered and dried. Table 6 describes the substituted p-phenyl- propionic acids. TABLE 6 CH. CH2 —COOH S.No. R- R? m.p.°C Reference 1 H methoxy 124 22 2 methoxy methoxy 97 24 3 methoxy ethoxy 130 16 4 ethoxy ethoxy 108 23 5 methylenedioxy 88 16 31 PreparatioD of substituted p~phenylproploaamlde Amides of the phenylpropionic acids described in Table 7 were prepared according to procedures described below. Method 'A' Amides of 3,4-dimethoxy, 3,4-diethoxy and 3-methoxy- 4-etho3qr phenylpropionic acid were prepared as follows:- 30 g of the appropriately substituted phenylpro- pionic acid was heated on an oil bath at 210-220®C and dry ammonia was bubbled through the melt for 3-4 hours. The hot syrupy mass was poured in cold dry benzene (150 ml) and cooled. The solid separated out in fine crystals, which Was filtered and was pure enough for Hoffmann reaction. Method 'B' 4-methoxy and 3,4-methylenedio3cy phenylpropionic acid were converted into amide through their acid chloride. (i) 4-methoxyphenyl)propionamide P-4-methoxyphenylpropionic acid (25 g) was refluxed with thionyl chloride (25 ml) for one hour. The excess of thionyl chloride was removed under suction, and acid chloride was poured slowly with shaking to an ice-cold solution of ammonia (400 ml). The solid which separated was collected and washed with cold water. 32 (ii) P-(3,4-'methylanedioxyphenyl)proploQamlde The acid (l7 g) was dissolved in chloroform (55 cc) and allowed to react at room temperature for five hours with 12 cc. of freshly distilled thionyl chloride. The reaction mixture was poured into a solution containing 250 cc. ammonia (30 per cent) and 7,5 g caustic soda and was shaken vigorously for a few minutes. The chloroform layer was separated and after removal of solvent, residue was poured in cold water. The white solid was filtered and crystallised with methanol. The amides are described in Table 7. TABLE 7 CHo— CH-,— CO — NH. S.No. Rc m.p.oc Reference 1 H methoxy 125 22 2 methoxy methoxy 121 15 3 methoxy ethoxy 124 16 4 ethoxy ethoxy 110 23 5 3,4-methylenedioxy 123-124 16,25 33 Preparation of p-phenylethylamines The amides described in Table 7 were subjected to the Hofftaann reaction with sodium hypochlorite or sodium hypobrpmite. p-4-methoxy, 3,4-dimethoxy, 3,4-diethoxy, and 3- methoxy-4-ethoxyphenylpropionamides (30 g) were suspended in a freshly prepared sodium hypochlorite solution (0.5 N, 500 ml.) and heated at 80^0 for 2 hours with occasional shaking. An oily layer of amine separated. The contents were cooled and potassium hydroxide (60 g) was added and heated for additional 20-30 minutes at 90°C, The mixture was cooled and extracted with benzene. After removal of the solvent, the residue was distilled under vacuum, p-(3,4-methylenedioxyphenyl)propionamide was converted into corresponding p-phenylethylamine by Hofftaann reaction using sodium hjrpobromite solution. To 14 g of finely powdered amide in 130 cc, water was added 130 cc, sodium hypobromite solution prepared by dropwise addition of 13,5 g of bromine to a cooled 130 cc, 255^ caustic soda solution with mechanical stirring. The mixture was shaken vigorously till all the amide dissolved and then heated at 70°C for an hour; After cooling to room temperature, 40 g of caustic soda was added and mixture heated for a further fifteen minutes at 80°C, then cooled 34 and extracted with ether. The amine was distilled after removal of ether. The substituted p-phenylethylamines prepared by this method are described in Table 1, Reaction of 2-chloroacetyl chloride, 2-chloro-, and 3-chloro- propionyl chloride with various substituted P-phenylethylamines The chloroacetyl chloride, 2-chloro-, and 3-chloro- propionyl chlorides were obtained by the action of thionyl chloride on monochloroacetic acid, 2-chloro-, and 3-chloro- propionic acids respectively. General procedure The appropriate chloroacyl chloride (0,1 mole) and an aqueous sodium hydroxide solution (130 ml., 8 per cent) were simultaneously added dropwise to a stirred suspension of the p-phenylethylamine (0,1 mole) in (50 ml) water at 0-5°C. The rate of addition of caustic soda was adjusted to maintain the alkalinity of the reaction mixture throughout. Stirring was continued at 0-5°C for 30 minutes and then at room temperature for an hour. The supernatant liquid was decanted off and the solid product thus obtained was tri- turated with dilute hydrochloric acid (l:l) to remove any unreacted amine. It was filtered washed with water and dried, and crystallized with aqueous methanol. The compounds thus prepared are described below: 35 1, N-Chloroacetyl-p-phenylethylamine^ Tcode No. ERL 50l) Condensation of P-phenylethylamine (20 g) with ohloroacetyl chloride (19. g) in presence of sodium hydroxide solution gave N-chloroacetyl-p-phenylethylamine. m.p. 7l°C yield 16 g (reported m.p. 72°C) Found C 60.58 H 6.29 N 7.34^ (197) requires 60.77 6.11 7.07 2. N-Chloroacetyl-P-(4-methoxyphenyl)-ethylamine (Code No. RRL 504) Condensation of p-4-m6thoxyphenylethylamine (20 g) with ohloroacetyl chloride (19 g) in alkaline medium resulted in N-.chloroacetyl-P-(4-methoxyphenyl)ethylamine. m.p. 102°C yield 20 g Found G 57.95 H 6.24 N 6.l6jg C11H14O2NCI (227) requires 58.02 6.14 6.15 ^-chloroacetyl-p-(3,4-dimethoxyphenyl)ethylamine (Code No. RRL 2501) Chloroacetyl chloride (l8 g) was reacted with homoveratrylamine (20 g) in aqueous caustic soda solution to give N-chloroacetyl-p-(3,4-dimethoxyphenyl)ethylamine. m.p. 940c yield 14 g 36 Found c 56,31 H 5.95 N 5.32^ C^^gH^^gOgNCl (257) requires 56.03 6.22 5.44 4. N-chloroaeetyl-p-(3-methoxy-4-ethoxypheayl)ethylamlne (Code No. RRL 2502) 20 g of 3-methoxy-4-ethoxy-p-pheaylethylamine \rfieii condeased with 18 g of chloroacetyl chloride in alkaline medium gave N-chloroacetyl-p-(3-methoxy-4-ethoxyphenyl)ethyl- amine. m.p. 103-104°C yield l7 g Found C 57.21 H 6.73 N 5.42^ CisHigiOsNCl (271) requires 57.56 6.64 5.16 5. N-chloroacetyl~p~(3,4-dietho3syphenyl)ethylamine (Code No. RRL 2503) p-3,4-diethoxyphenylethylamine (20 g) was reacted with chloroacetyl chloride (17 g) to give N-chloroacetyl-P- (3,4-diethoxyphenyl)ethylamine. m.p. 74°C yield 18 g Found C 58.58 H 7,31 N 5.02^ C14H20O3NCI (285) requires 58.94 7.01 4.91 37 6. N-chloroacetyl-p"(3,4-inethylen9dloxypheDyl)ethylamliie (Code No. RRL 2504) P-3,4-methyletiediox3rphetiylethylamine (20 g) and chloroacetyl chloride were condensed in the alkaline medium to give N-ehloroacetyl-p-(3,4-methylenedio3cyphenyl)ethylamine, m.p. 76-77°C yield 16 g Found C 54.18 H 5.23 N 5.87^ ^11^12^3^^! (241) requires 54.65 4.96 5.79 7. N-(2-chloropropionyl)-P-pfaenylethylamine (Code No. RRL 508) P-phenylethylamine (25 g) was reacted with 2-chloro- propionyl chloride (23 g) in presence of 8 per cent sodium hydroxide solution to get N-(2-chloropropionyl)-p-phenyl- ethylamine. m.p. 640c yield 23 g Found C 62.13 H 6.78 N 6.9^ (211) requires 62.46 6.62 6.62 8. N-(2-chloroproplonyl)-p-4-methoxyphenylethylamine (Code No. RRL 61l) Treatment of 2-chloropropionyl chloride (45 g) with p-4-methoxyphenylethylamine (50 g) in an alkaline medium gave.N-(2-chloropropionyl)-P-4-methoxyphenylethylamine. m.p. 92°C yield 47 g Found C 59.80 H 6.65 N 5,70^ (241) requires 59.73 6.64 5.81 9, N-(2-chloropropionyl)-P-3,4-dimethoxyphenylethy1amlne (Code No. RRL 2505) P-3,4-dimetho3!yphenylethylamine (20 g) and 2-ehloro- propionyl chloride (15 g) were condensed in the presence of aqueous sodium hydroxide to give N-(2-chloropropionyl)-P- 3,4-dimethoxyphenylethylamine. m.p. 79-80°C yield 17.5 g Found C 56.98 H 6.45 N C^gH^gOgNCl (27l) requires 57.45 6.62 5.15 10. N-(2-ehloropropionyl)-P-3-methoxy-4-ethox3rphenylethylamine (Code No. RRL 2506) N-(2-chloropropionyl)-P-3-methoxy-4-ethoxyphenyl- ethylamine was obtained by condensation of 2-chloropropionyl chloride (15 g) with p-3-methoxy-4-ethoxyphenylethylamine (20 g) in the presence of caustic soda solution, m.p. 90-91°C yield 16 g Found C 58.75 H 7.10 N 5,12^ C]^4H2o03NC1 (285) requires 58.84 7.00 4.90 39 ^•••(2-chloroproplonyl)-p-3,4-dietho:xyphenyletbylamlne (Code No. RRL 2507) p-3,4-diethoxyph0nyletiiylaniine (10 g) was condensed with 2-chloropropionyl chloride in the presence of 8 per cent sodium hydroxide to give N-.(2-chloropropionyl)-P-3,4-diethoxy- phenylethylamine. m.p, 84°C yield 7,5 g Found C 60.31 H 7.28 N 4.59?^ C^gHggOgNCl (299) requires 60.10 7.34 4,67 12. N-(2-ehloropropionyl)-p-3,4~methylenedio3qyphenylethylamine (Code No. RRL 2508) P-3,4-iDethylenedioxyphenylethylamine (10 g) reacted with 2-chloropropionyl chloride (8 g) in aqueous alkaline medium to give N-(2-chloropropionyl)-p-3,4-methylenedioxy- phenylethylamine. m.p, 100-101°C yield 8 g Found C 56.19 H 5.52 N 5.45^ ^12^14^3^01 (255) requires 56.36 5.48 5.48 3-chloropropionyl)-p-phenylethylamlne (Code No. RRL 515) p-phenylethylamine (25 g) was reacted with 3-chloro- propionyl chloride (23 g) in presence of 2>f of NaOH solution to get N-(3-chloropropionyl)-p-phenylethylamine. 40 m.p, 52°C yield 16 g Found C 62,21 H 6.65 N 6.5^ C^^H^^ONCl (211) requires 62.46 6.62 6.62 14, N-(3-chloropropionyl)"p-4-metho:xyphenylethylamine (Code No. RRiTsiS) Treatment of 3-chloropropionyl chloride (20 g) with p-4-methoxyphenylethylamine (22 g) in an alkaline medium gave N-(3-chloropropioayl)-p-4-metho3grphenylethylamine, m.p. 84°C yield 18 g Found C 59.79 H 6.61 N 5.92^^ C^gH^gOgNCl (241) requires 59.73 6.64 S.SljC 15. N-(3^chloropropionyl)-p-3,4-dimethoxyphenylethylanine (Code No. RRL 2509) P-3,4-dimethox3rphenylethylaBiine (20 g) with 3-ohloropropionyl chloride (15 g) was condensed in the presence of aqueous sodium hydroxide solution to give N-(3-chloropropionyl)-p-3,4-dimetho35yphenylethylamine . m.p, 101-102°C yield 17,5 g Found C 56,83 H 6,45 N 5.24 C^gH^gOgNCl (271) requires 57.45 6.62 5,15 41 16. N-(3-chloroproplonyl)-p-3"metho3y~4-ethoxyphenylethylamlne (Code No. RRL 2510) N-(2-chloropropio nyl)-p-3-methoxy-4-ethoxyp henyl- ethylamine was obtained by condensation of 3-ehloropropionyl chloride (15 g) with p-3-methoxy-4-ethoxyphenylethylamine (20 g) in the presence of caustic soda solution. ffl.p. 111-112°C yield 18 g Found C 58.93 H 7.10 N 4.885^ C^4H2q03NC1 (285) requires 58.84 7.00 4.90 17. N-(3"Chloropropionyl)-P-3,4-diethoxyphenylethylainine (Code No. RRL 2511) p-3,4-diethoxyphenylethylamine (lO g) was condensed with 3-chloropropionyl chloride (8 g) in the presence of 8^ sodiom hydroxide to give N-(3-chloropropionyl)-p-3,4-diethoxy- phenylethylamine . m.p. 95-96°C yield 8.5 g Found C 60.31 H 7.29 N 4.52^ C^gH2203NCl (299) requires 60,10 7.34 4.67 18. N-(3-chloropropionyl)-p-3,4-methylenedioxyphenylethylaiDine (Code No. RRL 2512) P-3,4-methylenedioxyphenylethylainine (lO g) reacted with 3-ehloropropionyl chloride ( 8 g) in aqueous alkaline medium to give N-(3-chloropropionyl)-P-3,4-methylenedioxy- phenylethylamine. m.p." 93-94°C yield 7,5 g Found C 56.28 H 5.42 N 5.43^ C^gH^^OgNCl (255) requires 56.36 5.48 5.48 42 REFERENCES 1. '-J.A. Jacobs and M. Heidelberger, J. Biol. Ghim., 20, 68^ (19IS). 2. Idem, ibid, 21, 103 (1916). Idem, ibid, 21, (l9l6). 4. R. Child ani F.I,. Pyman, J. Chem. See., 36 (l93l). 5. S. Chiav^rellital.i ,an d81 ,G.B 89. Marini-Bettolo(1951); Chem. ,Abs. Gazz, . Chim899. 0 (l95l) 6. S. Kushner, R.I. Cas'^ell, J. Morton, II, and J.H. '•filliams, J. Org. Chem., I6, 1283 (l95l). 7. N,K. Kochet^^ov and N.V. Dudykina, J. Gen. Chem., (l.S.S.P.), 27, 1481 (1957). 8. Idem, ibid, 29, 1635 (1959). 9. H.S. Sharadqmma, G.B. Maddi, S.N. Kulkarni, P.B. Sattur and K.S. Nargund, J. Karnatak Univ., 2, 19 (1957). 10. N.y. Kaverina,' Farmakol. i. Toksikol., 20, 20 (1957); Chem. Abs., 583 (l958). IT. G.S. Sidhu, P.B. Sattur and Y.S. Sadanandam, Personal communication. 12. G.S. Sidhu, P.B. Sattur, Salma Ansari, V.S. Bhaskar Rao and S.H. Zaheer, Personal communication. 13. Vfa. F, Bruce and J. Seifter, U.S. Patent, 2768,166 (1956); Chem, Abs., 424 (l958). 14. K.C, Pandya and T.A. Vahidy, Proc. Indian Acad. Sci., 5A, 437 (1937). 15. J.S. Buck and '•f.H. Perkin. Junr., J. Chera. Soc., 125, 1675 (1924). 16. K.H. Slotta and H. Heller, Ber., 63B, 3029 (1930). 17. W.3. Ide an72d 6J.S (1937). Buck. , J. Am. Chem. Soc., 59, 18. Karl Kindler, Arch. Pharm., 269, 70 (l93l); Chem. Abs., 2^, 2981 (1931). 43 19. E. Schlittler, Ber., 66, 988 (1933). 20. W.H. Perkin and R. Robinson, J. Chem. Soc., 91, 1079 (1907). 21. 'i. Borsche and C. Walter, Ber,, ^OB, 2112 (1927). 22. Max. P.J.M. Jansen, Rec. trav. chim., 291 (l93l). 23. K. Kindler and W. Peschke, Arch. Pharm., 272, 60 (1934). 24. ¥.H. Perkin, Jr., and H. Robinson, J. Chem. Soc., 21, 1073 (1907) H. Decker, Ann., 395, 282 (1913). 26. Ame Pictet and Marie Finkelstein, Ber., 42^ 1979 (1909). CHAPTER III 44 N-MINOACYL-P-PHENILETHYL AMINES This chapter describes the preparation of N-amino- acyl-P-phenylethylamines of the following general formula (XXVIII) (XXVIII) where R^ and R2 stand for H, methoxy in para position, 3:4- dimethoxy, 3-methoxy-4-ethoxy, 3:4-diethoxy and 3:4-methylene- dioxy groups. Y stands for alkyl chain such as -GHp-, -CH~, and -CH2-CH2- and -N z represents diethylamine, CH3 morpholine, piperidine, pyrrolidine and =<, p and Y-pipecolines. Compounds containing -NH-CO-linkage exhibit a variety of physiological actions and many of these compounds are employed in therapeutic practice as hypnotics, sedatives, anti- convulsants, local anesthetics and tranquillizers. 1. H3^notics and sedatives Of the various hypnotics available, barbiturates hold a distinct and dominant place. Barbiturates are the 45 derivatives derived from barbituric acid (XXIX) having various substitueats in position 5. (XXIX) The chemistry and pharmacology of barbiturates has been investigated thoroughly for the last over fifty years. The barbiturates act chiefly by depressing the central nervous system, especially the brain. The basal ganglia and the hypothalamus are first affected. The dura- tion of this depression and the intensity of action depends " on the structure of the drug, on its mode of administration and the amount used. The barbiturates have a quieting action in nervous and excited states in animals and in cases of hyperthyroidism^. The following are some of the barbiturates conmionly employed in therapy. 46 0=C2 AC = 0 'Ri HN' 6 IC oJl S.No. R Rl R2 Name H -C2H5 -C2H5 Barbital, Veronal, Barbitone. -CH-CH- Probarbital, Ipral, GH 3 H -C6H5 Phenobarbital, Luminal. -CH, •C2H5 -CgHg Mephobarbital, Prominal, /CH / 3 H -G2H5 -(CH2)2-CH. Amobarbital, Amytal. 3 47 THe mostsusccessfal cyclic noa-barbiturate hypnotics have been found among piperidine-2,4-diones^, such as 3,3- diethyl-2,4-dioxo-l,2,3,4-tetrahydropyridine (XXX) (Pyrithyl- dione, Presidone) is a long acting and well tolerated drug, H .N. c=o /C2H5 ^C 5 He II O (XXX) whereas 2,4 -dioxo- 3,3,-diethyl-5-methylpiperidine (XXXI) (methylprylon, Nodular)^ has been claimed to be superior to many barbiturates. (XXXI) Amongst glutarmides, <=(-ethyl-<=<-phenylglutarimide (XXXII) (glutethimide, Doridon) has been claimed to be a good sedative and hypnotic which produces six to eight hours of sleep at doses from 0.25 to 0.5 gm.^® 48 (XXXII) A most powerful and promising hypnotic activity- has been discovered in 4(3H)quinazolones. Zaheer and Kacker'^ synthesised a number of quinazolones of the general formula (XXXIII) and tested them for their analgesic activity. None (XXXIII) of these compounds possessed analgetic activity but showed promising hypnotic activity. One of the compounds i.e. 2-methyl-3-G-tolyl-4-(3H)quinazolone (XXXIV) (Melsedin, Hypnodyne, Rivonal) has been introduced into therapy as a safe hypnotic without any adverse side effects. In 49 continuation of this work, Sidhu, Sattur and Bhanumati^ synthesised various 2-methyl-3-phenylethyl-, and 2-methyl- 3-benzyl-4-(3H)quinazolones and tested them for their pharma- cological activity. However, those compounds do not hold much promise as hypnotic agents but exhibit powerful anti- tussive action. The following two derivatives (XXXV) and (XXXVI) are undergoing detailed investigation to assess CI CH,—CH. CH. (XXX7) 50 CI CH. (XXXVI) their clinical efficacy. 2. Anti convulsant s fi 7 Phenobarbital » is one of the most effective anti- convulsant employed in therapy today. Many of the hypnotics, in doses sufficient to produce anesthesia relieve convulsive attacks. The following are some of the compounds (XXXVIII- XL) resembling in structure to Phenobarbital (XXXVII) and are employed as antiepileptic agents. H H N. o=c c =o o=c c=o /C2H5 HN \ H5N CH—C2H5 CfiHs C6H5 (XXXVII) (XXXVIII) (Phenobarbital) (2-phenylbutyryl urea) 51 O H .N ii. H,C c=o H5N CH- C,2^H5 CH —C^Hg C6H5 CjjHB (XXXIX) (XL) (N-methyl-2-phenyl- (S-phenylbutyramide) butyramlde) Related to barbiturates are 5,5-disubstituted hydantoins which may be regarded as glycolylureides. One of the earliest hydantoins to be tried as an anticonvulsant and sedative was the analogue of phenobarbital i.e. phenyl- ethylhydantoin. (XLI) (Nirvanol)"^. C,21-1H 5 (XLI) Though this compound was found active in various types of convulsions but is no longer considered safe because of its toxicity. Merritt and Putnam®'® in their systematic study of hydantoins found that the sodium salt of diphenyl- hydantoin (XLII) (Dilantin) had the greater anticonvulsant 52 (XLII) activity, combined with low depressant activity. Although diphenylhydantoin is usually the choice drug for the control of psychomotor seizures and grandmal convulsions, several other hydantoin derivatives have been employed clinically. 3,6,6-trialkyloxazolidine-2,4-diones form another important class of compounds possessing anticonvulsant action. The most active of these compounds are 3,5,5,-trimethyl oxa- zolidine-2,4-dione (Trimethadione) (XLIII), 3,5-dimethyl-5- ethyl derivative CXLIV) (Paramethadione) and 3-methyl-5,5- di-n-propyl-derivative^® (XL7), H,C HgC c=o H3C o=c- N-CH, o=c- N—CH, (XLIII) (XLIV) 53 H7C3 C — 0 "c o=c N —CH3 (XL7) 3, Local anesthetics One of the earliest local anesthetic to be introduced into therapy containing the -NH-CO-llnkage is dibacaineH>12 (Nupercaine; Percaine) (XLVI). OC4H9 2 "5 CO —NH-CH,—CH,— In recent years c<-diethylamino-2,6-dimethyl- acetaailide (XLVII) (xylocaine, lidocaine) has been claimed to be the superior local anesthetic having a very few side reactions^^. 54 CH. /C2H5 NH- CO-CH,—N \ C2H5 (XLVII) Isomers of Lidocaine which do not have two methyl groups ortho to the -NHCO-grouping, exhibit a very weak action^'^. If, however, one alkyl group such as GHg is placed in ortho position and no other nuclear substituent is present, then these compounds possess much shorter duration of action 15 and are irritant Amides derived from cinnamic acids (XL7III) are / C2H5 CH=CH-CO-N—CH.-CHp-N CH. \C2H 5 o (XLYIII) claimed to possess promising anticonvulsant action. 55 4. Tranqalllisers A good tranquilising activity has been discovered 17 by Sidhu, Sattur, Rao and Sogani in a new class of compounds (XLIX) derived from 1,2-diphenylethylamines and p-phenyl- propionic acids. CH2—CH (XLIX) These compounds in general e3diibit mild sedation and decrease of locomotor activity. One of the compounds belonging to the above series i.e. (R = CH3; R^ = Rg = H) is currently undergoing clinical evaluation in human against anxiety neurosis. This compound shows 80-90 per cent remission of anxiety symptoms when administered for 3-5 days, Even prolonged treatment to the extent of 4-6 weeks does not give rise to any side effects. It is interesting to observe that the lower homologues (L) corresponding to structure (XLIX) exhibit good CNS depressant action. 56 NH —CO —CHa—CH2 (LD Some of the compounds derived from this series show mild to strong hjrpotension and antipyretic action. With a view to arrive at structure activity relationship in general, propionamides derived from the p-phenylethylamines of the general structure (LI) have also been prepared. NH—CO-CH2—CH2 (LI) These compounds show hypoactivity, mild to strong sedation and a powerful decrease of locomotor activity. 57 Present work It is apparent from the foregoing summary that the -NH-CO-linkage exhibits a variety of pharmacological actions depending upon the nature of groi^js attached to Nitrogen and the carbonyl group. The influence of a phenethyl group attached to the nitrogen and the carbonyl attached to the alkylene chain having a terminal nitrogen has not been investigated so far. Hence it was thought important to synthesise compounds of the structure(LII) (where Y forms a branched or straight alkylene chain) to study their NH CO —Y- N Z (LID pharmacological actions. This chapter describes the compounds incorporating the above structure and the compounds thus prepared are described in Tables 8, 9 and 10. 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The Condensations were carried out by methods outlined below. \ NH — CO - Y — C\ + Hbi Z V ^^ A. refluxing in benzene or B. heating at 130-140° without solvent C. heating in a glass autoclave (in case of low boiling amines) NH CO — Y — N \ \ / 70 Method 'A' Condensation of N-chloroacyl-P-phenylethylamiDes with various secondary amines usin^ benzene as a solvent: N-chloroacetyl or N-(3-chloropropionyl)-p-phenyl- ethylamine (0.1 mole) and secondary amine such as diethyl- amine, morpholine, piperldine, pyrrolidine, 2-, 3- or 4- methylpiperidine (0,2 mole) were dissolved in dry benzene (100-150 ml) and refluxed for six to eight hours. The re- action mixture was cooled, the secondary amine hydrochloride which separated out was filtered off and washed with benzene or ether. The filtrate was concentrated under reduced pressure and the residue was distilled under vacuum in case of liquids and crystallised with suitable solvent in case of solid reaction products. The compounds prepared by this method are described below: 1. N~(N-diethylamino)acetyl-p-phenylethylamlne (Code No, RKL 522) N-chloroacetyl-P-phenylethylamlne (20 g) was condensed with diethylamlne (15 g) in dry benzene according to method mentioned above to get N-(N-diethylamino)acetyl- P-phenylethylaraj.ne. b.p, 160°C/1.75 mm yield 18 g Found C 71,58 H 9.28 N 11,82^ Ci4H220N2(234) requires 71.75 9,46 11,96 71 N-(4-morphollno)acetyJ.-P-phenylethylamlne (Code No. RRL 523) From N-chloroacetyl-p-phenylethylamine (20 g) and morpholine (15 g) in lOO cc. dry benzene, N-(4-morpholino)- aeetyl-p-phenylethylamine was obtained. b.p, 208°C/1.5 mm yield 19 g Found C 67.67 H 7.88 N 11.42^ ^14^20^2% (248) requires 67.71 8.12 11.28 1 o 3. N-(i-piperidino)acetyl-p-phenylethylamine (Code'No. RRL 524) Condensation of N-chloroacetyl-P-plienylethylamine (20 g) with piperidine (18 g) gave N-(i-piperidino)acetyl-p- p henylethylamine. b.p. 182-184 C/0.9-1 mm yield 19 g Found C 72.96 H 9.18 N H. ^15^20^2 (246) requires 73.13 9.00 11.37 4. N-(i-pyrrolidino)acetyl-p-phenylethylamine (Code No. RRL 525) Reaction of N-chloroaeetyl-p-phenylethylamine (20 g) with pyrrolidine (l6 g) gave N-(i-pyrrolidino)acetyl-p-phenyl- ethylamine. b.p. l96~198°G/2 mm yield l7 g 72 Found C 72.61 H 8.66 N 12.12^ (232) requires 72.38 8,68 12.06 ^-(2-methylplperldltio)acetyl-P-phetiylethylamliie (Code No. RRL 526) N-chloroacetyl-p-pheaylethylamlne (12 g) was reacted with 2-methylpiperidine (13 g) to yield N-(2-methylpiperidino)- acetyl-P-phenylethylamine. b.p. 192°C/0.8 mm yield 10 g Found C 73.91 N 9.30 N 10,68^ (260) requires 73.80 9.29 10.76 6.N-(3-methylpiperidino)acetyl-P-phenylethylamine (Code No. RRL 527) K-chloroacetyl-p-phenylethylamine (l2 g) was condensed with 3-methyIpiperidine (13 g) to give N-(3- methylpiperidino)acetyl-p-phenylethylamine. b.p. 192°C/0.9-l mm yield 11 g Found C 73.81 H 9.26 N 10.60^ (260) requires 73.80 9.29 10.76 N-(4-methylpiperldino)acetyl-p-phenylethylamlne (Code No. RRL 528) 12 g of N-chloroacetyl-p-phenylethylamine and 13 g of 4-methylpiperidine were condensed to get N-(4-methyl- piperidino)acetyl-p-phenylethylamine. 73 b.p. 196-198OC/0.9 mm yield 10 g Found C 73.92 H 9.21 N 10,69^ requires 73.80 9.29 10.76 8. N-(N-diethylamliio)acetyl-p-4-metiioxypheQylethylamiiie (Code No. RRL 543) Starting from N-chloroacetyl-P-4-methoxyphenylethyl- amine (i5 g) and diethylamine (ll g), N-(N-diethylamino)acetyl- P-4-methoxyphenylethylamine (12 g) was obtained. b.p. 198-200°G/l mm yield 12 g Found C 67.92 H 9.12 N 10.52^ G15H24O2N2 (264) requires 68.15 9.15 10.60 9. N-(4-morpholino)acetyl-P-4-methoxyphenylethylamine (Code No. RRL~544) "" ~~~ Reaction between morpholine (10 g) and N-chloro- acetyl-P-4-methoxyphenylethylamine (l4 g) gave the title compound which distilled at 234°C/i,5 mm. yield 12 g Found C 64.52 H 7.94 N 10.365^ ^15^22^3% (278) requires 64.72 7.97 10.07 10. N-(i-piperidino)acetyl-P"4-methoxyphenylethylamine (Code No. RRL 545) N-chloroacetyl-P-4-methox3rphenylethylamine Cl2 g) was condensed with piperidine (9 g) and the product (ll g) was distilled at 188-190°C/0,6 mm which solidified afterwards. 74 m.p. 7l-72°C Found C 69.44 H 8.50 N 10.12^ C16H24O2N2 ^276) requires 69.53 8.75 10.14 )acetyl-P-4~methoxypheQylethylamlne (Code No. RRL 546) Pyrrolidine (15 g) was condensed with N-chloroacetyl- p-4-methoxyphenylethylamine (23 g). The product was distilled at 206^0/1.25 mm. yield 21 g Found C 68.59 H 8.42 N 12.1?^ (262) requires 68.67 8.45 12.20 12. N-(2-methylpiperidino)acetyl-p-4-methoxyphenylethylamine (Code No. RRL 547)~~~~" Reaction of N-chloroacetyl-P-4-methoxyphenylethylamine (7 g) with 2-methylpiperidine (6 g) yielded N-(2-methylpiperi- dino)acetyl-p-4-methox3rphenylethylamine (7 g). b.p. 2l8-220°C/0,7 mm Found G 70.53 H 9.09 N 9.48^ ^17^6^2% (290) requires 70.3 1 9,02 9.65 13. N.-(3"methylpiperidino)acetyl-P-4-methoxyphenylethylamine (Code No. RRL 548) N-.chloroacetyl-p-4-methoxyphenylethylamine (6 g) was reacted with 3-methylpiperidine (5 g) to get N-(3-methyl- piperidino)acetyl-p-4-methoxyphenylethylamine (6 g) having 75 b.p. 2l0°C/0.5 mm. Found C 70.23 H 9.1 N 9.51^ (290) requires 70.31 9,02 9.65 14. N-(4-methylplperidino)acetyl-P-4-metho3yphenylethylamlne (Code No. RRL 549) N-chloroacetyl-P-4-methoxyphenylethylamine (lO g) and 4-methylpiperidine (9 g) gave the title product, distilling at 220-222°C/0.5-0.6 mm and weighed 9 g. Pound C 70.31 H 8.91 N 9.375^ ^'17^602^2 (290) requires 70.31 9.02 9.65 15. N-(N-diethylamino)acetyl-p-3,4-dlmethoxyphenylethylamine (Code No. RKL 2513) N-chloroaeetyl-P~3,4-dimethoxyphenylethylamine (8 g) was reacted with diethylaraine (9 g) by refluxing in dry benzene for six haurs. The product was worked up as usual and was crystallised from petroleum ether 60-80°. m.p. 78°C yield 7.5 g Found C 64.86 H 9.37 N 9.58^ C^gHggOgNg (294) requires 65.28 8.90 9,52 16. N-(4~morpholino)acetyl-p-3,4-dimetho3cyphenylethylamine (Code No. RRL 2514) Morpholine (6 g) was condensed with N-chloroacetyl- p-3,4-dimethoxyphenylethylamine. The product was distilled 76 at 240-242°C/i-l.25 mm which solidified afterwards, m.p. 74®C yield 7.5 g Found C 61.94 H 8.15 N 8.88^ (308) requires 62.31 7.85 9,09 17. N-( l-plperldino )acetyl-P-3,4-dimetho3cyphenylethylamine (Code No. RRL 2515) N-chloroacetyl-p-3,4-dimethoxyphenylethylamine (8 g) OQ condensation with piperidine (6 g) yielded N-(i-piperidino)• acetyl-^-3,4-dimethoxyphenylethylamine. t).p, 228-229°C/0.9-l mm yield 8 g Found C 66.48 H 9.38 N 9.58^^ C^^HggOgNg (306) requires 66.64 8.55 9.14 18. N-(i-pyrrolidino)acetyl-P-3,4-dimethoxyphenylethylamine (ci^e No. BRL 2516^ N-.chloroacetyl-P-3,4-dimethox37phenylethylamine (8 g) and pyrrolidine (5.5 g) were refluxed in lOO cc. benzene for six hours. Pyrrolidine hydrochloride was removed by washing the benzene layer with water. After removal of solvent, residue solidified on cooling, m.p, 69-70°C (from petroleum ether 40-60°) yield 8 g Found C 66.15 H 8,62 N 9,70^ *^16^24®3^2 (292) requires 65.72 8.27 9.58 77 19. N- (2-methylpip eridi no)acetyl-p-3,4-dimethoxyphenylethy 1- amlae (Code No. RRL 25173 ~ 2-methylpiperidine (6,5 g) was condensed with N- chloroacetyl-p-3,4-dimethox3nphenyl6thylamine (8 g) to yield N-(2-methylpiperidino)acetyl-p-3,4-dimethoxyphenylethylamine. b.p. 239-24i°C/l.2-1.3 nun solidified on cooling m.p. 78-79°C yield 8 g Found C 67.89 H 8.72 N 9,07^ ^18^2803% (320) requires 67.47 8.81 8.74 20. N-(3-methylpiperidino)acetyl-P~3,4~dlmethox5rphenyl- ethylamine (Code No, RRL 2518) 3-methylpiperidine (6,5 g) was reacted with N- chloroacetyl-P-3,4-dimethoxyphenylethylainine (8 g) in benzene (lOO cc.) and the product after being worked up according to the procedure mentioned earlier distilled at 238°C/l mm. m.p, 65-66°C yield 8 g Found C 67.77 H 9.23 N 8.58?^ C^gHggOgNg (320) requires 67.47 8.81 8,74 21. N-(4-methyIpiperidino)acetyl-p-3,4-dimethoxyphenylethylamtne (Code No. RRL 2519) N-chloroacetyl-P-3,4-dimethoxyphenylethylamine (8 g) condensed with 4-methylpiperidine (6,5 g) to give the above compound. 78 b.p. 238-240°C/l mm yield 7,5 g Found C 67.41 H 8.55 N 9. ^18^2803% (320) requires 67.47 8.81 8.74 22. N-(N-diethylamino)acetyl-.p-3-methoxy-4-ethox3rphenylethyl- amine (Code No. RRL 2520) The condensation between diethylamine (8 g) and N-chloroacetyl-^-3-methoxy-4-ethoxyphenylethylamine (8 g) yielded N-(N-diethylamino )-p-3-metho5cy-4-ethoxyphenylethyl- amine. The viscous liquid was distilled at 214-218°C/2-2.5 mm. Yield 7.2 g Found C 66.06 H 9.33 N 9.32^ C17H28O3N2 (308) requires 66.20 9.15 9,08 23. N-(4--morpholino)acetyl~P-3-methoxy-4~ethoxyphenylethylamine (Code No. R1=IL 2521) N-chloroacetyl-p-3-methoxy-4-ethoxyphenylethylamine (10 g) was reacted with morpholine (7 g). The product N-(4- morpholino )acetyl-P-3-methoxy-4-ethoxyphenylethylamine was recrystallised from petroleum ether 60-80°. m.p. 97°C yield 7.7 g Found C 62.94 H 8.36 N 8.62^ C17H26O4N2 (322) requires 63.33 8.13 8.69 86 24. N-(l-plperlditio)acetyl-P~3~methoxy-4-ethoxyphenylethyl- amlne (Code No. RRL 2522) This was the product of condensation between N-chloro- acetyl-p-3-methoxy-4-ethoxyphenylethylamine (7 g) and piperidine (5 g). m.p. 88°C (crystallised from petroleum ether 60-80°) yield 7 g Found C 67.28 H 8.97 N 8.72^ C^gHggOgNg (320) requires 67.47 8.81 8.74 25. N-(l-pyrrolidino)acetyl-P-3-methoxy-4-ethoxyphenylethyl- amine (Code No7 RRL 2523) Starting from N-chloroacetyl-P-3-metho3?y-4-ethoxy- phenylethylamine (9 g) and pyrrolidine (6 g), N-(i-pyrrolidino)- acetyl-^-3-methoxy-4-6thoxyphenylethylamine was prepared. m.p. 82°C (crystallised from petroleum ether 60-80°) yield 7.8 g Found C 66.34 H 8.41 N 8.98^ C17H26O3N2 (306) requires 66.64 8.55 9.14 N-(2--methylpiperidino)acetyl-^-3-methoxy-4-ethoxyphenyl- ethylamine (Code No« RRL 2524) This substance was synthesised by the condensation of 2-m6thylpiperidine (7 g) with N-chloroacetyl-p-3-methoxy- 4-ethoxyphenylethylamine (9 g). b.p. 234°C/0.9-l mm yield 9 g Found G 68.11 H 9.18 N 8^15% G19H30O3N2 (334) requires 68.23 9.04 8.38 27. N-(3-methylpiperidino)acetyl-^-3-methoxy-4-ethoxyphenyl- ethylamlne (Code No. RPX 2525) N-chloroacetyl-p-3-inethoxy-4-.ethoxyphenylethylaniine (9 g) was reacted with 3-methylpiperidine (7 g) to give N-(3- methylpiperidino )acetyl-P-3-methoxy-4-ethoxypheaylethylaniine. b.p. 228-230 C/1 mm m.p. 57-58°C yield 9 g Found C 68.76 H 9.33 N 8.21^^ (334) requires 68.23 9.04 8.38 28. N-(4-methylpiperidino)acetyl-P--3-methoxy"4-ethoxyphenyl- ethylamine (Code No, RRL 2526) The reaction between N-chloroacetyl-P-3-methoxy-4- ethoxyphenylethylamine (10 g) and 4-methylpiperidine (8 g) gave N-(4-methylpiperidino)acetyl-p-3-methoxy-4-ethoxyphenylethyl- amine (9,5 g). b.p, 232-234°C/0.7 mm m.p, 69°C Found C 68.29 H 8,59 N 8.35^ C^^gHgoOgNg (334) requires 68.23 9.04 8.38 29. W-(N-diethylamino)acetyl-P-3,4-diethoxyphenylethylamine (Code No. RRL 2527) This was the product of condensation between SI diethylamine (lO g) and N-chloroacetyl-p-3,4-dietlioxyphenyl- ethylamine (8 g). m.p, 92°C (recrystallised from petroleum ether 60-80°) yield 7.5 g Found C 67,23 H 9,29 N 8.59^ (322) requires 67.05 9,38 8.68 30. N-.(4-morpholino)acetyl-^-3,4-diethoxyphenylethylainine (Code No. RRL 2528) N-chloroacetyl-P-3,4-diethoxyphenylethylamine (lO g) and morpholine (8 g) were condensed in a similar way as des- cribed above. The product was a viscous liquid which was distilled under vacuum. b.p. 240-242°C/0.5 mm yield 9«5 g Found C 64,72 H 8.28 N 8.29^5 (336) requires 64.26 8.39 8.33 31. N-(l-piperidino)acetyl-p-3,4-diethoxyphenylethylamine (Code No. RRL 2529) Reaction of piperidine (8 g) with N-chloroacetyl- P-3,4-dietho3jyphenylethylamine (lO g) yielded N-(i-piperidino)• acetyl-P-3,4-diethoxyphenylethylamine. b.p. 192-196°C/l-2 mm yield 9.2 g Found C 67.98 H 9,32 N 8.28^ G^gHgQOgNg (334) requires 68.23 9.04 8.38 82 32. N-(i-pyTrolidino)acetyl-p-3,4-diethoxyphenylethylaminG (Code No. RRL 2530) This substance was prepared by condensation of N- chloroacetyl-P-3,4-diethoxyphenylethylamine (lO g) with pyrro- lidine (7 g). The product obtained was colourless solid which was crystallised from petroleum ether. m.p. 66°C yield 10 g Found G 67.32 H 8.79 N 8.72^ ^IS^S^S^ (320) requires 67.47 . 8.81 8.74 ^-(2-methylpiperidino)acetyl-p-3,4--diethoxyphenylethylamine (Code" No. RRL 2531) N-chloroacetyl-p-3,4-diethoxyphenylethylamine (8 g) was reacted with 2-methylpiperidine (6 g) in dry benzene. The title compound was a viscous liquid which was purified by distillation under vacuum. b.p. 236°C/l,2 mm yield 8 g Found C 68.85 H 9.30 N 8. C20H32O3N2 (348) requires 68.93 9.26 8.04 34. N-(3,niethylpiperidino)acetyl-^-3,4-diethoxyphenylethylamine (Code No. RRL 2532) 3-ffiethylpiperidine (8 g) and N-chloroacetyl-P-3,4- diethoxyphenylethylamine (lO g) were condensed and the result- ing product was distilled under vacuum. 83 b.p. 236-238°C/0.8-0.9 mm .yield 10 g Found C 68.75 H 9.23 N S.OOjg C20H32O3N2 (348) requires 68.93 9.26 8.04 35. N-(4-methylpiperidino )acetyl-P-3,4-dlethoxypheQyle"fehylaPiiQe (Code No. RRL 2533) By reacting N-chloroacetyl-p-3,4-diethoxyphenylethyl- amine (lO g) with 4-methylpiperidine (8 g) in dry benzene, the title compound was obtained. It distilled at 234-238°C/l mm, yield 10.5 g Found C 68.85 H 9.32 N 8.21^ C20H32O3N2 (348) requires 68.93 9.26 8,04 36, N-(N-diethylamino)acetyl'^-3,4-methylenedioxyphenylethyl- amine (Code No. RRL 2534) ' N-ehloroacetyl-P-3,4-methylenediox3rphenylethylamine (10 g), diethylamine (12 g), in dry benzene (lOO cc.) were refluxed for six hours. The condensation product was worked up according to method described. b.p. 196°C/l-2 mm yield 9,2 g Found C 64.59 H 7,89 N 10,135^ C15H22O3N2 (278) requires 64.72 7.97 10.07 84 37. N-(4-morpholino)acetyl-p-3,4-methylenedioxyphenylethylamine (Code No. RRL 2635) Reacting N-chloroacetyl-p-3,4-inethylenedioxyphenyl- ethylamine (lO g) with morpholine (8 g) in benzene, the title compound was obtained. b.p. 234-236°C/l-2 mm yield 9,5 g Found C 61.49 H 6,78 N 9,39^ (292) requires 61.63 6.90 9,58 38. N-(i-piperidino)acetyl-p-3,4-methylenedi035yphenylethylamine (Code No. RRL 2536) N-ehloroacetyl-P-3,4-methylenedioxyphenylethylamine (10 g) on condensation with piperidine (8 g) gave N-(i-piperi- dino )acetyl-P-3,4-methylenedio3cyphenylethylamine, b.p. 234-236°C/l-2 mm yield 9,7 g Pound C 66.52 H 7,62 N 9,61% ^16^22°3% C290) requires 66,18 7,64 9,65 39. N- 3-(N-diethylamino)propionyl -p-phenylethylamine (Code No. RRL 601) Starting from N-(3-chloropropionyl)-p-phenylethyl- p amine (11 g) and diethylamine (8 g), N-[3-(N-diethylamino)- propionyl -P-phenylethylamine was obtained. b.p. 180-1S4°C/1,5 mm yield 9 g 85 Found C 72.48 H 9.42 N 11.17^ (248) requires 72,54 9.74 11.28 40. N- 3-(4-morpholino)propionyl -^-phenylethylamine (Code No. RRL 602) The condensation between morpholine (8 g) and N-(3- chloropropionyl)-p-phenylethylamine (ll g) resulted in the formation of N- 3-(4-morpholino)propionyl -P-phenylethylamine (10 g). b.p. 220°C/1.25 mm Found C 68.29 H 8.23 N l0.4l^ ^15^22*^2% (262) requires 68.67 8.45 10.68 41. N- 3-(l-piperidino)propionyl -P-phenylethylamine (Code No. RRL 603) N-(3-chloropropionyl)-p-phenylethylamine (7 g) and piperidine (6 g) were condensed to yield N- 3-(1-piperidino)• propionyl -p-phenylethylamine. b.p. 204-208 C/2 mm yield 6 g t , H 9.17 N l0.475^ Found C 73.29 9.29 10.76 C26H24ON2 (260) requires 73.80 42. N- 3-(1-pyrrolidino)propionyl -P-phenylethylamine (Code No. RRL 604) The condensation of pyrrolidine (7 g) with N-(3- A chloropropionyl)-P-phenylethylamine (8 g) gave N- 3-(l-pyrroli- dino)propionyl -p-phenylethylamine (7 g) which distilled at 86 190°C/l,5 mm. Found C 72.99 H 8.67 N 11,28% Cj^sHggONg (246) requires 73.13 9.00 11.37 43, N-L3-(2-methylpiperidino)propionyl -phenylethylamine (Code No. RRL 605) 2-methylpiperidine (5 g) was condensed with N-(3- chloropropionyl)-P-phenylethylamine (6 g) to get the title compound (5.5 g). b.p. 208-210°G/i-1.25 mm Found G 74.21 H 9.37 N 10.11^ ^17^26°% ^274) requires 74.41 9,55 10.21 44. N- 3-(3-methylpiperidino)propionyl -^-phenylethylamine (Code No. RRL 606) The title compound was prepared by the reaction of N-(3-chloropropionyl)-P-phenylethylamine (6 g) with 3-methyl- piperidine (5 g). The product (5 g) distilled at 192-198°C/ 1.5 mm. Found G 74.19 H 9.18 N 10.12^ C^^yHggONg (274) requires 74.41 9.55 10.21 45. N- 3_(4-niethylpiperidino)propionyl -P-phenylethylamine (Code No. RRL 607) 4-methylpiperidine (5 g) was condensed with N-(3- chloropropionyl)-P-phenylethylamine (6 g) to yield N- 3-(4- methylpiperidino)propionyl -p-phenylethylamine. 87 b.p. 206-208°C/l mm yield 5 g Found C 74,41 H 9,38 N 10.28^ C^^ggONg (274) requires 74.41 9.55 10.21 46. N- 3-(N-diethylamino)propionyl -p-4-methoxyphenylethyl- amine (Code No. RRL 619) Diethylamine (9 g) and N-(3-chloropropionyl)-^-4- metho2?yphenylethylamine (12 g) were condensed and the desired product was obtained as colourless viscous liquid on distilla- tion under vacuum. b.p. 220°C/2 mm yield 9 g Found C 69.11 H 9.70 N l0.235^ ^16^26^2^2 (278) requires 69.03 9.41 10,06 47. N- 3-(4-morpholino)propionyl - p - 4-m e t ho xy p he ny 1 e t hy 1 am i n e (Code No. RRL 620) This compound was prepared by the condensation of morpholine (8 g) with N-(3-chloropropionyl)-p-4-methoxyphenyl- ethylamine (lO g). b.p. 2l2-2l4°C/2,5 mm yield 10 g Found C 65.43 H 8.19 N 9.275^ "^16^24*^3% (292) requires 65.72 8.27 9.58 48. N-I 3-(l-piperidino)propionyl -p-4-methox3rphenylethylamine (Code No. RRL 621) N-(3-ehloropropionyl)-P-4-methoxyphenylethylamine (7 g) and plperidine (6 g) were taken in benzene (lOO cc.) and refluxed for eight hours. After heating was over, solvent was removed under vacuum, and residue poured in cold water. The solid N- 3-(1-piperidino)propionyl -P- 4-meth03^phenylethylainine separated out which was filtered and crystallised from dilute methanol. m.p. 86°C yield 8 g Found C 70.17 H 8.95 N 9.62^ C^yHggOgNg (290) requires 70.31 9,02 9.66 49. N- 3~(l-pyrrolidino)propionyl -P-4-methoxyphenylethylamine (Code No. RRL 622) N-(3-chloropropionyl)-^-4-methoxyphenylethylamine (7 g) and pyrrolidine (6 g) were reacted to give 3-(l- pyrrolidino)propionyl -P-4-methoxyphenylethylamine, b.p. 228-230°C/2 mm yield 6 g Found C 68.89 H 8.80 N 9,98% ^16^24^2^2 (276) requires 69.53 8.75 10.14 50. N- 3-(2-methylpipeiidino)propionyl -P-4-methox3rphenyl- ethylamine (Code No. RRL 623) The above compound was obtained by the condensation of N-(3-chloropropionyl)-p-4-ffietho3;yphenylethylamine (7 g) and 2-methylpiperidine (5.5 g). b.p. 2l0°G/2 mm yield 7 g S9 Found C 69.80 H 9,11 N 9.12^ ^18^28^2^2 ^304) requires 7l,0l 9,27 9.20 51. N- 3-(3-methylpiperidino)propionyl -P-4-methoxyTphenyl- ethylamlne (Code No. RRL 624) The condensation of 3-methylpiperidine (6 g) and N-(3-chloropropionyl)-P-4-metho3?yphenylethylamine (7 g) gave the title compound, b.p, 236-240°C/l.25 mm yield 6 g Found C 70.69 H 9.30 N 8.91^ C^gHggOgNg (304) requires 71.01 9.27 9.20 52. N- 3-(4-methylpiperidino)propionyl -p-4-methoxyphenyl- ethylamine (Code No. RRL 625) Condensation of N-(chloropropionyl)-^-4-methoxy- phenylethylamine (7 g) and 4-methylpiperidine (6 g) gave N_ 3-(4-methylpiperidino)propionyl -P-4-methoxyphenylethyl- amine. b.p. 212-215°C/1.25 mm yield 8 g Found C 69.92 H 9.06 N 9.14^ ^18^28^2% (304) requires 70.01 9.27 ».20 90 53. N-_3-(N-diethylamino )propionyl -p-3,4-dimethox3^henyl- ethylamlne (Code No. RBL 2561) N-(3-chloropropionyl)-p-3,4-dimethoxyphenylethyl- amine (8 g) was refluxed in dry benzene with diethylamine (6 g) for eight hours. The resulting condensation product after removal of diethylamine hydrochloride and benzene was distilled under reduced pressure. b.p. 200-202°G/l0 mm yield 6,8 g Found C 66,59 H 9,32 N 9.22^ C^^HggOgNg (308) requires 66.20 9,15 9,08 54. N- 3-(4-morpholino)propionyl -P-3,4-dimethoxyphenylethyl- amine (Code No. RBL 2562) The title compound was prepared by condensation of N-(3-chloropropionyl)-P-3,4-dimethoxyphenylethylamine (8 g) with morpholine (5 g). The colourless solid thus obtained was crystallised from benzene-petroleum ether. m.p, 88-89°G yield 7 g \ Found C 65.97 H 8,56 N 8,62^ G^7H2604N2 (322) requires 66,33 8,13 8.69 55. N- 3-( l-piperidino)propionyl -^-3,4-dimetho35yphenylethyl- amine (Code No. RRL 2563) This compound was prepared by reacting piperidine (5,5 g) with N-(3-chloropropionyl)-P-3,4-dimethoxyphenyl- ethylamine. The product was distilled at 244-245°C/l,5 mm, 91 which solidified duriag distillation. On crystallisation from benzene-petroleum ether it melted at 70®C. yield 6,8 g Pound C 67,32 H 8.62 N 8.69^ C^gHggOgNg (320) requires 67.47 8,81 8,74 56. N- 3-(l-pyrrolidino)propionyl -p-3,4-dimethoxyphenyl- ethylamine (Code No. RRL 2564) N-(3-chloropropionyl)-P-3,4-dimethoxyphenylethyl- amine (10 g) was condensed with pyrrolidine (7 g) according to procedure described. The product, N- 3-(l-pyrrolidino)- propionyl -?-3,4-dimethoxyphenylethylamine was distilled. b.p. 222-225°C/l0 mm yield 8 g Found G 66.28 H 8.49 N g.SOjT (306) requires 66.64 8,55 9,14 57. N- 3-(N-diethylamino)propionyl -P-3-methoxy-4-ethoxy- phenylethylamine (Code No. RRL 2565) Reaction of diethylamine (8 g) with N-(3-chloro- propioayl)-P-3-m3thoxy-4-ethoxyphenylethylamine (8 g) gave the title compound, b.p. 225-230°C/9 mm yield 7.5 g Found C 67,48 H 9,52 N 8,49^ ^18^003^2 ( 322) requires 67.05 9,38 8.68 n 58. N- 3-(4-morphollno)propionyl -p-3-inethoxy-4-.ethoxy- pheny1ethy1amine (Code No. RRL 2566) The title compound was prepared when morpholine (6 g) and N-(3-chloropropionyl)-p-3-methoxy-4-ethoxyphenyl- ethylamine (8 g) were refluxed in benzene for six hours. The product was a solid which was crystallised from petroleum ether-benzene. tn.p. 100°C yield 7.6 g Found C 64.53 H 8.72 N 8.28^ ^18%804N2 (336) requires 64.26 8.39 8.33 59. N- 3-( l-piperidino)propionyl -^-3-methoxy-4-ethoxy- phenylethylamine (Code No. RRL 2567) This substance was obtained as a result of condensa- tion between N-(3_chloropropiotiyl )-P-3-methoxy-4-ethoxyphenyl- 8thylamine (10 g) and piperidine (7 g). The solid obtained was crystallised from petroleum ether. m.p. 90-91°C yield 9 g Found C 68.62 H 9.20 N 8,35^ C^gHgQOgNg (334) requires 68.23 9.04 8.38 60. N- 3-(l-pyrrolidino)propionyl -^-3-methoxy-4-ethoxy- phenylethylamine (Code No. RRL 2568) Reaction between pyrrolidine (6 g) and N-(3- chloropropionyl)-P-3-methoxy-4-ethoxyphenylethylamine (8 g) gave the title compound. After recrystallisation from petroleum ether, it melted at 92-94°C and weighed 7 g. Found C 67.51 H 8.78 N 8.785^ (320) requires 67.47 8.81 8.74 61. N- 3-(N-diethylamino)propionyl -P-3,4-diethoxyphenyl- ethylamine (Code No. RRL 2569) Condensation of N-(3-chloropropionyl)-p-3,4-di- ethoxyphenylethylamine (6 g) with diethylamine (6 g) in dry benzene gave the title compound as solid which was crystallised from benzene-petroleum ether (60-80°). m.p. 85-86°C yield 5 g Found C 67.58 H 9.49 N 8.21^' ^19^32^3^2 (336) requires 67.82 9,59 8.33 62. N- 3-(4-morpholino)propionyl -^-3,4-diethoxyphenyl- ethylamine (Code No. RRL 2570) This compound was prepared by reaction of morpholine (6 g) with N-(3-chloropropionyl)-P-3,4-diethoxyphenylethyl- amine (8 g). m.p, 82-83°G (from petroleum ether-benzene) yield 7.5 g Found G 64.98 H 8.59 N 7.78^ (350) requires 65.11 8.63 7.99 94 63. N- 3-(l-piperidino)propionyl -p'-3,4-dietlio2ypheaylethyl- amine (Code Nq, RRL 257l) As a result of reaction between N-.(3-chloropropionyl)- p-3,4-diethoxyphenylethylamine (8 g) and piperidine (6 g), the title compound was obtained as a colourless solid, which was crystallised from petroleum ether (60-80°) and melted at 80- 8l°C. The yield of the product was 8 g. Found C 68.48 H 9.08 N 8.08^ C20H32O3N2 (348) requires 68.93 9.26 8.04 64. N- 3-(l-pyrrolidino)propionyl -p-3,4-diethoxyphenylethyl- amine (Code No. RRL 2572) This compound was prepared when pyrrolidine (6 g) was condensed with N-(3-chloropropionyl)-P-3,4-diethoxy- phenylethylamine (6 g). m.p. 83-85°C yield 5.2 g Found C 68,46 H 9.10 N 8,36^ (334) requires 68.23 9,04 8.38 65. N- 3-(N-diethylamino)propionyl -p-3,4-methylenedioxy- !st — phenylethylamine (Code No. RRL 2573) N-(3-chloropropionyl)-^-3,4-methylenedioxyphenyl- ethylamine (8 g) and diethylamine (8 g) were refluxed in benzene (lOO cc.) for eight hours. After removal of diethyl- amine hydrochloride by filteration and benzene by distillation, 95 residue was distilled under vacuum, b.p. 220°C/ll mm m.p. 50-52°C yield 6,5 g Found C 65.48 H 8.31 N (292) requires 65.72 8.28 9,58 66, N-^3-(4-morpholino)propionyl -P-3,4-methylenedioxy- phenylethylamine (Code No, RKL 2574) As a result of condensation between morpholine (6 g) and N-.(3>chloropropionyl)-p-3,4-methylenedioxyphenylethylamine (8 g), the title compound was obtained, m.p, 98-99°C (from benzene-petroleum ether) yield 7,6 g Found C 63.01 H 7,29 N 9.180 ^16^2204% (306) requires 62,72 7.24 9,14 67, N- 3-(1-piperidino)propionyl -^-3,4-methylenedioxy- phenylethylamine (Code Mo, RRL 2575) This compound was prepared by reacting piperidine (6 g) and N-(3_chloropropionyl )-p-3,4-methylenedio35yphenyl- ethylamine (8 g) in dry benzene. The solid product obtained was crystallised from petroleum ether (60-80°). m.p, 73-74°C yield 7 g Found C 66.92 H 7.88 N 9.46^ ^17%4°3% (304) requires 67.08 7.95 9.20 96 68. N- 3-(l-pyrrolidino)propion7l -p-3,4-methylenedioxy- phenylethylamine (Code No. RRL 2576) The title compound was obtained as a result of condensation between N-.(3-chloropropionyl)-p-3,4-niethylene- dioxyphenylethylamine (8 g) and pyrrolidine (6 g), b.p. 220-223°C/lO mm yield 7 g Found C 65.98 H 7.53 N 9,585^ C^gHggO^Ng (290) requires 66,18 7.64 9.65 Method '3' Heating N-(2-chloropropionyl)--P-phenylethylamlnes and secondary amines without solvent This method was used for condensation of heterocyclic amines i.e. morpholine, piperidine and pyrrolidine with N-(2- chloropropionyl)-P-phenylethylaraines. Heterocyclic amine (0.2 mole) and N-.(2-chloropropionyl)-^-phenylethylamines (0.1 mole) were mixed together, when a mild exothernic re- action occured. The mixture was heated at 130-140°C for four to six hours. The reaction mixture was cooled and poured in water, and extracted with ether or benzene. After removal of solvent, residue was distilled under vacuum in case of a liquid reaction product, and filtered and crystallised in case of a solid product. The compounds thus prepared are described below. 97 69. N- 2-(4-morpholino)propionyl -p-phenylethylamine (Code No. RRL 572) A mixture of N-(2-chloropropionyl)-p-phenylethyl- amine (12 g) and morpholine (8 g) was heated at 130-l40°C for four hours. The product, N-[2-(4-morpholino)propionyl P-phenylethylamine was worked up according to the procedure described above. b.p. 202-206°C/l.5 mm yield 11 g Found C 68.42 H 8.18 N 10.24^ ^15^22^2^2 (262) requires 68.67 8.45 10.68 70. N- 2-(l-piperidino)propionyl -p-phenylethylamine (Code No. RRL 573) The condensation between piperidine (6 g) and N-(2-chloropropionyl)-^-phenylethylamine (7 g) resulted in the formation of N- 2-(l-piperidino)propionyl -P-phenylethyl- amine. b.p. l76°C/0.5 mm yield 6 g Found C 73.68 H 9.02 N 10.81^ C^gH240N2 (260) requires 73.80 9,29 10.76 71. N- 2-(4-morpholino)propionyl -P-4-methoxyphenylethylamine (Code No. RRL 586) This compound was prepared by condensation of morpholine (4 g) with N-(2-chloropropionyl)-P-4-methoxy- 98 phenylethylamlne ( 5 g). b.p. 246-250°C/2.5 mm yield 4 g Found C 65.38 H 8.09 N 9, ^16^24^3^2 ^292) requires 65.72 8.27 9.58 72, N_|_2-( 1-piperidino )propionylJ -p-4-methoxyphenylethylamine (Code No. RRL 587) N-(2-chloropropiotiyl)-^-4-methox3rphenylethylamine (7 g) and piperidine (6 g) were condensed to get N- 2-(l- piperidino)propionyl -P-4-methox3rphenylethylamine (6 g). b.p. 222-2260C/2-2.5 mm yield 6,5 g Found C 70.15 H 9.11 N 9.20^ ^17^26^2% (290) requires 70.31 9.02 9.65 73. N- 2-(l-pyTrolidino)propionyl -p-4-methox3rphenylethylamine (Code No. RRL 588) The title compound was obtained as a result of condensation between pyrrolidine (4 g) with N-(2-chloropro- pionyl)-P-4-methoxyphenylethylamine. b.p. 2l6-2l8°C/2 mm yield 3 g Found C 69.12 H 8.60 N 9. (276) requires 69.53 8.75 10.17 99 74. N- ^2-(2~methylplperidino)proploaylJ-^-4-metho:xyphenyl- ethylamlne (Code No. RRL 589) The above compound was obtained by the condensation of N-(2-chloropropionyl)-p-4-methoxyphenylethylamine (7 g) and 2-methylpiperidine (6 g), b.p. 232°C/2 mm yield 6 g Found C 70.78 H 9,12 N 9.16^ C^gHggOgNg (304) requires 71.01 9.27 9.20 75. N- _2-(3-methylpiperidino )propionylj -^-4-methoxyphenyl- ethylamine (Code No. RRL 590) The condensation of 3-methylpiperidine (6 g) with N-(2-chloropropionyl)-P-4-.methoxyphenylethylamine (7 g) gave the title compound. b.p. 224-226°C/2 mm yield 6.2 g Found C 71.18 H 9.08 N 9.12^ C^gHggOgNg (304) requires 71.01 9.27 9,20 76. N- 2-(4-methylpiperidino)propionyl1-P-4-methoxyphenyl- lylamine {.Code No. HHL 59l) When 4-methylpiperidine (3 g) was reacted with N-(2-chloropropionyl)-?-4-methoxyphenylethylamine (4.5 g) the product was N- 2-(4~methylpiperidino)propionyl -p-4- methoxyphenylethylamine. 100 b.p, 220°G/l,5 mm yield 4 g Found C 70.69 H 9.12 N 8.97^ C^^gHggOgNg (304) requires 71.01 9.27 9,20 77. N- 2-(4-morpiiolino )propionyl -P-3,4-diinethoxyphenyl- ethylamine (Code No. RRL 2538) Reaction of N-(2-chloropropionyl)-p-3,4-dimethoxy- phenylethylamine (lO g) with morpholine (7 g) gave the title compound. b.p. 246°C/l mm yield 9.5 g Found C 66.58 H 8.29 N 8.62^ ^17^26^4% (322) requires 66.33 8.13 8.69 78. N- 2-(l-piperidino)propionyl -^-3,4-dimethoxyphenyl- ethylamine (Code No. RKL 2639) This compound was obtained when piperidine (5,5 g) was condensed with N-(2-chloropropionyl)-P-3,4-dimethoxy- phenylethylamine (8 g). b.p. 228-230°C/l mm yield 7.6 g Found C 67.19 H 8.78 N C^gHggOgNg (320) requires 67.47 8.81 8.74 79. N- 2-(l-pyrrolidino)propionyl -p-3,4-dimethoxyphenyl- ethylamine (Code No. RRL 2540) N-(2-chloropropionyl)-P-3,4-dimethoxyphenylethylamine iil (10 g) was condensed with pyrrolidine (8 g) using benzene as solvent. The product was distilled at 218-220°C/i.5-2 mm, yield 8,5 g Found C 66,28 H 8.47 N 9.11^ C^^HggOgNg (306) requires 66.64 8,55 , 9,14 80. N- 2-(2-methylpiperidino)propionyl -P-3,4-dimethoxy- phenylethylamine (Code No, RRL 2541) Condensation of 2-methylpiperidine (6 g) with N-(2-chloropropionyl)-p-3,4-dimethoxyphenylethylamine (8 g) gave the title compound, b.p, 232®C/l mm yield 8 g Found C 68.18 H 9.20 N 8,32^ ^19^30^3^2 ^334) requires 68,23 9,04 8,38 81, N- 2-(3-methylpiperidino)propionyl -^-3,4-dimethoxy- phenylethylamine (Code No, RRL 2542) . Reaction of N-(2-chloropropionyl)-p-3,4-dimethoxy- phenylethylamine (9 g) with 3-methylpiperidine (6,5 g) gave N- 2-(3-methylpiperidino)propionyl -^-3,4-dimethoxyphenylethyl- amine. b.p. 230-232°C/l,5 mm yield 8 g Found C 68,18 H 9.10 N 8,29^ C29H30O3N2 (334) requires 68.23 9,04 8,38 102 82. N- 2-(4-.methylpiperidino)propionyl -p-3,4-dimethoxy- phenylethylamine (Code No. RRL 2543) This compound was obtained when 4-methylpiperidine (6 g) was condensed with N-(2-chloropropionyl)-p-3,4-di- methoxyphenylethylamine (8 g), b.p. 240-242°C/l,5 mm yield 7.6 g Pound C 67.98 H 9,19 N 8.42^ ^19^30^3^2 (334) requires 68.23 9.04 8.38 N_ 2-(4-morpholino)propionyl -P-3-methoxy-4-ethoxy- phenylethylamine (Code No. R]R L 2545) Reaction of morpholine (5 g) with N-(2-ehloro- propionyl)-P-3-methoxy-4-ethoxyphenylethylamine (8 g) resulted in the formation of N- 2-(4-morpholino)propionyl P-3-methoxy-4-ethoxyph6nylethylamine. b.p. 242-244°C/l mm yield 7,2 g Found G 63.96 H 8.42 N 8.29^ ^18^28^4^2 (336) requires 64.26 8.39 8.33 84. N- 2-(1-piperidino)propionyl -P-3-methoxy-4-ethoxy- phenylethylamine (Code No. RRL 2546) The title compound was obtained when N-(2-ehloro- pTopionyl)-P-3-methoxy-4-ethoxyphenylethylamine (8 g) and piperidine (5 g) were heated together at 120-125°C for four ho ur s. 103 b.p. 226-228°C/0.6 mm yield 8 g Found C 68,49 H 9.18 N 8,26^ (334) requires 68.23 9,04 8,38 85. N- 2-(l~pyrrolidino)propionyl -P-3-methoxy-4-ethoxy- phenylethylamine (Code No, RRL 2547) The reaction between pyrrolidine (6 g) and N-(2- chloropropionyl)-P-3-methoxy-4-ethoxyphenylethylamine (8 g) resulted in the formation of N-2-(l-pyrrolidino)propionyl - ^-3-metho3 b.p, 2l6-2l8°C/l-2 mm yield 7,5 g Found G 67,32 H 8,92 N 8,68^ ^IS^S^SNS (320) requires ' 67.47 8,81 8,74 86. N- 2-(2-metbylpiperidino)propionyl -p-3-methoxy-4-ethoxy- phenylethylamine (Code No. RRL 2548) This compound was obtained when 2-methylpiperidine (6 g) was condensed with N-(2-chloropropionyl)-P-3-"methoxy- 4-Qthoxyphenylethylamine (9 g), b.p, 234-238°C/l,5 mm yield 8 g Found C 69,18 H 9.09 N 8,18% C20H32O3N2 (348D requires 68,93 9,26 8.04 104 87. N-^2-(3-methylpiperidino)propionyl] ,p-3-methoxy-4- ethoxyphenylethylamlne (Code No. RRL 2549) As a result of condensation between 2-methyl- piperidine (5 g) and N-(2-chloropropionyl)-p-3-methoxy-4- ethoixyphenylethylamine (8 g), the title compound was obtained as a viscous liquid, b.p. 238-242°C/l.5 mm yield 7.5 g Found C 68.68 H 9.16 N 8.00?^ ^2(^32^3^2 (348) requires 68.93 9,26 8.04 88. N- 2-(4-methylpiperidino)propionyl -P-3-methoxy-4- ethoxyphenylethylamine (Code No, RRL 2550) This compound was prepared by reacting 4-methyl- piperidine (5 g) with N-(2-chloropropionyl)-p-3-mGthoxy-4- ethoxyphenylethylamine (8 g). b.p. 238-240°C/l.5 mm yield 7.8 g Found C 68.75 H 9.21 N 8.12^ C20H32O3N2 (348) requires 68.93 9,26 8.04 89. N- 2-(4-morpholino)propionyl -p-3,4-diethoxyphGnyl- ethylamine (Code No. RRL 2552) The title compound was prepared by reacting N-(2-chloropropionyl)-^-3,4-diethoxyphenylethylamine (8 g) and morpholine (5 g), b.p. 246-248°C/0,8 mm yield 7.6 g 105 Found C 64.87 H 8.46 N 7.82^^ C19H3QO4N2 (350) requires 65.11 8.63 7.99 90. N- 2-(l-piperidino)propionyl -p-3,4-diethoxypheny1- ethylamine (Code No. RRL 2553) When N-(2-chloropropionyl)-p-3,4-dietho3q7-phenylethyl' amine (10 g) was condensed with piperidine (7 g), N- 2-(l- piperidino)propionylJ-P-3,4-diethoxyphenylethylamine was obtained. b.p. 228-230°C/l-2 mm yield 9.2 g Found C 69.16 H 9.34 N 8,11^ ^20^32^3^2 requires 68.93 9.26 8.04 91. N- 2-(l-pyrrolidino)propionyl -P-3,4-diethoxyphenyl- ethylamine (Code No. RRL 2554) Pyrrolidine (5 g) condensed with N-(2-chloro~ propionyl)-p-3,4-diethoxyphenylethylamine (8 g) to give the title compound which distilled at 234-236°C/l.5 mm and weighed 7 g. Found C 68.42 H 9.14 N 8.35^ ^19^30^3^2 requires 68.23 9.04 8.38 92. N_ 2-(2-methylpiperidino)propionylJ -P-3,4-diethoxyph6nyl- ethylamine (Code No. RRL 2555) This compound was prepared by condensation of N-(2-chloropropionyl)-P-3,4-diethoxyphenylethylainine (6 g) with S-methylpiperidine (3,5 g). b.p. 238-240°C/l.5 mm yield 5 g Found C 69.74 H 9.28 N 7.69^ C21H34O3N2 (362) requires 69,58 9.45 7.73 93. N- 2-(3-methylpiperidino)propionyl -P-3,4-dietho3?y- phenylethylamlne (Code No. RRL 2556) Reaction of N-(2-chloropropionyl)-P-3,4-diethoxy- phenylethylamine (8 g) with 3-methylpiperidine (5 g) resulted in the formation of the title compound. b.p. 238-240°C/l mm yield 7 g Found C 69.36 H 9,38 N 7,68 ^21^4*^3% (362) requires 69.58 9,45 7,73 94. N- 2-(4-methylpiperidino)propionyl ~p-3,4-diethoxy- phenylethylamine (Code No, RRL 2557) This compound was prepared by condensation of 4- methylpiperidine (6.5 g) with N-.(2-ehloropropionyl)-p-3,4- diethoxyphenylethylamine (lO g), b,p, 256-260°C/2,5 mm yield 9 g Found C 69,49 H 9,38 N 7,8^ (362) requires 69,58 9,45 7.73 107 96. N-L2-(4-morpholino)propionylJ-p-3,4-methylenedioxy- phepylethy1amine (Code No. RRL 2659) When morpholine (7 g) and N-(2-.chloropropionyl)-p- 3,4-methylenedioxyphenylethylamine (lO g) were heated at 125-130OC for five hours, the product was N-^2-(4-morpholino)- propionyl --p-3,4-methylenediox3rphenylethylamine. b.p. 254-258°C/2 mm yield 9.2 g Found C 62.82 H 7,18 N 9.12^ C]^6H2204N2 (306) requires 62.72 7.24 9,14 96. N- 2-(l-piperidino)propionyl -P-3,4-methylenedioxy- phenylethylamlne (Code No. RRL 2560) Reaction between piperidine (4 g) and N-(2-chloro- propionyl)-p-3,4-methylenedioxyphenylethylamine (6 g) resulted in the formation of the title compound, b.p. 228-230°0/1 mm yield 5 g Found G 66.87 H 7.82 N 9,28^ ^17^24^3^2 (SO'^) requires 67,08 7.95 9,20 Method 'C Condensation of N-(2-chloropropionyl)-P~phenylethylamines with diethylamine by heating in an autoclave N-(2-chloropropionyl)-P-phenylethylamine (0,1 mole) and diethylamine (0,4 mole) were heated in a glass autoclave 108 at 130-140°C for four to six hours. The autoclave was cooled and opened cautiously. The contents were dissolved in water, made alkaline with sodium hydroxide solution (10 per cent) and extracted with ether. After removal of ether, product was distilled under vacuum. The following compounds were prepared by this method. 97, N-{_2-(N-.diethylamiao)propionylJ-P--phenylethylamine (Code No. RRL 57l) N-(2-chloropropionyl-P-phenylethylamine (lO g) and diethylamine (15 g) were condensed by heating in an autoclave at 130-l40°C as described in the above method, b.p. 164-166°G/1 mm yield 9 g Found C 72.38 H 9.66 N 11.27^ C25H24ON2 (248) requires 72.54 9,74 11.28 98. W- 2-(N-diethylamino)propionylJ-p-4-methoxypheD7le^'^yl- amine (Code No. RRL 585) Diethylamine (9 g) reacted with N-(2-chloropropionyl)• P-4-methoxyphenylethylamine (10 g) to yield N-^2-(N-.diethyl- amino )propionyl -^-4-methoxyphenylethylamine, b.p. 196-198°C/l mm yield 6,5 g Found C 68.71 H 9,23 N 9.82^ ^16^26^2^2^278) requires 69.03 9,41 10.06 m 99. N-[2-(N_diethylainino)propionyl -p-3,4-dimethoxy- phenylethylamine (Code No. RRL 2537) Reacting N-(2-chloropropionyl)-P-3,4-dimethoxy- phenylethylamjne (8 g) with diethylamine (8 g) according to the procedure described earlier, the title compound was obtained. b.p. 200-.202°C/l-2 mm yield 6.5 g Pound C 66.42 H 9.23 N 9,14 (308) requires 66.20 9.15 9.08 100. N-[_2-(N-diethylamino)proplonyl -p-3-methoxy-4-ethoxy- phenylethylamina (Code No. RRL 2544) This compound was prepared when N-(2-chloro- propionyl)-P-3-methoxy-4-ethoxyphenylethylamine (lO g) was condensed with diethylamine (lO g), b.p. 204«206°G/1 mm yield 8 g. Found C 66.97 H 9,52 N 8.63^ C]^8H3o03N2 (322) requires 67.05 9,38 8.68 101. N- 2-(N-diethylamino)propionyl -^-3,4-diethoxyphenyl- ethylamine (Code No. RRL 2551) Condensation between diethylamine (8 g) and N-.(2- chloropropionyl)-p-3,4-dietho3cyphenylethylamine gave the title compound, b.p. 198-200°C/l-2 mm yield 6 g 110 Found C 67.68 H 9.48 N 8.42^ (336) requires 67,82 9,59 8,33 102. N- 2-(^-diethylaraino )propioayl -P-3,4-metliyleaedioxy- phenylethylamine (Code No. RRL 2558) Reaction of diethylamine (lO g) with N-(2-chloro- propionyl )-p-3,4-methylenedio5{yphenylethylamine (lO g) in an autoclave at 130-140°C yielded the title compound. b.p, 234°C/4 mm yield 7.8 g Found C 65.48 H 8.18 N 9.49^ (292) requires 65,72 8,27 9,58 118 REFER E NGES 1. A. Burger, Medicinal Chemistry, page 368 (i960), Interscience Publishers Inc., N.Y. 2. E. Sury, Tagmann, E. Sury and K. Hoffmann, Helv. Chim. Acta, 36, 1809 (1953). 3. A.H. Lutz and 0. Schnider, Helv. Chim. Acta, 39, 81 (1956). 4. S.H. Zaheer and I.K. Kacker, J. Indian Chera. Soc., 28, 344 (1951). 5. G.S. Sidhu, P.B. Sattur and K. Bhanumati, Personal communication. 6. A. Hauptmann, Munch, med. Wochschr., 1907 (1912). 7. Heyden Co.,33 Germa T,944n (1914)Pat.. .309,508 ; 310,426; 310,427; 8. H.H. Merritt and T.J. Putnam, Arch. Neurol. Psychiat., 29, 1003 (1938). 9. T.J. Putnam and H.H. Merritt, Science, 85, 525 (1937). 10. W.C. Brown, D.O. Schiffman, E.A. Swinyard and L.S, Goodman, J. Pharmacol. Exptl. Therap., ••107, 273 (1953). 11. K. Mieschfr, Helv. Chim. Acta, 15, 163 (l932). 12. J.L. Southwrth and C.H. D^bbs, Anesthesia and • Analgesia, 32, 159 (1953). 13. C.Y. Sung and A,P. Truant, J. Pharmacol. Exptl. ^heran., 112, 432 (1954). 14. I. Fischer and N.M. Lofgren, Acta, Chera. Scand., 4, 1408 (1950). 15. N.M. Lofgren and B. Takman, Acta Chem. Scand., 6, 1006 (1952). 16. D.T. Weston, J. Lancet, 76, 7 (1956). 17. G.S, Sidhu,Persona P.B. lSattur communicate'on, P. Rao an. d N.K. Sogani, 18. ¥m. F. Bruce and J. Seifter, U.S. Pat., 2,768,176 (1956); Chem, Abs., 52 , 424 (1958). CHAPTER IV 112 N-AMINOALKYL-p-PHBNYLBTHYLAMINES This chapter describes the preparation of N-amino- alkyl-p-phenylethylamines of the general structure (LIII) NH — CH- N ^Z (LIII) where R]^ and R2 stand for H, methoxy in para position, 3:4- dimethoxy, 3-methoxy-4-ethoxy, 3:4-diethoxy and 3:4-methylene- dioxy groups. Y stands for alkyl chain such as -CH2-, CH- CH„ -CH2-CH2- and -N Z represents diethylamine, morpholine, piperidine, pyrrolidine and p- and Y-pipecolines. A large number of drugs in clinical use for the treatment of management of withdrawal syndrome of drug addiction, acute alcoholism and antiallergic syndrome incorporate -N-Y-N Z group. Some of the more important ones are Phenothiazines^"''^ (LI"7) such as (LIV) (LV) Promazine R .(CH2)3N-(CH3)2 2 3 (LVI) Diethazine R .(CH2)2-N-(C2H5)2' 7 (L¥II) Trimeprazine R -CH2-CH-CH2-N-(CH3)2 CHo (LVIII) Pyrathiazine R = -CH2-CH2-N V Major advances have been made in recent years in the treatment of antiallergic syndrome with compounds contain- ing -N-C-C-N- structure. The highest antihistaminic activity among the structures of the type Ar-N-CH2CH2NR2 was observed k when Rj^represented benzyl or analogous heterocyclic group and R2 was methyl. The first useful drug in this series g was prepared by Halpern known as Antergan (LIX). .CH, CH,—N —CHo-CHo —N ^CH, o (LIX) 114 Replacement of the benzyl group by 2-thenyl (LX) confers less sedation than Antergan whereas 2-methylfuryl isostere (LXI) has the same order of activity as that of Antergan^' /CH3 CH,— N —CH,—CH,— N ^CH, o (LX) CHo—N—CHo—CH. •N CH, O (LXI) Structural modification of Antergan molecule led to more active members in the series. Bovet and co- workers foimd that N-(4-methoxybenzyl)-N-(2-pryidyl),N- dimethylethylenediamine (LXII) (Neoantergan, Pyranisamine, Anthisan) was many times more active and less toxic than AnterganH>l2, 115 -CH, HjCO CHj—N — CHj— CHj—N o (LXII) Some of the commonly employed antihistamines in therapy belonging to this class of compounds having minor modifications in structure are (LXIII-LXV)- Cl CH2—N — CH2—CH2—N CH, N (LXIII) (Synopen) /CH3 CH2—N —CH2—CH2—N An CH. u (LXIV) (Histadyl; Thenylpyramine) 116 CHj— N -CHg—CH2— N: ^CH. O (LXV) (Dlatrin; Methaphenilene) Ethylenediamine derivatives incorporating an acridan moiety on one of the nitrogen have been shown to possess anti-histaminic activity. Thus l0-(2-dimethyl- aminoethyl)acrldan (LXVI) has been claimed to possess seven times more activity than diphenhydramine 17 A systematic -n: XH. (LXTE) stady of the Ethylenediamine derivatives of the following type (LXVII) incorporating a benzylamine moiety 117 (LX7II) where Rj* ®2> R^represent H, chloro, d'ichloro, methoxy, dimethoxy and alkyl groups, R5 and Rg represent H, CHg, or C3H7 and-N Z represents a heterocyclic moiety such as morpholine, piperidine and pyrrolidine groups has been carried out by Sidhu, Sattur and Sadanandam^^. The compounds possess mild antihistaminic activity but in general exhibit ataxia, Irritability, gasping and increase of motor activity. It is also interesting to observe that some of the compounds exhibit good antipyretic and diuretic activity. The compounds are undergoing screening in experimental animals, In continuation of this work, Sidhu, Sattur, Salma Ansari and Bhaskar Rao synthesised a number of derivatives of the follow- ing tjrpe derived from P-phenylethylamine. NH --CH2 —CH2 n' (LX^nii) 118 / > where represents morpholine, piperidiae, pyrrolidine and diethylamine, with a view to establish structure r activity relationship. Present work It was thought worthwhile to synthesise structures of the type /—N where R]^ and R2 represent H, methoxy, dimethoxy and methylene- dioxy groups, Y stands for an alkylene chain such as -CH2-CH2-, -CH2-CH-, -CH2-CH2-CH2- and N Z represents CH3 , diethylamine, morpholine, piperidine, pyrrolidine, 2-, 3-, and 4-methylpiperidine, Compounds of this type may also be looked upon as open chain analogues of 2-benzyl-2-imidazoline (Prisco- 19 line, Benzazoline, Tolazoline) (LXIX) which is employed clinically as moderately effective adrenergic blocking agent. It is also employed for the clinical management of acute poliomyelitis; at doses large enough to produce lis N- N — c CHj-C- ^N- -N (LXIX) (2-benzyl-2-imidazoline) 20 flashing, pain and spasms appear to be relieved Compounds of the general structure (LIII) were synthesised by (A) Condensing basic alkyl chlorides with suitably substituted phenyl- ethylamines. 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A. Condensation of appropriately substituted p-phenylethyl- Mir^s_with alkylaminoaikyl chlorides Alkylarainoalkyl chlorides (Table 13-A) which were required for condensation of various P-phenylethylamines were obtained as described in literature. TABLE 13 (A) S.No. Compound b,p .^C/mm Reference 1 2-diethylaminoethyl 35/10 21 chloride 2 2-(4-raorphollno)ethyl 86-88/10 22 chloride 3 2-(l-piperidino )ethyl 65/7 23 chloride 4 3-(diethylamino)propyl 70-75/25 24 chloride 5 3-(4-morpholino)propyl 109-114/25 24 chloride 6 3-(l-piperidino)propyl 95-100/25 24 chloride 7 2-(diethylamino)propyl 75-78/6 chloride 8 2-(4-morpholino)propyl 120/50 25 chloride 9 2-(1-piperidino)propyl 60/25 chloride 130 General procedure The anpropriate P-phenylethylamine (0,l2 mole) and the freshly prepared alkylarainoalkyl chloride (0«1 mole) were mixed together and heated over an oil bath at 80-ll0°C for one to four hours. The mixture gradually became viscous or solid mass, which was cooled, dissolved in water and basified with 10^ caustic soda solution. The liberated b^se was extracted with ether and ethereal extract was dried over anhydrous sodium sulphate. The solvent was removed and residue was distilled under reduced pressure, Picrates were prepared by mixing up warm alcoholic solutions of the base and picric acid and were crystallised from ethanol or acetic acid, B. Reduction _q f - ami no acyl- P-p henyle t hy lamine s _wit h Lj. t hi ^ aluminium hydride N-aminoacyl-fS-phenylethylamine (10 g) dissolved in 50 ml of anhydrous tetrahydrofuran was added dropwise to a suspension of Lithium aluminium hydride (6 g) in tetrahydro- furan (100 cc.). After the addition was over, the mixture was refluxed with sstirring for five to six hours and cooled. Excess of Lithium aluminium hydride was decomposed by adding slowly moist ether and aqueous potassium hydroxide (40^), The solid was filtered, washed with ether and filtrate was dried over anhydrous sodium sulphate. After removal of solvent, residue was distilled under reduced pressure. 131 Picrates were prepared as in method 'A'. The compounds prepared by these methods are described below. _2-(N-dlethylamlno)ethylJ -P-phenylethylamlne (Code No. RRL 801) P-phenylethylamine (8 g) and diethylaminoethyl chloride (6 g) were mixed together and kept at 60-70°C for 3 hours. The condensation product was worked up as described a above and distilled under reduced pressure. b.p. 134-136°C/3 mm yield 6 g Found G 76.23 H 10.86 N I2.52f (220) requires 76.31 10.98 12.71 Pi crate m.p. 145°C (from ethanol) Found N 15.235^ ^20^27^7^6 (449) requires 15.57 2. N- 2-(4-morpholino)ethyl -P-phenylethylamine (Code No. RRL 8ll) The title compound was prepared by heating a mixture of p-phenylethylamine (8 g) with 2-(4-morpholino)ethyl chloride at 80-l00°C for three hours. The product was worked up as described in the general procedure and distilled. b.p. l74-l78°C/4~5 mm yield 6 g 32 Found G 71.46 H 9.27 N 11.76f> C234) requires 71.75 9.46 11,96 Picrate m.p. 212°C (from ethanol) Found N 1-5.04^ "^20^25^8% (463) requires 15.12 3. N- 2-(l-piperidino)ethyl -p-phenylethylamlne (Code No. RRL 818) Condensation of p-phenylethylamine (8 g) with 2-(l- piperidino)ethyl chloride (6 g) at 90-100°G for three hours gave N- ^2-( 1-piperidino )ethylj -P-phenylethylamine . b.p. l74°C/2-3 mm yield 6.4 g Found C 77.86 H 10.31 N 12.13f? ^15^24^2 (232) requires 77.98 . 10.34 12.06 Picrate m.p. 215°C (from ethanol) Found M 20.04^ C21H27O7N5 (461) requires 20.31 4. N- 2 - (2-me thylt) ip er i di no) e thylJ - ^-p henyle thylamin e (Code No. RRL 232) The above compound was prepared by reduction of N-(2-methylpiperidino)acetyl-^-phenylethylamine (8 g) with Lithium aluminium hydride (5 g) in tetrahydrofuran. b.p, 150-154°G/0.8 mm yield 5,5 g 133 Found C 78.17 H 10.28 N 11.23^ (246) requires 78.05 10.57 11.39 5. N- 2-(3-methylpiperidino )ethyl -P-phenylethylamine (Code No. RRL 833) Reduction of N-(3-methylpiperidino)acetyl-P-phenyl- ethylamine (7 g) with Lithium aluminium hydride (4 g) afforded the title compound. b.p. 156-160°G/1 mm yield 4.5 g Found G 77.83 H 10.42 N 11.32^ C^gHggNg (246) requires 78.05 10.57 11.39 6. N- 2-(4-methylpiperidino)ethyl -P-phenylethylamine (Code No. RRL 834) The above compound was obtained by reduction of N-(4-morpholino)acetyl-P-phenylethylamine (6 g) with Lithium aluminium hydride in tetrahydrofuran. b.p. l48-150°C/0.8 mm yield 4 g Found G 77.79 H 10.46 N 11.26^ C^gHggNg (246) requires 78,05 10.57 11.39 7. N- 2-(N-diethylamino)ethyl -p-4-methoxyphenylethylamine (Code No. RRL 804) The above compound was prepared by condensation of p-4-methoxyphenylethylamine (9 g) with diethylaminoethyl chloride (7 g). The reaction temperature was maintained between 80-ll0°C for three hours. b.p, 180-192°C/0.8 mm yield 6,5 g Pound C 71,68 H 10.32 N 11,08^ C^gHggONg (262) requires 71.95 10.47 11.19 Picrate m,p. 169°C (from ethanol) Found N 14.52^ ^21^29^8% requires 14,61 8. N- 2-(4-morpholino)ethyl -p-4-methoxyphenylethylamine (Code No. RRL 814) 2-(4-morpholino)ethyl chloride (6 g) was added to P-4-methoxyphenylethylamine (8 g) and heated at 90-l00°C for three hours. The reaction product was worked up as usual and distilled under reduced pressure. b.p. l88-190°C/0.5 mm _ yield 7.5 g Found C 67.98 H 9.12 N 10.47^ (264) requires 68.15 9,15 10,60 Picrate m,p, 188°C (from ethanol) Found N 14.51^ ^21^27^9% (493) requires 14.20 135 9. N- 2-( 1-piperidino)ethyl -^-4-methox3rphenylethylamine (Code No. RRL 82l) 2-(1-piperidinoOethyl chloride (6 g) and P-4-methoxy- phenylethylamine (9 g) were mixed together and kept at 85-l00°C for three hours. The reaction product was worked up according to the procedure described. b.p. l84-l88°C/0.5 mm yield 5.5 g Found C 73.16 H 10.10 N 10.52^ C^gHggONg (262) requires 73.24 9.99 10.68 Picrate m.p, 176°C (from ethanol) Found N a4.l7f> C22H2908% (491) requires 24.06 •10. H- 2-(2-methylpiperidino)ethyl -P-4-methoxyphenylethylamine (Code No. RRL 829) The reduction of N-(2-inethylpiperidino )acetyl-P-4- methoxyphenylethylamine (6 g) with Lithium aluminium hydride afforded the' title compound, b.p. 190~194°G/1 mm yield 3.5 g Found C 73.69 H 10,31 N 10.27^ C;j^7H280N2 (276) requires 73.86 10.21 10.14 ;i6 11. N- 2-(3-raethylpiperidlno )ethyl -p-4-meth.oxypheaylettiylainltie (Code No. RRL 830) The above compound was obtained by reduction of N-(3-methylpiperidino)acetyl-P-4-methoxyphenylethylamine (6 g) with Lithium aluminium hydride (4 g) in tetrahydrofuran. b.p. l92-196°C/0.9-l mm yield 4.2 g Found C 73.71 H 10.08 N 10.18^ C^^HggONg (276) requires 73.86 10.21 10.14 12. N- 2-(4-methylpiperidino)ethyl -p-4-methoxyphenylethylamine (Code No. RRL 831) The title compound was obtained when N-(4-raethyl- piperidino)acetyl-p-4-methoxyphenylethylamine (8 g) was reduced with Lithium aluminium hydride. b.p. 192-194°G/1,5 mm yield 5.5 g Found G 73.67 H 10.13 N 10.34^ C^yHggONg (276) requires 73.86 10.21 10.14 13. N- 2-(N-diethylamino)ethyl -§-3,4-dimethoxyphenylethylamine (Code No. RRL 2577) Condensation of 6-3,4-dimethoxyphenylethylamine (lO g) with N-diethylaminoethyl chloride was carried out by heating the mixture of the two substances at 100-110°C for four hours. The product was worked up according to procedure described earlier. b.p, l76-180°C/0.3 mm yield 7,2 g 137 Pound C 68.55 H 9.46 N 9.74^ C^gHggOgNg (280) requires 68.53 10.07 9.99 Picrate m.p, 184-186°C (from ethanol) Found N I5,39f, C28H34O16N8 (738) requires 15.16 14. N. 2-(4-morpholino)eth7l -p-3,4-dimethoxyphenylethylamine (Code No. RRL 2578) P-3,4-dimethox3rphenylethyiamine (10 g) was mixed with 4,morpholinoethyl chloride (6 g) and heated at loo-lio'^c for three hours. The product was distilled under redueced pressure, b.p. 206-208°C/l mm yield 6.5 g Found G 6n.76 H 8.91 N 9.34^- ^16^2603% (294) requires 65.28 8.90 9.52 Picrate m.p. 207°G'(from ethanol) Found JJ 14,52^ ^28^32^17^8 ("^52) requires 14.88 15. N-L2-(l-piperidino)ethyl -p-3,4-dimethoxyphenylethylamlne (Code No. RRL 2579) Condensation of P-3,4-dimethoxyphenylethylamine (8 g) with N-( i-piperidino)ethyl chloride (-5 g) was carried out by heating the mixture of the two substances at 90-ll0°G for three hours. The product was worked up as described earlier and distilled._ b.p. 2l2-2l4°C/2.5 mm yield 5.8 g Found C 70.26 H 10.48 N 9.43^ ^17^28^2^2 (292) requires 69.82 9.85 9.58 Picrate m.p. 200-202°G (from ethanol) Found N 15.23^ C^SO) requires 14.92 16. N- 2-(1-pyrrolidino)ethyl -P-3,4-dimethoxyphenylethylamine (Code No. RRL 2580) The above compound was obtained by reduction of l-pyrrolidino )acetyl-.P-3,4-dimethoxyphenylethylamine (8 g) with Lithium aluminium hydride (5 g) in tetrahydrofuran. b.p. 186-188OC/0.5 mm yield 6.5 g Found C 69.50 H 8.89 N 10.21^ C^gHggOgNg (278) requires 69.03 9,41 10.06 Picrate m.p. 202-203°C (from ethanol) Found N 13.53^ C22H29O9N5 (507) requires 13.80 17. N- 2-(2-methylpiperidino)ethyl -P-3,4-dimethoxyphenylethylamine (Code No. RRL 258l) Reduction of N-(2-methylpiperidino)acetyl -§-3,4- dimethoxyphenylethylaraine (8 g) with Lithium aluminium hydride (5 g) in tetrahydrofuran gave the title compound. 139 b.p. 206-210 C/0.9 mm yield 5.8 g Found C 70.29 H 9.68 N 9.38?^ C^gHgQOgNg (306) requires 70.55 9.68 9.38 Picrate m.p. 203-204°C (from ethanol) Found N 13.36^ ^2#3309% (535) requires 13.08 18. N- 2-(3-methylpiperidino)ethyl -p-3,4-dimethoxyphenyl- ethylamine (Code No. RRL 2582) N-(3-methylpiperidino)acetyl-P-3,4-dimethoxyphenyl- ethylamine (10 g) was reduced with Lithium aluminium hydride (6 g) in"tetrahydrofuran. The resulting product was worked up according to general procedure of method 'B' and distilled under reduced pressure, b.p. 204~210°C/1 mm yield 8,5 g Found C 69.98 H 9.74 N 9.38^ ^18^30^2% (306) requires • 70.5-^ 9.87 9.14 Picrate m.p. 20l-202°C (from ethanol) Found N 13.20^, ^24^3'^9% (535) requires 13.08 19. N- 2-(4-methylpiperidino)ethyl -P-3,4-dimethoxyphenyl- ethylamlne (Code No. RRL 2583) Reduction of N-(4-methylpiperidino)acetyl-P-3,4- dimethoxyphenylethylamine (10 g) with Lithium aluminium hydride in tetrahydrofuran was carried out by refluxing for six hours. The product was worked up as described earlier and distilled under reduced pressure. b.p. 208-2l0°C/l mm yield 8 g Found C 71.10 H 9.49 N 9.42^ G^gHgQOgNg (306) requires 70.55 9.87 9.14 Picrate m.p. 2l7-2l8°C (from ethanol) Found N 14.29^ ^30^36^16% (764) requires 14.65 20. N- 2-(N-diethylamino)ethyl -P-3-methoxy-4-ethox7phenylethyl- amine (Code No. RRL 2584) N-diethylaminoethyl chloride (5 g) and p-3-methoxy-4- ethoxyphenylethylamine (7 g) were mixed together and heated at 100-110°C for four hours. The condensation product was worked up as described in general procedure and distilled under reduced pressure. b.p. 182°C/1.2 mm yield 4.5 g Found C 69.58 H 10.45 N 9.4:1^ C^^HgQOgNg (294) requires 69.34 10.27 9.52 141 Picrate m.p. 15^-156°C (from ethanol) Found N l4.56f (752) requires 14.88 21. N- 2-(4-morpholino )ethyl -P-3-methoxy-4-etho3?yphenylethyl- amine (Code No. RRL 2585) The condensation of P-3-methoj?y-4-ethoxyphenylethylamlne (8 g) with 2-(4-morpholino)ethyl chloride (5 g) was carried out by heating the mixture of two substances at 90-ii0°C for three hours. The product was distilled under reduced pressure. b.p. 195-198°C/1 mm yield 6 g Found C 65.97 H 9.38 N 9,29% C^yHggOgNg (308) requires 66.20 9.15 9.08 Picrate m.p. 196-198°C (from ethanol) Found N 14.585^ ^29^340x7% (766) requires 14.61 22. N- 2-(1-piperidino)ethyl -p-3-raethoxy-4-ethoxyphenylethyl- amine (Code No. RRL 2586) The title compound was obtained by condensation of p-3-methoxy-4-.ethoxj^phenylethylamine (10 g) with 1-piperidino- ethyl chloride (7 g) at 90-ll0°C for three hours. b.p. l98-202°C/0.6 mm yield 7.5 g Found C 70.25 H 10.15 N 9.39^ C28H30O2N2 (306) requires 70.55 9.87 9.14 142 Pi crate m.p, 189-190°C (from ethanol) Fouad N 14.48^ CgoHggO^gNg (764) requires 14.65 23. N- 2-(l-pyrrolidino)ethyl -P-3-methox7-4-ethoxyphenylethyl- amine (Code No. RRL 2587) The above compound was prepared by reduction of N-(i- pyrrolidino )acetyl-p-3-methoxy-4-eth.oxyphenylethylamine (10 g) with Lithium aluminium hydride (6 g) in tetrahydrofuran, b.p. 190-195°C/1 mm yield 8.5 g Found C 69.92 H 9.75 N 9.63fj C^yHggOgNg (292) requires 69.82 9,65 9.58 Picrate m.p. 194-195°C (from ethanol) Found N 14.78^ ^29^4*^16^8 ^750) requires 14.92 24. W- 2-(2-methylpiperidino)ethyl -P-3-methoxy-4-ethoxy- phenylethylamlne (Code No. RRL 2588) N-(2-methylpiperidino)acetyl-p-3-methoxy-4-ethoxy- phenylethylamine (8 g) in tetrahydrofuran (40 cc.) was added to a suspension of Lithium aluminium hydride (5 g) in tetra- hydrofuran and refluxed for five hours. The reduction product was worked up and distilled, b.p. 205-2l0°C/0.5 mm yield 6.8 g 143 Found C 71.36 H 9.77 N 8.62^ C^gHggOgNg (320) requires 71.21 10.07 8.74 Picrate m.p. t78-180°C (from ethanol) Pound N 12. (549) requires 12.74 N- 2-(3-methylpi;oeridino )ethyl -p-3-niathoxy-4-ethoxy- pheny1ethy1amine (Code No. RRL 2589) N-(3-m6thylpiperldino)acetyl-^-3-methoxy-4-ethoxy- phenylethylamine (8 g) was reduced with Lithium aluminium hydride and worked up according to procedure described in method 'B' . b.p. 198-204°C/0,5 mm yield 6.5 g Found C 71.62 H 9.82 N 8,58^ C19H32O2N2 (320) reauires 7l.2l 10.07 8.74 Picrate m.D. 186-187°C (from ethanol) Found N 14.52^ ^31^38^16% requires 14.38 26. N- 2-(4-methylpiperidino)ethyl -p-3-methoxy-4-ethoxyphenyl- ethylamine (Code No. RRL 2590) Reduction of W-(4-methylpiperidino)acetyl-p-3~methoxy- 4-ethoxyphenylethylamine (8 g) with Lithium aluminium hydride (5 g) in tetrahydrofuran was accomplished by refluxing the reaction mixture for five hours. The product was v/orked up as usual and distilled under deduced pressure. 144 b.p. 210-814°C/l ram yield 6,3 g Found C 71,66 H 10.39 N 8.7l< C^gHggOgNg (320) requires 71.21 10.07 8.74 Picrate m.p. 185-186°C (from ethanol) Found N 14.60^ Cg^HggO^gNg (778) requires 14.38 27. N- 2-(N-diethylamino)ethyl -p-3,4-diethoxyphenylethylamine (Code No. RRL 259l) Condensation of P-3,4-dietho2yplienylethylamine (8 g) with diethylaminoethyl chloride (5 g) was carried out by heating the mixture of two substances at 110-120°C for three hours. The product was worked up as usual and distilled under reduced pressure. s b.p. 186-190°G/1.5 mm yield 6 g Found C 70.28 H 9.98 N 9,l7f, C^gHggOgNg (308) requires ' 70.09 10.46 9.08 Picrate m.p. 149-1.50°C (from ethanol) Found N 14.28^ CgoHggO^gNg (766) requires 14.42 28. N- 2-(4-raorpholino)ethyl -P-3,4-diethoxyphenylethylamine (Code No. RRL 2592) 4-raorpholinoethyl chloride (5 g) and P-3,4-dietho7y- 145 phenylethylamine (8 g) were mixed together and heated at il0-120OC for three hours. The prodaet was worked up and distilled under reduced pressure. b.p, 210-212°C/0.6 mm yield 5.2 g Found C 66,92 H 9.26 N 8.435^ ^18^3003^2 (322) requires 67.05 9.38 8,68 Picrate m.p. 175-177°C (from ethanol) Found N 14, ^30^36^17% requires 14.65 29. N- 2-(l-piperidino)ethyl -P-3,4-diethoxyphenylethylamine (Code No. RRL 2593) The above compound was prepared by reacting p-3,4- diethoxyphenylethylamine (8 g) with l-piperidinoethyl chloride (5 g) at 100-110 C for three hours. b.p. 202-206°C/0,7 mm yield 5.4 g Found C 70.96 H 10.03 N 8.625^ ^19^32^2% (320) requires 71.21 , 1G»07 8.74 Picrate m.p. 175-177°C (from ethanol) Found M 14. Cg^HggO^gNg (778) requires 14.65 30. N- 2-(l-pyrrolidino)ethyl -P-3,4-diethoxyphenylethylaraine (Code No. RRL 2594) The title compound was prepared by reduction of N-(l- pyrrolidino )acetyl-P-3,4-di9thoxyphenylethylamine (lO g) with Lithium aluminium hydride in tetrahydrofuran. b.p. 186-188 C/0.9 nun yield 8.5 g Found C 70.38 H 10.09 N 9.31^ C^LgHgQOgNg (308) requires 70.55 9.87 9.14 Picrate m.p. 145-147°C (from ethanol) Found N I4.34f, C3oH3g0^gNg (764) requires 14.13 31. N- 2-.(2-methylpiperidino )ethyl -p-3,4-diethoxyphenylethyl- amine (Code No. RRL 2595) N-(2-methylpiperidino)acetyl-P-3,4-diethoxyphenyl- ethylamine (8 g) was reduced with Lithium aluminium hydride (5 g) in tetrahydrofuran to get the title compound, b.p. 2l6-220°C/0.5 mm yield 6,2 g Found C 71.59 H 10.34 N 8.52^ '^20^34°2% (334) requires 7l.8l 10.25 8.38 Picrate m.p. 173-175°C (from ethanol) Found N 14.82^ ^32^40° 16% ('''SS) requires 14.65 147 32. N- 2-(3-methylpiperidino )ethyl -P-3,4-diethox3npheayl- ethylamlne (Code No. BRL 2596) N-(3-methylpiperidino)acetyl-P-3,4-diethoxyphenyl- ethylamine (8 g) in tetrahydrofuran was added dropwise to a suspeasion of LiAlH4 (5 g) in tetrahydrofuran and refluxed for five hours. The reduction product was worked up and distilled under reduced pressure. b.p, 192-194°C/0.5 mm yield 6 g Found C 72.02 H 10.39 N 8.62^^ ^20^34*^2^2 (334) requires 71.81 10.25 8.38 Picrate m.p. 173-174°C (from ethanol) Found N 14.45^ ^32^40^16^8 requires 14.13 33. N- 2-(4-methylpiperidino)ethyl -^-3,4-diethoxyphenylethylamine (Code No. RRL 2597) The above compound was prepared by reduction of N-(4- methylpiperidino)aGetyl-p-3,4-diethoxyphenylethylamine (8 g) with LiAlH^ in tetrahydrofuran. The product was distilled under reduced pressure. b.p. l96-198°C/0..5 mm yield 6.2 g Found 0 71.72 H 10.49 N 8. ^20^34^2% (334) requires 71.81 10.25 8.38 Picrate m.p. l74-l75°C (from ethanol) Found N ^32^40° 16% ^792) requires 14.13 34. N- 2-(N-diethylamlno)ethyl -p-3,4-methylenedioxyphenyl- ethylamine (Code No. RRL 2598) The title compound was prepared by condensation of diethylaminoethyl chloride (5 g) with p-3,4-methylenedioxyphenyl- ethylamine (8 g) at 100-110°G for three hours. b.p. 156-l60°C/l-2 mm yield 5.4 g Found C 68.34 H 9.52 N 10.32^ C^^Hg^OgNg (264) requires 68.15 9.15 10.06 Pi crate m.p. 182-184°C (from ethanol) Found N 14,78^ ^27^30° 16^8 ^'^22) requires 14.50 35. N- 2-(4-morpholino)ethyl -p-3,4-methylenedioxyphenyl- ethylamine ( P-3,4-methylenediox3irphenylethylamine (8 g) was mixed and heated with 4-raorpholinoethyl chloride at l"i.0-l20OC for four hours. The condensation product was worked up as usual and distilled under reduced pressure. b.p. 178-180°G/l-1.5 mm yield 5 g Found C 64.58 H 8.12 N 9.83^ ^15^2°3% (278) requires 64.72 7.97 10.07 d Picrate m,p, 220-222°0 (from ethanol) Found N ^27^28° 17^8 requires 15.21 36. N- 2-(l-piperidino)ethyl -p-3,4-methylenedioxyphenylethyl- amine (Code No. RBL 2600) The above compound was obtained by reacting P-3,4- methylenedioxyphenylethylaraine (8 g) and l-piperidinoethyl chloride (5 g) at 100-110°C for 3 hours. b.p. 176-178°C/1-1,5 mm yield 4.8 g Found C 69.38 H 8.92 N I0.39f C^gHg^OgNg (276) requires 69.53 8.75 10.14 Picrate m.p. 194-196°C (from ethanol) Found N 15,; ^28^30^16^8 requires 15,25 37. N_ 2-(4-morpholino)propyl -P-phenylethylamine (Code No. RRL 839) P-phenylethylamine (6 g) was reacted with 2-(4- morpholino)propyl chloride (5 g) at 90-110°G for three hours, The product was worked up according to general procedure of method 'A', and distilled under reduced pressure. b.p. 176°C/1.5 mm yield 3.5 g Found C 72.37 H 9.62 N 11.17^ ^15^40^2 ^248) requires 72.54 9.74 11.28 iSO 38, N-[2-(1-piperidino)propyl -p-phenylethylamine (Code No. RRL 846) The above compound was prepared by condensation of P-phenylethylamine (7 g) with 2-(l-piperidino)propyl chloride (5 g) at 90-ll0°C for three hours. b.p. l60°C/l,o mm yield 4,2 g Found C 78.10 H 10.28 N 11.03^ G^gHggNg (246) requires 77,99 10,64 11.37 39. N- 2-(4-raorpholino)propyl -p-4-methoxyphenylethylamine (Code No. RRL 842) P-4-methoxyphenylethylamine (8 g) was mixed with 2-(4-morpholino)propyl chloride (6 g) and kept at 100-110°C for four hours. The condensation product was distilled under reduced pressure. b.p, 198°C/1.5 mm yeild 5,5 g Found C 68,81 H 9.28 N 9,9li C^gHgQOgNg (278) requires 69,03 9,41 10.06 40, N- 2-(l-piperidino)propyl -P-4-methoxyphenylethylamine (Code No, RRL 849) Condensation between P~4-raethoxyphenylethylamine (8 g) and 2-(l-piperidino)propyl chloride (5 g) was carried out by heating at 110-120 C for four hours. The product was worked up as usual and was distilled under reduced pressure. b.p, 180-184°G/1.5 mm yield 5,2 g si Found C 73.64 H 10.18 N 10.09^ C]^7H280N2 (276) requires 73.84 10.21 10.14 € 41. N-[_2-(N-diethylamino )propyl -P-3,4-dimethoxyphenylethylamine (Code No. RRL 260l) P-3,4-dimethoxyphenylethylamine (8 g) and 2-(N>(jiethyl- amino )propyl chloride (5 g) were mixed together and heated at n.0-120°C for four hours. The condensation product was worked up according to general procedure of method 'A' and distilled under reduced pressure. b.p. l76-l80°C/l-2 mm yield 5.5 g Found C 68.98 H 10.52 N 9.38^ C^yHgQOgNg (294) requires 69.34 10.27 9.52 Picrate m.p. 174-175°C (from ethanol) Found N 15.10^ requires 14.88 42. N- _2-(4-morpholino )propylJ -p-3,4-dimethoxyphenylethylamine (Code No. RRL 2602) The above compound was prepared by reacting P-3,4- methoxyphenylethylamine (8 g) with 2-(4-morpholino)propyl chloride (6 g) at 110-120°C for four hours. b.p. 212°C/1.25 mm yield 5.6 g Found C 66.18 H 9.38 N 9.32^ C^yHggOgNg (308) requires 66.20 9.15 9.08 152 Pi crate m.p. 194-196°C (from ethanol) Found N 14,28^ ^766) requires 14.61 43. N. 2-( 1-piperidino )propyl -^-3,4-dimethoxyphenylethylaniine (Code No. RRL 2603) The above compound was prepared by condensation of P-3,4-dimetlioxyphenylethylamine (8 g) with 2-(1-piperidino)propyl chloride (5 g) at 100-120°G for four hours. b.p. 206-210°G/l mm yield 6 g Found C 70.48 H 9,59 N 9.42^ C^gHgQOgNg (306) requires 70.55 9.87 9,14 Picrate m.p. 215°C (from ethanol) Found N 14, ^30^36° 16% (764) requires 14.65 44. W- 2-(l-pyrrolidino)propyl -P-3,4-dimethoxyphenylethylamine (Code No. RRL 2604) Reduction of N- 2-(l-pyrrolidino)propionyl -P-3,4- dimethoxyphenylethylamine (lO g) with LiAlH^ in tetrahydrofuran was carried out by refluxing for six hours. The product was distilled under reduced pressure. b.p. 182-184°C/l-2 mm yield 8,5 g Found C 70.14 H 9,42 N 9.37^ C^^HggOgNg (292) requires 69.82 9.65 9.58 IS Picrate m.p. 206-207°C (from ethanol) Found N 14.73^ ^29^34° 16^8 requires 14,92 45. N- 2-(2-methylpiperidino )propyl -P-3,4-dlmethox3rphenyl- ethylamine (Code No. RRL 2605) Reduction of N- 2-(2-methylpiperidino)propionyl -6- 3,4-dlmethoxyphenylethylamine (8 g) with LiAlH^ gave the title compound. b.p. 212-216°C/1-1.5 mm yield 6.5 g Found C 71.52 H 10.28 N 8.49^ (320) requires 71.21 10.07 8.74 Picrate m.p. 19S-200°C (from ethanol) Found N 14.42^5 ^31%80i6N8 (778) requires 14.38 46. N- 2-(3-methylpiperidino)propyl -P-3,4-dimethoxyphenyl- ethylamlne (Code No. RRL 2606) N- ^2-(3-methylpiperidino )propionylJ -p-3,4-dimethoxy. phenylethylamine (8 g) in tetrahydrofuran was added dropwlse' to a suspension of LiAlH4 (5 g) in tetrahydrofuran and then refluxed for six hours. The reduction prroduct was worked up as usual and distilled under reduced pressure. b.p. 218-220°C/i-1.5 mm yield 6.5 g Found C 71,62 H 10.34 N 8.58f G^gHggOgNg (320) requires 71.21 10.07 8.74 Picrate m.p. 208-210°C (from ethanol) Found N 14.58^ Cg^^HggO^^gNg (778) requires 14.38 47. N~ 2-(4-methylpiperidino)propyl -p-3,4-dimethor.yphenyl- ethylanine (Code No. RRL 2607) The above compound was prepared by reduction of N- 2-(4- methylpiperidino)propionyl -^-3,4-dimethoxyphenylethylamine (8 g) with LiAlH^ in tetrahydrofuran. b.p. 218-220°C/1.5 ram yield 6,3 g Found C 70.97 H 10.28 N 8.49f- (320) requires 71.21 10,07 8.74 Picrate m.p. 196-l98°C (from ethanol) Found N I4.57f^ ^31^38^16^8 requires 14.38 48. N- 2-^N-diethylaminq)propyl -P-3-methoxy-4-ethoxyphenyl- ethylamine (Code No, RRL 2608) 2~(N-diethylamino)propyl chloride (5 g) and P-3-methoxy- 4-ethoxyphenylethylamine (8 g) were mixed at heated at 110-120°C for four hours. The condensation product was worked up as described in general procedure for method 'A'. b.p. l80-l84°C/l-2 mm yield 4.5 g 'j5 5 Found C 69.82 H 10.38 N 9.35^ C^gHggOgNg (308) requires 70.09 10.46 9.08 Picrate m.p. l72-l74°C (from ethanol) Found N 14.09^, ^30^38°16% (766) requires 14.42 49. N- 2-(4-morpholino )propyl -P-3-methoxy-4-eth.oxyphenylethyl- amine (Code No. RRL 2609) The title compound was prepared by condensation of 2-(4-morpholino)propyl chloride (4 g) with P-3-methoxy-4-ethoxy- phenylethylamine (8 g) at 110-120°C for four hours. ^.p. 198-202°G/2 mm yield 5.5 g Found C 67.19 H 9.26 W 8.49^ ^18^30^3% (322) requires 67.05 9.38 8.68 Picrate m.p. 194-195°C (from ethanol) Found N 14.57^ ^30^36^17% (780) requires 14.35 50. N- 2-(1-piperidino)propyl -p-3-methoxy-4-ethoxyphenyl- ethylamine (Code No. RRL 2610) P-3-methoxy-4-ethoxyphenylethylamine (8 g) was reacted with 2-(l-.piperidino)propyl chloride (5 g) at ll0-120°C for four hours. The product was worked up as usual and distilled under reduced pressure. b.p. 206-208°C/l mm yield 5.8 g 156 Found C 71.53 H 9.84 N 8.56^ C^gHggOgNg (320) requires 71.21 10.07 8.74 Picrate m.p, 172-174°C (from ethanol) Found W 14.07% ^31^38^16^8 requires 14.38 51. N- 2-(l-pyrrolidino)propyl -p-3-methoxy-4-ethoxyphenyl- ethylamine (code No. BRL 26ll) The above compound was prepared by reduction of N- 2-(l-pyrrolidino)propionyl -P-3-methoxy-4-ethoxyphenylethyl- amine (8 g) with Lithium aluminium hydride (5 g) in tetrahydro- furan by re fluxing for six hours. b.p. l86-188°C/0,9 mm yield 6.5 g Found C 70,29 H 9.58 N 9.28^i C^gHgQOgNg (306) requires 70.9.87 9.14 Picrate m.p. 178-179°C (from ethanol) Found N 14.58^! ^30^36^16^8 requires 14.65 52. N- 2-(2-methylpiperidino)propyl -p-3-methoxy4-ethoxy- phenylethylamine (Code No. RRL 2612) N- 2-(2-methylpiperidino)propionyl -p-3-methoxy-4- ethoxyphenylethylamine (7 g) was reduced with LiAlH^ in tetra- hydrofuran by refluxing for six hours to get the title compound which was worked up as usual and distilled under reduced pressure, b.p. 204-210°C/1 ram yield 5.5 g Found C 71.59 H 10.14 N 8.09f, CgQHg^OgNg (334) requires 7l,8l 10.25 8.38 Pierate m.p. 204-205°C (from ethanol) Found N 13.92^ CggH^QO^gNg (792) requires 14.13 53. N- 2-(3-methylpiperidino )propyl -^-3-methoxy-4-ethox3rphenyl- ethylamine (Code Wo. RRL 2613) The above compound was obtained by reduction of N- 2-(3-raethylpiDerldino)propionyl -p-3-methoxy-4-ethoxyphenyl- ethylamine (8 g) v/j.th Lithium aluminium hydride (5 g) in tetra- hydrofuran. b.p. 228-234°C/6 mm yield 5.2 g Found C 71.39 H 10.48 N 8,52% ^^20^34^2% (334) requires 71.81 10,25 8.38 Picrate m.p. 202-203°C (from ethanol) Found N 14.395! CggH^QO^gNg (792) requires 14.13 54. N- 2-(4-methylpiperidino )propyl -P-3-methoxy--4-ethoxy- phenylethylamine (Code No. RRL 2614) N- 2-(4~methylpiDeridino )propionyl -p-3-methoxy--4- 1S8 ethox3rpheiiylethylamine (8 g) in tetrahydrofuran was added to a suspension of LiAlH4 (5 g) in tetrahydrofuran and refluxed for six hours. The product was worked up as already described in procedure of method 'B', and distilled under reduced pressure. b.p. 212-2160C/1 mm yield 6.5 g Found C 72.12 H 10.42 N 8.46^ ^20^34^2^2 (334) requires 7l,8l 10.25 8.38 Picrate m.p. 206-208°C (from ethanol) Found N 14.3955 ^32^40^16^8 C^SiS) requires 14,13 55. N- 2-(N-diethylamino)propyl -P-3,4-diethoxyphenylethylamine (Code No. RRL 2615) 4-diethoxyphenylethylamine (10 g) was reacted with 2-(N-(iiethylamino)propyl chloride (7 g) at 100-120°C for five hours. The condensation product was worked up and distilled under reduced pressure. b.p. 188-192°C/1.5 mm yield 7.5 g Found C 70.58 H 10,79 N 8.48^ (322) requires 70.76 10.63 8.69 Picrate m.p, 168-170°C (from ethanol) Found N I4.52f. C3^H4Q03^gNg (780) requires . 14.35 159 56. N- 2-(4-morpholino)propyl -p-3,4-diethoxyphenylethylamine (Code No. RRL 26l6) Condensation of p-3,4-diethoxyphenylethylamine (8 g) with 2-(4-morpholino)propyl chloride (6 g) was carried out at in0-120OG for four hours. b.p. 2l0-212°G/0.6-0,7 mm yield 5.2 g Pound C 67.69 H 9.63 N 8.52f C^^gHggOgNg (336) requires 67.82 9.59 8.33 Picrate m.p. 175-176°C (from ethanol) Found N 13.82^ Cg^HggO^^Ng (794) requires 14.09 57. N- 2-(l-piperidino)propyl -P-3,4-diethoxyphenylethylamine (Code No. RRl. 2617) P-3,4-diethoxyphenylethylamine (8 g) and 2-(l-piperidino)• propyl chloride (6 g) were mixed together and heated at 100-120°C for five hours. The condensation product was worked up as des- cribed earlier and distilled under reduced pressure. b.p. 202-206°C/0.7 mm yield 6 g Found C 71.65 H 10.39 N 8.46f: C2QH34O2N2 (334) requires 71.81 10.25 8.38 Picrate m.p. 176-17S°C (from ethanol) Found N 14.52^ ^32^40^16^8 requires 14,13 Si 58. N- 2-(1-pyrrolidino)propyl -p-3,4-dlethoxyphenylethylamine (Code No. RRL 2618) N- [2-(1-pyrrolidino)propionyl -P-3,4-diethoxyphenyl- ethylamine (8 g) was reduced with LiAlH^ in tetrahydrofuran by refluxing for six hours. The product was worked up and distilled under reduced pressure. b.p. 186-l88°C/0.9 mm yield 5.9 g Found G 71.50 H 9,82 N'8.56f. C^gHggOgNg (320)requires 71.21 10.07 8.74 Picrate m.p. 164-166°C (from ethanol) Found N 14.49^ Cg^HggO^gNg (778) requires 14.38 59. N- 2-(2-methylpiperidino)propyl -P-3,4-diethoxyphenylethyl- amine (Code No. RRL~ 2619) The title compound was prepared by reduction of N- 2- (2-methylpiperidino)proplonyl -P-3,4-diethoxyphenylethylamine (8 g) with LiAlH4 . b.p. 2l4-220°C/0.5 mm yield 6.5 g Found G 72.19 H 10,52 N 8.l6f Cg^Hc^gOgN^ (348) requires 72.37 10.41 8.04 I Picrate m.p. 180-182°G (from ethanol) Found N l4.06f Gg^H^O^gNg (806) requires 13.89 161 60. N- 2-(3-methylpiperidino)propylJ-p-3,4-diethoxyphenyl- ethylamine (Code No. RRL 2620) N- 2-(3-methylpiperidiiio)proplonyl -P-3,4-diethoxy- phenylethylamlne (8 in tetrahydrofuran was added to a sus- pension of LiAlH^ (5 g) in tetrahydrofuran and refluxed for six hours. The reduction product was worked up as usual and distilled. b.p. l92-194°G/0.5 mm yield 6.2 g Found C 72.62 H :i0.38 N 8.29^ Cg^H^gOgNg (348) requires 72.37 10.41 8.04 Pierate m.D. 198-199°C (from ethanol) Found N 13.50^ ^33^42*^16^8 ^806) requires 13.89 6"" . N- 2-(4-methylpiperidino )propyl -P-3,4-dietho3 The above compound was prepared by reduction of N- 2-(4- methylpiperidino)pTopionyl -^-3,4-dietho7?yphenylethylamine (8 g) with Lithium aluminium hydride. The product was worked up as described in general procedure of method 'B' and distilled. b.p. 196-l98°c/0,5 mm yield 6 g Found C 72.58 H 10.32 N 8.29^ ^21^36*^2% (348) requires 72,37 10.41 8,04 Picrate m.p. 180-182°C (from ethanol) iqZ Found N 14.06?^ c33^42016% (806) requires 13.89 62. N-i2-(N-diethylamino)prop7l -P-3,4-methylenedioxyphenyl- ^thylamine (Code No. HRL 2622) S-3,4-methylenedio-xyphenylethylamine (7 g) and 2-(N- d2ethylaniino)propyl chloride (4.5 g) were mixed together and heated at 100-120°C for five hours. The condensation product was worked up according to procedure described in method 'A' and distilled under reduced pressure. b.p. l70-l74°C/l-2 ram yield 4.5 g Found C 69.21 H 9.14 N 9.89^ C^^gHggOgNg (278) requires 69.03 9.41 10.06 Pi crate ra.p. 220°G (from ethanol) Found N 14.98^ (736) requires 15.20 63. N- 2-(4-morpholino)propyl -p-3,4-methylenedioxyphenylethyl- amine (Code No. RRL 2623) P-3,4-methylenedio-xyphenylethylamine (8 g) was condensed with 2-(4-morphollno)propyl chloride (5 g) at 90-ll0°G for six hours. The condensation product was worked up as usual and distilled under reduced pressure. b.p. 1920C/1 mm yield 5,5 g U3 Found C 65.49 H 8.46 N 9.39^ C^gHg^OgNg (292) requires 65.72 8.27 9.58 Picrate m.D. 172-174°G (from ethanol) Found N 14.78^ ^28^30^17^8 requires 14.92 64. N-r2-(l-Dlperidino)propyl -p-3,4-methylenedioxyphenylethyl- amine (Code No. RRL 2624) The above compound was obtained by condensation of ^-3,4-methylenediox7phenylethylaraine (6 g) with 2-( l-piperidino propyl chloride (4 g) at ll0-l20°C for five hours. The product was distilled. b.p. l84-l86°G/l-2 mm yield 5 g Found C 70.52 H 8.83 N 9.n8f. 0^^712602^2 (290) requires 70,31 9.02 9.65 Picrate m.p. 204-206°C (from ethanol) Found N 14.88^ CggHggO^gNg (748) requires 14.96 65. N- 3-(N-diethylamino)propyl -P-phenylethylamine (Code No. RKL 853) 0-phenylethylaraine (6 g) and 3-(N-diethylamino)propyl chloride (4 g) were mixed together and heated at 100-120°C for four hours. The product was worked up as described in general procedure and distilled under reduced pressure. 84 b.p. 134-.138°C/0.7 mm yield 5 g Foand C 76.85 H 11.29 N 11.78^ C^^gHgeNa (234) requires 76.93 11.11 11.97 66, N- 3-(4-morpholino)propyl -p-phenylethylamine (Code No. RRL 857) Condensation of p-phenylethylaraine (8 g) with 3-(4- morpholiao)propyl chloride (5 g) was carried out at 100-ll0°C for four hours. The product was worked up and distilled under reduced pressure. b.p. 188-192°C/0.5 mm yield 6 g Found C 72.42 H 9.83 N 11,24^ ^15^24°% ^248) requires 72.57 9.68 11.29 67. N- 3-(l-piperidino)propyl -p-phenylethylamine (Code No. RRL 864) p-phenylethylamine (8 g) was reacted with 3-(l-piperi- dino)propyl chloride (6 g) at 110-120®C for five hours. The product was worked up and distilled. b.p. 160°C/l mm yield 6,2 g Found C 7E,12 N 10.46 N 11.235^ ^16^26^2 (246) requires 77.99 10.64 11.30 Picrate m.p. 148°C (from ethanol) Found N 23,525^ '^28^32° 14% (704) requires 23.33 68. N- 3-(N-diethylamino)propyl -p-4-methoxyphenylethylaralne (Code No. RRL 856) 3-(N-diethylaniino )propyl chloride (6 g) and p-4-methoxy- phenylethylamine (8 g) were mixed and kept at 80T100°C for four hours. The resulting product was distilled under reduced pressure, b.p. 162-166°C/1 mm yield 6 g Found C 72.48 H 10.58 N 10.4:^' C16^280% (264) requires 72.68 10.67 10.66 69. N- 3-(4-morpholino)propyl -P-4-methoxyphenylethylaraine (Code No. RRL 860) Condensation of P-4-methoxyphenylethylaraine (8 g) with 3-(4-morpholino)propyl chloride (6 g) was carried out by heating the mixture of two substances at SO-llO^C for four hours. b.p. 194°C/1 mm yield 5.5 g Found C 69.22 H 9.34 N 10,18^ Cj^gHggOgNg (278) requires 69.03 9.41 10.06 Pi crate m.p, 168-170°C (from ethanol) Found N 17.64^ CggHggO^gNg (736) requires 17,51 70. N- 3-(1-piperidino)propyl^-P-4-methoxyphenylethylamine (Code No. RRL 867) P-4-methoxyphenylethylamine (8 g) was mixed v/ith 3-(l-piperidino)propyl chloride (6 g) and heated for three hours igg at 90-ll0°C. The resulting product was worked up and distilled under reduced pressure. b.p. 190-192°G/1.5 mm yield 5.8 g Found G 73.42 H 10,30 N I0.28f, G3^7H280N2 (276) requires 73.86 10.21 10.14 Picrate m.p. 199-202°C (from ethanol) Found N 15.60^ ^29^34^15% (734) requires 15.24 71. N- 3-(2-methyrpiperidino)propyl -p-4-raethoxyphenylethylaniine (Gode No. RRL 874) The title compound was prepared by reduction of N- U3 - (2-methylpiperidino)propionyl -B-4-raethoxyphenylethylaraine (8 g) with Lithium aluminium hydride (5 g) in tetrahydrofuran by reflux- ing for five hours. b.p. 182-186°C/0.7 mm yield 6.5 g Found C 74.41 H 10.36 N 9.54$S G^gH^QONg (290) requires 74.43 l0.4l ,9.65 72. N- 3-(3-methylpiperidino)propyl -P-4-methoxyphenylethylami Reduction of N- 3-(3-methylpiperidino)pro-Dionyl -P-4- methoxyphenylethylamine (8 g) with LiAlH4 afforded the title compound which was v/orked up as described in general procedure and distilled under reduced pressure. 67 b.p. 186-190°C/1 mm yield 5.8 g Found C 74.35 H 10.26 N 9.52f C^gHgQONg (290) requires 74.43 10.41 9.65 73. N- 3-(N-diethylamino)propyl -p-3,4-dimethoxyphenylethylamine (Code No. RRL 2625) P-3,4-dimethoxyphenylethylamine (8 g) was mixed with 3-(N-diethylamino)propyl chloride (6 g) and heated at 100-ll0°C for four hours. The product was worked up and distilled under reduced pressure. b.p. 194-198°G/10 mm yield 5.4 g Found C 69.52 H 10.15 N 9.43f C^^HgQOgNg (294)requires 69.34 10.27 9.52 Picrate m.p, 188-190°C (from acetic acid) Found N 14.69^ GggH^gO^gNg (752) requires 14.88 74. N- 3-(4-morpholino )propyl -i5-3,4-dlmethoxyphenylethylamine (Code No. RRL 2626) The title compound was obtained by condensation of P-3,4-dimethoxyphenylethylamine (8 g) with 3-(4-morpholino )- propyl chloride (6 g). The reaction temperatuiTR'was maintained between 80-l00°C for four hours. b.p. 238-240°G/5 mm yield 6 g iS8 Found C 65.98^ H 9.24 N 9.32^ C^yHggOgNg (308) requires 66.20 9.15 9.08 Picrate m.p. 204-205°C (from ethanol) Found N 14.48^ ^29^34° 17^8 requires 14.61 75. N- 3-( 1-piperidino )propyl -p-3,4-dimetho5Qrphenylethylamine (Code No. RRL 2627) Condensation betv/een (3-3,4-dimethoxyphenylethylamine (8 g) and 3-(l-piperidino)propyl chloride (5.5 g) was carried out by heating the mixture of two substances at 100-110°C for three hours. The resulting product w?>s distilled under reduced pressure. b.p. 218-220°G/1-1.5 mm yield 6 g Found C 70.42 H 9.72 N 9.26fi G^gHgQOgNg (306) requires 70.55 9.87 9,14 Picrate m.p. 220-222°Q (from ethanol) Found N 14.4855 '"30^36*^16% requires 14.65 76. N- 3-(N-diethylamino)propyl -^-3-metho3 3-(N-diethylamino)propyl chloride (6 g) was heated with p-3-methoxy-4-etho:(yphenylethylamine (8 g) at 100-110°C 177 for four hours. The condensation product was worked up accord- ing to procedure described for method 'A' and distilled under reduced pressure. b.TD. 210-214°C/13 mm yield 5.8 g Found C 70.23 H 10.28 N 9.26^ C^gHggOgNg (308) requires 70,09 10.46 9.08 Pi crate m.p. l52-ln3°C (from ethanol) Found N 14.56^ CgQHggO^gNg (766) requires 14.42 77. N- 3-(4-morpholino)propyl -P-3-methoxy-4-ethoxyphenyl- ethylamine (Code No. RRL 2629) The above compound was obtained by condensation of P-3-methoxy-4-ethoxyphenylethylamine (8 g) with 3-(4-morpholino )• propyl chloride (6 g) at 100-110°G for four hours. b.p. 240-242°C/5 mm yield 6 g Found C 66.89 H 9.52 N 8.59^ C^gHgQOgNg (322) requires 67.05 9.38 8.68 Pi crate m.p. 186-188°C (from ethanol) Found N 14.48^ ^30%6°l7% ^^^^^ requires 14.35 78. N- 3-( l-piperidino )propylJ-p-3-metho3(y-4-ethox3nphenyl- ethylamlne (Code No. RRL 2630) Condensation between 3-(l-piperidino)propyl chloride (6 g) and P-3-methoxy-4-ethoxyphenylethylamine (8 g) was carried out by heating the mixture of two substances at lOO-llO°C for four hours. The resulting product was worked up as usual and distilled under reduced pressure. b.p. 240-242°G/7-7.5 mm yield 6 g Found C 71.30 H 9.21 N 8.68f> C^gHggOgWg (320) requires 7i.2l 10.07 8.74 Pi crate m.p. 168-i70°C (from ethanol) Found N l4.49?g C^^HggO^gNg (778) requires 14.38 79. N- 3-(N-diethylafflino)propyl -P-3,4-diethoxyphenylethylamine (Code No. RKL 2631) p-3,4-diethoxyphenylethylamin« e (8 g) and 3-(N-diethyl- amino)propyl chloride (6 g) were mixed together and heated at 90-l00°C for three hours. The condensation product was distilled under reduced pressure. b.p. 215-218°C/12 mm yield 5.6 g Found C 70.58 H 10.59 N 8,64^ (322) requires 70.76 10.63 8.69 Picrate m.p. 119-121°C (from ethanol) 171 Found N 14. Cg^H^QO^gNg (780) requires 14.35 80. N- 3-(4-morpholino )propyl --S-3,4-diethoxyphenylethylaraine (Cade No. RRL 2632) P-3,4-diethoxyphenylethylamine (8 g) was reacted with 3-(4-morpholino )propyl chloride (6 g) at 90-:i0°C for four hours, The reaction product was distilled under reduced pressure. b.p. 250-255°G/9-l0 mm yield 5.8 g Found C 67.67 H 9.68 N 8.42^ C^gHggOgNg (336) requires 67.82 9.59 8.33 Picrate m.p. 198-l99°C (from ethanol) Found N 13.26^ Cg^HggO^r^Ng (794) requires 14.09 81. N- 3-( l-piperidino )propyl -P-3,4-dietho- 3-( l~plperidino )propyl chloride (5 g) was mixed with P-3,4-diethoxyphenyaethylamine (8 g) and heated at 100-110°G for three hours. The product was worked up as usual and distilled under reduced pressure. b.D. 238-240°C/11-12 mm yield 5,5 g Found C 71.68 H 10,29 N 8,42% C20H34O2N2 (334) requires 7l.8l 10.25 8.38 i Picjate m.p. 18P-189°C (from acetic acid) Found N 14,20^ ^32^40^16^8 requires 14.13 82. N- 3-(N-diethylamlno )propyl -p-3,4-metliylenedioxyphenylethyl- amlne (Code No. RRL 2634) The title compound was obtained by condensation of P-3,4-ffiethylenedioxyphenylethylaraine (8 g) with 3-(l-piperidino)• propyl chloride (6 g) at 80-l00°C for four hours, b.p. 220-225°C/l0 mm yield 5.6 g Found C 68.88 H 9.28 N 10.165^ C-^gH^gOgNg (278) requires 69.03 9.41 10.06 83. N- 3-( 4-morpholino )propyl -p-3,4-methylenedioxyr>henylethyl- amine (Code No. RRL 2635) Condensation betv/een P-3,4-methylenediox3rphenylethyl- amine (8 g) with 3-(4-morpholino)propyl chloride (6 g) was carried out by heating the mixture of tv/o substances at lOO-nO°C for three hours. The product was distilled under reduced pressure. b.p. 240-245°C/7-8 mm yield 5.8 g Found C 65.68 H 8.23 N 9.62^ ^16^24^3% (292) requires 65.72 8.28 9.58 Picrate m.p. 204-206°C (from ethanol) 173 Fo;md N 14.78^ ^28^30^17% (750) requires 14,92 84. N- 3-(1-piperidino)Dropyl -P-3,4-methylenedioxyphenyl- ethylamine (Code No. RRL 2636) The above compound was prepared by condensation of P-3,4-methylenedio?yphenylethylamine (8 g) with 3-( 1-piperidino )> propyl chloride (6 g) at 100-110°C for four hours. b.p. 238-240°C/5-6 mm yield 5.5 g Found C 70.16 H 9.21 N 9.4 (290) requires 70.31 9.02 9.65 Picrate m.p. 216-218 C (from acetic acid) Found N 14.82^ CggHggO^gNg (748) requires 14.96 LU RSFERENCSS 1. P. Charr)entier, U.S. Pat. 2,519,886 (1950); Chem. Abs., 45, 67-3 (l9^l). 2. N.B. Reid, Jr.. J.B. '^Ight, H.G. Kolloff", and ••^.H. Hunter, J. Am. Che-.. Soc., 70, 3100 (1948). 3. E.'-^J. De Maar, Arch, intei^n. phaT-macodynaraie, JLQ^, 349 (19^6). 4. C.P. Huttrer, Enzymolof^ia, 12, 277, 293 (l948). 5. P. Char^entier, U.S. Pat. 264^,640 (1953). 6. S.S. BergChem' an.d Abs.J.N,. Ashley47, 698, 9U.S (1953). Pat.. , 2607,773 (1952); 7. A. Bur-^er, Medicinal Chemistry, Interscience Publishers, Inc. N.Y, I960 pa^^e 407. 8. B.N. Halpern and R. Ducrot, GomiDt., rend. soc. biol., 140, 361 (1946). 9. R.N. Ercoli, R.J. Schachter, W.C. Hueper and M.N. Lewis, J. Pharmacol, E:5Cptl. Therap,, 92, 210 (1948). 10. F. Leonard and U.7. Solrassen, J. Am. Chem. Soc., 70, 2064 (1948). n. D. Bovet and A.M. Staub, Compt. rend. soc. biol., TpA, 547 (1937). 12. B.M. Haloern and F. ¥althert, Comnt. rend. soc. biol., .139 , 402 (1945). 13. J.R. Vaughan, G.W. Anderson, R.C. Glapp, J.H. Clark, J.P. English, K.L. Howard, H.¥. Mar son, L.H. Sutherland and J.J. Denton, J. Org. Chem., 14,. 228 (1949). 14. B. Folkow, K. Hae^er and G. Kahlson, Acta Physiol. Scand., 15, 264 (1948). ]5. L.P. Kyrides, F.C. Meyer and F.B. zienty J. Am. Chem. Soc., 69, 2239 (1947). 16. M.J. Vander Brook, K,J. Olson, M.T. Richmond and M.H. Kuizfnga, J. Pharmacol, Exptl. Therat)., 94v 197 (1948K 175 17. M. Protiva, -J.O. Jilek, Z.J. Vejdelek, and 0. Exner, Chem. listy, 46, 551 (1952); Chem. Abs., 48, 2710 (1954). 18. G.S. Sidhu, P.B. Sattur and Y.S. Sadanandara (Personal communication). 19. M. Hartmann and H. Isler, Arch. exp. Pathal. Pharmakol., 192, I4l (1939). 20. E. Smith, D.J. Graubard, J. Falcone, T.B. Givan, P. Rosenblatt, and A. Feldman, J. Am. Med. Assoc., JJJ, 213 (1950). 21. D.S. Breslow, R.S. Yost, H.G. talker and C.R. Hauser, J. Am. Chem. Soc., 66, 1921 (1944). 22. J.P. Mason and H.W. Block, J. Am. Chem. Soc., 62, 1443 (1940). 23. H. Gilman and L.A. Woods, J. Am. Chem. Soc., 67, 1843 (1945). 24. R.R. Adams and F.C. ''/hitmore, J.Am. Chem. Soc., 67 V 736 (1945). 25. A.H. Sommers, M. Freifelder, H.B. Wright and A.''7. Weston, J. Am. 6hem. Soc., 75, 57 (1953). CHAPTER 176 PHARMACOLOGY The compoands described in Chapters II, III and IV have been submitted for evaluation and pharmacological activity in experimental animals at Riker Laboratories, North- ridge, California and at Seth G.S. Medical College, Bombay. The screening of such compounds to assess their activity is an expensive and time consuming job. The results are sommarised in Tables 14 to 21. The data is not yet sufficient to determine structure activity relationships but a preliminary attempt in this direction i s made. 177 m -P •H o I C H •H fH Ti £3 nH •H I tJ o O +5 O ft O o ftC •H ffi o i c ® -Sp ( 0 •p CO *> o CH or o o® as® a O © TH ® m TJ o •H C W •p O •H •p •P O CO o ® O o O-H ffi ffi • m a c s O ® •H o ffi-P P PH m a o H T) +9 ffi ® CO o ffi -H o ® -H •H O m ® "C! ® O m •H 03 +3< ft ® CO CO ffi Offi TJ iH O O CO ® to r-i • © • O fH W •P >0 X O -P h® S>> H ft ft C! 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H CO 00 w H W 05 00 N o CV3 CO to to 1 .iS CO ® CO O •P TJ CO r-i CO JH •H Fm O W m o CO >, ® -P C f^•H -P -P IS o o o CO •H O S'H S ® XI > H CO ® txO 3 ^ f-iH CO -P +3 5 -p CO O 03 > a -P CO a a m. CO 03 to coo • a o O -HO CO O •H +S ffi •H H CO to • -P "H CO -P -H G ® m CO XI • o (0 8* O M O TJ -H t>,'rf >i •H tH m ® Xl -P ® CO 03 O tnC O -H rH C ® ^ CO TJ -H jd > x: Hm-P UD H CO +5 C 6iD nH O O n^ •H -P O O G •H s « CO xl S « CO O CO Xi o o o to o 10 -O w C\3 -P c o o iH W (a CO o CO CO CQ CO CO <£) to (M w w to 00 199 N-Ghloroacyl-p-phenyletfaylamines This group of compounds coald be expected to possess anticonvulsant action against electroshock seizures in mice on account of structural resemblance to Hibicon i.e. S-chloro- propionylbenzylamine. In general these compounds exhibit sedation and decrease of locomotor activity. Compounds bearing Code No. 2501, 2502, 2505 possess mild to strong protection against electroshock seizures in mice. CO CI Code No. Activity 2501 -OCH3 -OCH3 -CHg- Decrease in motor activity 2502 -OCH. -OC2H5 -CHg. Decrease in loco- motor activity 2505 -OCH3 -OCH3 -CH- Relaxation, I decrease in loco- CH, motor activity i.il Code No, 2505 also possesses a strong muscle relaxation property. It is proposed to investigate it further. N-Aminoacyl-p-phenylethylamines These compounds in general possess hyperactivity, irritability, ataxia, convulsions and in some cases laboured respiration. Straub tail effects are also exhibited. Compounds bearing Code Nos. 523, 2521, 522, 524, 545 exhibit mild to strong hypotensive activity. NH CO N Z Code No. R-, -N Z Activity 523 H H -CHg- -N p Mild hypo- —' tensive 2521 -OCH, -OCgHg -CH„- Sedative \ f mild hypo- tensive X2H5 522 H H -CHo- - N' Mild hjrpo- ^C2H5 tensive lit Code -N Activity No. 524 H H -CH2- -N Hypotensive and antipy- resis r 545 H -OCH, -CHg- N Hsrpotensive V. Code No. 2521 i.e. N-(4-morpholino)acetyl-P-3-methoxy- 4-ethoxyphenylethylaraine has been selected for a detailed investigation to study its hypotensive action in other animals, Code No, 2535 and 2519 exhibit powerful antipyretic activity NH —CO—CH,—N O H5C2O ^ \ / (Code No.2521) and currently undergoing screening for their antiinflammatory activity in experimental animals. CH, o (Code No. 2635) r NH— CO— CH2—N CH, ' V (Code No. 2519) Mild diuresis and respiratory stimulation is exhibited by Code No. 573. A NH—CO —CH - N 1 V CH3 (Code No. 573) 194 N»Amlaoalkyl-p-phenyle thy1amine s Very few compounds have been screened in this series. Hence it is not possible to make an assessment of the activity. In general these compounds exhibit more of a stimulant character than a depressant one. Irritability, convulsions, ataxia, tremor, twitching and a decrease of locomotor activity are observed. The reduction of -NH-CO-linkage, in N-aminoacyl derivatives, to -NH-CH2-linkage present in N-aminoalkyl deri- vatives leads to pronounced diuretic and mild hypotensive activity, such as in Code Nos. 811, 814, 801, 818, 2593. / \ Code •N 2 Activity No. / \ 811 H H -N O Antipyresis \ / / \ 814 H -OCH, -N O Mild hypotensive, \ / diuresis 11)5 Code R2 -N z Activity No. 801 H H -N Mild hypo- X C2H5 tensive, diuresis r 818 H H -N Hyperactivity, V. diuresis r 2593 -OCH, .OC2H5 -N Diuresis Code Nos. 2578, 2602, 2580 exhibit antipyretic and hypoglycemic properties. These are being investigated in detail. CHc—CH — N Z R^ Rg Rg Z Activity 2578 -OCH3 -OCH3 H -NO Hypoglycemia 2602 -OCH3 .OCH3 -CH3 -N O Aatipyresis, \—/ hjrpoglycemia 2601 -OCH3 -OCH3 -CH3 -N^ Hypoglycemia 2580 -OCH3 -OCH3 H -N HjTpoglycemia V When more pharmacological data are available, an attempt will be made to correlate structure with activity. Toxicity studies The following studies are based on the LDsq values expressed in mgAg i.p. in mice. In the N-chloroacyl series, the effect of introduction of methyl group in chloroacyl residue does not lead to increase of toxicity. NH-CO-CH2-CI NH-CO-CH-CI H3CO (Code No. 2501) (Code No. 2505) ID50 570 mgAg. i.p. mice LD5Q 850 mgAg. i.p. mice H,CO 'ion NH-C0-CH2-C1 NH-CO-CH-CI H5C20' H5C2 I CH, (Code No. 2502) (Code No. 2506) LD50 695 mgAg. i.p. mice LD50 1^00 mgAg. i.p. mice It is also evident from the above data that increase of alkoxy groups in p-position i.e. 4-methoxy (Code Nos. between 2501, 2502 and Code Nos. 2505, 2506) to ethoxy does not lead to increase.of toxicity, but on the other hand leads to compounds of less toxicity. In the N-aminoacyl series, ^050 values in morpholine series appear to be highest and hence morpholine series seems to be less toxic among other heterocyclic moieties. NH—CO—CH, —N Z Code •N Z LDsomgAg No. i,p. mice 523 H H N 720 \ / yC.Hs 522 H H -N 300 A 524 H H -N 285 525 H H 400 CH. 526 H H -N 220 ,CH. 527 H H 290 V A Code R. Rc •N Z LD50 mgAg \ / No. ^—^ i.p. mice /• 528 H H N CH. 180 V IntrodactioQ of alkoxy groups in the phenyl nucleus does not appreciably change the LDso values in morpholino series whereas in diethylamino and methylpiperidino series, the introduction of methoxy groups in 3:4-position leads to less toxicity as can be seen from Code Nos. 525, 2513 and 528, 2519. X2H5 NH — CO—CH2—N' X2H5 Code No. LD50 mgAg i.p> mice 52S H H 30© 25113 OCH„ OCH. 590 9 CH, NH— CO —CH,— N V Code No. R, LD50 mgAg i.p. mice 528 H H 180 2519 OCH» OCH, 740 APPENDIX 201 APPENDIX A num'her of metho^^s for the r»reparation of ^-phenyl- ethylamines are available in the literature. These may be broadly clas'=^ifier' a'=! follows: 1. Reduct-ion o"^ Benzyl cyanide, oximes or w-njtrostyrenes. 2. Degradation of acids or acid amides by Schmidt or Hoffmann reaction. Miscellaneous methods. 1. Reductive methods; Reduction of nitriles, oximes OT W-nitrostyrenes has been carried out chemically, by catalytic hydro^enation, or by electrolytic reduction. a) Chemical reduction methods^ Nitriles, oximes or nitrostyrenes have been reduced with a variety of reae^ents to 1 2 the corresponding amines. Zinc and mineral acids ' , sodium in 3—5 6 amyl alcohol or ethanol" ^, zinc nickel couple , sodium 7 8 amalgam in acetic acid and benzenesulohonyl chloride are the reagents employed for the reduction of benzylcyanide. Reduc- tion of oximes is carried out by sodium amalgam in acetic acid or by dropping oxime in acetic acid to a solution of methanol- sulphuric acid®. Aluminium amalgam or zinc dust with glacial acetic acid, or iron and hydrochloric acid are also used for the reduction of w-nitrostyrenes^^"^^. Lithium aluminium hydride has been extensively used for the reduction of nitriles^-'^"^''^. ^^ Catalytic reduction: Hydrogenation of oximes, nitriles and nitrostyrenes has been successfully carried out in the presence of a variety of catalysts. Raney nickel in methanol or ethanol saturated with am-nonia^^*liquid 1 T S ammonia , ten per cent tetralin has been used for the reduc- tion of w-nitrostyrenes or njtriles. Palladiun/carbon in ethanol, hydrochloric acid , 20 21 acetic acid-sulT)huric acid , o"^ pyridine v;as used for the reduction of oximes and nitriles. Good results were obtained when solution of crimes in acetic acid was added drop by drop to a suspension of Adam's catalyst in acetic acid-sulrjhuric acid 3n the reduction chamber^, Urushibara nickel catalyst (IT-Ni-NH3) and Urushibara cobalt catalyst (U-CO-B) have also 22 been used for such redn^-^t-ions Slectrolytlc reduction: Ben.'syl cyanide has been reduced to f^-phenjrlethylamine when alkalin or acid solution is placed in cathode compartment p5o3 of an electrolytic cell #. w-Nitrostyrenes have also been ,24 electrolytically reduced*^ 2-Degradatlon of Acid or Amides: Schnidt .reaction: A ^ood yiel^^ of 8-phenylethyl- amine is obtained by Schmidt reaction of phenylpropionic 2:13 acid^'^"^'^. The acid is converted to its azide by reaction of hydrazoi^ acid liberated in situ from sodium azide and sulphuric acid in benzene or chloroform solution, b) Hoffrcann reaction; This method has been extensively used for the preTDaration of P-phenylethylamines from correspond- in? amides usinp alkali hypochlorite or hypobroraite. In the preparation of alkoxy substituted p-phenylethylamines, this method has been found to be most suitable and has been extensively ,28,29 used ' Miscellaneous methods: P-TDhenylethylamines have also been prepared by methods not commonly employed for preoarative purposes. Direct introduc- tion of 2-arainoethyl gjroup in the benzene nucleus was effected 30 with ethyleneimine in the presence of AICI3 . Various primary amines were obtained by condensin? 0- methyl-hydroxylamine (MeOMHg) v/ith alkylmagnesium chloride in ether"^^. Dry distilla- tion of alanine resulted in the formation of P-phenylethyl- amine^^. Condensation of" phenylethyl chloride v/ith hexa- methylenetetramine in ethanol and then treatment with hydro- chloric acid gave P-phenylethylamine hydrochloride from which amine is generated by addition of alkali solution^-'^. REFERENCES 1. J.C. Robinson, Ov^an^^ synthesis, vol. 23, 7i (1943). 2. P. Spica, Gazzetta, 9, 555| Soc. Abs., 28, 241 (1880). 3. A. Ladenbnrr, Ber., 19, 783 (l886). 4. K. KindlPT, Ann., 43,1, 187 (1923). S. Einiecki, L. Rylski, P. Kubikowski, J. Maijcherczyk and -T. ^zvmanska, ^nn. pharm. franc., 23, 249 Chem. Abs., 4096 (1956). 6. Pr. Pat. 971,429 (l9.Sl); Chem. Abs., £7, 2193 (l9^n>. G. Mannich and ¥, Jacobsohn, Ber., 43, 189 (l9lO). 8. T.E. Johnson and H.C-, Guest, Am'. Chem. J., 340 (1946). 9. 0. Schales, Ber., 1943 (l935). 10. A. Bischler and B. Naoieralski, Ber., 26, 1903 (1893). 11. K. Rosenmind, Ber., 42, 4778 (1909). 12. Max. P.J.M. Jansen, Rec. trav. cWm., 50, 291 (l93l); Chem. Ab^., 2f, 5404 (l93l). 13. R.F. Nystrom and ''7,0. Brown, J. M, Chem. Soc., 70, 3738 (1948). 14. W.N. Gannon, C.E. Pavell and R,G. Jones, J. Grp. Chem., 22, T^P-^ (19''7). 15. F. Beninpton, R.D. Morin and L.C. Clark, Jr., J. Or?. Chem., 25, 2066 (1960). 16. P. Rugcli and B. Priis, Heiv. Chim. Acta., 674 (l95a). 17. M. Semonsky and V. Zikan, Chem. Li sty, 47, 1374 (1953); Chem. Abe.. 1069 (1955). 18. J.Y. Braun and G. Blessing, Ber., 56B, 2153 (1923). 19. W.H. Hartuno-, J. Am. Chem. Soc., fO, 3370 (1928). 20. J.S. Ruck, J. Chem. Soc., 55, 3388 (1933). 21. B. ReicheT't and K. Koch, Arch. Pharm., 273, 265 (1935); Chem. Abs., 29, 4742 (l935). 22. S. Nishimura and A. Su^'imori, Nippon Kagaku Zasshi., 81, 314 (i960); Chem. Ahs., 364 (1962). 23. F.B. Ahren?. Zelt, Ele^^trochem., 99 (1896); SoG. Abs., 72, 313 (l897). 24. Y. Tanaka and T. Midzuno, J. Pharm. Soc. Jacan, 255 (1929); Chem. Abs., 2^, 3214 (1929). 25. M. Oesterlin, 7. Angev Chem., 45, 536 (1932). 26. A. McCoubrey and D.'-f. Mathieson, J. Chem. Soc., 696 (1949). 27. R. Huiseen and H. Konig, Ber., 92, 203 (l959). 28. J.S. Buck, J. Am. Chem. Soc., 54, 3661 (l932). 29. G. Barker and G.S. ^alpole, J. Chem. Soc., 1721 (1909). 30. G.I. Braz, Doklady. Aksd. Nauk. S.S.S.R. 589 (1952); Chem. Abs., 48, 113 (1954). 31. R. Brown and ^"J.E. Jones, J. Chem. 3oc., 7Pl (1946). 32. E. Erlenmeyer and A. Lipp, Ann., 2T9, 179; 33. A. GalSoc at. anAbs.d G,. Elion99,3 J(1883). Am. .Chem . Soc., gj., 3585 (1939) SUMMARY a S TJ M M A R Y P-Phenylethyl amine and its derivatives form an important class of physiologically active compounds. Interest In these compounds was aroused in the beginning of this century when epineDhrine was shown to be a deriva- tive of 8-phenylethyl amine. Many other 3-phenylethylamine derivatives were later shoi^m to have an action on the sympathetic nervous system, very similar to the action of epinephrine. These were named s3mipathomimetic amines. An extensive study of the chemistry and pharmacology of P-phenyl- ethylamines and many of its derivatives has been made by several vjorkers to find out structure activity relationship in this field. rever, a study of literature reveals that the effect of acylamino and alkylamino substituents on nitrogen atom of P-T)henylethylamine molecule has not been studied so far. The present wo-R'K w^S taken UD to study the ef-fect of variation of such groups to arrive at structure activity relationship. Thus compounds of following general structures were synthesised and submitted for phaTrnacolo°-ical evaluation, NH — CO —Y —CI (I) •T) a ly /jO t / N — CO—Y N Z (II) / ^ (III) where H, methoxy or ethoxy H, methoxy or ethoxy % methylenedloxy -CHG-, -CH-, -CHG-CHG- CH 3 -N Z diethylamino, morpholino, piperidino, pyrrolidine, <=<-, p- or Y-pipecolino. The present thesis consists of five chapters. Chanter I. The chemistry and pharmacology of B-ohenylethyl amines is briefly reviewed in th3 s chauter. Chapter IT. This chapter describes the preparation of Jj8 W-chloroacyl-e-Dhenyiethylamlnes of the general structure I. These were preparpfl bj*- reaction of appropriately substituted S-phenylethylamines with chloroacetyl chloride, 2- and 3- chloroprooionyl chlorides. Chapter III. This chapter deals with the DreDaration of various N-aminaoacyl-B-TDhenylethylamines of general structure II. They vrere preuared by condensation of appropriately substituted N-chloroacyl-P-phenylethylamines with a few secondary amines viz., diethylamine, raorpholine, piperidine, pyrrolidine and c<-, P- or Y-pipecolines. Chapter IV. The preparation of a number of N-aminoalkyl-P- phenylethylamines of general structure III is described in this chapter. These were prepared by condensation of diethyl- amino, morpholino and piperidinoalkyl chlorides with various alkoxy substituted 3-phenylethylamines or in some cases by the reduction of N-aminoacyl-p-phenylethylamines (described in Chapter III) with the lithium aluminium hydride. Chapter V. The results of preliminary pharmacological screening of some of the compounds described in chapter II, III and IV which were available till the time of writing of this thesis are incorporated in this chapter. An attempt has been made to establish structure activity relationship from the avail- able data. The Dharmacolo^ical evaluation of other comDounds is in progress. ffi f-i P, e •H o •H 1 Q s fU 03