DERIVATIVES OF ~-~-AMINO-~-PIPERIDIKECBIZBOXAMIIUES
Septeiuher, 19(i4 TABLE VI11
IAOCAT. .kSESTHETIC .ACTIVITY"
No.
Concentration of test material, % 0.05 0 10 0.23 0.50
Carbonyl freqiioncy, II
It 21 5l
1r 2c 5c Lidocaine'
75 70
81 85
... ...
0
...
0
10 30 2
...
63
21 92
66 95
...
. ..
90
1UU
96 B6 36 10* 68 95
5.9 6.91
5.81 5.8 5.8 5.8
...
pK, of parent. a d 7.23
7.51 6.77 5.94 6.12 5.35
...
Calculated as 100 - % response (see test). * The value is a t 0.3% concentration, 0.5% irritated t,he eye. The local anes~ ~l i % , and at 1% is 100%. thetic activity of lidocaine a t 0 . 0 1 is a
the methoxy group decreases the potency as in 2c. A more sensitive method, ionization constants, was used to determine minor changes in electron density. I n the trans series, the pKa values of the a-phenylcinnamic acids parallel with the carbonyl stretching frequency of the amino esters and are directly proportional to the local anesthetic activity. In the cis series, the pK, values of the acids are inversely proportional to the local anesthetic activity. The activity of I t and 2t is approximately the same as that of lidocaine \Then tested by the corneal reflex method. Experimental l5 @-Dimethylaminoethyl a-Phenyl-trans-cinnamates.-The acid chlorides were prepared by heating the acids6 with a 10% excess of thionyl chloride in refluxing benzene for 30 min. One drop of pyridine per gram of acid was added to the reaction mixture. The solvent and excess thionyl chloride were removed in a rotatory evaporator. The acid chloride was dissolved in hexane and the evaporation repeated. I n 3 cases ( Z t , 5t, and 9 t ) the acid chlorides were recrystallized from hexane and analyzed (Table I). This was found t o be unnecessary since the crude acid chlorides afforded good yields of the esters. I n most cases the acid chloride in benzene, when treated with 1 mole of the amino alcohol a t room temperature, afforded the solid ester hydrochloride which was cwllected by filtration. With Zt, 7t, and 9t, 2 moles of the amino alcohol were allowed to react with the acid chloride and t,he solid amino alcohol hydrochloride was removed by filtration. (15) Melting points were taken o n a Fisher-Johns melting point block and are corrected. Xicroanalyses were performed in t h e microanalytical laboratory, D e p a r t m e n t of Chemistry, University of California, 13erkeley. Calif.
619
The filtrate was washed wit,h water, dried over anhydrous sodium sulfate, and evaporated to dryness in uacim. An et,her solution of the free ester was treated with dry hydrogen chloride to give the ester hydrochloride, which was collerted hy filt>ration. When ij-dimethylaminticthy1 ~-p-riitroph~nyI-fran~~-p-nitrocinnamate \vas rrystallized from 'JS(;l ethanol, it was converted to the ethyl ester, m.p. 166-l6i0, confirmed by its identit,y with an aut,hentic sample prepared from the acid chloride and ethanol. l h t a on these preparations are in Table I and the analytical dat,a are in Table 111. @-Dimethylaminoethyl a-Phenyl-cis-cinnamates.-The optimum conditions for conversion of the cis acids6 to acid chlorides are out,lined in Table 11, the analyses are in Table 111. After removal of solvent and excess thionyl chloride, the crude acid chloride or mixture of acid chlorides in ether was h a t e d with 2 moles of t,he amino alcohol. After removal of the aminoethanol hydrochloride and conversion to the ester hydrochloride as described above for 2t, 7t, and 9t, the cis amino esters were purified by repeated fractional crystallization. The higher melting isomer (trans except for 2c) crystallized first. The purity of the cis isomer was followed by disappearance of the infrared carbonyl absorption band associated with the trans isomer. Further proof of identity and purity was obtained from the ultraviolet spectra. The spectra of the cis ester hydrorhlorides were in all cases nearly identical with t,hose of the corresponding cl's acids but markedly different from the trans ester hydrochlorides or acids. Since the carboxy and the carbalkosy groups are essentially equivalent chromophores, the same curves for the esters and the acids w r e taken as proof of identity of the esters. Isomerization Studies on a-Phenyl-cis-p-methoxycinnamic Acid.-Reaction of the cis acid in benzene a t 80 and 25" afforded exclusively the trans acid chloride as evidenced by the infrared spectra and melting point of the ester product. The cis acid (0.25 g., 0.99 mmole) was stirred with thionyl chloride (0.144 g., 0.09 nil., 1.2 mmoles) and a vatalytice amount of pyridine (0.5 drop) in ether for 60 to 90 min. in a bath maintained at - 10 to -So, or a t -60 to -55' and treated n i t h the amino alcohol after removal of excess thionyl chloride. At t,he lower temperature only the free trans arid was obtained; when carried out a t -10 to - S o , a mixture of acid rhlorides and later amino ester hydrochlorides containing approximately 557c cis and 45y0 trans was obtained. These values were estimated from the relative intensities of the two infrared carbonyl absorption bands in the acid chlorides and amino ester hydrochlorides (Table IV).
Acknowledgment.-The authors are indebted to Dr. Violette Sutherland and Nr. Mass Rikimaru for their help and guidance in the design and interpretat'ion of the pharmacological studies. The technical assistance of Misses Sharon Sousa and Sui 3Iei h i is also acknodedged.
4-Substituted Piperidines. I. Derivatives of 4-t-Amino-4-piperidinecarboxamides CORNELIS v . 1 DE ~ WESTERISGH,par-^ VAS D IELE, BERTHERMAKS, CYRIELVANDER EYCKES, ,JOZEF BOEY,A N D PAULA. ,J. JA?;SSEN Janssen Pharnkaceutica Research Lahoratoria, Beerse, Belgium Keceiiied Jfarch 16, 1964 A number of derivatives of 4-t-amino-4-piperidinec.arboxamides have been prepared. The pharmacologicai screening has shown that 1-( y-butyrophenone) derivatives may be classified as neuroleptic agents, whereas the l-,(a,a-diphenyl-ybutyronitrile) derivatives constitute analgesic agents. The latter eonipounds elirit relatively minor addirtion symptoms.
Our interest in therapeutic agents derived from piperidine led us to prepare a large number of 4,4disubstituted and 4-substituted piperidine derivatives. The purpose of this first paper is to describe compounds
of the general foriuula I, in which S.1A' represents a nitrile or a carboxaniide group. 1, is much less clearly defined and can represent a number of different substituent groups,
'I'AH1.6
7
.
1.IHI.E
L-d-yX XAK
I
,Isthe chemistry is virtually the same for all of the conipounds involved, regardless of the nature of L. this paper will deal only with the most important aiid representative species of this series; for the related compounds, reference is made to the patent literature.' Chemistry.-The first step of the preparation of all rompounds involves the synthesis of 4-ryaiio-4-cyrloalkyleiieimino (or dialkylamino-) piperidine deriratiles. These compounds belong to the class of cyaniiiio nitriles, whirh in general can be prepared con\ eiiiently by reaction of ai1 appropriately chosen ketone or aldehyde with a secaondary amine and hydrogel) c*yaiiideiuider a variety of rear tioii roiiditions. Tno major inodifications of tJhis reaction are dcscribed in the literature. I n method A, the TieniaiiStrecker synthesis, the ketone is treated with hydrogel) cyanide and the secondary amine, either in a one-step reaction or in two successive steps, whereas in iiiethod 13. thc Tinoevenagel synthesis, an adduct of the ketone aiid sodiuiii bisulfite is fornied firbt ; this is then allowed to react with the amine and hydrogen cyanide, again i i i a one- or two-step reaction sequelice. .\lthough the preparation of such amino nitriles ( h i v e d from cyclo ketones such as cyclohexanone is \ ('1 y ell known, the use of heterocyclic ketones, as far as we know, has iiever beeii described. Wc t o w d that starting froni S-substituted 4piperidones, i l l yome cases, fair to excellent yields of the desired animo nitriles could be obtained. The S-benzyl deyivativc vas chosen as starting compound since, in suhsequent reactions, this blockiiig group can be rCtissen,
L-
-
Patents 3 , 0 4 1 , I d i and .I 080,d66 (1963)
1
I1
iiioved easily by hydrogenolysis, thus allowiiig for the subsequent introduction of other substitueiits in this position. I n most cases, iiiethod A or B gave fair to good yields. However, of the cyclic iiiiiiies, the hexaniethyleiickiniine derivative could be obtained 01113' hy iiiethod 13; for 2-niethylpiperidine, the reaction failed altogcthci. Of thc dialkylaniinc+, only diniethylaniiiie g a w good results. Th(1 reartioii failed for the higher honiologh.. although sevclral niodificatioiis of both iii~thodsw r ( ~ applied. JTc>can oflc~rno siniple explanation tor o u i ' failures, wcept i i i thc. cab(' of 2-nic~thy.lpipci~itliii(~. where steric factors might play a rolc. 111 Table 1 thv compounds prepared by either 01 thv two iiiethods ai(> iiidicatetl. 111 the Expwiiiiviital part each of tlw iucthods i.s illustrated hy oiic cxaniplr T h e cheinical propcdcs of cy-aiiiiiio iiitrilcs i n grneml are deterniiiitd to a laigc wttwt hy the fact that thry bear ail electropositive, and an electronegative group o i i the same carbon atom, and the properties of this clasi of coinpounds aica rathw ui1ique.l For the i i i t i i h discussed here, thr situation is EVCKI niore coiiiplicatcd, due to the pi'cstlnce of anothcr aiuiiir fuiictioii i i i t h o lllolcculc~. It \\a- thrrciol~cllot 1lilrupc~cttYlthat thc. preparation ot clveii rathcr biniplc dciivativcbs ot t l i ~ , compounds could irot a l \ ~ a y s acronipliahcd ,1 straight forward wart ioii-. In t h r litei*ature \w i'ouiid 110 esaiiiplc of thc, dii w t alcoholysis oi a11 a-aiiiiiio nitrile (derived iroiii a k(.tone) to the cor1espoiidiiig ester, aiid upoii applying this reaction t o our coinpounds, the desired esters roul(l iiot hc obtaiiied \-e then tried to prepare t t i v t,stci> 1 in the free acids and acid chlorides. .llthouglr t h c k ( 2 ) I'crr d. inore detailed d i s c i i s ~ i o nof this class of
