September 1968
pN(@ I
0
R o/o NU.
1%
Rlp, "C
yield
tlecrystn solventa
Furinula"
58 51 29 48 51
110-112 0 CiaHi,I'JzO? 113-114 C-C~HI~ 0-B Ci8H2zNq09 94-95.5 CHS 0-E Ci3HiaX20s 131-132 CaHjCHz 0-B Ci9Hi8Xj201 134-135.5 5 i-CsH; 0-B CijHiaN202 B-P CisH16N&? 6 CbHj JO 153-15-5 4 0 = isooctalie, B = CtiH,, E = i-Pr20, P = petroleum ethei (bp 60-110). * All compounds were analyzed for. C, H, K. CyHj
1 2 3 4
1035
1-SUBSTITUTED 3-PYRROLIDISYLUREAS
--
were t8hen injected intravenouslj , 111 this experimental situation the two 3-phthalimidopyrrolidiries tested (1 and 2 in Table I) exhibited antiarrhythmic activity comparable to that of quinidine sulfate. These conipourids are cyclic analogs of a group of K(w-aminoalky1)phthalimidiries that were reported to have antifibrillant activity.8 Testing for local anesthetic activity involved intradermal administration to guinea pigs and rabbits arid application of painful stimuli to the skin overlying the injected area. Of the compounds tested only 2 was found to be active. Compounds 1 and 26 were inactive while 4-6 were considered borderline, primarily because of the inconsistency of the results. Anesthetized dogs and conventional sensing and recording devices were used in a general screening procedure. Experimental compounds were given in
TABLE 11 2-AMINOPYRROLIDINES
H
I
R NO.
7
R
i-C3117
RI
H x &6H11 TI 0 C~H~CII, I€ IO CsHj €1 CsH, 11 C~H~CI&CI~.I CsH, 12 C II,=CHCH,! See Esperimeiital Section. ' I = i-PrOH, 11 Dihydrochloride. e Difumarate. J Fumarate.
Prepn methodu
'A
hlii or bp ( m m ) , "C
yield
I
69 I 60 I 62 I 60 I 46 I1 58 = MeOH, E = i-PrrO, 0 Hydrochloride.
compounds not previously described are given in Table 11. In the case of the 1-phenylpyrrolidine compounds the tosylatc procedure was necessary sirice 1-phenyl-3-pyrrolidinol gave only intractable tars when treated with thionyl chloride under the usual reaction conditions. The substituent on the 1 position of the &anilinopyrrolidiries mas varied by catalytically hydrogenating the 1-benzyl-3-anilinopyrrolidine to the corresponding secondary amine4 and alkylating with an appropriate alkyl halide. The various substituted ureas described in Table 111 were prepared (Chart I) by the reaction of the 3-aminopyrrolidine with (1) alkyl or aryl isocyanates, ('2) carbamoyl chlorides, (3) nitrourea,5 (4) potassium cyanate, or (.i) p-toluenesulionyl carbamide.6 Pharmacologic Studies.-llost of the compounds described in this paper (Tables 1-111) \\ere included in at least one of a battery of pharmacologic tests. The more note\\-orthy findings are summarized beloll. Antiarrhythmic activity was investigated using a method described by Winbury, et aL7 Cardiac arrhythmias were produced in two ways: (a) an area in the region of the sinoatrial node was crushed and then stimulated electrically, and (b) aconitine was injected into the wall of the right atrium. Test materials ( 5 ) J. 9 . Buck a n d C. W Ferry, J . .4m Ckem. Soc , 68, 854 (1936). (b) E Haack a n d R. Jacob, East German Patent 9.688 ( i p n l 21. 1955). ( i ).\I 11 UinlJury, 11. L. Hemmer. and D Calhoun, Aclu Physzol I'hurmucol Seer1 , 5, 468 ( l Y 5 7 ) .
=
Recrybtn solvent'
Forniiilnc
11)!)-200 , 5 I CiHiaClaNra 156- 157 1I-I Ci sH.~sNd& 174-17.5 11-1 CIjHaoNd.laf 170-172 I-E CiOHijClX;'~ 173-174 ( 0 . 0 4 ) CIBHpISr 6,567 0 CI,~HIBS? isooctane. c h l l compoluidu were aiialyzed for C, H, ?i.
increasing intravenous doses, usually until lethality was reached. In this experimental situation 9, 10, 12, and 42 elevated and 1-3, 7, 17, 26,39, 43, 46, arid 53 lowered arterial blood pressure. These changes were never marked and they persisted only with 12. Compounds 1, 2 (low doses), and 10 caused tachycardia, an effect of long duration with the last compound; the opposite effect was produced by 2 (other than low doses), 3, 43, 46, and 53. Respiratory effort was enhanced by two compounds (9, 12) that elevated blood pressure. Compounds 6, 58, and 59 were essentially without pharmacologic action in these experiments. When administered in doses below the lethal range, no compound caused meaningful changes in venous blood pressure, the pattern of the electrocardiogram, activitJ- of the small intestine, urine flow, or autonomic nervous system function. Effects on the central nervous system were investigated in mice that were observed for gross changes iv behavior following intraperitoneal administration of test compounds. Evidence of C S S depression was seen with 14, 18, 19, 24-28, 31, 33, 43, and 58; 15, 22, 23, and 29 had the opposite effect. The results with 30 suggested skeletal muscle relaxant activity. Acute intraperitoneal LDjo estimates (mouse) encompassed a wide range with the compounds investigated. Compounds 20, 21, 23, 28, and 50 were among (8) K . Hlder and H. 0. Hankovsdk,, J . M c d . Chem., 8 , 257 (l'Jb5).
10X
September 1968
1-SUBSTlTUTED ?I-~-'YRROLIDIXYLUPLEAS CHART
1 Rl
Rl
1
I
l,iNH I
R
NCONHR, (1)
I
R I1
R,
R,
I
I
w""KRJCCCI
I
R
(NJNCONRZRJ
(2)
I
R
n
RI
I
81
I
[ T N H
LJNCONH2
H,NCONHN020rKNCO
I
(3)
I
R
I1 RI
I
1,1NH
pCH,C,H,SO,NHCQNH,
I
R
I1
I,r
~ C O N H S O , C ~ ~ C H (4) ,-~
I
k 3-Phthalimidopyrrolidines (Table 1).-.4 rapidly stirred suspension of 0.80 mole of potassium phthalimide, 0.80 mole of the 3-chloropyrrolidine, and 700 ml of D,1/ISO was heated a t 110-113° for 16 hr and filtered while hot to remove the inorganic salt. The crystalline product which usually formed when the filtrate was cooled and treated with HzO was separated by filtration and recrystallized from the appropriate solvent. 3-Aminopyrrolidines (Table 11). Procedure I. By Reaction of 3-Phthalimidopyrrolidines with Hydrazine.--A mixture of 0.10 mole of the phthalimidopyrrolidine, 0.11 mole of 85% hydrazine hydrate, and 100 ml of 95% EtOH was heated a t reflux for 2 hr, rooled, and treated with concentrated HCI until the solution was s t r o n ~ l yaridic. The voluminous precipitate of phthalhydrazide \vas filtered OR and washed with four 15-ml portionsof 9554 EtOH. The filtrate !vas cwnrentrated to 50 ml and 50 ml of HIO was :&id to the flask; any insoluble material was removed by filtration. The filtrate was evaporated to dryness under redurcd pressure. After the residue \vas treated with 50% SaOH, the oil which formed was separated and dried over SaOH pellets.
1037
The free base w a fractionally ~ distilled arid cnonvcrtcti to a solid addition salt. Procedure 11. By Alkylation of 3-Anilinopyrrolidine.-- A wliitioii of 0.123 mole of alkyl bromidr in 50 ml of absolute EtOH \vas added dropwise to a stirred mixture of 0.123 mole of ~-aniliiiopyrrolidine4 and 30 g of KICO3 iii 100 ml of abxolut e E t O H under SI. After stirring overnight at room temperature the mixture was treated with 200 ml of H,O and the resrilting siispenrioii was extracted into CHCI,. The combiiied extracia were dried (hIgSO4) and evaporated t o an oil. The crude produvt was purified by distillation or column chromatography. 3-Ureidopyrrolidines (Table 111). Procedure 111. By Reaction of the 3-Aminopyrrolidine with Alkyl or Aryl Isocyanates. --To a stirred solution of 0.1 mole of the 3-aminopyrrolidine ill 100 ml of dry C6Htiat, room temperature was added slowly 0.1 mole of thc alkyl or aryl isocyanate in 20 ml of dry CtiHti. After the addition \vas rompletc, the mixture \vas stirred for several minutes and the solvent \vas evaporated a t reduced pressure. Crude prodwts (solid free bases or addition salts) were purified
Procedure IV. By Reaction of 3-Aminopyrrolidines with Carbamyl Chlorides.-To a stirred suspmsion of 0.3 mole of SaLX)a in 100 ml CHCla Fvere added 0.1 mole of the 3-amiriopyrrolidine and 0.1 mole of the carbamyl chloride. The mixture was heated a t gcntle reflux for 16 hr and then treated with 100 nil of H20. The organic layer was separated and dried (RlgSO4) arid the solvent was evaporated. The products in the form of frcr bases or arid addition salts were purified by recrystallization. Procedure V. By Reaction of the 3-Aminopyrrolidine with Nitrourea.-A niixtiire of 0.05 mole of the 3-aminopyrrolidinc~, 0.06 mole of the nitrourea, and 50 ml of EtOH was heated gently until the evoliilion of gas ceased (15-20 min) and then the solvent was evaporated at reduced pressure. The product \vas purified by recrystallization. Procedure VI. By Reaction of the 3-Aminopyrrolidine with Potassium Cyanate.-A solution of 0.03 mole of the 3-aminopyrrolidine in 31 ml of 1 S HC1 was treated all at once with 0.03 mole of KSCO in 5 ml of HsO. The mixture was stirrcd for 4 hr a t room temperature, then the resulting precipitatc was filtered, washcd (HZC)),and purified by recrystallization. Procedure VII. By Reaction of the 3-Aminopyrrolidine with p-To1uenesulfonyIcarbamide.--A mixture of 0.05 mole of the ;
