NOTES
551
TABLE I THIO-AND SULFONYLMETHYLTETRAZOLES RXCH2C-NH
II
I
"\" N NO.
X
1 2 3 4
S
MP, 'C
Crystn solvent
Formulae
99.5-100.5 a C4H5F3N4S 195-196 a C4H5FJJ402S S 109-110 a CSHIOX~S so2 155.5-156.5 b C5HioKi402S a S 129-130 CaHs~aS2 SO2 160 dec a C6H6?1T4082 S 159-160 a CsHiClNaS SO2 225 dec C CsH7ClX402S S 103-104 a CgHgClXaS so2 234 dec d CgHgCIS402S S 142-143 a CgHioSaS so2 211 dec C CgHioS4OsS All compounds were analyzed for C, H, S, and neut equiv.
so2
e5
6 7 8 9 10 11 12 a Et2O.
e
TABLE 11 T H I O ICETONITRILES
RSCH2Cn' R
Rlp or bp (mm), OC
FormulaC
88-90 (23) C,HgSS (CH3)zCH C6H1NS2 3-thienyl 96 (0.1) 84-85 CsHeClSS p-CICsHha 109 (0.1) CgH8ClXS p-ClCgHaCH2 41-42 CgHgSS p-CH3CaH4b a E. 4 . Falco, B. Roth, and G. H. Hitchings, J . Org. Chem., 26, 1143 (1961). J. AI. van der Zanden, J. Kieuwenhuis, and H. J. T. Bos, Rec. Trav. Chzm., 76, 669 (1957). All compounds were analyzed for C, H. 300 ml of H20, and 300 ml of EtlO. The ether layer was separated, dried (RlgS04), and concentrated to dryness zn vacuo. The residue was triturated with pentane and filtered. The thioacetonitriles listed in Table 11 were synthesized by analogous procedures.
Potential Antihypertensive Agents. IV.1 Unsymmetrically 1,4-Disubstituted Piperazines. I1 RAJ SAKDAX PRASAD A N D KARINTIETJE
Research Department, dbbott Laboratories Ltd., Jlontreal, Quebec, Canada Received January 7 , 1969
In these laboratories, for a number of years, we have been interested in piperazine derivatives as antihypertensive agents. This report presents the syntheses of several 1-alkyl- (or 1-aryl- or 1-aralkyl-) 4-?j-substituted carbamoyl- (or thiocarbamoyl-, ureido-, or thioureido-) piperazines and the evaluation of their biological activities. The compounds prepared and tested in this series are listed in Tables I and 11. The PI;-substituted carbamoyl and thiocarbamoyl derivatives (1-11, Table 1) were obtained by the reaction of the monosubstituted piperazines with the corresponding isocyanates or isothiocyanates in a suitable solvent. ( 1 ) For paper 111, see R. N. Prasad, J . Med. Chem., 12, 290 (1969).
Apparent P K ~
4.9 5.4 4.0 5.3 4.2 5.1 4.0 5.3 4.0 5.3 4.2
Reaction of 1-methylhomopiperazine with benzyl isothiocyanate, however, gave an oil which could not be induced to crystallize. Treatment of the oil with Me1 gave methyl r\;-benzy1-4-methyl-l-homopiperazinethiocarboximidate (12) as a hydriodide salt in 24% over-all yield. Other S-methyl derivatives (13, 14) were prepared from the corresponding thiocarbamoyl derivatives (7,6)in excellent yields. Reaction of 13 with methanolic NHI gave N-cyclohexyl-4-phenyl-1-piperazinecarboxamidine (15) in poor yield. The thioureido and ureido derivatives (16-25, Table 11) were prepared similarly from 1-substituted 4-aminopiperazines. Reaction of some 1-substituted 4-(/3-aminoethyl)piperazines with isothiocyanates similarly gave the corresponding thioureas (26-28, Table 11). Pharmacology.-The piperazines were ex aluated for antihypertensive activity by the method reported before.2 Of these, only 1, 5, 6, and 26 showed a sustained moderate decrease in blood pressure at 5-10 mglkg. Compounds 4, 7, 10-12, 16, and 20 caused an unsustained fall in blood pressure, whereas 19 produced a transient hypertensive effect. The remaining compounds were inactive. Experimental Sections
Following are representative examples of the preparative methods employed. The solvents used in the preparation and the reaction periods are indicated in Tables I and II. Method A. l-(N-Cyclohexylcarbamoyl)-4-phenylpiperazine (l).-A solution of cyclohexyl isocyanate (13.7 g, 0.11 mole) in Et20 (300 ml) was added dropwise (under anhydrous conditions) to a well-stirred solution of nT-phenylpiperazine (16.2 g, 0.1 mole) in CsH.3 (200 ml) a t room temperature. The mixture was refluxed for 0.5 hr and the product was filtered. One recrystallization (C&) gave the pure product (Table I). Method H. l-(N-Henzylthiocarbamoyl)-4-phenylpiperazine (6).--A solution of benzyl isothiocyanate (18.4 g, 0.123 mole) in Et20 (50 ml) was added t o a solution of N-phenylpiperazine (20 g, 0.123 mole) in Et20 (200 ml) at 10-20". The mixture was stirred for 0.25 hr, allowed to stand 15 hr a t room temperature, (2) F. Fried, R . N . Prasad, and A. P. Gaunce, zbid., 10, 279 (1967). (3) All melting points mere determined in open capillary tubes with a Thomas-Hoover capillary melting point apparatus and are corrected. The elemental analyses were performed by Messrs. Orville Kolsto and Victor Rauschel and Staff of Abbott Microanalytical Laboratory, North Chicago, Ill. Where analyses are indicated only by symbols of the elementa, analytical results obtained for those elements were within zk0.401, of the theoretical values.
and then filtered. One recrystallization from EtOH anti another from alcoholic DMF gave the pure product (Table I). Methyl N-Benzyl-4-methyl-1-homopiperazinethiocarboximidate Hydriodide (12).-A mixture of benzyl isothiocyanate (6.5 g, 0.0439 mole) and I-methylhomopiperazine (5.0 g, 0.0439 mole) in Kt20(100 ml) was reflused for 2 hr. The clear solution on evaporation gave an oil. The oil ~ - 2 t dtaken up in 3IeOH (50 nil) anti mixed with excess Me1 (15 nil), and the mixture was allowed to stand overnight at room temperature. The product (4.4 g, 24c,7-over-all yield from the homopiperazine) was filtered :~iid recrystallized (JIeOH), mp 188-190 '. I n a l . ( C E H ? ~ S. H ~ PI C, H, I, S,S. Methyl N-Cyclohexyl-4-phenyl-l-piperazinethiocarboximidate Hydriodide (13).--A mixture of 7 (3.0 g, 0.01 mole) and Me1 (4.26 g, 0.03 mole) in EtOH (50 ml) was refluxed for 2 hr. The clear solution so obtained was evaporated and the residue, 011 trituration with ISt?O, gave 3.4 g (77%) of t,he product, mp 166I71 '. Recrystallization from hIeOH-EtaO gave the pure product. KIP 169-173'. d l n ~ l (. c i ~ H u S k 4 . H I )C, H, I, K, S. Methyl N-benzyl-4-phenyl-1-piperazinethiocarboximidatehydriodide (14) (mp 152-155", lfeOH-EtzO) was similarly prepared in 70% yield from 1-(S-l,enzylthiocarbamoyl)-4-phenylpiperazine ( 6 ) and XeI. 3 t d (C15H2sS3S.HI)C, H, I, K, S. N-Cyclohexyl-4-phenyl-1-piperazinecarboxamidineHydrochloride (15).--.1 solution of 13 (3.0 g, 0.0067 mole) in dry MeOH ( 1 5 ml) was mixed with :L saturated solution of S H 3 (prepared at. 0 " ) i n LTeOH (20 ml', rand the mixture was allowed to stand
at room temperature for 15 hr.
The clear iiolutioii was ihcw refluxed for 3 hr while S H 3 gas hubhled slowl>-through t h e r i ~ i ( , t>ion mixture. The reaction mixture was evaportited a i i t l t tit, remaining oil was taken up in dry MeOH (70 nil) aiid 11 through a column of .\mberlite resin 1R.k-400 (HCI form). Tht, eluate n-as evaporated and the residue 011 trituration with Me,CO gave the crude product. One recrystallization (hIeOH-I.:t,O I and mother from H.0 gave t,he pure product in 14( yic.ltl, mp 272-273". .lnd. (CITH~&*.HCI) C, H, C1, S . Method C. l-Phenyl-4-(N-benzylthioureido)piperazine(20 1.. .I solution of 1-amino-Pphenylpiperazine (8.85 g, 0.05 niiile ) in ahsolute EtOH (190 ml) was heated with a solution of li(:nz>,l isothiocyanate (7.45 g, 0.05 mole) in Et20 (100 ml). \!'lien :til the Et20 boiled off, the mixture was refluxed for 3 hr and ( ~ ~ o l e t l t o room temperature. The product (15.9 g, 97';) wxs f i l t c w t i (mp 201-202 dec) and purified by recry~tallizationfrom SIeaCO C,H6 (Table 11).
Acknowledgment.- The authors wish to express tli& appreciation to Dr. .J. H. Short for many helpful discussions mid to Dr. H. Shoepke, Dr. Tholiias Darkly, Mr. Leo Wiemeler, and Mr. Charles Shaiiiioii of tl e Pharmacology Departineiit of hbbott Lalmratorios. Sorth Chicago, Illinois. for pharmacological iiivcstipations and permissioii to use their data.
