July 1968
HYPOTENSIVE CYANOGUANIDINES
C.-Same as method A except a solution of equal volumes of EtOH and diglyme was used as solvent. D.-To a solution of 0.4 mole of NaOH in 7.5 ml of H,O was added 0.2 mole of 2 and 500 ml of diglyme. To this mixture was added 0.2 mole of 1 and the mixture was stirred under reflux for 60 hr. The mixture was cooled, diluted with HqO, and acidified. The precipitate was filtered, washed (T120)>dried, and recry?tallized. Substituted 3-(2-Aminophenoxy)-2-chlorobenzoicAcids (4az ) (Table II).--.A soliition of 3 in aqueolis EtOH was prepared hy dissolving 3 in EtOH and adding HyO until the soliltion became cloudy (risiially 1:l). A 4 g-atom excess of Fe powder was added and the mixture was stirred and heated to reflux. A 9 Jf excess of AcOH was added dropwioe and the mixtiire was heated an additioilal I h r after the addition had been compleled. The mixture wai cwoled to room temperature atid made hasic with aqueou.: XI%. Air was drawn through the stirred mixture for ?-.i hr to ensure romplete conversion of the dissolved Fez+ to the more eaiily filtered Fe(OH)3. The mixture of unreacted Fe and Fe(OH)a was filtered through a mat of Supercel, and t,he filter cake was washed thoroughly with dilute aqueous SH,. The comhiiied filtrates were concentrated to remove E t O H and excess NH,. The concentrate way acidified carefully wit,h dilute HCl until a drop of acid produced no further precipitation. The solid amino acid was filtered, washed with T-T,O, and dried. This material was usually pure enough for the preparation of the N-formyl derivative 5 . Substituted 2-Chloro-3-(2-formamidophenoxy)benzoic Acids (sa-2) (Table III).-A mixtiire of 4 and 97-100s formic acid (10 ml/g of 4 ) was stirred and refluxed for 2-18 hr (the reaction was followed by tlr using the same system that was used in the preparation of 3). The solution n-as cooled and poured into several volnmes of IIZO with vigoroiis stirring. The solid was filtered and washed well with H2O. The crude product was usually contaminated with trace amounts of unreacted 4 but was sufficiently pure for the next reaction. Substituted Phenoxazine-I-carboxylic Acids (sa-x) (Table IV). A.-A mixture of 0.01 mole of 5 , 0.02 mole of K2C03,
811
0.1 g of Cu bronze, and 100 ml of dry D l I F was stirred and refluxed under N, for 30-60 min. The hot, mixture was filtered int,o several volumes of warm H20. The filter cake was washed with a small volume of H,O and the combined filtrates were acidified with dilute HCI. The result,ing yellowish green precipitate was cooled, filtered, and redissolved in dilute XHaOH. The solution was filtered and acidified again. The precipitate was filtered, washed, dried, and recrystallized. B.-The reaction was carried out as described in A except, dry diglyme waq w e d in place of D J I F and refluxing was continued for 3 hr. Methyl Phenoxazine-1-carboxylate.-A mixture of 330 mg of 6aJ in 90 ml of NeOH wax cooled and saturated with dry HCI. The mixtiire was stirred iinder reflux for 4 hr and the resulting soliition was cooled and diliited with H20. The JIeOII was distilled and the aqiieoiis residue was extracted (EtnO). The ether was washed ( 5 5 , KaHCOs, HPO), dried (JIgSOa), and distilled. The residue was sublimed and recrystallized from EtOH-H?O to give 200 mg of ester, mp 128-129'. Anal. (ClaHIlN03) C, H,
3-.
The methyl ester prepared from 6a obtained from the cyclization route melted a t 127-128' (Et,OH). Anal. (Cl.tHllXOs) C , H, N. 3 4 2-Amino-3-carboxyphenoxy)-2-chlorobenzoicAcid.-A mixture of 5b and 5 S KOH was heated 2 hr on a steam$ath. The solution was filtered, cooled, and neturalized. The solid was filtered, washed with HnO, dried, and recrystallized from EtOAc, mp 273" dec. -Anal. (ClaH1oCIN0,) C, H , C1, N.
Acknowledgment.-We wish to thank Dr. James H. Birnie for the biological test data and members of the Analytical and Physical Chemistry Section, Smith Kline and French Laboratories, for elemental analyses. We would also like to thank Miss Suzanne R. Cohen for preparing 3p and the methyl ester of 6a.
Hypotensive Activity of Some Cyanoguanidines SHREEKRISHNa 31. GADEKSR, SOPHIA ?;1B1,
ASD
ELLIOTTC O H E N
Organic Chemical Research Section, Lederle Laboratories, d Division of Bmerican Cyanamid Company, Pearl River, S e w I-orli 10965 Received January 15, 1968
A 5erie\ of 5iihstitiited c\ anogiianidines was synthesized and screened for hypotensive activity. theie, 1-t-amyl-3-cyanogiianidine (2), was selected for further animal Qtudies.
Several years ago 1-t-butyl-3-cyanoguanidine'(1) was found to have appreciable hypotensive activity in a random screening test carried out in normotensive rats.* Since the simple unbranched homologs were devoid of activity, and we were not aware of any reported hypotensive activity for cyanoguanidines. we *et out to prepare a number of analogous compounds. There are, of course, many examples in the literature of guanidine derivatives possessing hypotensive activi t i e ~ . This ~ report deals with the synthesis and
hypotensive activity of the series of substituted cyanoguanidines listed in Table I. Chemistry.-The synthesis of monosubstituted cyanoguanidines was accomplished by a well-established procedure4 consisting of the condensation of the hydrochloride of the appropriate amine with sodium (or lithium) dicyanamide. The reactions were carricd out in either 1-butanol or in HzO. In a few cases the choice of solvent was critical. RNH2.HC1
(1) R . SI. .\cheson, G . ,\. Taylor, and 31. L. Tomlinson. J. Chem. Soc., : ( i s 0 (1958). ( 2 ) .I. R.Cumminos, .I. I,. Grace, and C . N. Latimer, J . l'hrirm. .a, Donnigan, and T. D. Letli, .I. M e d . Chem.. 6 , 275 (1Y68); ((1) J . .\rigstein. S . SI. Green, A. h i . Llonro, G. IV. H. Potter, C. R . \I-orthinp, and T. I. \I-ripley, iDid., 8 , 446 (1'365): (e) R . P. M u l l , R . €1. Miazoni, SI. R. Dapero, and SI. E. Egbert, i t i d . , 5 , Y44 (1962).
One of
+
NaN(CN1,
-
YCN
RNHCNH2
+
NaCl
To prepare compounds with substituents on both nitrogens, two ndditiot1:il methods were employed. 111 the first case, heating a mixture of l-cyano-2,3-dimethyl-%thiopseudourea, t-butylamine, arid ethanol in an autoclave yielded l-tbutyl-2-cyano-3-methylguanidirie (17). This procedure has heen used by Curcl to prepare substituted di~yandiamides.~ ( 4 ) F H. S. Curd, J. A . Hendry, T. S . Kenny, 1.G . AIurry, and F. L Rose, J . Chem. Soc., 1630 (1948).
s12
\*ol. 11
II
I1 I 1I 11
II i
I I,
s
1
(;,
x
(:, II;S,' 178-1 T!l
11
I1
L S H
I1
NCN (CH,),CNH,
II
-I- CHjNHCSCHj
-
I1
C', 11, N
II
c, Ills
NCN
II
(CH3)3CNHCNHCHJ 17
'I'hc synthesis of l-cyclohexy1-2-cyuno-:Z.-(morpIlo1iiiocthyl)guaiiidine (18) w a b nccomplishcd b\- the procedure of Lecher, et al., which uses a thiourca with
rcactiori. The varbodiimide 11, prepared fro111 thi.~ corresponding tliiourea I b l t h e method of oil treatmelit n-itli cy:tiiamide also failed to form 111. ii ('S P tlNCN
r---++
I/
RNHFHR
HYPOTENSIVE CYANOGUANIDINES
July 196s
guariylated by the method of' Iinthke7 to yield products 19 and 20.
CI R N*c 19, R = C(=NH)NH2 20, R = CH2CH2NC(=NH)NH2
;\lost of the amine intermediates used in these syntheses were known compounds. -411 new prep arations or modifications of existing procedures are described in the Experimental Section. The methods used to screen and evaluate compounds for hypotensive activity have been previously described.2 Pharmacological Activity.-Seven of the reported compounds (1-4 and 13-15) were found active as hvpotensive agents in rats (ie., a 30-mm or more drop in blood pressure). It has been reported that guanylation of certain hypotensive amines possessing ganglioplegic action results in the retention of the hypotensive effect and loss of the undesired ganglion-blocking activityS8 When the corresponding cyanoguanidines were prepared, in three cases (8-10) no activity was found and in two cases (13 and 14) the products were, indeed, hypotensive but still possessed ganglion-blocking activity. Compound 15, like 1-4, was devoid of ganglioplegic activity. The reported hypotensive activity of t-butylguanidine3c (with its obvious similarity to 1) prompted us to prepare the "cyano" analog 7 of guanethidine. However, it was devoid of activity. In a similar fashion, since 15 was active, the guanidines 19 and 20 were prepared but they were also inactive as hypotensives. Slight variations of structure 1 such as an additional methyl group on the terminal nitrogen (see 17) or gros i changes leading to an adamantylamirie derivative (see 12) resulted in total loss of activity. l l o s t of the other variations were chosen to provide highly branched groups adjacent to the nitrogen (e.q., 5 , 6, and 10) but none of these compounds possessed any activity. The most active compound, 1-t-amyl-3-cyanoguanidineg (guancydine, 2) was selected for further evaluation in animals.'O Experimental Section The melting points were determined in open capillary tubes and are uncorrected. Where analyses are indicated only by symbols of the elements, analytical results obtained for those elements were within &0.4% of the theoretical values. a,a-Dimethylcyclohexaneethylamine (1V).-A4 mixture containing 9.2 g (0.05 mole) of p-ip-chloropheny1)-a,a-dimrthylethylaminr, 0.25 g of PtOi, and 100 ml of AcOH (glacial) was hr.drogenated at room temperature and pressure for 2 hr. There was practically no uptake of Ha. An additional 0.5 g of the (7) B. Rathke, Ber.. 14, 1774 (1881). (8) (a) Farhenfabriken Bayer A.G., Belgian Patents 607,479 and 608,905 (1961). (h) T h e hypotensive and ganglion blocking effects of t h e amines were reported b y S. Rossi. C. Valvo, and W.Britts, Gam. Chim. Ital., 89, 1164 (1959). I n our tests, t h e amines used to prepare 8-10 were found inactive as hypotensives. (9) This compound was originally prepared by Dr. D. E. Nagy a t Stamfurrl Lahoratories Division of American Cyanamid Co. (10) J . R. Cumminps. A . N. Welter, J. L. Grace, J r . , and L. 11. Lipchuck, J . Pharmacol. E r p . Ther.. in press.
813
catalyst was added and hydrogenation was continued for 5 more hr, but a t 80". Only 10% of the required uptake of hydrogen resulted. Finally a large amount (1.5 g) of the catalyst was added and the reduction was continued for 6 hr a t 60-65' until the theoretical amount of H2 was consumed. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo to a syrup. This was dissolved in 50 ml of H20 made alkaline and extracted with Et2O. The distillation of the extract in vacuo provided 5.4 g (69%) of a fraction boiling a t 42-45' (0.4 mm), nZ3D1.5950. Anal. (CloHzlN2) C, H, N. 3-Azabicyclo [3.3.2] nonane-3-acetonitrile (V).--A solution rontaining 3.5 g (0.028 mole) of 3-azabicyclo[3.3.2]nonane,2.1 g (0.028 mole) of 7 5 7 , aqaeous glvcolonitrile, and 20 ml of EtOH was refluxed for 4 hr. ,4hroirn oil \\as obtained on evaporation of the mixture in vucuo which soon solidified to give 3.5 g (76Vc) of a crystalline compound, mp 51-52' ; recrystallized from EtOH, mp 59-60'. Anal. (CioHiGN2) C, H , l-Cyanomethyl-2,2,6,6-tetramethylpiperidine(VI).-Fo'lowing the procedure described in the preceding preparation this nitrile was prepared from the corresponding amine" in a 55% yield, mp 39-40". Anal. (CllII,oNz)C, H ; N : calcd, 15.5; found, 16.0. The method was applicable also to the preparation of 7-chloro-6methyl-l,3-dihydro-2H-pyrrolo [ 3,4-c]pyridine-2-ace tonitrile (VII) from the analogous secondary amine.12 h 49% yield of a crystalline material, mp 90-91', from petroleum ether, was obtained. Anal. (CloHIoCIN,jC,H, N. 2-Aminoethvl-7-chloro-6-methvl-1,3-dihvdro-2H uyrrolo 13,4clpyridine Trihydrochloride (VIIi).--To a- suspension- of 0.38 g (0.010 mole) of LiAlHI in 35 ml of anhydrous Et20 was added a soliltion of 1 04 g (0.005 mole) of 7-chloro-6-methyl-l,3-dihydro2H-p\~rrolo[3,4-c]prridine-2-acetonitrile in 45 ml of EM). The mixture \%asrefluxed for 6 hr, cooled in an ice bath, and then treated with 0.8 ml of 7.5y0NaOH and 1.2 ml of HiO. T h e qiispension was filtered and the solvent was removed in vacuo. The resultant oil was converted to the trihydrochloride with ethanolic HCI and EtpO to give 0.73 g (4370)of a yellow solid. The hygroscopic salt was recrystallized from a mixture of LIeOH, EtOH, and E t 2 0 ; mp 255-257" dec. Anal. ( C I O H ~ ~ C I N ~ . ~ H C I ) C, H, N. 3-(2-Aminoethyl iazabicyclo [3.2.2]nonane dihydrochloride (IX) was similarlv prepared from the corresponding nitrile. The base which boiled a t 80-82' (0.75 mm) was obtained in 867, yield: C, H , N. mp >300° as a dihydrochloride. ilnal. (CLOHZONZ.~HCI) 1-(2-Aminoethyl)-2,2,6,6-tetramethylpiperidine Dihydrochloride iX).-The LiAIH4 reduction of the corresponding nitrile provided this diamine as a base in 54% yield, mp 252-253' as dihydrochloride. Anal. (CnH24N2.2HCI) C, H, N. 3-(2-Methyl-2-nitropropyl)-3-azabicylo[3.2.2]nonane (X1).l3A solution containing 25 g (0.2 mole) of 3-azabicyclo[3.2 21nonane, 17.8 g (0.2 mole) of 2-nitropropane, and 60 ml of 1,4dioxane was treated a t 0-3" with 16.2 g of (37%) aqueous H,CO and 8 ml of (2Yc)NaOH. The mixture \Vas stirred for 1 hr and then heated over steam for another 1 hr. Addition of 100 ml of HzO to the cooled mixture afforded a semisoft solid, mp 6872"; recrystallized from EtOH, 29.1 g (64%), mp 72-73'. Anal. (Cl2H2,N2Oz)C, H, N. 3-(2-Amino-2-methylpropyl)-3-azabicyclo [3.2.2] nonane Dihydrochloride (XII).-A solution of 13 g (0.057 mole) of the nitroamine in 115 ml of MeOH was hydrogenated with 1.15 g of R a ( S i ) a t 77 33 kg/cm2 pressure. Another 0.5 g of the cata l l s t mas added 3 hr later and the reduction \vas continued for a total of 6 hr when 927, of the theoretical amount of H? was consumed. .%fter removal of the catal>st the fitrate was cooled and saturatrd n i t h HC1 gas. Evaporation of LIeOH gave a brown residiie which on recrystallization from E t O H gave 6.3 g =InaE. (C12Hx(41%) of the dihydrochloride, mp 283-285'. iV2.2HC1) C , H, N. l-t-Butyl-3-cyanoguanidine1(1 ).-A mixture of 110 g (1.00 mole) of t-hutrlamine hydrochloride, 80 g (1.00 mole) of lithium dicranamide ( 9 4 5 purity). and 500 ml of n-RuOH mas refluxed with stirring for 18 hr. The mixture was cooled to 0" and the salt was filtered and washed with 100 ml of EtOH. The combined filtrate n as concentrated to a slurry zn t'acuo, dissolved in
y.
-
(11) N. J. Leonard and E. TT. Kommensen. J . A m . Chem. Sac., 71, 2808 (1949). (12) 8 . RI. Gadekar. J. L. Frederick, J. Semb, and J. R. Vaughan, Jr., J. O w . Chem., 26, 468 (1961). (13) G . B. Butler and F. N. 1\IcRlillan, J . Am. Chem. Soc.. 73,2878 (1950).
2 0 0 nil of hot EtOH, and c,larifietl, HnC) W : ~ Sadded, and t h e C ~ ~ I I ( J giianidirie (1) precipitated. Using a similar procediire and the same molar qiiantities of t Ill, react:int,s, l-f-amyl-3-c~~aiiogiianidine (2j was prepared froin tht,
cvrresporiding amine hydrochloride.
N-Cyano-3-carboxamidino-3-azabicyclo 13.2.21 nonane
( 8 j.
'1'0 it rollition of 1.25 g of the nzahicyclononaiir i n 1 nil ~i coni~(:ntr:itctl HCI and 4 ml of HyO \vas :tddetl 0.:) g (0.01 niolr) oi sodiiiin dicyanarnide. The mistlire \vas rrflused for 2 h r : Iio\vo w r . \\.ithiti 20 min of rc:fliixing :I solid hat3 pr~?cij~it:rtcti.'I'hc. react ion mixture was cooled and t h e d i d was filteied ofl :iiicl .tallized from aqueous EtOIl. l-l-Butyl-2-cyano-3-methylguanidine 17 1. .I stod :irito('1:tvPrquipprd with a glass liner \vas rharged \\.it11 3.2 g 10.025 triol:,) of I-c~~~:irio-%,3-dimrth~l-2-thiop~~~iidoiirc~i, 15 ml of t-l>iityl:tmiiics, :itid fiO ml of EtOH and was henttd :it 125' for 6 fir. ,> 1 lit, V C ~ S R ~ ~ I \vas i d f v l , and t h r light h r o ~ v n ~ o l i i t i ~\\-as n rexniovrd :inti waporatrd t o :I syrup. \Vhen this syriip \viis &solvctl i n :I SO'; K t O F l - H ~ (1 mistiirc I)!. warining anti t h c s o l ~ ~ t i o i l ~v:is d(v*olorizrti x i t h rharcsoiil. 0.2 g of an iiiiitlrntificd ni:ittlri:al nic~lling:it 201- 21 1" \vas ol)taincd. The fi1tr:itc from i t , on flirther diliition with 30 In1 of IT?(), gave 0.7 g of t h e (lerirrd prodrict. It was recryhtallizetl from dilute EtOH. 1-Cyclohexyl-2-cyano-3-iZ-morpholinoethyl~gu
.\ mistrirr c.ontnining 2.61 g (0.000 molt? of 1~ i i o r ~ ~ h o l i r i o c)thioiirra th~-i irildrirh Chcniical Co. niolc4 of lrad ryanamidc, : ~ n d I f i nil of EtOH w a s stirrrci tinti r c ~ f l i i s r dfor 18 Irr. Thih rc,tic+ioii was not ro~npletras o b a c m w l t)y thv formation of merciirir siilfidt, w h t n :i vlarifird aliqiiot of t ti(> niistiirr \\-as hr:rtrtl ivitli yc~llon. mrrriiric oxidr. .\nothrr. (J.5 g of I'hS ield :tftw
