added. The precipitated VI was isolated (6.2 g, 95yo) and twice recrystallized from EtOH to give pure VI, mp 102-194' dec. B d . (c,HiClx4s) C, HI S. Step 2. VI1c.-Na (0.46 g, 0.02 g-atom) was dissolved in hIeOH (.50 ml); 2-amino-2-imidazolirie.HCI (2.44 g, 0.02 rriole) was added, aiid the solution refluxed for 15 Inin. The NaCl was removed by filtration, the filtrate was treated with VI (2.0 g, 0.01 mole), and the mixture was refluxed for 30 min. After cooling, the product that separated was removed by filtration, washed with water, dried, and purified by reprecipitation. Method C. N-Amidino-3-amino-5-dimethylamino-6-chloroMethod B. 3-Amino-5-dimethylamino-6-chloropyrazinecar- pyrazinecarboxamidine (VIIb).-Na (460 mg, 0.02 g-atom) was bonitrile (IVj).-A s;oliitioii of IVa (10.0 g, 0.05 mole) in DllSO dissolved in i-PrOH (50 ml), guariidine.HC1 (1.91 g, 0.02 mole) (.TO m l ) was stirred and treated v,-ith 23c7, aqiieoiis Me2NH (20 was added, and the mixture was refluxed for 30 min. '4fier coolnil). The mixtiire was heated at 6.5" for 1.5 min and poured into ing, IYj (3.95 g, 0.02 mole) was added, and the sohition was 11 (150 nil). The precipitate which separated was removed by evaporated in V ~ C Z L Oto a volume of 10 ml. Aft'er standing a t filtratii)~~ washed , with H20, dried, and recryst,allized. 23" for 2 hr, H20 (100 nil) was added; the precipitate that formed Fiji. the synthesis of related conipoiinds, t,he piire liquid or was removed by filtrat>ionand piirified hy reprecipit atioii. g i w o i i ~amities were iised. 5. 2,4-Diaminopteridines(VIII). 2,4-Diamino-6-chloropteri4. K-Amidinopyrazinecarboxamidines (VII). Method A. Ndine (VIIIe).-Na (020 mg, 0.04 g-atom) was dissolved in NeOH Amidino-3-aminopyrazinecarboxamidine (VIIa).-3-Aminopyr(50 ml), giianidirie.HCI (4.0 g, 0.048 mole) was added, and the :iziiiecxrb')iiitrile6 (2.2 g, 0.018 mole) was added to HC1 (10 g) in mixture was refluxed for 30 min. After filtratioii, the filtrate was F:tOII (100 nil), and the mistlire was allowed to stand overnight. cooled and treated with IVd (2.0 g, 0.013 mole); the mixture wa? The imiiio ether hydrochkiride iV) which separated was removed refluxed for 30 min. Cpon chilling, VIIIc (1.9 g, 75%) separated. hy filtration aiid dried, mp 205" dec; it was iised in the following The product was removed by filtration and purified by reprecipireartii)n withoiit piirification or characterization. tation. A solrition of giiaiiidine in l I e O H \\-as prepared by dissolving 6. Other Syntheses. 3-Amino-6-chloropyrazinethioearboxNa ((J.!)2 g, 0.04 g-atom) in l I e O H (-50 ml), adding guanidine amide (X).-A suspension of VI (2.0 g, 0.01 mole) in pyridine hydrochloride (4.0 g, 0.04 mole), and stirring for 15 min. Com(20 ml) was stirred, and a steam of H2S gas was admitted below poiuid \. was added, and within a few minutes a solid began to the surface of the solvent for 2 hr. The solvent was evaporated separate. Aft,er 2 hr, the solid was rollected on a filter, suspended in oucuo and the residual yellow solid was recrystallized from in H,O, and dissolved by adding dilute HCI. Precipitation of the C6H6; yield 1.8 g (98Yc), mp 193-193". -4nal. (cdf;clX48) prodiict with dilute NaOH gave T X a . C, H, Y. Method B. N-( 2-Imidazolin-2-yl)-2-amino-6-chloropyrazine3-Amino-6-chloropyrazinecarboximidicAcid Hydrazone (IX). carboxamidine (VIIc). Step 1. Methyl 3-amino-6-chloropyra-To a solution of NH2NIT2(1.34 g, 0.042 mole) in EtOIl (65 zinethiocarboximidate (VI).-CH$TI (2.3 g, 0.033 mole) was ml) was added I T d (6.5 g, 0.042 mole), and the soliition was admitted below the surface of EtOR (100 ml) containing ,5y0 refluxed for 1.5 hr. After cooling, the precipitate was separated NaOH ( 2 drops). The sdiition was stirred, IVd (5.0 g, 0.032 by filtration; yield 3.4 g (697,), mp 168-170". Recrystallization mole) was added, and the mixture was heated to effect solution. from EtOH gave material melting a t 169-lil". Anal. ( C ~ H ~ C ~ E ' G ) After stirring at room temperature for 13 min, € 1 2 0 (100 ml) was c, I€, ri.
spoiitaneoiialy rose to aboiit 80"; this temperature was maintained for 10 mill by application of heat'. The resulting solution was poiired onto criished ice (1 kg) and neiitralized with NH4OIT. The prodiict was separated by filtration, dried, and recrystallized; the yield was 14.2 g. 3. 3-Aminopyrazinecarbonitriles(IV). Method A. 3-Amino6-chloropyrazinecarbonitrile (IVd).-A soliition of I I I d (4.0 g, 0 . 0 2 mole) in 2..5vc €IC1 (100 ml) was stirred and heated on a steam bath for 10 min. The product began separating during the heatiiig: after cooling, the mixture was filtered, dried, and re-
Antidepressants. Tetrabenazine-Antagonizing Activity in a Series of 5H-Dibenzo[a,d]cycloheptene-5-propylamines ED~-AR L.DESGELHARDT,' ~ I A H CE. I ACHRISTY, C. DPLIONCOLTOX, MARKB. FREEDJIAN, CAROLE C. BOLAND, Merck Sharp 6 Dohnie Research Laboratories, Division of JIerck Le. Co., Inc., W e s t Point, Pennsylvania
LATVREKCE 11. HALPERS, VERNONG. YERXIER,AND CLEMEXTA. STOSE N e r c k Institute f o r Therapeutic Reseal ch, Dwision of W e r c k & Go., Inc., W e s t Point, Pennsylvania Rrcaiaed Sovember 6 , 1,967
h heries of 3H-dibenzo [a,([]cycloheptene->-propylamine derivative? has been synthesized and atiidied for tetrabenazine-antagonizing activity. In both t,he nortriptyline ( I a ) and protriptyline (11)series, activit,y was maximal in compounds with a 10,ll double bond. Nuclear substitiients rediiced potency in both series. A striking difference in activity between geometric isomers was observed in the two pairs st'udied. I n one pair, demethglation of the tertiary amine that is the more active in blocking condit'ioned avoidance gives rise to t,he more potent tetrabenazine antagonist. The primary amine congeners of nortriptyline and protriptyline have reduced activity, relative to the parent compounds.
Demethylation to desipramine is one of the transformations occurring in the metabolism of imipramine.2*3 Studies in these laboratories415 demonstrated that N-demethylation is involved in the metabolism of amitriptyline. (1) T o whom inquires should be addressed. (2) R. Herrmann, T\-. Schindlrr, and R. Pulver, X e d . E x p . , 1, 3 8 1 (1959). (3) D. Herrmann and R. Pulver, Arch. I n t . Phmrmncodynam. Ther., 126, 454 (1960). (4) H. 13. Hucker and C. C. Porter, F e d . Proc., 2 0 , 172 (1961). ( 5 ) H. 3.Hucker, Phur?nucologzat, 4, 171 (1Y62).
Sulser, Watts, and Brodie6 found desipramine to be a potent antagonist of the central effects of reserpine and 2-ethyl-l,3,4,6,7,1lb-hexahgdro-3-isobutyl-9,lO-dimethoxy-2H-benzo [a]yuinolizin-%-01. Sortriptpline (Ia) was found to retain the antiberizoquinolizinc action of amitriptyline (Ib).6,7 ( 6 ) F. Sulser, J. W a t t s , and B. (1962).
n. Brodie, A n n . .V.
Y. A nrl. Sci.,96, 279
( 7 ) V. G. Vernier, F. R . Alleva. H. A f , Hanson, and C. -1. Stone. F e d . Pro'., 21, 419 (1962).
H
CH,CH2CH2NHCH,,
l~oIlo\viiig t lie c:~rl>,studies o i l iiiirtrii)t>.liiic, related (:o~ii~)ouiids \rere sj,rithesized arid studied in the tetral)cii:izitic-:tiitagoiiisni test . I 2 This w-orli culminated i i i tliv wlcctioti of l)rotril)tyline (11)I s for clinical trial. 111 : i n i n i d studies, i)rotriptylitie \vas fouiid to be x 1110re Iioteiit tetrabenazine antagonist than amitriptyline :itid t o t i c considerably freer from trariquilizing activit?. St udit.s i t i 1ii:iii hnvc confirmed predictions that prot rii)t!.liiic \vould he a potent :intidepressant with less sod;itivc> l)rol)crties.l 4 Thc I)resent communicatioii i q o r t s t he> s!,iithesis :itid structure-ucti~.ity relatiotishiits of co~ii~ioutids in the ~)rotril~tyliiie series. Chemistry.-Demethylation of t h e ttrtiary ainiries 111 a i i d IT:1swas effected readily by converting them t o t hi: c*y:iiiamidc cia the vo11 RriiuIi cyanogen bromide 1v:ict i ( 1 i . 'Ii f ( )lI( 1r w d b j- hydro 1) . This method also i ~ a sw:cdsuccessfully to rernovc t h e methyl groul) from tiitrogcti i t i T.
March 196s
32'7
L ~ S T I D E P K E b S A X T5H-DIBENZO [U,d]CYCLOHEPTENE-~-PROPYL~4MINES
SCHEME I1
T.IUI,E I ISTEHMEDI.\TE TEK'TI.U~Y AMIXES
9.
0
(CHd,N(CH,),
s
Y
Yield, "i;
l\lp or lip (mrn), O C
F o r riiulad
iwiw c20n2acixn , , , l.5;2-1.5.5 ClrH&1N04h CTI=CII CH=CI-I 8 8 ~ 20t?-21.5 C21HpsXS (0.3) S02K(CHI), 54c 244-24.; C2~H:j~N&iSe~' CH=CH dec a Tlydrochloride. Hydrogen maleate. Yield of utidistilled base. d All compotinds were analyzed for C, H, X . e Dilitiirate. f C: calcd, 56.00; foritid, 5.5.08.
cfr=cII
II C1 SCH,
.XI
triptyline- arid control vehicle treated mice were studied simultaneously for positive and negative controls. Twenty animals were used at each dose level. The appropriatevehicle is indicated in the tables. After 30 min, 2-oxo-3-isobutyl-9,lO-dimet hoxy- 1.2 >3 ,A, G,7hexahydro-1 1bH-benzo [a]quinolizine (tetrabenazine) was adininiqtered (32 nig/kg ip). One hour following injection of test compound, or 30 min following administration of tetrabenazine, the mice were examined for depression of exploratory behavior and for the presence or absence of ptosis. The time of observation following tetrabenazine was found earlier to correspond to the period of maximal depression after tetrabenazine in unprotected mice.'* After being placed upon an elevated 20 X 30 cm stainless steel mesh. normal mice "explore" their new environment. The following criteria were adopted to measure this exploratory activity: (a) movement to the edge of mesh, (b) turning of head + l P 3 O to the left and right, and (c) walking in a half circle. The preceding phenomena occur within 10 qec of placement in normal mice. Presence of a, b, or c indicates exploratory behavior during the test procedure and is recorded as such. Tetrabenazine abolished this exploratory behavior and, in addition, caused distinct ptosis of the eyelids. Protection, by the test compounds, against these effects of tetrabenazine was adjudged t o have resulted if the mouse exhibited any one of the three criteria of exploratory behavior and if the eyelids were not closed by more than one-third. The proportion of mice protected at each dose level was used to estimate ED5O's by the method of Litchfield and Wilcouon.18 The data are recorded in Tables I1 and 111. Structure-Activity Relationships.-In the nortriptyline series (Table 11), introduction of a l0,ll-double bond increased potency. Nuclear substituents redwed potency. The difference in activity between geometric isomers is noteworthy. The cis isomer of the 3-chloro pair is only slightly less active than the unsubstituted compound, while the trans form is markedly less potent. This difference is interesting in view of tbe fact that antiavoidance activity is much stronger in the cis than in the tyans isomer of the corresponding N,S-dimethyl compounds. This observation calls to mind the findings of Bickel, Sulser, and BrodieIg that (18) .J T. Litchfield, .Jr , and r 71 dcoxon, .l. Phnrmrtrol C z p T h r m p 96, 99 (1949). (19) AI H Bickel F. Sulser, and I! I3 I!roJie. Lzfe Scz , 4, 247 (1963).
.
0
VI1 SCHEME I11
VI
+
BrMg(CH2),0C2H5
- q@ H-
(cH,),oc,H, VI11
SCHEJIEIV
CH,
Ix demethyltrifluyroniazirie is a inore potent ant,ibenzoquinolizine than deniethylproniazine. The marked difference in potency between the isomers with a 10-bromo substituent is also noteworthy. The configurat'ions of these isomers are not known. Protriptyline (11) is clearly the most' potent tetrabenazine antagonist found in this study. In this series (Table 111) as in the nortriptyline series, saturating the 10,ll-double bond or introducing nuclear mbst'ituents lowers activity. The 1)riniary :mine con-
a l l ciinipoiuids were ailalyzed f o r C, h1 = niethocel. i Protriptyline = 1.
TI, S .
IIydlochloride.
Experimental Section?'I Tertiary Amines 111. Geometric Isomers of 3-Chloro-N,N-dimethyl-dH-dibenzo[n,d]cycloheptene-~~.~-propylamine (IIIa).I n oiir hands 1 he CY-geometricisomer of IIIa formed a hydrovhloride melting a t 229.5-230.5'. The p isomer was ohtained i n the foi,m of the base, mp i4-73", arid as the hydrogen maleate, mp 137-1.58". Winthrop, et al.,"d report 2227-229 and 165-166" :I\ the melting points of the hydrochlorides of t.he CY and /3 forms, iwpectively. I t has been shown that the form we designate 0 ha- the cis coiifigiiration,2~ lO-Bromo-5-(3-dimethylaminopropyI)-5H-dibenzo [a,d]cyclohepten 5 01.--10- Bromo- 5H -dibenzo[a,d]cyclo h e p t e n - 5 - 0 11 e (20.0 g, 0.07 niole) dissolved i i i 40 nil of dry T H F was added tl ri ipw ise to :I solution (if 3-dimethylaminopropylmagnesii mi chloride that was prepared from 3-dimethylamiiiopropyl chloride (17.0 g, 0.14 mole) in 30 ml of TI1F.22 The solution was cooled
- -
( P O ) .\I1 meltiiig points uere determined uitli cnlil~ratedtliermoineters in a Thomas-Hoover capillary melting point apparatus. Where analyses itre indirated only b y symhols of t h e elements, analytical results ohtained f o r t h o s e elements were within &0.4% of the theoretical values. (21) Karst Hoogstpen, A c t a CryPt., 21, A116 (1966). (22) (a) T . D. Perrine, J . O r g . Chsm., 18, 1356 (1953): (b) J. AI. Spranue a n < l 1,;. I.. bhwiliarclt, U. S. Patent 2,951,082 (1960); (c) G. E. Honvicino, 11. G . .\rlt, .TI., Iombiiiedorganic extract.: wei'e wahhed ([I?O), dried (Sx,S04), and evaporated iinder rediiced preshrire. I)is;tillatioii of the residiie gave 4.14 g of c k ~ i ~ dyellow y oil, 1111 l ~ ~ ~ - l . Y (0.1 ~ o nim). The product wa3 dissolved ill
petroleum ether and refrigerated overnight. After filtration from a trace of white solid, the solvent was evaporated and the residue was redistilled to yield 3.10 g (45%) of clear yellow oil, bp 145-148' (0.1 mm), n25~1.6086. Anal. (C2&0) H. 54 3-1odopropyl)-BH-dibenzo[a,d]cyc1oheptene.-With astream of NPpassing through the stirred $ohtion, 5-(3-et,hoxypropyl)-5Hdibenzo[a,d]cycloheptene(1.6 g, 0.00575 mole) in 9 ml of AcnO was heated to 65'. H I ( 5 5 4 8 % ) (4 ml) was added in 0.5-ml portions keeping the temperature below 80". When the addition was completed, the mixture was held a t 78" for 45 min. After cooling to room temperature, the mixture was poured into 75 ml of ice water and the oily product was extracted (CsH,). The benzene extract was washed (HLO, satwated NazS2O3,HrO, saturated NaHCOa, H20). Distillation of the benzene under reduced pres*lire left 1.76 g of yellow oil. This material gave a positive test for I- with alcoholic Ag?;03, hilt the ir spectrum indicated contaminatmionwith acetate. The crude product was suitable for aiibseyuent use and no attempt was made to obtain a pure sample. N-(5H-Dibenzo [a,d]cycloheptene-5-propyl)phthalimide.-A solution of crude 5-(3-iodopropyl)-5H-dibenzo[a,d] cycloheptene (1.76 g, 0.0049 mole) in 10 ml of D M F was stirred with potassium phthalimide (925 mg, 0.005 mole) a t 90" for 45 min. The cooled mixture was diluted with 25 ml of CHCI, and poured into 50 ml of H,O. The aqueous layer was separated and extracted with two 25-ml portions of CHCls, and the combined CHC13 extracts m-ere washed (H20, 1% XaOH, HZO) and dried (NaUSO4). Evaporation of the CHCl3 under reduced pressure left an oily solid which was freed from oil by t'rituration with 15 ml of 1 : 1 ether-petroleum et,her. The yield of white solid, mp 123-126", was 900 mg (48Yc). An analytical sample from another experiment melted at 125.3-131.5" after recrystallization from i-PrOH; ,,A, EtOH 292 mp ( E 6002). Anal. (CW,H~,SO,) C, H, N . The ir Epectriini ( K B r ) showed strong maxima at' 5.62 and 5.85 p (CO). 5H-Dibenzo[a,d]cycloheptene-5-propylamine.-A solution of N-( 5H-dibenzo [a,d]cycloheptene-5-propy1)phthalimide (2.15 g, 0.0054 mole) in 50 ml of boiling 95% EtOH was treated with 0.6 ml of 100% hydrazine hydrate and refluxing was continued for 2 hr. The solution was cooled in an ice bath and acidified to pH 2 with concentrated HCl. The voluminous precipitate of phthalhydrazide was separated by filtration and washed n i t h two 4-ml portions of cold 95cc EtOH. The filtrate was concentrated under reduced pressure to a volume of approximately 5 ml, diluted with 40 ml of H20, filtered from a small amount' of solid, and concentrated under reduced pressure until solid started to separate. Sfter cooling, the precipitate of t,he amine hydrochloride was collected to yield 1.35 g (87.5%), mp 254-2517' dec. Repeated recrystallizations from i-PrOH gave material melting a t 263-?66;i" dec, :A," 290 mp ( E 12,724). The ir spectrum ( K B r ) showed maxima a t 3.4, 6.25, 6.7, 6.95, 7.2J 8.6, 12.45, and 13.15 p.
c,
N-Methyl-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene-5propylamine (IVd).-A solution of X,S-dimethj-l-3-methylmercapt o-5H-dibenzo [a,d]cyclohept ene-j-propylamine (2.05 g, 0.0063 mole) in 12 ml of dry C6H6 was added dropwise to a st,irred solution of ethyl chloroformate (2.0 ml) in 8 ml of C6H6 at room temperature. A viscous yellow oil separated but redissolved when the mixture was heated to refluxing for 3 hr. The cooled solnt,ion was diluted with additional benzene and washed (H,O, 3 S HC1, HnO). Distillation of the benzene under reduced pressure left' 2.0 g (83%) of a yellow viscous oil. A solution of this product in 20 ml of AcOH was stirred and cooled to 12'. H n 0 2 (30%, 2 ml) was added dropwise with continued cooling in an ice bath, and the reaction mixture t,hen was stirred for 40 hr a t room temperature. Bft,er dilution to a volume of ca. 100 ml with H20,the mixture was extracted (CGH6). Evaporation of the washed and dried benzene ext,ract under reduced presslire left 2.1.; g (YiC;) of a yellow viscous oil. This product, t>heiirethaii IT;, w-as hydrolyzed to the secondary amine. Solid KOH (1.6 g, 0.026 mole) %-as added to a sollition of the urethan (2.4 g, 0.00567 mole) in 24 ml of n-BuOH. The redbrown mixtiire was heat,ed to refliixing with stirring under KZ for 12 hr. TTZO was added to dissolve the insoluble material and the mixture was evaporated to dryness on a film evaporator. The residue was partitioned between CsH, and HnO, the benzene layer was separated, and the aqueous layer was extracted further (CBHs). The utnihitied 1)eiiLetie ext,i,ac.t,swei'e extracted with :3.5 ml of O..; AI citric. acid iii two port,ions. The acid extract %-acooled in ice and made basic with 40',; NaOH. The product was extiactc:d (C81fti), the extract \vah wished (TT,O), a i d C6ITG was
Synthesis aiid Central Nervous System Depressant i i c tiviLy of New Piperazine Derivatives. I
E'ii'ry-i \I (1 S',S4-dihiibstituted piperaziiie derivatives, i i i which The S I siilJhtitiieiita are 9,-i,.i-tiii:ietlios2.belizoyl or ::,4,.i-triniethosyt)eii~(~~-lnl~yl a i d the ?;'siibstitiieiith are methyl, 2-(2'-hydrosyethoxy)ei hyl, cyclohesyl, Ireiizyl, in-met hj-1- o r p-t-hritylt)etizyl, 2-phenethyl, pheiiyl, chloio- 01'rnethoxypheiiyl, tolyl, 2,,B-sylylJ , 2-pyi,iniidyl, or 2-thiazolyl grorip:', have been ithesixed aiid wreeiied for CXS activity. Thr a, >h(i\vii by gross observatioii of int,act animal. of the compoiiiids produced CXS depressatit effe couditioiied-avoidaiice behavior. rmed by motor activity stiidies aiiti iii some ca>eb
forniuln
S'-(aroylalli\.l~-S'-~bub~tituted)~)il,cl.:dw been studied. one of which, Si- [rip-fluoroberizo\.l)prop!.l] - S4 - (0 -met hoxyphenyl) pigcrazine (haloanisone) . I 1 is :it prewiit uridergoing clinical trinls. ;iccordinglj-, the >yrithe5is of thc compouiitls liaviiig general forniu1:i I rvab uiiciertalieri. era1
:txiiiebii1 have
OCH
j
