September 19titi
3-PHESYLCISXOLINES.
1
665
TABLEI Structurea
7-c,
Crystn solventb
IIIb Ivb
XIp,
Calcd
o c
% 7
Found
--€I %-, Calcd Found
----N, Calcd
%---. Found
7-R3 Calcd
%-Found
Ee A Ee Aa Eec E A SKC 1Ic B Ee
190-191 72.71 72.47 4.58 4.61 10.60 10.56 207-208 72.71 72.65 4.58 4.63 10.60 10.45 IIIc 173-175 68.56 68.36 4.32 4.37 10.00 9.94 11.07 11.28 IVC 249-250 68.56 68.54 4.32 4.39 10.00 10.04 11.07 10.85 1-(: 111-112 76.25 76.56 5.12 5.10 13.13 13.28 IIId 2 37-23 8 63.28 63.15 3.19 3.24 9.84 9.65 11-d 210-211 63.28 63.61 3.10 3.35 9.84 9.69 1.d 146.5-147.5 69.86 70.16 3.77 4.07 11.64 11.86 14.73 14.55 IIIe 223-224 67.16 66.98 3.38 3.76 10.45 10.68 I\:e 216-217 67.16 67.22 3.38 3.57 10.45 10.63 7.08 6.95 IIIf 150-15ld 11.11 10.74 I1.f B 222-2233 10.58 10.68 1.f 31 139.6-14O.3J 12.72 12.91 IIg Ee-SKB 147.5-148.5 68.71 68.77 5.35 5.46 14.49 14.69 IIIg Ee 216-217 9.38 9.34 11.87 12.16 Iv g B 211-2 12 64.33 64.23 3.71 3.90 9.38 9.54 1-g 11 185-186 70.72 70.97 4.35 4.59 11.00 11.01 13.92 14.01 I1,-hf Aa 229-230 68.56 67.91 4.32 4.45 10.00 10.26 b Ee, ethyl ether; E, ethanol; SK (Skellysolve, see ref 20); A, acetone: Aa, acet,ic acid: J I c , methylene chloride; B, a See Chart I. britanone; AI, methanol; C, chloroform; Bz, benzene. c The principal contaminant aft,er decarboxylation is the demethylated material which is best removed by ext,raction by dilute potassium hydroxide before crystallization. d Baiimgarten arid Furnas2give melting points of IIIf, 145-145.5'; IT'f, 229-229.5"; T'f, 138.5-139.5°. e This hydrazone was prepared i l l refllixing Skellysolve L.*O f 111a single experiment the iyatin was not obtained crystalline; t'he oil obtained by evaporation of the dried CH2C12 solutioii (see I I I a ) was rearranged without purification.
For t'he acids IV in Table I, the solitary activity found in any of the tests8-12 was the antiinflammat'ory8action of IVd. Reduction of 3-phenylcinnoline with zinc dust' and barium hydroxideI4" yielded a dihydro derivative,14b undoubtedly the 1,4,15which tautomerized on reaction with butylmalonyl dichloride t80 yield the derivat'ive IaS4" Catalytic reduction furnished the corresponding tetrahydrocinnoline (Ib). The structures of these conipounds are confirmed by the similarity of their infrared absorption spectra to those of other malonyl derivatives3 and to t.hat of phenylbutazone, and by their showing the expected nmr spectra.'; Unfortunat'ely, neit'her showed antiinflammatory activity819 a t the screening dose. 13a Reaction of the acids IV with t,hionyl chloride provided t'he acid chlorides VI which were treat'ed as described below, and which were used to prepare the amides, hydrazides, and esters in Tables 11-VI.
CHARTI
"
a
S
H
I
N=CH O
R
1. fCOCI), 2. AIC1,
*
I1
111
V
IV
R'
R
a b
H H
H CH, OCH,
e
H
f
CH,
g
CH3 CHI0
c d
h
H H
c1 F H C1 H
the experimental variations are by no means exhausted, a further examination might broaden the usefulness of the reaction.' (7) T h e author wishes t o acknowledge t h e excellent technical assistance of h l r . Richard J. Salzmann in the preparation of several of the compounds in Table I.
(8) Compounds v e r e tested as inhibitors of yeast-induced foot edema in male, Badger rats (120 g ) . T h e minimal effective dose of phenylbutazone was 120 mg'kg subcutaneously, 175 mgjkg orally. (9) \$-e are indebted t o Drs. F. J. Saunders and E. F. Nutting and their staff for the d a t a from these tests in ref 8 and 10. (10) Inhibition of cotton pellet induced granuloma growth was measured in adrenalectomized, male, Sprague-Dawley rats (200 g) for a 2-day period. A screening dose of 200 mgikg/day orally was used. The minimal effective dose of phenylbutazone was 2 5 mg/kgiday orally. (11) (a) Hypotensive activity: the decrease in mean pressure following injection of the test compound in t h e femoral rein was directly recorded from arterial cannulation of normal dogs anesthetized with pentobarbital sodium, The screening dose \\-as 5 mg/kg. (b) .Intiulcer activity: following intragastric administration of t h e test compound t o male Charles River rats (250 g), inhibition was observed of ulceration induced b y pyloric ligation a s described b y H. Shay, 8. A. K a m a r o r , D . Meranque, hl. Gruenstein, and H. Siblet, Gastroenterology, 6 , 43 (1945). (c) Diuretic activity: t h e diuresis produced in 5 hr b y intragastric administration of the test compound in saline-primed, male, Sprague-Dawley rats (300 g) was compared with t h a t of controls treated with hydrochlorothiazide. (12) We are indebted t o Dr. D. L. Cook and Rlr. R. 9. Jacobs and their staff for data from t h e tests in ref 11. (13) (a) 80 mgikg subcutaneously; (b) 320 mp/kg orally. (14) (a) XI. H. Duval, B u l l . Soc. Chim. France, [4] 7 , 727 (1910). fb) This compound was obtained along with 3-phenylcinnoline by t h e Li.UH4 reduction of 3-phenyl-4-cinnolinol: C. >I, htkinson and C. J. Sharpe, 3 . Chem. Soc., 2858 (1959). (15) L. S. Besford, G. Allen, and J. 12. Druce, J . Chem. Soc., 2867 (1868).
ri'\ril>l,
II
\ 21 I Ilt..
CO-Am
\ "2
SH, "2
"2 "2 "2
SH('H h
Nrl
U
111
September 1966
I
~-~'HENYLCISNOLINES.
667
TABLE V
HYURAZIUES
&cbHj
Mp, "C
---C, Calcd
198-200 201-203 237-240 191-194 223-226 216:-"S
Cry*;t11
n
So."
solventb
NHNHz
1 2 3 4 5
BZ
A NH?J=C( CH3)2 AI NHX( CH8)z N( C H ~ ) N ( C H ~ ) Z AI A NHXH-(-JCH,
6
KHX
A
YCHJ
A-SKB
cyc---.
7--
---s,yc----.
n, %--
Found
Calcd
Found
Calcd
Found
68.17 71.03 69.84 70.56 69.78
68.17 70.86 69.68 70.24 69.92
4.58 5.30 5.52 5.92 6.41
4.65 5.54 5.53 5.94 6.22
21.20 18.41 19.17 18.29 19.38
21.03 18.16 19.12 18.07 19.44
89.14
ti9.11
8.09
0.11
20.16:
20.28
U
a Compound 1 was prepared as 5 ill t,he Experimeutal Sect.ion hut, o i l niakiiig t,he hydroxide extract, iieiitral, the product crystallized. It was filtered off, dried, and recrystallized from benzene. Compound 2 was prepared from 1 by refluxing in, t,heii crystallizing from, acetone. Compound 3 was prepared as 5 , but the hydroxide extraction wax omitted. The residue on evaporatioii was stirred with ether, filtered off, and crystallized as indicated i n t,he table. Compounds 4 and 6 were prepared as 3.
T-IBLEVI EJTEits CO,R
---c,
Cryat11
N0.a
It
wlvent"
AIL),
c/o---.
_._~_ 11, ";-----
&-,
oc
Caled
Koiind
Calcd
Found
('alcd
yti ~oi111d
1
(CHz)sS(C H ~ ) , . C I I I I O ~ ~
A
153-155
63.85
64.07
5.58
5.46
9.31
9.13
2
CH,CH~N~NH.(C,H,O,,~~
E
150-151
59.20
59.17
5.30
5.61
9.21
9.25
u
These compouiids were prepared as 1, Table 111; the maleic acid salts of the crude products were crystallized from t,he solvent indicated. b See Table I, footnote b. E Maleic acid salt.
bond, followed by taut~merization'~to the 4-H derivative; and the dihydro ester Xa, formed by reduction by the Grignard. A related ester (Xb) was isolated in low yield in an attempt to prepare the primary hydrazide (see related hydrazides, Table Ti) from methylhydrazine in refluxing butanol; hydrazines are known to cause reduction of azo bonds under similar conditions. l6 The structure of the dihydro ester X a is derived from the infrared and nmr spectra. A single, D,O-exchangeable proton is seen at 2.9 p and a t 483 cps, respectively. The carbonyl band at 5.77 p and the ethoxy pattern in the nmr (quartet centered a t 245 cps integrating for two protons, triplet at 65 cps, three protons) establish the ester. The 4-hydrogen occurs as a single peak, one proton, a t 308 cps. Nine aromatic hydrogens are seen as complex multiplets from 400 to 480 cps. These data rule out the isomeric structures, 1,2-dihydro, 1-aminoindole, or 3,4-dihydro, and are in agreement with similar data on other 1,4-dihydro~innolines.~5 The same arguments apply to the butyl ester Xb which shows the same 4-H absorption and the expected aliphatic absorption in going from ethyl to butyl in the Iimr spectrum. The 1-phenyl derivative XI differs only by the lack of an exchangeable hydrogen and by an increased absorption in the ninr due to the five phenyl protons. B ~ r d e r l i n e ' ~antiinflainniatory activity* was found in 3-phenylcinnoline-4-carboxamide (1) and encouraged (16) S. Kubota, T. Akita, and T Yukoslrima, J Pharm SOC.J a p a n , 7 8 , 1184 (1958).
an extension of this series, shown in Table 11. Unfortunately, only the N-benzyl analog (10) showed even equal subcutaneous activity, and both were inactive in adrenalectomized ani mal^.^^'^ The series showed no interesting activity in other screening tests.llb,c,1- (These amides were too insoluble to allow intravenous injection for the hypotensive test."&) Table I11 shows aminoalkyl amides. The most interesting activity found a t screening levels was hypotensive11a,12for 1 arid 2, and antiinflammatory8>l3 for 4. By contrast, the best activity shown for the piperazine amides of Table IV was antiulcerllb at 10 mg/kg by 1. The primary hydrazides (-COKHN=) of Table V were soluble in dilute potassium hydroxide but were precipitated by addition of carbon dioxide. This behavior was used to separate 5, formed in 50% yield, from the isomeric secondary hydrazide XI1 in the re-
@ \
C O N e M e
I
z"
XI1
action of 1-methyl-4-hydrazinopiperidine and the acid chloride VIa. The best activity of these compounds was that of 2 in the antiinflammatory test,8"3a while of the esters iu Table VI was that of 2 in this te~t.~~'~
I\' R =H c, R = OCH,
a,
VI
w n
VI1
OCH
I
VI11 U.
IX
h , R'
-
Bu
I
C,H, s1
Experimental Section17 1tie 1)rep:iraiiotis below illlistrate the modific:xtioii> of tlie procedurei of Banmgarten and Furnay.2 N-Benzylideneaminoisatin (IIIa).--To 126 g (1.0 mole) (if osnlyl (ahloride iii 1.5 1. of refluxing CH2C1, was added dropwiso i i i 'L hr with stirring 196 g (1.0 mole) of benzaldehyde phenglh>-drazorie dissolved in 2.0 1. of CH2Cl2. The solutioii v a s stirred arid refluxed 2 hr morr, then 450 g (3.4 moles) of AlCI, XIS added portionwise but rapidly, ; i d t,he mixt,ure was st,irred overtiight. It wa$ decomposed by pouring or1 ice, the cirgtrniv 1:iyer WE separ:ited, washed with dilute HCI. dried first by shakiiig with a saturated soluiioti of NaCl arid then by filteriiig lowly through ?r'a,SO1, and imreritrated t c i 1 1. Upon dilutiori wit,h 2 1. of et,haiiol arid cioolirrg to O0, red prisms separated.]* These were filtered and dried; yield 174 g (io?)), mp 14% O"."J Ail additional 24 g (107;) of less pure material, nip 0-14.io, was obtained by cottceritratiiig the mother liyuc~t~ in cmlo t o 500 ml. All thi- material was sufficiently piire for converGiori to the acid. A portioti of the first crop was recrystallized from a large volume of ether 10 >-ielti oraiige needles, r n l 1 149..? - 1 19 llized froni Siti:ill portioris of thehe isatilia were Liest cther ,qitic.e refliixiiig in higher boiling aolverit,5 as etliaiiol WYLt'oririd to cause plow decomposition. 3-Phenylcinnoline-4-carboxylicAcid (IVa).--T(i 1 1. of 60', KOH T T R , ~added 15j g of the combined crops from the previous csptrinieiit. The suspension was heated with oc,rnbionnl shaking , 7
O.
I T ) .\ll i n r l ~ i n pi i u i n t s are uvrrected and were t a k m i n a Ilersliberg all1Iicroanalyvsis \rere performe,i b y t tie Llicroanalytical Department under I l r . X.T. Dillon. Infrared spectra were recorded on a Beckman I l t 4 . K m r , rerorrleil on a Varian A-60, is given in cycles per second (cpe) of don.nfield shift from tetrametiiylsilane as a n internal reference standard. (181 Alternatively, the methylene chloride solution may be evai>oratecl iic I ' U C : L O t o drgncbs and tlie residue stirred \\-it11ether t o induce cwsstallizativii. (1!l) F o r tlir purified conipouriils. I h u m g a r t e n and Filmas? givp inrltiric i t c 1 ~ 1 1 t . ( I f I I I u , 148-14Q'; I V a , % 2 4 - 2 2 i . . j o ; Vji, 118,.5-11!1'. I
Immtiis.
C, 75 b l 11, (i.60 X,\ 41 3-Phen~lcinnoline-4-carbony1 Chloride (VIa 1.
Fti~uiil
l'hc
,ii i d
I\
i
September 1966
3-PHENYLCINNOLISES.
Anal. Calcd for C,HsN20: C, 77.57; H, 3.47; N, 12.06. Found: C,77.63; H,3.69; N, 12.02. 3-( 4-Methoxyphenyl)-4-benzoylcinnoline (VIIIc) and 9-Methoxy-llH-indeno[ 1,2-c]cinnolin-11-one (VIIc).-A mixture of 3.0 g of VIc and 2.6 g of AlC1, was stirred in 150 ml of benzene for 21 hr. After decomposition with ice, washing with acid and base, and drying as in the previous example, the solution was evaporated arid the rejidue in benzene was chromatographed on alumina. Elution with 5c:; ethyl acetate-benzene, followed by rellization from ethaiiol of the first fractions, yielded VIIIc BS yellow prisms, mp 165.5-166.5', 6.0 p (C=O), and VIIc 5.8 p (C=O), in later fractions its red needle,., mp 214-215", ::.A; in a ratio of about 6 : 1. Anal. of JTIIc. Calcd for C?2H16N202: C, 77.63; €1, 4.74; N,11.23; OCHa, 0.12. Foulld: C, 77.61; H, 4.81; N, 8.36; OCII,, 9.24. Anal. of VIIc. Calcd for C~~HIONYO~: C, 73.27; H, 3.84; S , 10.68; Found: C, 73.11; H, 3.78; S , 10.61. Ethyl 3-Phenylcinnoline-4-carboxylate (IX).-A solution of 48.0 g of VIa iii 1 1. of ethaiiol was refluxed 1 hr, then evaporated zn U Q C U O . The residue in methyleiie chloride was washed with dilute K2C03,the solution way dried (see VIIa), and the solvent was evaporated in vacuo. Crystallization from ethyl acetateSkellyholve C Z oafforded 41.0 g (77%) of yellow prisms, mp 8590'. A11 analytical sample was recrystallized from methanol, mp 02-93". Anal. Calcd for CnH14N20~: C, 73.36; H, 5.07; K, 10.07. Found: C, 73.06; IS,5.10; 5 , 9.$?1. Ethyl 1,3-Diphenyl-1,4-dihydrocinnoline-4-carboxylate(XI) and Ethyl 3-Phenyl-1,4-dihydrocinnoline-4-carboxylate(Xa).To 20.6 g (0.074 mole) of I Y dissolved in 1.5 1. of anhydrous ether was added dropwise with stirring 18.1 g (0.1 mole) of phenylmagnesium bromide ill 50 ml of ether. After stirring 2 hr, the solution was decomposed with water and washed first with dilute HC1 and then with dilute KOH. I t was dried (see VIIa) and evaporated. Chromatography of the residue (27 g) on silica aiid elution furiiished the priiicipal products in this order: biphenyl (4.7 g, eluted with 209% benzene-Skellysolve BZ0), S I (1.3 g, 7576 C~H~-SkellysolveBZo),Xa (6.4 g, 10070 C6H6)j I X (starting material, 10.2 g, 557; ethyl acetate-benzene). X I wab crystallized from Skellysolve B;20tan clusters, mp 111-112". Anal. Calcd for C23HZoN202: C, 77.50; H, 5.66; N, 7.86. Found: C, 76.97; H, 5.65; Tu', 8.23. Xa was crystallized from ether-Skellysolve A;2o white blades, mp 82-84". Anal. Calcd for CnH,,N202: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.91; H, 5.64; N, 10.13. Butyl 3-Phenyl-1,4-dihydrocinnoline-4-carboxylate(Xb).-A solution of 11.5 g (0.04 mole) of I X and 12 g (0.3 mole) of methylhydraziiie in 70 ml of butanol was refluxed 15 hr. The residue after evaporation in 2iacuo was stirred with ether, and the yellow powder was filtered off aiid dried; 5.3 g, mp 160-165". Repeated recrystallization from methanol and from et,hanol failed t'o yield a homogeneous product. The ether filtrate was evaporated and the residiie was chromatographed on silica. Elution wit'h benzene gave first (along with
I
669
starting material later) crystalliiie fractions which when recrystallized from Skellysolve B*o formed 0.42 g of white needles, mp 64-66 '. Anal. Calcd for C1gH20?J202: C, 74.00; H, 6.54; N, 9.09; mol wt, 308.37. Found: C, 73.78; H, 6.41; N,9.03; mol wt, 309. 3-Phenylcinnoline-4-carboxamide(Table 11, I).-To 2.7 g of VIa in 300 ml of butanone was added 10 ml of concentrated KH40H, and the solution refluxed 1.5 hr. After evaporation of the solvent in vucuo, the residue was stirred with dilute NaOH, and the solid was filtered off, washed well with wat,er, and then with a small amount of methaiiol. Cryst,allizat,ion twice from ethanol afforded 1.6 g of yellow prisms described in Table 11. 3-Phenylcinnoline-4-(N-benzyl)carboxamide(Table 11, lo).To a solution of 5.3 g (0.05 mole) of benzylamine in 150 ml of CH2Cl2 was added slowly a solut,ion of 4.6 g (0.017 mole) of VIa in 50 ml of methylene chloride. The solution stood overnight. I t was diluted with CH2Cl2,washed with dilute HCl, dilute KOH, and water, and then dried (see VIIa). The residue obtained by evaporation of the solvent in vaeuo was crystallized from chloroform, yielding 4.4 g of white needles described iii Table 11. 3-Phenylcinnoline-4-[N-(3-dimethylaminopropyl)]carboxamide (Table 111, l).-To a solution of 3.0 g (0.03 mole) of 3-dimethylaminopropylamine and 3.0 ml (0.022 mole) of pyridine in 150 ml of methylene chloride was added slowly a solution of 5.4 g (0.02 mole) of VIa in 50 ml of CHZCl2. After standing overnight, the solutio11 was diluted with CH2C12and washed well with dilute KOH. I t was dried (as VIIa) and evaporated in vucuo. The residue was dissolved in dilute HC1, which was washed with ether and then made basic with dilute KOH. The suspension \vas extracted with CII2Cla which was dried and evaporated. Crystallization of the residue from methylene chloride-Skellysolve B2o afforded 4.0 g of yellow flakes described in Table 111. 3-Phenyl-4-( 1-piperazinylcarbonyl)cinnoline (Table IV, 1).A solution of 26.9 g (0.1 mole) of VIa in 500 nil of butanone was added dropwise with st,irring in 1 hr to 25 g (0.3 mole) of piperazine dissolved in 150 ml of butaiione. After st,irring 1 hr the piperazine monohydrochloride was filtered off, and the filtrate was evaporated in vacuo. The residue was dissolved in dilute IICl, which was filtered to remove a small amount of solid and then worked up as in the preparation above of 1, Table 111. The maleic acid salt of the product was prepared in met'hanol and is described in Table IV. 1-( 3-Phenylcinnoline-4-carbonyl)-2-( 1-methyl-4-piperidinyI)hydrazine (Table V, 5).-A solution of 10.8 g (0.04 mole) of VIa in 100 ml of methylene chloride was added dropwise with stirring disto 13.0 g (0.10 mole) of l-niethy1-4-hydrazinopiperidi1ie~~ solved in 200 ml of CH2C1*. After standing 2 days the solution was washed with a 55%K,C03 solution, then extracted with 1 0 5 ~ KOH. This extract was neutralized to p H 7 arid ext'racted wit,h methylene chloride, which was dried (as VIIa) and evaporated in vacuo. Crystallization of the 7-g residue from acetone yielded 4.8 g of shiny, pale yellow plates, described in Table T. (21) A. Ebnother, E. Jucker, A . Lindenmann. E. Rissi, R. Steiner. R. Suess, and A. Vogel, Helo. Chim. Acta, 42, 533 (1959).
