January 1970
ASTIFERTILITYAGEKTS. IT’
et a1.,3by the condensation of p-benzylozybenzoin with various phenols. As this method gave extremely poor yields with phenols carrying 110 activating group a t the meta position, alternative methods were investigated for the synthesis of 2-phenyl-3-(p-hydroxyphenyl)benzofuran (20). 2-Pheny1-3-(p-methoxyphenyl)-Btosyloxybenzofuran (17), prepared from 16, was recovered unchanged after treatment with H, and Raney Xi. This difficulty in hydrogenolysis of 17 is inexplicable particularly since 2,3-bis(p-methoxyphenyl)-6-tosyloxybenzofuran (14) could be smoothly hydrogenolyzed under the .ame conditions to give the corresponding 2,3-bis(p-methoxyphenyl)benzofurari (15). Compound 19 could, however, be prepared by the hydrogenolysis of 2-pheny1-3-(p-methoxyphenyl)6-(1-phenyl-5-tetrazo1y1)benzofuran(18) by the method of Musliner and Gates.4 I t was also obtained in reasonable yield by the condensation of phenol and 4methoxybenzoin using boric acid5 as the condensing agent in place of HC1 used earlier. 1,2-Diphenylnaphtho[2,l-b]furans (11)were prepared by the condensation of the appropriate 2-naphthols with 4-benzyloxybenzoi~iusing the condition of Brown, et aL3 1-Saphthol when condensed with 4-benzyloxybenzoin in presence of boric acid gave 111. Condensation of resorcinol and 2,6-dihydroxynaphthalene with 4benzyloxybenzoin gave the corresponding difurans V and VI,respectively. In the condensation of 3,4-polymethylenephenols with alkoxybenzoins, 3,6-polymethylenebenzofurans (“linear”) and the sterically less favored 4,5-polymethylenebenzofurans (“angular”) could be formed. With 3,4-tetramethylenephenoland 4-benzyloxybenzoin the “linear” benzofuran 48 was exclusively formed, since dehydrogenation with DDQ of 2-phenyl3-(p-@- pyrrolidinoethox yphenyl) tetramethylenebenzofuran (50) obtained from 48 gave a naphthofurari which was found to be different from the angular 1(p-~-pyrrolidinoethoxyphenyl)-2-phenylnaphtho [2,l-b1furan (26) prepared from 2-naphthol. 2,3-Bis(pmethoxyphenyl) - 3,6 - tetramethylenebenzofuran, on DDQ dehydrogenation, however, gave a mixture of the linear and the angular naphthofurans. The chemical shift of the two _\le0 groupq in the two naphthofurans was different. In the nmr spectrum of the angular naphthofuran, obtained directly from ’-naphthol, the signals for the two O C H , appeared at T 6.10 and 6.30, whereas in the linear form the signals for the two OCH, were at 7 6.13 and 6.23. The ratio of the angular form in the mixture, as deduced from the nmr spectrum, appeared to be ca. 20%. The thiophenol39 was prepared from the corresponding phenol 22 by condensation with dimethylthiocarbamoyl chloride followed by thermal rearrangement and hydrolybis according to the method of Sewman.6 The various hydroxyl and mercapto compounds were converted into the corresponding p-t-aminoalkoxy derivatives by condensation with p-t-aminoalkyl halides in acetone in presence of potassium carbonate. (3) R . R. B r o n n . G. t Somerfield and P. D. J \Veit7rnan. J . Chem. Soc , 4305 (1958). (4) \V. J 3Iusliner and J. I\-. Gates, .Jr , J . i m e r . Chem. SOC. 88, 42T1 (1966).
( 5 ) B. Ar\entiev. H Wexler, a n d .\I. Strul, A c a d Rep Populare Rorntne, Fzlzala I a s t , Studzz Cerectarz Stzznt , Chzm., 11, 63 (1960), Chem. Abstr 66, 15433 (1961) (6) AI. S h e n i n a n , J . 0 7 g Chern , 31, JYSO (1966).
Experimental Section The compounds were routinely checked by ir spectroscopy; tlc was carried out on silica gel G plat’esaiid the compomids were detected under a uv lamp or by exposure to iodine vapors; the melting points were determined iii an H,SO, bath by the capillary tube method.
Hydroxydiphenylbenzo-, naphtho-, and polymethylenebenzofurans were synthesized by the general method of Brown, et The preparations described below illustrate a few of the experimental modifications of the general reaction conditions t o suit individual cases. The intermediate hydroxy compounds were purified either by chromatography on silica gel or by coiiversion to acetates followed by sapoiiificatiou. The compounds thus synthesized are reported ill Table I. l-(p-Hydroxyphenyl)-2-phenylnaphtho[2,1-b] furan (22). (a) 2-Xaphthol (4.38 g, 0.03 mole) aiid p-benzyloxybenzoin (9.54 g, 0.03 mole) iii peroxide-free dioxane (140 ml) were heated ~ i n d e rreflux wit,h concentrated HC1 (43 ml) for 24 hr. -411additional amount of HC1 (43 ml) was added aiid refluxing coiitiiiued for 48 hr. The reaction mixtlire was diluted ( 1 1 ~ 0and ) extracted (Et,O). The EtrO was washed ( 2 S NaOH,’ H,O), then dried aZ.3
( S a 2 S 0 4 ) and concentrated to give an oily product. It was purified by passing through a column of silica gel using benzenehexane (1: 1)as eluent’; yield 4.6 g (42Yc). (b) Compound 23 (4.80 g ) was refluxed in 2 X aqueous-methanolic NaOH (100 ml) for 2 hr. After the removal of solvent, the residue was acidified and extracted ( E h O ) . The Et20 extract was washed (HzO) to neutral and dried and the solvent was removed; yield 4.5 g (87%). 1 i~-Aeetoxvohenvl)-2-~henv~na~htho [2,1 -blI furan 123).-The . - . . oily [esidue obtained in a above (7.5 g ) x-as dissolved i;i dry pyridine (30 ml), ALc,O (12 ml) was added, and the solrition was allowed to stand for 16 hr. The reaction mixture \vas poured over ice and HCI. The oil which separated was t,aken up in Et,rO, washed (55; SasCOa soliit)ion, HrO), dried (Sa2Y04),and concentrated, and the residue was crystallized from SleOH; yield 4.8 g (8TyO7,). l-(p-Benzyloxyphenyl)-2-phenylnaphtho[2,1-b]furan(24).2-Saphthol (4.38 g, 0.03 mole) and p-beiizyloxybenzoin (9.54 g, 0.03 mole) \?-ere refluxed in peroxide-free dioxane (140 ml) aiid coriceritrated HC1 (43 ml) for 24 hr. The reaction mixtiire wab worked up in the Iisiial mariner and the residue was crystallized from Et,OH; yield 2.6 g ( 2 O r ; ) . The mothel, liqiior n-heii roiiceiitrated and crystallized from beiizeiie-hesane gave 22; yield 2.1 g (42%). The mixture of 22 aiid 24 obtaiiied above could also be separated by chromatography over a column of silica gel 180 mesh). Elution with benzene-hexane (1 : 3 ) gave 24. Further elutioii with benzene-hexane (1: 1)furiiished 22. 1-[p-(6-Diethylaminoethoxy)phenyl] -2-phenylnaphtho[2,1-b] furan (25).-The method described below for t.he preparatioii of 25 is representative of the general method followed for the alkylation of h3.droxydiphenSlberizo-, naphtho-, and polymethyleiiebenzofurans with w-t-aminoalkyl halide>. l-(p-Hydroxy~hei1yl)-2-phenyliiaphtho[2,1-b]fura1i(22) (0.XSti g, 0.001 mole) was heated under reflux in anhydroiis A4c31e17.5 ml) with anhydrous K2COs (1.3 g ) aiid EtJ(CH2),Cl.HC1 (0.264 g, 0.0012 mole) for 12 hr. K2COswas removed by filtration, the filtrate was coiiceiitrated uiider reduced pressm’e, and H20 was added. The oil which separated was takeii up iii E t d l , and the ether layer was washed with wat,er t o neutral, dried (Na2S04)and concentrated. The re-idlie was coiiverted to its hydrochloride in E t 2 0 . Crystallizntioti fmm Et,,0H-Et20 gave 25; yield 0.43 g (88%). 2,3-Bis(p-methoxyphenyl)-6-tosyloxybenzofuran114).-pTolueiiesulfoiiyl chloride (0.382 g. 0.02 mole) iv:~.. added to 2,:3~ ~ i s i p - m e t h o x y p h e i i y l ) - 6 - h ~ d r o x y l ~ e 1 i z(ot)i:iiiied ~ ~ ~ 1 1 r ~ 1 by i the condeiisatioii of resorcinol with aiiisoiii) (0.69 g, 0.0’2 mole) dis-
-
I
-
( 7 ) These compounds vere insoluble in aqueous alkali presumably hecause t h e 3-p-OH group, being in conjugation v i t l i the furan ring oxygen acvtn, is rendered less acidic as shown.
Sa.
S or
s
.i
I
l'h
19 11 20 l f 21 11
11 I1
11
(1,
OCIIJ
c:,
11, N
L!
It
11
c, 1 1
II
C', 11, s
L!
11
c, I1 C, H, S
>4
II
c:, I1 cy, 11, N
I
11
c, I1
11 11
II
c:,
11
ASTIFERTILITYAGEXTS. IV
January 1970
57
TABLE I (Continued)
No.
R'
R
X'
S or x
Solvent, Yield, of1 Alp or bp crystna ( m m ) , 'C
%:1
€I
79
Viscous oil
37 IT S 8 I1 39 I1
I1 1%
OCSX(CHJ)~
H
SCON (CH3)2
H
SH
I1 H
80 I> $10 c, (35 B
182 133 213
40
1%
sc n CH.N(J
€I
65
c
239
1%
MEDia Formula
Analyses
mg/kg
R
xX&
IZ' 111
41 I1 42 I%
11 H
I1 H
1.iA 83 I3
154 163
43 H
H
H
70 C
208
33 B 79 A
184 I35
81 72 31 82
207 134 146 109 228-229
IV 44 45
1 1
46 47 48 49 50
1 1 2 2 2
II H
H OCHI
H H H
51 3 52 3
R
C
A B A 89 C
xR H
33
B
138
H
87
c
251
R'
R
V OH
53 54 53
OCOCH3 OCH~CH~N(C~IL)Z
H H H
91 B 10 A 90 C
249 230 266
29 E 93 F
280 223
VI
H H
36 37 5
Reportedla in an earlier communicaA, EtOH; B, CsHG-C6H,,:C, EtOH-EtzO; D, C6Hs-EtOIl; E, MeAc; F, CH~ClZ-lleOH. c Lit.3 mp 91-92". d Lit.3 mp 136-137. 6 mp 148-149, yield 2.45;. Lit.3 mp 116-117'.
tioll.
January 1970
AXTIFERTILITY AGENTS. IV
39
TABLE 111 ANTIIKFLAMMATORY A c m w Y OF 8
Drug
IYater 8
a
Dose, mdkg
100 1-58 275 12
Prediiiaolone Indomethacirie a S u m b e r of rats used is ill parentheses.
-
Carrageenin-induced -hygroma in ratshlean wt of Yo reduction from control hygroma, g
1.410(5)5 0.979(5) 0.878(5) 0.842(5) 0.935(10)
of 10 mg/l\-g. This regime did induce implantations even though the number was less than that in the controls. These results sugge.t that the antifertility activity of this compound may in part be due to inhibition of deciduoma formation by virtue of its antiprogestational activity; tubal transport, fertilization, and development and viability of ova were unaffected. Subacute Toxicity Studies.-In subacute toxicity studies 26 when administered to rats at 50 and 25 mg/kg caused death in most of the animals after 15 and 21 days, respectively, of administration. KO apparent cause of death could be found. Structure-Activity Relationship.-Quite early in this n ork, it was found that 2-phenyl-3- [p-(p-pyrrolidinoethoxy)phenyl]-6-methoxybenzofuran (2) had antiimplantation activity and prevented pregnancy in rats at a dose of 4 m g k g . Further efforts in molecular modification were, therefore, directed toward finding out the contribution of each part of the molecule in determining its biological activity. The two main modifications carried out were in the 3-phenyl ring and the benzene part of the heterocyclic residue. Removal of the 6-1Ie0 (21) decreased the activity to one-fifth and the introduction of an additional Ale0 at position 5 (6) resulted in a fall of activity to onetwentieth. The 5,B-dimethyl analog (7) was completely devoid of activity. Surprisingly, when these two :\le in 7 were made a part of a homocyclic ring system, 1;he resulting 5,B-polymethylene compounds possessed fignificant activity. among the polymethylenebenzofuran\, the tetramethylene compound 50 was active a t 2 mg/kg. The corresponding tri- and pentamethylene compounds (46 and 52, respectively) were much less active, being 80 and 1007, effective at 10 mg/kg and were much more toxic, their TADio, being between 13 and 20 mg/ kg. The significant diff ererice in the antifertility activity of naphtho [2,1-b]furans (26, 1IEDloo 2 mg) and naphtho [1,2-b]furans (43, AIEDloo 20 mg) would point to the fact that increase in planar area of the heterocyclic rc4due p e r se does iiot increase the activity and it specific orientation of the molecules seems to be of importance. Compound 33 carrying the basic side
30 6 37.6 40.3 47.9
Carrageenin-induced rat paw edema Mean paw 7"reduction vol, mi from control
0.82(5) 0.28(5) 0.26(5)
65.9 68.3
0.50(5)
39.1
chain in the naphthalene residue a t position 8 was active a t 4 mg/kg. When the same change mas made in benzofurans the resulting 13, surprisingly, did not show any activity. I n the naphthofuran series, 3p-hydroxyphenyl and 3-p-acetoxyphenyl compounds (22, 23) did not have any antifertility activity, thus showing the presence of a t-aminoalkyl residue to be necessary for antifertility activity. I n general, compounds carrying a p-pyrrolidinoethoxy chain (2 and 26) were more active than the corresponding P-dimethylaminoethoxy compounds (1 and 25). Compounds 3 and 4, however, had the same magnitude of activity. Lengthening of P-t-aminoethoxy chain to y-t-aminopropoxy residue (3,4) or the replacement of P-pyrrolidinoethoxyl residue (22) by P-pyrrolidinoethylmercapto residue (40) appreciable decreased the activity. The compounds carrying side chains a t both 2- and 3-phenyl rings of the benzofurans (10) did not show any activity. Benzodifuran (55) and naphthodifuran (57) also did not have any activity. Antiinflammatory Activity.-In view of the recently reported antiinflammatory activity of some 2,3-diphenylindole and 2,3-diphenylben~ofurans~~ some of the benzofurans now synthesized ( 5 , 8 , 11,27, and 47) were also tested for their antiinflammatory activity. Only 2,3-bis(p-methoxyphenyl)-5,6-dimethylbenzofuran(8) shon-ed significant antiinflammatory activity. It proved to be a relatively potent antiinflammatory agent against carrageenin-induced hygroma and carrageenininduced rat paw edema, when administered intragastrically. Its efficacy in comparison to predisolone and indomethacine is recorded in Table 111. Acknowledgment.-We express our gratitude to the Ford Foundation and the U n i s t r y of Health, Family Planning and Urban Development, Government of India, S e w Delhi, for financial support of this investigation, to Drs. S. I
