Benzo[b]thiophene derivatives. XVI. Sulfur isosteres of melatonin

Apr 25, 1970 - 6. 1205. Benzo[b]thiophene Derivatives. XYI. The Sulfur Isosteres of Melatonin,. Bufotenine, 5-Hydroxy tryptophan, and Related Structur...
0 downloads 0 Views 485KB Size
Benzo[b]thiophene Derivatives. XVI. The Sulfur Isosteres of Melatonin, Bufotenine, 5-Hydroxytryptophan, and Related Structures'a"'

The isosteric relationship which exists bet,weeii indole and beriao[b]thiophene has created coilbiderable iiilerest ill the syntheses and pharmacological properties of beiizo [ b ]thiophene analogs of biologically active iiidole derivativer.2-6 I n corinectiori with this interest n e recently reported on t,he synthesis and pharmacology of the S aiialog of serotonin (SAS).i.8 We now report, 011 the syiitheses of the berizo[b] thiophene analogs of 5-hydroxytryptophan (IV), melatonin (VId), bufotenine (VIIIa), and some closely related derivatives, with preliminary pharmacological results.

The key intermediate required for the preparation of IV was .i-berizo~loxy-3-bromomethylbenzo [blthiophene (I) described in a previous paper.* Condensation of I with diethyl formamidomaloiiate gave the crude ester I I a in quantitative yield9 according to a modified procedure of Avakian. The triester was hydrol? zed arid decarboxylatedll to produce the desired amino acid isostere IV in 39% overall yield from I. -4fter converting I into 5-hydroxy-3-cyanomethylbenzo [blthiophene (Va),bwe encountered some difficulty in preparing T7b. Seither NaOH in Ne2S0, nor CHlN2arid BF,.Et?O in Et20 would afford methylation of the phenolic OH. This was overcome. however, by preparing the solid S a salt of Va and then refluxing it in DAIF containing AIeI. T'b was reduced to VIb, the methoxy S analog of serotonin, and acetylated t o T I d , the S analog of melatonin. I n a similar fashion Va was convert

I flrlerucjcl O i r i n 2 , 211

(IYIijl

I n I'IIIa aiid YIIlb the cliemicd shift difference rrlutive t o t h e J value \vas large enough so that with tlir aid of a 220-MHz instrument me could obtain J arid 6 values. Biological Evaluation.--Tt+ ertty rats J\ ere pretreated uith iproniazid (50 rng kg base, po). T n e r i t j -1 n o hours later, .i rat nt'rv givrn 5-HTI' (33 my Ag. i p ) , 1 rat recc4vtd 110 mg kg, ip. These r a t h 4i(1nc d niarlit~dt r m ~ o r h:irid piloerectioii nithi11 15 mi11 'rli(,

Journal of Medicinal Chcmistry, 1870, Vol. 14, S o . 6

sympathomimetic response progressed to clonic convulsions and death. This procedure was repeated using the S analog. There were no sympathomimetic effects evident at 30 min, a t which time 2 rats were given -AI mg/kg of 5-HTP. There was no protection. One hr after the 110-mg/kg 5-HTP dose, the rat was challenged with 55 mg/kg of 5-HTP. There was no protection. The results, based on the fact that 5-HTP is converted in vivo into serotonin whose oxidation is then inhibited by an JIAO inhibitor, indicate that the S analog neither mimicked nor blocked the effects of 5H T P . 2 L Since it has been shown previously that the lethal effects of VI, SAS, are greatly potentiated by pretreatment of mice with an N A O inhibitor' it seems probable that IV is not decarboxylated in vivo. Further C S S tests (anti-Tremorine and antinicotine in mice) with IV yielded negative results although 5HTP was also inactive in these tests.2z Preliminary testing has been completed on VIIIa, J'IIIb, VIIIc, and VIb. Three mice each were injected ip a t different dose levels and their behavior was observed as presented in Table II.?' While it took

Pltl.l.lMlN \ H Y

.j-OXYGI;N .IT I,:D

C'oinpd

T.\BLI:I1 BloLoGlC.\L I>.\T.\

FOR

6oMlr:

3-p-Anll~oeTHY LB KNZO Ib]T H l O P H I,;N I1s

LIIV (mice, ip, ----Dose free Iiase. inp:kg) 25 50

level [mmoles/kg (free hase) I--100 200 400

C, 1)(3/3) C, 1)(3/3) 123 s 3s c, L)(3/3) C, 1>(3!3) ss, t 5 c, U(3;3)b c, D ( 1 I l ) ( + ) Slight hyperactivity; ( + + ) definite hyperactivity; ( d ) slight depression: (dd) definite depression; (s) slight sedation; (ss) definite sedation; ( t ) tremors; ( C ) convulsions; ( I ) ) death, parentheses give number in trial that died: ( - ) no apparent effect. Dose level was 300 mmoles 'kg (free base).

VIIIa VIIIb VIb VIIIC

155

15%

+I'

+

d

dd

++ ++, C

C, U ( 2 i 3 ) C, 1)(2/3)

about 30 miri a t the 3 lowest dose levels for VIIIa to show activity and 15 min for the deaths to occur, the activity of VIIIb mas apparent very fast a t low dose levels and the deaths occurred within 1 min of injection. These findings are in accord with those of Gessner and l'ageZ4 mho showed that methoxybufotenine acted faster and more effectively than bufotenine in a C S S test designed t o measure the conditioned avoidance response of trained rats. Screening of these indole isostere~ is continuing. The melatonin analog, VId, had no specific antifertility effect on the male rat in a preliminary screen.?Z The compound was implanted subcutaneously in male rats in a silastic tubule which permitted sustained release. Animals were castrated unilaterally at meekly intervals t o determine effect on testicular function and histological damage to semeniferous tubules. Some loss of weight in the testes and signs of exfoliation were observed. -4fter S weeks, the remaining animals were (21) V. Shetty. Strasenbnrgh Laboratories. Rochester, S . I . 14623, personal communication. (22) S. J. Corne, The Nicholas Research Institute, Slough, Bucks, England, personal communication. (23) R . P. Maickel, Department of Pharmacology, Indiana University, Illoomin@on. Ind. 47401, personal communication. (24) P. Gessnerand I. Page, Amer. J . Physiol., 203, 167 (1962). (25) Lye are indebted t o Dr. l i . .i, Laurence, .issociate Director, EioMedical Division. The Population Council, Rockefeller Cniversity, N.Y., for the description and results of this test.

1207

mated without difficulty, indicating no specific effect on Leydig cells nor specific interference with sperm physiology. All female mates delivered normal sized litters of healthy pups.

Experimental Section2G Ethyl 5-Benzoyloxy-3-benzo [b]thienylformamidomalonate (Ha).-To a solution of 0.45 g (19.6 mmoles) of S a iii 100 ml of abs EtOH was added 3.75 g (18.5 mmoles) of diethyl formamidomalonate (Aldrich Chemical Co.) followed 5 mill later by 6.45 g (18.5 mmoles) of I. The light yellow soliit.ion was allowed to reflux for 3 hr whereupon it wm diluted with 500 ml of an iceH20 mixture and extracted with four 100-ml portions of EtsO. The EtoO was dried (Sa2604) and evaporated to yield 8.65 g (lOOVo)of a yellow oily solid which could be used directly t o make the desired amino acid IV. An analytical sample prepared by recrystallization (abs EtOH) gave white needles, mp 140-141". Anal. (C24H&07S) C, H. p-(5-Hydroxy-3-benzo[b] thieny1)-u-aminopropionicAcid (IV ). -A suspension of 11.7 g (25 mmoles) of crude I I a i n 75 ml of loc/; S a O H was allowed to reflux for 5 hr after which time most of the formamidomalonate had dissolved. The hot yellow solution was filtered and 16 ml of concd HC1 was added. A small amount of oil floated to the top of the solution and COYwas immediately given off. The mixtiire was allowed to refliix for ariot'her hour and was then decanted from the dark oil which stuck to the side of the refluxing flask. The solution, which now had a pH of 1-2, was cooled and the yellowish needle-like ppt that formed was collected and dried. Its ir(KBr) was identical with that of an authentic sample of BzOH (2.35 g, 85%). The light yellow filtrate was now made to pH 5-6 ( K H 4 0 H )and coricd to O..i it, initial vol on a hot plate. Cooling afforded a white ppt, 4.1 g (39y0). Recrystallization (hot H2O) gave a white powder which darkened at 250" aiid melted a t 268-270" dec. Anal. (CIIHIIKO&) C, H, N, S. 5-Methoxv-3-cvanomethvlbenzoibl thioohene(Vb).-Va (11 mmoles, 2.08 g ) was dissolved iri 120 -ml df 0.1 11- IL'aOH and the sohition was evapd to obtain the solid ?;a salt of Va. This material was then dissolved in 20 ml of I ) l I F containing 100 mmoles of Me1 and refluxed for 3 hr. The resulting light yellow solution was diluted with 100 ml of a salt-HlO-ice mixture and extracted with foiir 100-ml portions of Et&. The Eta0 was dried (NaaSO4) and evapd to give a yellow oil which solidified upon further pumping (0.3 mm, 4 hr). Itecrystallization from EtOAc-petroleum ether (40-60") gave white needles, 1.90 g (8.5%), mp 102-104". The analytical material had mp 10.i106". .Linal. (CiiHgNOS) C, H . 5-Methoxy-3-(p-aminoethyl)benzo[b] thiophene HCI (VIb).To L.4H (0.228 g, 6 mmoles) in 40 ml of dry Et20 was added quickly 0.80 g (6 mmoles) of AlClr in 65 ml of dry EtaO. Five minutes after the last addition of AlCl,, 2 mmoles of Vb in 65 ml of dry Et20 was added slowly to the stirred mixture. Ten miiiU t e s after the last addition of nitrile the excess reducing agent was decompd carefully with H 2 0 and then the mixture was poured into 100 ml of HC1 (pH 5). The Eta0 layer was sepd and the aq phase was extracted with fresh EtvO at p H 6, X, 10, and 14. The combined Et20 fractions were dried (?;a2S04) aiid dry HC1 gas was bubbled into the clear solut,ion. Fine white needles pptd (0.29 g, 60%), mp 206-207" from MeOH-EtOAc. -4nal. (CIIHl4C ~ N O SC, ) H, ci, s. 5-Methox~-3-(B-acetaminoethvl~benzolblthio~hene (V1dj.A solution of 0.486.g (2 mmoler) ofVIb in 7'ml of H20was shakeii with 6 mmoles of Ac20, then 6 mmoles of SaOAc in 2 ml of HYO was added. The mixture, from which an oil sepd, was theii dililted with Ha(), extracted with EtvO, dried (lIgSO4), aiid the Et20 evapd. The residue was recrystd (ETOAc-petroleum ether) to give white needles, 400 mg, SO(;;, mp 99-100'. .Linal. (CISHI;KO~H) C, H, N , S. 5-Hydroxy-3-(@-acetaminoethyl)benzo [b]thiophene (VIc).This material was prepared similarly to VId. The fine white needles were recrystd from hIeOH-CCL, yield 55Tc, mp 165166". .anal. (C12HiSNOvS) C, H, Tu', S. (26) Melting points were measured on a Mel-Temp capillary melting point apparatus and are corrected. Ir spectra \\ere determined with a Perkin-Elmer Model 137 Infracord and were as expected. The microanalyses were performed hy Midwest Jlicrolabs, Inc., Indianapolis, Ind. Where analyses are indicated only by symhols of the elements, analytical results obtained for these elements were within z t O , 4 % of the theoretical values.