Catechol amines. I. Sulfur analogs of norepinephrine - ACS Publications

Studies of Catecholamines. I. Sulfur Analogs of Norepinephrine. ScHNEUR R.ACHLIN AND .11,NS ExEMARK ía o Pharmaceutical Products, Balltrup, Denmark...
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1os9

Soveinber 1969

KOTES

junction was conducted by Rice and coworkers.2 Several of the p-fluoroaroylalkylazaspirane derivatives were found to possess C S S depressant, hypotensive, and antiinflammatory activity and were also found to be clinically effective tranquilizers a t doses of 5-10 mg.2f X- [y- ( p - 1~luorobcnzoyl)propyl] - 3 -azaspiro [5.5Iundecane posse5~edmarked antipqychotic effect a t low doqage, and its behavioral and toxicity effect> mere similar to those of haloperidol.?' 3 , 4 I n continuation of our previous n ork,dit was decided to iynthesize a similar type of compounds having 3-azaspiro [5.5]undecane as a baqic fragment. Accordingly, the compounds of the general formula I were synthesized and studied for their C S S activity.

trimethoxyacetophenonell were prepared by the literature -pChloro-3,4,5-trimethoxybutyrophenone was obmethods. tained as described earlier.6 N- (3,4,5-Trimethoxybenzoyl)-3-azaspiro [5.5]undecane (1).To a solution of 3.06 g (0.02 mole) of 3-azaspiro[5.5]undecane and 4.0 g (0.04 mole) of EtJ i n 25 ml of anhydrous CHCls, was added slowly a solution of 4.6 g (0.02 mole) of 3,4,5-trirnethoxybenzoyl chloride in 25 in1 of ~ l i h y d ~ l J l CIICl,. lS The reaction mixture viarefluxed for -1 hr aiid then cooled, washed (IIYO), dried (Sa2S04). and coiiceiitrated. Traces of CHCla aiid Et3S were removed in vacuo. The residue solidified when treated with hexane. The solid was then crystallized first from boiling hexane and theii from EtOH, mp 122-123'. Anal. (C20H,9XO4)C, H, K. N-(3,4,5-TrimethoxyphenacyI)-3-azaspiro[~.5]undecaneHydrochloride (2).-.4 solution of 3.18 g (0.011 mole) of a-bromo3,-1,5-trimethoxyacetophenone in 30 ml of EtOH wah added sloidy to a aolrition of 1.53 g (0.01 mole) of 3-azabpiro[5.5]iiiidecane and 2.0 g (0.02 mole) of Et& in 30 ml of EtOH. The mixture \vas refluxed for 6 hr and theii concentrated. H2O was added and the residue was extracted with CHCh. The extracts were dried (Sa2S04)and conceiit,rated in vucz~o. The resalting oil was taken iip i n anhydrous E t 2 0 and added to 5 ml of 2propanolic HC1 ( 2 2 % ) . This on dilution with ether gavea white solid which was filtered and recrystallized (EtOH), mp 236-258" dec. .lna/. (CL1H~,XO4.HCl) C. H. S . N- [ p- (3,4,5-T~methoxybenzoyl)ethyl] -3-azaspiro [5.5]undecane Hydrochloride (3).--To R solution of 3.8 g (0.02 mole) of 3-azaapiro [ 5 . 5 ]rrndecane hydrochloride iii 60 ml of EtOH, lvere added 3 ml (-0.03 mole) of aqueous HCHO (37-415) and a solution of 4.G2 g (0.022 inole) of 3,4,5-trimethoxyacetophenone in 30 ml of EtOH. The reaction mixture was refluxed for 7 hr. Additional aqueous C H y O (3 ml) was added and reflux continued further for 7 hr. I t was then concentrated to otie-fourth of its volume and allowed t o cool, when a white solid separated out which was filtered arid crystallized from EtOAc-i-PrOH and then from I-PrOH, mp 210-212" dec. -4nal. (CrlH3&0,.HC1) C, H, N. N- (3,4,5-Trimethoxybenzoyl )propyl] -3-azaspiro [5.5]undecane Hydrochloride (4).--A mixture of 2.73 g (0.01 mole) of y-chloro-3,4,5-trimethoxybutyrophenoiieand 3.06 g (0.02 mole) of 3-azaupiro[5.5]undecane was gently warmed so as to form a homogeneous mixtiire and left overiiight at room temperature. The next, day, it was heated a t 100" for 4 hr. After cooling, water was added to it and ext.racted twice with 40 ml of CHCL. The extracts were dried (Na2S04) and concentrat,ed in vucuo. The residual oil was taken up in anhydrous Et20and added t,o5 ml of isopropanolic HC1 (22%). The resultant white solid was filtered and recrystallized (EtOH), mp 172-174" dec. Anal. (CZaHs5NOI.HCl) S.

OCHj

I

OCH,

I, h

=

CO, COCH2, COCHJCH,, COCHZCHzCH?

Chemistry.--S-(3,4,5-TrimethoxybenzoJ-l)-3-azaspiro[5.5]undecane (I, A = CO), S-(3,4,5-trimethoxyphenacyl)-3-azaspiro [5.5]undecane (I, A = COCH2), and S-[ y-(3,4,5-trimet hoxybenzoyl)propyl]-3-azaspiro[5.5]undecane (I, -1 = COCH2CH2CH2)were synthesized by the condensation of 3-azaspiro [5.5]undecane with 3,4,5-trimethoxybenzoyl chloride, a-bromo-3,4,5trimethoxyacetophenone, and y-chloro-3,4,5-trimethoxybutyrophenone, respectively. N- [9-(3,4,5-Trimethoxybenzoyl)ethyl]-3-azaspiro[5.5Iundecane (I, B = COCHJCHJ resulted from the llannich reaction on 3,4,5-trimethoxyacetophenorie and 3-azaspiro [5.5]undecane hydrochloride. All these compounds were tested for CKS activity in mice. The study of gross behavior and spontaneous motor activity revealed that none of the compounds in this series possessed any significant C S S depressant activity .

[A-

Acknowledgment.-The authors wish to thank lh. 11. K. Jaokar for microanalyses and Dr. U. I