analgetics. ii. relation between structure and activity of some β-amino ketones - j. med. chem.,...

8/4/2019 Analgetics. II. Relation between structure and activity of some β-amino ketones - J. Med. Chem., 1969, 12 (6), pp …

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K Of 1

I. R = H,C(;H->.C,,HjC'HI.i -C;H,,

Rl=H.OCH,

R = H, a l k y l . a lk e i iy l o r acyl

1V. K = H O('H o r OH

K a n d R- =H r ('H

K = a l k y l a m t n o 01 d ia lk y l , imin o

L' R = ( ' H H I1-C H'l'lic 1.2,.4.l-tc~trdi?ti~o-i-cliiiiioliiiol~ 'l'ublc 1 ) I\ (' I

prepared f rom the c o r r e q m i d i n g hetone by S:iBI-I IT-

duction (method A) or 1)) the addi t ion of :iGrigrinrtlreagent (method B). While we were unable to c.terif>the ter t iary alcoholh, ti \ CJ of th e hecoridary alcoholh were

fully b y C'H2C0 t o t he corresporidiiig-diliydro-4-cjuiiiolo~iehaving :L p>r-

rolidinoprop~ group I I I the :<positiori \\ ah prepared b ja luminum r*opropoxide ouidatiori of the previouhl!reported 3- 13-(l--p\wlidinoprop> 1) ]-12,8,4trt a h j -< 1ru-4-c [ulnollrlol.



995

ix0

1

>

3't

I

c,

7

\

!I

IO

I 1

12

1

14

1.iI6

17

H I R?

€I H

H

H

7-OCH3S-OCHj

7-OCHj\-OCII {

7-OCH,

\-OCH,

H

7-OCHjH

H

HH

8-OCHj

.\Ietliod

A

A

A

A

A

A

A

A

A

xA

h

B

B

B

B

€3

RLHp (mm) or

rnp,' O C

13%137 (0 31,

78-7gb

llX-ll9b

197-198'

14d-150 (0.2)

67-6gd

ti.> 66'1

100-112 (0 01)

133-140 (0 05)

120-124 (0.01)

167-170 (0 2)165-170 (0.15)

150-155 (0.2)

165-167 (0.2),

83-84'

131-132<

1 e ld ,

70

7 2

69

69

6d

63

.iti0

7.i

,j

5 8

71

58

81

67

76

_ _<>.a

- -35

-Hydrobromide%-

M p , Goc Formula'

85-86J CgHl,Br?r'O

206-20% CliHe0Brh'O

All coniporinds were analyzed for C, H, N . b Recrystallized from CdTfi-Iigroiii. e Recrystallized from EtOH. d Recrystallizedfrom Et2O-ligroiii. e Recrystallized f ro m ligroin. f Recrystallized from MeOH-EhO. Recryst.allized from CHC13-Et20.

p-Aminopropiophenones mere prepared by treatingthe proper ly subs t i tu ted ace tophenone wi th CHZO a ndthe desired amines (Table 11). p-Phenyl-@-amino-propiophenones were synthesized by t he add it ion of th erequisi te i tmir ie to the corresponding chalcone (Table11).

Th e 1-alkyloctahydro-4-yuinolones were prepared bythe reaction of 1-acetylcyclohexene, formaldehyd e, andthe desired amine by a procedure similar to that re-por ted by Grabe arid L ~ t z . ~ince these amines ortheir sal ts in th e absence of CH,O fai led to add to thedouble b ond of 1-acetylcyclohexene, i t ' appears t ha t theexpected l lannich reaction occurred f irst , fol lowed bycyclization to give 1-alkyloctahydro-4-quinolones. -~\lethyloctahydro-4-quinolone as been previously char-acter ized by Smissman, e t ~ 1 . ~ 5ho, because of thepresence of Bowman bands in i ts infrared spectrum , hassuggested a trans structure. Similar band s are foundin the infrared spectra of 1-ethyl- and l-propylocta-hydro-4-yuinolone.

Biological Activity.-The com pou nds prepa red in thiss tudy were eva lua ted for ana lge t ic ac t iv i ty by theHaffner tai l pinch meth od6 on female Swiss white miceand were administered b y interper i toneal injectior i.

T h e 1,2,3,4-tetrahydro-4-quinolinols,he est 'ers, andth e 3-(S-pyrrolidinopropyl)-2,3-dihydroquinoline, e-spite their structural resemblance to the previously re-ported 2,3-dihydro-4-quinolones,ailed to show anal-getic activity. This lack of activity coupled with thelo w potency of the 2,3-dihydro-4-quinolones (EDjo

values over 200 mg/kg) prompted us to examine theopen-chain analogs of the biologically active 2,3-di-

(1) . A . Grahe and H. .I. L u t z , H elc . C h i m . A r t i t. 4 8 , 79 1 (1963).

( 5 ) E. E. Smisuxnan and 31. Steinman, .I . .\fed. C h e m . .9 , 455 (1966).

( 0 ) C . I3ianchi and J. E'rancescl~ini, r i t . J . Phurmumd., 9 , 280 ( l Y j . 4 )

hydro-4-quinolones . I t was hoped tha t such compoundsmight achieve a better f i t on the receptor s i te thanmould th e previously examined com pounds possessing ar igid r ing system. I n order to test this hypothesis, i twas decided to prepare a ser ies of subs t i tu ted p-aminopropiophenones (Table 11). These compounds

conta in the ke tone func t ion, the benzene r ing, and t heamino group which were also present in the active 1-methyl-2,3-dihydro-4-quinolones, but because of freerota t ion, the amino group can absume any number ofspatial relat ionships with respect to th e carbony l groupand the benzene r ing. Th e importance of these groupsto analgetic activity was at least par t ial ly establishedby evaluating the analgetic activity of a number ofcompounds analogous to l-methyl-S-methoxy-2,3-di-

hydro-4-quinolone or its biologically active analogs butlacking in each case one of t he gro ups which wereassumed to be necessary for analgetic activity. Fo rexample, 1-methy 1-&me hoxy- 1,2,3,4- etrahydroquino-l ir1ej7 a compound lacking the carbonyl group, was

devoid of activity. Th e importance of the amino groupand the 5ize of the subs t i tuent a t tached to i t wasrealized earlier when i t wab foun d th at alte ration s of th ealkyl group on the nitrogen drastically affected theactivity of the bubztituted 2,3-dihydro-4-quinolones.Furthermore, when the amino group was deleted fromotherwise similar ly consti tuted r ing systems, such as in5- and 6-methoxy-l- tetralones, no analgetic propert iescould be detected by our test ing procedure. Th e lackof analgetic activity in 1-methyl- , 1-ethyl- , and 1-propyloctahydro-4-quinolones,s found by us, indicatesthe im por tance of the a romat ic r ing.

The presence of analgetic activity (Table 11) in p-

( 7 ) 0. Fisher an d C . .I. i u l r n , B e r . , 19 , 1040 (1886).



KI



S o v e m b e r 1969 ASALGETIC~.1 997

time> with Et 20 . The combined Et& extracts were washed withH20 and dried (11gS04). After evaporation of t he solvent, theresidue was distilled to yield 10.6 g (72%) of a whit,e solid. Afterrecrystall ization from CsHG-ligroin (b p 67-75") it melted a t

Method B. Grignard Reaction.-1,2,3,4-Tetrahydro-4-q~iino-

linols with aii alkyl or aryl group in th e 4 position were preparedbj- the reaction of th e appropriately substituted 2,3-dihydro-i-quinoloiie3 with a Grignard reagent. The procedure employedfor the synthesis of l-merhgl-4-heiizyl-1,2,3,4-telrahydro-4-

cliiinoliiiol will serveas

an example.111a flask in which the ai r has beeii replaced wi th Kz a.: placedaiihydi,oiis Et90 (2 0 ml) and M g urnings (3.6 g, 0.15 g-atom).This suspension was stir red and a solution of benzyl chloride(19.0 g, 0.13 mole) in Et,O 110ml)was added dropwise. Wheiithe reaction ceased, the mixture was added slowly iuider S , t o

a wlutioii of l-methyl-%,3-dihydi,o-4-quinolone8.0 g, 0.0: mole)in anhydrous E t 2 0 (40 ml). After the reaction ceased, the ~o l u -t ion was heated under reflux for 4 hr and was then cooled to 0'

aiid decomposed hy the addition of H,O. The organic layerwas separated, washed with H,O, and dried (hIgsO4). The Et20was removed arid the residue distilled to yield 7.3 g (5SC4)of 1-1nethyl -4-benzyl - l, 2 ,~~,4- te t rahydro-4-q i1 inol ino lsee Table I) .

l-Methyl-4-acetoxy-l,2,3,4-tetrahydroquinoline ydrobro-mide.-A solution of l-methyl-l,2,3,4-tetrahydro-4-quinolinol

(1.5 g, 0.01 mole) i i i aiihydroiis E t?O (150 ml) was cooled in anice bath and a stream of CHGO was passed through the solutionfor 6 hr. The solvent was removed in C ~ C Z I O t 0" and t he residuewas chromatographed f r m alumina (Alcoa F-20). After elutionwith a 1: 3 mixture of CsHfi-%PrOH, 0.9 g ( 4 2%) of a n oil wasobtained. Anal. (C12HljS0,).

Afterrecrystal lization from CHC18-EtyO, it melted a t 119-120'.-4nal. (C12H,6BrN0,)C, H, 3 .

1 Methyl-8-methoxy-4-acetoxy-l,2,3,4-tetrahydroquinoline

Hydrobromide.-A solution of l-methyl-8-methoxy-1,2,3,4-tet-

rahydro-4-yriiiiolinol 12.0 g, 0.008 mole) in Et20 (100 ml) was

treated with CHyCO at 0" as dewribed in the last preparation.After removal of most of the EtrO, the re d u e was treated withanhydrous HBr to yield 2.0 g (6 3 2 ) of the desired salt. Aftertwo recrgstallizatioiis from 11eOH-E t20 , the white solid melteda t 106-107". .lnal. ~Cl; jH,&O~Br), H, S .

3- 3-N-Pyrrolidinopropyl)] 2,3-dihydro-4-quinolone.-To a

solkit ion of 3- [3-(S-pyrrolidiiiopropyl)]-1,2,3,4-tetrahydro-i-quiii-olino13 (4.5 g, 0.01i mole) i n 11e2C0 (200 m l) and dry CsH6

(300 ml) war added alriminiim isopropoxide (9.0 g, 0.044 mole).The resulting mixture wa9 heated under reflux fo r 40 hr. Solventsn-ere distilled off and t he residue was extracted several times withEt&. Th e Et20 extracts were washed with 5ycNaOH, thenwith H,O, aiid dried (Na2s04). After removal of t he Et 20 , the

allized from Et.&ligroin to give colorless

I-Methyloctahydro-4-quinolone.-A mixture of l-acetylcyclo-hexene (12.4 g, 0 .1 mole), lIeSH2,HC1 6 . i g, 0.1 mole), aiid

78-79'.

The hydrobromide was prepared in the usual manner.

), mp 102-103°. ;inal. iC16HpZXj20)C, H, N .

paraformaldehyde (5.0 g ) ill 50 ml of absolute EtOH was boiledunder reflux for 16 hr . Solvents were removed and t'he mixturewas treated with l0 yo HC1 (100 ml). Th e resulting solution \vas

extracted with Et20and the Et20 was discarded. The aqueouslayer was made alkaline with SaOH and was extracted withEt&. The Et20 extrac t was dried (Sa2SOa) and dist illed. Afraction boiling at 85-92' (0.5 mm) was collected. I t weighed9.2 g and posessed an ir spectrum identical with thatreported previously.:

I-Ethyloctahydr0-4-quinolone.-~i similar reaction of 1-

acetylcyclohexene(12.4

g, 0.1 mole), Et ?r;H?.HCl (8.2 g,0.1

mole), and paraformaldehyde (5.0g) n 50ml of absolute ethanol asdescribed above for 1-methyloctahydro-4-quinolone yielded upon

distillation ai l oil (11.2 g, 62Yc),bp 93-99' 10.5 mm). rl picrateof the oil n-as prepared in the usual manner, mp 182-184".

l-Propyloctahydro-4-quinolone.-When 1-acetylcyclohexene(412.4 g, 0.1 mole), PrSH2 (6.0 g, 0.1 mole), paraformaldehyde(5.0 g) , aiid 10 ml of HC1 were refluxed with 50 ml of absoluteEtOH follo\viiig the procedure employed for the synthesis o f

l-ineth?-loctahydrr,-4-qiiiiioloiie, 0.5 g (54%) of the prodiic'twas obtained. I t boiled at 102-110" (0.5 mm).

A picrate was prepared by the usual procedure. It melted a1

tallization from CsHs. alnal. (C18H2,S40,IC, H, S .

Synthesis of (3-Aminopropiophenones.-A mixture of t he ap-propriate aretophenone (0.1 mole) and the amine hydrochloride(0.15 mole) was heated iii EtO H (15 ml) at the reflux. Para-formaldehyde (3.6 g) was added aiid the resulting mixture washeated for i h r. Another portion of paraformaldehyde (1.5 g )was added and the heating vas continued for an additional 2 hr.A t thi+ time 1 ml of HC1 was added and the heating was continuedfor an additional 2 hr, after which the solvent was evaporatedand the i,esidiie was dissolved in 20 ml of HZO. This aqueoussolutioii w a s washed twice with an equal volume of Et20, ooled,made alkaline xith 50% SaOH soliition, and extracted withEt,( ). The Et2<) soliitioii was washed with water and dried(Sa2S04) .

0 1 1 paisiiig HC1 throiigh the filtered Et 20 yolution, th e hydro-chloride salt was precipitated and vas purified by rerrystalliza-t i o i i .

a+-Dimethyl-p-aminopropiophenoneswere prepared fromi~ob~ityropheiioi~es,le2XH.HC1, and paraformaldehyde by aprocedure identical vith that employed for the preparation ofthe P-amiiiol)ropiophenoiies.

Preparation of p-Aryl-p-aminopropiophenones.-'rhe appro-priate benzalacetophenone (0.06 mole) and the amine (0.08mole) were dissolved ii i 50 ml of anhydrous Et20 and heatedunder reflux for 10 hr. Toluene (20 ml) 11-as added and thesolverits were evaporated in vacuo. Additional portions of toluenewere added and removed by distillation in vacim until the distil-late gave a negative test for tmhe mine. The residue was theiidissolved i n dr y Et& and the hydrochloride precipitated in theiihiial maiiirer. The salt n-as purified by recrystallization.

A l n a l . CiiH?,N,O8) C, H, X.

analgetics. ii. relation between structure and activity of some β-amino ketones - j. med. chem.,...

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