1330 Journal ofMedieinal Chemistq, 1973, Vol. 16, No. 12
Or,?. ('hem.. 28, 178 (1963). (117) R. Schwyzer, R. Schiller, S. Seelig, and G. Sayers, FEBS I x t t , 19, 229 (1971). ( 3 X ) S. Seelig and G . Sayers, Arch. Biochem. B i o p h ~ s . .154, 230 (1973). (39) M . W. Draper, R. B. Merrifield, and M. A. Rizack, Fed. !'roc.., Fed. Amer S o c E x p . Bioi.. 32, 490 (1973). (40) R. B. Merrif'ield,Adcan. Enr?mol., 32, 221 (1969).
(41) cJ. Blake and C . H. Li, J. Amrr. Chem. Soc.. 90,5882 (1968). (42) G . R. Marshall in "Pharmacology of Hormonal Polypeptides
and Proteins." N . Back, L. Martini. and R. Paoletti, Ed.. Plenum Press, New York, N. Y.. 1968, p 48. (4:t)L. I). Markley and I,. C . Dorman, Tetrnhdron L e t t . . 1787 (19701. ( 4 4 ) S . Sakakibara, Y. Shimonishi, Y. Kishida, M. Okada, and H. Sugihara. Bull. Chem. S o c . J a p . . 40, 2164 (1967). ( 4 5 ) J. Lenard and A . B. Robinson. J Amer Chem. S o c . . 89, 181 (19671. (46) ?VI. Rodbell, J . Biol. Chem.. 239,375 (1964). (471 R. .I. Ho, Anal. Biochem., 36, 105 (1970).
M .S. Rahen, R. Landolt, F. A. Smith, K. Hofmann. and H. Yajima. .\'atwe ( L o n d o n ) ,189, 681 (1961). (49) E. ,I. Ariens and A . 11. Simonis. ,I Pharm. Pharmacal.. 16, 137 (19641. (501 .r R e ' . , I'ommun , 35, 175 (1969). (701 Y,P. Dole. .J. ( ' / i n ( f l r t s i . 3 5 , 150 (19561.
2-Aminoindans of Pharmacological Interest Everett Solomonst a n d Joseph S a m * l)c~p,nrtm~rit i~ Mf~ d i c i n a C'hemistr?, l The Cniuersity of .Mississippi. C'nicersit?, Mississippi 38677. ReceiL:ed M a > 14. 19i:1 2-Aminoindans in which the amine moiety consists of' various cyclic amine derivatives including morpholino. hexamethyleneimino (potential sympathomimetic agents). and 4-acyloxy-4-phenylpiperidinoderivatives (potential analgetic agents) were prepared and tested for antiinflammatory, analgetic. pharmacodynamic, and neuropharmacologic activity. S o marked antiinflammatory or blood pressure effects were noted. Compound lOj exhibits strong amphetamine type activity; 10h and 18c, respectively. possess analgetic activity approximately equal to and one-half'that of meperidine 2-Aminoindans have been noted t o possess interesting biological properties. For example, 2-aminoindan ( 1) exhibits significant bronchodilatingl a n d analgesic properties2 a n d 2-benzylaminoindan ( 2 ) possesses significant bronchodilating properties.] Both 1 a n d 2 may be considered cyclic analogs of a m p h e t a m i n e ( 3 ) .
1
2
various conformations. In view of the variation of biological activity with changes in conformation of drug molecules, it was of interest to synthesize a n d to study pharmacologically compounds such as 4 a n d 5 in which the conformational variations have been restrained. T h e in-
3
Because of ( a ) the limited information available on 1(2'-indanyl) cyclic amine derivatives, ( b ) the pronounced 4 6, R = phenethyl analgesic activity of 2-aminoindan, a n d ( c ) other signifi7,R=CH, cant biological activity3 of existing 2-aminoindans, a n u m b e r of 1-(2'-indanyl) cyclic amines 4 were investivestigation of 4 (R = CH3) was undertaken with the goal gated. Furthermore, 1-(2'-indanyl)-4-pheny1-4-piperidyl of producing derivatives in which rotation about t h e indan propionate (5) represents a conformationally restrained C-2 to nitrogen bond is restrained by steric interaction of relative of the corresponding analgesic 6. T h e former also t h e methyl group with t h e methylene hydrogens adjacent is a hybrid of 2-aminoindan a n d l-methyl-4-phenyl-4-pito t h e nitrogen. Further impetus for the synthesis of deperidyl propionate (71, both analgesics. I n compounds such as 6, t h e N-arylalkyl substituent is free to assume t Abstracted in part trom a dissertation submitted by E. S . to the Graduate School. L'niversity ot Mississippi. in partial fulfillment of Ph.D. degree requirements, 1970.
8
Journal of Medicinal Chemistry, 1973, Vol. 16, No. 12 1331
2-Arninoindans
Table I. 2-Aminoindenes 9 a n d Indans 10
9 -N
No.
9a 9b 9c 9d 9e 10a 10b 1oc 10d 10e 10f log 10h
Method
Morpholino 3-Azabicyclo [3.2.2 Inon-3-yl Hexamethyleneimino 4-H ydroxypiperidino 4-Hydroxy-4-phenylpiperidino Morpholino 3-Azabicyclo [3.2.2 Inon-3-yl Hexamethyleneimino 4-Hydroxypiperidino 4-Acetoxypiperidino 4-Hydroxy-4-pheny lpiperidino 4-Acetoxy-4-phenylpiperidino 4-Propionoxy-4-phenylpiperidino Piperidino P yrrolidino 4-Morpholinocarbonylpiperidino 4-Pyrrolidinocarbonylpiperidino 3-P yrrolidinocarbonylpiperidino 4-E thylenedioxypiperidino
1Oi lOj 10k 101 10m
10n
10
A A A A A B, C B B B E B, D E E
D D D D D D
Yield, %
M p , "C (recrystn solvent) a
100 93 75 97 95 57, 42 52 85 52 60 65, 36 55 50 55 56 65 44 25 35
Formulab
196-197 5 (C-E) 150-152 5 dec (C-E) 103 5-105 (C-E) 137-139 dec (C-E) 181-183 dec (C-E) 87 5-88 ( H ) 88 5-89 5 iH) 234-236 dec (A) 164-165 (MC-E) 92-93 ( H ) 155 5-157 (C-Et) 247 5-248 dec (A)e 236-236 5 dec (A)/ 60-61 (H-Et) 46-47 5 (sublimed) 164-165h 156-157 ICY-B) 247-249 (E-Et) 96 8-98l
aA = acetonitrile; B = benzene; C = chloroform; Cy = cyclohexane; E = ethanol; Et = ether; H = n-hexane; M C = methylene chloride. bInfrared and nmr spectra are consistent with the assigned structures; analyzed for C, H , and N. cReference 6. W : calcd, 81.87; found, 81.28. eBase, m p 175-177" ( C ) . 'Base, m p 130-131.5" ( E t ) . QC: calcd, 83.37; found, 83.96. H: calcd, 9.15; found, 8.65. hEluted through neutral alumina (grade I) using methylene chloride-ethanol 13:2, v v) as eluent. 'Eluted through neutral alumina (grade I) using n-hexane as eluent. rivatives of general structure 4 is gained from the report of White' a n d coworkers t h a t t h e structurally similar t e t r a lin derivative 8 possesses potent analgesic properties. T h e synthesis of the 2-aminoindans 10 a n d 18 was accomplished as shown in Schemes I a n d I1 by the catalytic reduction of the l-(2'-indenyl) cyclic amines 9 a n d 17 which were prepared by the condensation of the appropria t e cyclic amine with 2-indanones 12 a n d 165.6 in accordance with the procedure of Blomquist a n d Moriconi.6 Appropriate physical d a t a are presented in Table I. An alternate synthesis of 1-(2,-indanyl)morpholine (loa) was accomplished by t h e reaction of morpholine with 2-indanyl tosylate ( 1 3 ) 7 according to a procedure similar to t h a t used by Sekera a n d Marvel.8 T h e reduction of a mixture of 2-indanone (12) a n d various heterocyclic amines also was observed to proceed readily to give 10 in good yield. Attempts to prepare 10a from 2-morpholino-1-indanone ( 11) by catalytic hydrogenation a n d other reduction procedures$-11 were unsuccessful.
plished by methylation of indene to give 14, followed by hydroboration using a procedure utilized by Brown a n d Rao.12 T h e oxidation of the alcohol 15 using Jones reagent according to the procedure described by Djerassi a n d associatesl3 provided 1-methyl-2-indanone ( 16) along with o-acetylphenylacetic acid. Contrary to the observation reported by Blomquist a n d Moriconi,'j the 1-methyl-2-indanone obtained by this method appears t o be relatively stable. No decomposition was noted after 3 m o n t h s a t 0". Scheme I1 CH3
CHB
1
14
I
15
16
Scheme I
0
11
T
18 17 T h e stereochemistry of 1-(l'-methyl-2'-indanyl)-4-phenyl-4-piperidyl propionate (18c) was investigated cia the Cope reaction14 since the n m r spectrum was not sufficiently useful to permit delineation of the structure. Moreover, Huebner a n d associates15 have reported t h a t the use of n m r d a t a for stereochemical investigation of 1,2-disubstituted indans may not be unequivocal. T h e N-oxide 19 was prepared by the method of Cope a n d Ciganek.16 Pyrolysis was performed by injection of a n ether solution of the N-oxide into a gas chromatograph with the injection chamber a t 200". T h e respective methylindenes were confirmed by injection of authentic s a m ples. T h e composition of t h e mixture formed from 19 was found to be approximately 86% 1-methylindene (20) a n d
- e?!! i /
10
eo m
12
t o
T
s
13
T h e synthesis of 1-methyl-2-indanol (15) was accom-
I332 eJournal of Medicinal Chemistp, 1972, Vol. 16, No. 12
14% 3-methylindene (14). From t h e n a t u r e of t h e Cope reaction a n d consideration of molecular models of 19, this ratio of methylindenes indicates a predominance of the cis isomer of 1%.
C',H , OR I
1) s
I
18b.R = H 1&, R = COC-H
CH,,
PCm?H1
A 14
20
Biological R e s u l t s . All of the compounds in T a b l e I, with t h e exception of 9a-c a n d lOj, were tested for a n t i inflammatory activity using the E v a n s blue carrageenan pleural fusion modell: a n d found t o be inactive at a n oral dose of 316 mg/kg. Little or no activity against cathepsin D18 a t 1.00 m M concentration was observed for lOc, IOf, lOk, a n d IOm. Compounds l o b , lOc, lOe, lOk, lorn, a n d 17a, screened for pharmacodynamic effects in a c u t e anesthetized dogs a t iv doses of 1-8 mg/kg, caused a slight decrease in arterial pressure of short duration with t h e exception of 1Om which was of long duration. An increase in respiratory rate a n d m i n u t e volume was noted with lob, lOc, lOe, a n d 18a. T h e heart rate a n d intestinal tone a n d motility were decreased with 1Ok a n d 10m. S o m e evidence of adrenergic blockade was observed with 1Oe a n d 1Om. Compounds lOj, lOk, 10m, a n d 18a were screened ip (six mice per dose) for neuropharmacologic activity.Ig A strong a m p h e t a m i n e - t y p e activity was noted with lOj a t 30 m g / k g (1 d e a t h ) , 10 m g / k g (1 d e a t h ) . a n d 3 m g / k g (no deaths). A long duration of activity occurred a t 10 mg/kg. Mild C N S depression occurred with 10k a t 100 mg/kg (no deaths); 30 m g j k g produced no a p p a r e n t effects. Mild to moderate C N S stimulation was produced by 18a a t 100 mg/kg ( n o deaths); 30 m g / k g resulted in mild sedation. Compound 10m a t 100 m g / k g (4 d e a t h s ) produced mild clonic convulsions a n d loss of righting reflex; a t 30 m g / k g ( n o d e a t h s ) transient clonic convulsions a n d disorientation occurred. T h e method of Nilson2O as modified by Funderburk. et n / . , z l was used to determine ip analgetic activity of 1Oh 8.3 m g / k g ) . 1Og (inactive at 10 mg/kg a n d only slightly active a t 20 m g / k g ) , a n d 18c (ED50 15.0 m g j k g j . T h e LDso of 10h a n d 18c was observed to be 325 a n d 350 mg/kg, respectively. M a r k e d CNS depressant activity was noted with 18c at analgetic doses. Additional studies are necessary in order to delineate the relationship of stereochemistry in t h e a m p h e t a m i n e series to biological activity; however, t h e marked amphet a m i n e type activity of lOj suggests t h a t conformational rigidity in t h e a m p h e t a m i n e series may have a positive effect on activity. T h e conformational rigidity of lOh, on the other h a n d , h a s a n adverse effect on analgetic activity since 10h is a b o u t equal to, whereas 6 is approximately 23 times a s active as, meperidine.22 Placing further restrictions on t h e flexibility of the molecule as in 1 % causes a further reduction in analgetic activity. O n t h e basis of t h e limited d a t a available it appears t h a t conformational flexibility ot t h e :V-aralkyl group is i m p o r t a n t in analgetics related t o 6 . Studies are continuing in order to more clearly det'ine these conformational requirements.
E x p e r i m e n t a l Section: I-(2'-Indenyl) Cyclic Amines 9 (Table I ) . ,Method A . A slightly modified procedure of Blomquist and hloriconi'j was lolloweti, 2-Indanone and the appropriate secondary amine were respect ive1y dissolved in dry ( ' ~ H s(20 mlL0.01 mol of 2-indanonei anti refluxed until H20 ceased to collect in a H2O separator. The si)Iution was concentrated to about one-third volume and cooled 'l'he product was removed b y filtration and recrystallized or recovered as an oil by evaporation of the solvent. I-(2'-Indanyl) Cyclic Amines 10 (Table I). Method B. The enamine was dissolved in warm glacial HOAc or absolute EtOH and hydrogenated o\-er Pd I C or PtOz (preferred) on a Parr hydrogenator at approximately 50 psi and at 40-60" for 24 hr. 'l'he cdtalyst was removed by filtration and the solvent evaporated under n-ater aspirator pressure. The residual HOAc was neutralized with 10% NazCO3 and the product extracted into CHCIJ. The CHC13 solution wap washed with HzO and dried over SaZSO,. Evaporation of the d v e n t and recrystallization of the residuc gave the desired product. LVhen EtOH was used as solvent. the product was recovered as in method I). Method c'. A mixture of 3 ml (0.034 mol) of' morpholine. :io ml oi toluene. 0.3 g of' IizCO3. and 5 g (0.017 mol) of' 2-indanyl tcihylate (prepared ti3 the method of Bodot. .Jullien. and LeBIanc' from 2-indanoli was retluxed f'or about 24 hr. The reaction \vas followed by tlc [Brinkmann's M N silica gel S-HR sheets were used: chromatograms were developed with CHClS--EtOH ( 1 O : l i and visualized in an iodine chamber] until no tosylate could Lie detected. The mixture thereafter was treated with 40 mi ! i t CHC13. filtered, washed with HzO, and dried over S ~ Z S O I Evaporation of the solvent gave a product with a melting point and infrared spectrum identical with that obtained csia method H. ,Method D. A modified procedure similar to that described hy Hancock and Cope23 was used. A solution of 2-indanone (,0.038 mol) and 0.05 mol of the appropriate secondarv amine in ahsolute EtOH was hydrogenated in the presence of PtO, on a Parr hydrogenator at approximately 50 psi at room temperature tor 24 h r . The catalyst was removed by filtration and the scdvent evapcirated. The residue was dissolved in hexane and eluted two times with hexane through a neutral alumina (grade I ) column. LVhen glacial HOAc was used as the solvent. the product was obtained as descrihed in method B. I-(2'-Indan~l)--l-ac~los?.piperidines 10e,g,h (Table I ) . Method E. A mixture of the appropriate alcohol. CeHs (0.00,'i mol ( i f alcohoi '10 ml of C'sHs). i).CJ2 mol of C5H5N, and excess anhydride (molar ratio ( i f alcnhol IO anhydride. 1 : I O ) was refluxed f'or 1 Z days. The reaction was followed by tlc as described in m e t h d (~ until the alcohol wai no longer detected. The mixture was then concentrated under reduced pressure. The residue was t r e a t d with cold 10% I i ~ f ' 0 3 . \\ashed Lvith HzO. and extracted with CHC13. The extract \vas treated with a mixture t i t activated charcoal and grade I neutral alumina i 1 : l . wt wt). warmed. and f i tered. Evaporation of the CHCI:+ and recrystallization iit the residue gave the desired esters. The hydrochlorides were prepared hy passing HCI t hrough 2t solution of the ester in CljHs. :I-Methylindene ( 14). A procedure resembling that descrihed hy Thiele and H ~ h n e \vas r ~ used. ~ A stirred solution of 100 g (0.86 moll of indenr. NlO ml ( i t dry Et,(). and 130 g (0.92 moll of ('H:il wah treated in portion>. ; Gooch addition technique. with 150 :: 11.:1,1mol) of t,,rt~BuOl(.The reaction mixture was stirred i n c r night. washed with H20. and dried over llgSO4. Evaporation 111' the EtzO produced an oil nhich \vas distilled through a spinning band column t o give ti6 g (6.1%) of product. bp 80-84"(18 nimi l l i t . 2 5 hp 76--7Ri 11 mm)]. (;IC indicated 96% purit volume \vas identical with 3-niethylindene synthe method similar tn that descrihed b\- Elsner and Parker2" tor the synthesis of aliiylindenes; ir iC'S2i \vas identical with that reported for :
