Shelver. Schreibman, Tanner. Rao
120 Journal ofMedicina1 Chemistry, 1974, Vol. 17, No. I
(10) J . Van Dijk and H. D. Mold, Recl. Trau. Chim. Pays-Bas, 78,22 (1959); 80,573 (1961). (11) A. A. Larsen, W . A . Gould, H. R. Rath, W. T. Comer, and R. H. Uloth, J. Med. Chen., 10,462 (1967). (12) R. A. Uloth, J. R. Kirk, W. A. Gould, and A. A. Larsen, ibid., 9,88 (1966). (13) H. Konzett and R. Rossler, i~aunq'n-SchmiedebergsArch. Exp. Pathol. Pharmakol., 195,71 (1940).
(14) 0. H. Siegmund, H. R. Granger, and A. M. Lands, J . Pharmacol. Exp. Ther., 90,254 (1947). (15) D. T. Collins, D. Hartky, D. Jack, H. H. Lunts, J. C. Press. A . C. Ritchie, and P. Toon, J.Med. Chem., 13,674 (1970).
(16) K. Kindler, K. Schrader, and B. Middlehoff, Arch Phamz. ( Weinheim),283,184 (1950). (17) J. R. Corrigan, M. Sullivan, H. W. Bishop, and A. W . Ruddy, J. Amer. Chem. SOC.,75,6258 (1953).
Synthesis of Monoaryl- and Diarylphosphorus Analogs of Methadone William H. Shelver,*.t Martin Schreibman,: Department of Pharmaceutical Chemistry and Bionucleonics
N. Stevan Tanner, a n d V. Subba Raos Llepartment of Pharmacology and Toxicology, College of Pharmacy, North Dakota State Unil;ersit>',Fargo, North Dakota 58102. Rereiced May 30, 197,3 Fourteen monoarylphosphorus analogs of methadone belonging to three structural types (4, 5 , and 6) were synthesized by reacting various chloroalkylamines with the appropriate phosphorus compounds. The phosphorus compounds were selected to vary the steric, electronic, and solubility properties of the final products. Ten diarylphosphorus analogs of methadone of two structural types (7 and 8) were synthesized in a similar manner. The success of the alkylation reaction for both series was markedly affected by the solvent system utilized. Pharmacological screening by the hot-plate and acetic acid writhing methods revealed moderate analgetic activity in some of the compounds apparently related to the lipophilicity of the molecule. The research of Bockmuhl, Erhart, a n d Schaumann which produced methadone (1) has stimulated other researchers1 t o explore t h e relationship of chemical structure t o pharmacological activity of various arylpropylamines. T h e introduction of propoxyphene (2) as a n analgetic with low addiction liability was t h e result of such a systematic exploration of arylpropylamines. Recently t h e use of methadone (1) as a morphine substitute in the treatment of narcotic addiction has stimulated further interest in the exploration of arylpropylamines as analgetics. 0
posed by Hansch4 for many other types of medicinal agents. Others have explored t h e relationship between lipophilicity and analgetic a ~ t i v i t y . ~ Other groups may be substituted for polar groups containing carbon. Previously, Slenk, Suter, a n d Archer6 had synthesized a series of sulfones 3 related t o methadone and found reasonable analgetic activity. Consequently, SO,Et
0
1I
1I
OCEt
CEt (=&(!-CH2CHNMe2
I
I
I
1
3
@CH,--C--CHCH2NMe2
I
I
2
The general feature of t h e analgetic receptor proposed by Beckett and Casy,2 a n aromatic group with the proper orientation and distance from a basic nitrogen, encompasses the structure of most active analgetics. Methadone and meperidine both contain a polar side chain emanating from the carbon attached to the aromatic group. The function of the polar side chain remains a matter of conjecture although changes in this group can markedly affect the activity of the compound. The existance of an optimum in the chain length of the alkyl group attached to the polar side chain3 implies a parabolic relationship between analgetic activity and solubility of t h e type prot This paper is dedicated to my former major professor, Dr. Alfred Burger, to whom medicinal chemistry owes much. $ Taken in part from the dissertation presented by M ,S.. July 1970. to the Graduate School of N. D. S. U. in partial fulfillment of the requirements for the Doctor of Philosophy Degree. $Taken in part from the dissertation presented by V . S. R., August 1971. to the Graduate School of N. D. S. U.in partial fulfillment of the requirements for the Master of Science Degree.
the authors synthesized a n d evaluated some phosphorus analogs of methadone of t h e types shown by 4, 5 , and 6 (monarylphosphorus analogs of methadone) and 7 and 8 (diarylphosphorus analogs of methadone), each series utilizing a different phosphorus-containing group in place of 0
t
PX?
4, X = C,H,; NR, = dialkylamino
5, X = OEt; NR, = dialkylamino 6, X = E t ; NR, = dialkylamino
0 A
PX-
7. X = C,H,; NR, = dialkylamino 8, X = OEt; NR, = dialkylamino
Journal of Medicinal Chemistry, 1974, Vol. 17, No. 1 121
Monoaryl- and Diarylphosphorus Analogs of Methadone
Table I. Physical Constants of Monoarslphosphorus Analogs of Methadone H
0
O
I t
Q i _ p (Ro A) z Compd no.
0
RB
R
CR
Crystn solvent
Mp,
O c a
Yield, %
1- (1-Phenyl-3-dialkylaminoalkyl)diphenylphosphine Oxides (A) 66 EtOH-Hz0 183-184 CHzCH2N(Me)? 148-150 59 EtOH-Hz0 CHzCHzN (Et)z 201-202 83 EtOH-Hz0 CHzCHz-c-NCdHs 66 Methylcyclo187-189 CHzCHz-c-NCaHio hexane 213-2 14 78 EtOH-HzO CHzCHz-C-N(CHzCHz)2 0 48 EtOH-H20 202-205 CHCH;CH2N (Me)z 179-181 76 EtOH-Hz0 C H2CHzCH 2 N(Me)
4a 4b 4c 4d 4e
4f &
Empirical* formula CZ~HZ~NOP CzjHaoNOP CzjHzsNOP C26H3oNOP C&J.zaNOzP C24H2sNOP CNHZ~NOP
5d
Diethyl 1-(1-Phenyl-3-dialkylaminoalkyl)phosphonateHydrochlorides (B) 130-131 36 C H 2 C H z N ( M e ).HC1 z i-PrOH-(i-Pr)zO CHzCHzN (Et)z.HC1 i-PrOH-(i-Pr) 2O 120-121 30 CHzCHz-c-NCsHio .HC1 i-PrOH-(i-Pr) 156-1 57 38 CHzCHZ-C-N(CHzCH2)zO.HC1 i-PrOH- (i-Pr)20 163-164 23
C ~ S H ~ ~ NHC1 O~P. Ci7H3oNOzP. HC1 CisHzoN03P. HC1 CI,HtsN04P ‘HC1
6a 6b 6c
1- (1-Phenyl-3-dialkylaminoa1kyl)diethylphosphine Oxide (C) 46 CHCla-EtOAc 165-166 CH2CH2NMe2. HC1 218-219 49 CHzCHa-c-NCaHio .HC1 i-PrOH- (i-Pr)zO 47 i-PrOH-( i-Pr)2O 216-2 18 CHzCHz-C-N(CHzCH2)zO .HC1
CijH2SNOP .HC1 C IsHaoNOP .HC1 CiTH28NOzP .HC1
5a 5b 5c
aAll melting points are uncorrected. bAllcompounds were analyzed for C, H , and N. the propionyl group of methadone (1). The substituents on t h e phosphorus atom were varied to provide a spect r u m of solubility, electronic, and steric properties in t h e series for increased probability of obtaining analgetic activity. Since t h e monoarylphosphorus analogs of methadone (4, 5 , a n d 6) m e t the requirements of the analgetic receptor and t h e necessary intermediates were readily available, the synthesis shown in Scheme I was undertaken. The alkylation of benzyldiphenylphosphine oxide with t h e ap-
sulfinylmethide in dimethyl sulfoxide. The synthesis of the diarylphosphoms analogs of methadone (7 a n d 8) was carried out according t o the method shown in Scheme 11. The extra phenyl group adjacent t o the phosphoryl group of the starting material will stabilize
Scheme I
W Y - H 0
@CH,!X2
+ C1CHzCH2NR2
-
Scheme I1 0
t
-
I
+ C1CH,CH2NRz
base
A
base
0
t
0
DYH!X2
PX,
+
base.HC1
(&
k-CH,CHzNR2
+
base.HC1
CHZCHZNRL
X = OC,H,, CzH,, or C,H, NR, = dialkylamino or cycloalkylamino propriate chloroalkylamines t o produce 1-(1-phenyl-3-dialkylaminoalky1)diphenylphosphine oxides (4) proceeded smoothly in refluxing toluene with sodium hydride a s t h e base. The properties of these compounds are described in Table I. T h e second series of phosphorus analogs of methadone, diethyl 1-(l-phenyl-3-dialkylaminoalkyl)phosphonates ( 5 ) , were more difficult to prepare. Reaction of diethyl benzylphosphonate with t h e appropriate chloroalkylamine in the presence of sodium methylsulfinylmethide in dimethyl sulfoxide produced t h e desired compounds (Table I). The fipal structural variation in t h e series of monoarylphosphorus analogs of methadone (6) contained a diethylphosphoryl group a n d was synthesized by reacting benzyldiethylphosphine oxide with t h e appropriate chloroalkylamine. Several solvent systems were required; the dimethylamino analog was synthesized in toluene with sodium hydride a s t h e base and t h e piperidino a n d morpholino analogs were prepared using sodium methyl-
X = OC,H, or C,H, NR, = dialkylamino o r cycloalkylamino the negative charge produced by attack of base on t h e parent compound, b u t the steric hindrance caused by t h e extra phenyl group will cause t h e carbanion t o be less reactive toward chloroalkylamines. T h e first series of diarylphosphorus analogs of methadone, the 1-(1,l-diphenyl-3dialkylaminoalky1)diphenylphosphine oxides (7), was prepared. The synthesis of these compounds failed in refluxing toluene, b u t when t h e higher boiling solvent xylene was used good yields of the products were obtained. The physical properties of these compounds (7) are described in Table 11. T h e synthesis of the second series of diarylphosphorus analogs of methadone, diethyl 1-(1,l-diphenyl-3-dialkylaminoalkyl)phosphonates (8), required t h e use of two solvent systems. The dimethylamino derivative 8a was synthesized using sodium hydride in xylene and the diethylamino (8b) and t h e piperidino (812) derivatives
Sheluer, Schretbman, I'anner, h a o
122 Journal of Medicinal Chemistry, 1974, Vol. 17, No. I
Table 11. Phvsicil Constants of Diarvlphosphorus Analogs of Methadone
0
0
n Compd no. 7a 7b 7c 7d 7e 7f 7g Sa 8b 8c
R
E M p , "C,;
Crystn solvent
Yield,
5%
Empirical" formula
1-(l,l-Diphenyl-3-dialkylaminoalkyl)diphenylphosphine Oxide Hydrochlorides ( D ) CH,CK2N(Me),.HC1 i-PrOH-(i-Pr)20 194-196 dec 54 CH2CHZN (Et),'HC1 i-PrOH- (i-Pr)*O 153-154 dec 52 CH?CH,-c-NCJHS HC1 i-PrOH-(i-Pr),O 236-238 dec 58 CH?CH?-c-NCaHio HCl i-PrOH-(i-Pr),O 172-175 dec 52 CH2CH2-C-N(CH&H?)O .HC1 i-PrOH- (i-Pr)$0 218-220 57 CHCH,CH?N(Me), 'HC1 i-PrOH-(i-Pr) ?O 186-188 39 CH2CHyCH2N (Me)2. H C l i-PrOH-(i-Pr,)O 238-240 57
CZgH3oNOP 'HC1 C3iH34NOP HC1 C I I H ~ N O PHCI . Ca2H34NOP. HC1 CaiH3YN02P .HC1 C3oHazNOP .HC1 C3uH3YNOP 'HC1
Diethyl 1-(l,l-Diphenyl-3-dialkylaminoalkyl)phosphonate Hydrochlorides ( E ) CH2CH,N(Me)r . H C l i-PrOH-(i-Pr),O 154-155 38 C H ? C H a N ( E t ) ?HCl . i-PrOH-(i-Pr) 2O 154-155 dec 37 CHzCHy-c-NCjHio.HC1 i-PrOH-(i-Pr),O 162-164 dec 34
C?iHaoNO3P.HC1 CmHa4N03P HCl CZ~H~~N 'HC1 O~P
-
.___
see footnotes, Table I. T a b l e 111. Pharmacological Properties of Monoarylphosphorus Analogs of Methadone
0
0
F Compd no.
R Morphine
0
G H L D z ~ mg/'kg ~,~ Hot-plate ED:o,~ mg,'kg Acetic acid EDno,cmg,/kg (95 % confidence limits) (95% confidence limits) (95% confidence limits) 495 . 3 (482 .O-508 .9)
1 . 3 2 (1.06-1.50)
1 . 3 0 (1.07-1.60)
4d lie 4f
1-(I-Phenyldialkylaminoalkyl) diphenylphosphine Oxides (F) 8 5 . 1 (81 .1-89 . 3 ) 228.4 (226.7-230.4) CH2CH2N(CHs)? 174.2 (169 .6-178.8) 6 . 2 (5 .O-7.6) CH,CHrN(CH:CH3). 4 7 . 9 (44.4-51 . 7 ) 1 6 7 . 1 (165.7-168.5) CHpCHy-c-NC~H~ 2 4 . 7 (20.9-29.2) 8 4 . 8 (81.O-88.9) CH?CH?-c-NCaHlo 151.3 (146.8-156.0) 1 0 . 1 (8.7-11.7) CH,CH2-c-N(CH1CHy)r0 1 9 . 7 (16.3--23.7' 148.4 (145.8-151 . l ) CHCH:CH?N(CHs)
5a 5b 5~ 5d
Diethyl 1-(1-Phenyl-3-dialkylaminoalky1)phosphonate Hydrochlorides (G 1 248.7 (240.5-257.2) 596.9 (594.4-598.3) CHICHPN(CH3)P.HC1 1 4 4 . 2 (140.5-147.9) 391.7 (387.5-395.9) CH?CH2N(CHyCH,)r , H C l CHzCH,-c-NC:,Hio.HCl 3 3 2 . 3 (329.1-335.4) 105.0 (100.5-109.8) 1 0 4 . 4 i99.6--109.4) 507.9 (500.8-515.2) CH,CH?-c-N(CHZCHz),O.HCl
6b
(I-Phenyl-3-piperidinopropy1)diethylphosphine Oxide Hydrochloride (H ! CHsCHz-c-NCiHin .HC1 5O0-7OOd 191 (184-198) 196 (183-210
4a 4b 4c
84.4 6.8 55.1 21.2 7.0 18.9
(75.1-94.8) (5.1--9.2) (46.9-64.8) (18.4-24.4) (4.9-10.0) (15 .0--23.9j
260.3 (249.9-270.9) 1 4 1 . 3 (134.4-148.4) 102.4 (100.0-105.4) 105.6 (100.0--111. 4 ) I
"Determined by the method of Litchfield and Wilcoxon." "Determined by the method of Eddy and Leimbach."
