J.M e d . Chem. 1989,32, 2301-2306
2301
Oral Hypoglycemic Agents. Discovery and Structure-Activity Relationships of Phenacylimidazolium Halides Samuel J. Dominianni* and Terence T. Yen Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285. Received March 28, 1988
Blood glucose levels in viable, yellow, obese, diabetic mice are reduced following oral administration of phenacylimidazolium halides. Compounds 2 and 3 produced reductions of ca. 40% 2 h after doses of 100 mg/kg PO. Since these mice do not respond to sulfonylureas, the glucose-lowering activity of phenacylimidazolium salts in this model suggests a mechanism other than that of stimulating insulin secretion. Only phenacylimidazolium halides with electron-donating groups were active; other azolium salts or variations in the phenacyl portion (alterations in the keto function; chain lengthening or extensive branching) produced inactive compounds.
Currently, diabetes mellitus is treated by diet restriction, insulin administration, sulfonylureas, or a combination of these. However limitations of these treatments require the continuous search for improved oral hypoglycemic agents.' The present investigation was initiated by the discovery that 1-methyl-3-phenacylimidazoliumchloride (1)2 decreased blood glucose levels in mice that do not respond to ~ulfonylureas,~ and since 1 produced a similar hypoglycemic response in alloxan diabetic rats, it is possible that an extrapancreatic mechanism is, at least in part, responsible for the reduction of blood glucose. Earlier reports of hypoglycemic activity of quaternary salts include phenacylphosphoranes and phosphonium salts,4substituted 2-arylthiazolo[3,2-a]pyridiniumsalts,5 isoxazolylpyridinium salts,e and 4-[3(5)-pyrazolyl]pyridinium salts,' in which it was specifically noted that the phenacyl salt was devoid of hypoglycemic activity. Reports of biological activity of imidazolium salts have included antibacterial and antifungal (l-alkyl-3-(alkylthi0)imidazolium chlorides8), thromboxane synthetase inhibition (1,3-disubstituted imidazolium halidesg), antiinflamatory (enol betaines of phenacyl halideslO), and antiarrhythmic (1,3-disubstituted imidazolium halides'l) activity. Recently, phenacylimidazolium salts have been used as intermediates in a regiospecific synthesis of 3substituted L-histidines.12 In an attempt to define the structural parameters necessary for hypoglycemic activity, we chose as synthetic targets compounds of general structure I: Z-X-Ar(R) I Sarges, R. Progress in Medicinal Chemistry 18; Elsevier/ North Holland Biomedical Press: Amsterdam, 1981; pp 191-223. Mohrbacker, R. J.; Kiorpes, T. C.; Bowden, C. R. Annual Reports in Medicinal Chemistry; Academic Press: New York, 1987;pp 213-222. Boekelheide, V.; Fedoruk, N. A. J . Am. Chem. SOC.1968,90, 3830. Yen, T. T. Life Sci. 1987,41, 2349. Blank, B.; DiTullio, N. W.; Deviney, L.; Roberts, J. T.; Saunders, H. L. J . Med. Chem. 1975,18, 952. Blank, B.; DiTullio, N. W.; Krog, A. J.; Saunden, H. L. J. Med. Chem. 1978,21,489. Bauer, V. J.; Fanshawe, W. J.; Dalalian, H. P.; Safir, S. R. J. Med. Chem. 1968,11, 984. Bauer, V. J.; Dalalian, H. P.; Fanshawe, W. P.; Safir, S. R.; Tocus, E. C.; Boshart, C. R. J. Med. Chem. 1968, 1 1 , 981. Pernak, J.; Skrzypzzak, A.; Kucharski, S.; Krysinski, J. Arch. Pharm. 1984,317,430. US.Patent 4,461,905,1984. U.S. Patent 3,852,301,1974. Lis, R.; Morgan, T. K., Jr.; DeVita, R. J.; Davey, D. D.; Lumman, W. C., Jr.; Wohl, R. A.; Diamond, J.; Wong, S. S.; Sullivan, M. E. J . Med. Chem. 1987,30,696. Chivikas, C. J.; Hodges, J. C. J . Org. Chem. 1987,52, 3591. 0022-2623/89/1832-2301$01.50/0
in which the nature of the heterocycle Z, the presence or absence of charge, the length, branching, and nature of the intervening chain X, and the nature of the aryl (or alkyl) could be changed, as compared with those of 1. The effect on hypoglycemic activity on each variation from 1 could then be assessed. Chemistry The compounds prepared in this study are listed in Table I. Azolium salts 2-12,15-46,48-50, and 52-54 were prepared by treatment of the heterocycle with the appropriate a-halo ketone in acetonitrile or ethyl acetate (Figure 1). Tertiary halides were of course very sluggish in this reaction; useful quantitites of, e.g., 53 were obtained only after several weeks a t room temperature. l-Methy1-4,5-dihydro-lH-imidazole was prepared by condensation of N-methylethylenediamine with DMF acetal. 3-(n-Propyloxy)acetophenone was obtained by alkylation of 3-hydroxyacetophenone, brominated with copper(I1) bromide,13 and used directly to prepare 33. Procedure B (Figure 2) summarizes some standard synthetic transformations to manipulate functional groups. Alkylation of imidazole with 3'-methoxy-l-bromoacetophenone14 to produce 14 was accompanied by small amounts of the bis compound 60. Formation of 60 could largely be suppressed by using a large excess of imidazole in DMF, followed by aqueous workup. Quaternization of 14 produced 47; 51 was also prepared by quaternization. Borohydride reduction of 14, followed by quaternization produced 56. Cleavage of the methoxyl group in 14 was effected with HBr/HOAc. Neutralization followed by quaternization provided 34. Similar sequences of alkylation and transformation were used for 13 and 55. Procedure C (Figure 31, a Mannich exchange reaction,15 was carried out in aqueous 1-propanol or toluene at reflux; quaternization of the product provided 59. Treatment of 46 with methoxide in methanol, followed by aqueous acid hydrolysis, cleanly produced 57. Attempts to use aqueous bases always gave mixtures of 57 and 58. Refluxing 46 in N-methylpyrrolidone gave 58 (Figure 4). Pharmacology The mice used in this study have been described previously.16 Six mice were gavaged with the test compound, in saline-2% Emulphor, a t 100 mg/kg. S i x other mice were gavaged with vehicle. The mice were bled from the tail before dosing and 2 and 4 h after dosing. Blood glucose (13) King, L.C.;Ostrum, G . K. J . Org. Chem. 1964,29,3459. (14) Nardi, D.; Tajana, A.; Leonardi, A.; Pennini, R.; Portioli, F.; Magistretti, M. J.; Subissi, A. J . Med. Chem. 1981,24, 727. (15) Tramontini, M. Synthesis 1973,703. (16) Yen, T. T.; McKee, M. M.; Stamm, N. B. Znt. J. Obes. 1984, 8 (Suppl. l), 65. 0 1989 American Chemical Society
Dominianni and Yen
2302 Journal of Medicinal Chemistry, 1989, Vol. 32, No. 10 Table I. Physical and Activity Data for 1-59 X-Y-Ar (R) compd (proced)
X
mp, “C solvent4
Y
152-156 A 148-1 51 M/EA 171-173 A/EA 211-213 dec M/EA 215-219 dec M/EA 207 dec M/EA
CHZCO CH,N CH,N CH,N
+”
+
CHzCO
r=\ N’
CHpCO
”+
CHZCO
w
+
CHZCO CHpCO CHpCO
C6H4CH3-4
cNH :3
CHpCO
Ph
QN ,+,,
CHpCO CHzCO CHzCO 128 (A)
CH,CO A
CH2CO
N
vN
A
N
vN
CHZCO CHZCO
CH,N CH,N CH,N CH,N CH,N CH,N CH,N CH,N
”+
+
CHZCO
A
CH&O
A N’
CHZCO
I=\
CHzCO
+”
CHzCO
vN’ v
w N’
+ ”+ +
CHzCO
A N’
CHpCO
/=I
CHZCO
w
w N’ CH,NAN*w
CHzCO CHZCO
CH,N
+”
w
CHZCO CHpCO CH,CO CHzCO CHpCO CHZCO
C6H4CH3-4
215-217 dec M/THF 290-294 dec M/EA
formula anal.*
blood ducosec 2h 4h 74 f 4d
71 f 7d
C13H15BrN20
57 f 4d
53 f 5d
C, H, N, Br C13H15BrNZ02 C, H, N
58 f 4d
72 f 4d
C1ZH13BrNZ0
C, H, N
C13H12BrN30
C, H, N,Br C12HlZBrN02S C, H, N, S C13H14BrN04
105 f 4
106 f 5
105 f 9
123 f 10
95 f 5
97 f 7
C, H, N 83 f 9
82 f 8
C, H, N,Br C14H14C1N0 C, H, N
105 f 7
103 f 5
245-247 dec M/EA
C13H13BrNZ0
105 f 4
111 f 3
201-202 dec M/EA
C13H13BrN20
122 f 7d
112 f 9
167-171 dec M/EA
C17H15BrNZ0
115 f 11
108 f 11
256-257 dec M/THF
C16H14BrNOS C, H, N, S
106 f 5
108 f 6
168-1709 M/THF 106-108 THF/H 156-159 A/THF 147-150 M/EA 175-177 A/ET 182-185 dec M/EA 178-180 dec I/ET 233-236 dec M/EA 184-186 dec M/THF 229-232 dec M/EA 237-240 dec M/ET 146-148 A/THF 165-167 M/EA 156-159 M/ET 239-241 dec M/EA 230-233 dec M/THF 215-217 dec A/EA 207-210 dec A/EA 143-146 dec M/EA
Cl1HloN20~HBr C, H, N C12HlZN202
103 f 5
C13H15BrN20
C, H, N, Br C, H, N,Br C, H, N, Br
C13H17BrN202
C, H, N ClzHlzBrCINzO C, H, N C12H12BrC1N20 C, H, N, Br ClzHllClzBrNzO C, H, N, C1 ClzHlzBrFNzO C, H, N C13H14BrN302 C, H, N
90 f 10
110 f 5
121 f 6
81 f 9
97 f 7
94 f 8
93 f 5
107 f 8
112 f 8
94 f 11
79 f 9
91 f 8
99 f 7
100 f 5
95 f 5
C13H12F31NZ0
95 f 6
97 f 4
C, H, N C16H15BrN20 C, H, N, Br
90 f 5
110 += 17
C16H15BrN20
89 f 5
99 f 8
C, H, N, Br C10H11BrN202 C, H,N
72 f 7d
92 f 9
C13H15BrN202
90 f 9
97 f 13
C, H, N, Br C13H15BrN202 C, H, N, Br
70 f 4d
77 f 5d
C14H17BrN203
83 += 5
69 f 5
C, H, N, Br C14H17BrN203 C, H, N
86 f 7
81 f 4
C14H17BrN203
83 += 9
88 f 10
78 f 5d
86 f 7
103 f 15
104 f 5
C, H, N C14H17BrN203
C, H, N, Br C14H17BrN202 C, H, N, Br
Journal of Medicinal Chemistry, 1989, Vol. 32, No. 10 2303
Oral Hypoglycemic Agents
Table I (Continued) compd (Droced)
X
mp, "C solvent"
Y
137-138 M/EA 84-86 M/EA 96-98 dec M/THF 251-254 dec M/THF 202-204 M/THF 152-154 A/ET 185-187 A/ET 179-181 A/EA 163-165 M/EA 221-224 dec A/ET 177-179 A/EA 247-250 dec MIA 180-183 A/EA
328 (A) 338 (A) 34k (A) 35O (A) 368 (A) 378 (A) 388 (A) 39B (A) 408 (A) 418 (A) 428 (A) 438 (A) 448 (A) 45O (A)
Ph
478 (B)
C6H4OCH3-3
4Se (A)
Ph
49a (A)
CeH4OCH3-3
50e (A)
CH3
518 (B)
Ph
528 (A)
Ph
538 (A)
Ph
54O (A)
Ph
55i (B)
C6H4CH3-4
5W (A)
C6HdOCH3-3
57 (D)
C6HdOCH3-3
247-250 dec A/EA
C14H17BrN202
blood glucosec 2h 4h 63 i 5d
64 f 6
63 f 4d
72 f 5
93 f 6
87 f 8
108 f 4
107 f 8
100 f 5
109 f 5
C, H, N, Br C15H19BrNZ02
C, H, N C19H20N205S
C, H, N, S C12H13C1N203
C, H, N
80 f 8d
87 f 8
78 f 5d
73 f 7
C14H17BrN20
62 f 7d
79 f 10
C14H17BrN20
83 f 4
95 f 4
94 f 4
97
77 f 5d
88 f 6
C13H15BrN20 C, H, N, Br C13H15BrN20 C, H, N, Br C, H, N, Br C, H, N, Br C15H19BrN20
C, H, N, Br C14H17BrN20 C, H, N, Br
f
6
C18H17BrNZ0
103 f 7
103 f 7
C25HZ3BrNZ0
102 f 17
105 f 21
90 f 8
81 f 8
101 f 7
121 f 12
C, H, N, Br C, H, N, Br Cl3Hl5C1N20 C, H, N, C1
177-179 dec M/THF 148-150 A/THF 146-148 M/EA 171-173 M/EA 123-126 A/THF 167-170 M/ET 137-140 M/EA 175-178 M/EA 104-106 M/ET 162-165 M/EA 98-100 EA/H 135-137 I/H
59' (C)
formula anal.*
C13H14NZ0ZS
79 f 5d
83 f 8
79 f 7d
79 f 7d
96 f 9
91 f 11
105 f 5
109 f 4
89 f 9
84 f 9
70 f 6
61 f 7
104 f 5
113 f 4
94 f 12
83 f 4
86 f 12
81 f 8
106 f 3
103 f 7
101 f 9
103 f 12
99 f 17
80 f 7
C, H, N, S
120-122 C14H171N20Z 91 f 5 94 f 6 M/ET C, H, N Recrystallization solvents: A, acetonitrile; E, ethanol; EA, ethyl acetate; ET, diethyl ether; H, hexanes; I, 2-propanol; M, methanol; THF, tetrahydrofuran. *Analyses for the indicated elements were within 0.3% of the calculated values. Values as Dercent of zero time (dose 100 mg/kg PO; mean values f S E of the mean for six mice. dValue significantly different (p < 0.05) from vehicie control over the s&ne time period. e Quaternary chloride. 'Literature2 mp 153-155 "C. 8Quaternary bromide. Hydrobromide salt. ' d,Z mixture. 'Quaternary iodide. Quaternary p-toluenesulfonate. Methanol solvate. CHN ,+ "
e
2304 Journal of Medicinal Chemistry, 1989, Vol. 32, No. 10
nl
Figure 1. Procedure A.
(I)
Me1 MeCN r t
'
56
Figure 2. Procedure B. lmiaazoie I - P ~ O H 1000, 41
I-CHSOC~H~COCH,CH,N(CH~)~
~
m
YvNCbiCL2COA-
Me1 Ye:'.
l=l
Cri3hv/h+C4?CH2COAr
-:
-
59
Figure 3. Procedure C.
Dominianni and Yen
the corresponding unquaternized base (14)was not. Introduction of a 2-substituent produced an inactive imidazolium salt (46 and 45). The 1-substituent was limited to small unfunctionalized alkyls (47 and 48), as evidenced by the inactivity of e.g. 50. The 4,5-dihydro- (15) and the 4,5-diphenyl- (42) imidazolium salts were inactive. The intervening chain, X, was optimally two carbons in length; extension by an additional atom (59) abolished activity. Small a-substituents could be tolerated (52) but not larger ones (54). Di-a-substitution (53) abolished activity; it is not clear that this is only a substituent effect since a-disubstitution would also preclude ylide formation. Ylide formation is important in the chemistry of phenacylimidazolium halides;2 whether is is important in the hypoglycemic activity of, e.g., 1 or 3 remains an open question since we have so far been unable to prepare and isolate a characterizable ylide in this series. Reduction of the keto group in X or conversion to an oxime produced inactive salts (55 and 56). The Ar(R) moiety in I was also relatively inflexible. Electron-withdrawing substituents had a deleterious effect on activity (4 and 16-21). Electron-donating substituents do not present a wholly consistent picture. Thus, whereas the 3'-methoxy and 3',5'-dimethoxy analogues (3 and 27) represented improvements over the parent 1, other alkoxy substitution patterns were less active (e.g., 25,28, and 29). Small alkyl groups usually gave active compounds (2, 37-40, and 44) , but the 2',4',6'-trimethyl analogue 41 was inactive. Very narrow ranges of structural variation have been noted in other hypoglycemic ~ e r i e s . ~ ~ ~ J ' Because we believe our animal model is indicative of efficacy in type I1 diabetes and because of the possibility that the phenacylimidazolium salts may be operating through a novel hypoglycemic mechanism, some examples of the series have been chosen for more detailed examination. Future publications will report our studies of pharmacology, absorption, and metabolic routes, together with studies designed to elucidate the mechanism of action.
Experimental Section
46
Figure 4. Procedure D.
was determined by the glucose oxidase method with a Technicon Autoanalyzer Model 12-60. The percent changes a t 2 and 4 h of the treated mice were considered significant at p < 0.05 when compared with controls by using Student's t test. Results and Discussion Blood glucose values, reported as percentage of controls, are recorded in Table I. Of the compounds examined, only 1-3,26-27, 30, 32-33,38-40, 42,47,48, and 52 could be regarded as active, producing reductions of blood glucose of 20-40 % . Phenacyltriphenylphosphonium bromide, which was active in 48-h fasted rats,4 was inactive in the yellow, diabetic mice; conversely, our compounds did not show hypoglycemic activity in fasted rats. In short, of the heterocycles examined, hypoglycemic activity was confined to the imidazoles and even within the imidazoles our results place severe constraints on structure I. Only imidazolium salts were active; e.g., 3 was hypoglycemic but
Melting points were determined in a Thomas-Hoover capillary melting point apparatus and are uncorrected. Thin-layer chromatography (TLC) was performed on precoated silica gel F254 plates (E. Merck). Analytical and spectral data (IR, NMR, and MS) were all in accord with the assigned structures. Examples of Procedure A. 4,5-Dihydro-3-[2-(3-methoxyphenyl)-2-oxoethyl]-l-methyl-lH-imidazolium Bromide (15). A solution of 25 g of 1-methylethylenediaminein 20 mL of T H F was added dropwise to a stirred solution of DMF dimethyl acetal in 50 mL of T H F over 0.5 h. After the addition was complete, the solution was refluxed for 8 h and kept a t room temperature for 8 h under a drying tube, and the solvent removed by distillation. The residue was purified by distillation; l-methyl-4,5dihydro-1H-imidazole was obtained as a clear, colorless liquid, bp 39-41 OC (6 mm) in 48% yield. A stirred solution of the dihydroimidazole (2.29 g) in 20 mL of MeCN was treated with 0.90 g of l-bromc-3'-methoxyacetophenone. The solution was kept at room temperature for 24 h; TLC (CHCld showed that the halide had been consumed. The solvent was removed in vacuo and the oily residue was triturated with THF. The resulting solid crystallized from MeCN/THF as fine, matted needles of 15, mp 157-159 OC in 66% yield. 1-Methyl-3-[ 2-oxo-2(3-propoxyphenyl)ethyl]-1H imidazolium Bromide (33). 3-Hydroxyacetophenone was alkylated (PrBr, EtOH/H20, K,CO,, 12-h reflux) and freed from unconsumed starting material by extraction with 2 N NaOH. 3-Propoxyacetophenone was obtained as tan crystals, mp 23 "C from cold 30-60 petroleum ether. Bromination (CuBr2, (17) Shroff, J. R.; Bandurco, V.; Desai, R.; Kobrin, S.; Cervoni, P. J. Med. Chem. 1981,24, 1521.
Oral Hypoglycemic Agents
Journal of Medicinal Chemistry, 1989, Vol. 32, NO. 10 2305
CHC13/EtOAc,reflux 6 h) produced the a-bromo ketone as nearly white crystals from cold MeOH, mp
