J . Med. Chem. 1993,36, 2486-2493
2486
Antihyperglycemic Activity of Novel Naphthalenyl3H-1,2,3,5-Oxathiadiazole 2-Oxides John W. Ellingboe,' Louis J. Lombardo, Thomas R. Ales&+Thomas T. Nguyen, Frieda G U Z Z O , ~ Charles J. Guinosso,g James Bullington,ll Eric N. C. Browne, Jehan F. Bagli, Jacqueline Wrenn, Kurt Steiner, and Michael L. McCalebl Division of Exploratory Chemistry and Division of Cardiovascular and Metabolic Disorders, Wyeth-Ayerst Research, CN 8000,Princeton, New Jersey 08543-8000, and Division of Chemical Development, Wyeth-Ayerst Research, 1025, Boulevard Laurentien, Saint-Laurent, Quebec H4R 1 J6 Received March 11, 1993
A series of naphthalenyl 3H-1,2,3,5-oxathiadiazole2-oxides was prepared and tested for antihyperglycemic activity in the dbldb mouse, a model for type 2 (non-insulin dependent) diabetes mellitus. Substitution a t the 1-,5-, or 8-positions of the naphthalene ring with a halogen was found to be beneficial to antihyperglycemic activity. 4-[(5-Chloronaphthalen-2-yl)methy1]-3H-1,2,3,5oxathiadiazole 2-oxide (45), one of the most potent compounds in this series, was selected for further pharmacological evaluation. Drugs'currently available for the control of the hyperglycemia associated with type 2 (non-insulin dependent) diabetes mellitus (sulfonylureas,biguanides, glucosidase inhibitors) possess significant liabilities or efficacy limitations. Thus, considerable effort has been directed recently toward the development of novel, orally active antihyperglycemicdrugs. Many of these new compounds incorporate a relatively acidic heterocycle which serves as the pharmacophore responsible for antihyperglycemic activity. These heterocycles include the thiazolidine-2,4dione,l tetrazole,2 and oxazolidine-2,4-dione3rings. A series of structurally novel 3H-1,2,3,5-oxathiadiazole2-oxides was also described re~ently.~ In this latter series, various heterocyclic (benzofuran, benzothiophene,and indole) as well as carbocyclic(indan, tetrahydronaphthalene, dihydronaphthalene, and naphthalene) groups were appended to the 3H-1,2,3,5-oxathiadiazole 2-oxide ring via a methylene bridge. The resultant compounds were examined in the genetically diabetic dbl db mouse, an animal that exhibits many of the pathologies present in type 2 diabetes.6 The compound with a 2-naphthalenylsubstituent, 4- [(naphthalen-2-y1)methyll3H-1,2,3,5-oxathiadiazole2-oxide (1)emerged as the most efficacious. This result prompted the synthesis of a series of naphthalenyl oxathiadiazolesin which the effects of two structural factors on activity were examined (1)variation of the tether linking the 2-position of the naphthalene ring to the oxathiadiazole ring; and (2) the addition of substituents on the naphthalene ring of naphthalen-2ylmethyl compounds (e.g. compound 1). From this group of compounds, 4- [(5-chloronaphthalen-2-yl)methyll-3H1,2,3,5-oxathiadiazole 2-oxide (45) (WAY-120,744) was selected for further evaluation and development. Reported in this paper are the synthesis of the series of naphthalenyl oxathiadiazoles, their effect on plasma glucose in the dbldb mouse, and the characterization of compound 45 in additional animal models. t Present address: 8 Present address:
Schering-PloughResearch, Kenilworth, NJ. Hahnemann University, Philadelphia, PA. Present address: Isia Pharmaceuticals, Carlabad, CA. I Present address: Ortho Pharmaceuticals, Raritan, NJ. Present address: Miles Research Center, West Haven, CT.
Chart I H
45
1
Scheme I. 1,2,3,5-0xathiadiazole2-Oxides (Method A)
J
4
Scheme 11. 2-Naphthaleneacetonitriles Method B C02CH3 (H) 1) DIBAL-H, UAIH,, or B H ~ 2) SOCII. ZnCI,, dioxane
or Card. Pphj, THF
qTC1y&
acH3 Method C
CN
H2O. CHsCN / R
NBS, AIBN, CCli
R
R
Q
Chemistry The oxathiadiazoles 5 were prepared in two steps from a substituted nitrile 3 by (1)treatment with hydroxylamine to give an amidoxime (4),and (2) cyclization with thionyl chloride: as illustrated in Scheme I (method A). The substituted nitriles were prepared as shown in Schemes I1 and 111. 2-Naphthaleneacetonitriles 10 were derived from either a naphthoic acid or ester 6 via reduction, halogenation, and cyanide displacement (Scheme 11, method B) or from a methylnaphthalene 8 by NBS brominationand cyanidedisplacement (Scheme11,method C). The 2-naphthalenylnitriles other than acetonitrileswere prepared as shown in Scheme 111. Thus 2-naphthalenebutanenitrile (12) was synthesized from 2-naphthaleneethanol (11) by oxidation to an aldehyde with DessMartin periodinane,3O reaction with diethyl (cyanomethyl)phosphonate, and catalytic hydrogenation. The next higher homologue, 2-naphthalenepentanenitrile (141, was prepared from 2-naphthalenepropanenitrile(13) (synthesized according to Robertson et al.6) by DIBAL-H reduction of the nitrile to an aldehyde, reaction with diethyl
OO22-2623/93/1836-2485$04.00/0 0 1993 American Chemical Society
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2486 Journal of Medicinal Chemistry, 1993, Vol. 33, No.17
Scheme 111. Other Nitriles" a, b,c 11
Ellingboe et al.
Table I. 5-Substituted 2-Naphthoates COzCH3
P
COzCH3
Reagent
12
R'
Br
CN
d, b. c
CN
*
13
% reagent R1 yield CuC1, DMSO, 105-110 "C c1 100 NaOCH3, CUI, pyridine, CHaOH, CHsO 100 reflux; 2.5 N NaOH' 6d NaSCHs, Cu20, N-methylCH3S 76 pyrrolidinone, refluxb 6e CHdHSnBus, (Ph$)$d, CHdH 92 toluene, reflux 6f MeaSiCCH, (Ph&adClz, CUI, CHC 62 EhNH, 20 "C; 1N KOH, CH3OH' 6g CF&02Na, CUI, N-methylCFs 48 pyrrolidinone, refluxc 6h CHsLi, CHsI, THF,-78 "C to CH3 a7 20 "Cd Isolated a~ acid. * Ester reduced to alcohol prior to reaction. Ethyl ester used. Ester hydrolyzed to acid prior to reaction.
fPh 1
CN
* 18
15
Q
XH
XVCN
L
20a: X.0 20b: X-9
0 hI 23
Scheme IV. Tetralone Route (Method D)"
22
21
& 24
6
compd 6b 6c
14
CN
6a
NHOH J,k
R'-
"2
26
27
25
(a) Dess-Martin periodinane, CH2Cl2; (b) (EtO)zP(O)CH2CN, NaH, THF; (c) H2,5% Pd/C, EtOH (d) DIBAL-H, ether; (e) NaH, CHd,DME; (f) NaH, PhCHzBr, DMR; (g) K&Os, ClCHnCN,acetone; (h)nBuLi, CHsCN,THF; (i) NaH, (CH3)2SO4,THF; c j ) "OH-HCl, NaOCH3, CHsOH; (k) CF&02H, 40 "C.
(cyanomethyl)phosphonate,and catalytic hydrogenation. Alkylation of 2-naphthaleneacetonitrile (15) according to a procedure of Hauser7*with sodium hydride and methyl iodide yielded the mono- and dimethyl compounds 167b and 17.7cAlkylation of 15 withsodium hydrideand benzyl bromide gave compound The (2-naphthaleny1oxy)and (2-naphthaleny1thio)acetonitriles20a9and 20b1°were prepared from 2-naphthol (19a) and 2-naphthalenethiol (19b), respectively, by alkylation with chloroacetonitrile and potassium carbonate. Treatment of 2-acetylnaphthalene (21) with diethyl (cyanomethy1)phosphonateand catalytic hydrogenation yielded 3-(2-naphthalenyl)butanenitrile (22). An aldol-type reaction of 2-naphthaldehyde (23) with lithioacetonitrile and subsequent methylation with sodium hydride and dimethyl sulfate gave 3-methoxy-3-(2-naphthalenyl)propanenitrile(24). The vinyl tether in compound 25 was introduced at a later stage by an eliminationreaction on the amidoxime derived from compound 24. The mono- and disubstituted naphthoates 6 and methylnaphthalenes 8 used to prepare the substituted 2-naphthaleneacetonitriles were synthesized by a variety of methods. A number of 2-naphthoates were derived from the useful intermediate, methyl 5-bromo-2-naphthoate (6a)l' (Table I). Thus, the 5-chloro group (6b)12 was introduced with copper(1) chloride in DMS0;13 the 5-methoxy group (6c) with sodium methoxide and copper(1) iodide in pyridine and methanol; the 5-methylthio group (6d) by reduction of the ester to an alcohol with DIBAL-H and treatment with sodium thiomethoxide and the 5-vinyl copper(1) oxide in N-methylpyrr~lidinone;'~ group (6e) with vinyltributyltin and tetrakis(triphenylphosphine)palladium(O)in toluene;15the 5-ethynyl (60 group with (trimethylsilyl)acetylene,bis(tripheny1phosphine)palladium(II) chloride, and copper(1) iodide in
R1-cCH3 /
mo
IC d R1-
/
8a: i-m, 7 . ~ 1 4 ~ 8b: 1 4 , 7-CH3 8C: 2 4 , 7-CH3 8d: 2-F, 6 - C H 3
28
eorf
e
8a
80: X=CN 81: XsSCHa
mCH3 gorh
F
t
8d
a
(a) SOC12, DMF, CH2C12; (b) AlClS, ethylene, CHCl2, -20 OC to
-10 "C; (c) TiCL, CHsMgCl, THF,CHzClg, -40 "C to 0 "C; (d)
PhsCOH,CFsCOzH (e)CuCN,N-methylpyrrolidinone; (f) NaSCb, Cu20, N-methylpyrrolidinone; (g) Bra, HOAc; (h) S02C12, CH2Cl2.
diethylamine;ls the 5-trifluoromethyl group (6g) with sodium trifluoroacetate and copper(1) iodide in N-methylpyrr~lidinone;'~ and the 5-methyl group (6h) by hydrolysis of the ester and treatment of the resultant naphthoic acid with methyllithium and methyl iodide in THF. Bromination of compound 6c with bromine yielded 8-bromo-5-methoxy-2-naphthoic acid (6i). The preparation of 7-or 6-methylnaphthalenes 8 with a substituent in the 1, 2, or 3-position was most readily achieved by the synthesis of a 2-tetralone 27 (Scheme IV, method D). The 2-tetralones 27 were prepared from a substituted phenylacetic acid 26 by formation of the acid chloride and cyclization by treatment with aluminum chloride and ethylene.Ia The resultant 2-tetralones27 were
Antihyperglycemic Naphthalenyl Oxathiadiazoles
Journal of Medicinal Chemistry, 1993, Vol. 36,No. 17 2487
methylated with titanium(IV)chloride/methylmagnesium ~hl0ride.l~ It is necessaryto use this nonbasicmethylating reagent because of the facile enolization of 2-tetralones. Cerium(II1) chloride/methyllithiumm was also used for the methylation reaction, but the yields were generally lower than with the titanium reagent. Aromatization of the alcohols 28 with triphenylmethanol in trifluoroacetic acidz1 gave the 7- or 6-methylnaphthalenes 8. The tetralone route was used to prepare the l-bromo, l-chloro, and 2-chloro-7-methylnaphthalenes(8a-c) and 2-fluoro6-methylnaphthalene (8d). Compound 8a was converted to the l-cyano compound (8e)by treatment with copper(1) cyanide and to the 1-methylthio compound (Sf) with sodium thiomethoxide and copper(1) oxide in N-methylpyrrolidinone. Upon NBS bromination (method C) of 8f, the product resulting from bromination of the naphthalene ring at the 5-position and a lesser amount of the 2-(bromomethyl)-5bromocompound were produced. None of the desired monobrominated compound, 74bromomethyl)-l-(methylthiohaphthalene,was obtained. Compound 8d was converted to 1-bromo-6-fluoro-2-methylnaphthalene (8g) with bromine in acetic acid and to l-chloro-6-fluoro-2-methylnaphthalene (8h)with sulfuryl chloride in dichloromethane. Additional naphthoic acids (or derivatives) and methylnaphthalenes were prepared by literature methods or as described below: l-chloro-2-naphthoicacid (6j),=3-chloro2-naphthoic acid (6k),223-bromo-2-naphthoicacid (61),23 4-bromo-2-naphthoic acid (6m),116-bromo-Bnaphthoic acid (6n),"J1 7-bromo-2-naphthoicacid (60),11 l-methoxy2-naphthoic acid ( 6 ~by) methylation ~ ~ of l-hydroxy-2naphthoic acid, 3-methoxy-2-naphthoic acid by methylation of 3-hydroxy-2-naphthoicacid, 6-methoxy2-naphthaldehyde (619:~ 7-methoxy-2-naphthoic acid (6s),11l-methyl-2-naphthoicacid (6t)F77-methyl-2-naphthoic acid (6u),11l-ethyl-2-naphthoicacid (6v)by the same acid procedure as for 6t, l-methoxy-4-chloro-2-naphthoic ( 6 ~ ) : 1,3-dimethyl-2-naphthoic ~ acid (6s) by the same procedure as for 6t, 8-bromo-7-methyl-2-naphthoic acid (6y) by bromination of 6u, 1-fluoro-2-methylnaphthalene (8i),29l-bromo-2-methylnaphthalene(8j),273-methyl-2(trifluoromethy1)naphthalene(8k)by trifluoromethylation'" of 2-bromo-3-methylnaphthalene, and l-bromo-2,3dimethylnaphthalene (81) by bromination of 2,3-dimethylnaphthalene. Also, the 5-ethyl group was introduced at a later stage by catalytic hydrogenation of 5-ethynyl-2naphthaleneacetonitrile (1Oc).
Table 11. Variations of Tether
Results and Discussion The compounds were tested in a postprandial assay in the db/db mouse (see Experimental Section). Reported in Tables II-IV are the % changes in plasma glucose after 4 days of drug treatment (PO). A reduction of 50430% represents a normalization of plasma glucose levels in the db/db mouse. In Table 11,the results of an examination of the tether portion of this series of compounds are outlined. As reported earlier: compound 1lowered plasma glucose by 37 % a t a dose of 20 mg/kg. In compound 29, removal of the methylene linker between the naphthalene and the oxathiadiazole groups decreased the activity (less than -15% change in plasma glucose vs control). An increase in the length of the linker by one methylene to give compound 30 did not affect activity, but any further increase in chain length yielded less potent compounds (31 and 32). Also,replacement of the ethylene tether of
compd
X
mp, OC
bond 137-138 CH2 145-147 (CH2)2 114-115 (CH2)s 139-140 (CH2)r 94-95 CH=CH 146-147 OCH2 101-103 102-103 SCH2 CH(CH3) Oil C(CHd2 146-147 CH(CH8h) 61-62 CH(CH3)CHz 99-101 CH(OCHs)CH2 137-138 asatisfactory C, H, and N elemental analyses (*0.4%) were obtained. bValues (mean SE) are percent changes relative to vehicle-treated group with use of 4-6 mice per group. Less than -15% change. p < 0.05. e -28 5%dat 100 mg/kg. !& 1 30 31 32 33 34 38 36 37 38 39 40
*
*
compound 30 with an alkenyl group (33) or ether linkage (34) resulted in a less than -15 % changein plasma glucose. However, with the sulfide linker of compound 36, plasma glucose was lowered by 40%. Monomethylation of the tether of compound 1 to give compound 36 improved activity whereas dimethylation to give compound 37 decreased activity (-49% and less than -15 % , respectively). Also, benzylation (38) lowered the activity. In the case of compound 30, monomethylation (39) or methoxylation (40) of the ethylene linker lowered the glucose decreaseto-27 % and lessthan -15 % ,respectively. Thus, in the linker region of this series of compounds, only a small degree of variation in chain length, lipophilicity, and steric volume is tolerated a chain length of one or two carbons (1 and 301, replacement of a carbon with a sulfur (35), and monomethylationof the methylene linker (36). An examination of substitutions on the naphthalene ring is reported in Table 111. The compounds listed in thistable all have the methylene linker found in compound 1. Only results for the lower doses of 5 and 1mg/kg are included. At 5 mg/kg, compound 1lowered plasma g l u m by less than 15% and was therefore not tested at 1mg/kg. The introduction of a substituent on the naphthalene ring of 1 led, in many cases, to an improvement in activity. However, the degree of improvement was influenced by the electronic and steric character of the substituent and especially by the position of substitution on the naphthalene ring. Substitution at positions 1,5, or 8 was found to give the best activity. This trend is best illustrated by compounds 48-64, in which a bromine has been placed at each position of the naphthalene ring. Compounds 48 (1-Br),61 (5-Br),and 54 (&Br) lowered plasma glucose by 40,47, and 59%, respectively, at a dose of 5 mg/kg. The remaining bromo compounds (49, 60, 62, and 53) lowered glucose by less than 30%. At the lower dose of 1mg/kg, only the 1-, 5-, and &bromo compounds produced a significant drop in plasma glucose (-21, -35, and -48%, respectively). In some cases, 3-substituted compounds were comparable to 1-,5-, or &substituted compounds. For example compounds 61 (l-CHs), 62 (3-CH3), and 63 (5-CH3)lowered plasma glucose at 5 mg/kg by 36,36, and 37%, respectively, and compounds 44 (3-C1), 46 (5-C1),
Ellingboe et al.
2488 Journal of Medicinal Chemistry, 1993, Vol. 36,No.17
Table 111. 2-Naphthalenylmethyl Oxathiadiazoles 8
R'
compd 1
41 42 43 44 45 46 47 48 49 50
H 6-F l-F 1x1 3-C1 541 7-C1
aci
synthesis method (of 10)
D,C C C B B
D,c D,C
1
mp, OC 145-147 168-169 158-159 130-132 161-162 169-170 185-186 149-150 140-142 153-154 164-165 159-160 164-165 145 (dec) 169-160 143-144 143-145 137-138 146-147 147-148 151-152 118-119 146-147 166-157 165-166 106-107 145-147 146-146 175-176
formulaa C12HloN202S CiaHeFNzOzS C12HeFNaOB CiaHeCNOaS CizHsClNaOzS CizHeClNzOB CizHeC~zOB CizHsCWM ClzHeBrNzOzS ClzHeBrNzOzS CiaHeBrNzOnS ClzHeBrNzOzS ClzHsBrNzOB ClzHeBrNzOzS ClaHeBrNzOzS CiaHizNzOsS CiaHizNzOaS CisHizNaOsS Ci3HizNz03S CisHizNzOsS CiaH12N202S2 CisHizNzOzS CiaHizNzOzS CiaHizNzOzS CisHizNzOzS CirHirNzOzS
1mg/k d d C C C
-21 d
5 mg/k C
e
-39*4f -27 7f -44*2f -44*3f
*
* 5f
C
-65*2f l-Br -21 6 f -40*2f C 3-Br -28 11 C B 4Br -21 6 C B 51 5Br -35k2f -47*9f B 52 6-Br -26 4 c B 53 7-Br C d B 54 8-Br -69+2f -48+8f D,C 55 1-OCH3 C -43*4f B 56 3-OCH3 B -16 4 8 57 5-OCH3 C C B 58 6-OCH3 d h B 59 7-OCH3 -19 4 d B 60 5-SCHs d C B 61 l-CH3 -20*2f -38*3f B 62 3-CH3 -20*2f -36*7f B 63 5-CH3 -37+2f c B 64 7-CH3 B d 1 65 l-CHsCH2 C -24*7f B 66 5-CHsCH2 clrHlrN20B C -23 3f B 67 3-CF3 -30+4f CiaHeFsNzOzS c C 68 5-CF3 ClaHeFaNZ02Sj C -30 6f B 69 5-CHdH -17 7 CirHizNzOzS d B 166-168 70 5-CH=C ClrHloNZOZSk -19 3 -45*3f B 175-176 71 8-CN C13H&30d C C D,C 177-179 a Satisfactory C, H, and N elemental analyses (*0.4%) were obtained,except ae noted. * Valuea (mean SE)are percent changea relative to vehicle-treated group with use of 4-6 mice per group. e Less than -15 % change. Not teeted. -26 2% f at 100 mg/kg. f p < 0.06.fi -50 & 3%f a t 20 mg/kg. Less than -15% a t 20 mg/kg. '-36 A 2% f a t 20 mg/kg. j C: calcd,49.68; found, 49.11. C calcd, 62.21; found, 60.70. C
*
* * *
*
*
*
and 47 (843) lowered glucose by 44, 44, and 55%, respectively. In addition to the position of substitution, the steric and electronic nature of the substituent was found to be important. An example of a possible steric effect can be seen in the decrease in activity on replacing a methyl group with an ethyl group. As mentioned above, the 1-CH3and 5-CH3 compounds (61 and 63) lowered plasma glucose by about 36% at 5 mglkg. The corresponding ethyl compounds (65 and 66) brought about only 24 and 23% decreases. Changingthe degreeof saturation of the 5-ethyl group to yield a 5-vinyl substituent (69) did not improve activity (-17%). In contrast, the 5-ethynyl group (70) lowered plasma glucose by 45% at 5 mg/kg. This significant improvement in activity may result from the difference in electronic character of the substituent. Electroniceffects are further illustrated by the following series of 5-substituted compounds, with test results at a dose of 5 mg/kg: 45 (541, -44%), 51 (5-Br, -47%), 57 (5OCHs,
