954
J. Med. Chem. 1988,31,954-959
fish-skin bioassay, skins become light in response to MCH due to ~elanosomeaggregation within melanocytes; the skins can then be redarkened by the addition of MSH, which causes redispersion of melanosomes within melanocytes. Movement of melanosomes within melanocytes results in color changes that can be monitored by a photov& reflectometer. Changes in &in color (reflectance) are recorded as percent changes from the initial base (zero) value. The frog ( R pipiens) ~ ~skin~bioassaywas utilized as previously described.’*J9
Acknowledgment. This work was supported by grants from the US. Public Health Service (AM 17420), the
National Science Foundation, PCM-8412084 and DCB8615706, and from Consello Nacional de Desenvolvimento Cientifico, TechnDl~gico4071g6/87, ~ ~ ~ ~ i l . Registry No. 1, 112794-06-6;2, 112794-07-7;3, 112794-08-8; 43112794-09-9;5, 112794-10-2; 6, 112794-11-3;7, 112794-12-4; 8, 112794-13-5;9, 112794-14-6;BOC-Glu(OBzl),13574-13-5;BOCTrP(For),47355-10-2;BOC-Cys(4-Me-BzlL61925-77-7;BOC-Pro, 15761-39-4; BOC-Arg(Tos),13836-37-8;BOC-Tyr(2,6-C12-Bzl), 40298-71-3;BOC-Val, 13734-41-3;BOC-Met, 2488-15-5;BOC-Ala, 15761-38-3;BOC-Thr(Bzl),15260-10-3;BOC-Asp(OBzl),7536-58-5; BOC-Gly, 4530-20-5.
Nonsteroidal Antiandrogens. Synthesis and Structure-Activity Relationships of 3-Substituted Derivatives of 2-Hydroxypropionanilides Howard Tucker,* J. W. Crook, and G. J. Chesterson Imperial Chemical Industries PLC, Pharmaceuticals Division, Mereside, Alderley Park, Macclesfield, Cheshire, SKlO 4TG Great Britain. Received September 29, 1987 A series of 3-(substitutedthio)-2-hydroxypropionanilidesand some corresponding sulfones and sulfoxides of general structure 7,in which R’ is methyl or trifluoromethyl, were prepared and tested for antiandrogen activity. Members of the trifluoromethyl series (7, R’ = CF3)generally exhibited partial androgen agonist activity whereas the members of the methyl series (7,R’ = CH,) were pure antagonists. Lead optimization in the methyl series has led to the discovery of novel, potent antiandrogens, which are peripherally selective. One of these, (RS)-4’-cyano-3-[(4fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3’-(trifluoromethyl)propionanilide, 40 (IC1176334), is being developed currently for the treatment of androgen-responsivebenign and malignant disease.
Cancer of the prostate is the second most common cause of death in American males with about 25 OOO deaths from this condition being recorded in 1974.’ The growth of the prostate tumors is stimulated by androgens, the male sex hormones. Since the pioneering work of Huggins and Hodges in 1941,2which showed the hormone dependence of this tumor, the mainstay of treatment for prostate cancer has been the withdrawal of androgens either by castration (orchidectomy) or estrogen therapy. Both ?f these therapies have disadvantages. Orchidectomy is unpopular with the patients and can result in psychological problems, and it exposes the elderly patients to the trauma of surgery. Estrogen therapy is effective in most patients but is accompanied by severe side effects including cardiovascular complications (cardiac failure, edema, and thromboembolism), painful gynecomastia, impotence, and loss of 1ibid0.~ Both these approaches lead to the withdrawal of the androgens produced by the testes; however, the adrenal glands also produce androgens, so a more effective therapeutic agent would be a compound that prevented the natural androgens from interacting with their receptors, i.e., an antiandrogen. There are two antiandrogens currently available commercially, cyproterone acetate (1) and the nonsteroidal anilide flutamide (2), whose active form in vivo is the hydroxylated metabolite, hydroxyflutamide (3). In addition to its antiandrogen activity, cyproterone acetate is also a potent progestin and inhibits gonadotrophin se~ r e t i o n .It ~ is effective in the treatment of prostate cancer but among its side effects may be listed loss of libido, gynecomastia, fluid retention, and thrombosis. Flutamide is a pure antiandrogen; that is, it does not exhibit other (1) DeKernion, J. B. In Cancer Treatment; Haskell, C. M., Ed.; W. B. Saunders: Philadelphia, 1980; p 358. (2) Huggins, C.; Hodges, C. V. Cancer Res. 1941, 1, 293. (3) Byar, D. P. Bull. N . Y. Acad. Med. 1972, 48, 751. (4) Neumann, F. In Pharmacology and zlinical uses of inhibitors of hormone secretion and action; Furr, B. J. A., Wakeling, A. E., Eds.; Bailliere Tindall: London, 1987; p 132.
CI
1
0
CF3
3
R:OH
hormonal activities. It is effective in the treatment of prostate cancer, the main side effect reported being gynec~mastia.~One consequence of its pure antiandrogenic profile is that it prevents androgens from exerting their negative feedback mechanism on the hypothalamus, which results in an increased pituitary secretion of, interalia, luteinizing hormone (LH), which stimulates androgen production by the testes.6 The antagonist, therefore, brings about the increased production of the natural agonist, which effectively diminishes its efficacy at the target organ. Our objective was to find a pure antiandrogen that was selective for the accessory sex organs, that is, had little or no effect on pituitary LH and consequently testosterone secretion. This paper describes our successful preparation of such a selective antiandrogen, which should have clinical advantages over existing antiandrogens in the treatment of prostate cancer. Chemistry Two general synthetic routes were used to prepare the anilides listed in Tables 1-111. The route outlined in Scheme I was used for the preparation of anilides 7. This involved coupling of an a-hydroxy acid chloride, prepared in situ by treating the a-hydroxy acid 5 with thionyl ( 5 ) Neri, R. 0.;Florance, K.; Koziol, P.; van Cleave, S. Endocrinology 1972, 91, 427. (6) Neumann, F.; Jacobi, G. H. Clin. Oncol. 1982, I , 49.
0022-2623/88/1831-0954$01.50/00 1988 American Chemical Society
Journal of Medicinal Chemistry, 1988, Vol. 31, No. 5 955
Nonsteroidal Antiandrogens
Table I
compd
RZ
R3
R4
synth route"
X
mp, "C formula anal. ED5,, agonismb CF3 CF3 H S 1 139-140 C17H12FeN204S C, H, N 33% at 2.5c 34 S 1 144 C18H12F6N202S C, H, N 0.7 30 CF3 CF3 H CF3 CF3 H so 1 175-176 C18H12F6N203S C, H, N 0.3 so2 1 175-176 C ~ ~ H I ~ F ~ N ~ O ~ S C, H, N 0.5 32 CF3 CF, H C1 CF, H S 1 152 C, H, N 0.9 21 15 S 1 104 C1 CF, H 11% at 5OC 110-112 S 1 H CH3 .H NA 1.7 81.5-83 S 1 CF3 CH3 H NA 1.4 so 1 164-165 CF3 CH3 H NA 1.8 172-173.5 soz 1 CF3 CH3 H . 1.0 S 1 103-105 CF3 CH3 H NA 1.0 126.5-127.5 so 1 CF3 CH3 H NA 1.5 149-151 so2 1 CFB CH3 H NA 2.5 S 1 60-62 C1 CH3 H 44% at 25c 85-86 S 1 C1 CH3 H 0.5 88-90 S 1 C1 CH3 H NA 36% at 50' 77-78 S 1 NO2 CH3 H 50 98-99 S 1 CH3 CH3 H 11 178-179 S 1 CF3 CF3 4-C1 23% at 2.5c 43 147-148 S 1 CF3 CF3 4-C1 NA 1.6 101-103 S 1 CF3 CH3 4 4 1 NA 18 132-133 S 11 CF3 CH3 3 4 1 5 98-99.5 S 11 CF3 CH3 2-c1 NA 1.1 112-113 S 11 CF3 CH3 4-F 0.4 188-189 soz 11 CF3 CH3 4-F NA 20 139-141 S 11 CF3 CH3 4-NO2 10 108-111 S 11 CF3 CH3 4-CN NA 16 120-121 11 CFx CHx 4-CHq0 S NO, CF, CHj 4-CH;S S 11 111-112 c;,H;;F,N~o;s, C;H,N 5 S C, H, N 0.5 NA 11 116-117 C18H14F4N202S CN CF3 CH3 4-F 40 C, H, N 0.5 NA so2 11 191-193 ClaH14F4N204S CN CF3 CH3 4-F 41 C, H, N 4 NA S 1 137-138 ClgH14ClF3N202S CN CF3 CH3 4-C1 42 C, H, N 25 11 125-126 C19H17F3NzOzSz CN CF3 CH3 4-CH3S S "In the case of sulfoxides and sulfones, the synthetic route refers to the preparation of the parent sulfide. *The number quoted is the weight of the ventral prostate (mg). Control values are in the range 10-14 mg. NA indicates no statistically significant increase in ventral prostate weight compared to controls. Testosterone propionate when dosed at 0.5 mg/kg sc in this test gave a prostate weight of 48 mg. cPercentage inhibition at the dose stated. dC: calcd, 52.4; found, 51.9. 'C: calcd, 52.4; found, 52.9. fN: calcd, 9.4; found, 8.9. gH: calcd, 3.3; found, 2.8. 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
R' NO2 CN CN CN CN
Scheme I
Scheme I1
RS?" HO
HCI. AmH
C02H
I
KCN. HzSO4
R S / X R ' HO
CN
7
chloride in dimethylacetamide at -20 "C, with an aniline at the same temperature. The a-hydroxy acids 5 were prepared by acid hydrolysis of cyanohydrins 4, which were obtained from the corresponding thio ketones by standard means. The hydrolysis of the cyanohydrins 4 with concentrated hydrochloric acid in Carius tubes at 110 "C was problematic, giving a 3:2 mixture of the required acid 5 and the intermediate amide 6. Hydrolysis could be ef-
R s o 2 + L H ~ c N HO
CHg CF3
fected by using a mixture of glacial acetic acid (ca 20% by volume) and concentrated HC1 and by heating the mixture on a steam bath overnight to give a 4:l mixture of 5 and 6 in higher overall yield. The thio ketones were
Tucker et al.
956 Journal of Medicinal Chemistry, 1988, Vol. 31, No. 5
Table I1
~
~~
~~
~~
~~
~
~~
70 inhibn at
compd
R1 R2 R3 43 CN CH3 C1 44 CN C1 n-C3H7 45 c1 CzH5 C1 n-C3H7 46 c1 C1 47 CN CF3 CH3 48 CN CF3 CzH5 49 CN CFB CzH5 CF, i-C3H7 50 CN 51 CN CF3 n-C3H7 52 NOz CF3 n-C3H7 Refers to synthesis of parent sulfide.
X S S S S S S
synthroute 1 1 1 1 1 1
SO2
10
S S S
1 1 1
mp, "C 121-122.5 89-90 57-59 60-61 120.5-122 119-120 164-165 107-109 88-90 67-68
formula ClzH1oClF3NzO~S C14H14ClF3N202S C12HizC12F3N02S C13H14Cl2F3N02S C~~H~OF~N C14H12F6N202S
C14H12F6N204S C15H14F6N202S C15H14F6N202S
C14H14F6N204S
anal. C, H, N C, H, N C, H, N C, H, N ~C, O H, ~ SN C, H, N C, H, N C, H, N c , H, N C, H, N
2.5 mg/kg 95 98 75 80
68 74 68 77 72 30
agonism 36 26 28 32 50 31 32 33 42
Table I11
compd
R' R2 R3 X synth routeP! mp, "C formula 1 53 SO2 118-119 CN CF3 CzH5 C14H15F3N204S 1 54 so 110-112 C,,H,,FqN,OqS CN CFq CVH, 1 108.5-109.5 55 CN CFj CH31 98-100 CN CF3 i-C3H7 56 117.5-119 1 57 CN CF, i-CnH7 1 109-110 58 NO2 CF3 CH; 135-136 1 59 NO2 CF3 C2H5 66-68 1 60 NO2 CF3 i-C3H7 1 118-1 19 61 NO2 CF3 n-C3H7 104-105 11 62 NO2 CF3 n-C5H11 136.5-138 11 63 NOz CF3 t-C,Hg 131-132 11 64 NO2 CF3 2-thiazolyl 155-157 11 65 NO2 CF3 2-pyridyl 137-139 11 66 CN CF3 2-pyridyl 149-150 11 67 NO2 CF3 3-pyridyl 135-136 11 68 CN CF3 3-pyridyl 193-195 11 69 NO2 CF3 4-pyridyl 120-12 1 11 70 CN CF3 2-pyrimidyl 101-103 11 71 CN CF3 2-thienyl 109-111 11 72 NO2 CF3 5-methyl-2-1,3,4-thiadiazolyl 11 178-180 73 CN CF3 2-benzothiazolyl 160-162 11 74 NO2 CF3 4-methyl-2-thiazolyl 2 flutamide In the case of sulfoxides and sulfones, the synthetic route refers to the preparation of the parent sulfide. significant increase in ventral prostate weight. C: calcd, 42.2; found, 42.7. C: calcd, 53.5; found, 54.0. '
anal. C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C,H,Nc C, H, N C, H, N C, H, N C, H, N C, H, Nd C, H, N C,H,N C,H,N C,H, N C,H, N C, H, N C, H, N C, H, N
EDSo agonismb 1.1 NA 1.3 NA NA 2.5 NA
