Protocols for amide high-speed analoging. Preparation of novel, small molecule cathepsin D inhibitors

Tetrahedron Letters

Volumn 40, Issue 52, 1999, Pages 9195-9199

  Chen, Jinshan ^a   Dixon, Brian R ^a   Dumas, Jacques ^a   Brittelli, David ^a  

^a BAYER CORPORATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANILINE; CARBOXYLIC ACID DERIVATIVE; CATHEPSIN D INHIBITOR; CHLORIDE; HYDRAZIDE; NITROGEN; POLYMER; SILVER DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DRUG SYNTHESIS; MOLECULAR SIZE; REACTION TIME;

EID: 0033601435     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(99)01972-3     Document Type: Article

References (23)

1. Cathepsin D has been associated with Alzheimer's disease and cancer. See Ladror, U. S.; Snyder, S. W.; Wang, G. T.; Holzman, T. F.; Kraft, G. A. J. Biol. Chem. 1994, 269, 18422. Rochefort, H.; Liaudet, E.; Garcia, M. Enzyme Protein 1996, 49, 106. Lah, T. T.; Calaf, G.; Kalman, E.; Shinde, B.; Somers, R.; Estrada, S.; Salero, E.; Russo, J.; Daskal, I. Breast Cancer Research and Treatment 1996, 39, 221.
2. Cathepsin D has been associated with Alzheimer's disease and cancer. See Ladror, U. S.; Snyder, S. W.; Wang, G. T.; Holzman, T. F.; Kraft, G. A. J. Biol. Chem. 1994, 269, 18422. Rochefort, H.; Liaudet, E.; Garcia, M. Enzyme Protein 1996, 49, 106. Lah, T. T.; Calaf, G.; Kalman, E.; Shinde, B.; Somers, R.; Estrada, S.; Salero, E.; Russo, J.; Daskal, I. Breast Cancer Research and Treatment 1996, 39, 221.
3. Cathepsin D has been associated with Alzheimer's disease and cancer. See Ladror, U. S.; Snyder, S. W.; Wang, G. T.; Holzman, T. F.; Kraft, G. A. J. Biol. Chem. 1994, 269, 18422. Rochefort, H.; Liaudet, E.; Garcia, M. Enzyme Protein 1996, 49, 106. Lah, T. T.; Calaf, G.; Kalman, E.; Shinde, B.; Somers, R.; Estrada, S.; Salero, E.; Russo, J.; Daskal, I. Breast Cancer Research and Treatment 1996, 39, 221.
4. For small molecule cathepsin D inhibitors recently reported in the literature, see: (a) Kick, E. K.; Roe, D. C.; Skillman, A. G.; Liu, G.; Ewing, T. J. A.; Sun, Y.; Kuntz, I. D.; Ellman, J. A. Chem. Biol. 1997, 4, 297.
5. (b) Lee, C. E.; Kick, E. K.; Ellman, J. A. J. Am. Chem. Soc. 1998, 120, 9735.
6. (c) Whitesitt, C. A.; Simon, R. L.; Reel, J. K.; Sigmund, S. K.; Phillips, M. L.; Shadle, J. K.; Heinz, L. J.; Koppel, G. A.; Hunden, D. C.; Lifer, S. L.; Berry, D.; Ray, J.; Little, S. P.; Liu, X.; Marshall, W. S.; Panetta, J. A. Bioorg. Med. Chem. Lett. 1996, 6, 2157.
7. (d) Dumas, J.; Brittelli, D.; Chen, J.; Dixon, B.; Hatoum-Mokdad, H.; Koenig, G.; Sibley, R.; Witowsky, J.; Wong, S. Bioorg. Med. Chem. Lett. 1999, 9, 2531.
8. Since the initiation of our efforts, several groups have published results in this area. See: (a) Parlow, J. J. Tetrahedron Lett. 1995, 36, 1395.
9. (b) Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman, B. A.; Hahn, P. Tetrahedron Lett. 1996, 37, 7193.
10. (c) Siegel, M. G.; Hahn, P.; Dressman, B. A.; Fritz, J. E.; Grunwell, J.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357.
11. (d) Flynn, D.; Crich, J.; Devraj, R.; Hockerman, S.; Parlow, J.; South, M.; Woodard, S. J. Am. Chem. Soc. 1997, 119, 4874.
12. (e) Gayo, L. M.; Suto, M. J. Tetrahedron Lett. 1996, 38, 513.
13. (f) Booth, R.; Hodges, J. J. Am. Chem. Soc. 1997, 119, 4882.
14. (g) Parlow, J. J.; Flynn, D. L. Tetrahedron 1998, 54, 4013.
15. (h) Suto, M. J.; Gayo-Fung, L. M.; Palanki, S. S.; Sullivan, R. Tetrahedron 1998, 54, 4141.
16. Poly(4-vinylpyridine), chloride ion-exchange resin and polymer-bound sulfonic acid were purchased from Aldrich.
17. 1H NMR and MS. Purity data were based on HPLC: C8 column, gradient elution 5% to 95% acetonitrile in water with 0.1% TFA, UV detection at 254 nM.
18. Silver cyanide has been used to facilitate the coupling of acyl chlorides with highly hindered alcohols, see: Takimoto, S.; Inanaga, J.; Katsuki, T.; Yamaguichi, M. Bull. Chem. Soc. Jpn. 1976, 49, 2335.
19. Silver content was measured in prepared samples in row E (Table 1). All analogs contained less than 200 ppm of silver, as determined by ICP emission spectrophotometry (Robertson Microlit Laboratories, Madison, NJ).
20. Products D8, E8 and F8 (Table 1) (0.05 mmol in l mL THF) were treated with 200 mg aminomethylated polystyrene (0.2 mmol) at room temperature for 2 days. The samples were filtered and concentrated to furnish the products.
21. Amide formation has also been achieved by using polymer-bound EDC. See: Desai, M. C.; Stramiello, L. M. S. Tetrahedron Lett. 1993, 34, 7685. Polymer-bound carbodiimide is now commercially available.
22. Compound 3 was prepared from the coupling of 1-fluorenecarboxylic acid with the corresponding acyl hydrazide. Compound 4 was prepared from 3,5-dichloro-2-hydroxybenzoyl chloride with the corresponding acyl hydrazide.
23. For cathepsin D assay conditions, see Ref. 2d.