Synthesis of Benzazepinone and 3-Methylbenzothiazepinone Analogues of Diltiazem

Journal of Organic Chemistry

Volumn 55, Issue 21, 1990, Pages 5572-5579

  Floyd, David M ^a   Moquin, Robert V ^a   Atwal, Karnail S ^a   Ahmed, Sved Z ^a   Spergel, Steven H ^a   Gougoutas, Jack Z ^a   Malley, Mary F ^a  

^a Squibb Inst for Medical Research   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 BENZAZEPIN 2 ONE DERIVATIVE; 1,5 BENZOTHIAZEPIN 4(5H) ONE DERIVATIVE; DILTIAZEM DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; NONHUMAN; NUCLEAR MAGNETIC RESONANCE;

EID: 0025104166     PISSN: 00223263     EISSN: 15206904     Source Type: Journal    
DOI: 10.1021/jo00308a013     Document Type: Article

References (40)

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23. Crystallographic data for 3, 4, 5, 6, and 10 are supplied as supplementary material to this paper. We have examined the solid state structures of over 30 benzazepinone and benzothiazepinone derivatives. Without exception, monosubstituted cis derivatives crystallize in the “M” twist-boat configuration with the C3 substituent in an equatorial position. For C3 disubstituted derivatives, greater variation has been observed. For example, whereas 10 adopts the “M” twist-boat configuration of 5, 4 has a flat conformation in which all of the cyclic atoms of the fused benzazepinone nucleus except C4 are nearly coplanar.
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25. We have adopted nomenclature previously employed to describe ring conformations of diltiazem. See: Glaser, R.; Sklarz, B. J. Chem. Soc., Perkin Trans. II 1989, 1031. Although the benzazepinone analogues are racemic, we limit our discussion to enantiomers having the S configuration at C4 to facilitate a comparison of their structures to that of diltiazem (S,S absolute configuration). The twist-boat conformation of diltiazem in the solid state has been designated as “M” on the basis of the negative cyclic torsional angle S1-C2-C3-C4. We have applied the “M” and “P” descriptors to the benzazepinone series independent of the priority of the substituent at C3 and C4 to simply identify the minus or plus sign of the C2-C3-C4-C5 torsional angle. The “M” conformation of 5 is very similar to the (M, 2S,3S) twist-boat conformation described for the solid-state conformation of diltiazem. Although previously unobserved in the solid state, the P twist-boat conformation has been suggested for the minor (1:12) conformational component noted during NMR studies with diltiazem.
26. Substituents at C4 cannot be designated as axial or equatorial since they are oriented symmetrically with respect to the 2-fold axis and the mean plane of the two enantiomeric twist-boat conformations.
27. Derwent Abstracts 84-185470/30, 84-185471/30, and 85-0709034/13. These abstracts of Japanese Patents describe the reduction of a benzothiazepin-3,4-dione with sodium borohydride to give predominantly the cis 2-aryl-3-hydroxy precursor of diltiazem.
28. Predicated on the report of Ohno et al. (see ref 15f) that thermal condensation of 2-aminothiophenol with 2-methyl-3-phenylpropenoic acid gave cis-3-methyl-4-phenylbenzothiazepinone as a minor component (6.7%), we attempted the identical reaction employing 2-methyl-3-(4-methoxyphenyl)propenoic acid. In our hands, we were only able to isolate trans-17 in less than 15% yields. Additionally, conversion of trans-17 to its 5-(dimethylamino)ethyl derivative followed by attempted epimerization of the methyl substituent under a variety of conditions was not found to be a useful method to prepare 18.
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35. Determination of the concentration of test compound necessary to cause 50% relaxation of 110 mM K+ contracted rabbit aorta (IC50 value) were made in the laboratory of S. Moreland, Squibb Institute for Medical Research Pharmacology Department; see: Brittain, R. J.; Moreland, S. Physiologist 1985. 24. 325.
36. Alkylidenemalonates can be employed in the initial reaction with nitrotoluene. For example, the reaction between cyclohexylidene-malonate and 5-chloro-2-nitrotoluene gave a 78% yield of product, which was converted by the procedures described in this work to an analogue of 8 containing a cyclohexyl ring at C4 in place of the p-methoxyphenyl group, mp 238.5-239.5 °C dec. Anal. Calcd for C22H31N2O3HCl. 0.25 H20: C, 58.98; H, 7.31; N, 6.26; Cl, 15.83. Found: C, 58.98; H, 7.28; N, 6.22; Cl, 15.64. Derivatives of the 3-hydroxybenzazepines have been used to prepare analogues with a variety of 3-thio and amino analogues. Additionally, 3-allyl analogues, prepared by the procedures described above, have been converted into functionalized 3-alkyl derivatives. Das, J.; Floyd, D. M. U.S. Patent 4,767,756, 1988.
37. Das, J. U.S. Patents 4,771,047 and 4,774,239, 1988.
38. This may be related to the different conditions used for this cyclization reaction. In additional studies with the benzazepinone system, we have found that alterations in the solvent and base strength can have a marked effect on both the rate and stereoselectivity of cyclization with these alkylated diester intermediates. Floyd, D. M.; Moquin, R. V. Unpublished results.
39. Some of the structure-activity studies and a brief description of the synthetic procedures described in this paper were presented at the 198th National Meeting of the American Chemical Society, Miami Beach, September 10–15, 1989. See: Floyd, D. M.; Kimball, S. D.; Krapcho, J.; Das, J.; Moreland, S.; Hedberg, S. A.; White, R. E. Abstracts of Papers; american Chemical Society: Washington, DC, 1989; Med Chem, 86 and
40. Das, J.; Floyd, D. M.; Moreland, S.; Hedberg, S. A. Abstracts of Papers; American Chemical Society: Washington, DC, 1989; Med Chem 93.