Mecigestone

Mecigestone
Clinical data
Other names	Pentarane B; 6α-Methyl-16α,17α-cyclohexanoprogesterone
Identifiers
	IUPAC name (4aR,4bS,6aS,6bS,10aR,11aS,11bR,13S)-6b-Acetyl-4a,6a,13-trimethyl-4,4b,5,6,7,8,9,10,10a,11,11a,11b,12,13-tetradecahydro-3H-indeno[2,1-a]phenanthren-2-one;
CAS Number	58212-84-3;
PubChem CID	124372;
ChemSpider	110790;
UNII	N3UWJ2K7NF;
CompTox Dashboard (EPA)	DTXSID30973778 ;
Chemical and physical data
Formula	C26H38O2
Molar mass	382.588 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@H]1C[C@@H]2[C@H](CC[C@]3([C@H]2C[C@@H]4[C@]3(CCCC4)C(=O)C)C)[C@@]5(C1=CC(=O)CC5)C;
	InChI InChI=1S/C26H38O2/c1-16-13-20-21(24(3)11-8-19(28)15-22(16)24)9-12-25(4)23(20)14-18-7-5-6-10-26(18,25)17(2)27/h15-16,18,20-21,23H,5-14H2,1-4H3/t16-,18+,20+,21-,23-,24+,25-,26-/m0/s1; Key:OAICPORQJIVREU-SGCXAXHESA-N;

Mecigestone, also known as pentarane B, as well as 6α-methyl-16α,17α-cyclohexanoprogesterone, 6α-methylcyclohexano[1',2';16,17]pregn-4-ene-3,20-dione, or 17α-acetyl-6α-methyl-16β,24-cyclo-21-norchol-4-en-3-one, is a steroidal progestin that was developed by the Zelinskii Institute of Organic Chemistry of the Russian Academy of Sciences and has been proposed for clinical use as a progestogen but has not been marketed.^[1]^[2]^[3]^[4]^[5] It is the 6α-methylated analogue of pentarane A, which is also known as D'6-pentarane or pregna-D'6-pentarane.^[5]

Synthesis

The synthesis has been reported:^[6] Patent:^[7] Precursor:^[8] Micronization technology:^[9]

The Diels-Alder reaction of 16-DPA [979-02-2] (1) with butadiene gives PC99565806 (2). It is important to recognize that for mecigestone the stereochemistry about the E-ring is cis and not trans. The trans isomer is PC99565808.
Ex 1: Epoxidation of the olefin with ethereal Monoperphthalic acid [2311-91-3] occurs to give (3). A search of the pubchem registry only gave the trans configuration about the E-ring (PC11873237), and not the expected cis stereochemistry.
The reaction with methyl magnesium iodide occurs with a regioselectivity to the 6 position from the beta face. Saponification of the acetate ester also occurs during the work-up to give (4).
The Jones oxidation leads to the enone of the finished product. Epimerization of the beta-methyl group also occurred during this step. Thus, completing the synthesis of mecigestone (5).

References

↑ Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 8–. ISBN 978-1-4757-2085-3.
↑ Fedyushkina IV, Skvortsov VS, Romero Reyes IV, Levina IS (2014). "Molecular docking and 3D-QSAR of 16α,17α-cycloalkanoprogesterone derivatives as ligands of the progesterone receptor". Biochemistry (Moscow) Supplement Series B. 8 (2): 168–176. doi:10.1134/S1990750814020048. ISSN 1990-7508. S2CID 96191380.
↑ Kamernitzky AV, Levina IS, Kulikova LE, Ignatov VN, Korkhov VV, Nikitina GV, Terekhina AI (January 1982). "Pregna-D'-pentaranes - a new class of active gestagenes". Journal of Steroid Biochemistry. 16 (1): 61–67. doi:10.1016/0022-4731(82)90144-3. PMID 7062740.
↑ Nazarov AK, Zavarzin IV, Nazarov GV, Aksenov AV, Levina IS (2016). "Preparation and Bioavailability Evaluation of Micronized Steroidal Mecigestone Drug Substance". Pharmaceutical Chemistry Journal. 49 (10): 706–710. doi:10.1007/s11094-016-1357-6. ISSN 0091-150X. S2CID 6216213.
1 2 Bhakta A, Herman M, Levina IS, Moudgil VK (August 1993). "Interaction of cycloalkanoprogesterones with mammalian progesterone receptor: binding of pregna-D'-pentaranes in the calf uterine cytosol". Molecular and Cellular Biochemistry. 125 (2): 153–161. doi:10.1007/BF00936444. PMID 8283970. S2CID 20319611.
↑ Kamernitskii, A. V.; Kulikova, L. E.; Levina, I. S.; Korkhov, V. V.; Nikitina, G. V. (September 1980). "Biological activity of transformed steroids XV. Synthesis and hormonal activity of 6-methyl-substituted 16α, 17α-cyclohexanoprogesterones". Pharmaceutical Chemistry Journal. 14 (9): 632–635. doi:10.1007/BF01156378.
↑ , GB1427645 (1976 to Inst Orch Khim); CA, 85, 21727
↑ Nazarov, A. K.; Sigay, N. V.; Zavarzin, I. V.; Levina, I. S. (September 2014). "Synthesis of 6-methylidene-16α,17α-cyclohexapregn-4-ene-3,20-dione". Russian Chemical Bulletin. 63 (9): 2064–2066. doi:10.1007/s11172-014-0701-9.
↑ Nazarov, A. K.; Zavarzin, I. V.; Nazarov, G. V.; Aksenov, A. V.; Levina, I. S. (January 2016). "Preparation and Bioavailability Evaluation of Micronized Steroidal Mecigestone Drug Substance". Pharmaceutical Chemistry Journal. 49 (10): 706–710. doi:10.1007/s11094-016-1357-6.

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[Elks2014-1] Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 8–. ISBN 978-1-4757-2085-3.

[FedyushkinaSkvortsov2014-2] Fedyushkina IV, Skvortsov VS, Romero Reyes IV, Levina IS (2014). "Molecular docking and 3D-QSAR of 16α,17α-cycloalkanoprogesterone derivatives as ligands of the progesterone receptor". Biochemistry (Moscow) Supplement Series B. 8 (2): 168–176. doi:10.1134/S1990750814020048. ISSN 1990-7508. S2CID 96191380.

[pmid7062740-3] Kamernitzky AV, Levina IS, Kulikova LE, Ignatov VN, Korkhov VV, Nikitina GV, Terekhina AI (January 1982). "Pregna-D'-pentaranes - a new class of active gestagenes". Journal of Steroid Biochemistry. 16 (1): 61–67. doi:10.1016/0022-4731(82)90144-3. PMID 7062740.

[NazarovZavarzin2016-4] Nazarov AK, Zavarzin IV, Nazarov GV, Aksenov AV, Levina IS (2016). "Preparation and Bioavailability Evaluation of Micronized Steroidal Mecigestone Drug Substance". Pharmaceutical Chemistry Journal. 49 (10): 706–710. doi:10.1007/s11094-016-1357-6. ISSN 0091-150X. S2CID 6216213.

[BhaktaHerman1993-5] 1 2 Bhakta A, Herman M, Levina IS, Moudgil VK (August 1993). "Interaction of cycloalkanoprogesterones with mammalian progesterone receptor: binding of pregna-D'-pentaranes in the calf uterine cytosol". Molecular and Cellular Biochemistry. 125 (2): 153–161. doi:10.1007/BF00936444. PMID 8283970. S2CID 20319611.

[6] Kamernitskii, A. V.; Kulikova, L. E.; Levina, I. S.; Korkhov, V. V.; Nikitina, G. V. (September 1980). "Biological activity of transformed steroids XV. Synthesis and hormonal activity of 6-methyl-substituted 16α, 17α-cyclohexanoprogesterones". Pharmaceutical Chemistry Journal. 14 (9): 632–635. doi:10.1007/BF01156378.

[7] , GB1427645 (1976 to Inst Orch Khim); CA, 85, 21727

[8] Nazarov, A. K.; Sigay, N. V.; Zavarzin, I. V.; Levina, I. S. (September 2014). "Synthesis of 6-methylidene-16α,17α-cyclohexapregn-4-ene-3,20-dione". Russian Chemical Bulletin. 63 (9): 2064–2066. doi:10.1007/s11172-014-0701-9.

[9] Nazarov, A. K.; Zavarzin, I. V.; Nazarov, G. V.; Aksenov, A. V.; Levina, I. S. (January 2016). "Preparation and Bioavailability Evaluation of Micronized Steroidal Mecigestone Drug Substance". Pharmaceutical Chemistry Journal. 49 (10): 706–710. doi:10.1007/s11094-016-1357-6.

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Mecigestone

Synthesis

See also

References