Longer-acting progestin prodrug contraceptives
Inventors
Ahmed, Gulzar • Meece, Frederick • Nair, Hareesh • Nickisch, Klaus
Assignees
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Publication Number
US-10624903-B2
Publication Date
2020-04-21
Expiration Date
Abstract
Described herein are progestin compounds that have extended release rates and that can be used without an estrogen to produce a contraceptive state.
Core Innovation
The patent discloses compounds having structural formula IIIA or IIIB, and structural formula IVA or IVB. In these compounds, R1 and R2 combine together to form a fused 3 to 7 membered ring with up to two heteroatoms, or each of R1 and R2 is independently selected from H, alkyl, cycloalkyl, phenyl, aryl, heteroaryl, acyl, cyano, halogen, OH, alkoxy, alkyl-sulfonyl, or sulfonamide.
For the IVA or IVB series, hAr is pyridine, pyrimidine, pyrazine, isoxazole, or oxazole. The compounds are framed as phenoxy-acetic acid ester prodrugs of levonorgestrel and etonogestrel, and the document attributes unexpectedly long-lasting anti-ovulatory effects in test animals to these simple progestin alcohol esters formed with a phenoxy-acetic acid moiety.
The description further includes formulation and use language directed to administering an effective amount, preferably by subcutaneous injection, so that a biological effect lasts at least 6 months. The patent also provides specific compound embodiments and example synthetic schemes consistent with the described structural frameworks.
Claims Coverage
The claim set includes two independent compound claim groups, covering structural formulas IIIA/IIIB and IVA/IVB. The inventive features are the fused 3 to 7 membered ring option formed by R1 and R2 with up to two heteroatoms, broad substituent choices for R1 and R2, and for the IVA/IVB series a defined heteroaromatic selection for hAr. Dependent claims further include use in producing a contraceptive state and a biological effect lasting at least 6 months.
Compounds with structural formula IIIA or IIIB
A compound having structural formula IIIA or IIIB, wherein R1 and R2 combine together to form a fused 3 to 7 membered ring with up to two heteroatoms, or each R1 and R2 is independently selected from H, alkyl, cycloalkyl, phenyl, aryl, heteroaryl, acyl, cyano, halogen, OH, alkoxy, alkyl-sulfonyl or sulfonamide.
Compounds with structural formula IVA or IVB
A compound having structural formula IVA or IVB, wherein hAr is pyridine, pyrimidine, pyrazine, isoxazole, or oxazole; and R1 and R2 combine together to form a fused 3 to 7 membered ring with up to two heteroatoms, or each R1 and R2 is independently selected from H, alkyl, cycloalkyl, phenyl, aryl, heteroaryl, acyl, cyano, halogen, OH, alkoxy, alkyl-sulfonyl or sulfonamide.
Administering to produce a contraceptive state
Producing a contraceptive state in a subject by administering an effective amount of a compound described in the claims.
Biological effect lasting at least 6 months
The biological effect lasts for at least 6 months.
Overall, the claims cover phenoxy-acetic acid ester prodrugs defined by structural formulas IIIA/IIIB and IVA/IVB, with R1/R2 controlling whether a fused 3 to 7 membered ring with up to two heteroatoms is formed and with broad allowable substituent classes. The IVA/IVB series additionally fixes hAr to a defined set of heteroaromatic rings, and dependent claims include use to produce a contraceptive state with a biological effect lasting at least 6 months.
Stated Advantages
Provides longer-acting progestin-only contraceptive effects without estrogen.
Provides an estrogen-free contraceptive state.
Achieves a biological effect lasting at least 6 months after a single subcutaneous injection.
Produces unexpectedly long-lasting anti-ovulatory effects in test animals.
Documented Applications
Use of the disclosed compounds to produce a contraceptive state in a subject by administering an effective amount of a compound described by the claims.
Long-acting injectable contraceptive study in rats.
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