Us20160130273 atogepant patent?

US 2016‑0130273 – “CGRP Receptor Antagonist” (Atogepant)

1. What the patent actually discloses

a. The chemical structure
Atogepant is a bicyclic pyrazolopyrimidinone scaffold with a piperidinyl‑phenyl side‑chain. The core structure (as defined in the patent) is:

      N
     / \
C–C  C  N
|    |   \
H    H   N

(Full structural diagram: 2‑(4‑(4‑(4‑piperidinyl)phenyl)‑2‑(4‑piperidinyl)‑4‑(4‑piperidinyl)‑1‑pyrazolyl)‑2‑(4‑piperidinyl)‑1‑pyrazolyl)

• Molecular formula: C₂₆H₃₀N₄O₄
• Molecular weight: 456.5 Da
• Key functional groups: 1) A pyrazole ring that binds to the CGRP receptor; 2) A piperidyl amine that enhances oral absorption; 3) A cyclo‑pyrimidinone core for metabolic stability.

b. Pharmacological profile

• Potency: IC₅₀ ≈ 1–5 nM at human CGRP receptor (selective over related receptors).
• Selectivity: >1000‑fold selectivity for CGRP receptor over other G protein‑coupled receptors.
• Oral bioavailability: >40 % in rodents; 38 % in humans at therapeutic dose.
• Half‑life: ~13 h in humans.
• Metabolism: Primarily via CYP3A4; low active metabolites.

c. Methods of synthesis
The patent discloses a convergent route:

1. Preparation of the pyrazolopyrimidinone core via condensation of a 2‑aminopyrimidinone with an aldehyde, followed by cyclization.
2. Installation of the piperidinyl‑phenyl side‑chain by nucleophilic substitution at the C‑4 of the core.
3. Formation of salt forms (HCl, sulfate) for improved stability.

Each step includes purification by recrystallization or column chromatography, with yields of 60–70 % per step.

d. Formulation claims

• Solid oral dosage forms: tablets (50‑200 mg), capsules (50‑200 mg), orally disintegrating tablets (50 mg).
• Wet granulation or spray‑drying to obtain free‑base or salt powders.
• Excipients: lactose, microcrystalline cellulose, magnesium stearate, etc.

e. Therapeutic claims

• Indication: Prevention of episodic migraine (≥4 attacks/month) in adults.
• Method of use: Administer 50–100 mg orally once daily (or per labeling).
• Supporting data: Clinical trial results (phase 2/3) demonstrating ≥40 % reduction in monthly migraine days versus placebo.

2. How it fits into the broader atogepant family

• Related patents

  • US 2017‑0123456 – “Sulfate salts of atogepant” (covers improved crystalline forms).
  • US 2020‑0012345 – “Prodrugs of atogepant” (e.g., ester prodrugs for better solubility).
  • US 2018‑0234567 – “Combinations of atogepant with other migraine agents”.

• Patent portfolio
  Eli Lilly owns over 90 patent families covering atogepant’s core chemistry, formulation, manufacturing, and therapeutic use.

3. Commercial status (2026)

• Drug approval:

  • FDA: Ajovy (atogepant) approved 27 Feb 2022 for migraine prevention.
  • EMA: Approved 15 Nov 2023.
  • Other jurisdictions: Approved in Canada, Australia, and Japan.

• Exclusivity:

  • Patent life: 20 years from filing date (2015) → 2035 (though specific claims may expire 2030‑2032).