Pirenperone, R 47465

Figure imgf000044_0003

ON THE LEFT OR ABOVE

3-(2- {4-[(4-fluorophenyl)carbonyl]piperidin- 1 -yl} ethyl)-2-methyl-4H-pyrido[ 1 ,2- α]pyrimidin-4-one

3-(2-{4-[(4-fluorophenyl)carbonyl]piperidin-1-yl}ethyl)-2-methyl-4H-pyrido[1,2-α]pyrimidin-4-one

3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyri- midin-4-one

pirenperone CAS : 75444-65-4

C₂₃ H₂₄ F N₃ O₂

4H-Pyrido[1,2-a]pyrimidin-4-one, 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-

R 47465

Cardiovascular disease; Inflammatory disease; Neoplasm; Pain

Calcium channel modulator T-type

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http://www.google.co.in/patents/US4342870

http://www.google.co.in/patents/EP0037265A1

Example XXIV

A solution of 2 parts of 3-[2-[4-(4-fluorobenzoyl)-1 -piperidinyl]ethyl]-2 -methyl-4H -pyricio[1, 2 -a]pyrimidin-4-one in 64 parts of 2-propanol is warm acidified with 2-propanol saturated with hydrogen chloride. The formed hydrochloride salt is allowed to crystallize. It is filtered off and dried, yielding 2 parts (85. 5%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyri- midin-4-one dihydrochloride; mp. + 300°C.
In a similar manner there are also prepared:
- 3-[2 -[4-(4-fluorobenzoyl)-1-piperidiny]yethyl7-2 -methyl-4H-pyrido-[1, 2 -a]pyrimidin-4-one sulfate (1 : 2); mp. 254. 7°C; and
- 3-[2-[4-(4-fluorobenzoyl)-1 -piperidinyl]ethyl]-2-methyl-4H-pyrido-[1, 2-a]pyrimidin-4-one phosphate (1 : 2) ; mp. 243.8°C.

WO-2014143915

http://www.google.com/patents/WO2014143915A1?cl=en

Vm Therapeutics Llc

Novelcrystalline polymorphic forms of pirenperone, useful for treating disorders associated with T-type calcium ion channels such as pain syndrome, neoplasm, cardiovascular disease or inflammation. VM Discovery, from which VM Therapeutics was spun out, was investigating the VMD-C300 series of compounds which act as T-type calcium channel modulators, including VMD-3816 and VMD-3222, for treating cancer, pain, neurological diseases and cardiovascular diseases; but as of September 2014, this program was assumed to be discontinued. See WO2009108798, (by the inventor, assigned to VM Discovery) claiming use of the same compound for treating same indications.

It was first disclosed in the now-expired US Patent No. 4,342,870 (Claim 5), and intended to be used as potential anti-anxiety drug. However, the early human clinical studies has shown that the compound did not show any dose-related anti-anxiety effects as hoped, but otherwise the compound was safe in human (ref. Ansseau M, Doumo t A, Thlry D, Gelders Y. “Pilot study of a specific serotonergic antagonist, pirenperone, in the treatment of anxiety disorders”, Acta Psychiatr Belg, 1983 Sep-Oct;83(5):517-24). in the US Patent No. 4,342,870, there is no crystalline polymorphic form disclosed, nor disclosure of potential uses for management of pain and treatment of other related diseases or disorders.

It was further disclosed in the PCT patent application WO/2009/108798 as “Compound 10 (pirenperone)^‘” to be used for novel T-type calcium ion channel antagonist for management of pain and treatment of other diseases or disorders associated to the T-type calcium ion channels.

Surprisingly, we have found that there are many crystalline polymorphic forms of this compound which may affect the compound’s pharmaceutical safety and pharmacology properties.