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CN-122003419-A - Therapeutic compounds, methods of preparation and uses thereof

CN122003419ACN 122003419 ACN122003419 ACN 122003419ACN-122003419-A

Abstract

The present disclosure provides compounds of formula Ib or formula IIb or a hydrate thereof, pharmaceutical compositions, such as spray-dried pharmaceutical compositions, comprising compounds of formula Ib or formula IIb or a hydrate thereof, and methods of preparing the same, and their use in the treatment and/or prevention of one or more of sexual dysfunction, erectile dysfunction, ejaculatory dysfunction, hyposexuality, psychotic disorder, neurological disorder.

Inventors

  • DOWNING KYIA
  • H. Booker
  • S. KUMAR
  • J. WESTMAN
  • C. Malmberg

Assignees

  • 迪科特制药公司

Dates

Publication Date
20260508
Application Date
20240823
Priority Date
20240328

Claims (20)

  1. 1. Compound of formula IIb IIb Or a hydrate thereof, Wherein R 1 and R 2 are independently C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of OH, cl, br, F and I, wherein the compound or hydrate thereof is in substantially solid form.
  2. 2. The compound of claim 1, wherein R 1 is methyl and R 2 is isopropyl, thereby providing a compound of formula V V (V) Or a hydrate thereof.
  3. 3. The hydrate of claim 1 or 2, wherein the hydrate is a combination of a compound of formula IIb and water in a ratio of 1:n, thereby providing a hydrate of formula VI: VI (VI) Wherein n has a value of 0.5 to 100.
  4. 4. A hydrate according to claim 3, wherein n is 1, thereby providing a monohydrate of formula VII: formula VII.
  5. 5. A compound according to claim 1 or 2, or a hydrate thereof, or The hydrate according to claim 3 or 4, Wherein the compound of formula IIb is provided as a stereoisomer of formula IIc: formula IIc.
  6. 6. A compound of formula III: Formula III Or a salt thereof, such as a pharmaceutically acceptable salt and/or stereoisomer thereof, Wherein R 1 is C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of OH, cl, br, F and I.
  7. 7. A compound of formula IV: IV (IV) Or a salt thereof, such as a pharmaceutically acceptable salt and/or stereoisomer thereof, Wherein R 1 is C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of OH, cl, br, F and I.
  8. 8. A compound according to any one of claims 1, 2 or 5 to 7, or a hydrate thereof, or a hydrate according to claim 3 or 4, Characterized by being substantially crystalline.
  9. 9. A compound according to any one of claims 1,2 or 5 to 8, or a hydrate thereof, or a hydrate according to claim 3, 4 or 8, It is characterized in that Having a chemical purity equal to or greater than about 90%, such as about 95%, such as about 99%, and/or Chemical stability equal to or higher than about 90%, such as about 95%, such as about 99%.
  10. 10. A spray-dried pharmaceutical composition, the pharmaceutical composition comprising: (a) A compound according to any one of claims 1, 2, 5 to 7 or 9, or a hydrate thereof, or a hydrate according to any one of claims 3,4 or 9, or a compound of formula Ib: or a hydrate thereof, and (B) Excipients suitable for spray drying.
  11. 11. The spray-dried composition according to claim 10, wherein the spray-dried suitable excipient comprises a polymer or copolymer capable of forming a physicochemical interaction with a compound according to claim 1, 2, 5 to 7 or 9 or a hydrate thereof or a hydrate according to claim 3, 4 or 9, thereby enabling resolubilization of the compound.
  12. 12. The spray-dried composition of claim 11, wherein the spray-drying compatible excipient comprises one or more of a cellulose ester, an N-vinylpyrrolidone-vinyl acetate copolymer, a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and a methacrylic acid-methyl methacrylate copolymer.
  13. 13. The spray-dried composition according to any of claims 10 to 12, wherein the excipient suitable for spray drying comprises a cellulose ester such as a nonionic cellulose ester.
  14. 14. The spray-dried composition of claim 13, wherein the cellulose ester is hydroxypropyl methylcellulose (HPMC) or a derivative thereof.
  15. 15. The spray-dried composition of claim 14, wherein the derivative of HPMC is HPMC-AS or HPMC-P.
  16. 16. The spray-dried composition according to any one of claims 13 to 15, wherein the HPMC or derivative thereof is HPMC-AS, such AS class M HPMC-AS.
  17. 17. The spray-dried composition of any of claims 10 to 16, wherein the ratio between the compound or hydrate and the excipient is from about 1:5 to about 5:1, such as from about 1:4 to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1, or about 1:1.
  18. 18. The spray-dried composition of claim 17, wherein the ratio of the compound or the hydrate to the excipient is about 1:3.
  19. 19. A spray-dried composition according to any one of claims 10 to 18, wherein the compound is as defined in claim 5, or a hydrate thereof, or a hydrate as defined in claim 4.
  20. 20. The spray-dried pharmaceutical composition according to any of claims 10 to 19, wherein the particles in the composition have a particle size distribution with Dv90 of 120mm or less, such as 100mm or less, such as 10mm to 120 mm.

Description

Therapeutic compounds, methods of preparation and uses thereof Technical Field The present disclosure relates to compounds derived from phragmalin or a portion thereof and novel pharmaceutical compositions comprising the compounds, and their use in the treatment and/or prevention of sexual dysfunction. The present disclosure also relates to methods of preparing the above compounds and compositions. Background It will be appreciated that the listing or discussion of an existing-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or common general knowledge. Sexual dysfunction is very common in both men and women and has a significant impact on mood, self-esteem, personal relationships and overall quality of life. Sexual dysfunction can be caused by a variety of causes and is often age-related. Sexual dysfunction may be caused by physical conditions such as diabetes, heart disease, hypertension and/or obesity, while psychological factors such as depression, anxiety, sped, stress and relation conflict may also play a role. Neurological disorders, hormonal imbalances, and certain medications may also lead to sexual dysfunction, and lifestyle factors such as smoking, excessive alcohol consumption, and lack of exercise may also increase the risk of sexual dysfunction. Most sexual dysfunction definitions are based on a four-phase model of the sexual response cycle, which includes sexual desire, sexual arousal, orgasm/climax and regression phases. Based on this model, four main categories of sexual dysfunction have been identified, including sexual desire disorders, sexual arousal disorders, orgasmic disorders, and sexual pain disorders, which may occur in one or more of these four respective phases. Hyposexuality (HSDD) is characterized by a sustained lack of sexual illusion or craving for any form of sexual activity. In many cases, HSDD is secondary to another sexual dysfunction. However, HSDD can also be caused by medical and psychiatric disorders (especially chronic diseases and depression) and relation conflicts and loss of attractiveness. Sexual arousal disorder is characterized by the inability to achieve adequate physiological or subjective arousal during sexual stimulation. In women, this disorder is known as Female Sexual Arousal Disorder (FSAD) and is characterized by the inability of the vagina and labia to reach a sufficient lubrication-swelling response to complete sexual activity, or a lack of subjective arousal during sexual activity. The prevalence of FSAD increases with age and is associated with psychological factors such as anxiety and depression. In men, this disorder is known as male erectile dysfunction (ED or MED), or commonly also known as erectile dysfunction or impotence, and is characterized by the inability to achieve or maintain an erection sufficient for intercourse. The prevalence of ED also increases with age and is related to physical conditions such as diabetes, heart disease and hypertension, and psychological factors such as depression. Female and male orgasmic disorders are characterized by persistent or recurrent difficulties in achieving orgasm despite adequate sexual stimulation. Contextual or secondary orgasmic disorders are characterized by the ability to achieve orgasm through masturbation or sexual pre-play with a companion, but not during sexual intercourse. Primary orgasmic disorders or loss of sexual pleasure are characterized by inability to reach orgasm by any means of stimulation, and this is more common in women. The occurrence of rapid and uncontrolled ejaculation is known as Premature Ejaculation (PE) and is the most common sexual disorder in men. Sildenafil (Viagra ®), a drug introduced in the 90 s of the 20 th century, is a major breakthrough in the treatment of erectile dysfunction. The medicament is a so-called PDE5 inhibitor, i.e. an inhibitor of phosphodiesterase 5. Other drugs that exert their activity through this mechanism of action have been developed, including tadalafil, vardenafil and avanafil. The development of these drugs is a great advance in the sexual medicine field and also significantly improves the sexual health of many patients. However, about one third of all men with ED are reported to be unresponsive to treatment. Furthermore, the onset of action and duration of treatment require planned activity, and the treatment is incompatible with nitrate drugs, for example, for the treatment of angina pectoris. Plant-based extracts and medicaments have also been proposed for the treatment of sexual dysfunction. WO 2008/145996 discloses extracts and medicaments from Neobeguea mahafalensis, their preparation and their use in initiating sexual enhancement and in the treatment of sexual dysfunction, in particular erectile dysfunction and hyposexuality. This document describes that Entandophragma species are useful sources of raw materials for the synthesis of