OXA-Diazaspiro compounds having activity against pain

• US 10,689,398 B2
• Filed: 10/21/2016
• Issued: 06/23/2020
• Est. Priority Date: 10/23/2015
• Status: Active Grant

• Current Assignee: Esteve Pharmaceuticals S.A. (Corporation Quimico Farmaceutica Esteve SA)
• Original Assignee: Esteve Pharmaceuticals S.A. (Corporation Quimico Farmaceutica Esteve SA)
• Inventors: Virgili-Bernado, Marina, Almansa-Rosales, Carmen, Alegret-Molina, Carlos
• Primary Examiner(s): Stockton, Laura L
• Application Number:
  US15/769,754
• Publication Number:
  US 20190002475A1
• Time in Patent Office: 1,341 Days
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 498/10 Spiro-condensed systems

Abstract

The present invention relates to oxa-diazaspiro compounds having pharmacological activity towards the sigma (σ) receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

Claims

1. A compound of general Formula (I):

2. The compound according to claim 1, which is a compound of Formula (I′

)

3. The compound according to claim 1, which is a compound of Formula (I^2′

), (I^2a′

), (I^2b′

) or (I^2c′

)

4. The compound according to claim 1, which is a compound of Formula (I^3′

), (I^3a′

), (I^3b′

) or (I^3c′

)

5. The compound according to claim 1, which is a compound of Formula (I^4′

), (I^4a′

) (I^4b′

) or (I^4c′

)

6. The compound according to claim 1, wherein R_1′

is selected from the group consisting of substituted or unsubstituted C_1-6 alkyl and substituted or unsubstituted aryl.

7. The compound according to claim 6, wherein R_1′

is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl or substituted or unsubstituted phenyl.

8. The compound according to claim 1, wherein R₂ is selected from the group consisting of substituted or unsubstituted C_1-6 alkyl and substituted or unsubstituted aryl.

9. The compound according to claim 8, wherein R₂ is selected from the group consisting of substituted or unsubstituted isopropyl, substituted or unsubstituted isobutyl or substituted or unsubstituted phenyl.

10. The compound according to claim 1, wherein R₃ and R_3′

, together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl.

11. The compound according to claim 10, wherein R₃ and R_3′

form a substituted or unsubstituted cyclopropyl.

12. The compound according to claim 1 which is selected from the group consisting of:

12-ethyl-7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,

12-ethyl-7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,

13-ethyl-8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

13-ethyl-8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

7-benzyl-10-ethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,

10-ethyl-7-isopentyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,

7-phenethyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,

7-isopentyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-phenethyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

8-isopentyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

7-benzyl-12-ethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-benzyl-13-ethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

7-benzyl-10-ethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,

8-benzyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

7-benzyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,

13-ethyl-8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane,

7-benzyl-12-ethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,

12-ethyl-7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,

7-phenethyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,

7-isopentyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,

8-benzyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane and

8-phenethyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane.

13. The compound according to claim 1, which is selected from the group consisting of:

7-benzyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,

(7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-yl)(phenyl)methanone,

(7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-yl)(phenyl)methanone,

(7-isobutyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-yl)(phenyl)methanone,

(8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)methanone,

(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)methanone,

(8-isobutyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)methanone,

4-ethyl-2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

4-ethyl-9-isopentyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

4-ethyl-9-isobutyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

10-benzyl-7-phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,

(2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone,

10-ethyl-7-(2-isopropoxyethyl)-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,

(R)-8-ethyl-2-isopentyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(S)-8-ethyl-2-isopentyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(R)-8-ethyl-2-isobutyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(S)-8-ethyl-2-isobutyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(R)-2-isopentyl-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(S)-2-isopentyl-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(R)-2-isobutyl-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(S)-2-isobutyl-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(S)-2-(3,3-dimethylbutyl)-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(R)-2-(3,3-dimethylbutyl)-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(2R,6S)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2R,6R)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2S,6S)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2S,6R)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(9-(2-isopropoxyethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone,

(7-benzyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-yl)(phenyl)methanone,

(8-benzyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)methanone,

9-benzyl-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

4-((4-ethyl-2,2-dimethyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile,

(2R,6S)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2R,6R)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2S,6S)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2S,6R)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2R,6S)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2R,6R)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2S,6S)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2S,6R)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

4-(((2R,6S)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile,

4-(((2R,6R)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile,

4-(((2S,6S)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile,

4-(((2S,6R)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile,

8-benzyl-13-methyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-4-one,

8-(4-fluorobenzyl)-13-methyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

4-((13-methyl-14-oxo-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-8-yl)methyl)benzonitrile,

(S)-8-ethyl-6-methyl-2-neopentyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(R)-8-ethyl-6-methyl-2-neopentyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(S)-8-isopropyl-6-methyl-2-neopentyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(R)-8-isopropyl-6-methyl-2-neopentyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

7,12-dibenzyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*),

12-benzyl-7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*),

12-benzyl-7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*),

12-benzyl-7-isobutyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*),

8,13-dibenzyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*),

13-benzyl-8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*),

13-benzyl-8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*),

13-benzyl-8-isobutyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*),

9-benzyl-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecane,

4-ethyl-2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecane,

4-ethyl-9-isopentyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecane,

4-ethyl-9-isobutyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecane,

10-benzyl-7-phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecane,

(7-Phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-10-yl)(phenyl)methanone,

(R)-8-benzyl-3-ethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

(S)-8-benzyl-13-ethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

(R)-(2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone and

(S)-(2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone.

14. The compound according to claim 1, which is selected from the group consisting of:

((2S,6R)-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone,

((2S,6S)-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone,

((2R,6R)-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone,

((2R,6S)-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone,

(R)-(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)methanone and

(S)-(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)methanone.

15. A process for the preparation of the compound according to claim 1, wherein R₁ is —

(CR₄R_4′

)_pR_1′

, which process comprises;

a) an intramolecular cyclization of a compound of formula VIIa

16. A process for the preparation of the compound according to claim 1, wherein R₁ is —

(CR₄R_4′

)_pR_1′

, Y represents CO and R₃ and R_3′

, together with the carbon atom to which they are attached, form a cyclopropyl (compounds of formula Id),

17. A process for the preparation of the compound of Formula (I) according to claim 1, employing a compound of Formula II, IIP, III, IIIP, IVa, IVb, Vb, VbP, XII, XIIP, Va, VaP, VI, VIIb, VIIbP, XIII, XIIIP, VIIa, VIIaP, XVI, XVIP, XVIH, XIV, XIVP, XIVH, Ia, VIIIP, VIIIH, XV, IX, X, XI, Ie, XXP, XXH, XXI, XXIP, XXIH, Ib, XVIIP, XVIIH, Ic, XVIIIP, Id, XIXP, XIXH, XXIII, XIIP XXIIIP, XXIIIH, XXV, XXVP, XXVH, XXII, XXIIP, XXIIH, XXIV, XXIVP, XXIVH, If, XXVIP, XXVIH, XXVIIa, Ig, XXVIIIP, XXVIIIH, XXVIIb, Ih, XXIXP, XXIXH, XXVIIIc, Ib, XVIIP, XVIIH, XXXII, XXXIIP, XXXIIH, XXXIV, XXXIVP, XXXIVH, XXXI, XXXIP, XXXIH, XXXIII, XXXIIIP, XXXIIIH, XXXV, Ij, XXXVIP, XXXVIH, Ih, XXIXP, XXIXH, Ii, XXXP or XXXH,

18. A pharmaceutical composition which comprises the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

19. A method of treating pain in a subject in need thereof, comprising administration of an effective amount of the compound according to claim 1.

20. The method according to claim 19, wherein the pain, is selected from the group consisting of medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain, neuropathic pain, allodynia and hyperalgesia.