FATTY ACID AMIDE HYDROLASE (FAAH) CLEAVABLE PRODRUGS OF BRAIN TARGETING ACTIVES AND COMBINATION WITH PERIPHERALLY RESTRICTED FAAH INHIBITORS

20240261414 · 2024-08-08

Inventors

Cpc classification

International classification

Abstract

Provided herein are fatty acid amide (FAAH) cleavable prodrugs of compounds that modulate a target in the brain including sphingosine-1-phosphate receptor (S1P1), lysophosphatidic acid receptor 1 (LPA1), G-protein coupled receptor 120 (GPR120), prostacyclin (PGI2), and transthyretin (TTR). Pharmaceutical compositions comprising these prodrugs, including in combination with a peripherally restricted FAAH inhibitor, and at least one pharmaceutically acceptable excipient, are also provided, and the use of these compounds and compositions in the treatment of CNS diseases or disorders.

Claims

1. A pharmaceutical composition comprising a fatty acid amide hydrolase (FAAH) cleavable prodrug of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, ##STR00241## wherein: R.sup.1 is an amide prodrug moiety, wherein the prodrug of Formula (I) is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release ##STR00242## is a moiety that modulates a target in the brain; and a pharmaceutically acceptable excipient; further comprising a peripherally restricted FAAH inhibitor.

2. The pharmaceutical composition of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the target is selected from sphingosine-1-phosphate receptor 1 (S1P1), lysophosphatidic acid receptor 1 (LPA1), G-protein coupled receptor 120 (GPR120), prostacyclin (PGI2), and transthyretin (TTR).

3. The pharmaceutical composition of claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the target is S1P1.

4. The pharmaceutical composition of claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is selected from ##STR00243##

5. The pharmaceutical composition of claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the target is LPA1.

6. The pharmaceutical composition of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is selected from ##STR00244##

7. The pharmaceutical composition of claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the target is GPR120.

8. The pharmaceutical composition of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is ##STR00245##

9. The pharmaceutical composition of claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the target is TTR.

10. The pharmaceutical composition of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is selected from ##STR00246##

11. The pharmaceutical composition of claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the target is PGI2.

12. The pharmaceutical composition of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is ##STR00247##

13. The pharmaceutical composition of any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is selected from optionally substituted C.sub.1-6alkyl, optionally substituted C.sub.3-6cycloalkyl, optionally substituted C.sub.2-9heterocycloalkyl, optionally substituted C.sub.6-10aryl, and optionally substituted C.sub.1-9heteroaryl.

14. The pharmaceutical composition of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is selected from optionally substituted C.sub.1-6alkyl, optionally substituted C.sub.3-6cycloalkyl, optionally substituted C.sub.2-9heterocycloalkyl, optionally substituted C.sub.6-10aryl, and optionally substituted C.sub.1-9heteroaryl, wherein C.sub.1-6alkyl, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, C.sub.1-9heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, CN, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C(O)OH, C(O)OC.sub.1-6alkyl, C(O)NH.sub.2, C(O)N(H)(C.sub.1-6alkyl), C(O)N(C.sub.1-6alkyl).sub.2, C(O)C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, S(O).sub.2NH.sub.2, S(O).sub.2N(H)(C.sub.1-6alkyl), S(O).sub.2N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl.

15. The pharmaceutical composition of any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is selected from unsubstituted C.sub.1-6alkyl, unsubstituted C.sub.3-6 cycloalkyl, unsubstituted C.sub.2-9heterocycloalkyl, unsubstituted C.sub.6-10aryl, and unsubstituted C.sub.1-9heteroaryl.

16. The pharmaceutical composition of any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein the R.sup.1 is selected from ##STR00248##

17. The pharmaceutical composition of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the fatty acid amide hydrolase (FAAH) cleavable prodrug of Formula (I) is selected from: ##STR00249## ##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259##

18. The pharmaceutical composition of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

19. A method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof.

20. The method of claim 19, wherein the CNS disease or disorder is selected from multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease.

21. The method of claim 19, wherein the CNS disease or disorder is selected from epilepsy, ischemic stroke, traumatic brain injury, and autoimmune encephalomyelitis.

22. The method of claim 19, wherein the CNS disease or disorder is selected from ischemic stroke, schizophrenia, depression, mood disorders, attention deficit hyperactivity disorder, post-traumatic stress disorder, and Alzheimer-type dementia.

23. The method of claim 19, wherein the CNS disease or disorder is selected from familial amyloidotic polyneuropathy, familial leptomeningeal amyloidosis, Alzheimer's disease, stroke, dementia, transitory focal neurological episodes, cognitive dysfunction, and CNS amyloidosis.

24. The method of claim 19, wherein the CNS disease or disorder is selected from Degos disease, reversible cerebral vasoconstriction syndrome, Sneddon's syndrome, amyloid-beta-related angiopathy, Susac syndrome, and neurosarcoidosis.

25. A method of increasing the ##STR00260## concentration in the brain of a patient comprising administering to the patient a pharmaceutical composition of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof; wherein the ratio of brain to periphery ##STR00261## concentration is increased to greater than 1:1.

26. The method of claim 25, wherein the ratio of brain to periphery ##STR00262## concentration is increased to greater than 2:1.

27. A compound, or a pharmaceutically acceptable salt or solvate thereof, of Formula (II): ##STR00263## wherein: R.sup.1 is an amide prodrug moiety, wherein the amide prodrug moiety is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release ##STR00264## is a moiety that modulates S1P1 in the brain.

28. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is selected from ##STR00265##

29. A compound, or a pharmaceutically acceptable salt or solvate thereof, of Formula (III): ##STR00266## wherein: R.sup.1 is an amide prodrug moiety, wherein the amide prodrug moiety is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release ##STR00267## is a moiety that modulates LPA1 in the brain.

30. The compound of claim 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is selected from ##STR00268##

31. A compound, or a pharmaceutically acceptable salt or solvate thereof, of Formula (IV): ##STR00269## wherein: R.sup.1 is an amide prodrug moiety, wherein the amide prodrug moiety is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release ##STR00270## is a moiety that modulates GPR120 in the brain.

32. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is ##STR00271##

33. The compound of any one of claims 27-32, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is selected from optionally substituted C.sub.1-6alkyl, optionally substituted C.sub.3-6cycloalkyl, optionally substituted C.sub.2-9heterocycloalkyl, optionally substituted C.sub.6-10aryl, and optionally substituted C.sub.1-9heteroaryl.

34. The compound of any one of claims 27-33, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is selected from C.sub.1-6alkyl, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10 aryl, and C.sub.1-9heteroaryl, wherein C.sub.1-6alkyl, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, CN, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C(O)OH, C(O)OC.sub.1-6alkyl, C(O)NH.sub.2, C(O)N(H)(C.sub.1-6alkyl), C(O)N(C.sub.1-6alkyl).sub.2, C(O)C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, S(O).sub.2NH.sub.2, S(O).sub.2N(H)(C.sub.1-6alkyl), S(O).sub.2N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl.

35. The compound of any one of claims 27-34, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is selected from unsubstituted C.sub.1-6alkyl, unsubstituted C.sub.3-6cycloalkyl, unsubstituted C.sub.2-9heterocycloalkyl, unsubstituted C.sub.6-10aryl, and unsubstituted C.sub.1-9heteroaryl.

36. A compound, or a pharmaceutically acceptable salt or solvate thereof, of Formula (V): ##STR00272## wherein: R.sup.1 is an amide prodrug moiety, wherein the amide prodrug moiety is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release ##STR00273## is a moiety that modulates TTR in the brain.

37. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is ##STR00274##

38. The compound of claim 36 or claim 37, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is selected from C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.3-6cycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl, wherein C.sub.3-6cycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, CN, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C(O)OH, C(O)OC.sub.1-6alkyl, C(O)NH.sub.2, C(O)N(H)(C.sub.1-6alkyl), C(O)N(C.sub.1-6alkyl).sub.2, C(O)C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, S(O).sub.2NH.sub.2, S(O).sub.2N(H)(C.sub.1-6alkyl), S(O).sub.2N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl.

39. The compound of any one of claims 36-38, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is selected from unsubstituted C.sub.1-4alkyl, unsubstituted C.sub.3-6cycloalkyl, unsubstituted C.sub.6-10aryl, and unsubstituted C.sub.1-9heteroaryl.

40. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is ##STR00275##

41. The compound of claim 40, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is selected from CH.sub.3, C.sub.1-6haloalkyl, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl, wherein C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, CN, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C(O)OH, C(O)OC.sub.1-6alkyl, C(O)NH.sub.2, C(O)N(H)(C.sub.1-6alkyl), C(O)N(C.sub.1-6alkyl).sub.2, C(O)C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, S(O).sub.2NH.sub.2, S(O).sub.2N(H)(C.sub.1-6alkyl), S(O).sub.2N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl.

42. The compound of claim 41, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is selected from CH.sub.3, unsubstituted C.sub.3-6cycloalkyl, unsubstituted C.sub.2-9heterocycloalkyl, unsubstituted C.sub.6-10aryl, and unsubstituted C.sub.1-9heteroaryl.

43. A compound, or a pharmaceutically acceptable salt or solvate thereof, of Formula (VI): ##STR00276## wherein: R.sup.1 is an amide prodrug moiety, wherein the amide prodrug moiety is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release ##STR00277## is a moiety that modulates PGI2 in the brain.

44. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is ##STR00278##

45. The compound of claim 44, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is selected from CH.sub.3, optionally substituted C.sub.3-6cycloalkyl, optionally substituted C.sub.2-9heterocycloalkyl, optionally substituted C.sub.6-10aryl, and optionally substituted C.sub.2-9heteroaryl, wherein C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, C.sub.1-9heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, CN, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C(O)OH, C(O)OC.sub.1-6alkyl, C(O)NH.sub.2, C(O)N(H)(C.sub.1-6alkyl), C(O)N(C.sub.1-6alkyl).sub.2, C(O)C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, S(O).sub.2NH.sub.2, S(O).sub.2N(H)(C.sub.1-6alkyl), S(O).sub.2N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl.

46. The compound of claim 45, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is selected from CH.sub.3, unsubstituted C.sub.3-6cycloalkyl, unsubstituted C.sub.2-9heterocycloalkyl, unsubstituted C.sub.6-10aryl, and unsubstituted C.sub.1-9heteroaryl.

47. The compound of any one of claims 27-46, or a pharmaceutically acceptable salt or solvate thereof, wherein the R.sup.1 is selected from ##STR00279##

48. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula (II) is selected from: ##STR00280## ##STR00281## ##STR00282## ##STR00283##

49. The compound of claim 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula (III) is selected from: ##STR00284## ##STR00285## ##STR00286##

50. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula (IV) is selected from: ##STR00287## ##STR00288## ##STR00289##

51. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula (V) is selected from: ##STR00290## ##STR00291## ##STR00292##

52. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula (VI) is selected from: ##STR00293## ##STR00294##

53. A pharmaceutical composition comprising a compound of any one of claims 27-52, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

54. The pharmaceutical composition of claim 53 further comprising a peripherally restricted FAAH inhibitor.

55. The pharmaceutical composition of claim 54 further comprising a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

56. A method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of any one of claims 53-55, or a compound of any one of claims 27-52, or a pharmaceutically acceptable salt or solvate thereof.

57. The method of claim 56, wherein the CNS disease or disorder is selected from multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease.

58. The method of claim 56, wherein the CNS disease or disorder is selected from epilepsy, ischemic stroke, traumatic brain injury, and autoimmune encephalomyelitis.

59. The method of claim 56, wherein the CNS disease or disorder is selected from ischemic stroke, schizophrenia, depression, mood disorders, attention deficit hyperactivity disorder, post-traumatic stress disorder, and Alzheimer-type dementia.

60. The method of claim 56, wherein the CNS disease or disorder is selected from familial amyloidotic polyneuropathy, familial leptomeningeal amyloidosis, Alzheimer's disease, stroke, dementia, transitory focal neurological episodes, cognitive dysfunction, and CNS amyloidosis.

61. The method of claim 56, wherein the CNS disease or disorder is selected from Degos disease, reversible cerebral vasoconstriction syndrome, Sneddon's syndrome, amyloid-beta-related angiopathy, Susac syndrome, and neurosarcoidosis.

62. A method of increasing the ##STR00295## concentration in the brain of a patient comprising administering to the patient a pharmaceutical composition of any one of claims 53-55, or a compound of any one of claims 27-52, or a pharmaceutically acceptable salt or solvate thereof, wherein the ratio of brain to periphery ##STR00296## concentration is increased to greater than 1:1.

63. The method of claim 62, the ratio of brain to periphery ##STR00297## OH concentration is increased to greater than 2:1.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0045] Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids and can hydrolyze select amide prodrugs. FAAH is highly conserved between species and is expressed in many tissues, including the central nervous system (CNS), to varying degrees. Select carboxylic acids can be converted to more permeable amide prodrugs which are then capable of passing through the blood brain barrier where they can be converted to active molecules through the action of FAAH upon the prodrug. This results in the delivery of higher amounts of the carboxylic acid to the CNS as compared to dosing the parent alone. However, peripherally expressed FAAH simultaneously hydrolyzes the prodrug resulting in a considerable amount of non-productive prodrug conversion. Co-administration of a peripherally restricted FAAH inhibitor with a CNS permeable FAAH convertible prodrug increases the selectivity of prodrug delivery to the CNS. It also results in lower exposures of the parent molecule in plasma and peripheral tissue than what is observed when dosing the prodrug alone.

Certain Terminology

[0046] The singular forms a, an, and the include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a drug includes reference to one or more of such drugs, and reference to an excipient includes reference to one or more of such excipients. When ranges are used herein, all combinations and sub-combinations of ranges and specific embodiments therein are intended to be included. The term about when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range varies between 1% and 15% of the stated number or numerical range.

[0047] The terms formulation and composition, as used herein, are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some aspects the terms formulation and composition may be used to refer to a mixture of one or more active agents with a carrier or other excipients.

[0048] The terms active agent, active pharmaceutical agent, drug, active ingredient, and variants thereof are used interchangeably to refer to an agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a significant or effective amount.

[0049] Pharmaceutically acceptable salt includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable base addition salts.

[0050] Pharmaceutically acceptable acid addition salt refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.

[0051] Pharmaceutically acceptable base addition salt refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0052] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms (solvates). Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of product formation or isolation with pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile, and the like. In one aspect, solvates are formed using, but not limited to, Class 3 solvent(s). Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.

[0053] The terms effective amount or therapeutically effective amount as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an effective amount for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease. An appropriate effective amount in any individual case may be determined using techniques, such as a dose escalation study.

[0054] The terms subject, individual, and patient are used interchangeably herein to refer to a mammal. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets.

[0055] The term peripherally restricted FAAH inhibitor as used herein, refers to a fatty acid amide hydrolase (FAAH) inhibitor that inhibits FAAH to a greater extent in the periphery than in the central nervous system from a systemic dose. In some embodiments, the peripherally restricted FAAH inhibitor is 60% peripherally restricted. In some embodiments, the peripherally restricted FAAH inhibitor is 70% peripherally restricted. In some embodiments, the peripherally restricted FAAH inhibitor is 80% peripherally restricted. In some embodiments, the peripherally restricted FAAH inhibitor is 90% peripherally restricted. In some embodiments, the peripherally restricted FAAH inhibitor is 95% peripherally restricted.

[0056] The term target in the brain as used herein, refers to a biological target wherein the biological target is activated in the brain, but the target itself is present in the CNS or both the CNS and periphery. In some embodiments, the target is in the CNS. In some embodiments, the target is in the CNS and periphery. As a result of target activation in the brain, the activated target may elicit a biological effect in the CNS, periphery, or both the CNS and periphery. In some embodiments, the activated target elicits a biological effect in the CNS. In some embodiments, the activated target elicits a biological effect predominantly in the CNS. In some embodiments, the activated target elicits a biological effect in the periphery. In some embodiments, the activated target elicits a biological effect in both the CNS and periphery. In some embodiments, the term target in the brain refers to a target in a mammal brain. In some embodiments, the term target in the brain refers to a target in a mammal brain, wherein the mammal is a human.

Targets

S1P1

[0057] Sphingosine-1-phosphate receptor 1 (S1P receptor 1 or S1P1), also known as endothelial differentiation gene 1 (EDG1) is a Class A G-protein coupled receptor expressed on lymphocytes, neural cells, and the endothelium. There are five GPCRs (S1P1-5) in the family which recognize sphingolipid shinosine-1phosphate (S1P) and perform a variety of functions. S1P1 regulates vascular development and lymphocyte trafficking and agonists thereof have been approved for the treatment of relapsing forms of multiple sclerosis. Sustained activation (agonism) of S1P1 expressed on lymphocytes results in receptor internalization and proteasomal degradation, resulting in functional antagonism of S1P1. It has been reported that S1P1 agonists that can efficiently penetrate the CNS can induce receptor signaling and degradation of S1P1 expressed on neurons and astrocytes, resulting in reduced disease severity in experimental autoimmune encephalomyelitis (EAE) in mice.

LPA1

[0058] Lysophosphatidic acid receptor 1 (LPA1) is a G protein-coupled receptor that binds extracellular lysophosphatidic acid (LPA) activating second messenger pathways and eliciting a number of cellular responses that regulate cellular activity, cell motility, cytoskeletal rearrangement and cell growth. LPA1 activation induces microglial activation in the CNS and the receptor is a key regulator of neuroinflammation. LPA1 activation also plays a key role in the induction of demyelination. Inhibition of LPA1 activity in the CNS may have beneficial effects in multiple CNS diseases which involve neuroinflammation and demyelination.

GPR120

[0059] GPR120/FFAR4 is a receptor of unsaturated long-chain fatty acids expressed in macrophages, eosinophils, and adipose tissue reported to mediate anti-inflammatory mechanisms. In C.sub.57BL/6 models of middle cerebral artery occlusion (MCAO) and an in vitro model of oxygen-glucose deprivation (OGD), increased GPR120 expression was observed in microglia and neurons following MCAO-induced ischemia. Treatment with RAR agonists inhibited OGD-induced inflammatory response in primary microglia and murine microglial BV2 cells, whereas silencing of GPR120 strongly exacerbated the inflammation induced by OGD and abolished the anti-inflammatory effects. Additionally, knockdown of GPR120 impaired the antiapoptotic effect of RAR agonists in OGD-induced rat pheochromocytoma (PC12) cells. GPR120 activation has also been reported to protect against focal cerebral ischemic injury by preventing inflammation and apoptosis.

PGI2 Analogues or Prostaglandin I2 (IP) Receptor Agonists

[0060] Prostacyclin (prostaglandin I.sub.2) is a metabolite of arachidonic acid or prostaglandin endoperoxides and is released from vascular endothelial cells. The I-type prostaglandin receptor (IP3 receptor) is a G protein-coupled receptor that is coupled to the activation of adenylate cyclase, which catalyzes the formation of 3,5 cyclic adenosine monophosphate (cAMP), a second messenger involved in vascular tone. IP receptors are expressed on vascular smooth muscle and platelets and serve as a vasorelaxant in smooth muscle and an inhibitor of platelet aggregation. Prostacyclin has also been reported to promote axonal remodeling of injured neuronal networks after CNS inflammation. Additionally, studies under pathological conditions revealed that after occlusion of the middle cerebral artery, a stable analog of prostacyclin reduced brain edema. It is thought that prostacyclin signaling directly acts on endothelial cells and enhances endothelial barrier function, reducing edema formation. Signaling in perivascular cells, such as pericytes, contributes to reducing capillary hydraulic permeability under pathological conditions in the adult CNS. Prostacyclin receptor signaling inhibitors have been reported to impair motor recovery, IP receptor agonists promote axonal remodeling and motor recovery after the induction of EAE. These findings revealed that angiogenesis plays an important role in neuronal rewiring and suggest that prostacyclin is a promising molecule for enhancing functional recovery in CNS diseases.

TTR Stabilizer Analogues

[0061] Transthyretin (TTR) is a homo-tetramer composed of 127 amino acid subunits that carries thyroxine and holo-retinol binding protein (holo-RBP) in the blood. It is secreted by liver into the blood at a steady state concentration of about 3-6 ?M and by the choroid plexus (CP) into the cerebrospinal fluid (CSF) at a steady state concentration of approx. 300 nM. Misfolding, aggregation, and deposition (amyloidogenesis) of TTR is linked to amyloid diseases, including senile systemic amyloidosis, familial amyloid polyneuropathy or cardiomyopathy. The TTR tetramer is non-amyloidogenic, but undergoes dissociation, monomer misfolding, and misassembly into numerous aggregated structures including amyloid under partially denaturing conditions. TTR has also been reported to counteract the neurotoxic effects of A3 peptides by reducing their aggregation and enhancing clearance of the oligomers and plaques in the brain.

Pharmaceutical Compositions and Compounds

[0062] In some embodiments described herein is a pharmaceutical composition comprising a fatty acid amide hydrolase (FAAH) cleavable prodrug of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

##STR00029## [0063] wherein: [0064] R.sup.1 is an amide prodrug moiety, wherein the prodrug of Formula (I) is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release

##STR00030##

is a moiety that modulates a target in the brain; and a pharmaceutically acceptable excipient; further comprising a peripherally restricted FAAH inhibitor.

[0065] In some embodiments, the target is selected from sphingosine-1-phosphate receptor 1 (S1P1), lysophosphatidic acid receptor 1 (LPA1), G-protein coupled receptor 120 (GPR120), prostacyclin (PGI2), and transthyretin (TTR).

[0066] In some embodiments, the target is S1P1. In some embodiments, the target is S1P1, wherein R.sup.2 is selected from

##STR00031##

[0067] In some embodiments, the target is LPA1. In some embodiments, the target is LPA1, wherein R.sup.2 is selected from

##STR00032##

[0068] In some embodiments, the target is GPR120. In some embodiments, the target is GPR120, wherein R.sup.2 is

##STR00033##

[0069] In some embodiments, the target is TTR. In some embodiments, the target is TTR, wherein R.sup.2 is selected from

##STR00034## ##STR00035##

[0070] In some embodiments, the target is PGI2. In some embodiments, the target is PGI2, wherein R.sup.2 is

##STR00036##

[0071] In some embodiments, R.sup.1 is optionally substituted C.sub.1-6alkyl. In some embodiments, R.sup.1 is C.sub.1-6alkyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, CN, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C(O)OH, C(O)OC.sub.1-6alkyl, C(O)NH.sub.2, C(O)N(H)(C.sub.1-6alkyl), C(O)N(C.sub.1-6alkyl).sub.2, C(O)C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, S(O).sub.2NH.sub.2, S(O).sub.2N(H)(C.sub.1-6alkyl), S(O).sub.2N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl. In some embodiments, R.sup.1 is C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl. In some embodiments, R.sup.1 is C.sub.1-6alkyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C.sub.1-6haloalkyl, and C.sub.1-6alkoxy. In some embodiments, R.sup.1 is unsubstituted C.sub.1-6alkyl.

[0072] In some embodiments, R.sup.1 is optionally substituted C.sub.3-6cycloalkyl. In some embodiments, R.sup.2 is C.sub.3-6cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, CN, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C(O)OH, C(O)OC.sub.1-6alkyl, C(O)NH.sub.2, C(O)N(H)(C.sub.1-6alkyl), C(O)N(C.sub.1-6alkyl).sub.2, C(O)C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, S(O).sub.2NH.sub.2, S(O).sub.2N(H)(C.sub.1-6alkyl), S(O).sub.2N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl. In some embodiments, R.sup.1 is C.sub.3-6cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl. In some embodiments, R.sup.1 is C.sub.3-6cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6alkoxy. In some embodiments, R.sup.1 is unsubstituted C.sub.3-6cycloalkyl.

[0073] In some embodiments, R.sup.1 is optionally substituted C.sub.2-9heterocycloalkyl. In some embodiments, R.sup.1 is C.sub.2-9heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, CN, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C(O)OH, C(O)OC.sub.1-6alkyl, C(O)NH.sub.2, C(O)N(H)(C.sub.1-6alkyl), C(O)N(C.sub.1-6alkyl).sub.2, C(O)C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, S(O).sub.2NH.sub.2, S(O).sub.2N(H)(C.sub.1-6alkyl), S(O).sub.2N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl. In some embodiments, R.sup.1 is C.sub.2-9heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl. In some embodiments, R.sup.1 is C.sub.2-9heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6alkoxy. In some embodiments, R.sup.1 is unsubstituted C.sub.2-9heterocycloalkyl.

[0074] In some embodiments, R.sup.1 is optionally substituted C.sub.6-10aryl. In some embodiments, R.sup.1 is C.sub.6-10aryl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, CN, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C(O)OH, C(O)OC.sub.1-6alkyl, C(O)NH.sub.2, C(O)N(H)(C.sub.1-6alkyl), C(O)N(C.sub.1-6alkyl).sub.2, C(O)C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, S(O).sub.2NH.sub.2, S(O).sub.2N(H)(C.sub.1-6alkyl), S(O).sub.2N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl. In some embodiments, R.sup.1 is C.sub.6-10aryl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl. In some embodiments, R.sup.1 is C.sub.6-10aryl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, and C.sub.1-6alkoxy. In some embodiments, R.sup.1 is unsubstituted C.sub.6-10aryl.

[0075] In some embodiments, R.sup.1 is optionally substituted C.sub.1-9heteroaryl. In some embodiments, R.sup.1 is C.sub.1-9heteroaryl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, CN, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C(O)OH, C(O)OC.sub.1-6alkyl, C(O)NH.sub.2, C(O)N(H)(C.sub.1-6alkyl), C(O)N(C.sub.1-6alkyl).sub.2, C(O)C.sub.1-6alkyl, S(O).sub.2C.sub.1-6alkyl, S(O).sub.2NH.sub.2, S(O).sub.2N(H)(C.sub.1-6alkyl), S(O).sub.2N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl. In some embodiments, R.sup.1 is C.sub.1-9heteroaryl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-6cycloalkyl, C.sub.2-9heterocycloalkyl, C.sub.6-10aryl, and C.sub.1-9heteroaryl. In some embodiments, R.sup.1 is C.sub.1-9heteroaryl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, OH, NH.sub.2, N(H)(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6 haloalkyl, and C.sub.1-6alkoxy. In some embodiments, R.sup.1 is unsubstituted C.sub.1-9heteroaryl.

[0076] In some embodiments, R.sup.1 is CH.sub.3. In some embodiments, R.sup.1 is CH.sub.2CH.sub.3. In some embodiments, R.sup.1 is CH.sub.2CH.sub.2CH.sub.3. In some embodiments, R.sup.1 is CHCH.sub.3).sub.2. In some embodiments, R.sup.1 is

##STR00037##