Lipid prodrugs of neurosteroids

Abstract

The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a disclosed lipid prodrug or a pharmaceutical composition thereof.

We claim: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  and R 2  are each independently hydrogen, an acid-labile group, a lipid, or —C(O)R 3 ; 
 each R 3  independently is a saturated or unsaturated, straight or branched, optionally substituted C 1-37  hydrocarbon chain; 
 X is —O—, —NR—, —S—, —O(C 1-6  aliphatic)-O—, —O(C 1-6  aliphatic)-S—, —O(C 1-6  aliphatic)-NR—, —S(C 1-6  aliphatic)-O—, —S(C 1-6  aliphatic)-S—, —S(C 1-6  aliphatic)-NR—, —NR(C 1-6  aliphatic)-O—, —NR(C 1-6  aliphatic)-S—, or —NR(C 1-6  aliphatic)-NR—, wherein 0-2 methylene units of the C 1-6  aliphatic group are independently and optionally replaced with —O—, —NR—, or —S— and the C 1-6  aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms; 
 each R independently is hydrogen or an optionally substituted group selected from C 1-6  aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 Y is absent or is —C(O)—, —C(NR)—, or —C(S)—; 
 L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C 1-30  hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —C(S)—, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-; or 
 L is 
 
       
         
           
           
               
               
           
         
         
           wherein either the right-hand side or left-hand side of L is attached to 
         
       
       
         
           
           
               
               
           
         
         each -Cy- independently is an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         each R 4  and R 5  independently is hydrogen, deuterium, halogen, —CN, —OR, —NR 2 , —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a C 1-6  aliphatic group optionally substituted with —CN, —OR, —NR 2 , —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or the C 1-6  aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or 
         two instances of R 4  or R 5  attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
       
       -M- is a self-immolative group; 
       n is 0-18; 
       each m independently is 0-6; and 
       
         
           
           
               
               
           
         
       
       is a therapeutic agent that is a naturally-occurring or non naturally-occurring neurosteroid or an analogue or prodrug thereof. 
     
     
         2 . The compound according to  claim 1 , wherein R 1  and R 2  are —C(O)R 3 . 
     
     
         3 . The compound according to  claim 1  or  2 , wherein each R 3  independently is a saturated or unsaturated, unbranched C 2-37  hydrocarbon chain. 
     
     
         4 . The compound according to any one of  claims 1 - 3 , wherein X is —O—. 
     
     
         5 . The compound according to any one of  claims 1 - 4 , wherein Y is —C(O)—. 
     
     
         6 . The compound according to any one of  claims 1 - 5 , wherein L is a saturated or unsaturated, straight or branched, optionally substituted bivalent C 7-20  hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —C(S)—, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-. 
     
     
         7 . The compound according to any one of  claims 1 - 5 , wherein L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C 1-30  hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —C(S)—, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or an amino acid selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and wherein 1 methylene unit of L is optionally replaced with -M-;
 L is 
 
       
         
           
           
               
               
           
         
       
       wherein either the right-hand side or left-hand side of L is attached to 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound according to any one of  claims 1 - 5 , wherein L is a saturated bivalent C 1-25  hydrocarbon chain optionally substituted with 1, 2, 3, or 4 groups selected from deuterium, halogen, —CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a C 1-6  aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; wherein 0-4 methylene units of L are independently replaced by —O—, —OC(O)—, —C(O)O—, or —C(O)—; and 1 methylene unit of L is optionally replaced with -M-. 
     
     
         9 . The compound according to any one of  claims 1 - 8 , wherein -M- is selected from one of the following: 
       
         
           
           
               
               
           
         
         wherein each R 6  independently is hydrogen, deuterium, C 1-5  aliphatic, halogen, or —CN; 
         each R 7  independently is hydrogen, deuterium, halogen, —CN, —OR, —NR 2 , —NO 2 , —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a C 1-6  aliphatic group optionally substituted with —CN, —OR, —NR 2 , —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C 1-6  aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; 
         each Z 1  independently is —O—, —NR—, or —S—; 
         each Z 2  independently is —O—, —NR—, —S—, —OC(O)—, —NRC(O)O—, or —OC(O)NR—; 
         each Z 3  independently is ═N— or ═C(R 7 )—; and 
         each Z 4  independently is —O—, —NR—, —S—, —C(R 6 ) 2 —, or a covalent bond. 
       
     
     
         10 . The compound according to  claim 9 , wherein -M- is selected from 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 9  or  10 , wherein -M- is selected from 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound according to any one of  claims 1 - 11 , wherein each R 4  independently is hydrogen, deuterium, halogen, —CN, or C 1-4  aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R 4  attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         13 . The compound according to any one of  claims 1 - 12 , wherein each R 5  independently is hydrogen, deuterium, halogen, —CN, or C 1-4  aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R 5  attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         14 . The compound according to any one of  claims 1 - 13 , wherein each R 4  and R 5  independently is hydrogen or C 1-4  alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 
     
     
         15 . The compound according to any one of  claims 1 - 13 , wherein 
       
         
           
           
               
               
           
         
       
       is allopregnanolone, pregnanolone, pregnenolone, ganaxolone, alfaxalone, 3β-dihydroprogesterone, isopregnanolone, epipregnanolone, or 21-hydroxyallopregnanolone. 
     
     
         16 . The compound according to any of  claims 1 - 14 , wherein 
       
         
           
           
               
               
           
         
       
       is allopregnanolone. 
     
     
         17 . The compound according to any one of  claims 1 - 11 , wherein 
       
         
           
           
               
               
           
         
       
       is a non naturally-occurring (synthetic) excitatory neurosteroid. 
     
     
         18 . The compound according to  claim 1 , wherein the compound is one of those in Table 1. 
     
     
         19 . A pharmaceutically acceptable composition comprising a compound according to any of  claims 1 - 18 , and a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle. 
     
     
         20 . The pharmaceutically acceptable composition according to  claim 19 , further comprising an additional therapeutic agent. 
     
     
         21 . The pharmaceutically acceptable composition according to  claim 19  or  20 , wherein the composition is formulated for oral administration. 
     
     
         22 . A method of treating or preventing a disease, disorder, or condition in which an increased level of a pregnane neurosteroid is beneficial, or a disease, disorder, or condition caused by a deficiency in a pregnane neurosteroid, comprising administering to a subject in need thereof an effective amount of a compound according to any one of  claims 1 - 18 . 
     
     
         23 . A method of treating a disease, disorder, or condition caused by deficient activation of GABA A , comprising administering to a subject in need thereof an effective amount of a compound according to any one of  claims 1 - 18 . 
     
     
         24 . The method of  claim 22  or  23 , wherein the disease, disorder, or condition is selected from post-partum depression, depression, major depressive disorder, bipolar disorder, a mood disorder, anxiety, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety, memory loss, poor stress tolerance, Niemann-Pick disease type C or an associated neurological or physical symptom, epilepsy, essential tremor, an epileptiform disorder, NMDA hypofunction, migraine, status epilepticus, a sleep disorder, Fragile X Syndrome, depression induced by a 5 alpha reductase inhibitor, PCDH19 female pediatric epilepsy, sexual dysfunction, Parkinson's disease, and Alzheimer's disease. 
     
     
         25 . The method of  claim 24 , wherein the disease, disorder, or condition is selected from post-partum depression, depression, major depressive disorder, bipolar disorder, Niemann-Pick disease type C, epilepsy, essential tremor, an epileptiform disorder, NMDA hypofunction, status epilepticus, super-refractory status epilepticus (SRSE), Parkinson's disease, and Alzheimer's disease. 
     
     
         26 . The method of  claim 22  or  23 , wherein the disease, disorder or condition is Fragile X syndrome or Fragile X-associated syndrome. 
     
     
         27 . The method of  claim 22  or  23 , wherein the disease, disorder or condition is Fragile X-associated tremor/ataxia syndrome (FXTAS). 
     
     
         28 . The method of  claim 22  or  23 , wherein the disease, disorder or condition is epilepsy or an epileptic disorder. 
     
     
         29 . The method of  claim 28 , wherein the epileptic disorder is acute repetitive seizures, treatment refractive seizures, status epilepticus, or epileptic seizures or spasms. 
     
     
         30 . The method of  claim 28 , wherein the epileptic disorder is an epileptic seizure selected from tonic-clonic (Grand Mal) seizure, partial (Focal) seizure, catamenial seizure, acute repetitive seizure, psychomotor (complex partial) seizure, absence (Petit Mal) seizure, and myoclonic seizure. 
     
     
         31 . The method of  claim 22  or  23 , wherein the disease, disorder or condition is a demyelinating disease. 
     
     
         32 . The method of  claim 31 , wherein the demyelinating disease is multiple sclerosis, neuromyelitis optica, optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy and adrenomyeloneuropathy, Guillain-Barre syndrome, anti-myelin associated glycoprotein peripheral neurophathy, Charcot-Marie-Tooth disease, progressive inflammatory neuropathy, chronic inflammatory demyelinating polyneuropathy, or amyotrophic lateral sclerosis (ALS). 
     
     
         33 . The method of  claim 31 , wherein the demyelinating disease is multiple sclerosis. 
     
     
         34 . The method of  claim 33 , wherein the multiple sclerosis is relapsing remitting multiple sclerosis or primary progressive multiple sclerosis. 
     
     
         35 . The method of  claim 22  or  23 , wherein the disease, disorder or condition is a lysosomal storage disorder. 
     
     
         36 . The method of  claim 35 , wherein the lysosomal storage disorder is Farber disease, Krabbe disease, Fabry disease, Schindler disease, GM1 gangliosidosis, GM2 gangliosidosis, Tay-Sachs disease, Sandhoff disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, sulfatidosis, metachromatic leukodystrophy, Hurler syndrome, Scheie syndrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialidosis, I-cell disease, phosphotransferase deficiency, mucolipidin 1 deficiency, neuronal ceroid lipofuscinoses, Wolman disease, alpha-mannosidosis, beta-mannosidosis, aspartylglucosaminuria, fucosidosis, cystinosis, pycnodysostosis, Salla disease, infantile free sialic acid storage disease, Pompe disease, Danon disease, cholesteryl ester storage disease, or lysosomal disease. 
     
     
         37 . The method of  claim 22  or  23 , wherein the disease, disorder or condition is a sleep disorder.