HETEROARYL AMIDE DERIVATIVES

Heteroaryl amide derivatives are provided, of the Formula: wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies. COPYRIGHT KIPO & WIPO 2010 ...

Cyclic amino acids and derivatives thereof useful as pharmaceutical agents

The invention is a novel series of cyclic amino acids which are useful in the treatment of epilepsy, faintness attacks, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, gastrointestinal disorders such as irritable bowel syndrome (IBS), and inflammation, especially arthritis. A pharmaceutical composition containing a compound of the invention as well as methods of preparing the compounds and novel intermediates useful in the preparation of the final compounds are included.

Use of (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl) butanoic acid for treating urinary incontinence

Use of (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid for treating urinary incontinence is disclosed.

5-Membered Heterocyclic Amides And Related Compounds

5-Membered heterocyclic amides and related compounds are provided, of the Formula: wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies. 1122-. (canceled)126. A compound or salt or hydrate thereof according to claim 123 , wherein Y is C-Ccycloalkyl claim 123 , 6- to 10-membered aryl or 5- to 10-membered heteroaryl claim 123 , each of which is substituted with from 0 to 4 substituents independently chosen from halogen claim 123 , hydroxy claim 123 , cyano claim 123 , amino claim 123 , C-Calkyl claim 123 , C-Calkenyl claim 123 , C2-Calkynyl claim 123 , C-Chaloalkyl claim 123 , C-Chydroxyalkyl claim 123 , C-Calkoxy claim 123 , and mono- or di-(C-Calkyl)amino.127. A compound or salt or hydrate thereof according to claim 123 , wherein Y is phenyl or a 5- or 6-membered heteroaryl; each of which is optionally fused to a 5- to 7-membered carbocycle or a 5- to 7-membered heterocycle; and each of which phenyl claim 123 , heteroaryl claim 123 , carbocycle and heterocycle is substituted with from 0 to 4 substituents independently chosen from halogen claim 123 , hydroxy claim 123 , cyano claim 123 , amino claim 123 , C-Calkyl claim 123 , C-Calkenyl claim 123 , C-Calkynyl claim 123 , C-Chaloalkyl claim 123 , C-Chydroxyalkyl claim 123 , C-Calkoxy claim 123 , and mono- or di-(C-Calkyl)amino.129. The compound of selected from the group consisting of1-(4-amino-5-methylpyrimidin-2-yl)-N-[2-(4-chlorophenyl)-4-methylpentyl]-3-methyl-1H-pyrazole-4-carboxamide;1-(4-amino-5-fluoropyrimidin-2-yl)-N-[2-(4-chlorophenyl)-4-methylpentyl]-3-methyl-1H-pyrazole-4- ...

ALPHA 2 DELTA LIGANDS FOR FIBROMYALGIA AND OTHER DISORDERS

This invention relates to a method of treating a disorder selected from OCD, agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, PTSD, restless legs syndrome, premenstrual dysphoric disorder, hot flashes, and fibromyalgia by administering a compound of the formula 1 or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms or phenyl; and R² is straight or branched alkyl of from 4 to 8 carbon atoms, straight or branched alkenyl of from 2 to 8 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, alkoxy of from 1 to 6 carbon atoms, -alkylcycloalkyl, -alkylalkoxy, -alkyl OH, -alkylphenyl, -alkylphenoxy, or -substituted phenyl. The invention also relates to a method of treating the above disorders by administering the compound (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid.

5-membered heterocyclic amides and related compounds

The invention provides 5-Membered heterocyclic amides and related compounds of the following formula, wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

Oral Dosage Forms of Methyl Hydrogen Fumarate and Prodrugs Thereof

Improved oral dosage forms of methyl hydrogen fumarate and prodrugs thereof are disclosed. Methods of treating diseases such as multiple sclerosis and psoriasis using such dosage forms are also disclosed. 1. An oral pharmaceutical tablet , comprising:(A) a tablet core comprising (i) a compound selected from (a) methyl hydrogen fumarate (MHF), (b) a prodrug of MHF, (c) pharmaceutically acceptable salts of (a) or (b), and (d) combinations of any of the foregoing, and (ii) one or more core tableting excipients; and(B) a compressed coating layer surrounding said tablet core, the coating layer comprising a material that is either (i) a proton-donating acidic material having a pKa of greater than 8, (ii) a proton-accepting basic material having a pKa of less than 2, (iii) a natural gum or polysaccharide, (iv) a neutral polymer salt, or (v) a lipid,the coating layer releasing no more than 20% of the compound over a period of 2 hours after the tablet is placed in an aqueous solution free of the compound.2. The oral pharmaceutical tablet of claim 1 , wherein the coating layer material is a non-ionizable polymer substantially free of carboxylic acid moieties.3. The oral pharmaceutical tablet of claim 1 , wherein the coating layer material is selected from non-ionizable cellulosic polymers claim 1 , non-ionizable vinyl polymers claim 1 , and non-ionizable polyvinyl alcohol polymers.4. The oral pharmaceutical tablet of claim 1 , wherein the tablet core comprises an immediate release formulation.5. The oral pharmaceutical tablet of claim 1 , wherein the tablet core comprises a sustained release formulation.6. The oral pharmaceutical tablet of claim 1 , wherein at least one of the tablet core and the coating layer comprises a sustained release agent.7. The oral pharmaceutical tablet of claim 6 , wherein the sustained release agent is selected from hydroxypropylmethyl cellulose and ethyl cellulose.8. The oral pharmaceutical tablet of claim 1 , the tablet having a core weight to: ...

PHARMACEUTICAL USES FOR ALPHA2DELTA LIGANDS

The invention relates to a method of treating central nervous system disorders and other disorders by administering an alpha2delta ligand such as, for example, a compound of the formula or a pharmaceutically acceptable salt thereof, wherein R₁ is hydrogen or straight or branched lower alkyl, and n is an integer of from 4 to 6.

PHARMACEUTICAL USES FOR ALPHA2DELTA LIGANDS

The invention relates to a method of treating central nervous system disorders and other disorders by administering an alpha2delta ligand such as, for example, a compound of the formula or a pharmaceutically acceptable salt thereof, wherein R₁ is hydrogen or straight or branched lower alkyl, and n is an integer of from 4 to 6.

USE OF (3R)-4--3-(4-CHLOROPHENYL) BUTANOIC ACID FOR TREATING URINARY INCONTINENCE

Use of (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl) butanoic acid for treating urinary incontinence is disclosed.

Morpholinoalkyl Fumarate Compounds, Pharmaceutical Compositions, and Methods of Use

Morpholinoalkyl fumarates, pharmaceutical compositions comprising the morpholinoalkyl fumarates, and methods of using morpholinoalkyl fumarates and pharmaceutical compositions for treating neurodegenerative, inflammatory, and autoimmune disorders including multiple sclerosis, psoriasis, irritable bowel disorder, ulcerative colitis, arthritis, chronic obstructive pulmonary disease, asthma, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are disclosed. 131-. (canceled)33. A compound of claim 32 , wherein n is 2.34. A compound of claim 32 , wherein Q is a morpholino group.35. A compound of claim 32 , wherein the compound is a pharmaceutically acceptable salt.36. A compound according to claim 32 , wherein the compound is a HCl salt.37. A pharmaceutical composition comprising a pharmaceutically acceptable vehicle and a therapeutically effective amount of a compound of .38. A method for treating in a mammal in need thereof a disease or condition which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound of .39. The method of claim 38 , wherein the disease or condition is selected from a neurodegenerative disease claim 38 , an inflammatory disease claim 38 , and an autoimmune disease.40. The method of claim 38 , wherein the disease or condition is selected from multiple sclerosis claim 38 , psoriasis claim 38 , irritable bowel disorder claim 38 , ulcerative colitis claim 38 , arthritis claim 38 , chronic obstructive pulmonary disease claim 38 , asthma claim 38 , Parkinson's disease claim 38 , Huntington's disease claim 38 , and amyotrophic lateral sclerosis.41. The method of claim 38 , wherein the disease or condition is multiple sclerosis.42. The method of claim 38 , wherein the disease or condition is psoriasis. This application is a continuation of U.S. patent application Ser. No. 13/761,864, filed Feb. 7, 2013, which claims the benefit of U.S. Provisional Patent Application No. 61/ ...

GAMMA-AMINO-BUTYRIC ACID DERIVATIVES AS GABAB RECEPTOR LIGANDS

Gamma-amino-butyric acid derivatives that are GABAB receptor ligands, pharmaceutical compositions comprising such derivatives, and methods of using such derivatives and pharmaceutical compositions thereof for treating diseases are disclosed.

Amino acids with affinity for the alpha2delta-protein

Certain beta-amino acids that bind to the alpha-2-delta (alpha2delta) subunit of a calcium channel are disclosed. These compounds and their pharmaceutically acceptable salts are useful in the treatment of a variety of psychiatric, pain and other disorders.

Oral Dosage Forms Having a High Loading of a Methyl Hydrogen Fumarate Prodrug

Oral dosage forms and granulations with a high loading of a methyl hydrogen fumarate prodrug are disclosed. 1. A solid pharmaceutical granulation comprising at least about 95 wt % (N ,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1 ,4-dioate and one or more pharmaceutically acceptable excipients.2. The granulation of claim 1 , comprising at least about 97 wt % (N claim 1 ,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1 claim 1 ,4-dioate.3. The granulation of claim 1 , wherein the pharmaceutically acceptable excipient comprises a binder.4. The granulation of claim 3 , wherein the binder comprises a polymer selected from hydroxypropyl cellulose claim 3 , hydroxypropylmethyl cellulose claim 3 , polyvinyl pyrrolidone and combinations thereof.5. A mixture comprising the solid granulation of claim 1 , and at least one additional pharmaceutically acceptable excipient.6. The mixture of claim 5 , wherein the at least one additional excipient is selected from fillers claim 5 , diluents claim 5 , binders claim 5 , lubricants claim 5 , disintegrants claim 5 , glidants claim 5 , sustained release agents and combinations thereof.7. The mixture of claim 5 , comprising a glidant claim 5 , so as to improve flowability of said mixture.8. The mixture of claim 7 , comprising up to about 3 wt % silicon dioxide glidant.9. The mixture of claim 7 , comprising up to about 1 wt % silicon dioxide glidant.10. The mixture of claim 7 , comprising about 0.1 to about 0.5 wt % silicon dioxide glidant.11. The mixture of claim 8 , wherein the silicon dioxide glidant has an average particle size of less than 200 nm.12. An oral dosage form comprising the mixture of .13. The dosage form of claim 12 , wherein the dosage form comprises a capsule containing the mixture.14. The dosage form of claim 12 , wherein the dosage form comprises a tablet.15. The dosage form of claim 13 , comprising from about 100 mg to about 1 claim 13 ,200 mg (N claim 13 ,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1 claim 13 ...

Oral Dosage Forms of Methyl Hydrogen Fumarate and Prodrugs Thereof

Improved oral dosage forms of methyl hydrogen fumarate and prodrugs thereof are disclosed. Methods of treating diseases such as multiple sclerosis and psoriasis using such dosage forms are also disclosed. 1. An oral dosage form comprising:a core comprising a therapeutically effective amount of a compound selected from (i) methyl hydrogen fumarate (MHF), (ii) a prodrug of MHF, (iii) pharmaceutically acceptable salts of (i) or (ii), and (iv) combinations of any of the foregoing;a barrier layer surrounding said core, the barrier layer comprising a material that is (i) a weakly acidic (proton-donating) material having a pKa of greater than 8, (ii) a weakly basic (proton-accepting) material having a pka of less than 2, (iii) a natural gum or polysaccharide derivative (iv) a neutral polymer salt, (v) a sugar, (vi) a lipid, or (vii) combinations of any of the foregoing; the barrier layer preventing direct contact between the core and an enteric coating; andthe enteric coating surrounding said barrier layer and comprising an enteric polymer having carboxylic acid moieties, the enteric polymer (i) being soluble in aqueous solutions having a pH above 7.5, and (ii) starting to become soluble in an aqueous solution at a pH in the range of 4.3 to 7.5.2. The oral dosage form of claim 1 , wherein the barrier layer material is a non-ionizable polymer substantially free of carboxylic acid moieties.3. The oral dosage form of claim 1 , wherein the barrier layer material is selected from non-ionizable cellulosic polymers claim 1 , non-ionizable vinyl polymers claim 1 , and non-ionizable polyvinyl alcohol polymers.4. The oral dosage form of claim 1 , wherein the hairier layer material is a sugar.5. The oral dosage form of claim 1 , wherein the harrier layer comprises at least 5 wt % of the coated core for cores having a size of 2 mm or less.6. The oral dosage form of claim 1 , wherein the barrier layer comprises at least 0.5 wt % of the coated core for cores having a size greater than 6 ...

GAMMA-AMINO-BUTYRIC ACID DERIVATIVES AS GABAB RECEPTOR LIGANDS

Gamma-amino-butyric acid derivatives that are GABA B receptor ligands, pharmaceutical compositions comprising such derivatives, and methods of using such derivatives and pharmaceutical compositions thereof for treating diseases are disclosed.

PHARMACEUTICAL USES FOR ALPHA2DELTA LIGANDS

The invention relates to a method of treating central nervous system disorders and other disorders by administering an alpha2delta ligand such as, for example, a compound of the formula or a pharmaceutically acceptable salt thereof, wherein R₁ is hydrogen or straight or branched lower alkyl, and n is an integer of from 4 to 6.

Alpha2delta ligands for the treatment of fibromyalgia and other disorders

The invention relates to a method of treating fibromyalgia and other disorders in a mammal by administering a compound compound of Formula I R₁ is straight or branched unsubstituted alkyl of from 1 to 5 carbon atoms, unsubstituted phenyl, or unsubstituted cycloalkyl of from 3 to 6 carbon atoms; R₂ is hydrogen or methyl; and R₃ is hydrogen, methyl, or carboxyl, or a pharmaceutically acceptable salt thereof.

Oral Dosage Forms of Methyl Hydrogen Fumarate and Prodrugs Thereof

Improved oral dosage forms of methyl hydrogen fumarate and prodrugs thereof are disclosed. Methods of treating diseases such as multiple sclerosis and psoriasis using such dosage forms are also disclosed. 1. An oral pharmaceutical tablet , comprising:(A) a tablet core comprising (i) a compound selected from (a) methyl hydrogen fumarate (MHF), (b) a prodrug of MHF, (c) pharmaceutically acceptable salts of (a) or (b), and (d) combinations of any of the foregoing, and (ii) one or more core tableting excipients; and(B) a compressed coating layer surrounding said tablet core, the coating layer comprising a material that is either (i) a proton-donating acidic material having a pKa of greater than 8, (ii) a proton-accepting basic material having a pKa of less than 2, (iii) a natural gum or polysaccharide, (iv) a neutral polymer salt, or (v) a lipid,the coating layer releasing no more than 20% of the compound over a period of 2 hours after the tablet is placed in an aqueous solution free of the compound.2. The oral pharmaceutical tablet of claim 1 , wherein the coating layer material is a non-ionizable polymer substantially free of carboxylic acid moieties.3. The oral pharmaceutical tablet of claim 1 , wherein the coating layer material is selected from non-ionizable cellulosic polymers claim 1 , non-ionizable vinyl polymers claim 1 , and non-ionizable polyvinyl alcohol polymers.4. The oral pharmaceutical tablet of claim 1 , wherein the tablet core comprises an immediate release formulation.5. The oral pharmaceutical tablet of claim 1 , wherein the tablet core comprises a sustained release formulation.6. The oral pharmaceutical tablet of claim 1 , wherein at least one of the tablet core and the coating layer comprises a sustained release agent.7. The oral pharmaceutical tablet of claim 6 , wherein the sustained release agent is selected from hydroxypropylmethyl cellulose and ethyl cellulose.8. The oral pharmaceutical tablet of claim 1 , the tablet having a core weight to: ...

Heteroaryl amide derivatives

Heteroaryl amide derivatives are provided, of the Formula: wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

Method of treating tinnitus

The invention relates to a method of treating tinnitus by administering an alpha2delta ligand such as, for example, a compound of Formula and pharmaceutically acceptable salts thereof, wherein R₁ is hydrogen or straight or branched lower alkyl, and n is an integer of from 4 to 6.

Heteroaryl amide analogues

Compounds, pharmaceutical compositions, and methods of use are disclosed for heteroaryl amide analogues of formula Ia and/or Ib. In certain embodiments, the heteroaryl amide analogues are agonists and/or ligands of dopamine receptors and may be useful, inter alia, for the treatment of a condition responsive to P2X7 receptor modulation, for example, pain, inflammation, a neurological or neurodegenerative disorder, a cardiovascular disorder, an ocular disorder or an immune system disorder.

Heteroaryl Amide Derivatives

Heteroaryl amide derivatives are provided, of the Formula: wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

Methods of Use for Monomethyl Fumarate and Prodrugs Thereof

Methods of therapeutic treatment using monomethyl fumarate and prodrugs of monomethyl fumarate are disclosed. 1. A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound selected from: (i) monomethyl fumarate , (ii) a prodrug of monomethyl fumarate , and (iii) combinations thereof , wherein the disease is chosen from balo concentric sclerosis , bronchiolitis obliterans organizing pneumonia , central nervous system vasculitis , Charcott-Marie-Tooth Disease , childhood ataxia with central nervous system hypomyelination , diabetic retinopathy , graft versus host disease , monomelic amyotrophy , neurodegeneration with brain iron accumulation , neurosarcoidosis , pareneoplastic syndromes , subacute necrotizing myelopathy , Susac syndrome and transverse myelitis.2. The method of claim 1 , wherein the compound comprises monomethyl fumarate.3. The method of claim 1 , wherein the compound comprises a prodrug of monomethyl fumarate.4. The method of claim 3 , wherein the compound comprises dimethyl fumarate.6. The method of claim 5 , wherein each of Rand Ris hydrogen.7. The method of claim 5 , wherein one of Rand Ris hydrogen and the other of Rand Ris chosen from methyl claim 5 , ethyl claim 5 , n-propyl claim 5 , isopropyl claim 5 , n-butyl claim 5 , isobutyl claim 5 , and sec-butyl.8. The method of claim 5 , wherein Rand Rare independently chosen from hydrogen and Calkyl.9. The method of claim 5 , wherein Rand Rtogether with the nitrogen to which they are bonded form a Cheterocycloalkyl ring.10. The method of claim 5 , wherein one of Rand Ris hydrogen and the other of Rand Ris chosen from hydrogen and Calkyl; and Rand Rtogether with the nitrogen to which they are bonded form a ring chosen from morpholine claim 5 , piperazine claim 5 , and N-substituted piperazine.11. The method of claim 5 , wherein one of Rand Ris hydrogen; and the other of Rand Ris chosen from hydrogen and ...

Gamma-amino-butyric acid derivatives as GABAB receptor ligands

Gamma-amino-butyric acid derivatives that are GABAB receptor ligands, pharmaceutical compositions comprising such derivatives, and methods of using such derivatives and pharmaceutical compositions thereof for treating diseases are disclosed.

5-membered heterocyclic amides and related compounds

5-membered heterocyclic amides and related compounds

5-Membered heterocyclic amides and related compounds are provided, of the Formula: wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

METHODS OF TREATING FRAGILE X SYNDROME, DOWN'S SYNDROME, AUTISM AND RELATED DISORDERS

Disclosed herein are methods of treating fragile X syndrome, fragile X-associated tremor/ataxia syndrome, Down's syndrome and other forms of mental retardation, and/or autism comprising administering a GABAagonist prodrug to a subject suffering therefrom. The GABAagonist prodrugs can be compounds of Formula (I), (II) or (III) as disclosed herein. 4. The method of claim 1 , wherein Ris selected from phenyl claim 1 , 4-chlorophenyl claim 1 , 4-fluorophenyl claim 1 , 2-chlorophenyl claim 1 , thien-2-yl claim 1 , 5-chlorothien-2-yl claim 1 , 5-bromothien-2-yl claim 1 , 5-methylthien-2-yl and 2-imidazolyl.5. The method of claim 1 , wherein Ris selected from Calkyl claim 1 , substituted Calkyl claim 1 , Ccycloalkyl claim 1 , phenyl claim 1 , substituted phenyl claim 1 , Cphenylalkyl and pyridyl.6. The method of claim 1 , wherein Ris methyl claim 1 , ethyl claim 1 , n-propyl claim 1 , isopropyl claim 1 , n-butyl claim 1 , isobutyl claim 1 , sec-butyl claim 1 , tert-butyl claim 1 , phenyl claim 1 , cyclohexyl or 3-pyridyl.7. The method of claim 1 , wherein Rand Rare independently selected from hydrogen claim 1 , Calkyl claim 1 , substituted Calkyl claim 1 , Calkoxycarbonyl claim 1 , Ccycloalkyl claim 1 , Ccycloalkoxycarbonyl claim 1 , phenyl claim 1 , substituted phenyl claim 1 , Cphenylalkyl and pyridyl.8. The method of claim 1 , wherein Ris hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , n-propyl claim 1 , isopropyl claim 1 , n-butyl claim 1 , isobutyl claim 1 , sec-butyl claim 1 , tert-butyl claim 1 , cyclopentyl claim 1 , cyclohexyl claim 1 , methoxycarbonyl claim 1 , ethoxycarbonyl claim 1 , isopropoxycarbonyl claim 1 , cyclohexyloxycarbonyl claim 1 , phenyl claim 1 , benzyl claim 1 , phenethyl claim 1 , 2-pyridyl claim 1 , 3-pyridyl or 4-pyridyl and Ris hydrogen.9. The method of claim 1 , wherein Ris hydrogen claim 1 , methyl claim 1 , n-propyl or isopropyl and Ris hydrogen.10. The method of claim 1 , wherein Ris selected from hydrogen claim 1 , Calkyl claim 1 , ...

Oral Dosage Forms of Methyl Hydrogen Fumarate and Prodrugs Thereof

Improved oral dosage forms of methyl hydrogen fumarate and prodrugs thereof are disclosed. Methods of treating diseases such as multiple sclerosis and psoriasis using such dosage forms are also disclosed. 1. An oral dosage form comprising:a core comprising a therapeutically effective amount of a compound selected from (i) methyl hydrogen fumarate (MHF), (ii) a prodrug of MHF, (iii) pharmaceutically acceptable salts of (i) or (ii), and (iv) combinations of any of the foregoing;a barrier layer surrounding said core, the barrier layer comprising a material that is (i) a weakly acidic (proton-donating) material having a pKa of greater than 8, (ii) a weakly basic (proton-accepting) material having a pKa of less than 2, (iii) a natural gum or polysaccharide derivative (iv) a neutral polymer salt, (v) a sugar, (vi) a lipid, or (vii) combinations of any of the foregoing; the barrier layer preventing direct contact between the core and an enteric coating; andthe enteric coating surrounding said barrier layer and comprising an enteric polymer having carboxylic acid moieties, the enteric polymer (i) being soluble in aqueous solutions having a pH above 7.5, and (ii) starting to become soluble in an aqueous solution at a pH in the range of 4.5 to 7.5.2. The oral dosage form of claim 1 , wherein the barrier layer material is a non-ionizable polymer substantially free of carboxylic acid moieties.3. The oral dosage form of claim 1 , wherein the barrier layer material is selected from non-ionizable cellulosic polymers claim 1 , non-ionizable vinyl polymers claim 1 , and non-ionizable polyvinyl alcohol polymers.4. The oral dosage form of claim 1 , wherein the barrier layer material is a sugar.5. The oral dosage form of claim 1 , wherein the barrier layer comprises at least 5 wt % of the coated core for cores having a size of 2 mm or less.6. The oral dosage form of claim 1 , wherein the barrier layer comprises at least 0.5 wt % of the coated core for cores having a size greater than 6 ...

Heteroaryl amide derivatives

Heteroaryl amide derivatives are provided, of the Formula: wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

PHARMACEUTICAL USES FOR ALPHA2DELTA LIGANDS

The invention relates to a method of treating central nervous system disorders and other disorders by administering an alpha2delta ligand such as, for example, a compound of the formula or a pharmaceutically acceptable salt thereof, wherein R₁ is hydrogen or straight or branched lower alkyl, and n is an integer of from 4 to 6.

PHARMACEUTICAL USES FOR ALPHA2DELTA LIGANDS

The invention relates to a method of treating central nervous system disorders and other disorders by administering an alpha2delta ligand such as, for example, a compound of the formula or a pharmaceutically acceptable salt thereof, wherein R₁ is hydrogen or straight or branched lower alkyl, and n is an integer of from 4 to 6.

Benzoxazinone dopamine D4 receptor antagonists

This invention relates to compounds that are antagonists of dopamine D4 receptors, to methods of treating psychosis and schizophrenia using a compound that is an antagonist of dopamine D4 receptors, and to pharmaceutically acceptable compositions that contain a dopamine D4 receptor antagonist.

Heteroaryl Amide Analogues

Compounds, pharmaceutical compositions, and methods of use are disclosed for heteroaryl amide analogues of formula Ia and/or Ib: In certain embodiments, the heteroaryl amide analogues are agonists and/or ligands of dopamine receptors and may be useful, inter alia, for the treatment of a condition responsive to P2X7 receptor modulation, for example, pain, inflammation, a neurological or neurodegenerative disorder, a cardiovascular disorder, an ocular disorder or an immune system disorder.

Substituted heteroaryl CB1 antagonists

Compounds of Formula I are provided. In which the variables are as described herein. Such compounds may be used to modulate CB1 activity in vivo or in vitro, and are particularly useful in the treatment of conditions responsive to CB1 modulation in humans, domesticated companion animals and livestock animals, including appetite disorders, obesity and addictive disorders. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies and various in vitro assays.

Morpholinoalkyl fumarate compounds, pharmaceutical compositions, and methods of use

Morpholinoalkyl fumarates, pharmaceutical compositions comprising the morpholinoalkyl fumarates, and methods of using morpholinoalkyl fumarates and pharmaceutical compositions for treating neurodegenerative, inflammatory, and autoimmune disorders including multiple sclerosis, psoriasis, irritable bowel disorder, ulcerative colitis, arthritis, chronic obstructive pulmonary disease, asthma, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are disclosed.

METHOD OF TREATMENT OF FRAGILE X SYNDROME, DOWN'S SYNDROME, AUTISM AND RELATED DISORDERS

Disclosed herein are methods of treating fragile X syndrome, fragile X-associated tremor/ataxia syndrome, Down's syndrome and/or autism, comprising administering a prodrug of acamprosate to a subject suffering therefrom, wherein, in certain embodiments, the acamprosate prodrugs comprise compounds of Formula (I).

Heteroaryl amide derivatives

Heteroaryl amide derivatives are provided, of the Formula: wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies. 261-. (canceled) This application claims priority to U.S. Provisional Application 60/867,248, filed Nov. 27, 2006, which is hereby incorporated by reference in its entirety.This invention relates generally to heteroaryl amide derivatives that have useful pharmacological properties. The invention further relates to the use of such compounds for treating conditions related to P2Xreceptor activation, for identifying other agents that bind to P2Xreceptor, and as probes for the detection and localization of P2Xreceptors.Pain perception, or nociception, is mediated by the peripheral terminals of a group of specialized sensory neurons, termed “nociceptors.” A wide variety of physical and chemical stimuli induce activation of such neurons in mammals, leading to recognition of a potentially harmful stimulus. Inappropriate or excessive activation of nociceptors, however, can result in debilitating acute or chronic pain.Neuropathic pain, which typically results from damage to the nervous system, involves pain signal transmission in the absence of stimulus, pain from a normally innocuous stimulus (allodynia) and increased pain from a normally painful stimulus (hyperalgesia). In most instances, neuropathic pain is thought to occur because of sensitization in the peripheral and central nervous systems following initial damage to the peripheral system (e.g., via direct injury or systemic disease). Neuropathic pain is typically burning, ...

MORPHOLINOALKYL FUMARATE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE

Morpholinoalkyl fumarates, pharmaceutical compositions comprising the morpholinoalkyl fumarates, and methods of using morpholinoalkyl fumarates and pharmaceutical compositions for treating neurodegenerative, inflammatory, and autoimmune disorders including multiple sclerosis, psoriasis, irritable bowel disorder, ulcerative colitis, arthritis, chronic obstructive pulmonary disease, asthma, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are disclosed. 2. The compound according to claim 1 , wherein Ris methyl claim 1 , ethyl claim 1 , n-propyl claim 1 , isopropyl claim 1 , n-butyl claim 1 , isobutyl claim 1 , tert-butyl claim 1 , n-pentyl claim 1 , pentyl-2-yl claim 1 , 2-methylbutyl claim 1 , isopentyl claim 1 , 3-methylbutan-2-yl claim 1 , neopentyl claim 1 , tert-pentyl claim 1 , n-hexyl claim 1 , hexan-2-yl claim 1 , 2-methylpentyl claim 1 , 3-methylpentyl claim 1 , 4-methylpentyl claim 1 , 3-methylpentan-2-yl claim 1 , 4-methylpentan-2-yl claim 1 , 2 claim 1 ,3-dimethylbutyl claim 1 , or 3 claim 1 ,3-dimethylbutyl.3. The compound according to claim 1 , wherein Ris methyl.6. The compound according to claim 1 , wherein the compound is a pharmaceutically acceptable salt.7. The compound according to claim 1 , wherein the compound is a HCl salt.8. A compound selected from the compounds listed in Table 1.10. The compound according to claim 9 , wherein the compound is a HCl salt.12. The pharmaceutical composition according to claim 11 , wherein Ris methyl.13. The pharmaceutical composition according to claim 11 , wherein Ris methyl claim 11 , ethyl claim 11 , n-propyl claim 11 , isopropyl claim 11 , n-butyl claim 11 , isobutyl claim 11 , tert-butyl claim 11 , n-pentyl claim 11 , pentyl-2-yl claim 11 , 2-methylbutyl claim 11 , isopentyl claim 11 , 3-methylbutan-2-yl claim 11 , neopentyl claim 11 , tert-pentyl claim 11 , n-hexyl claim 11 , hexan-2-yl claim 11 , 2-methylpentyl claim 11 , 3-methylpentyl claim 11 , 4-methylpentyl claim 11 , 3- ...

Treatment of Multiple Sclerosis and Psoriasis Using Prodrugs of Methyl Hydrogen Fumarate

Improved methods of treating multiple sclerosis and/or psoriasis using prodrugs of methyl hydrogen fumarate are disclosed. The methods comprise administering certain prodrugs of methyl hydrogen fumarate. The methods are able to achieve high blood plasma concentrations of the active metabolite, methyl hydrogen fumarate, without causing significant gastrointestinal irritation. New prodrugs of methyl hydrogen fumarate are also disclosed. 2. The method of claim 1 , wherein the prodrug exhibits a human in vivo metabolism to MHF over 24 hours that is sufficient to achieve a ratio of AUC:AUCof at least 3:1.4. The method of claim 1 , wherein the MHF prodrug is selected from Methyl 2-morpholin-4-ylethyl (2E)but-2-ene-1 claim 1 ,4-dioate (HCl salt) claim 1 , Methyl 3-morpholin-4-ylpropyl (2E)but-2-ene-1 claim 1 ,4-dioate (HCl salt) claim 1 , Methyl 6-morpholin-4-ylhexyl (2E)but-2-ene-1 claim 1 ,4-dioate (HCl salt) claim 1 , Methyl 5-morpholin-4-ylpentyl (2E)but-2-ene-1 claim 1 ,4-dioate (HCl salt) claim 1 , Methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1 claim 1 ,4-dioate (HCl salt) claim 1 , (N-cyclopropyl-N-ethylcarbamoyl)methyl methyl 2(E)but-2-ene-1 claim 1 ,4-dioate claim 1 , (N claim 1 ,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1 claim 1 ,4-dioate claim 1 , (N claim 1 ,N-Dimethylcarbamoyl)methyl methyl (2E)but-2-ene-1 claim 1 ,4-dioate claim 1 , (N-cyclopropyl-N-methylcarbamoyl)methyl methyl (2E)but-2-ene-1 claim 1 ,4-dioate claim 1 , Methyl 2-morpholin-4-yl-2-oxoethyl (2E)but-2-ene-1 claim 1 ,4-dioate claim 1 , and Methyl 2-oxo-2-pyrrolidinylethyl 2(E)but-2-ene-1 claim 1 ,4-dioate.5. The method of claim 1 , wherein the MHF prodrug exhibits an average gastrointestinal irritation score in an Annamalai-Ma gastrointestinal irritation rat model of no more than 2.5 after orally administering a solution or suspension the prodrug to rats at a dose of 180 mg-equivalents of MHF per kg of body weight claim 1 , dosed once per day over 4 consecutive days.6. The method of claim 5 ...

Treatment of multiple sclerosis and psoriasis using prodrugs of methyl hydrogen fumarate

Improved methods of treating multiple sclerosis and/or psoriasis using prodrugs of methyl hydrogen fumarate are disclosed. The methods comprise administering certain prodrugs of methyl hydrogen fumarate. The methods are able to achieve high blood plasma concentrations of the active metabolite, methyl hydrogen fumarate, without causing significant gastrointestinal irritation. New prodrugs of methyl hydrogen fumarate are also disclosed.

ORAL DOSAGE FORMS OF METHYL HYDROGEN FUMARATE AND PRODRUGS THEREOF

Improved oral dosage forms of methyl hydrogen fumarate and prodrugs thereof are disclosed. Methods of treating diseases such as multiple sclerosis and psoriasis using such dosage forms are also disclose. 1. An oral dosage form comprising:a core comprising a therapeutically effective amount of a compound selected from (i) methyl hydrogen fumarate (MHF), (ii) a prodrug of MHF, (iii) pharmaceutically acceptable salts of (i) or (ii), and (iv) combinations of any of the foregoing;a barrier layer surrounding said core, the barrier layer comprising a material that is (i) a weakly acidic (proton-donating) material having a pKa of greater than 8, (ii) a weakly basic (proton-accepting) material having a pKa of less than 2, (iii) a natural gum or polysaccharide derivative, (iv) a neutral polymer salt, (v) a sugar, (vi) a lipid, or (vii) combinations of any of the foregoing; the barrier layer preventing direct contact between the core and an enteric coating; andthe enteric coating surrounding said barrier layer and comprising an enteric polymer having carboxylic acid moieties, the enteric polymer (i) being soluble in aqueous solutions having a pH above 7.5, and (ii) starting to become soluble in an aqueous solution at a pH in the range of 4.5 to 7.5.2. The oral dosage form of claim 1 , wherein the barrier layer material is a non-ionizable polymer substantially free of carboxylic acid moieties.3. The oral dosage form of claim 1 , wherein the barrier layer material is selected from non-ionizable cellulosic polymers claim 1 , non-ionizable vinyl polymers claim 1 , and non-ionizable polyvinyl alcohol polymers.4. The oral dosage form of claim 1 , wherein the barrier layer material is a sugar.5. The oral dosage form of claim 1 , wherein the barrier layer comprises at least 5 wt % of the coated core for cores having a size of 2 mm or less.6. The oral dosage form of claim 1 , wherein the barrier layer comprises at least 0.5 wt % of the coated core for cores having a size greater than 6 ...

CRYSTALLINE FORMS OF C-C CHEMOKINE RECEPTOR TYPE 4 ANTAGONIST AND USES THEREOF

Crystalline forms of a C-C chemokine receptor type 4 (CCR4) antagonist, oral dosage forms of same and methods of using and preparing same, are provided. 1. Compound 2-((R)-3-(1-(1-((R)-1-(2 ,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3 ,4-13]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzene sulfonate in crystalline form.2. The compound of claim 1 , having characteristic absorption peaks (2θ) at 18.4°±0.3° claim 1 , 22.9°±0.3° claim 1 , 21.2°±0.3° claim 1 , and 15.9°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.3. The compound of claim 1 , having characteristic absorption peaks (2θ) at 12.2°±0.3° claim 1 , 23.8°±0.3° claim 1 , and 25.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.4. The compound of claim 1 , having characteristic absorption peaks (2θ) at 23.1°±0.3° claim 1 , 20.0°±0.3° claim 1 , and 16.2°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.5. The compound of claim 1 , having an X-ray powder diffractogram using Cu Kα radiation illustrated in .6. The compound of claim 1 , having a melting point between about 170° C. and about 173° C. as determined by differential scanning calorimetry at a scan rate of 5° C./minute.7. The compound of claim 2 , having a characteristic absorption peak (2θ) at 12.2°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.8. The compound of claim 2 , having a characteristic absorption peak (2θ) at 23.8°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.9. The compound of claim 2 , having a characteristic absorption peak (2θ) at 25.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.10. The compound of claim 2 , having a characteristic absorption peak (2θ) at 23.1°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.11. The compound of claim 2 , having a characteristic absorption peak (2θ) at 20.0°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.12. The compound of claim 2 , having a characteristic absorption peak (2θ) ...

ORAL DOSAGE FORMS OF METHYL HYDROGEN FUMARATE AND PRODRUGS THEREOF

Improved oral dosage forms of methyl hydrogen fumarate and prodrugs thereof are disclosed. Methods of treating diseases such as multiple sclerosis and psoriasis using such dosage forms are also disclose. 1. An oral dosage form comprising:a core comprising a therapeutically effective amount of a compound selected from (i) methyl hydrogen fumarate (MHF), (ii) a prodrug of MHF, (iii) pharmaceutically acceptable salts of (i) or (ii), and (iv) combinations of any of the foregoing;a barrier layer surrounding said core, the barrier layer comprising a material that is (i) a weakly acidic (proton-donating) material having a pKa of greater than 8, (ii) a weakly basic (proton-accepting) material having a pKa of less than 2, (iii) a natural gum or polysaccharide derivative, (iv) a neutral polymer salt, (v) a sugar, (vi) a lipid, or (vii) combinations of any of the foregoing; the barrier layer preventing direct contact between the core and an enteric coating; andthe enteric coating surrounding said barrier layer and comprising an enteric polymer having carboxylic acid moieties, the enteric polymer (i) being soluble in aqueous solutions having a pH above 7.5, and (ii) starting to become soluble in an aqueous solution at a pH in the range of 4.5 to 7.5.2. The oral dosage form of claim 1 , wherein the barrier layer material is a non-ionizable polymer substantially free of carboxylic acid moieties.3. The oral dosage form of claim 1 , wherein the barrier layer material is selected from non-ionizable cellulosic polymers claim 1 , non-ionizable vinyl polymers claim 1 , and non-ionizable polyvinyl alcohol polymers.4. The oral dosage form of claim 1 , wherein the barrier layer material is a sugar.5. The oral dosage form of claim 1 , wherein the barrier layer comprises at least 5 wt % of the coated core for cores having a size of 2 mm or less.6. The oral dosage form of claim 1 , wherein the barrier layer comprises at least 0.5 wt % of the coated core for cores having a size greater than 6 ...

PYRAZOLE PYRIMIDINE COMPOUNDS AND USES THEREOF

Disclosed herein are pyrazole pyrimidine compounds that modulate and/or inhibit hematopoietic progenitor kinase 1, as well as methods of making such compounds and therapeutic methods of using same. 3. The compound of claim 1 , wherein Ris a substituted or unsubstituted heteroalkyl claim 1 , a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl.4. The compound of claim 1 , wherein Ris H or a substituted heteroalkyl and Ris a substituted or unsubstituted alkyl.7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein n and m are each 1.8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein at least one of Y is CH or Z is CR.9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Z is CH.10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris H.11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris an unsubstituted heteroalkyl.12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris alkoxy.13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein L is a bond or —CH—.14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris a substituted cycloalkyl or a substituted heterocycloalkyl.16. The compound of claim 15 , wherein Ris —CH.17. The compound of claim 15 , wherein R claim 15 , R claim 15 , Rand Rare each independently —F.27. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable excipient.28. A method of treating a disease or disorder associated with activity of hematopoietic progenitor kinase 1 (HPK1) claim 1 , the method comprising administering to a patient in need thereof the compound of or a pharmaceutically acceptable salt thereof.29. The method of claim 28 , wherein the disease or ...

Treatment of multiple sclerosis and psoriasis using prodrugs of methyl hydrogen fumarate

Improved methods of treating multiple sclerosis and/or psoriasis using prodrugs of methyl hydrogen fumarate are disclosed. The methods comprise administering certain prodrugs of methyl hydrogen fumarate. The methods are able to achieve high blood plasma concentrations of the active metabolite, methyl hydrogen fumarate, without causing significant gastrointestinal irritation. New prodrugs of methyl hydrogen fumarate are also disclosed.

TREATMENT OF MULTIPLE SCLEROSIS AND PSORIASIS USING PRODRUGS OF METHYL HYDROGEN FUMARATE

Improved methods of treating multiple sclerosis and/or psoriasis using prodrugs of methyl hydrogen fumarate are disclosed. The methods comprise administering certain prodrugs of methyl hydrogen fumarate. The methods are able to achieve high blood plasma concentrations of the active metabolite, methyl hydrogen fumarate, without causing significant gastrointestinal irritation. New prodrugs of methyl hydrogen fumarate are also disclosed. 2. The compound of claim 1 , wherein Rand Rtogether with the nitrogen to which they are bonded form a four to ten membered heterocycloalkyl ring.3. The compound of claim 2 , wherein Rand Rtogether with the nitrogen to which they are bonded form a four to six membered heterocycloalkyl ring.4. The compound of claim 3 , wherein Rand Rtogether with the nitrogen to which they are bonded form a six membered heterocycloalkyl ring.5. The compound of claim 1 , wherein Rand Rtogether with the nitrogen to which they are bonded form a substituted four to six membered heterocycloalkyl ring.6. The compound of claim 5 , wherein Rand Rtogether with the nitrogen to which they are bonded form a substituted five membered heterocycloalkyl ring.7. A pharmaceutical composition claim 1 , comprising a therapeutically effective amount of the compound of claim 1 , and a pharmaceutically acceptable vehicle.8. The pharmaceutical composition of claim 1 , which is an oral formulation.9. The pharmaceutical composition of claim 1 , wherein the composition comprises a therapeutically effective amount of the compound for the treatment of multiple sclerosis.10. A pharmaceutical composition claim 4 , comprising therapeutically effective amount of the compound of claim 4 , and a pharmaceutically acceptable vehicle.11. The pharmaceutical composition of claim 4 , which is an oral formulation.12. The pharmaceutical composition of claim 4 , wherein the composition comprises a therapeutically effective amount of the compound for the treatment of multiple sclerosis.13. A ...

ORAL DOSAGE FORMS OF METHYL HYDROGEN FUMARATE AND PRODRUGS THEREOF

Improved oral dosage forms of methyl hydrogen fumarate and prodrugs thereof are disclosed. Methods of treating diseases such as multiple sclerosis and psoriasis using such dosage forms are also disclose. 149.-. (canceled)50. A controlled release tablet comprising:a. core comprising a therapeutically effective amount of (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;b. a barrier layer directly coating said core and preventing direct contact between the core and an enteric coating, said barrier layer having barrier layer materials consisting of a non-ionizable polymer; andc. an enteric coating directly surrounding said barrier layer.51. The tablet of claim 50 , wherein the barrier layer material is substantially free of carboxylic acid moieties.52. The tablet of claim 50 , wherein the non-ionizable polymer barrier layer material is selected from non-ionizable cellulosic polymers claim 50 , non-ionizable vinyl polymers claim 50 , and non-ionizable polyvinyl alcohol polymers.53. The tablet of claim 52 , wherein the barrier layer material is a non-ionizable cellulosic polymer is selected from the group consisting of methylcellulose claim 52 , ethylcellulose claim 52 , propylcellulose claim 52 , butylcellulose claim 52 , cellulose acetate claim 52 , cellulose propionate claim 52 , cellulose butyrate claim 52 , cellulose acetate butyrate claim 52 , cellulose acetate propionate claim 52 , methyl cellulose claim 52 , methyl cellulose acetate claim 52 , methyl cellulose propionate claim 52 , methyl cellulose butyrate claim 52 , ethyl cellulose acetate claim 52 , ethyl cellulose propionate claim 52 , ethyl cellulose butyrate claim 52 , hydroxymethyl cellulose claim 52 , hydroxyethyl cellulose claim 52 , hydroxyethyl methyl cellulose claim 52 , hydroxypropyl cellulose claim 52 , hydroxybutyl cellulose claim 52 , hydroxyethyl cellulose acetate claim 52 , hydroxyethyl ethyl cellulose claim 52 , low-substituted hydroxypropyl cellulose claim 52 , hydroxypropyl ...

Treatment of Multiple Sclerosis and Psoriasis Using Prodrugs of Methyl Hydrogen Fumarate

Improved methods of treating multiple sclerosis and/or psoriasis using prodrugs of methyl hydrogen fumarate are disclosed. The methods comprise administering certain prodrugs of methyl hydrogen fumarate. The methods are able to achieve high blood plasma concentrations of the active metabolite, methyl hydrogen fumarate, without causing significant gastrointestinal irritation. New prodrugs of methyl hydrogen fumarate are also disclosed.

Treatment of Multiple Sclerosis and Psoriasis Using Prodrugs of Methyl Hydrogen Fumarate

Improved methods of treating multiple sclerosis and/or psoriasis using prodrugs of methyl hydrogen fumarate are disclosed. The methods comprise administering certain prodrugs of methyl hydrogen fumarate. The methods are able to achieve high blood plasma concentrations of the active metabolite, methyl hydrogen fumarate, without causing significant gastrointestinal irritation. New prodrugs of methyl hydrogen fumarate are also disclosed.

Treatment of multiple sclerosis and psoriasis using prodrugs of methyl hydrogen fumarate

Improved methods of treating multiple sclerosis and/or psoriasis using prodrugs of methyl hydrogen fumarate are disclosed. The methods comprise administering certain prodrugs of methyl hydrogen fumarate. The methods are able to achieve high blood plasma concentrations of the active metabolite, methyl hydrogen fumarate, without causing significant gastrointestinal irritation. New prodrugs of methyl hydrogen fumarate are also disclosed.

PYRAZOLO-PYRIMIDIN-AMINO-CYCLOALKYL COMPOUNDS AND THEIR THERAPEUTIC USES

Disclosed herein are pyrozolo-pyrimidin-amino-cycloalkyl compounds, analogs thereof, pharmaceutical compositions comprising thereof and therapeutic uses therefor. 2. The compound of claim 1 , wherein Ris not a substituted or unsubstituted amine attached to ring A at the ortho position.3. The compound of claim 1 , wherein Ris not attached to ring A at the ortho position.4. The compound of claim 1 , wherein Land Lare a bond.5. The compound of claim 1 , wherein Land Lare independently substituted or unsubstituted C-Calkylene or substituted or unsubstituted 2 to 8 membered heteroalkylene.6. The compound of claim 5 , wherein Land Lare independently unsubstituted C-Calkylene or unsubstituted 2 to 8 membered heteroalkylene.9. The compound of claim 1 , wherein:{'sup': 6', '6, 'sub': 4', '7, 'ring A is R-substituted or unsubstituted C-Ccycloalkyl, or R-substituted or unsubstituted 4- to 7-membered heterocycloalkyl;'}{'sup': '6', 'sub': 3', '2', '2', '3', '2', '2', '3', '2', '2', '3', '2', '2', '3', '3', '3', '3', '2', '2', '2', '2', '2', '2', '2', '2', '3', '3', '2', '2', '3', '2', '2', '2', '3', '2', '3', '2', '2', '3', '3', '3', '2', '3', '3', '2', '2', '3', '3', '3', '3', '3', '3', '1', '8', '3', '8', '6', '10, 'Ris independently hydrogen, —F, —Cl, Br, —I, —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CBr, —CHBr, —CHBr, —CI, —CHI, —CHI, —OCF, —OCCl, —OCBr, —OCI, —OCHF, —OCHCl, —OCHBr, —OCHI, —OCHF, —OCHCl, —OCHBr, —OCHI, —N, —CN, —SH, —SCH, —SOH, —SOCH, —SONH, —SONHCH, —NHC(O)NH, —NHC(O)NHCH, —NO, —NH, —NHCH, —C(O)H, —C(O)CH, —C(O)OH, —C(O)OCH, —C(O)NH, —C(O)NHCH, —OH, —OCH, —NHSOH, —NHSOCH, —NHC(O)H, —NCHC(O)H, —NHC(O)OH, —NCHC(O)OH, —NHOH, —NCHOH, —NCHOCH, substituted or unsubstituted C-Calkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C-Ccycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C-Caryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.'}11. The compound of ...

5-membered heterocyclic amides and related compounds

Disclosed is a compound of the formula I or a pharmaceutically acceptable salt or hydrate thereof, e.g. 1-(4-Amino-5-fluoropyrimidin-2-yl)-N-((1-(pyridin-3-yl)cyclohexyl)methyl)-3- (trifluoromethyl)-1H-pyrazole-4-carboxamide wherein Z represents pyrazole, thiazole, imidazole, oxazole or thiophene and the other substituents are defined in the specification for treating pain, osteoarthritis, rheumatoid arthritis, arthrosclerosis, glaucoma, irritable bowel syndrome, inflammatory bowel disease, cirrhosis, lupus, scleroderma, Alzheimer's disease, traumatic brain injury, asthma, chronic obstructive pulmonary disease, or interstitial fibrosis.

Pyrido[2,3-f][1,4]thiazepines and pyrido[3,2-b][1,5]benzothiazepines

Novel pyrido[2,3-f][1,4]thiazepines and novel pyrido[3,2-b][1,5]benzothiazepinee are described. These compounds are useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibronchoconstric-tion activity. also described are methods of producing the novel compounds and intermediates thereof.

Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof

Improved oral dosage forms of methyl hydrogen fumarate and prodrugs thereof are disclosed. Methods of treating diseases such as multiple sclerosis and psoriasis using such dosage forms are also disclosed.

PYRIDO (2,3-F) (1,4) TIAZEPINES AND PYRIDO (3,2-B) (1,5) BENZOTIAZEPINES.

Morpholinoalkyl fumarate compounds, pharmaceutical compositions, and methods of use.

Se revelan fumaratos de morfolinoalquilo, composiciones farmacéuticas que comprenden los fumaratos de morfolinoalquilo y métodos de uso de fumaratos de morfolinoalquilo y composiciones farmacéuticas para el tratamientos de alteraciones neurodegenerativas, inflamatorias y autoinmunes que incluyen esclerosis múltiple, psoriaris, alteración de intestino irritable, colitis ulcerativa, artritis, enfermedad pulmonar obstructiva crónica, asma, enfermedad de Parkinson, enfermedad de Huntington y esclerosis lateral amiotrófica.

5-membered heterocyclic amides and related compounds

5-Membered heterocyclic amides and related compounds are provided, of the Formula: wherein variables are as described herein. Such compounds are liga nds that may be used to modulate specific receptor activity in vivo or in vi tro, and are particularly useful in the treatment of conditions associated w ith pathological receptor activation in humans, domesticated companion anima ls and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for usin g such ligands for receptor localization studies.

Heteroaryl amide analogues

Compounds, pharmaceutical compositions, and methods of use are disclosed for heteroaryl amide analogues of formula Ia and/or Ib: . In certain embodiments, the heteroaryl amide analogues are agonists and/or ligands of dopamine receptors and may be useful, inter alia, for the treatment of a condition responsive to P2X7 receptor modulation, for example, pain, inflammation, a neurological or neurodegenerative disorder, a cardiovascular disorder, an ocular disorder or an immune system disorder.

Pyrido (2,3-f) (1,4) thiazepine and pyrido (3,2-b) (1,5) benzothiazepine.

Novel pyrido[2,3-f] [1,4]thiazepines and pyrido[3,2-b][1,5]benzothiazepines

Novel pyrido[2,3-f][1,4]thiazepines and novel pyrido[3,2-b][1,5]benzothiazepines are described. These compounds are useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibronchoconstriction activity. Also described are methods of producing the novel compounds and intermediates thereof.

Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof

Improved oral dosage forms of methyl hydrogen fumarate and prodrugs thereof are disclosed. Methods of treating diseases such as multiple sclerosis and psoriasis using such dosage forms are also disclosed.

Morpholinoalkyl fumarate compounds, pharmaceutical compositions, and methods of use

P213451.WO.01 X-0179 WO Abstract Morpholinoalkyl fumarates, pharmaceutical compositions comprising the morpholinoalkyl fumarates, and methods of using morpholinoalkyl fumarates and pharmaceutical compositions for treating neurodegenerative, inflammatory, and autoimmune disorders including multiple sclerosis, psoriasis, irritable bowel disorder, ulcerative colitis, arthritis, chronic obstructive pulmonary disease, asthma, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are disclosed. 4842-2006-2738 -99-

Novel pyrido[2,3-f] [1,4]thiazepines and pyrido [3,2-b] [1,5]benzothiazepines

Novel pyrido[2,3-f][1,4]thiazepines and novel pyrido[3,2-b][1,5]benzothiazepines are described. These compounds are useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibronchoconstriction activity. Also described are methods of producing the novel compounds and intermediates thereof.

Morpholinoalkyl fumarate compounds, pharmaceutical compositions, and methods of use

Morpholinoalkyl fumarates, pharmaceutical compositions comprising the morpholinoalkyl fumarates, and methods of using morpholinoalkyl fumarates and pharmaceutical compositions for treating neurodegenerative, inflammatory, and autoimmune disorders including multiple sclerosis, psoriasis, irritable bowel disorder, ulcerative colitis, arthritis, chronic obstructive pulmonary disease, asthma, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are disclosed.

Heteroaryl amide derivatives

Heteroaryl amide derivatives are provided, of the Formula: wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

1h-pyrazolo[3,4-d]pyrimidin-6-yl-amine derivatives as hematopoietic progenitor kinase 1 (hpk1) modulators and/or inhibitors for the treatment of cancer and other diseases

The present invention relates to 1H-pyrazolo[3,4-d]pyrimidin-6-yl- amine derivatives of formula (I) as hematopoietic progenitor kinase 1 (HPK1) modulators and/or inhibitors for the treatment of cancer and other diseases, such as e.g. viral and/or bacterial infections, chronic infections that produce exhausted immune response, infection-mediated immune suppression, age-related decline in immune response, age related decline in cognitive function, infertility and proliferative disease other than cancer. Preferred exemplary compounds are e.g. 2-methyl-N-(1H- pyrazolo[3,4-d]pyrimidin-6-yl)-1,2,3,4-tetrahydroisoquinolin-7-amine derivatives such as e.g.

5-membered heterocyclic amides and related compounds

Gamma-amino-butyric acid derivatives as gabab receptor ligands

Gamma-amino-butyric acid derivatives of formula (I) that are GABAB receptor ligands, pharmaceutical compositions comprising such derivatives, and methods of using such derivatives and pharmaceutical compositions thereof for treating diseases are disclosed. R5 is chosen from -COOH, -SOOH, and -P(O)(OH)R8 wherein R8 is chosen from hydrogen and C1-4 alkyl.

CRYSTALLINE FORMS OF THE CHEMOKINE C ANTAGONIST TYPE 4 RECEPTOR AND USES THEREOF

FORMAS CRISTALINAS DO RECEPTOR DE QUIMIOCINA C-C ANTAGONISTA TIPO 4 E USOS DAS MESMAS. São fornecidas formas cristalinas de um antagonista do receptor de quimiocina C-C tipo 4 (CCR4), formas de dosagem oral das mesmas e métodos de uso e preparação das mesmas.

Prodrugs of alpha-2-delta ligands, pharmaceutical compositions and uses thereof

Prodrugs of alpha-2-delta ligands, pharmaceutical compositions of prodrugs of alpha-2-delta ligands, methods of making prodrugs of alpha-2-delta ligands, and methods of using prodrugs of alpha-2-delta ligands and pharmaceutical compositions of prodrugs of alpha-2-delta ligands to treat various diseases are disclosed.

Methods of making trans isomeric forms of g protein-coupled receptor modulators

Disclosed herein, inter alia, methods of synthesis of trans isomeric forms of G protein-coupled receptor modulators of high trans isomeric purity.

Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof

Improved oral dosage forms of methyl hydrogen fumarate and prodrugs thereof are disclosed. Methods of treating diseases such as multiple sclerosis and psoriasis using such dosage forms are also disclosed.

Pyrido(2,3-f)(1,4)thiazepine und pyrido(3,2- b)(1,5)benzothiazepine.

Pyrazole pyrimidine compounds and uses thereof

Disclosed herein are pyrazole pyrimidine compounds that modulate and/or inhibit hematopoietic progenitor kinase 1, as well as methods of making such compounds and therapeutic methods of using same.

Oral dosage forms having a high loading of a methyl hydrogen fumarate prodrug

Oral dosage forms and granulations with a high loading of a methyl hydrogen fumarate prodrug are disclosed.

Chemokine receptor modulators and uses thereof

Disclosed herein, inter alia, are compounds and methods of use thereof for the modulation of certain chemokine receptor activity.

Chemokine receptor modulators and uses thereof

Disclosed herein, inter alia, are compounds of formula (I) and methods of use thereof for the modulation of certain chemokine receptor activity.

Methods of making trans isomeric forms of g protein-coupled receptor modulators

Disclosed herein, inter alia, methods of synthesis of trans isomeric forms of G protein- coupled receptor modulators of high trans isomeric purity.

Methods of making trans isomeric forms of g protein-coupled receptor

Disclosed herein, inter alia, methods of synthesis of trans isomeric forms of G protein- coupled receptor modulators of high trans isomeric purity.

Methods of making trans isomeric forms of g protein-coupled receptor modulators

Methods of making trans isomeric forms of g protein-coupled receptor modulators

Disclosed herein, inter alia, methods of synthesis of trans isomeric forms of G protein- coupled receptor modulators of high trans isomeric purity.

Methods of making trans isomeric forms of G protein-coupled receptor modulators

Disclosed herein, inter alia, methods of synthesis of trans isomeric forms of G protein- coupled receptor modulators of high trans isomeric purity.

Formas cristalinas del antagonista del receptor de quimiocinas cc tipo 4 y usos de las mismas.

Se proporcionan formas cristalinas de un antagonista del receptor de quimiocinas C-C tipo 4 (CCR4), formas de dosificación oral de las mismas y métodos para su uso y su preparación.

Crystalline forms of c-c chemokine receptor type 4 antagonist and uses thereof

Crystalline forms of c-c chemokine receptor type 4 antagonist and uses thereof

Crystalline forms of a C-C chemokine receptor type 4 (CCR4) antagonist, oral dosage forms of same and methods of using and preparing same, are provided.

Crystalline forms of c-c chemokine receptor type 4 antagonist and uses thereof

Crystalline forms of a C-C chemokine receptor type 4 (CCR4) antagonist, oral dosage forms of same and methods of using and preparing same, are provided.

Methods of making trans isomeric forms of G protein-coupled receptor modulators

Disclosed herein, inter alia, methods of synthesis of trans isomeric forms of G protein- coupled receptor modulators of high trans isomeric purity.

Métodos para fazer formas transisoméricas de moduladores de receptores acoplados à proteína g

métodos para fazer formas transisoméricas de moduladores de receptores acoplados à proteína g. são divulgados no presente documento, entre outros, métodos de síntese de formas isoméricas trans de moduladores de receptores acoplados à proteína g de pureza transisomérica alta.

Methods of making trans isomeric forms of g protein-coupled receptor modulators

Disclosed herein, inter alia, methods of synthesis of trans isomeric forms of G protein- coupled receptor modulators of high trans isomeric purity.

Crystalline forms of C-C chemokine receptor type 4 antagonist and uses thereof

Crystalline forms of a C-C chemokine receptor type 4 (CCR4) antagonist, oral dosage forms of same and methods of using and preparing same, are provided.

Métodos para elaborar formas isoméricas trans de moduladores de receptores acoplados a proteínas g.

En la presente descripción se describen, entre otros, métodos de síntesis de formas isoméricas trans de moduladores de receptores acoplados a proteínas G 5 de pureza isomérica trans alta.

Substituted cyclohexylamines as central nervous system agents

Crystalline forms of c-c chemokine receptor type 4 antagonist and uses thereof

Crystalline forms of a C—C chemokine receptor type 4 (CCR4) antagonist, oral dosage forms of same and methods of using and preparing same, are provided.

Chemokine receptor modulators and uses thereof

Disclosed herein, inter alia, are compounds of formula (I) and methods of use thereof for the modulation of certain chemokine receptor activity.

Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof

Improved oral dosage forms of methyl hydrogen fumarate and prodrugs thereof are disclosed. Methods of treating diseases such as multiple sclerosis and psoriasis using such dosage forms are also disclosed.