WO2006063010A2 - Composes et procedes d'utilisation - Google Patents

Composes et procedes d'utilisation Download PDF

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WO2006063010A2
WO2006063010A2 PCT/US2005/044183 US2005044183W WO2006063010A2 WO 2006063010 A2 WO2006063010 A2 WO 2006063010A2 US 2005044183 W US2005044183 W US 2005044183W WO 2006063010 A2 WO2006063010 A2 WO 2006063010A2
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group
compound
amino
oxygen
arylalkyl
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PCT/US2005/044183
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WO2006063010A3 (fr
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Susan Marie Royalty
Jessymol Mathew
Bruno G. Bienfait
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Nuada, Llc
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Publication of WO2006063010A3 publication Critical patent/WO2006063010A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention concerns diphenyl sulfide compounds analogs thereof, pharmaceutical formulations concerning the same, and methods of use thereof, particularly for treating diseases relating to an M3 muscarinic receptor.
  • Muscarinic receptors mediate a wide variety of physiological responses to the neurotransmitter acetylcholine in the central and peripheral nervous systems.
  • M] muscarinic receptors play a role in learning and memory function in the brain and regulate gastric acid secretion in the stomach.
  • M 2 receptors regulate acetylcholine release in the central nervous system and control cardiac muscle contraction in the heart.
  • M 3 receptors help regulate smooth muscle contraction in a variety of tissues and promote secretion from exocrine glands.
  • M 4 receptors are thought to play a role in the perception of pain, while M 5 receptors are believed to regulate dopaminergic activity in the brain.
  • M3 muscarinic receptors can cause contraction and regulate smooth muscles in numerous organs and tissues in mammals.
  • M3 muscarinic receptors can assist in regulating the ciliary muscles and the iris sphincter muscle.
  • M3 muscarinic receptors can help regulate the tracheal and bronchial muscles.
  • M3 muscarinic receptors increase motility and parasympathetic tone.
  • glands i.e., lacrimal, salivary, bronchial, pancreatic, mucosal, and sweat (sympathetic), adrenal(sympathetic) muscarinic receptors can increase secretion.
  • M3 muscarinic receptors can help regulate the detrusor muscle. Additionally, in male sex organs, M3 muscarinic receptors cause release of nitric oxide in endothelial cells to assist in producing vasodilation. Furthermore, it is generally believed that muscarinic antagonists bind to muscarinic receptors and prevent acetylcholine from binding. This mechanism allows for reduction of airway diseases such as bronchialspasms and bronchodilation. Despite the large body of evidence supporting the use of anti-muscarinic receptor therapy for treatment of a variety of disease states, relatively few antimuscarinic compounds are in use.
  • Tiotropium bromide (commercially available as SPIRIV A®) is currently administered as an inhalation powder for the treatment of COPD. See also US Patent No. 5,610,163. Tiotropium bromide has the structure:
  • a first aspect of the present invention is a compound (sometimes also referred to as an "active compound” or “active agent”) of formula I
  • X 1 and X 2 are present or absent, and when present are oxygen; wherein A, B, C, D, E, F, G, H and J are the same or different and are each independently selected from the group consisting of carbon and nitrogen (optionally substituted with hydrogen); wherein R 1 and R 2 are the same or different and are each independently selected from the group consisting of hydrogen, loweralkyl, haloloweralkyl, loweralkoxycarbonyl, alkenyl, alkynyl, acyl, aminoacyl, aryl, arylalkyl, sulfonamide, sulfone, cycloalkyl, alkylcycloalkyl, heterocycle, and 5-, 6-, 7- or 8- membered organic rings containing 0 to 4 heteroatoms selected from the group consisting of N, O and S, which rings may be unsubstituted or substituted from 1 to 4 times with halo, loweralkyl, haloloweralkyl, haloloweral
  • a second aspect of the present invention is a compound (sometimes also referred to as an "active compound” or “active agent”) of formula II:
  • and R 2 are the same or different and are each independently selected from the group consisting of hydrogen, loweralkyl, haloloweralkyl, loweralkoxycarbonyl, alkenyl, alkynyl, acyl, aminoacyl, aryl, arylalkyl, sulfonamide, sulfone, cycloalkyl, alkylcycloalkyl, heterocycle, and 5-, 6-, 7- or 8- membered organic rings containing 0 to 4 heteroatoms selected from the group consisting of N, O and S, which rings may be unsubstituted or substituted from 1 to 4 times with halo, loweralkyl, haloloweralkyl, haloloweralkyloxy, loweralkoxy, hydroxyl, loweralkoxycarbonyl, carboxylic acid, alkenyl, alkynyl, acyl, azido,
  • a third aspect of the present invention is a compound (sometimes also referred to as an "active compound” or “active agent”) of formula III:
  • X 1 and X 2 are independently present or absent, and when present are oxygen; wherein Z is a heterocycle (which heterocycle is in a preferred embodiment indole, piperazine, pyrrolidine, pyrrolidinone, pyrrole, tetrahydroquinoline, pyrazole, imidazole, indoline, indazole, benzimidazole, imidazoline, pyrazolidine, piperidine, thiomorpholine, azobicyclooctane or morpholine, which may be substituted or unsubstituted); wherein Y is selected from the group consisting of hydrogen or lower alkyl; wherein R is selected from the group consisting of hydrogen, halo, loweralkyl, haloloweralkyl, haloloweralkoxy, loweralkoxy, hydroxyl, loweralkoxycarbonyl, carboxylic acid, alkenyl, alkynyl, acyl, azido, mer
  • a fourth aspect of the present invention is a compound (sometimes also referred to as an "active compound” or “active agent”) of formula IV:
  • X 1 and X 2 are present or absent, and when present are oxygen; wherein X 3 , and X 8 are present or absent, and when present are the same or different and are each independently selected from the group consisting of carbon, nitrogen, sulfur and oxygen; wherein X 4 , X 5 , X 6 , X 7 , X 9 , X 10 , and X 1 1 are the same or different and are each independently selected from the group consisting of carbon, nitrogen, sulfur and oxygen; wherein the bonds of the ring formed by X , X , X 5 , X 6 , X 7 and the carbon atom to which they are attached, are single or double as required to form an aromatic or heteroaromatic ring; wherein the bonds of the ring formed by X 8 , X 9 , X 10 , X 1 1 , and the two carbon atoms to which they are attached, are single or double as required to form an aromatic or heteroaromatic ring; wherein n is an integer from 1
  • X 1 and X 2 are present or absent, and when present are oxygen; wherein X 3 , and X 8 are present or absent, and when present are the same or different and are each independently selected from the group consisting of carbon, nitrogen, sulfur and oxygen; wherein X 4 , X 5 , X 6 , X 7 , X 9 , X 10 , and X 11 are the same or different and are each independently selected from the group consisting of carbon, nitrogen, sulfur and oxygen; wherein the bonds of the ring formed by X 3 , X 4 , X 5 , X 6 , X 7 and the carbon atom to which they are attached, are single or double as required to form an aromatic or heteroaromatic ring; wherein the bonds of the ring formed by X 8 , X 9 , X 10 , X 1 ', and the two carbon atoms to which they are attached, are single or double as required to form an aromatic or heteroaromatic ring; wherein Z is a heterocycle
  • a further aspect of the present invention is a method for treating a disease or disorder mediated by an M3 muscarinic receptor, comprising administering to a subject in need thereof an effective amount of an active compound as described herein.
  • diseases include but are not limited to Chronic Obstructive Pulmonary Disease (COPD), urinary incontinence, chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, irritable bowel syndrome, spasmodic colitis, gastroduodenal ulcers, gastrointestinal convulsions or hyperanakinesia, diverticulitis, pain accompanying spasms of gastrointestinal smooth musculature; urinary-tract disorders accompanying micturition disorders, neurogenic pollakisuria, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, incontinence associated with bladder spasms or chronic cystitis, urinary urgency or poll
  • COPD
  • a further aspect of the present invention is a method of administering to a subject an amount of a muscarinic receptor antagonist selective for the M3 muscarinic receptor wherein said muscarinic receptor antagonist selective for the M3 muscarinic receptor comprises an active compound as described herein, in an effective M3 muscarinic receptor antagonizing amount.
  • a further aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an active compound as described herein, in combination with a pharmaceutically acceptable carrier.
  • a further aspect of the invention is the use of a compound or active compound as described herein for the preparation of a medicament for carrying out a method as described herein.
  • Halo refers to any suitable halogen, including -F, -Cl, -Br, and -I.
  • Cyano as used herein refers to a -CN group.
  • Hydrophill refers to an -OH group.
  • Niro refers to an -NO 2 group.
  • Oxy refers to a -O- group.
  • Alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
  • Loweralkyl as used herein, is a subset of alkyl, in some embodiments preferred, and refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms.
  • Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.
  • Alkyl and loweralkyl groups may be unsubstituted or substituted one or more times with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O)m, haloalkyl- S(0)m, alkenyl-S(O)m, alkynyl-S(O)m, cycloalkyl-S(O)m, cycloalkylalkyl-S(O)m, aryl- S(0)m, arylalky
  • Alkenyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms which include 1 to 4 double bonds in the normal chain.
  • Representative examples of Alkenyl include, but are not limited to, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentyl, 3-pentyl, 2-hexenyl, 3-hexenyl, 2,4-heptadiene, and the like. These groups may be optionally substituted in like manner as described with alkyl above.
  • Alkynyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms which include 1 triple bond in the normal chain.
  • Representative examples of Alkynyl include, but are not limited to, 2-propynyl, 3-butynyl, 2- butynyl, 4-pentenyl, 3-pentenyl, and the like. These groups may be optionally substituted in like manner as described with alkyl above.
  • Alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy group.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
  • Acyl or “Alkanoyl” as used herein alone or as part of another group, refers to a - C(O)R radical, where R is any suitable substituent such as alkyl, alkenyl, alkynyl, aryl, alkylaryl, etc. as given herein.
  • Haloalkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
  • Alkylthio refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety.
  • Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert- butylthio, hexylthio, and the like.
  • Aryl refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings.
  • Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.
  • These rings may be optionally substituted with groups selected from halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O)m, haloalkyl-S(O)m, alkenyl-S(O)m, alkynyl- S(0)m, cycloalkyl-S(O)m, cycloalkylalkyl-S(O)m, aryl-S(O)m, arylalkyl-S(O)m, heterocyclo
  • Arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
  • Amino as used herein means the radical -NH 2 .
  • Alkylamino as used herein alone or as part of another group means the radical - NHR, where R is an alkyl group.
  • Arylalkylamino as used herein alone or as part of another group means the radical - NHR, where R is an arylalkyl group.
  • Alkoxycarbo or " Alkoxycarbonyl” as used herein alone or as part of another group means the group RO-C-O, where R is an alkyl group.
  • Disubstituted-amino as used herein alone or as part of another group means the radical -NR 3 R b , where R 3 and R b are independently selected from the groups alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.
  • Acylamino as used herein alone or as part of another group means the radical - NR 3 R b , where R 3 is an acyl group as defined herein and R b is selected from the hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.
  • Acyloxy as used herein alone or as part of another group means the radical -OR, where R is an acyl group as defined herein.
  • Ester as used herein alone or as part of another group refers to a -C(O)OR radical, where R is any suitable substituent such as alkyl, aryl, alkylaryl, etc.
  • Amide as used herein alone or as part of another group refers to a -C(O)NR 3 R b radical, where R 3 and R b are any suitable substituent such as alkyl, aryl, alkylaryl, etc.
  • Sulfonamide as used herein alone or as part of another group refers to a - S(O) 2 NR 3 R b radical, where R 3 and R b are any suitable substituent, such as H, alkyl, aryl, alkylaryl, etc.
  • Sulfone as used herein alone or as part of another group refers to a -S(O) 2 R radical, where R is any suitable substituent, such as H, alkyl, aryl, alkylaryl, etc.
  • Aminosulfonyl as used herein alone or as part of another group refers to a - N(R 3 )S(O) 2 R b radical, where R a and R b are any suitable substituent, such as H, alkyl, aryl, alkylaryl, etc.
  • Rea refers to an -N(R c )C(O)NR 3 R b radical, where R 3 , R b and R 0 are any suitable substituent such as H, alkyl, aryl, alkylaryl, etc.
  • Alkoxyacylamino as used herein alone or as part of another group refers to an - N(R 3 )C(O)OR b radical, where R 3 , R b are any suitable substituent such as H, alkyl, aryl, alkylaryl, etc.
  • aminoacyl as used herein alone or as part of another group refers to an - C(O)NR 3 Rb radical, where R 3 and R b are any suitable substituent, such as H, alkyl, aryl, alkylaryl, etc.
  • aminoacyloxy refers to an - OC(O)NR 3 Rb radical, where R 3 and R b are any suitable substituent, such as H, alkyl, aryl, alkylaryl, etc.
  • Cycloalkyl refers to a saturated or partially unsaturated cyclic hydrocarbon group containing from 3, 4 or 5 to 6, 7 or 8 carbons (which may be replaced in a heterocyclic group as discussed below).
  • cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. These rings may be optionally substituted with halo or loweralkyl.
  • Heterocyclic group or “heterocycle” as used herein alone or as part of another group, refers to a monocyclic- or a bicyclic-ring system.
  • Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur.
  • the 5 membered ring has from 0-2 double bonds and the 6 membered ring has from 0-3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3- dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine,
  • Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein.
  • Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3- benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, quinoline, quinoliz
  • These rings may be optionally substituted with groups selected from halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O)m, haloalkyl-S(O)m, alkenyl-S(O)m, alkynyl- S(0)m, cycloalkyl-S(O)m, cycloalkylalkyl-S(O)m, aryl-S(O)m, arylalkyl-S(O)m, heterocyclo
  • heteroaryl amines refers to pyrroles, pyrazoles, imidazoles, and indoles.
  • the aryl (ring) substructure of the heteroaryl amine can be optionally substituted with one or a combination of functional groups such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxyl, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, thiomorpholino, piperazinyl, phosphate, phosphonic acid, or phosphonate.
  • Oxoheterocyclic group refers to a heterocyclic group such as described above, substituted with one or more oxo groups, such as pyridine-N-oxide.
  • Arylthio refers to a group of the formula -S-R, where R is aryl as described above.
  • Haldroxyamino refers to a group of the formula -N(R)OH, where R is any suitable group such as alkyl, aryl, alkylaryl, etc.
  • Treat refers to any type of treatment that imparts a benefit to a patient afflicted with a disease, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the disease, etc.
  • antagonist may be generally defined as a substance that tends to nullify the action of another, i.e., as a drug that binds to a cell receptor without eliciting a biological response.
  • agonist is known in the art, and, as used herein, generally refers to a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances, thus triggering a biochemical response.
  • a "partial agonist” may itself cause agonist effects, but because they can displace through competitive action a full agonist from its receptor, the net effect is a reduction in drug effect.
  • a partial agonist depending on circumstance, can act as either in agonist or an antagonist.
  • “Pharmaceutically acceptable” as used herein means that the compound or composition is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable risk/benefit ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • Prodrugs may be ester, salts, hydrates, solvates, and combinations thereof. See also US Patent No. 6,680,299.
  • Examples include a prodrug that is metabolized in vivo by a subject to an active drug having an activity of active compounds as described herein, wherein the prodrug is an ester of an alcohol or carboxylic acid group, if such a group is present in the compound; an acetal or ketal of an alcohol group, if such a group is present in the compound; an N-Mannich base or an imine of an amine group, if such a group is present in the compound; or a Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidine of a carbonyl group, if such a group is present in the compound, such as described in US Patent No. 6,680,324 and US Patent No. 6,680,322.
  • Compounds of the present invention include diphenyl sulfide compounds, N-(2- (phenylthio)benzyl compounds, and derivatives thereof.
  • Active compounds of the invention include compounds of formula I:
  • X 1 and X 2 are present or absent, and when present are oxygen; wherein A, B, C, D, E, F, G, H and J are the same or different and are each independently selected from the group consisting of carbon and nitrogen (optionally substituted with H); wherein Ri and R 2 are the same or different and are each independently selected from the group consisting of hydrogen, loweralkyl, haloloweralkyl, loweralkoxycarbonyl, alkenyl, alkynyl, acyl, aminoacyl, aryl, arylalkyl, sulfonamide, sulfone, cycloalkyl, alkylcycloalkyl, heterocycle, and 5-, 6-, 7- or 8- membered organic rings containing 0 to 4 heteroatoms selected from the group consisting of N, O and S, which rings may be unsubstituted or substituted from 1 to 4 times with halo, loweralkyl, haloloweralkyl, haloloweralkyl
  • Examples of the foregoing include but are not limited to: N-(2-(phenylthio)benzyl) quinuclidin-3-amine, N-(2-(phenylthio)benzyl)-8-methyl-8-aza-bicyclo[3.2.1 ]octan-3 -amine, N-(2-(phenylthio)benzyl)- 1 -(4-methylpent-3-enyl)piperidin-4-amme, N-(2- (phenylthio)benzyl)- 1 -benzylpiperidin-4-amine, N-(2-(phenylthio)benzyl)( 1 -benzylpiperidin- 4-yl)methanamine, l-(2-(phenylthio)benzyl) piperadine, l-(2-(phenylthio)benzyl)-4-(4- methylpent-3-enyl)piperazine, and pharmaceutically acceptable salts and prodrugs thereof.
  • Active compounds of the invention include compounds of formula II:
  • Ri and R 2 are the same or different and are each independently selected from the group consisting of hydrogen, loweralkyl, haloloweralkyl, loweralkoxycarbonyl, alkenyl, alkynyl, acyl, aminoacyl, aryl, arylalkyl, sulfonamide, sulfone, cycloalkyl, alkylcycloalkyl, heterocycle, and 5-, 6-, 7- or 8- membered organic rings containing 0 to 4 heteroatoms selected from the group consisting of N, O and S, which rings may be unsubstituted or substituted from 1 to 4 times with halo, loweralkyl, haloloweralkyl, haloloweralkyloxy, loweralkoxy, hydroxyl, loweralkoxycarbonyl, carboxylic acid, alkenyl, alkynyl, acyl, azido, mer
  • Examples of the foregoing include but are not limited to l-(2-(phenylthio)benzyl)-4- (4-methylpent-3-enyl)piperazine, or a pharmaceutically acceptable salt or prodrug thereof.
  • Active compounds of the invention include compounds of formula III:
  • X 1 and X 2 are independently present or absent, and when present are oxygen; wherein Z is a heterocycle (which heterocycle is in a preferred embodiment indole, piperazine, pyrrolidine, pyrrolidinone, pyrrole, tetrahydroquinoline, pyrazole, imidazole, indoline, indazole, benzimidazole, imidazoline, pyrazolidine, piperidine, thiomo ⁇ holine, azobicyclooctane or mo ⁇ holine, which may be substituted or unsubstituted); wherein Y is selected from the group consisting of hydrogen or lower alkyl; wherein R is selected from the group consisting of hydrogen, halo, loweralkyl, haloloweralkyl, haloloweralkoxy, loweralkoxy, hydroxyl, loweralkoxycarbonyl, carboxylic acid, alkenyl, alkynyl, acyl, azido,
  • Examples of the foregoing include but are not limited to N-(2-(phenylthio)benzyl) quinuclidin-3-amine, N-(2-(phenylthio)benzyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-amine, N-(2-(phenylthio)benzyl)-l-(4-methylpent-3-enyl)piperidin-4- amine, N-(2- (phenylthio)benzyl)- 1 -benzylpiperidin-4-amine, and N-(2-(phenylthio)benzyl)(l - benzylpiperidin-4-yl)methanamine.
  • Active compounds of the invention include compounds of formula IV: wherein X 1 and X 2 are present or absent, and when present are oxygen; wherein X 3 , and X 8 are present or absent, and when present are the same or different and are each independently selected from the group consisting of carbon, nitrogen, sulfur and oxygen; wherein X 4 , X 5 , X 6 , X 7 , X 9 , X 10 , and X 11 are the same or different and are each independently selected from the group consisting of carbon, nitrogen, sulfur and oxygen; wherein the bonds of the ring formed by X 3 , X 4 , X 5 , X 6 , X 7 and the carbon atom to which they are attached, are single or double as required to form an aromatic or heteroaromatic ring; wherein the bonds of the ring formed by X 8 , X 9 , X 10 , X 11 , and the two carbon atoms to which they are attached, are single or double as required to form an aromatic or heteroaromatic
  • X 6 , X 7 , X 9 , X 10 and X 1 ' are each independently O, S, or NH, and n, m, R 1 , R 2 , R 3 , and R 4 are as given above.
  • Active compounds of the invention include compounds of formula V:
  • X 1 and X 2 are present or absent, and when present are oxygen; wherein X 3 , and X 8 are present or absent, and when present are the same or different and are each independently selected from the group consisting of carbon, nitrogen, sulfur and oxygen; wherein X 4 , X 5 , X 6 , X 7 , X 9 , X 10 , and X 11 are the same or different and are each independently selected from the group consisting of carbon, nitrogen, sulfur and oxygen; wherein the bonds of the ring formed by X 3 , X 4 , X 5 , X 6 , X 7 and the carbon atom to which they are attached, are single or double as required to form an aromatic or heteroaromatic ring; wherein the bonds of the ring formed by X 8 , X 9 , X 10 , X 11 , and the two carbon atoms to which they are attached, are single or double as required to form an aromatic or heteroaromatic ring; wherein Z is a heterocycle (
  • substitutents are as defined in connection with formula V above.
  • Some embodiments of the foregoing include but are not limited to compounds of formulas Vd-Vn: wherein X 6 , X 7 , X 9 , X 10 and X 1 ' are each independently O, S, or NH, and n, m, Ri, R 2 , R 3 , and R 4 are as given above.
  • Z is:
  • R is selected from the group consisting of hydrogen, loweralkyl, haloloweralkyl, loweralkoxycarbonyl, alkenyl, alkynyl, acyl, aminoacyl, aryl, arylalkyl, sulfonamide, sulfone, cycloalkyl, alkylcycloalkyl, heterocycle, and 5-, 6-, 7- or 8- membered organic rings containing 0 to 4 heteroatoms selected from the group consisting of N, O and S, which rings may be unsubstituted or substituted from 1 to 4 times with halo, loweralkyl, haloloweralkyl, haloloweralkyloxy, loweralkoxy, hydroxyl, loweralkoxycarbonyl, carboxylic acid, alkenyl, alkynyl, acyl, azido, mercapto, alkylthio, amino, heterocycleamino, alkylamino, dialkylamino, acyla
  • R is selected from the group consisting of:
  • Z is selected from the group consisting of:
  • each of said substituents may be the same or different.
  • each of said substituents may be the same or different.
  • the rings A, B may each independently be any suitable ring, such as furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, and thiazole, with phenyl, furan (including 2- and 3- furans), and thiophene (including 2- and 3- thiophenes) rings particularly preferred.
  • Active compounds useful for carrying out the present invention can be prepared in accordance with known techniques (see, e.g., Z. Polivka et al., Derivatives of N,N-dimethyl-2- (arylthio)benzylamine, their salts, methods of preparation and their use in pharmaceutical medicaments, PCT Application WO 97/17325; and L. Brieaddy, Substituted diphenylsulfides as serotonin uptake inhibitors, PCT Application WO 93/12080), in accordance with the techniques disclosed herein, or variations of the foregoing which will be apparent to those skilled in the art based on the disclosure provided herein.
  • the active compounds disclosed herein can, as noted above, be prepared in the form of their pharmaceutically acceptable salts or prodrugs.
  • Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of such salts are (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic
  • the active compounds described above may be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (9 th Ed. 1995).
  • the active compound (including the physiologically acceptable salts thereof) is typically admixed with, inter alia, an acceptable carrier.
  • the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.01 or 0.5% to 95% or 99% by weight of the active compound.
  • One or more active compounds may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy consisting essentially of admixing the components, optionally including one or more accessory ingredients.
  • formulations of the invention include those suitable for oral, inhalation, rectal, buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), topical ⁇ i.e., both skin and mucosal surfaces, including airway surfaces such as by inhalation) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used.
  • Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above).
  • the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
  • a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
  • Formulations suitable for buccal (sub- lingual) administration include lozenges comprising the active compound in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations of the present invention suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
  • Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents.
  • the formulations may be presented in unit ⁇ dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-i ⁇ jection immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • an injectable, stable, sterile composition comprising a compound of Formula (I), or a salt thereof, in a unit dosage form in a sealed container.
  • the compound or salt is provided in the form of a lyophilizate which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject.
  • the unit dosage form typically comprises from about 10 mg to about 10 grams of the compound or salt.
  • emulsifying agent which is physiologically acceptable may be employed in sufficient quantity to emulsify the compound or salt in an aqueous carrier.
  • emulsifying agent is phosphatidyl choline.
  • Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. Suitable formulations comprise citrate or bisMxis buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M active ingredient.
  • the present invention provides liposomal formulations of the compounds disclosed herein and salts thereof.
  • the technology for forming liposomal suspensions is well known in the art.
  • the compound or salt thereof is an aqueous-soluble salt, using conventional liposome technology, the same may be incorporated into lipid vesicles. In such an instance, due to the water solubility of the compound or salt, the compound or salt will be substantially entrained within the hydrophilic center or core of the liposomes.
  • the lipid layer employed may be of any conventional composition and may either contain cholesterol or may be cholesterol-free.
  • the salt When the compound or salt of interest is water-insoluble, again employing conventional liposome formation technology, the salt may be substantially entrained within the hydrophobic lipid bilayer which forms the structure of the liposome. In either instance, the liposomes which are produced may be reduced in size, as through the use of standard sonication and homogenization techniques.
  • Liposomal formulations containing the compounds disclosed herein or salts thereof may be lyophilized to produce a lyophilizate which may be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.
  • compositions may be prepared from the water-insoluble compounds disclosed herein, or salts thereof, such as aqueous base emulsions.
  • the composition will contain a sufficient amount of pharmaceutically acceptable emulsifying agent to emulsify the desired amount of the compound or salt thereof.
  • Particularly useful emulsifying agents include phosphatidyl cholines, and lecithin.
  • the pharmaceutical compositions may contain other additives, such as pH-adjusting additives.
  • useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate.
  • the compositions may contain microbial preservatives.
  • Useful microbial preservatives include methylparaben, propylparaben, and benzyl alcohol. The microbial preservative is typically employed when the formulation is placed in a vial designed for multidose use.
  • the pharmaceutical compositions of the present invention may be lyophilized using techniques well known in the art.
  • the present invention is primarily concerned with the treatment of human subjects, but the invention may also be carried out on animal subjects, particularly mammalian subjects such as mice, rats, dogs, cats, livestock and horses for veterinary purposes, and for drug screening and drug development purposes.
  • Subjects to be treated with active compounds, or administered active compounds, of the present invention are, in general, subjects in which the compound(s) act as an antagonist at the M3 muscarinic receptor.
  • Subjects in need of treatment with active agents as described herein include, but are not limited to, subjects afflicted with invasive diseases, infections, and inflammatory diseases or states, such as: chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, irritable bowel syndrome, spasmodic colitis, gastroduodenal ulcers, gastrointestinal convulsions or hyperanakinesia, diverticulitis, pain accompanying spasms of gastrointestinal smooth musculature; urinary-tract disorders accompanying micturition disorders, neurogenic pollakisuria, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, incontinence associated with bladder spasms or chronic cystitis, urinary urgency or pollakiuria, and motion sickness, alone or in combination with other compounds used to treat the said disease, in an amount effective to combat or treat the disease.
  • chronic obstructive lung disease
  • a particularly preferred category of diseases for treatment by the methods of the present invention are Chronic Obstructive Pulmonary Disease (COPD) and/or urinary incontinence.
  • COPD Chronic Obstructive Pulmonary Disease
  • urinary incontinence are particularly preferred categories of diseases for treatment by the methods of the present invention.
  • the therapeutically effective dosage of any specific compound will vary somewhat from compound to compound, and patient to patient, and will depend upon the condition of the patient and the route of delivery.
  • a dosage from about 0.05 or 0.1 to about 20, 50 or 100 mg/kg subject body weight may be utilized to carry out the present invention.
  • a dosage from about 0.1 mg/kg to about 50 or 100 mg/kg may be employed for oral administration; or a dosage of about 0.05 mg/kg to 20 or 50 mg/kg, or more, may be employed for intramuscular injection.
  • the duration of the treatment may be one or two dosages per day for a period of two to three weeks, or until the condition is controlled or treated. In some embodiments lower doses given less frequently can be used prophylactically to prevent or reduce the incidence of recurrence of the condition being treated.

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Abstract

L'invention concerne des composés de sulfure de diphényl, des analogues de ceux-ci et des formulations pharmaceutiques, ainsi que des procédés d'utilisation desdits composés pour le traitement de maladies et de troubles à médiation par des récepteurs muscariniques de M3.
PCT/US2005/044183 2004-12-08 2005-12-07 Composes et procedes d'utilisation WO2006063010A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6800652B2 (en) * 2002-08-16 2004-10-05 Pfizer Inc. Diaryl compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6800652B2 (en) * 2002-08-16 2004-10-05 Pfizer Inc. Diaryl compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors

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