WO2009143178A2 - Inhibiteurs de la pde10 et compositions et procédés associés - Google Patents

Inhibiteurs de la pde10 et compositions et procédés associés Download PDF

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WO2009143178A2
WO2009143178A2 PCT/US2009/044556 US2009044556W WO2009143178A2 WO 2009143178 A2 WO2009143178 A2 WO 2009143178A2 US 2009044556 W US2009044556 W US 2009044556W WO 2009143178 A2 WO2009143178 A2 WO 2009143178A2
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compound
disorders
alkyl
following structure
hydrogen
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PCT/US2009/044556
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WO2009143178A3 (fr
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Neil S. Cutshall
Jennifer Lynn Gage
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Omeros Corporation
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Publication of WO2009143178A2 publication Critical patent/WO2009143178A2/fr
Publication of WO2009143178A3 publication Critical patent/WO2009143178A3/fr

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    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
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Definitions

  • This invention relates generally to compounds having activity as PDElO inhibitors, and to compositions containing the same, as well as to methods of treating various disorders by administration of such compounds to a warm-blooded animal in need thereof.
  • Cyclic nucleotide phosphodiesterases are represented by a large superfamily of enzymes. PDEs are known to possess a modular architecture, with a conserved catalytic domain proximal to the carboxyl terminus, and regulatory domains or motifs often near the amino terminus. The PDE superfamily currently includes more than twenty different genes subgrouped into eleven PDE families (Lugnier, C, "Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents.” Pharmacol Ther. 2006 Mar; 109(3):366-98).
  • PDElO has the capacity to hydrolyze both cAMP and cGMP; however, the K m for cAMP is approximately 0.05 ⁇ M, whereas the K M for cGMP is 3 ⁇ M. In addition, the V m ⁇ X for cAMP hydrolysis is fivefold lower than for cGMP. Because of these kinetics, cGMP hydrolysis by PDElO is potently inhibited by cAMP in vitro, suggesting that PDElO may function as a cAMP-inhibited cGMP phosphodiesterase in vivo. Unlike PDE8 or PDE9, PDElO is inhibited by IBMX with an IC 50 (50% inhibitory concentration) of 2.6 ⁇ M. ⁇ See Soderling and Beavo, "Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions," Current Opinion in Cell Biology, 2000, 12:174-179.)
  • PDElO contains two amino-terminal domains that are similar to the cGMP-binding domains of PDE2, PDE5 and PDE6, which are domains conserved across a wide variety of proteins. Because of the wide conservation of this domain, it is now referred to as the GAF domain (for the GAF proteins: cGMP binding phosphodiesterases; the cynobacterial Anabaena adenylyl cyclase; and the Escherichia coli transcriptional regulator fhlA). Although in PDE2, PDE5 and PDE6 the GAF domains bind cGMP, this is probably not the primary function of this domain in all cases ⁇ e.g., E. coli are not thought to synthesize cGMP).
  • Inhibitors of the PDE family of enzymes have widely been sought for a broad indication of therapeutic uses.
  • Reported therapeutic uses of PDE inhibitors include allergies, obtrusive lung disease, hypertension, renal carcinoma, angina, congestive heart failure, depression and erectile dysfunction (WO 01/41807 A2).
  • Other inhibitors of PDE have been disclosed for treatment of ischemic heart conditions (U.S. Pat. No. 5,693,652).
  • More specifically, inhibitors of PDElO have been disclosed for treatment of certain neurological and psychiatric disorders including, Parkinson's disease, Huntington's disease, schizophrenia, delusional disorders, drug-induced psychosis and panic and obsessive-compulsive disorders (U.S. Patent Application No. 2003/0032579).
  • PDElO has been shown to be present at high levels in neurons in areas of the brain that are closely associated with many neurological and psychiatric disorders. By inhibiting PDElO activity, levels of cAMP and cGMP are increased within neurons, and the ability of these neurons to function properly is thereby improved. Thus, inhibition of PDElO is believed to be useful in the treatment of a wide variety of conditions or disorders that would benefit from increasing levels of cAMP and cGMP within neurons, including those neurological, psychotic, anxiety and/or movement disorders mentioned above. While advances have been made with regard to inhibition of PDElO, there remains a need in the field for inhibitors of PDElO, as well as the need to treat various conditions and/or disorders that would benefit from the same.
  • this invention is generally directed to compounds that have activity as PDElO inhibitors, as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same.
  • the compounds of this invention have the following general structure (I):
  • the compounds of this invention have one of the following general structures (H-A) or (H-B):
  • A, B, m, n, p, x, R, R 1 , R 2 , R 3 , R 5 and R 10 are as defined below.
  • the compounds of this invention have utility over a wide range of therapeutic applications, and may be used to treat a wide variety of conditions or disorders that would benefit from increasing levels of cAMP and cGMP, especially within neurons, including (but not limited to) psychotic disorders, anxiety disorders, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette's syndrome, schizophrenia, delusional disorders, bipolar disorders, post-traumatic stress disorders, drug-induced psychosis, panic disorders, obsessive-compulsive disorders, attention-deficit disorders, disruptive behavior disorders, autism, depression, dementia, cognitive disorders, epilepsy, insomnias and multiple sclerosis.
  • psychotic disorders anxiety disorders, movement disorders and/or neurological disorders
  • anxiety disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy,
  • the methods of this invention include administering an effective amount of a compound of structure (I), (H-A) or (H-B), typically in the form of a pharmaceutical composition, to a mammal in need thereof, including a human.
  • a pharmaceutical composition containing one or more compounds of structure (I), (H-A) or (H-B) in combination with a pharmaceutically acceptable carrier or diluent.
  • the present invention is directed generally to compounds useful as PDElO inhibitors, as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same.
  • Ci_ 6 alkyl means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 6 carbon atoms.
  • Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec- butyl, isobutyl, tert-butyl, isopentyl, and the like.
  • Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like.
  • Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl” or “alkynyl”, respectively).
  • Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3- dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2- butynyl, l ⁇ pentynyl, 2-pentynyl, 3 -methyl- 1-butynyl, and the like.
  • Heterocycle means a 4- to 7-membered monocyclic, or 7- to 10- membered bicyclic, heterocyclic ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring.
  • the heterocycle may be attached via any heteroatom or carbon atom.
  • An aromatic heterocycle is referred to herein as a "heteroaryl", and includes (but is not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, oxadiazolyl, thiadiazolyl, benzisoxazolyl, triazolyl, tetrazolyl, indazolyl and quina
  • substituents may be further substituted with one or more of the above substituents, such that the substituent is a substituted alkyl, substituted aryl, substituted arylalkyl, substituted heterocycle or substituted heterocyclealkyl.
  • R a and R b in this context may be the same or different and independently hydrogen, alkyl, haloalkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl.
  • the PDElO inhibitors of this invention have the following structure (I):
  • m, n and/? are individually 0 or 1; x is 0, 1, 2 or 3; y is 1, 2 or 3;
  • A is an optionally substituted heterocycle
  • B is -O-, -NR 6 - or -S(O) 2 - where z is 0, 1 or 2;
  • R is hydrogen or oxo
  • R 1 is absent or represents 1 , 2 or 3 substituents that are the same or different and independently halogen, Ci_6alkyl, -CHF 2 , -CF 3 , -CH 2 NH 2 , -CH 2 NH(C i- 6 alkyl) or -CH 2 N(C i_ 6 alkyl) 2 ;
  • R 3 , R 4 , R 5 and R 6 are the same or different and independently hydrogen or Ci_ 6 alkyl.
  • both m and n are 0 and/? is 1, and the compounds have the following structure (1-1) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • n, n and/? are 1, and the compounds have the following structure (1-2) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • n 0 and n and/? are both 1, and the compounds have the following structure (1-3) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • both m and/? are 1 and n is 0, and the compounds have the following structure (1-4) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • each of m, n and/? are 0, and the compounds have the following structure (1-5) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • B is -S-, -O- or -NR 6 -, respectively, and compounds have the following structures (I-3a), (I-3b) and (I-3c):
  • R .4 , ⁇ R5 and R are hydrogen.
  • R 2 is hydrogen, methyl, ethyl, difluoromethyl, 2-propeneyl, 2-methylpropyl, Cialkanediyl or -CH 2 CONH 2 .
  • R 2 is methyl.
  • j is l.
  • A is an optionally substituted quinolinyl.
  • A is an optionally substituted quinolin-4-yl.
  • a is 1, 2, 3 or 4
  • b is 1 or 2
  • R 7 and R 8 are the same or different and independently hydrogen, halogen, Ci_ 6 alkyl, -0(Ci_ 6 alkyl), Ci_ 6 haloalkyl or nitro
  • R 3 , R 4 and R 5 are hydrogen.
  • y is 1.
  • A is an optionally substituted l-benzyl-lH-benzo[ ⁇ i]imidazol-2-yl.
  • A is represented by structure (I-3a-ii):
  • c is 1, 2, 3, 4 or 5 and R 9 is hydrogen or halogen.
  • R 3 , R 4 and R 5 are hydrogen. In yet further specific embodiments, c is 1 and R 9 is hydrogen or chlorine.
  • A is 1-benzyl- lH-benzo[ ⁇ i]imidazol-2-yl, l-(2-chlorobenzyl)-lH-benzo[ ⁇ i]imidazol-2-yl or l-(4- chlorobenzyl)-lH-benzo[ ⁇ i]imidazol-2-yl.
  • any two R 2 groups, or any R 2 group and R 1 group may be taken together to form a Ci_ 6 alkanediyl.
  • a C ⁇ alkanediyl such as -CH 2 -
  • representative compounds of structure (I) have the following structure (1-6)
  • the PDElO inhibitors of this invention have one of the following general structures (H-A) or (H-B):
  • m, n and/? are individually 0 or 1; x is 1, 2 or 3;
  • A is an optionally substituted heterocycle
  • B is -O-, -NR 6 - or -S(O) 2 - where z is 0, 1 or 2;
  • R is hydrogen or oxo;
  • R 1 is absent or represents 1 , 2 or 3 substituents that are the same or different and independently halogen, Ci ⁇ alkyl, -CHF 2 , -CF 3 , -CH 2 NH 2 , - CH 2 NH(Ci_ 6 alkyl) or -CH 2 N(Ci_ 6 alkyl) 2 ;
  • R 3 , R 5 and R 6 are the same or different and independently hydrogen or Ci_ 6 alkyl
  • R 10 is Ci_ 6 alkyl, aryl, -OCi_ 6 alkyl, -O-aryl or -NC 1-6 alkyl.
  • Compounds of structures (H-A) and (H-B) may be viewed as novel prodrugs of the PDElO inhibitors disclosed in co-pending U.S. Patent Application No. 12/124,051, published as U.S. Patent Application Publication No. 2008/0300240, entitled "PDElO Inhibitors and Related Compositions and Methods" filed on the same day as the present application (which application is a continuation-in-part of U.S. Patent Application No. 11/944,270 filed November 21, 2007, which claims the benefit under 35 U.S.C. ⁇ 119(e) of U.S.
  • m, n and/? are individually 0 or 1; x is 1, 2 or 3;
  • A is an optionally substituted heterocycle
  • B is -O-, -NR 6 - or -S(O) 2 - where z is 0, 1 or 2;
  • R is hydrogen or oxo;
  • R 1 is absent or represents 1 , 2 or 3 substituents that are the same or different and independently halogen, Ci_6alkyl, -CHF 2 , -CF 3 , -CH 2 NH 2 , - CH 2 NH(Ci_ 6 alkyl) or -CH 2 N(Ci_ 6 alkyl) 2 ;
  • R 3 , R 4 , R 5 and R 6 are the same or different and independently hydrogen or Ci_ 6 alkyl.
  • both m and n are 0 and/? is 1, and the compounds have the following structure (II- 1) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • n, n and/? are 1, and the compounds have the following structure (II-2) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • n 0 and n and/? are both 1, and the compounds have the following structure (II-3) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • both m and/? are 1 and n is 0, and the compounds have the following structure (II-4) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • each of m, n and/? are 0, and the compounds have the following structure (II-5) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R 3 , R 4 and R 5 are hydrogen.
  • R 2 is methyl or difluoromethyl.
  • R 1 is absent and x is 3 with the R 2 groups at the 3, 4 and 5 positions, as represented by structure (II- Ia):
  • A is lH-indol-3- yl or 2H-benzo[6][l,4]thiazin-3(4H)-one-2-yl.
  • B is -S-, -O- or -NR 6 -, respectively, and compounds have the following structures (II-3a), (II-3b) and (II-3c):
  • R 3 , R 4 , R 5 and R 6 are hydrogen.
  • R 2 is hydrogen, methyl, ethyl, difluoromethyl, 2-propeneyl, 2-methylpropyl, Cialkanediyl or -CH 2 CONH 2 . In yet further specific embodiments, R 2 is methyl.
  • R 1 is absent or halogen
  • x is 2 with the R 2 groups located at the 3 and 4 positions
  • x is 3 with the R 2 groups located at the 3, 4 and 5 positions, as represented by structures (II-3d) and (II-3e), respectively:
  • R 1 is 2 substituents that are the same or different and independently halogen, such as fluorine, as represented by structure (II-3f):
  • R 2 is at each occurrence the same or different and independently, Ci_ 6 alkyl, -CHF 2 or -CF 3 .
  • A is , x is 2 or 3 and two of the -OR groups are located at the
  • R 1 is absent
  • R 2 is at each occurrence the same or different and independently Ci_ 6 alkyl, -CHF 2 or -CF 3 , R 3 , R 4 and R 5 are hydrogen, and R 7 is -O(Ci_ ealkyl).
  • A is an optionally substituted quinolin-4-yl as represented by structure (II-3g):
  • a is 1, 2, 3 or 4
  • b is 1 or 2
  • R 7 and R 8 are the same or different and independently hydrogen, halogen, Ci_ 6 alkyl, -O(Ci_ 6 alkyl), Ci_ 6 haloalkyl or nitro.
  • x is 1 with the proviso that R 1 is not hydrogen or methyl.
  • x is 1, 2 or 3
  • a is 1
  • b is 0,
  • R 1 is absent or represents 1, 2, or 3 substituents that are the same or different and independently halogen, Ci_ 6 alkyl, -CHF 2 , -CF 3 , -CH 2 NH 2 , -CH 2 NH(Ci_ 6 alkyl) or - CH 2 N(Ci_ 6 alkyl) 2
  • R 2 is at each occurrence the same or different and independently hydrogen
  • Ci_ 6 alkyl, -C( O)(Ci_ 6 alkyl)
  • benzyl -CH 2 CONH 2 , -CHF 2 or -CF 3
  • R 3 , R 4 and R 5 are hydrogen
  • R 7 is halogen or Ci_ 6 haloalkyl.
  • R 2 is at each occurrence the same or different and independently Ci_ ⁇ alkyl, -CHF 2 or -CF 3 .
  • R 1 is absent or represents 1, 2, or 3 substituents that are the same or different and independently halogen, C ⁇ alkyl, - CHF 2 or -CF 3 .
  • a is 1, 2, 3 or 4
  • b is 1 or 2
  • x is 1 , 2 or 3 with the proviso that when x is 1 , R 1 is not a single methyl substituent
  • R 1 represents 1 or 2 substituents independently halogen, d_ 6 alkyl, -CHF 2 or -CF 3
  • R 2 is at each occurrence the same or different and independently, hydrogen, Ci_ 6 alkyl, benzyl, -CH 2 CONH 2 , -CHF 2 , -CF 3 , or any two R 2 groups may be taken together to form a Ci_ 6 alkanediyl
  • R 3 , R 4 and R 5 are the same or different and independently hydrogen or C ⁇ alkyl
  • R 7 and R 8 are the same or different and independently hydrogen, halogen, C ⁇ alkyl, -O(Ci_ 6 alkyl), C ⁇ haloalkyl or nitro.
  • A is an optionally substituted 1 -benzyl- lH-benzo[ ⁇ i]imidazol-2-yl as represented by structure (II-3h):
  • c is 1, 2, 3, 4 or 5 and R 9 is hydrogen or halogen.
  • c is 1, 2, 3, 4 or 5, x is 1, 2 or 3, R 1 is absent or represents 1 or 2 halogens, R 2 is at each occurrence the same or different and independently, hydrogen, Ci_ 6 alkyl, benzyl, -CH 2 CONH 2 , - CHF 2 , or any two R 2 groups may be taken together to form a Ci_6alkanediyl, R 3 , R 4 and R 5 are the same or different and independently hydrogen or Ci_ 6 alkyl, and R 9 is at each occurrence the same or different and independently, hydrogen or halogen.
  • R 3 , R 4 and R 5 are hydrogen.
  • c is 1 and R 9 is hydrogen or chlorine.
  • A is 1-benzyl- lH-benzo[ ⁇ i]imidazol-2-yl, l-(2-chlorobenzyl)-lH-benzo[ ⁇ i]imidazol-2-yl or l-(4- chlorobenzyl)-lH-benzo[ ⁇ i]imidazol-2-yl.
  • any two R 2 groups, or any R 2 group and R 1 group may be taken together to form a Ci_6alkanediyl.
  • a Ci_6alkanediyl such as -CH 2 -
  • the compounds of the present invention may generally be utilized as the free acid or free base. Alternatively, the compounds of this invention may be used in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids.
  • Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids.
  • Base addition salts included those salts that form with the carboxylate anion and include salts formed with organic and inorganic cations such as those chosen from the alkali and alkaline earth metals (for example, lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like).
  • the term "pharmaceutically acceptable salt" of structure (I), (H-A) or (H-B) is intended to encompass any and all acceptable salt forms.
  • prodrugs are also included within the context of this invention.
  • Prodrugs are any covalently bonded carriers that release a compound of structure (I), (H-A) or (H-B) in vivo when such prodrug is administered to a patient.
  • Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
  • Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups.
  • prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of compounds of structure (I), (H-A) or (H-B).
  • esters may be employed, such as methyl esters, ethyl esters, and the like.
  • the compounds of structure (I), (H-A) and (II-B) may have chiral centers and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of structure (I), (H-A) and (H-B) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I), (H-A) and (H-B) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.
  • the compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples, or in some instances may be obtained from commercially available sources.
  • the compounds of structure (I), (II), (H-A) and (H-B) above may be made by the following reaction schemes, wherein all substituents are as defined above unless indicated otherwise.
  • Compounds of formula (5) in ethanol can then be reacted with a hydrazine compound, such as (6), at reflux to provide compounds of formula (7).
  • Compounds of formula (11) in ethanol can be reacted with a hydrazine compound such as (6) to obtain compounds of formula (12).
  • Compounds of formula (12) can then be reacted with a variety of benzaldehyde derivatives, such as (2), in alcoholic solvents, such as ethanol, and in the presence of a catalytic amount of acid, such as acetic acid, and under reflux to provide compounds of structure (1-4) or (II-4).
  • Compounds of formula (13) in ethanol can be reacted with a hydrazine compound, such as (6), to obtain compounds of formula (14).
  • Compounds of formula (14) can then be reacted with a variety of benzaldehyde derivatives, such as (2), in alcoholic solvents, such as ethanol, and in the presence of a catalytic amount of acid, such as acetic acid, and under reflux to provide compounds of structure (1-5) or (II-5).
  • Enolic prodrugs of structure (H-A) may be prepared by treating a compound of structure (II) with a base, such as triethylamine, in a solvent, such as dichloromethane, followed by the addition of an electrophile, such as acetyl chloride.
  • N-acylated prodrugs of structure (H-B) may be prepared via thermal rearrangement by heating a prodrug of structure (H-A) in a solvent, such as toluene. See, e.g., Carpino et al, J. Org.
  • prodrugs of structures (II-1A), (II-2A), (II-3A), (II-4A), (II-5A) (II-1B), (II-2B), (II-3B), (II-4B) and (II-5B) may be prepared from compounds of structures (H-I), (II-2), (II-3), (II-4) and (II-5).
  • prodrugs of structure (I) having the following structures (I -A) and (I-B) are included within the scope of this invention:
  • R 10 is Ci_ 6 alkyl, aryl, -OCi_ 6 alkyl, -O-aryl or -NCi_ 6 alkyl.
  • Enolic prodrugs of structure (I-A) may be prepared by treating a compound of structure (I) with a base, such as triethylamine, in a solvent, such as dichloromethane, followed by the addition of an electrophile, such as acetyl chloride.
  • N-acylated prodrugs of structure (I-B) may be prepared via thermal rearrangement by heating a prodrug of structure (I-A) in a solvent, such as toluene. See, e.g., Carpino et al., J. Org.
  • prodrugs of structures (I-1A), (I-1B), (I-2A), (I-2B), (1-3 A), (I-3B), (I-4A), (I-4B), (I-5A) and (I-5B) may be prepared from compounds of structures (1-1), (1-2), (1-3), (1-4) and (1-5).
  • compositions containing one or more compounds of structure (I), (H-A) or (H-B) are disclosed.
  • the compounds of the present invention may be formulated as pharmaceutical compositions.
  • Pharmaceutical compositions of the present invention comprise one or more compounds of the present invention and a pharmaceutically acceptable carrier and/or diluent.
  • the PDElO inhibitor is present in the composition in an amount which is effective to treat a particular disorder—that is, in an amount sufficient to achieve desired PDElO inhibition, and preferably with acceptable toxicity to the warm-blooded animal.
  • the pharmaceutical compositions of the present invention may include a PDElO inhibitor in an amount from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
  • a typical daily dosage might range from about 1 ⁇ g/kg to 100 mg/kg, preferably 0.01-100 mg/kg, more preferably 0.1-70 mg/kg, depending on the type and severity of the disease whether, for example, by one or more separate administrations. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs.
  • other dosage regimens may be useful. The progress of this therapy can be monitored by standard techniques and assays.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • compositions formulated as liquid solutions include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives.
  • the compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a PDElO inhibitor, diluents, dispersing and surface active agents, binders, and lubricants.
  • PDElO inhibitor one skilled in this art may further formulate the PDElO inhibitor in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990.
  • the present invention provides a method for treating diseases such as (but not limited to) psychotic disorders, anxiety disorders, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette's syndrome, schizophrenia, delusional disorders, bipolar disorders, post-traumatic stress disorders, drug-induced psychosis, panic disorders, obsessive-compulsive disorders, attention-deficit disorders, disruptive behavior disorders, autism, depression, dementia, cognitive disorders, epilepsy, insomnias and multiple sclerosis as discussed above.
  • diseases such as (but not limited to) psychotic disorders, anxiety disorders, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette's syndrome, schizophrenia
  • Such methods include administering of a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition.
  • "treat” includes prophylactic administration.
  • Such methods include systemic administration of a PDElO inhibitor of this invention, preferably in the form of a pharmaceutical composition as discussed above.
  • systemic administration includes oral and parenteral methods of administration, including subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraarticular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, intravenous, intradermal, inhalational, transdermal, transmucosal, and rectal administration.
  • suitable pharmaceutical compositions of PDElO inhibitors include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives and excipients.
  • the compounds of the present invention can be prepared in aqueous injection solutions which may contain, in addition to the PDElO inhibitor, buffers, antioxidants, bacteriostats, and other additives and excipients commonly employed in such solutions.
  • compositions of the present invention may be carried in a delivery system to provide for sustained release or enhanced uptake or activity of the therapeutic compound, such as a liposomal or hydrogel system for injection, a microparticle, nanoparticle or micelle system for oral or parenteral delivery, or a staged capsule system for oral delivery.
  • a delivery system to provide for sustained release or enhanced uptake or activity of the therapeutic compound, such as a liposomal or hydrogel system for injection, a microparticle, nanoparticle or micelle system for oral or parenteral delivery, or a staged capsule system for oral delivery.
  • compounds of structure (I), (II-A) and (H-B) are expected to avoid or reduce metabolic side effects associated with conventional antipsychotics, in particular the incidence of therapeutically induced obesity.
  • conventional antipsychotics in particular the incidence of therapeutically induced obesity.
  • olanzapine Zyprexa®
  • the most widely prescribed medication to treat schizophrenia, and related atypical antipsychotics is associated with significant metabolic side effects including obesity and associated conditions such as diabetes.
  • olanzapine In animals, subchronic treatment with olanzapine stimulates food intake and increases body weight, consistent with human situations. Furthermore, olanzapine acutely lowers blood leptin levels. Leptin is a satiety hormone produced from adipose tissues, and decrease of leptin level stimulates appetite. It is theorized that olanzapine could stimulate food intake at least partly by reducing leptin levels. Acute administration of olanzapine also changes the animal's response in glucose and insulin levels in glucose tolerance tests, which may also be directly linked to olanzapine's effect in food intake and body weight gain.
  • compositions of the present invention may be administered in combination with one ore more additional therapeutic agents, in combination or by concurrent or sequential administration.
  • additional agents i.e., adjuvants
  • Compounds of this invention may be assayed to determine their IC 50 values by a modification of the two-step method of Thompson and Appleman (Biochemistry 10; 311-316; 1971).
  • cAMP is spiked with ( 3 H)cAMP and incubated with PDElO and various concentrations of a compound of structure (I). After the appropriate incubation time, the reaction is terminated by heating. The mixture is then subjected to treatment with snake venom phosphatase. The phosphatase hydrolyzes any AMP in the mixture, but leaves unreacted cAMP intact.
  • the percent of inhibition can be determined.
  • IC 50 values can be calculated by performing the experiment at several concentrations using standard graphical means. A detailed description of the actual technique used for IC 50 assays are shown in Example 10. To this end, PDElO inhibitors of the invention have an IC 50 of lOO ⁇ M or less, generally less than 10 ⁇ M, and typically less than 1 ⁇ M.
  • the mixture was then concentrated under vacuum using a rotary evaporator.
  • the crude product was diluted with hexanes and triturated.
  • the precipitated solid product was transferred to a glass fiber funnel, the supernatant was removed by vacuum filtration and the solid was washed thoroughly with n-hexane twice to yield: 16 mg (61%) of 1-1.
  • the crude product was diluted with hexanes and triturated.
  • the precipitated solid product was transferred to a glass fiber funnel, the supernatant was removed by vacuum filtration and the solid was washed thoroughly with n-hexane twice to yield 104 mg (36%) of 2-1.
  • Step 4A Preparation of ethyl 2-(lH-benzordlimidazol-2-ylthio)acetate 4a
  • Step 4B Preparation of ethyl 2-(l-benzyl-lH-benzordlimidazol-2-ylthio)acetate 4b
  • Step 4C Preparation of 2-( 1 -benzyl- 1 H-benzordlimidazol-2-ylthio)acetohydrazide 4c
  • the water/ethyl acetate solution was decanted into a separating funnel and the organic layer isolated.
  • the aqueous layer was extracted with ethyl acetate (4 x 200ml), and the combined extracts were dried over magnesium sulfate.
  • the solution was filtered and concentrated in vacuo.
  • the resulting orange gel was purified by flash chromatography (50% EtOAc: 50% petroleum ether — > 100% EtOAc) to yield 5a as a yellow solid (1.70 g, 30%).
  • 2-methylquinoline-4-thiol 5a (1.00 g, 5.71mmol, 1.00 eq.) was dissolved in dimethylformamide (10 mL) at room temperature. Potassium carbonate (0.87 g, 6.28 mmol, 1.10 eq.) was added and the mixture was stirred for 15 minutes. Methyl bromoacetate (921 mg, 6.02 mmol, 1.05 eq.) was added dropwise to the solution, and the reaction was stirred at room temperature for 2.5 hours. Water (20 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (30 mL).
  • Example 5 C was performed in an analogous fashion to Example
  • Example 5D was performed in an analogous fashion to Example 4, Step 4D.
  • Step 6C was performed in an analogous fashion to Example 4, Step 4C.
  • Step 6D was prepared in an analogous fashion to Example 4, Step 4D.
  • Step 8A Preparation of acetic (!Z../V'E)-2-(2-methylquinolin-4-ylthioV./V-(3.4.5- trimethoxybenzylidene)acetohvdrazonic anhydride (Compound No. 8-1)
  • Step 8B Preparation of (E)-N-acetyl-2-(2-methylquinolin-4-ylthio)- ⁇ /'-(3.4.5- trimethoxy-benzylidene)acetohvdrazide
  • Step 9B Preparation of (E)-N-(3-cyano-4,5-dimethoxystyryl)-2-(2-methylquinolin-4- ylthio)acetamide
  • the phosphodiesterase (PDE) assay was performed using recombinant human PDE 1A3, 2 A3, 3 catalytic region, 4 catalytic region, 5 catalytic region, 7 A, 8 A, 9A2, 10Al and 1 IAl enzymes expressed in a baculoviral system using Sf9 cells.
  • PDE activity was measured using a modification of the two-step method of Thompson and Appleman described above which was adapted for 96 well plate format.
  • the effect of the PDE inhibitors was determined by assaying a fixed amount of the enzyme in the presence of test compound concentrations and a substrate concentration below that of the Km, so that Ki equals IC50.
  • the final assay volume was 110 ⁇ l with assay buffer (1OmM MgCl 2 ; 4OmM Tris.HCl; pH 7.4). Reactions were initiated with enzyme and incubated with ( 3 H) -substrate and substance for 20 minutes at 30° C. The reaction was terminated by denaturing the enzyme (heating the reaction to 70° C for 2 minutes). The reaction was then cooled at 4° C for 10 minutes before the addition of snake venom (Crotalus atrox, 0.2 mg/ml) for 10 minutes at 30° C, thus allowing non-specific hydrolysis of the tritiated substrate.
  • assay buffer 1OmM MgCl 2 ; 4OmM Tris.HCl; pH 7.4
  • Separation of the remaining unhydrolysed cyclic nucleotide was achieved by a batch binding of the mixture to activated Dowex (200 ⁇ l) anion exchange resin.
  • the anion exchange resin bound the charged nucleotides, leaving only hydrolysed ( 3 H) substrate in the soluble fraction.
  • the soluble fraction (50 ⁇ l) was then added to microscint-20 (200 ⁇ l) and counted on a Top Count Plate reader. Radioactivity units were plotted against inhibitor concentration and IC50 values obtained using Graph Pad Prism software.
  • phosphodiesterase activity was measured by scintillation proximity assay (SPA) with [ H] - cGMP as substrate.
  • Purified PDElO was diluted and stored in 25 mM Tris-Cl (pH 8.0)/100 mM NaCl/0.05% Tween 20/50% glycerol/3 mM DTT. Assays contained (final concentrations): 50 mM Tris-Cl (pH 7.5)/8.3 mM MgCVl .7 mM EGTA/0.5 mg/ml BSA/5% DMSO and 2 ng PDElO in a final volume of 0.1 mL. Inhibition was evaluated at 8 concentrations in duplicate.
  • the inhibition of other PDE enzymes by the PDElO inhibitors was evaluated under the same conditions described above for PDElO except the amount of enzyme added was optimized for each PDE. Fractional inhibition was evaluated at four concentrations (0.1, 1, 10, and 100 ⁇ M). In cases where inhibition at the highest concentration was less than 50%, the lower limit value in the logistic model was fixed to 0% activity.
  • compounds of this invention are PDElO inhibitors with an IC 50 of 100 ⁇ M or less, generally less than 10 ⁇ M, and typically less than 1 ⁇ M.
  • compounds 8-1, 9-1, 9-2 and 9-3 were found to have ICso's of less than or equal to 1 ⁇ M.
  • Schizophrenia has been associated with dysfunctions of dopaminergic, glutamatergic and serotonergic neurotransmission.
  • Psychostimulant drugs in these three classes dopaminergic agonists (such as amphetamine and apomorphine), glutamatergic antagonists (such as PCP and ketamine), and serotonergic agonists (such as LSD and MDMA), all induce psychotomimetic states (e.g., hyperactivity and disruption of prepulse inhibition) in animals that closely resemble schizophrenia symptoms in humans.
  • Known antipsychotic drugs including both typical antipsychotics (e.g., haloperidol) and atypical antipsychotics (e.g., olanzapine), reverse such psychotomimetic states in animals. The following methods may be utilized to evaluate representative compounds of the present invention and to compare the resulting effect to that of known antipsychotics.
  • Prepulse inhibition (PPI) of the acoustic startle response evaluates the brain's sensorimotor gating function that is often disrupted in schizophrenic and other psychotic conditions.
  • Psychostimulants such as PCP and amphetamine reduce or disrupt PPI, and many antipsychotics increase PPI and/or reverse psychostimulant- induced reduction of PPI.
  • the startle response to the loud noise itself is a measure of the basic sensorimotor reflex. The test is done using the SR-Lab System (San Diego Instruments, San Diego, CA). A test session consists of six trial types under the background noise of 70 dB.
  • One type uses a 40 msec, 120 dB noise as the startle stimulus.
  • Four types contain acoustic startle stimulus preceded by acoustic prepulses of different intensity: the 20-msec prepulse noise of 73, 76, 79, or 82 dB is presented 100 msec before the 120 dB startle stimulus.
  • the last trial type uses the 70 dB background noise with no startle stimulus to measure baseline reaction.
  • Six blocks of the six trial types are presented in pseudorandom order. The startle response is recorded for 65 ms starting with the onset of the startle stimulus. Measurements used to assess PPI are the maximum startle amplitude and the percent each of the 4 prepulses inhibits the startle response.
  • Psychostimulant-induced hyperactivity is measured by injecting animals with PCP or amphetamine and monitoring the animals' activity levels in the VersaMax chambers (Accuscan Instruments, Columbus, OH) measuring 40 x 40 cm.
  • Locomotor activity is detected by photobeam breaks as the animal crosses each beam. The animal is placed in the center of the field and left undisturbed for a period of time (20 min to 2 hr) to measure its spontaneous activity in a novel environment. Measurements used to assess locomotor activity include: horizontal activity, total distance traveled, vertical activity (rearing events - animal raises up on hindlimbs), rotation, stereotypy, and distance traveled in the center compared to total distance traveled (center: total distance ratio).
  • Psychostimulants including dopamine agonist amphetamine and NMDA antagonist PCP, induce psychosis-like conditions manifested as hyperactivity and increased stereotypic behavior.
  • Known antipsychotics are able to reverse psychostimulant-induced hyperactivity and increased stereotypy.
  • Conditioned avoidance response is a behavioral test to evaluate antipsychotic effect of a test compound. It utilizes a shuttle box (Med Associates, St. Albans, VT) with two equal chambers separated by a retractable door. Each chamber is fitted with metal grid floor that is capable of delivering electric shocks independently.
  • a computer program is used to implement the testing paradigm as well as record the animal's movement between the two chambers through infrared beam sensors. The testing paradigm is as the follows. A mouse is placed into one chamber. A light (conditioned stimulus, CS) comes on.
  • the animals are trained in such paradigm for 15-20 days, during which the average percentage of avoidance responses will improve to 60-80%. This indicates that animals have learned to avoid the onset of footshocks by moving to the opposite chamber upon activation of the CS (light). These trained animals are then used for compound testing using the same paradigm.
  • Known antipsychotics have been found to inhibit the conditioned avoidance response, and the ability of new compounds to inhibit this response is thought to be predictive of antipsychotic effect in humans.
  • the antipsychotic effect of a test compound may also be evaluated by a novel object recognition test.
  • a novel object recognition test mice are housed singly for 1-2 days and then injected with vehicle, PCP, or PCP plus the test compound. Twenty minutes after injection, the mice are presented with and allowed to explore two identical objects for 30 minutes. At the end of the exploration period the objects are removed. Twenty-four hours later each mouse is presented with a pair of objects, one familiar and one novel. After a variable delay, the mice begin to explore the objects. The time exploring each object is measured for 4 minutes starting from the first approach to either object. The fraction of total exploration time spent studying the novel object is recorded as a measure of novelty recognition.
  • FIGURES IA-I C Compound 9-1 (Table 6) was found to reduce PCP-induced hyperactivity as shown in FIGURES IA-I C.
  • C57BL/6 male mice were injected with either compound (10 mg/kg) or vehicle via i.p.
  • PCP 5 mg/kg
  • the mice were placed in the activity chambers 10 minutes after PCP injection and their locomotor activities were monitored by infrared beam breaks for 20 min.

Abstract

L'invention concerne des composés qui inhibent la PDE10 et sont utiles dans le traitement de divers états pathologiques, y compris notamment (mais pas exclusivement) les troubles psychotiques, l'anxiété, les troubles des mouvements et/ou des troubles neurologiques tels que la maladie de Parkinson, la maladie de Huntington, la maladie d'Alzheimer, l'encéphalite, les phobies, l'épilepsie, l'aphasie, la paralysie de Bell, l'infirmité motrice cérébrale, les troubles du sommeil, la douleur, le syndrome de Tourette, la schizophrénie, les troubles délirants, la psychose induite par les médicaments, la panique et les troubles obsessionnels-compulsifs. Ces composé présentent l'une des structures générales suivantes, dans lesquelles m, n, p, x, y, R, R1, R2, R3, R4, R5, R10, A, B et D sont tels que définis dans la demande, y compris les sels pharmaceutiquement acceptables, les stéréo-isomères, les solvates ou les promédicaments de ces composés. L'invention concerne aussi des compositions contenant un composé de l'invention combiné à un excipient pharmaceutiquement acceptable, ainsi que des procédés associés à l'utilisation de ces compositions en vue d'inhiber la PDE10 chez un animal à sang chaud nécessitant un tel traitement.
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EP2310016A1 (fr) * 2008-08-05 2011-04-20 Omeros Corporation Inhibiteurs de pde10 et compositions et procédés associés
CN102127182A (zh) * 2010-12-23 2011-07-20 南京医科大学 用于检测pde-5抑制剂的磁性分子印记聚合物的制备方法
WO2012112946A1 (fr) 2011-02-18 2012-08-23 Allergan, Inc. Dérivés de 6,7-dialkoxy-3-isoquinolinol substitués en tant qu'inhibiteurs de la phosphodiestérase 10 (pde10a)
US8278327B2 (en) 2006-11-21 2012-10-02 Omeros Corporation PDE10 inhibitors and related compositions and methods
US8343970B2 (en) 2010-03-12 2013-01-01 Omeros Corporation PDE10 inhibitors and related compositions and methods
WO2014071044A1 (fr) 2012-11-01 2014-05-08 Allergan, Inc. Dérivés de 6,7-dialcoxy-3-isoquinoline substitués à titre d'inhibiteurs de phosphodiestérase 10 (pde10a)
WO2014081617A1 (fr) * 2012-11-20 2014-05-30 Merck Sharp & Dohme Corp. Dérivés de pyridone substitués utilisés en tant qu'inhibiteurs de pde10
US9200016B2 (en) 2013-12-05 2015-12-01 Allergan, Inc. Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US9493447B2 (en) 2014-04-28 2016-11-15 Omeros Corporation Optically active PDE10 inhibitor
US9650368B2 (en) 2014-04-28 2017-05-16 Omeros Corporation Processes and intermediates for the preparation of a PDE10 inhibitor
US9879002B2 (en) 2015-04-24 2018-01-30 Omeros Corporation PDE10 inhibitors and related compositions and methods
US9920045B2 (en) 2015-11-04 2018-03-20 Omeros Corporation Solid state forms of a PDE10 inhibitor
CN111349038A (zh) * 2018-12-24 2020-06-30 天津师范大学 一类吲哚酰腙化合物及其制备方法和在防治植物病害中的应用

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WO2012112946A1 (fr) 2011-02-18 2012-08-23 Allergan, Inc. Dérivés de 6,7-dialkoxy-3-isoquinolinol substitués en tant qu'inhibiteurs de la phosphodiestérase 10 (pde10a)
US9670181B2 (en) 2011-02-18 2017-06-06 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US8772316B2 (en) 2011-02-18 2014-07-08 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE10A)
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