WO2015167968A1 - Optically active pde10 inhibitor - Google Patents
Optically active pde10 inhibitor Download PDFInfo
- Publication number
- WO2015167968A1 WO2015167968A1 PCT/US2015/027645 US2015027645W WO2015167968A1 WO 2015167968 A1 WO2015167968 A1 WO 2015167968A1 US 2015027645 W US2015027645 W US 2015027645W WO 2015167968 A1 WO2015167968 A1 WO 2015167968A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- disorders
- converting
- general scheme
- Prior art date
Links
- 0 COc1cc(-c2ccc[o]2)cc(OC)c1* Chemical compound COc1cc(-c2ccc[o]2)cc(OC)c1* 0.000 description 2
- NLQADJHGPVEMFL-UHFFFAOYSA-N CCCCc1ccc(-c(cc2OC)cc(OC)c2N)[o]1 Chemical compound CCCCc1ccc(-c(cc2OC)cc(OC)c2N)[o]1 NLQADJHGPVEMFL-UHFFFAOYSA-N 0.000 description 1
- QQHJRLKSCSRMEM-DEOSSOPVSA-N CCO[C@H](C(c1ccc(-c(cc2OC)cc(OC)c2Cl)[o]1)=O)c(cc1)ccc1-c1nnc(C)[s]1 Chemical compound CCO[C@H](C(c1ccc(-c(cc2OC)cc(OC)c2Cl)[o]1)=O)c(cc1)ccc1-c1nnc(C)[s]1 QQHJRLKSCSRMEM-DEOSSOPVSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- This invention is directed to enantiomerically pure compounds having activity as PDE inhibitors, and to compositions containing the same, as well as to methods of treating various disorders by administration of such compounds to a warmblooded animal in need thereof.
- the present invention is directed to ( «S)-1- (5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl- 1,3,4- thiadiazol-2-yl)phenyl)ethanone (Compound 2001), which is useful as a PDE10 inhibitor.
- 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).
- PDE 10 A recently described PDE, PDE 10, was reported simultaneously by three independent groups (Fujishige et ah, "Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A),” J Biol Chem 1999, 274: 18438-18445; Loughney et al, "Isolation and characterization of PDE10A, a novel human 3', 5'-cyclic nucleotide phosphodiesterase," Gene 1999, 234: 109-1 17; Soderling et ah, "Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A,” Proc Natl Acad Sci USA 1999, 96:7071-7076).
- PDE10 has the capacity to hydrolyze both cAMP and cGMP; however, the K m for cAMP is approximately 0.05 ⁇ , whereas the K M for cGMP is 3 ⁇ . In addition, the V max for cAMP hydrolysis is fivefold lower than for cGMP. Because of these kinetics, cGMP hydrolysis by PDE10 is potently inhibited by cAMP in vitro, suggesting that PDE10 may function as a cAMP-inhibited cGMP phosphodiesterase in vivo. Unlike PDE8 or PDE9, PDE10 is inhibited by IBMX with an IC 50 (50% inhibitory concentration) of 2.6 ⁇ . (See Soderling and Beavo, "Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions," Current Opinion in Cell Biology, 2000, 12: 174-179.)
- PDE10 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 PDE10 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).
- PDE10 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 PDE10 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 PDE10 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.
- A is:
- Ri is Ci_ 6 alkyl, Ci- 6 aralkyl, aryl, -(CH 2 ) complicat0(CH 2 ) ffl CH 3 or -(CH 2 ) obligeN(CH 3 ) 2 ;
- R 2 is (i) substituted or unsubstituted aryl or (ii) substituted or unsubstituted heterocyclyl;
- R3 is substituted or unsubstituted aryl
- R4 is hydrogen, Ci- 6 alkyl or
- n 1, 2, 3, 4, 5 or 6;
- n 0, 1, 2, 3, 4, 5 or 6.
- X is CI or Br
- R 1 , R 2 , and R 3 are each independently C ( i_6 ) alkyl.
- Q is S or O, and X is CI or Br.
- the present invention is directed to a pure enantiomer of Compound 1001, in particular, Compounds 2001 and 3001.
- the present invention is also directed to a crystal structure of Compound 2001, a pharmaceutical composition of Compound 2001, a method of inhibiting PDE10 with Compound 2001, and a process and particular individual intermediates used in the production of Compound 2001.
- the invention is directed to a compound having the following structure:
- Compound 2001 is enantiomerically pure (e.g, is present in an enantiomeric excess of at least about 98%).
- Compound 2001 is substantially free of its enantiomer.
- Compound 2001 comprises at least 80%, at least 90%, at least 95%, or at least 99% by weight of the designated enantiomer (e.g., the designated enantiomer is present in an enatiomeric excess of at least about 60%, 80%, 90%, or about 98%).
- the invention is directed to a compound having the following structure:
- Compound 3001 is enantiomerically pure (e.g, is present in an enantiomeric excess of at least about 98%).
- Compound 3001 is substantially free of its enantiomer.
- Compound 3001 comprises at least about 80%, at least about 90%, at least about 95%, or at least about 99% by weight of the designated enantiomer (e.g., the designated enantiomer is present in an enatiomeric excess of at least about 60%, 80%, 90%, or about 98%).
- the invention is directed to a compound having the following structure:
- the crystalline form of Compound 2001 can be characterized by X-ray powder diffraction measured using CuKa radiation at about 150 K, for example, 150 K ⁇ 10 K, or 150 K ⁇ 1 K, which provides a characteristic X-ray powder diffraction pattern having principle 2 ⁇ peaks at about 8, 11.2, 12, 13.8, 14.3, 16.5, 17.8, 18, 19.4, 21.2, 21.6, 22.2, 22.8, 23.9, 25.6, 27.5, 29, and 29.6.
- Compound 2001 has an X-ray powder diffraction pattern substantially the same as that shown in Figure 1.
- the invention is directed to a pharmaceutical composition
- a pharmaceutical composition comprising Compound 2001 and a pharmaceutically acceptable carrier or diluent.
- the invention is directed to a method for inhibiting PDE10 in a warm-blooded animal, comprising administering to the animal an effective amount of Compound 2001 or a pharmaceutical composition thereof.
- the method for treating neurological disorders in warm-blooded animals having said neurological disorders comprising administering to the animal an effective amount of Compound 2001 or a pharmaceutical composition thereof, wherein the neurological disorder is selected from the group consisting of psychotic disorders, anxiety disorders, 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, epilepsy, insomnias and multiple sclerosis.
- the neurological disorder is selected from the group consisting of psychotic disorders, anxiety disorders, Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep
- the neurological disorder is schizophrenia.
- the neurological disorder is post-traumatic stress disorder.
- the invention is directed to a process to prepare a compound of Formula (Il-a):
- X is CI or Br
- R 1 , R 2 , and R 3 are each independently C ( i_6 ) alkyl
- M is a Group I metal, a Group II metal, Cu, or Zn;
- R, R 2 , and R 3 are each independently C ( i_6 ) alkyl
- n 1, 2, 3, or 4;
- p 1, 2, 3, or 4;
- the compound of Formula (Il-a) is Compound 2001 :
- the invention is directed to a process to prepare a compound of Formula (Ill-a):
- M is a Group I metal, a Group II metal, Cu, or Zn;
- R is C(i_6)alkyl
- n 1, 2, 3, or 4;
- p 1, 2, 3, or 4;
- the compound of Formula (Ill-a) is Compound
- Figure 1 is an XRPD of the Dioxane Solvate of Compound 2001, measured at about 150 K ⁇ 1 K.
- Figure 2 is packing diagram of Compound 2001 Dioxane Solvate viewed down the crystallographic a axis.
- Figure 3 is packing diagram of Compound 2001 Dioxane Solvate viewed down the crystallographic b axis.
- Figure 4 is packing diagram of Compound 2001 Dioxane Solvate viewed down the crystallographic c axis.
- Figure 5 is an ORTEP Drawing of Compound 2001 Dioxane Solvate.
- FIG. 6 shows the inhibition of Human PDE10 by Compound 1001.
- Figure 7 shows the inhibition of Human PDE10 by Compounds 1001, 2001, and 3001.
- Amino refers to the - H2 radical.
- Niro refers to the -N0 2 radical.
- Ci_ 6 alkyl means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon radical 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, 1-pentynyl, 2-pentynyl, 3- methyl-l-butynyl, and the like.
- Ci_ 6 alkylene or “Ci_ 6 alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), and having from one to six carbon atoms, e.g., methylene, ethylene, propylene, w-butylene, ethenylene, propenylene, M-butenylene, propynylene, w-butynylene, and the like.
- the alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or double bond.
- the points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
- Ci_ 6 alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined above, for example, methoxy, ethoxy and the like.
- Aryl means a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
- the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
- Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
- Ci_ 6 aralkyl means a radical of the formula -Rb-R c where Rb is an alkylene chain as defined above and R c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like.
- Cycloalkyl or “carbocyclic ring” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
- Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
- Halo or halogen refers to bromo, chloro, fluoro or iodo.
- Ci- 6 haloalkyl refers to a Ci_ 6 alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
- Enantiomerically pure in reference to a particular stereoisomer (e.g., Compound 2001), means that it is substantially free of its enantiomer (e.g., Compound 3001). That is, an "enantiomerically pure" stereoisomer has an enantiomeric excess of at least about 98%, or at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.8%, or at least about 99.9%.
- Heterocycle or “heterocyclyl” 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
- heterocycles also include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, and the like.
- heterocycles also include benzothiophen-2-yl, 2,3-dihydrobenzo-l,4-dioxin-6-yl, benzo-l,3-dioxol-5-yl and the like.
- substituted as used herein (for example, in the context of a substituted heterocyclyl or substituted aryl) means that at least one hydrogen atom is replaced with a substituent.
- R a and R b in this context may be the same or different and independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl.
- the foregoing substituents may be further substituted with one or more of the above substituents.
- 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 -hydroxy ethylammonium, and the like).
- the term "pharmaceutically acceptable salt" of formulas (I) & (II) is intended to encompass any and all acceptable salt forms.
- the PDE10 inhibitor has the following structure of Compound 2001 :
- Compound 2001 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is enantiomerically pure (e.g, is present in an enantiomeric excess of at least about 98%).
- Compound 2001 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is substantially free of its enantiomer.
- Compound 2001 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, comprises at least 80%, at least 90%, at least 95%, or at least 99% by weight of the designated enantiomer (e.g., the designated enantiomer is present in an enatiomeric excess of at least about 60%, 80%, 90%, or about 98%).
- the invention is directed to a compound having the following structure:
- Compound 3001 is enantiomerically pure (e.g, is present in an enantiomeric excess of at least about 98%).
- Compound 3001 is substantially free of its enantiomer.
- Compound 3001 comprises at least 80%, at least 90%, at least 95%, or at least 99% by weight of the designated enantiomer (e.g., the designated enantiomer is present in an enatiomeric excess of at least about 60%, 80%, 90%, or about 98%).
- the PDE10 inhibitor has the following structure of Compound 2001 :
- Compound 2001 in crystalline form, has an X-ray powder diffraction pattern comprising principle 2 ⁇ peaks at about 8, 1 1.2, 12, 13.8, 14.3, 16.5, 17.8, 18, 19.4, 21.2, 21.6, 22.2, 22.8, 23.9, 25.6, 27.5, 29, and 29.6 when measured using CuKa radiation at about 150 K, for example, 150 K ⁇ 10 K, or 150 K ⁇ 1 K.
- Compound 2001 in crystalline form, has an X- ray powder diffraction pattern measured using CuKa radiation at about 150 K, for example, 150 K ⁇ 10 K, or 150 K ⁇ 1 K, substantially the same as that shown in Figure 1.
- the crystal structure of Compound 2001 was determined by single crystal X-ray structure analysis.
- compositions containing a compound of structure 2001 is 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 PDE10 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 PDE10 inhibition, and preferably with acceptable toxicity to the warm-blooded animal.
- the pharmaceutical compositions of the present invention may include a PDE10 inhibitor in an amount from 0.1 mg to 1,250 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 PDE10 inhibitor, excipients such as diluents, binders, and lubricants.
- PDE10 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 PDE10 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.
- Compound 1001 selectively inhibits PDE10 relative to other human cyclic nucleotide phosphodiesterases. These include PDE1A, PDE2A, PDE3A, PDE4A1A, PDE5A, PDE7A, PDE8A1, PDE9A2, PDE10A2, and PDE1 1A4.
- the selectivity profile of Compound 1001 is shown in Table 1. Selectivity ratios are the IC5 0 values for each PDE enzyme divided by the IC5 0 for PDE10.
- Compound 1001 was 879- fold less potent in inhibiting PDE2, more than 4800-fold less potent in inhibiting bovine PDE6, and more than 9200 fold less potent in inhibiting members of PDE families, 1, 3, 4, 5, 7, 8, 9, and 1 1.
- suitable pharmaceutical compositions of PDE 10 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 PDE 10 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.
- Compound 2001 is 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 Zaprexa®
- 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 or 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 PDE10 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. Thus, by separating cAMP from the mixture and determining its concentration (by radiography), 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 IC50 assays as set forth in following Examples.
- reactants used in the examples below may be obtained either as described herein, or if not described herein, are themselves either commercially available or may be prepared from commercially available materials by methods known in the art. Certain starting materials, for example, may be obtained by methods described in International PCT Application Publication No. WO 201 1/1 12828.
- reaction conditions and reaction times may vary depending upon the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Typically, reaction progress may be monitored by High Pressure Liquid Chromatography (HPLC) or Nuclear Magnetic Resonance (NMR) spectroscopy, if desired, and intermediates and products may be purified by chromatography on silica gel and/or by recrystallization or precipitation with or without treatment with carbon.
- HPLC High Pressure Liquid Chromatography
- NMR Nuclear Magnetic Resonance
- the present invention is directed to the multi-step synthetic method for preparing Compounds 1001, 2001, and 3001, as set forth in General Schemes (I) and (II).
- a process is provided to prepare a compound of Formula (Il-a):
- X is CI or Br
- R 1 , R 2 , and R 3 are each independently C(i-6)alkyl, according to the following General Scheme (I):
- M is a Group I metal, a Group II metal, Cu, or Zn;
- R, R 2 , and R 3 are each independently C ( i_6 ) alkyl
- n 1, 2, 3, or 4;
- p 1, 2, 3, or 4;
- Q is O. In further embodiments of the process of General Scheme (I), Q is S. In further embodiments of the process of General Scheme (I), X is CI. In further embodiments of the process of General Scheme (I), X is Br.
- M is a Group II metal.
- M is Mg.
- R 1 is methyl, ethyl or propyl.
- R 1 is ethyl.
- R 2 is methyl, ethyl or propyl.
- R 2 is methyl.
- R 3 is methyl, ethyl or propyl.
- R 3 is methyl
- R is butyl
- the acid catalyst used to create acetal CI is para-toluenesulfonic acid monohydrate.
- the suitable source of orthoformate is triethyl orthoformate.
- the metal catalyst of the cyanation step is a cobalt salt.
- the metal catalyst of the cynation step is C0CI 2 .
- the cyanide source is trimethylsilyl cyanide.
- the suitable acid of the hydrolysis step is HC1.
- the suitable base of the amidation step is triethylamine.
- the suitable coupling reagent of the amidation step is propylphosphonic anhydride.
- the source amine is ⁇ , ⁇ -dimethylhydroxylamine hydrochloride.
- the compound of Formula (Il-a is Compound 2001 :
- the compound of Formula (Il-b is Compound 3001 :
- M is a Group I metal, a Group II metal, Cu, or Zn,
- R, R 2 , and R 3 are each independently C ( i_6 ) alkyl
- X is CI or Br
- n 1, 2, 3, or 4
- p 1, 2, 3, or 4;
- R 2 is methyl, ethyl, or propyl.
- R 2 is methyl
- R 3 is methyl, ethyl, or propyl.
- R 3 is methyl
- R is butyl
- X is CI. In further embodiments of the process of General Scheme (II), X is Br. In further embodiments of the process of General Scheme (II), M is a
- M is a Group II metal.
- M is Mg. In further embodiments of the process of General Scheme (II), M is Cu.
- M is Zn.
- the lithium alkyl metal base is a lithium alky lmagnes ate base.
- the lithium alkyl metal base is Bu4MgLi2.
- the compound of Formula HI is a compound of Formula Hl-1 : wherein
- M is a Group I metal, a Group II metal, Cu, or Zn,
- R is C ( i-6 ) alkyl
- X is CI or Br
- n 1, 2, 3, or 4
- p 1, 2, 3, or 4.
- the compound of Formula H 1-1 is:
- the present invention is directed to the multi-step synthetic method for preparing Compounds 1001, 2001, and 3001, as set forth in General Schemes (III) and (IV).
- a process is provided to prepare a compound of Formula (Ill-a):
- M is a Group I metal, a Group II metal, Cu, or Zn;
- R is C(i_6)alkyl
- n 1, 2, 3, or 4;
- p 1, 2, 3, or 4;
- M is a Group II metal.
- M is Mg.
- R is butyl.
- the acid catalyst used to create acetal Cl-1 is para-toluenesulfonic acid monohydrate.
- the suitable source of orthoformate is triethyl orthoformate.
- the metal catalyst of the cyanation step is a cobalt salt. In further embodiments of the process of General Scheme (III), the metal catalyst of the cynation step is C0CI 2 .
- the cyanide source is trimethylsilyl cyanide.
- the suitable acid of the hydrolysis step is HC1.
- the suitable base of the amidation step is triethylamine.
- the suitable coupling reagent of the amidation step is propylphosphonic anhydride.
- the source amine is ⁇ , ⁇ -dimethylhydroxylamine hydrochloride.
- the compound of Formula Ill-a) is Compound 2001 :
- the compound of Formula Ill-b) is Compound 3001:
- M is a Group I metal, a Group II metal, Cu, or Zn,
- R is C ( i-6 ) alkyl
- X is CI or Br
- n 1, 2, 3, or 4
- p 1, 2, 3, or 4;
- a lithium alkyl metal base from R n -Li and a metal halide comprising M, wherein n is 1, 2, 3 4, or 5;
- X is Br.
- M is a Group (I) metal.
- M is a Group II metal.
- M is Mg. In further embodiments of the process of General Scheme (IV), M is Cu. In further embodiments of the process of General Scheme (IV), M is Zn. In further embodiments of the process of General Scheme (IV), R is butyl.
- the lithium alkyl metal base is a lithium alky lmagnes ate base.
- the lithium alkyl metal base is Bu 4 MgLi 2 .
- the compound of Formula H 1-1 is a compound of Formula HI -la:
- Additional embodiments of the invention are directed to the individual steps of the multistep general synthetic methods described above in (I), (II), (III), and (rV) and the individual intermediates used in these steps. These intermediates of the present invention are described in detail below. All substituent groups in the intermediates described below are as defined in the multi-step method above.
- Preferred anionic coupling reagents are selected from a compound having a structure according to Formula HI : wherein
- M is a Group I metal, a Group II metal, Cu, or Zn,
- R, R 2 , and R 3 are each independently C ( i_6 ) alkyl
- X is CI or Br
- n 1, 2, 3, or 4
- p 1, 2, 3, or 4.
- Preferred anionic coupling reagents are selected from a compound having a structure according to Formula Hl-1 :
- M is a Group I metal, a Group II metal, Cu, or Zn,
- R is C(i_6)alkyl
- X is CI or Br
- n 1, 2, 3, or 4
- p 1, 2, 3, or 4.
- M is Mg.
- Preferred anionic coupling reagents are selected from a compound having a structure according to Formula HI- la:
- X is CI
- X is Br
- the anionic coupling reagent has the following structure:
- a preferred nitrile intermediate has the following structure:
- a preferred acetal intermediate has the following structure:
- reaction progress may be monitored by High Pressure Liquid Chromatography (HPLC), if desired, and intermediates and products may be purified by chromatography and/or by recrystallization or precipitation with or without treatment with carbon.
- HPLC High Pressure Liquid Chromatography
- the present invention is directed to the multi-step synthetic method for preparing Compound 2001 as set forth in Examples 1-9.
- steps to form El-la from Bl-la can be performed without isolation of purified synthetic intermediates.
- Bl-la (100.4 g, 0.490 mol) with para- toluenesulfonic acid (catalytic amount) and toluene at room temperature. Ethanol and triethyl orthoformate were charged, followed by a toluene rinse each.
- the batch was heated to 45 °C. More para-toluenesulfonic acid (catalytic amount) was added and heating was continued for 2 hours.
- Anhydrous K2CO 3 was added and the batch was partially concentrated under vacuum. Toluene was added, and the batch was again partially concentrated. The batch was filtered to remove solids. The reactor and filter were rinsed with toluene.
- the wet cake of Dl-la was charged to a reactor followed by concentrated HC1 and water at 20-25 °C. The batch was heated to 60 °C for 3.5 hours. Celite and acetonitrile were added and the batch was filtered over Darco G60 carbon and Celite. The filtrate was charged to the reactor and heated to 60-70 °C. Water was slowly added and then cooled down to 25 °C. The solid was collected by filtration, washed with water and dried to give 105 g El-la (77% yield) as a white solid.
- Tetrakis(triphenylphosphine)palladium (0.46 g, 0.4 mmol) was added and the mixture was degassed again then heated at 60 °C for 17 hrs. Volatiles were removed in vacuo then methanol (10 mL) was added and the slurry was stirred at 60 °C for 2h. The mixture was cooled to room temperature, and the solids were collected. The solid was slurried in hot methanol then filtered and dried to give 2-(4-chloro-3, 5- dimethoxyphenyl) furan (3.18 g, 67% yield).
- Optical rotation of each enantiomer was measured under USP standards.
- Compound 2001 (5 mg) was dissolved in 1,4-dioxane (10 ⁇ ) at ambient temperature, resulting in a clear solution. The solution was then frozen, leaving the sample in a freezer for about 1 day, generating crystals. The sample was held at ambient temperature for about 12 days, generating additional crystals. A few of these crystals were used to seed a separate ambient-temperature solution of Compound 2001 (13 mg) in 1,4-dioxane (25 ⁇ ), resulting in instant precipitation of crystals throughout the sample. The crystals were isolated / gently separated in Paratone-N oil.
- Cell constants and an orientation matrix for data collection were obtained from least-squares refinement using the setting angles of 29360 reflections in the range 2° ⁇ ⁇ ⁇ 63°.
- the refined mosaicity from DENZO/SCALEPACK was 0.99° indicating moderate crystal quality.
- the data were collected to a maximum 2 ⁇ value of 126.8°, at a temperature of about 150 ⁇ 1 K.
- a calculated XRPD pattern was generated for Cu radiation using PowderCell 2.3 and the atomic coordinates, space group, and unit cell parameters from the single crystal structure. Because the single crystal data are collected at low temperatures (about 150 K, for example 150 ⁇ 10 K, or 150 ⁇ 1 K), peak shifts may be evident between the pattern calculated from low temperature data and the room temperature experimental powder diffraction pattern, particularly at high diffraction angles.
- the ORTEP diagram was prepared using the ORTEP III program within PLATON. Atoms are represented by 50% probability anisotropic thermal ellipsoids. Assessment of chiral centers was performed with the PLATON software package. Absolute configuration is evaluated using the specification of molecular chirality rules. Packing diagrams and additional figures were generated with the Mercury 3.1 visualization package.
- the single crystal structure of Compound 2002 was determined to confirm the molecular structure.
- the structure was determined to be a dioxane solvate, composed of one Compound 2002 molecule and one dioxane molecule in the asymmetric unit.
- the absolute structure was determined from the crystal structure to be S configuration at CI 2.
- the PDE assay medium consisted of (final concentrations); 50 mM Tris- HCL, pH 7.5; 8.3 mM MgCl 2 ; 1.7 mM EGTA; 0.5 mg/mL bovine serum albumin ; and substrate (H-cAMP or H-cGMP).
- the BSA was lyophilized powder, essentially fatty acid free, > 96% pure from Sigma (A6003).
- 89 ⁇ of assay medium and 1 ⁇ of Compound 1 in 100% DMSO were added to a 96-well SPA plate and incubated for 1 minute at 30°C. The assay was initiated by addition of ⁇ of PDE10, and incubated for 21 minutes.
- the substrate was 125 nM H-cGMP.
- the substrates were 37 nM H-cAMP for PDEs 3, 4, 7, and 8; and 37 nM H-cGMP for PDEs 1, 2, 5, 9, 10, and 1 1. In all cases substrate concentrations were below the KM. The consumption of substrate was less than 6%, indicating that substrate concentrations did not change appreciably during the assay.
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2015253463A AU2015253463B2 (en) | 2014-04-28 | 2015-04-24 | Optically active PDE10 inhibitor |
KR1020167031125A KR102558505B1 (en) | 2014-04-28 | 2015-04-24 | Optically active pde10 inhibitor |
RU2016146097A RU2016146097A (en) | 2014-04-28 | 2015-04-24 | OPTICALLY ACTIVE INHIBITOR PDE10 |
JP2016564604A JP2017513913A (en) | 2014-04-28 | 2015-04-24 | Optically active PDE10 inhibitor |
CN201580023106.6A CN106255690B (en) | 2014-04-28 | 2015-04-24 | Optically active PDE10 inhibitors |
BR112016024523-7A BR112016024523B1 (en) | 2014-04-28 | 2015-04-24 | PROCESS FOR PREPARING OPTICALLY ACTIVE PDE10 INHIBITOR COMPOUNDS |
EP15785340.9A EP3137461B1 (en) | 2014-04-28 | 2015-04-24 | Method of preparing an optically active pde10 inhibitor |
CA2946754A CA2946754C (en) | 2014-04-28 | 2015-04-24 | Optically active pde10 inhibitor |
ES15785340T ES2895487T3 (en) | 2014-04-28 | 2015-04-24 | Method of preparing an optically active PDE10 inhibitor |
IL248586A IL248586B (en) | 2014-04-28 | 2016-10-27 | Optically active pde10 inhibitor, compositions comprising same, proceses for preparing same and uses thereof |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461985381P | 2014-04-28 | 2014-04-28 | |
US61/985,381 | 2014-04-28 | ||
US201462047569P | 2014-09-08 | 2014-09-08 | |
US62/047,569 | 2014-09-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015167968A1 true WO2015167968A1 (en) | 2015-11-05 |
Family
ID=54359189
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2015/027645 WO2015167968A1 (en) | 2014-04-28 | 2015-04-24 | Optically active pde10 inhibitor |
Country Status (13)
Country | Link |
---|---|
US (2) | US9493447B2 (en) |
EP (1) | EP3137461B1 (en) |
JP (1) | JP2017513913A (en) |
KR (1) | KR102558505B1 (en) |
CN (1) | CN106255690B (en) |
AU (1) | AU2015253463B2 (en) |
BR (1) | BR112016024523B1 (en) |
CA (1) | CA2946754C (en) |
ES (1) | ES2895487T3 (en) |
IL (1) | IL248586B (en) |
NZ (2) | NZ716462A (en) |
RU (1) | RU2016146097A (en) |
WO (1) | WO2015167968A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3137462A4 (en) * | 2014-04-28 | 2017-12-27 | Omeros Corporation | Processes and intermediates for the preparation of a pde10 inhibitor |
EP3285760A4 (en) * | 2015-04-24 | 2018-09-26 | Omeros Corporation | Pde10 inhibitors and related compositions and methods |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104710385B (en) * | 2010-03-12 | 2018-11-09 | 奥默罗斯公司 | PDE10 inhibitor and compositions related and method |
NZ716462A (en) * | 2014-04-28 | 2017-11-24 | Omeros Corp | Optically active pde10 inhibitor |
US20160284909A1 (en) * | 2015-03-27 | 2016-09-29 | Gabriel Harley | Multi-diode solar cells |
CA3003611C (en) | 2015-11-04 | 2022-11-01 | Omeros Corporation | Solid state forms of a pde10 inhibitor |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060074102A1 (en) * | 2004-05-14 | 2006-04-06 | Kevin Cusack | Kinase inhibitors as therapeutic agents |
US7449486B2 (en) * | 2004-10-19 | 2008-11-11 | Array Biopharma Inc. | Mitotic kinesin inhibitors and methods of use thereof |
US20110224202A1 (en) * | 2010-03-12 | 2011-09-15 | Omeros Corporation | Pde10 inhibitors and related compositions and methods |
US8278327B2 (en) * | 2006-11-21 | 2012-10-02 | Omeros Corporation | PDE10 inhibitors and related compositions and methods |
US20130158081A1 (en) * | 2006-09-25 | 2013-06-20 | Ptc Therapeutics, Inc. | Crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid |
Family Cites Families (67)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK178590D0 (en) | 1990-07-26 | 1990-07-26 | Novo Nordisk As | 1,4-DISUBSTITUTED PIPERAZINES |
PT100905A (en) | 1991-09-30 | 1994-02-28 | Eisai Co Ltd | BICYCLE HYGIENEOUS HETEROCYCLIC COMPOUNDS CONTAINING BENZENE, CYCLOHEXAN OR PYRIDINE AND PYRIMIDINE, PYRIDINE OR IMIDAZOLE SUBSTITUTES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
CZ141795A3 (en) | 1992-12-02 | 1995-11-15 | Pfizer | 4-substituted catechol diethers as such and for treating diseases and pharmaceutical preparations based thereon |
DE4323192A1 (en) | 1993-07-10 | 1995-01-12 | Basf Ag | Process for the preparation of homopolymers and copolymers of alk-1-enes |
DE4325846C1 (en) | 1993-07-31 | 1995-01-19 | Herberts Gmbh | Use of furan-modified aromatic pinacol derivatives as initiators and furan-modified aromatic pinacol derivatives as such |
DE4343286A1 (en) | 1993-12-17 | 1995-06-22 | Hoechst Ag | Phthalzine cpds. used in liq. crystal mixt. to reduce memory angle |
DE4409501A1 (en) | 1994-03-19 | 1995-09-21 | Didier Werke Ag | Wear lining of a shaft furnace and stone therefor |
DE69526790T2 (en) | 1994-06-24 | 2003-03-06 | Euro Celtique Sa | COMPOUNDS TO INHIBIT PHOSPHODIESRERASE IV |
US5789434A (en) | 1994-11-15 | 1998-08-04 | Bayer Corporation | Derivatives of substituted 4-biarylbutyric acid as matrix metalloprotease inhibitors |
TW424087B (en) | 1995-04-06 | 2001-03-01 | Janssen Pharmaceutica Nv | 1,3-dihydro-1-(phenylalkenyl)-2H-imidazol-2-one derivatives |
TW332201B (en) | 1995-04-06 | 1998-05-21 | Janssen Pharmaceutica Nv | 1,3-Dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatives |
US6037370A (en) | 1995-06-08 | 2000-03-14 | Vertex Pharmaceuticals Incorporated | Methods and compositions for stimulating neurite growth |
CN1209809A (en) | 1996-01-22 | 1999-03-03 | 藤泽药品工业株式会社 | Noval chemical compound |
WO1998008830A1 (en) | 1996-08-26 | 1998-03-05 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Thiazole derivatives useful as selective inhibitors of pde-iv |
JPH1087543A (en) | 1996-09-17 | 1998-04-07 | Chisso Corp | Alkoxybenzene derivative, liquid crystal composition, and liquid crystal display element |
US6548490B1 (en) | 1997-10-28 | 2003-04-15 | Vivus, Inc. | Transmucosal administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction |
WO1999045914A1 (en) | 1998-03-13 | 1999-09-16 | Maruho Kabushikikaisha | Alkyl amine derivative and local anesthetic agent using the same |
GB9807354D0 (en) * | 1998-04-07 | 1998-06-03 | Glaxo Group Ltd | Antiviral compound |
SE9804212D0 (en) | 1998-12-04 | 1998-12-04 | Astra Pharma Prod | Compounds |
WO2000034251A1 (en) | 1998-12-07 | 2000-06-15 | Smithkline Beecham Corporation | A method for quantitative determination of amino acids |
DE60014603T2 (en) | 1999-03-12 | 2006-02-16 | Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield | Heterocyclic urea and related compounds as anti-inflammatory agents |
US7141593B1 (en) * | 1999-06-04 | 2006-11-28 | Abbott Laboratories | Pharmaceutical formulations |
GB9929552D0 (en) | 1999-12-14 | 2000-02-09 | Proteus Molecular Design | Compounds |
JP2004511434A (en) | 2000-06-15 | 2004-04-15 | ファルマシア・コーポレーション | Heteroarylalkanoic acids as integrin receptor antagonists |
US20030032579A1 (en) | 2001-04-20 | 2003-02-13 | Pfizer Inc. | Therapeutic use of selective PDE10 inhibitors |
HUP0400446A2 (en) * | 2001-05-22 | 2004-09-28 | Pfizer Products Inc. | Crystal forms of azithromycin |
US6821502B2 (en) * | 2002-06-12 | 2004-11-23 | Chevron U.S.A. Inc. | Method of making aluminum-containing zeolite with IFR structure |
AU2003254481A1 (en) | 2002-07-27 | 2004-02-16 | Astrazeneca Ab | Chemical compounds |
MXPA05003762A (en) | 2002-10-08 | 2005-07-22 | Scripps Research Inst | Inhibitors of fatty acid amide hydrolase. |
ATE412415T1 (en) | 2002-10-30 | 2008-11-15 | Via Pharmaceuticals Inc | CYCLIC NUCLEOTIDE PHOSPHODIESTERASE INHIBITORS, HAVING A BENZODIAZEPIN STRUCTURE, AND THEIR USE IN THERAPY |
TW200410921A (en) | 2002-11-25 | 2004-07-01 | Hoffmann La Roche | Mandelic acid derivatives |
WO2004052859A1 (en) | 2002-12-06 | 2004-06-24 | Kowa Co., Ltd. | Erythropoietin production accelerator |
JP2006518333A (en) | 2002-12-20 | 2006-08-10 | ファルマシア・コーポレーション | Heteroarylalkanoic acids as integrin receptor antagonists |
WO2004071509A1 (en) | 2003-02-12 | 2004-08-26 | Nippon Chemiphar Co., Ltd. | Oligodendrocyte differentiation promoters |
JP2006523719A (en) | 2003-04-18 | 2006-10-19 | メモリー・ファーマシューティカルズ・コーポレイション | Pyrazole derivatives as phosphodiesterase 4 inhibitors |
AR047541A1 (en) * | 2004-02-13 | 2006-01-25 | Sandoz Ag | PHOSPHATE OF 5 - [[4- [2-METHYL-2-PYRIDINYL-AMINO-ETOXI] PHENYL] METHYL] -2,4 THYZOLIDINADION (ROSIGLITAZONE) AND ITS POLYMORPHIC FORMS |
EP1753735A1 (en) | 2004-04-20 | 2007-02-21 | Transtech Pharma, Inc. | Substituted thiazole and pyrimidine derivatives as melanocortin receptor modulators |
US7351833B2 (en) * | 2004-07-23 | 2008-04-01 | Abbott Laboratories | (1S,5S)-3-(5,6-dichloropyridin-3-yl)-3,6-diazabicyclo[3.2.0]heptane benzenesulfonate |
US8436176B2 (en) * | 2004-12-30 | 2013-05-07 | Medicis Pharmaceutical Corporation | Process for preparing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine |
EP1841757B1 (en) | 2005-01-07 | 2010-06-30 | Pfizer Products Incorporated | Heteroaromatic quinoline compounds and their use as pde10 inhibitors |
CA2597134C (en) | 2005-02-04 | 2015-05-26 | Senomyx, Inc. | Compounds comprising linked heteroaryl moieties and their use as novel umami flavor modifiers, tastants and taste enhancers for comestible compositions |
EP1871770A1 (en) | 2005-04-22 | 2008-01-02 | Kalypsys, Inc. | Ortho-terphenyl inhibitors of p38 kinase and methods of treating inflammatory disorders |
UA91546C2 (en) * | 2005-05-03 | 2010-08-10 | Бьорінгер Інгельхайм Інтернаціональ Гмбх | Crystalline form of 1-chloro-4-(я-d-glucopyranos-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
MY152185A (en) * | 2005-06-10 | 2014-08-29 | Novartis Ag | Modified release 1-[(3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(s)-carbonitrile formulation |
EP1928848A2 (en) | 2005-08-04 | 2008-06-11 | Apogee Biothechnology Corporation | Sphingosine kinase inhibitors and methods of their use |
WO2007027525A1 (en) * | 2005-08-29 | 2007-03-08 | Sanofi-Aventis U.S. Llc | Novel crystalline form of a pyridazino [4 , 5-b] indole derivative |
ATE496933T1 (en) * | 2005-09-13 | 2011-02-15 | Sicor Inc | PURE ROCURONIUM BROMIDE |
PL1954684T3 (en) | 2005-11-15 | 2014-10-31 | Otsuka Pharma Co Ltd | Oxazole compound and pharmaceutical composition |
BRPI0620373A2 (en) | 2005-12-23 | 2011-11-08 | Astrazeneca Ab | pharmaceutically and pharmacologically acceptable salts and salts thereof, and enantiomers of the compound and salts thereof, use thereof, optionally in combination with a gabab receptor agonist, and, pharmaceutical composition |
CA2650976A1 (en) | 2006-05-02 | 2007-11-15 | Pfizer Products Inc. | Bicyclic heteroaryl compounds as pde10 inhibitors |
US20080090834A1 (en) | 2006-07-06 | 2008-04-17 | Pfizer Inc | Selective azole pde10a inhibitor compounds |
EP2059234B1 (en) | 2006-09-08 | 2011-11-02 | Ore Pharmaceuticals Inc. | Method for reducing or alleviating inflammation in the digestive tract |
AU2007300532A1 (en) * | 2006-09-28 | 2008-04-03 | Merck Sharp & Dohme Corp. | Pharmaceutical compositions of HDAC inhibitors and chelatable metal compounds, and metal-HDAC inhibitor chelate complexes |
US20090253918A1 (en) | 2006-10-02 | 2009-10-08 | Janssen Pharmaceuticals, N.V. | Novel intermediate for glyt1 inhibitor |
US7837978B2 (en) * | 2006-10-13 | 2010-11-23 | Chevron U.S.A. Inc. | Process for preparing aluminum-containing molecular sieve SSZ-26 |
EP2083819B1 (en) * | 2006-11-21 | 2017-02-22 | Omeros Corporation | Pde10 inhibitors and related compositions and methods |
PE20081506A1 (en) * | 2006-12-12 | 2008-12-09 | Infinity Discovery Inc | ANSAMYCIN FORMULATIONS |
WO2009008906A2 (en) | 2007-02-06 | 2009-01-15 | The Trustees Of The University Of Pennsylvania | Therapeutic compounds for blocking dna synthesis of pox viruses |
WO2008143500A1 (en) * | 2007-05-22 | 2008-11-27 | Ultimorphix Technologies B.V. | Tenofovir disoproxil hemi-fumaric acid co-crystal |
EP2017264A1 (en) | 2007-07-16 | 2009-01-21 | Bayer Cropscience Ag | Substituted phenyl propargyl compounds, method for their manufacture and their use as herbicides and plant growth regulators |
WO2009049022A1 (en) | 2007-10-10 | 2009-04-16 | Ore Pharmaceuticals Inc. | Method for treatment of pancreatitis |
TW200944520A (en) * | 2008-01-29 | 2009-11-01 | Glaxo Group Ltd | Spiro compounds as NPY Y5 receptor antagonists |
WO2009143178A2 (en) | 2008-05-20 | 2009-11-26 | Omeros Corporation | Pde10 inhibitors and related compositions and methods |
TWI501965B (en) | 2008-06-20 | 2015-10-01 | Lundbeck & Co As H | Novel phenylimidazole derivatives as pde10a enzyme inhibitors |
CA2733378C (en) | 2008-08-05 | 2017-04-25 | Omeros Corporation | Pde10 inhibitors and related compositions and methods |
NZ716462A (en) * | 2014-04-28 | 2017-11-24 | Omeros Corp | Optically active pde10 inhibitor |
NZ630810A (en) * | 2014-04-28 | 2016-03-31 | Omeros Corp | Processes and intermediates for the preparation of a pde10 inhibitor |
-
2014
- 2014-09-10 NZ NZ716462A patent/NZ716462A/en unknown
- 2014-09-10 NZ NZ630803A patent/NZ630803A/en unknown
-
2015
- 2015-04-24 RU RU2016146097A patent/RU2016146097A/en not_active Application Discontinuation
- 2015-04-24 ES ES15785340T patent/ES2895487T3/en active Active
- 2015-04-24 CN CN201580023106.6A patent/CN106255690B/en active Active
- 2015-04-24 WO PCT/US2015/027645 patent/WO2015167968A1/en active Application Filing
- 2015-04-24 BR BR112016024523-7A patent/BR112016024523B1/en active IP Right Grant
- 2015-04-24 AU AU2015253463A patent/AU2015253463B2/en active Active
- 2015-04-24 US US14/696,295 patent/US9493447B2/en active Active
- 2015-04-24 KR KR1020167031125A patent/KR102558505B1/en active IP Right Grant
- 2015-04-24 CA CA2946754A patent/CA2946754C/en active Active
- 2015-04-24 EP EP15785340.9A patent/EP3137461B1/en active Active
- 2015-04-24 JP JP2016564604A patent/JP2017513913A/en active Pending
-
2016
- 2016-10-12 US US15/291,948 patent/US9850238B2/en active Active
- 2016-10-27 IL IL248586A patent/IL248586B/en active IP Right Grant
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060074102A1 (en) * | 2004-05-14 | 2006-04-06 | Kevin Cusack | Kinase inhibitors as therapeutic agents |
US7449486B2 (en) * | 2004-10-19 | 2008-11-11 | Array Biopharma Inc. | Mitotic kinesin inhibitors and methods of use thereof |
US20130158081A1 (en) * | 2006-09-25 | 2013-06-20 | Ptc Therapeutics, Inc. | Crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid |
US8278327B2 (en) * | 2006-11-21 | 2012-10-02 | Omeros Corporation | PDE10 inhibitors and related compositions and methods |
US20110224202A1 (en) * | 2010-03-12 | 2011-09-15 | Omeros Corporation | Pde10 inhibitors and related compositions and methods |
Non-Patent Citations (1)
Title |
---|
See also references of EP3137461A4 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3137462A4 (en) * | 2014-04-28 | 2017-12-27 | Omeros Corporation | Processes and intermediates for the preparation of a pde10 inhibitor |
EP3285760A4 (en) * | 2015-04-24 | 2018-09-26 | Omeros Corporation | Pde10 inhibitors and related compositions and methods |
Also Published As
Publication number | Publication date |
---|---|
CA2946754C (en) | 2022-08-30 |
US20170096420A1 (en) | 2017-04-06 |
NZ630803A (en) | 2016-03-31 |
ES2895487T3 (en) | 2022-02-21 |
RU2016146097A3 (en) | 2018-11-15 |
BR112016024523B1 (en) | 2022-10-11 |
CN106255690A (en) | 2016-12-21 |
US20160024070A1 (en) | 2016-01-28 |
NZ716462A (en) | 2017-11-24 |
CA2946754A1 (en) | 2015-11-05 |
EP3137461A4 (en) | 2017-09-13 |
CN106255690B (en) | 2020-07-17 |
RU2016146097A (en) | 2018-05-30 |
IL248586A0 (en) | 2016-12-29 |
AU2015253463A1 (en) | 2016-11-03 |
EP3137461A1 (en) | 2017-03-08 |
US9493447B2 (en) | 2016-11-15 |
KR20160141845A (en) | 2016-12-09 |
AU2015253463B2 (en) | 2018-12-06 |
BR112016024523A2 (en) | 2017-08-15 |
IL248586B (en) | 2019-09-26 |
KR102558505B1 (en) | 2023-07-21 |
EP3137461B1 (en) | 2021-08-11 |
JP2017513913A (en) | 2017-06-01 |
US9850238B2 (en) | 2017-12-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9850238B2 (en) | Optically active PDE10 inhibitor | |
TW495498B (en) | Amide derivative and a pharmaceutical composition containing the same as a Ca2+ release activated Ca2+ channel inhibitor | |
CA2891976C (en) | Imidazopyridine compounds | |
CA2802216C (en) | Tetrahydrocarboline derivative and its use as an enpp2 inhibitor | |
RU2545456C2 (en) | Pde10 inhibitors and compositions containing them and methods | |
AU2008304439B2 (en) | (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluorethoxy)pyrimidin-4-yl)phenyl)propanoate | |
CA2683936A1 (en) | Triazolopyridine carboxamide derivatives and triazolopyrimidine carboxamide derivatives, preparation thereof and therapeutic use thereof | |
JP2008526966A (en) | Amino-imidazolones for the inhibition of β-secretase | |
CA2915561A1 (en) | Novel substituted bicyclic compounds as bromodomain inhibitors | |
KR20160038008A (en) | Novel quinazolinones as bromodomain inhibitors | |
EP3148539B1 (en) | Histone deacetylase inhibitors and compositions and methods of use thereof | |
JP2010500999A (en) | Imidazoleamine as an inhibitor of beta-secretase | |
KR20150011838A (en) | Pyrrolopyrazone inhibitors of tankyrase | |
EA021150B1 (en) | Imidazolidine derivatives as inhibitors of glutaminylcyclase | |
KR20170040299A (en) | Imidazopyridazine compounds | |
EP2742029B1 (en) | N-(benzimimdazol-2-yl)-cyclopropane carboxamides as lysophosphatidic acid antagonists | |
JP2022527925A (en) | Use of aromatic amine compounds in the manufacture of AR and BRD4 double inhibitors and regulators of the compounds. | |
US9879002B2 (en) | PDE10 inhibitors and related compositions and methods | |
KR20180101568A (en) | 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-2-carboxamide compound | |
JPWO2019044940A1 (en) | Cyclic amine derivative and its pharmaceutical use | |
JPWO2019088057A1 (en) | Anilide derivatives and their pharmaceutical uses | |
FR2972454A1 (en) | NOVEL DIHYDRO-OXAZOLOBENZODIAZEPINONES DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM | |
CA3222543A1 (en) | Use of substituted 5-(4-methyl-6-phenyl-4h-benzo[f]imidazo[1,5-a][1,4] diazepin-3-yl)-1,2,4-oxadiazoles in the treatment of inflammatory conditions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15785340 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2946754 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2016564604 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 248586 Country of ref document: IL |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112016024523 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2015253463 Country of ref document: AU Date of ref document: 20150424 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20167031125 Country of ref document: KR Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2015785340 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015785340 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2016146097 Country of ref document: RU Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 112016024523 Country of ref document: BR Kind code of ref document: A2 Effective date: 20161020 |