WO2011102794A1 - Processes for making cyclopropyl amide derivatives and intermediates associated therewith - Google Patents

Processes for making cyclopropyl amide derivatives and intermediates associated therewith Download PDF

Info

Publication number
WO2011102794A1
WO2011102794A1 PCT/SE2011/050171 SE2011050171W WO2011102794A1 WO 2011102794 A1 WO2011102794 A1 WO 2011102794A1 SE 2011050171 W SE2011050171 W SE 2011050171W WO 2011102794 A1 WO2011102794 A1 WO 2011102794A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
reacting
prepared
moles
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/SE2011/050171
Other languages
English (en)
French (fr)
Inventor
Robert Stranne
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=44370080&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2011102794(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to EP20110744974 priority Critical patent/EP2536685B1/en
Priority to NZ60211011A priority patent/NZ602110A/en
Priority to JP2012553849A priority patent/JP2013520413A/ja
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Priority to RU2012139082/04A priority patent/RU2012139082A/ru
Priority to AU2011218491A priority patent/AU2011218491C1/en
Priority to HK13105221.5A priority patent/HK1178142B/en
Priority to BR112012020782A priority patent/BR112012020782A2/pt
Priority to SG2012059473A priority patent/SG183274A1/en
Priority to MX2012009473A priority patent/MX2012009473A/es
Priority to CA 2790040 priority patent/CA2790040A1/en
Priority to US13/579,605 priority patent/US9012452B2/en
Priority to ES11744974.4T priority patent/ES2541857T3/es
Priority to CN201180019632.7A priority patent/CN103168027B/zh
Priority to KR20127024174A priority patent/KR20130004296A/ko
Publication of WO2011102794A1 publication Critical patent/WO2011102794A1/en
Priority to IL221431A priority patent/IL221431A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61P25/14—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
    • A61P25/18—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
    • A61P25/28—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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

Definitions

  • cyclopropyl amide derivatives of formula I and/or pharmaceutically acceptable salts thereof, and intermediates associated therewith. At least one cyclopropyl amide derivative of formula I, or pharmaceutically acceptable salt thereof is useful to treat at least one histamine H3 receptor associated condition.
  • the histamine H3 receptor is of current interest in developing new medicaments.
  • the H3 receptor is a presynaptic autoreceptor located both in the central and peripheral nervous systems, the skin, and in organs, such as, for example, the lung, the intestine, probably the spleen, and the gastrointestinal tract.
  • the H3 receptor has intrinsic, constitutive activity in vitro as well as in vivo (i.e., it is active in the absence of an agonist). Compounds acting as inverse agonists can inhibit this activity.
  • the histamine H3 receptor has been shown to regulate the release of histamine and also of other neurotransmitters, such as, for example, serotonin and acetylcholine.
  • histamine H3 ligands such as, for example, a histamine H3 receptor antagonist or inverse agonist may increase the release of neurotransmitters in the brain, whereas other histamine H3 ligands, such as, for example, histamine H3 receptor agonists may inhibit the biosynthesis of histamine, as well as, inhibit the release of neurotransmitters. This suggests that histamine H3 receptor agonists, inverse agonists, and antagonists could mediate neuronal activity. As a result, efforts have been undertaken to develop new therapeutics that target the histamine H3 receptor.
  • U.S. patent application publication no. 2009/0076020 describes the synthesis of a number of cyclopropyl amide derivatives, such as, for example, 4-((trans)-2-[(4- cyclobutylpiperazin-yl)carbonyl]-cyclopropyl ⁇ -benzamide (enantiomer 1; Example 43). Improved processes of making these compounds would be advantageous, especially processes amenable to large scale synthesis.
  • a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product; the type of transformation is limited only by the inherent incompatibility of other functional groups contained in the molecule to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood by one skilled in the art of organic synthesis.
  • amino-protecting group refers to art-recognized moieties capable of attaching to an amino group so as to prevent the amino group from taking place in reactions occurring elsewhere on the molecule to which the amino group is attached.
  • Acceptable amino-protecting groups include but are not limited to, for example, amino-protecting groups described in "Protective Groups in Organic Synthesis", 4 th edition, Wiley Interscience, 2006.
  • the amino-protecting group may be, for example, a urethane type protective group (which is also referred to as a carbamate protective group), which includes but is not limited to, for example, arylalkyloxycarbonyl groups, such as, for example, benzyloxycarbonyl; and alkoxycarbonyl groups, such as, for example, methoxycarbonyl and tert-butoxycarbonyl.
  • a urethane type protective group which is also referred to as a carbamate protective group
  • arylalkyloxycarbonyl groups such as, for example, benzyloxycarbonyl
  • alkoxycarbonyl groups such as, for example, methoxycarbonyl and tert-butoxycarbonyl.
  • the amino-protecting group is tert-butoxycarbonyl.
  • Ci_ 6 alkyl refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 6 carbon atoms.
  • exemplary “Ci_ 6 alkyl” groups include, but are not limited to, for example, methyl; ethyl; propyl; isopropyl; 1-methylpropyl; n-butyl, t-butyl; isobutyl; pentyl; hexyl; and isohexyl.
  • PG is an amino-protecting group; and R is H or a Ci_ 6 alkyl.
  • Ci_ 6 alkyl is selected from methyl, ethyl, propyl, and isopropyl.
  • the amino protecting group is tert-butoxycarbonyl.
  • R is H
  • R is methyl
  • the compounds of formula II, III and IV are compounds of formula Ila, lib, Ilia, Illb, IVa and IVb, respectively:
  • the compounds of formula II, III and IV are selected from formula Ila, formula lib, formula Ilia, formula Illb, formula IVa, and formula IVb.
  • compounds in accordance with formula II, III, or IV may be in the form of a suitable salt, such as, for example, the acetate or dihydrochoride.
  • the compounds of formula IVa and IVb may be in the form of the dihydrochloride salt.
  • Step 1 Compounds in accordance with formula III can be obtained by treating compounds in accordance with formula II with cyclobutanone and a suitable reducing agent, such as, for example, sodium triacetoxyborohydride or sodium cyanoborohydride, in a suitable solvent, such as for example, 1 ,2-dichloroethane, tetrahydrofuran, ethanol, or acetic acid, or a solvent mixture comprising two or more solvents, such as, for example, a solvent mixture comprising ethanol and acetic acid.
  • a suitable reducing agent such as, for example, sodium triacetoxyborohydride or sodium cyanoborohydride
  • Compounds in accordance with formula II are commercially available and include, for example, (i?)-Boc-2-methylpiperazine, which is commercially available from Lanzhou Boc Chemical Co., and N-Boc-piperazine, which is commercially available from Sigma- Aldrich.
  • the compounds in accordance with formula III are not isolated, but instead are carried through to step 2.
  • Compounds in accordance with formula IV can be obtained by treating compounds in accordance with formula III with a suitable reagent to deprotect the amino group, such as for example, an acid, such as for example, hydrochloric acid, trifluoroacetic acid, or sulfonic acid, in a suitable solvent, such as, for example, dioxane, dichloromethane, 2-propanol or a suitable mixture comprising two or more solvents, such as, for example, a solvent mixture comprising 2-propanol and toluene.
  • a suitable reagent such as for example, an acid, such as for example, hydrochloric acid, trifluoroacetic acid, or sulfonic acid
  • a suitable solvent such as, for example, dioxane, dichloromethane, 2-propanol or a suitable mixture comprising two or more solvents, such as, for example, a solvent mixture comprising 2-propanol and toluene.
  • X is CI, Br, or I and LG is CI, Br, I, tosylate, brosylate, nosylate, or mesylate.
  • X is Br.
  • LG is CI.
  • LG is CI, Br, I, or tosylate.
  • X is BR and LG is CI.
  • compounds in accordance with formula VI can be obtained by adding a compound in accordance with formula V, which is dissolved in a suitable solvent, such as, for example, tetrahydrofuran, 2-methyl-tetrahydrofuran, toluene, dichloromethane, or a mixture of two or more thereof, to a solution comprising i) a suitable reducing agent, such as, for example, borane*THF or borane dimethylsulfide in a suitable solvent, such as, for example, tetrahydrofuran, 2-methyl-tetrahydrofuran, toluene, dichloromethane, or a mixture of two or more thereof, and ii) a chiral oxazaborolidine, such as, for example, (i?)-(+)-methyl- CBS-oxazaborolidine (CAS-No. 112022-83-0).
  • a suitable solvent such as, for example, tetrahydrofuran, 2-methyl-tetrahydro
  • compounds in accordance with formula VII can be obtained by treating a compound of formula VI in a suitable first solvent, such as, for example, dichloromethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, or a mixture of two or more thereof, with a phase-transfer catalyst, such as, for example, an ammonium salt (e.g., methyl tributyl ammonium chloride or tetrabutylammonium chloride), a heterocyclic ammonium salt (e.g., l, -dibenzyl-4,4'-bipyridinium dichloride, 1,2,3-trimethylimidazolium methyl sulfate), or a phosphonium salt (e.g., tetrabutylphosphonium chloride or tetraphenylphosphonium chloride), with a suitable base, such as, for example, sodium hydroxide diluted in a suitable second solvent, such as, for example, water.
  • compounds in accordance with formula VII can be obtained by treating a compound of formula VI with a suitable base, such as, for example, sodium hydroxide or lithium hydroxide, in a suitable solvent, such as, for example, methanol, ethanol, tetrahydrofuran, dioxane, water, or a mixture of two or more thereof.
  • a suitable base such as, for example, sodium hydroxide or lithium hydroxide
  • a suitable solvent such as, for example, methanol, ethanol, tetrahydrofuran, dioxane, water, or a mixture of two or more thereof.
  • the base is sodium hydroxide when X is Br and LG is CI.
  • compounds in accordance with formula VI are not isolated, but instead carried through to step 2.
  • compounds in accordance with formula VII are not isolated, but instead carried through to step 3.
  • compounds in accordance with formula VIII can be obtained by preparing a solution of i) a suitable first base, such as, for example, alkyl lithium (e,g., n- hexyl lithium) in a suitable solvent, such as, for example, hexane, and ii) a suitable triCi_ 6 alkyl phosphonoacetate (e.g., triethyl phosphonoacetate, trimethyl phosphonoacetate, and methyl diethylphosphonoacetate) in a suitable solvent, such as, for example, tetrahydrofuran, 2-methyl-tetrahydrofuran, or mixture thereof, and combining therewith a compound in accordance with formula VII in a suitable solvent, such as, for example, tetrahydrofuran, 2- methyl-tetrahydrofuran, or mixture thereof.
  • a suitable first base such as, for example, alkyl lithium (e,g., n- hexyl lithium) in
  • the resulting mixture is further treated with a suitable second base, such as, for example, sodium hydroxide or lithium hydroxide.
  • a suitable second base such as, for example, sodium hydroxide or lithium hydroxide.
  • an unisolated intermediate is formed containing an alkylester, such as, for example, ethyl ester where the free carboxylic acid group of the formula VIII compound is present.
  • the unisolated intermediate that is formed prior to the addition of the second base is isolated.
  • the compound in accordance with formula VIII is purified by recrystallization using a suitable solvent, such as, for example, ethanol, water, toluene, isooctane, or a mixture of two or more thereof.
  • a suitable solvent such as, for example, ethanol, water, toluene, isooctane, or a mixture of two or more thereof.
  • the first base is n-hexyl lithium; the triCi_ 6 alkyl phosphonoacetate is triethylphosphonoacetate; and the second base is sodium hydroxide.
  • Compounds in accordance with formula V are commercially available and include (IS, 2S)-2-(4-bromophenyl)cyclopropanecarboxylic acid, which is commercially available from, for example, BOC Sciences.
  • a compound in accordance with formula IX can be obtained by treating a compound in accordance with formula VIII in a suitable solvent, such as, for example,
  • a suitable metal such as zinc (e.g., zinc dust); a suitable catalyst, such as, for example, bis(tri-t-butylphosphine)palladium(0); and a suitable metal cyanide, such as, for example, zinc-(II)-cyanide.
  • a suitable metal such as zinc (e.g., zinc dust)
  • a suitable catalyst such as, for example, bis(tri-t-butylphosphine)palladium(0)
  • a suitable metal cyanide such as, for example, zinc-(II)-cyanide.
  • compounds in accordance with formula IX are not isolated, but instead carried through to step 5.
  • a compound in accordance with formula la can be obtained by treating a compound in accordance with formula IX in a suitable solvent, such as, for example, water, with a suitable base, such as, for example, sodium hydroxide, and a suitable peroxide, such as, for example, hydrogen peroxide, followed by treatment with a suitable acidic solution, such as, for example, an aqueous solution of sodium hydrogen sulfate.
  • a suitable solvent such as, for example, water
  • a suitable base such as, for example, sodium hydroxide
  • a suitable peroxide such as, for example, hydrogen peroxide
  • a compound in accordance with formula lb can be obtained by treating a compound in accordance with formula la, with a suitable activating agent, such as, for example, 1,1 '- carbonyldiimidazole, in a suitable solvent, such as, for example, tetrahydrofuran, chloroform, dimethylformamide, 2-methyl-tetrahydrofuran, or mixtures of two or more thereof, and subsequently adding a compound in accordance with formula IVa or a suitable salt thereof, such as, for example, the dihydrochloride, and a suitable base, such as, for example, triethylamine or diisopropylethylamine.
  • a suitable activating agent such as, for example, 1,1 '- carbonyldiimidazole
  • a suitable solvent such as, for example, tetrahydrofuran, chloroform, dimethylformamide, 2-methyl-tetrahydrofuran, or mixtures of two or more thereof
  • a compound in accordance with formula lb can be obtained by treating a compound in accordance with formula la, with a compound of formula IVa or a suitable salt thereof, such as, for example, the dihydrochloride, in the presence of a suitable base, such as, for example, N-methylmorpholine, diisopropylethylamine, or triethylamine and a suitable activating agent, such as, for example, 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate, 0-(benzotriazol- 1 -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate, 1,1 '-carbonyldiimidazole, or a mixture of 1- hydroxybenzotriazole and l-ethyl-3-(3-dimethylaminopropyl)carbod
  • a compound in accordance with formula Ic can be obtained by treating a compound in accordance with formula la, with a compound of formula IVb or a suitable salt thereof, such as, for example, the dihydrochloride, in the presence of a suitable base, such as, for example, N-methylmorpholine or diisopropylethylamine, and a suitable activating agent, such as, for example, 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
  • hexafluorophosphate or a mixture of 1-hydroxybenzotriazole and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, in a suitable solvent, such as, for example, dimethylformamide, dimethylsulphoxide, water, or mixture thereof.
  • a suitable solvent such as, for example, dimethylformamide, dimethylsulphoxide, water, or mixture thereof.
  • a compound in accordance with formula Ic can be obtained by treating a compound in accordance with formula la, with a suitable activating agent, such as, for example, 1,1 '-carbonyldiimidazole, in a suitable solvent, such as, for example, tetrahydrofuran, chloroform, dimethylformamide, 2-methyl-tetrahydrofuran, or mixture of two or more thereof, and subsequently adding a compound in accordance with formula IVb or a suitable salt thereof, such as, for example, the dihydrochloride, and a suitable base, such as, for example, triethylamine or diisopropylethylamine.
  • a suitable activating agent such as, for example, 1,1 '-carbonyldiimidazole
  • One aspect of the invention is a compound of formula la, or a pharmaceutically acceptable salt thereof,
  • the solvents used in preparing the example compounds were commercial anhydrous grades and were used without further drying or purification.
  • MeTHF 2-methyl-tetrahydrofuran; br.: broad; Bu: butyl; calcd: calculated; Celite® : brand of diatomaceous earth filtering agent, registered trader of Celite Corporation; d: doublet; dd: doublet of doublet; ddd: doublet of doublet of doublet; dddd: doublet of doublet of doublet of doublet; DABCO: l,4-diazabicyclo[2.2.2]octane; DCE: dichloroethane; DCM:
  • DMEA dimethyl ethylamine; dq: doublet of quartet; dt: doublet of triplet; EDC: l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride; ESI: electrospray ion source; EtOAc: ethyl acetate; EtOH: ethanol; g: gram; h: hour(s); HBTU: 0-Benzotriazole-N,N,N',N'- tetramethyl-uronium-hexafluoro-phosphate; HOBT: N-Hydroxybenzotriazole; HRMS: high resolution mass spectrometry; iPrOH: iso-propanol; MeOH: methanol; mg: milligram;
  • MgS0 4 anhydrous magnesium sulfate (drying agent); MPLC: medium pressure liquid chromatography; MTBE: methyl tert-butyl ether; NaHC0 3 : sodium bicarbonate; NH 4 C1: ammonium chloride; q: quartet; quin: quintet; rt: room temperature; sat: saturated; t: triplet; TEA: triethylamine; tBuOH: tert-butanol; td: triplet of doublet; TFA: trifluoroacetic acid; and THF: tetrahydrofuran.
  • MPLC medium pressure liquid chromatography
  • MTBE methyl tert-butyl ether
  • NaHC0 3 sodium bicarbonate
  • NH 4 C1 ammonium chloride
  • q quartet
  • quin quintet
  • rt room temperature
  • sat saturated
  • t triplet
  • TEA triethylamine
  • tBuOH
  • the mass spectra were recorded on a Waters MS consisting of an Alliance 2795 (LC (mobile phase: 5-90% B; A: H 2 0 with 0.1% formic acid, B: CH 3 CN, 8.6 min run) on Xbridge C18 column, 3.0 x 50mm, 2.5 ⁇ particale size) and Waters Micromass ZQ detector at 120 °C.
  • the mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode. The mass spectrometer was scanned between m/z 120-800.
  • ESI electrospray ion source
  • Example 2 obtained in a 2-MeTHF solution can be stored at 5 °C for 140 h or used directly in the next synthetic step.
  • Hexyl lithium in hexane (21 L, 48.3 moles, 2.3 M) was added at a rate to maintain tinner below 0°C.
  • the charging vessel was rinsed with 2-MeTHF (3 L) and the reaction solution was left stirring at °C.
  • Example 2 as a 2-MeTHF solution (33.6 moles, 30 L) was added during 20 min.
  • the 2-MeTHF solution was diluted with EtOH (14.5 L) at °C and H 2 0 (16 L) was added over 20 min.
  • the reaction mixture was cooled to °C over 6 h and left stirring for at least 1 h. Additional H 2 0 (8 L) was added during 40 min. and the product was filtered off and washed with cold H 2 0 (10 L).
  • Example 3 (21.5 moles, 84%> w/w), 64%> yield over four steps from 7.84 kg l-(4-bromo-phenyl)-2- chloro-ethanone (33.6 moles).
  • Example 3 (29.8 moles, 97%> w/w), 44% yield over four steps from 7.84 + 7.93 kg l-(4-bromo-phenyl)-2-chloro-ethanone (67.5 moles).
  • Example 3 (3.7 kg, 14.9 moles, 97% w/w) and zinc-dust (98%+, ⁇ 10um) (99 g, 1.51 moles) were mixed with DMF (13.5 L) and the slurry was stirred at °C. The mixture was inerted and left with N 2 pressure of 0.1-0.2 bar. Bis(tri-t- butylphosphine)palladium (0) (27.5 g, 0.054 moles) was added to the slurry, and the vessel was inerted and left with N 2 pressure of 0.1-0.2 bar.
  • Example 4 (2.24 kg, 11.2 moles, 93.2% w/w), 75% yield.
  • Example 4 (4.46 kg, 22.0 moles, 92.5% w/w) was mixed in H 2 0 (40 L) at
  • the H 2 0 phase was extracted with toluene (5.5 L) at °C.
  • the organic phase was combined with a second batch, started with (i?)-Boc-2-methylpiperazine (300 g, 1.47 moles, 98% w/w).
  • the obtained toluene solution with the intermediate can be stored at 5 °C for several days.
  • the toluene solution was diluted with 2-propanol (2 L) at
  • Example 6 (620 g, 2.63 moles, 96.3%> w/w), 83% yield.
  • the organic phase was cooled to °C and extracted with 10% H 3 PO 4 in H 2 0 (charged until pH 2.5, 110 mL). The lower aq. phase was collected and the remaining organic phase was re-extracted withl0% H 3 PO 4 in H 2 0 (50 mL).
  • the combined aq. phases were basified to pH >12 with 5M KOH and extracted with MeTHF twice (200 mL, 50 mL).
  • the combined organic phases were extracted with brine (50 mL) and filtered to remove inorganic salts.
  • the assay of Example 7 in the organic phase was determined by 1H NMR and the volume of the organic phase was reduced to 6 relative volumes (14.4 g of Example 7, 86 mL).
  • N-Boc-piperazine 46 g, 0.25 moles
  • SAFC SAFC
  • EtOH 415 mL
  • Acetic acid 140 mL
  • cyclobutanone 26.5 g, 0.37 moles
  • EtOH was distilled off under vac proximately 650 mL.
  • the water phase was extracted with toluene ( and the obtained organic phase was concentrated under vacuum at mately 250 mL.
  • the toluene solution was diluted with 2-propanol (14 d H 2 0 (2.2 mL, 0.12 moles) was added.
  • Example 8 (0.20 moles, 95.9% w/w), 80 % yield.
  • Example 5 (5.52 g, 26.7 mmoles, 99.1% w/w) and Example 8 (6.07 g, 28.0 mmoles, 98.40% w/w) were mixed in DMSO (82mL) at N-Methylmorpholine (2.94 mL, 27.2 mmoles) was added over 5 min.
  • the charging vessel was rinsed with DMSO (2.8 mL).
  • HOBt/NMM solution (1.80 g, 2.66 mmoles, 20%> w/w) was added in one portion.
  • the charging vessel was rinsed with DMSO (2.8 mL).
  • EDCI x HC1 (7.16 g, 38.0 mmoles) was added over 10 min.
  • the chiral purity of the product was analyzed on a chiral column with UV-detection (250 nm) using isocratic method (mobile phase: Heptane/EtOH (80/20) + 0.1% Diethylamine) on Chiralpak AD-H, 4.6 x 150mm, giving an enantiomeric purity of >99% ee.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Anesthesiology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Child & Adolescent Psychology (AREA)
  • Psychology (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Epoxy Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/SE2011/050171 2010-02-18 2011-02-17 Processes for making cyclopropyl amide derivatives and intermediates associated therewith Ceased WO2011102794A1 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
KR20127024174A KR20130004296A (ko) 2010-02-18 2011-02-17 시클로프로필 아미드 유도체의 제조 방법 및 그와 관련된 중간체
SG2012059473A SG183274A1 (en) 2010-02-18 2011-02-17 Processes for making cyclopropyl amide derivatives and intermediates associated therewith
JP2012553849A JP2013520413A (ja) 2010-02-18 2011-02-17 シクロプロピルアミド誘導体及びそれに関連する中間体の製造方法
CA 2790040 CA2790040A1 (en) 2010-02-18 2011-02-17 Processes for making cyclopropyl amide derivatives and intermediates associated therewith
RU2012139082/04A RU2012139082A (ru) 2010-02-18 2011-02-17 Способы получения производных циклопропиламида и связанных с ними промежуточных соединений
AU2011218491A AU2011218491C1 (en) 2010-02-18 2011-02-17 Processes for making cyclopropyl amide derivatives and intermediates associated therewith
HK13105221.5A HK1178142B (en) 2010-02-18 2011-02-17 Processes for making cyclopropyl amide derivatives and intermediates associated therewith
BR112012020782A BR112012020782A2 (pt) 2010-02-18 2011-02-17 composto, e, processo para preparar um composto
MX2012009473A MX2012009473A (es) 2010-02-18 2011-02-17 Procesos para preparar derivados de ciclopropilamidas e intermedios asociados con estas.
EP20110744974 EP2536685B1 (en) 2010-02-18 2011-02-17 Processes for making cyclopropyl amide derivatives and intermediates associated therewith
NZ60211011A NZ602110A (en) 2010-02-18 2011-02-17 Processes for making cyclopropyl amide derivatives and intermediates associated therewith
US13/579,605 US9012452B2 (en) 2010-02-18 2011-02-17 Processes for making cyclopropyl amide derivatives and intermediates associated therewith
ES11744974.4T ES2541857T3 (es) 2010-02-18 2011-02-17 Procesos para preparar ciclopropilamidas e intermedios asociados con estas
CN201180019632.7A CN103168027B (zh) 2010-02-18 2011-02-17 制备环丙基酰胺衍生物的方法及其相关中间体
IL221431A IL221431A (en) 2010-02-18 2012-08-13 Processes for the preparation of affluent cyclopropyl derivatives and their intermediates

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US30558310P 2010-02-18 2010-02-18
US61/305,583 2010-02-18

Publications (1)

Publication Number Publication Date
WO2011102794A1 true WO2011102794A1 (en) 2011-08-25

Family

ID=44370080

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/SE2011/050172 Ceased WO2011102795A1 (en) 2010-02-18 2011-02-17 New crystalline form of a cyclopropyl benzamide derivative
PCT/SE2011/050171 Ceased WO2011102794A1 (en) 2010-02-18 2011-02-17 Processes for making cyclopropyl amide derivatives and intermediates associated therewith

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/SE2011/050172 Ceased WO2011102795A1 (en) 2010-02-18 2011-02-17 New crystalline form of a cyclopropyl benzamide derivative

Country Status (19)

Country Link
US (2) US20110201623A1 (enExample)
EP (2) EP2536702A4 (enExample)
JP (3) JP2013520414A (enExample)
KR (2) KR20130002316A (enExample)
CN (2) CN103168027B (enExample)
AR (2) AR080204A1 (enExample)
AU (2) AU2011218492B2 (enExample)
BR (2) BR112012020629A2 (enExample)
CA (2) CA2790040A1 (enExample)
CL (2) CL2012002259A1 (enExample)
CO (1) CO6592109A2 (enExample)
ES (1) ES2541857T3 (enExample)
IL (1) IL221431A (enExample)
MX (2) MX336333B (enExample)
NZ (2) NZ601920A (enExample)
RU (2) RU2012136148A (enExample)
SG (3) SG182732A1 (enExample)
TW (2) TWI520945B (enExample)
WO (2) WO2011102795A1 (enExample)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8993577B2 (en) 2009-02-20 2015-03-31 Astrazeneca Ab Cyclopropyl amide derivatives
US9012452B2 (en) 2010-02-18 2015-04-21 Astrazeneca Ab Processes for making cyclopropyl amide derivatives and intermediates associated therewith
US9029381B2 (en) 2007-08-22 2015-05-12 Astrazeneca Ab Cyclopropyl amide derivatives

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2012009537A (es) * 2010-02-18 2012-08-31 Astrazeneca Ab Formas solidas que comprenden un derivado de ciclopropilamida.
FR3003466B1 (fr) * 2013-03-22 2015-08-07 Servier Lab Utilisation du 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1h)-yl]propoxy}benzamide pour le traitement des douleurs neuropathiques
CN111718281A (zh) * 2013-03-22 2020-09-29 默克专利有限公司 用于制备有机电致发光器件用材料的合成结构单元
CN103342655A (zh) * 2013-07-02 2013-10-09 扬州大学 取代乙二酮双苯胺希夫碱合成取代酰胺的新方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090076020A1 (en) * 2007-08-22 2009-03-19 Astrazeneca Ab Cyclopropyl Amide Derivatives 978
US20100216812A1 (en) * 2009-02-20 2010-08-26 Astrazeneca Ab Cyclopropyl Amide Derivatives

Family Cites Families (96)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL297170A (enExample) 1963-04-04 1900-01-01
NL128365C (enExample) 1963-11-05
US3449427A (en) 1965-06-03 1969-06-10 Smithkline Corp Aminocyclopropane derivatives of 5h-dibenzo(a,d)cycloheptenes
US3697506A (en) 1970-08-07 1972-10-10 Pfizer Crystalline alkali metal salts of {60 -carboxybenzylpenicillin and process therefor
US3686335A (en) 1970-12-21 1972-08-22 Smith Kline French Lab 5-vinyl-5h-di benzo(a,d)cycloheptenes
US4432987A (en) * 1982-04-23 1984-02-21 Pfizer Inc. Crystalline benzenesulfonate salts of sultamicillin
US4547505A (en) 1983-03-25 1985-10-15 Degussa Aktiengesellschaft N-Phenyl-N-'-cycloalkylalkanoylpiperazine useful as analgetics and process for its production
CS244821B2 (en) 1983-06-16 1986-08-14 Boehringer Ingelheim Ltd Production method of new substituted phenylalkyl(piperazinyl or homopiperazinyle)-prpylureas or thioureas
DE3418167A1 (de) 1984-05-16 1985-11-21 Bayer Ag, 5090 Leverkusen Verwendung von amiden zur verbesserung der kulturpflanzen-vertraeglichkeit von herbizid wirksamen heteroaryloxyacetamiden
DE3600288A1 (de) 1986-01-08 1987-07-16 Bayer Ag Verwendung von amiden zur verbesserung der kulturpflanzen-vertraeglichkeit von herbizid wirksamen sulfonylharnstoff-derivaten
DE3618004A1 (de) 1986-05-28 1987-12-03 Bayer Ag Verwendung von amiden zur verbesserung der kulturpflanzen-vertraeglichkeit von herbizid wirksamen sulfonyliso(thio)-harnstoff-derivaten
CA2071897A1 (en) 1989-12-28 1991-06-29 Richard A. Glennon Sigma receptor ligands and the use thereof
CA2033390A1 (en) 1989-12-29 1991-06-30 Susumu Nakagawa 2-(2-cyclopropylpyrrolidin-4-ylthio) carbapenem derivatives
HUT66301A (en) 1991-08-22 1994-11-28 Monsanto Co Safening herbicidal pyrazolylsufonylureas
DE4131139A1 (de) 1991-09-19 1993-03-25 Bayer Ag Verfahren zur herstellung von 1-fluor-cyclopropan-1-carbonsaeure
ES2157254T3 (es) 1993-03-12 2001-08-16 Upjohn Co Ceftiofur (acido libre) cristalino.
BR9509760A (pt) 1994-11-23 1998-06-30 Neurogen Corp Composto
US5604253A (en) 1995-05-22 1997-02-18 Merck Frosst Canada, Inc. N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors
US5859246A (en) 1997-01-30 1999-01-12 Neurogen Corporation 1-phenyl-4-benzylpiperazines: dopamine receptor subtype specific ligands
US6124299A (en) 1997-02-24 2000-09-26 Zymogenetics, Inc. Calcitonin mimetics
US6160134A (en) 1997-12-24 2000-12-12 Bristol-Myers Squibb Co. Process for preparing chiral cyclopropane carboxylic acids and acyl guanidines
UA59433C2 (uk) 1998-01-27 2003-09-15 Авентіс Фармасьютікалс Продактс Інк. ЗАМІЩЕНІ ОКСОАЗАГЕТЕРОЦИКЛІЧНІ ІНГІБІТОРИ ФАКТОРА Хa ТА ПРОМІЖНІ СПОЛУКИ ДЛЯ ЇХ ОТРИМАННЯ
US6268367B1 (en) 1998-02-23 2001-07-31 Zymogenetics, Inc. Piperazine derivatives for treating bone deficit conditions
AU4531499A (en) 1998-06-26 2000-01-17 Chugai Seiyaku Kabushiki Kaisha Fine powder of l-alpha-aminoadipic acid derivative, oral solid preparations containing the same, and method for treatment of bulk powders
US6284761B1 (en) 1999-01-08 2001-09-04 Neurogen Corporation 1-phenyl-4-(1-[2-aryl]cyclopropyl)methylpiperazines: dopamine receptor ligands
CA2359989A1 (en) 1999-01-08 2000-07-13 Xiaoyan Zhang 1-phenyl-4-(1-[2-aryl]cyclopropyl) methylpiperazines: dopamine receptor ligands
GB9913083D0 (en) * 1999-06-04 1999-08-04 Novartis Ag Organic compounds
US6936602B1 (en) 1999-06-16 2005-08-30 Takeda Chemical Industries, Ltd. Benzazepine derivatives, process for the preparation of the same and uses thereof
WO2001022963A1 (en) 1999-09-27 2001-04-05 Merck & Co., Inc. Method of preventing osteoporosis
SK9742002A3 (en) 2000-01-07 2003-02-04 Transform Pharmaceuticals Inc High-throughput formation, identification, and analysis of diverse solid-forms
US6521619B2 (en) * 2000-06-29 2003-02-18 Icos Corporation Aryl phenylcyclopropyl sulfide derivatives and their use as cell adhesion inhibiting anti-inflammatory and immune suppressive agents
AU2001268724B2 (en) 2000-06-29 2005-06-16 Abbott Laboratories Aryl phenycyclopropyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents
KR20030024799A (ko) 2000-07-20 2003-03-26 뉴로젠 코포레이션 캡사이신 수용체 리간드
KR20030062447A (ko) 2000-12-25 2003-07-25 아지노모토 가부시키가이샤 광학 활성 할로하이드린 화합물의 제조방법
BR0207526A (pt) 2001-02-23 2004-03-09 Merck & Co Inc Composto, composição farmacêutica, e, métodos para o tratamento da dor, da enxaqueca, depressão, ansiedade, esquizofrenia, doença de parkinson ou derrame cerebral
AU2002344951A1 (en) 2001-07-02 2003-01-21 Boehringer Ingelheim International Gmbh Substituted piperazine and diazepanes as histamine h3 receptor agonists
CA2456754A1 (en) 2001-08-08 2003-02-20 Yuji Iizawa Benzazepine derivative, process for producing the same, and use
JP2005508321A (ja) * 2001-09-26 2005-03-31 メルク　エンド　カムパニー　インコーポレーテッド 結晶形態のエルタペネムナトリウム
AU2002363236A1 (en) * 2001-10-30 2003-05-12 Millennium Pharmaceuticals, Inc. Compounds, pharmaceutical compositions and methods of use therefor
US6861432B2 (en) 2001-11-23 2005-03-01 Schering Aktiengesellschaft Piperazine derivatives that destabilize androgen receptors
US20050113309A1 (en) 2002-03-22 2005-05-26 Aeri Kim Crystalline forms(2s)-n-5[amino(imino)methyl]-2-thienylmethyl-1-(2r)-2[(carboxymethyl) amino]-3,3-diphenylpropanoyl-2-pyrrolidinecarboxamide nh2o
WO2003103666A2 (en) 2002-06-07 2003-12-18 Altana Pharma Ag Novel 4,5-dihydro-imidazo[4,5,1-ij]quinolin-6-ones
US20040209858A1 (en) * 2002-10-22 2004-10-21 Bennani Youssef L. Cycloalkylamides and their therapeutic applications
US20040077618A1 (en) 2002-10-22 2004-04-22 Bennani Youssef L. Cycloalkylamides and their therapeutic applications
JPWO2004046110A1 (ja) 2002-11-15 2006-03-16 アステラス製薬株式会社 メラニン凝集ホルモン受容体拮抗剤
WO2004055010A2 (en) 2002-12-13 2004-07-01 Smithkline Beecham Corporation Cyclopropyl compounds as ccr5 antagonists
MXPA05011352A (es) 2003-04-23 2005-11-28 Glaxo Group Ltd Derivados de piperazina y su uso para el tratamiento de enfermedades neurologicas y psiquiatricas.
DE602004029242D1 (en) 2003-05-01 2010-11-04 Bristol Myers Squibb Co Pyrazolamidverbindungen
TWI339206B (en) 2003-09-04 2011-03-21 Vertex Pharma Compositions useful as inhibitors of protein kinases
WO2005058884A2 (en) 2003-12-15 2005-06-30 Japan Tobacco Inc. Cyclopropane compounds and pharmaceutical use thereof
BRPI0418939A (pt) 2004-07-06 2008-04-08 Xenon Pharmaceuticals Inc derivados de nicotinamida e sua utilização como agentes terapêuticos
TW200621760A (en) 2004-09-09 2006-07-01 Mitsubishi Pharma Corp 2-morpholino-4-pyrimidone compound
CA2581179A1 (en) 2004-09-29 2006-04-06 Mitsubishi Pharma Corporation 6-(pyridinyl)-4 pyrimidone derivatives as tau protein kinase 1 inhibitors
DK1802307T3 (da) 2004-10-15 2008-06-30 Glaxo Group Ltd Pyrrolidinderivater som histamin-receptor-ligander
WO2006071730A1 (en) 2004-12-27 2006-07-06 Astrazeneca Ab Pyrazolone compounds as metabotropic glutamate receptor agonists for the treatment of neurological and psychiatric disorders
EP1844052A1 (en) * 2005-01-26 2007-10-17 Pharmacia & Upjohn Company LLC Thieno[2,3-d]pyrimidine compounds as inhibitors of adp-mediated platelets aggregation
ATE517867T1 (de) 2005-02-15 2011-08-15 Glaxo Group Ltd Verbindungen, die den glutamatrezeptor verstärken und anwendungen davon in der medizin
AU2006215080B2 (en) 2005-02-17 2011-03-10 Astellas Pharma Inc. Pyridyl non-aromatic nitrogenated heterocyclic-1-carboxylate ester derivative
JP2008534488A (ja) 2005-03-25 2008-08-28 ファルマシア・アンド・アップジョン・カンパニー・エルエルシー 血小板凝集阻害剤としての４−ピペラジニルチエノ［２，３−ｄ］ピリミジン化合物
JP2008534573A (ja) 2005-03-28 2008-08-28 ファルマシア・アンド・アップジョン・カンパニー・エルエルシー 血小板凝集阻害剤としての４−ピペラジノチエノ［２，３−ｄ］ピリミジン化合物
CA2603041A1 (en) 2005-03-28 2006-10-05 Pharmacia & Upjohn Company Llc 4-piperazinylthieno [2, 3-d] pyrimidine compounds as platelet aggregation inhibitors
WO2006103545A1 (en) 2005-03-28 2006-10-05 Pharmacia & Upjohn Company Llc 4-piperazinylthieno [2,3-d] pyrimidine compounds as platelet aggregation inhibitors
WO2007011623A1 (en) 2005-07-15 2007-01-25 Schering Corporation Quinazoline derivatives useful in cancer treatment
TW200740779A (en) 2005-07-22 2007-11-01 Mitsubishi Pharma Corp Intermediate compound for synthesizing pharmaceutical agent and production method thereof
WO2007016496A2 (en) 2005-08-02 2007-02-08 Neurogen Corporation Dipiperazinyl ketones and related analogues
KR101336106B1 (ko) * 2005-09-16 2013-12-05 얀센 파마슈티카 엔.브이. 히스타민 ｈ3 수용체의 조절제로서 사이클로프로필 아민
US8158673B2 (en) 2005-10-27 2012-04-17 Pfizer Inc. Histamine-3 receptor antagonists
EP1951699B1 (en) 2005-10-31 2012-10-10 Janssen Pharmaceutica NV Processes for the preparation of cyclopropyl-amide derivatives
CN101365686A (zh) 2005-12-21 2009-02-11 沃泰克斯药物股份有限公司 作为离子通道调节剂的杂环衍生物
WO2007076140A2 (en) 2005-12-23 2007-07-05 University Of Cincinnati Treatment methods employing histamine h3 receptor antagonists, including betahistine
RU2008132966A (ru) 2006-01-13 2010-02-20 Ф.Хоффманн-Ля Рош Аг (Ch) Производные циклогексилпиперазинилметанона и их применение в качестве модуляторов гистамин н3 рецептора
CN101384581B (zh) 2006-02-17 2013-09-18 弗·哈夫曼-拉罗切有限公司 作为5ht2/d3调节剂的苯甲酰基-哌啶衍生物
JP2009528240A (ja) 2006-03-01 2009-08-06 セメンテク・ピーティーワイ・リミテッド メーソンリー部材用マトリックス及びその製造方法
JP2009132621A (ja) 2006-03-13 2009-06-18 Ajinomoto Co Inc シクロプロピルアミド化合物の製造方法
EP2004619A1 (en) 2006-03-23 2008-12-24 Amgen Inc. 1-phenylsulfonyl-diaza heterocyclic amide compounds and their uses as modulators of hydroxsteroid dehydrogenases
US7834190B2 (en) 2006-05-26 2010-11-16 Kaneka Corporation Process for production of optically active-3-amino-2-hydroxypropionic cyclopropylamide derivatives and salts thereof
US9108948B2 (en) * 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
KR20090024811A (ko) 2006-06-23 2009-03-09 아보트 러보러터리즈 히스타민 ｈ3 수용체 조절제로서의 사이클로프로필 아민 유도체
JP2009541460A (ja) 2006-07-03 2009-11-26 ベレナギング ヴォー クリスタラク ホガー オンダーヴェイル ヴェーテンザパーリク オンダージーク エン パシェンテンゾーク ヒスタミンｈ４受容体と相互作用する縮合二環式化合物
GB0615620D0 (en) * 2006-08-05 2006-09-13 Astrazeneca Ab A process for the preparation of optically active intermediates
WO2008024284A2 (en) 2006-08-21 2008-02-28 Merck & Co., Inc. Sulfonylated piperazines as cannabinoid-1 receptor modulators
TW200828371A (en) * 2006-09-21 2008-07-01 Matsushita Electric Industrial Co Ltd Chip-type filter
DE102006056526A1 (de) 2006-11-30 2008-06-05 Archimica Gmbh Verfahren zur stereoselektiven Synthese von chiralen Epoxiden durch ADH-Reduktion von alpha-Abgangsgruppen-substituierten Ketonen und Cyclisierung
US7737149B2 (en) 2006-12-21 2010-06-15 Astrazeneca Ab N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide and salts thereof
WO2008147864A2 (en) 2007-05-22 2008-12-04 Xenon Pharmaceuticals Inc. Methods of using piperazine compounds in treating sodium channel-mediated diseases or conditions
WO2008150364A1 (en) 2007-05-23 2008-12-11 Merck & Co., Inc. Cyclopropyl pyrrolidine orexin receptor antagonists
CA2688585A1 (en) 2007-06-11 2008-12-18 F. Hoffmann-La Roche Ag Cyclohexyl derivatives
KR101178674B1 (ko) 2007-10-04 2012-08-30 에프. 호프만-라 로슈 아게 사이클로프로필 아릴 아마이드 유도체 및 이의 용도
CL2009000004A1 (es) 2008-01-15 2010-02-19 Lilly Co Eli Forma cristalina de r-2-(4-ciclopropansulfonil-fenil)-n-pirazin-2-il-3-(tetrahidropiran-4-il)-propionamida; composicion farmaceutica que comprende a dicha forma cristalina; y uso para el tratamiento de diabetes o hiperglicemia.
DE102008049371A1 (de) 2008-03-06 2009-09-10 Mühlbauer Ag Einrichtung mit einem RFID-Transponder in einem elektrisch leitfähigen Gegenstand und Herstellungsverfahren hierfür
JP2011525478A (ja) * 2008-03-20 2011-09-22 フォレスト・ラボラトリーズ・ホールディングス・リミテッド ステアロイル−ＣｏＡデサチュラーゼの阻害剤としての新規ピペラジン誘導体
US8691804B2 (en) * 2008-05-08 2014-04-08 Evotec Ag Azetidines and cyclobutanes as histamine H3 receptor antagonists
US8586607B2 (en) 2008-07-28 2013-11-19 Syddansk Universitet Compounds for the treatment of metabolic diseases
CN101462980B (zh) 2009-01-05 2013-01-09 扬州天辰精细化工有限公司 2，6—二氟苯甲酰胺的工业化生产方法
MX2012009537A (es) 2010-02-18 2012-08-31 Astrazeneca Ab Formas solidas que comprenden un derivado de ciclopropilamida.
US20110201623A1 (en) 2010-02-18 2011-08-18 Uczynski Michael A Crystalline Form Of A Cyclopropyl Benzamide Derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090076020A1 (en) * 2007-08-22 2009-03-19 Astrazeneca Ab Cyclopropyl Amide Derivatives 978
US20100216812A1 (en) * 2009-02-20 2010-08-26 Astrazeneca Ab Cyclopropyl Amide Derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2536685A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9029381B2 (en) 2007-08-22 2015-05-12 Astrazeneca Ab Cyclopropyl amide derivatives
US8993577B2 (en) 2009-02-20 2015-03-31 Astrazeneca Ab Cyclopropyl amide derivatives
US9012452B2 (en) 2010-02-18 2015-04-21 Astrazeneca Ab Processes for making cyclopropyl amide derivatives and intermediates associated therewith

Also Published As

Publication number Publication date
KR20130004296A (ko) 2013-01-09
AU2011218491B2 (en) 2014-11-06
MX2012009473A (es) 2012-09-12
RU2012139082A (ru) 2014-03-27
AR080204A1 (es) 2012-03-21
TW201136897A (en) 2011-11-01
CA2790040A1 (en) 2011-08-25
AU2011218491A1 (en) 2012-10-04
WO2011102795A1 (en) 2011-08-25
SG10201501226VA (en) 2015-04-29
IL221431A (en) 2015-11-30
KR20130002316A (ko) 2013-01-07
TW201144272A (en) 2011-12-16
CL2012002286A1 (es) 2013-01-25
US9012452B2 (en) 2015-04-21
JP2016006103A (ja) 2016-01-14
AU2011218492B2 (en) 2014-11-13
CN102869651A (zh) 2013-01-09
NZ602110A (en) 2014-09-26
BR112012020629A2 (pt) 2018-06-19
MX2012009480A (es) 2012-09-12
EP2536685B1 (en) 2015-04-08
CN103168027B (zh) 2015-08-26
AU2011218492A1 (en) 2012-08-23
CN103168027A (zh) 2013-06-19
NZ601920A (en) 2014-08-29
BR112012020782A2 (pt) 2016-05-03
EP2536702A1 (en) 2012-12-26
SG182732A1 (en) 2012-08-30
EP2536702A4 (en) 2013-07-10
US20110201623A1 (en) 2011-08-18
HK1178142A1 (en) 2013-09-06
JP2013520414A (ja) 2013-06-06
MX336333B (es) 2016-01-15
AU2011218491C1 (en) 2015-05-14
JP2013520413A (ja) 2013-06-06
US20130172560A1 (en) 2013-07-04
EP2536685A1 (en) 2012-12-26
AR080205A1 (es) 2012-03-21
IL221431A0 (en) 2012-10-31
TWI494301B (zh) 2015-08-01
ES2541857T3 (es) 2015-07-27
TWI520945B (zh) 2016-02-11
CO6592109A2 (es) 2013-01-02
CL2012002259A1 (es) 2012-11-30
EP2536685A4 (en) 2013-07-10
RU2012136148A (ru) 2014-03-27
SG183274A1 (en) 2012-09-27
CA2788444A1 (en) 2011-08-25

Similar Documents

Publication Publication Date Title
AU2011218491C1 (en) Processes for making cyclopropyl amide derivatives and intermediates associated therewith
Wang et al. Recent approaches for asymmetric synthesis of α-amino acids via homologation of Ni (II) complexes
CA2776407C (en) Method of preparing sitagliptin and intermediates used therein
KR102396059B1 (ko) 신규 화합물 및 이의 제조방법
WO2012025944A2 (en) Sitagliptin, salts and polymorphs thereof
US20230227459A1 (en) Method for producing 3,6-disubstituted-imidazo[1,2-b]pyridazine derivative
CA3188344A1 (en) Preparation of a pyrimidinyl-3,8-diazabicyclo[3.2.1]octanylmethanone derivative and salt thereof
EP3280721B1 (en) Process for preparation of nitrogen mustard derivatives
AU2017381739A1 (en) New picolinic acid derivatives and their use as intermediates
US20180079715A1 (en) Method for producing alkylamine derivative and its production intermediate of alkylamine derivative
HK1178142B (en) Processes for making cyclopropyl amide derivatives and intermediates associated therewith
Chen et al. An efficient reduction of N-substituted carbonylimidazolides into formamides by NaBH4
KR20160002822A (ko) Bace1 억제제의 합성
WO2005000810A1 (ja) 含窒素複素環化合物の製造方法
WO2025125353A1 (en) Method of preparation of zavegepant, synthesis intermediates of zavegepant and methods of preparation thereof
EP4330229A1 (en) Method for producing pyrrolidine compound
HK40002783A (en) New compound and process
HK40002783B (en) New compound and process
JP2004196697A (ja) ピペラジン誘導体の製造方法

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: 11744974

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 221431

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2790040

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: MX/A/2012/009473

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 7161/DELNP/2012

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2012002286

Country of ref document: CL

Ref document number: 2012553849

Country of ref document: JP

Ref document number: 12140269

Country of ref document: CO

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2011744974

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2011218491

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 20127024174

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2012139082

Country of ref document: RU

ENP Entry into the national phase

Ref document number: 2011218491

Country of ref document: AU

Date of ref document: 20110217

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 13579605

Country of ref document: US

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112012020782

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112012020782

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20120817