WO2000040560A1 - Aminoalcohol derivatives and their use as beta 3 adrenergic agonists - Google Patents

Aminoalcohol derivatives and their use as beta 3 adrenergic agonists Download PDF

Info

Publication number
WO2000040560A1
WO2000040560A1 PCT/JP1999/007203 JP9907203W WO0040560A1 WO 2000040560 A1 WO2000040560 A1 WO 2000040560A1 JP 9907203 W JP9907203 W JP 9907203W WO 0040560 A1 WO0040560 A1 WO 0040560A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydroxy
ammo
phenyl
mixture
alkyl
Prior art date
Application number
PCT/JP1999/007203
Other languages
French (fr)
Inventor
Kiyoshi Taniguchi
Minoru Sakurai
Takeshi Kato
Naoaki Fujii
Kenichi Washizuka
Yasuyo Tomishima
Hisashi Takasugi
Yutaka Kohno
Nobuhiro Yamamoto
Naoko Tanimura
Hirohumi Ishikawa
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
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
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to EP99961305A priority Critical patent/EP1140849A1/en
Priority to JP2000592269A priority patent/JP2002534415A/en
Publication of WO2000040560A1 publication Critical patent/WO2000040560A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/20—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • 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
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to new aminoalcohol derivatives and salts thereof.
  • new aminoalcohol derivatives and salts thereof which act as selective j33 adrenergic receptor agonists and therefore have gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence and anti-pollakiuria activities, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to a method for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer caused by non steroidal anti-inflammatory drugs, or the like;
  • One object of this invention is to provide new and useful aminoalcohol derivatives and salts thereof which have gut selective sympathomimetic, anti-ulcerous, lipolytic, anti-urinary incontinence and anti-pollakiuria activities.
  • Another object of this invention is to provide processes for the preparation of said aminoalcohol derivatives and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said aminoalcohol derivatives and salts thereof.
  • Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in human beings or animals, using said aminoalcohol derivatives and salts thereof.
  • X ⁇ _ is bond or -OCH 2 - ⁇
  • X 2 is -(CH2- n -, in which n is 1, 2 or 3;
  • X3 is bond, -0-, -S-, -OCH 2 * or -NH-
  • R ,1 x is phenyl or pyridyl, each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, halogen, amino, [ (lower) alkylsulfonyl] amino, nitro, benzyloxycarbonylamino and benzyloxy; R is hydrogen, (lower) alkoxycarbonyl, benzyl or benzyloxycarbonyl ;
  • R is hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl or halo (lower ) alkyl;
  • R ⁇ is aryl or an unsaturated heterocyclic group containing nitrogen, each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, halo ( lower) alkyl, halogen, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, cyano, carboxy, (lower) alkoxycarbonyl, lower alkanoyl, carbamoyl, (mono or di) (lower) - alkylcarbamoyl, [ (lower) alkylsulfonyl] carbamoyl, amino, nitro, ureido, [ (lower) alkylcarbonyl] amino, [ (lower ) alkylsulfonyl] amino and (arylsulfonyl) amino, and a salt thereof.
  • substituent selected from the group consisting of hydroxy, lower alkyl, lower alkoxy,
  • the object compound [I] or a salt thereof can be prepared by the following processes.
  • Rfj and R are each ammo protective group, Q is protected hydroxy
  • X is halogen, and is aryl or an unsaturated heterocyclic group containing nitrogen, each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, halo (lower) alkyl, halogen, hydroxy (lower) alkyl, (lower ) alkoxycarbonyl, lower alkanoyl, carbamoyl, (mono or di) (lower) - alkylcarbamoyl, [ (lower) alkylsulfonyl ] carbamoyl, amino nitro, ureido, [ (lower) alkylcarbamoyl ] amino,
  • lower is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • Suitable "lower alkyl” and “lower alkyl” moiety in the terms of "[ (lower) alkylsulfonyl] amino” , "hydroxy (lower) - alkyl”, etc. may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
  • Suitable "lower alkoxy” and “lower alkoxy” moiety in the terms of " (lower) alkoxycarbonyl” , “ (lower) alkoxy (lower) - alkyl”, etc. may be a straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, 1-ethylpropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, and the like, in which the preferred one may be C- ⁇ -C ⁇ alkoxy, and the most preferred one may be methoxy.
  • Suitable “lower alkanoyl” may include formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl and the like.
  • Suitable "halogen” may be fluoro, chloro, bromo and iodo.
  • Suitable "aryl” and “aryl” moiety in the term of " (arylsulfonyl ) amino" may include phenyl, naphthyl, anthryl, and the like, in which the preferred one may be phenyl.
  • Suitable "an unsaturated heterocyclic group containing nitrogen” may include an unsaturated, monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom. And especially preferable unsaturated heterocyclic group containing nitrogen may be ones such as an unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4- triazolyl, 1H-1, 2 , 3-triazolyl, 2H-1, 2, 3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazoly
  • Suitable "hydroxy protective group” in the term “protected hydroxy” may include commonly protective group or the like.
  • Suitable common protective group may include acyl as mentioned below, mono (or di or tri) phenyl (lower) alkyl which may have one or more suitable substituent (s) (e.g. benzyl, 4- methoxyphenyl, trityl, etc.), trisubstituented silyl [e.g., tri (lower) alkylsilyl (e.g., trimethylsilyl; t-butyldimethylsilyl, etc.], tetrahydropyranyl and the like.
  • suitable substituent e.g. benzyl, 4- methoxyphenyl, trityl, etc.
  • trisubstituented silyl e.g., tri (lower) alkylsilyl (e.g., trimethylsilyl; t-butyldimethylsilyl, etc.]
  • Suitable "acyl” may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
  • acyl may be illustrated as follows; carbamoyl; carboxy; aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 2, 2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl , octadecanoyl, nonadecanoyl, icosanoyl, etc.); cyclo ( lower) alkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutyl
  • Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar (lower) alkanoyl [e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanol, phenylbutanoyl , phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthtyl (lower) alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, naphthylisobutanoyl, etc.); ar (lower) alkenoyl [e.g., phenyl (lower) alkenoyl (e.g., phenylpropenoyl, phen
  • Heterocyclic acyl such as heterocyclic carbonyl; heterocyclic (lower) alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic (lower) alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; or the like; and the like.
  • heterocyclic (lower) alkanoyl e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.
  • heterocyclic (lower) alkenoyl e.g., heterocyclicpropenoyl, hetero
  • Amino protective groups in the context of the invention are the customary amino protective groups used in peptide chemistry. These include benzyloxycarbonyl, 2, 4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, phthaloyl, 2, 2, 2-trichloroethoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, 2-chloroacetyl, 2, 2, 2-trifluoroacetyl, 2, 2, 2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2, 4-dinitobenzyl, 4-nitrophenyl, 4-methoxyphenyl, triphen
  • Suitable salts of the object aminoalcohol derivatives [I] are pharmaceutically acceptable salts and include conventional non-toxic salts such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an alkali metal salt [e.g. sodium salt, potassium salt, etc.] or the like.
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic acid addition salt e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, methanesulfonate, benzen
  • Preferred embodiments of the object compound [I] are as follows:
  • X ⁇ is bond or -0CH 2 -;
  • X 2 is -(CH 2 ) n - in which n is 1;
  • X 3 is -0-
  • R-i is phenyl which may be substituted with one or two substituent (s) selected from the group consisting of halogen, nitro, amino, benzyloxy, benzyloxycarbonylamino, hydroxy and loweralkylsulfonylamino; or pyridyl which may have amino.
  • R 2 is hydrogen.
  • R is hydroxy (lower) alkyl
  • R4 is pyridyl which may be substituted with carbamoyl, lower alkoxycarbonyl, carboxy, cyano, nitro, amino, hydroxy (lower) alkyl, mono (or di) (lower) - alkylcarbamoyl, lower alkyl, halogen, lower alkylsulfonylamino, phenylsulfonylamino or lower alkanoyl; phenyl which may be substituted with halogen; quinolyl which may be substituted with lower alkoxycarbonyl, nitro, carbamoyl, carboxy, halogen or lower alkoxy; naphthyl; benzothiazolyl; pyridyl N-oxide; pyrimidinyl; naphthyridinyl; pyrazinyl; imidazo [1 , 2-a] pyridyl ; quinoxalinyl which may be substituted with halogen; acridinyl
  • More preferred embodiment of the object compound [I] are llows: X j _ is bond or -OCH 2 -;
  • X 2 is ⁇ (CH 2m- -"- n n i cl1 n i- s 1 ;
  • X 3 is -0-;
  • R is phenyl which may be substituted with one or two substituent (s) selected from the group consisting of halogen, nitro, amino, benzyloxy, benzyloxycarbonylamino, hydroxy and lower alkylsulfonylamino;
  • R 2 is hydrogen;
  • R3 is hydroxy (lower) alkyl ; and R ⁇ is pyridyl which may be substituted with carbamoyl, lower alkoxycarbonyl, carboxy, cyano, nitro, amino, hydroxy (lower) alkyl, mono (or di) (lower ) alkylcarbamoyl, lower alkyl, halogen, lower alkylsulfonylamino, phenylsulfonylamino or lower alkanoyl; phenyl which may be substituted with halogen; quinolyl which may be substituted with lower alkoxycarbonyl, nitro, carbamoyl, carboxy, halogen or lower alkoxy; naphthyl; benzothiazolyl; pyridyl N-oxide; pyrimidinyl; naphthyridinyl; pyrazinyl; imidazo [ 1 , 2-a] pyridyl; quinoxalinyl which may be
  • More preferred embodiment of the object compound [I] are as follows:
  • X- ] _ is bond or -OCH 2 ⁇ ;
  • X is ⁇ (CH ) n - in which n is 1;
  • X 3 is -0-;
  • R ⁇ is pyridyl which may have amino;
  • R 2 is hydrogen;
  • R3 is hydroxy ( lower) alkyl
  • R4 is pyridyl which may have hydroxy (lower) alkyl .
  • the object compound [I] or a salt thereof can be prepared by reacting a compound [II] with a compound [III] or a salt thereof.
  • Suitable salt of the compound [III] may be the same as those exemplified for the compound [I].
  • the reaction is preferably carried out in the presence of a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri (lower) alkylamine [e.g. trimethylamine, triethylamine, etc.], picoline or the like.
  • a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri (lower) alkylamine [e.g. trimethylamine, triethy
  • the reaction is usually carried out in a conventional solvent, such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
  • the object compound [lb] or a salt thereof can be prepared by subjecting a compound [la] or a salt thereof to elimination reaction of the amino protective group.
  • Suitable salts of the compounds [la] and [lb] may be the same as those exemplified for the compound [I].
  • This reaction can be carried out in the manner disclosed in Example 8 or Example 30, or similar manners thereto.
  • the object compound [Ic] or a salt thereof can be prepared by reacting a compound [III] or a salt thereof with a compound [IV] .
  • Suitable salts of the compound [III] may be the same as those exemplified for the compound [I].
  • the reaction can be carried out in the presence of the base such as an alkali metal carbonate [e.g., sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g., magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g., sodium bicarbonate, potassium bicarbonate, etc.], tri (lower) alkylamine [e.g., trimethylamine, triethylamine, etc.], picoline or the like.
  • the base such as an alkali metal carbonate [e.g., sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g., magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g., sodium bicarbonate, potassium bicarbonate, etc.], tri (lower) alkylamine [e.g., trimethyl
  • the reaction is usually carried out in a conventional solvent, such as an alcohol [e.g., methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not have adverse effect on the reaction.
  • a conventional solvent such as an alcohol [e.g., methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not have adverse effect on the reaction.
  • the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
  • the reaction can also be carried out in the manner disclosed in Example 72 or similar manner thereof.
  • the object compound [Id] or a salt thereof can be prepared by reacting a compound [V] or a salt thereof with a compound [VI ] .
  • Suitable salts of the compound [V] may be the same as those exemplified for the compound [I].
  • reaction can also be carried out in the manner disclosed in Example 78 or similar manners thereto.
  • the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like, and converted to the desired salt in conventional manners, if necessary.
  • the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention. It is further to be noted that isomerization or rearrangement of the object compound [I] may occur due to the effect of the light acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention. It is also to be noted that the solvating form of the compound [I] (e.g. hydrate, etc.) and any form of the crystal of the compound [I] are included within the scope of the present invention.
  • the object compound [I] or a salt thereof possesses gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic and anti-pollakiuria activities, and are useful for the treatment and/or prevention of gastrointestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to methods for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer causes by non steroidal anti-inflammatory drugs, or the like; for the treatment and/or prevention of dysuria such as pollakiuria, urinary incontinence or the like in case of nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prost
  • the object compound (I) or a pharmaceutically acceptable salt thereof can be usually administered to mammals including human being in the form of a conventional pharmaceutical composition such as capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, suppository or the like.
  • the effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 50 mg/kg, one to four times a day. However, the above dosage may be increased or decreased according to age, weight, conditions of patients or methods of administration.
  • the organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo.
  • the residue was dissolved in ethanol, and treated with aqueous sodium hydrogen sulfite for 10 minutes. After evaporation in vacuo and partition between ethyl acetate and water, the aqueous layer was made basic with aqueous sodium carbonate and extracted with ethyl acetate twice. The organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo.
  • N, N-dimethylformamide (10 ml) was stirred at room temperature for 9 hours.
  • the mixture was diluted with ethyl acetate and poured into water.
  • the organic layer was washed with aqueous 10% potassium hydrogensulfate and brine, dried over sodium sulfate and evaporated in vacuo.
  • Example 7 Under nitrogen, to a solution of [(2R)-2-(3- chlorophenyl) -2-hydroxyethyl] [ ( IS) -1- [ 4- ( 3-formylpyr ⁇ dm-2- yloxy) benzyl] -2-hydroxyethyl ] carbamic acid tert-butyl ester (0.24 g) in methanol (4.5 ml) was added sodium borohydride (17 mg) at 5°C, and the mixture was stirred at the same temperature for 10 minutes. The mixture was evaporated in vacuo. To the residue was added water and extracted with ethyl acetate. The organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo.
  • Example 8 To a solution of [ (2R) -2- ( 3-chlorophenyl ) -2- hydroxyethyl] [ (IS) -2-hydroxy-l- [4- ( 3-hydroxymethylpy ⁇ dm-2- yloxy) benzyl] ethyl] carbamic acid tert-butyl ester (0.14 g) in ethyl acetate (5.2 ml) was added 4N hydrogen chloride in ethyl acetate (1.3 ml) and the resulting mixture was allowed to stand at room temperature for 2 hours. The mixture was evaporated in vacuo. To the residue was added aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel
  • Example 11 A mixture of 6- [ 4- [ (2S) -2- [ (2R) -2- ( 3-chlorophenyl ) -2- hydroxyethylammo] -3-hydroxypropyl] phenoxy] nicotinic acid methyl ester dihydrochloride (0.26 g) and aqueous 28% ammonium hydroxide (26 ml) in 1,4-dioxane (5.2 ml) was stirred at room temperature for 1 day. The mixture was evaporated in vacuo, followed by partition between ethyl acetate and water.
  • 6- [4- [ (2S) -2- [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethylammo] -3- hydroxypropyl ] phenoxy] nicotmamide was treated with 4N hydrogen chloride in ethyl acetate, followed by crystallization from methanol-ethyl acetate to give 6- [4- [ (2S) -2- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethylammo] -3- hydroxypropyl ] phenoxy] nicotmamide dihydrochloride (57 mg) .
  • Example 13 To a solution of 6- [ 4- [ (2S) -2- [ (2R) -2- ( 3-chlorophenyl ) - 2-hydroxyethylammo] -3-hydroxypropyl] phenoxy] nicotmic acid methyl ester dihydrochloride (0.18 g) in methanol (3.6 ml) was added with aqueous IN sodium hydroxide (1.4 ml), and the mixture was stirred at room temperature for 4.5 hours. To the mixture was added aqueous IN hydrogen chloride (1.2 ml) and evaporated m vacuo.
  • Example 14 Under nitrogen, a solution of (S) -2-am ⁇ no-3- [4- (3, 5- d ⁇ chloropyr ⁇ dm-4-yloxy) phenyl] propan-1-ol hydrochloride (0.39 g) , (R) -3-chlorostyrene oxide (0.50 g) and N,N- dnsopropylethylamme (0.19 ml) in a mixture of methanol (1 ml) and 1,4-dioxane (1 ml) was refluxed for 14.5 nours . The mixture was evaporated in vacuo.
  • Example 16 Under nitrogen, a suspension of (S)-4-[4-(6- chloropy ⁇ dm-2-yloxy) benzyl ] oxazol ⁇ dm-2-one (0.49 g) , (R)- 3-chlorostyrene oxide (0.49 g) and potassium carbonate (0.44 g) in N, N-dimethylformamide (4.9 ml) was stirred at 80°C for 96 hours. The mixture was diluted with ethyl acetate and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in a mixture of ethanol (8 ml) and water (7 ml) .
  • Example 18 To a solution of ( 4S) -3- [ (2R) -2- ( 3-chlorophenyl) -2- hydroxyethyl]-4-[4-(py ⁇ dm-2-yloxy)benzyl]oxazol ⁇ dm-2-one (0.67 g) in ethanol (6.7 ml) was added aqueous 4N sodium hydroxide (4 ml), and the mixture was refluxed for 2 hours. After evaporation in vacuo and partition between water and ethyl acetate, the organic layer was washed with brme, dried over sodium sulfate, and evaporated m vacuo.
  • Example 25 Under nitrogen, a solution of 2- [4- [ (2S) -2- [ (2S) -2- hydroxy-3-phenoxypropylammo] -3-hydroxypropyl ] phenoxy] - nicotmonitrile (3.0 g) , di-tert-butyl dicarbonate (1.8 g) in tetrahydrofuran (20 ml) was stirred at room temperature for 9 hours.
  • Example 34 The following compound was synthesized according to a similar manner to that of Example 33.
  • Example 39 To a solution of (2S) -2- ( (2S) -2-hydroxy-3-pnenoxypropyl- amino) -3- [4- ( 3-n ⁇ tropy ⁇ dm-2-yloxy) phenyl] propanol (100 mg) in dioxane (3 ml) was added 4N hydrogen chloride in dioxane (3 ml) at room temperature, and the solution was stirred at the same temperature for 3 hours.
  • Example 42 A mixture of 2- (4- ⁇ 3-hydroxy- (2S) -2- [ (2S) -2-hydroxy-3- ( 4-benzyloxyphenoxy) propylamino] propyl ⁇ phenoxy) nicotmamide (150 mg) , 10% palladium on activated carbon (50% wet, 50 mg) and methanol (10.0 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 1 hour, and filtered. The filtrate was evaporated m vacuo.
  • Example 55 A mixture of N- [2-benzyloxy-5- (( IR) -l-hydroxy-2- IS) -1- nydroxymethyl-2- [ 4- (qumolm-3-yloxy) phenyl] ethylammo ⁇ - ethyl) phenyl ] methanesulfonamide (20 mg) and 10% palladium on activated carbon (50% wet, 10 mg) in methanol (3 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 2 hours.
  • Example 60 The following compound was obtained according to a similar manner to that of Example 55.
  • Example 61 The following compounds were obtained according to a similar manner to that of Example 53.
  • the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo.
  • To the residue was added 4N hydrogen chloride in 1,4- dioxane in order to decompose the boran complexes, followed by evaporation in vacuo.
  • the residue was dissolved into a mixture of saturated aqueous sodium hydrogencarbonate and dichloromethane. After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo.
  • Potassium hydroxide powder (85% purity, 35.3 mg, 0.535 mmol) was added to dimethyl sulfoxide (5.0 ml) at room temperature and the mixture was stirred at the same temperature for 1 hour.
  • 4-chloroqu ⁇ nolme (103 mg, 0.203 mmol) in dimethyl sulfoxide (0.5 ml) was added and the mixture was stirred at 100°C for 5 hours.
  • Potassium hydroxide powder (85% purity, 53.4 mg, 0.809 mmol) was added to dimethyl sulfoxide ( 6.0 ml ) at room temperature and the mixture was stirred at the same temperature for 80 minutes.
  • 4- [ (2S) -2- [benzyl [ (2S) -2-hydroxy-3-phenoxypropyl ] ammo] -3- hydroxypropyl] phenol 300 mg, 0.736 mmol
  • 4-chloro-7-methoxyqumolme (171 mg, 0.883 mmol) was added and the mixture was stirred at 100°C for 3.5 hours.
  • Potassium hydroxide powder (85% purity, 53.4 mg, 0.809 mmol) was added to dimethyl sulfoxide (6.0 ml) at room temperature and the mixture was stirred at the same temperature for 1 hour.
  • dimethyl sulfoxide 6.0 ml
  • 4-[(2S)-2- [benzyl [ (2S) -2-hydroxy-3-phenoxypropyl ] ammo] -3-hydroxypropyl] phenol 300 mg, 0.736 mmol
  • 4-chloro-6-fluoroqumolme 160 mg, 0.881 mmol was added and the mixture was stirred at 100°C for 24 hours.
  • Example 81 Potassium hydroxide powder (85% purity, 55.0 mg, 0.833 mmol) was added to dimethyl sulfoxide ( 8.0 ml ) at room temperature and the mixture was stirred at the same temperature for 1 hour. To the mixture was added 4-[(2S)-2- [benzyl [ (2R) -2- ( 4-benzyloxy-3-n ⁇ trophenyl ) -2-hydroxyethyl] - ammo] -3-hydroxypropyl] phenol (400 mg, 0.757 mmol) and stirred for 40 minutes. Further, 4-chloro-6-fluoroquinol e (179 mg, 0.986 mmol) was added and the mixture was stirred at 100°C for 96 hours.
  • reaction mixture was warmed to room temperature and stirred for 15 minutes.
  • the reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml x 2), brme (10 ml x 1), dried over magnesium sulfate. Evaporation of the solvent gave an orange foam (97.6 mg) .
  • Example 88 The following compound was obtained by a similar manner to that of Example 94 followed by a reduction of the nitro group as described in Example 88.
  • Example 95 A mixture of 2- ⁇ 4- [ (2S) -3-hydroxy-2- ( (2S) -2-hydroxy-3- phenoxypropylammo) propyl] phenoxy ⁇ qumolme-3-carboxylic acid methyl ester (270 mg) and aqueous 28% ammonium hydroxide (5.0 ml) m 1,4-dioxane (5.0 ml) was stirred at room temperature for 2 days. The mixture was evaporated in vacuo, followed by partition between ethyl acetate and water. The organic layer was washed with brme, dried over sodium sulfate and evaporated in vacuo.

Abstract

A compound of formula (I) wherein X1 is bond or -OCH2-; X2 is -(CH2)n-, in which n is 1, 2 or 3; X3 is bond, -O-, -S-, -OCH2-, or -NH-; R1 is phenyl or pyridyl each of which may have one or two substituent(s) selected from the group consisting of hydroxy, halogen, etc.; R2 is hydrogen, (lower)alkoxycarbonyl, etc.; R3 is hydroxy(lower)alkyl; halo(lower)alkyl, etc.; R4 is aryl or unsaturated heterocyclic group, each of which may have one or two substituent(s) selected from the group consisting of lower alkyl, hydroxy, carbamoyl, halogen, lower alkoxy, etc.; and a salt thereof which is useful as a medicament.

Description

AMINO ALCOHOL DERIVATIVES AND THEIR USE AS BETA 3 ADRENERGIC
AGONISTS
DISCLOSURE OF INVENTION This invention relates to new aminoalcohol derivatives and salts thereof.
More particularly, it relates to new aminoalcohol derivatives and salts thereof which act as selective j33 adrenergic receptor agonists and therefore have gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence and anti-pollakiuria activities, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to a method for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer caused by non steroidal anti-inflammatory drugs, or the like; for the treatment and/or prevention of dysuria such as pollakiuria, urinary incontinence or the like in case of nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis or the like; for the treatment and/or prevention of pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia, hypertension, atherosclerosis, glaucoma, melancholia, depression and the like, and for the treatment and/or prevention of a wasting condition, weight loss, emarciation or the like.
One object of this invention is to provide new and useful aminoalcohol derivatives and salts thereof which have gut selective sympathomimetic, anti-ulcerous, lipolytic, anti-urinary incontinence and anti-pollakiuria activities.
Another object of this invention is to provide processes for the preparation of said aminoalcohol derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said aminoalcohol derivatives and salts thereof.
Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in human beings or animals, using said aminoalcohol derivatives and salts thereof.
The object aminoalcohol derivatives of this invention are new and can be represented by the following general formula [I] :
Figure imgf000004_0001
wherein
Xτ_ is bond or -OCH2-<
X 2 is -(CH2-n-, in which n is 1, 2 or 3;
X3 is bond, -0-, -S-, -OCH 2* or -NH-
R ,1x is phenyl or pyridyl, each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, halogen, amino, [ (lower) alkylsulfonyl] amino, nitro, benzyloxycarbonylamino and benzyloxy; R is hydrogen, (lower) alkoxycarbonyl, benzyl or benzyloxycarbonyl ;
R is hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl or halo (lower ) alkyl; and
R^ is aryl or an unsaturated heterocyclic group containing nitrogen, each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, halo ( lower) alkyl, halogen, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, cyano, carboxy, (lower) alkoxycarbonyl, lower alkanoyl, carbamoyl, (mono or di) (lower) - alkylcarbamoyl, [ (lower) alkylsulfonyl] carbamoyl, amino, nitro, ureido, [ (lower) alkylcarbonyl] amino, [ (lower ) alkylsulfonyl] amino and (arylsulfonyl) amino, and a salt thereof.
The object compound [I] or a salt thereof can be prepared by the following processes.
Process 1
Figure imgf000005_0001
[II] [III] or a salt thereof or a salt thereof
Figure imgf000005_0002
[I] or a salt thereof Process 2
Figure imgf000006_0001
[la] or a salt thereof elimination reaction of amino protective group
Figure imgf000006_0002
[lb] or a salt thereof
Process 3
Figure imgf000006_0003
[III] [IV] or a salt thereof or a salt thereof
Figure imgf000006_0004
[IC] or a salt thereof Process 4
Figure imgf000007_0001
[V] [VI] or a salt thereof or a salt thereof
Figure imgf000007_0002
[id; or a salt thereof
wherein X-^, X2, X3, R , R , R and R4 are each as defined above,
9 ? Rfj and R are each ammo protective group, Q is protected hydroxy,
X is halogen, and is aryl or an unsaturated heterocyclic group
Figure imgf000007_0003
containing nitrogen, each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, halo (lower) alkyl, halogen, hydroxy (lower) alkyl, (lower ) alkoxycarbonyl, lower alkanoyl, carbamoyl, (mono or di) (lower) - alkylcarbamoyl, [ (lower) alkylsulfonyl ] carbamoyl, amino nitro, ureido, [ (lower) alkylcarbamoyl ] amino,
[ (lower) alkylsulfonyl] carbamoyl and (arylsulfonyl ) amin
In the above and subsequent description of the present specification, suitable examples of the various definition to be included within the scope of the invention are explained in detail in the following.
The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
Suitable "lower alkyl" and "lower alkyl" moiety in the terms of "[ (lower) alkylsulfonyl] amino" , "hydroxy (lower) - alkyl", etc. may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
1-methylpentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl and the like.
Suitable "lower alkoxy" and "lower alkoxy" moiety in the terms of " (lower) alkoxycarbonyl" , " (lower) alkoxy (lower) - alkyl", etc. may be a straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, 1-ethylpropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, and the like, in which the preferred one may be C-^-C^ alkoxy, and the most preferred one may be methoxy.
Suitable "lower alkanoyl" may include formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl and the like.
Suitable "halogen" may be fluoro, chloro, bromo and iodo.
Suitable "aryl" and "aryl" moiety in the term of " (arylsulfonyl ) amino" may include phenyl, naphthyl, anthryl, and the like, in which the preferred one may be phenyl.
Suitable "an unsaturated heterocyclic group containing nitrogen" may include an unsaturated, monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom. And especially preferable unsaturated heterocyclic group containing nitrogen may be ones such as an unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4- triazolyl, 1H-1, 2 , 3-triazolyl, 2H-1, 2, 3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.; an unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.; and the like.
Suitable "hydroxy protective group" in the term "protected hydroxy" may include commonly protective group or the like.
Suitable common protective group may include acyl as mentioned below, mono (or di or tri) phenyl (lower) alkyl which may have one or more suitable substituent (s) (e.g. benzyl, 4- methoxyphenyl, trityl, etc.), trisubstituented silyl [e.g., tri (lower) alkylsilyl (e.g., trimethylsilyl; t-butyldimethylsilyl, etc.], tetrahydropyranyl and the like.
Suitable "acyl" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable examples of said acyl may be illustrated as follows; carbamoyl; carboxy; aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 2, 2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl , octadecanoyl, nonadecanoyl, icosanoyl, etc.); cyclo ( lower) alkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopentylcarbonyl, etc.), protected carboxy such as commonly protected carboxy [e.g., esterified carboxy such as lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, iso- propyloxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.] or the like; lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.); lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.); di (lower) alkoxyphosphoryl (e.g., dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, dibutoxyphosphoryl, dipentyloxyphosphoryl, dihexyloxyphosphoryl, etc. ) ;
Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar (lower) alkanoyl [e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanol, phenylbutanoyl , phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthtyl (lower) alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, naphthylisobutanoyl, etc.); ar (lower) alkenoyl [e.g., phenyl (lower) alkenoyl (e.g., phenylpropenoyl, phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl (lower) alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.); ar (lower ) alkoxycarbonyl [e.g., phenyl (lower) alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.]; aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.); aryloxy (lower) alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.); arylcarbamoyl (e.g., phenylcarbamoyl, etc.); arylthiocarbamoyl (e.g., phenylthiocarbamoyl, etc.); arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.); arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or the like.
Heterocyclic acyl such as heterocyclic carbonyl; heterocyclic (lower) alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic (lower) alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; or the like; and the like.
Amino protective groups in the context of the invention are the customary amino protective groups used in peptide chemistry. These include benzyloxycarbonyl, 2, 4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, phthaloyl, 2, 2, 2-trichloroethoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, 2-chloroacetyl, 2, 2, 2-trifluoroacetyl, 2, 2, 2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2, 4-dinitobenzyl, 4-nitrophenyl, 4-methoxyphenyl, triphenylmethyl, etc.
Suitable salts of the object aminoalcohol derivatives [I] are pharmaceutically acceptable salts and include conventional non-toxic salts such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an alkali metal salt [e.g. sodium salt, potassium salt, etc.] or the like.
Preferred embodiments of the object compound [I] are as follows:
X^ is bond or -0CH2-;
X2 is -(CH2)n- in which n is 1;
X3 is -0-;
R-i is phenyl which may be substituted with one or two substituent (s) selected from the group consisting of halogen, nitro, amino, benzyloxy, benzyloxycarbonylamino, hydroxy and loweralkylsulfonylamino; or pyridyl which may have amino. R2 is hydrogen.
R is hydroxy (lower) alkyl ; and
R4 is pyridyl which may be substituted with carbamoyl, lower alkoxycarbonyl, carboxy, cyano, nitro, amino, hydroxy (lower) alkyl, mono (or di) (lower) - alkylcarbamoyl, lower alkyl, halogen, lower alkylsulfonylamino, phenylsulfonylamino or lower alkanoyl; phenyl which may be substituted with halogen; quinolyl which may be substituted with lower alkoxycarbonyl, nitro, carbamoyl, carboxy, halogen or lower alkoxy; naphthyl; benzothiazolyl; pyridyl N-oxide; pyrimidinyl; naphthyridinyl; pyrazinyl; imidazo [1 , 2-a] pyridyl ; quinoxalinyl which may be substituted with halogen; acridinyl which may be substituted with halogen and lower alkoxy; or isoquinolyl which may be substituted with halogen;
More preferred embodiment of the object compound [I] are llows: Xj_ is bond or -OCH2-;
X2 is ~(CH2m- -"-n nicl1 n i-s 1 ; X3 is -0-;
R is phenyl which may be substituted with one or two substituent (s) selected from the group consisting of halogen, nitro, amino, benzyloxy, benzyloxycarbonylamino, hydroxy and lower alkylsulfonylamino; R2 is hydrogen;
R3 is hydroxy (lower) alkyl ; and R^ is pyridyl which may be substituted with carbamoyl, lower alkoxycarbonyl, carboxy, cyano, nitro, amino, hydroxy (lower) alkyl, mono (or di) (lower ) alkylcarbamoyl, lower alkyl, halogen, lower alkylsulfonylamino, phenylsulfonylamino or lower alkanoyl; phenyl which may be substituted with halogen; quinolyl which may be substituted with lower alkoxycarbonyl, nitro, carbamoyl, carboxy, halogen or lower alkoxy; naphthyl; benzothiazolyl; pyridyl N-oxide; pyrimidinyl; naphthyridinyl; pyrazinyl; imidazo [ 1 , 2-a] pyridyl; quinoxalinyl which may be substituted with halogen; acridinyl which may be substituted with halogen and lower alkoxy; or isoquinolyl which may be substituted with halogen;
More preferred embodiment of the object compound [I] are as follows:
X-]_ is bond or -OCH2~; X is ~(CH )n- in which n is 1; X3 is -0-;
R^ is pyridyl which may have amino; R2 is hydrogen;
R3 is hydroxy ( lower) alkyl ; and
R4 is pyridyl which may have hydroxy (lower) alkyl .
The processes for preparing the object compound [I] are explained in detail in the following.
Process 1 The object compound [I] or a salt thereof can be prepared by reacting a compound [II] with a compound [III] or a salt thereof.
Suitable salt of the compound [III] may be the same as those exemplified for the compound [I]. The reaction is preferably carried out in the presence of a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri (lower) alkylamine [e.g. trimethylamine, triethylamine, etc.], picoline or the like.
The reaction is usually carried out in a conventional solvent, such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
Process 2
The object compound [lb] or a salt thereof can be prepared by subjecting a compound [la] or a salt thereof to elimination reaction of the amino protective group.
Suitable salts of the compounds [la] and [lb] may be the same as those exemplified for the compound [I].
This reaction can be carried out in the manner disclosed in Example 8 or Example 30, or similar manners thereto.
Process 3 The object compound [Ic] or a salt thereof can be prepared by reacting a compound [III] or a salt thereof with a compound [IV] .
Suitable salts of the compound [III] may be the same as those exemplified for the compound [I]. The reaction can be carried out in the presence of the base such as an alkali metal carbonate [e.g., sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g., magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g., sodium bicarbonate, potassium bicarbonate, etc.], tri (lower) alkylamine [e.g., trimethylamine, triethylamine, etc.], picoline or the like.
The reaction is usually carried out in a conventional solvent, such as an alcohol [e.g., methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not have adverse effect on the reaction.
The reaction temperature is not critical, and the reaction can be carried out under cooling to heating. The reaction can also be carried out in the manner disclosed in Example 72 or similar manner thereof.
Process 4
The object compound [Id] or a salt thereof can be prepared by reacting a compound [V] or a salt thereof with a compound [VI ] .
Suitable salts of the compound [V] may be the same as those exemplified for the compound [I].
The reaction can also be carried out in the manner disclosed in Example 78 or similar manners thereto.
The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like, and converted to the desired salt in conventional manners, if necessary.
It is to be noted that the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention. It is further to be noted that isomerization or rearrangement of the object compound [I] may occur due to the effect of the light acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention. It is also to be noted that the solvating form of the compound [I] (e.g. hydrate, etc.) and any form of the crystal of the compound [I] are included within the scope of the present invention.
The object compound [I] or a salt thereof possesses gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic and anti-pollakiuria activities, and are useful for the treatment and/or prevention of gastrointestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to methods for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer causes by non steroidal anti-inflammatory drugs, or the like; for the treatment and/or prevention of dysuria such as pollakiuria, urinary incontinence or the like in case of nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis or the like; and for the treatment and/or prevention of pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia, hypertension, atherosclerosis, glaucoma, melancholia, depression, and the like, and the treatment and/or prevention of a wasing condition, weight loss, emerciation or the like.
The object compound (I) or a pharmaceutically acceptable salt thereof can be usually administered to mammals including human being in the form of a conventional pharmaceutical composition such as capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, suppository or the like. The effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 50 mg/kg, one to four times a day. However, the above dosage may be increased or decreased according to age, weight, conditions of patients or methods of administration.
In order to show the usefulness of the ethanolamine derivative in the present invention for the prophylactic and therapeutic treatment of above-mentioned diseases in a human being or an animal, the pharmacological test data of the representative compound thereof is shown in the following.
Test 1
Effect on the increase in intravesical pressure induced by carbachol in anesthetized dog
Test Compound
2 (S) -2-[ (2S)-2-hydroxy-3- (phenoxy) propylamino] -3- [ 4- (7- methoxyquinolin-4-yloxy) phenyl] propan-1-ol
(This compound was obtained according to Example 78.)
Test Method
Female Beagle dogs weighing 8.0-15.0 kg were fasted for 24 hours and maintained under halothane anesthesia. A 12F Foley catheter was lubricated with water soluble jelly, inserted into the urethral orifice and advanced approximately 10 cm until the balloon tip was placed well inside the bladder. The balloon was then inflated with 5 ml of room air and catheter slowly withdrawn just part the first resistance that is felt at the bladder neck. Urine was completely drained out thought the catheter, and 30 ml of biological saline was infused. The catheter was connected to pressure transducer, and intravesical pressure was continuously recorded. The test compound was injected by intra-duodenal route at 30 minutes before the administration of carbachol ( 1 . 8 μg/ kg ]
Test Results
Treatment Increase in intravesical pressure (mmHg)
Control 9.3
Test Compound
(0.32 mg/kg) 5.5
(N=2:
The following Preparations and Examples are given for the purpose of illustrating this invention.
Preparation 1
Under nitrogen, a mixture of 2-chloronicotinic acid (1.6 g) , methyl iodide (0.69 ml) and potassium carbonate (1.5 g) in N, N-dimethylformamide (20 ml) was stirred at room temperature for 4 hours. To the mixture was added ethyl acetate, and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed successively with water and brine, dried over sodium sulfate, and evaporated in vacuo to give 2-chloronicotinic acid methyl ester (1.7 g) .
NMR (CDCI3, δ) : 3.97 (3H, s), 7.34 (1H, dd, J=4.8,
7.7Hz), 8.18 (1H, dd, J=2.0, 7.7Hz), 8.53 (1H, dd, J=2.0, 4.8Hz)
Preparation 2
Under nitrogen, to a solution of 2-chloronicotinic acid methyl ester (1.7 g) in toluene (9.9 ml) was added diisopropylaluminum hydride (0.94M in hexane, 23 ml) at
-78°C, and the mixture was stirred for 5 minutes. To the mixture were added aqueous 1M Rochelle salt and ethyl acetate, and the mixture was vigorously stirred in a warm water bath for 30 minutes. The organic layer was separated. The aqueous layer was extracted with ethyl acetate 3 times. The combined organic layers were washed successively with aqueous 1M Rochelle salt and brine, dried over sodium sulfate, and evaporated in vacuo to give (2-chloropyridin-3- yl)methanol (1.3 g) . NMR (CDC13, δ) : 2.57 (1H, br s), 4.80 (2H, s) , 7.29
(1H, dd, J=4.8, 7.6Hz), 7.91 (1H, dd, J=1.9, 7.6Hz), 8.31 (1H, dd, J=1.9, 4.8Hz)
Preparation 3 The following compound was obtained according to a similar manner to that of Preparation 2.
(6-Chloropyridin-3-yl) methanol
NMR (CDCI3, δ) : 4.72 (2H, s), 7.32 (1H, d, J=8.2Hz), 7.70 (1H, dd, J=2.4 , 8.2Hz), 8.32 (1H, d, J=2.3Hz)
Preparation 4
Under nitrogen, a mixture of (2-chloropyridin-3- yl)methanol (1.3 g) and manganese (IV) oxide (6.3 g) in dichloromethane (13 ml) was stirred at room temperature for 5 days. The mixture was diluted with dichloromethane. Therein was added silica gel and the mixture was stirred for 30 minutes. After filtration, the filtrate was evaporated in vacuo to give 2-chloropyridine-3-carbaldehyde (1.0 g) . NMR (CHCI3, δ) : 7.43 (1H, ddd, J=0.8, 4.8, 7.7Hz),
8.25 (1H, dd, J=2.1, 7.7Hz), 8.62 (1H, dd, J=2.0, 4.7Hz), 10.46 (1H, d, J=0.8Hz)
Preparation 5 Under nitrogen, a mixture of (S) - [ l-hydroxymethyl-2- (4- hydroxyphenyl) ethyl] carbamic acid tert-butyl ester (J. Med. Chem. 1992, 15, 1259-1266) (1.3 g) , 2-chloropyridine-3- carbaldehyde (1.0 g) and potassium carbonate (0.97 g) in N,N- dimethylformamide (13 ml) was stirred at 60°C for 72 hours. The mixture was diluted with ethyl acetate, and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed successively with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 50:1) to give (S) - { 2- [ - (3- formylpyridin-2-yloxy) phenyl] -1-hydroxymethylethyl } carbamic acid tert-butyl ester (1.2 g) .
NMR (CDC13, δ) : 1.44 (9H, s), 2.36 (1H, br s) , 2.88 (2H, d, J=7.1Hz), 3.5-3.8 (2H, m) , 3.89 (1H, br s) ,
4.7-4.9 (1H, m) , 7.1-7.2 (3H, m) , 7.30 (2H, d, J=8.5Hz), 8.25 (1H, dd, J=2.0, 7.5Hz), 8.34 (1H, dd, J=2.1, 4.9Hz), 10.55 (1H, s)
Preparation 6
The following compounds were obtained according to a similar manner to that of Preparation 5.
(1) (S) -(2- [4- (3-Cyanopyridin-2-yloxy)phenyl] -1- (hydroxymethyl) ethyl } carbamic acid tert-butyl ester
NMR (CDCI3, δ) : 1.43 (9H, s) , 2.88 (2H, d, J=7.1Hz),
3.5-4.0 (3H, m) , 7.05-7.15 (3H, m) , 7.25-7.35 (2H, m) , 8.01 (1H, dd, J=2.0, 7.6Hz), 8.31 (1H, dd, J=2.0, 5.0Hz)
(2) (S) -(2- [4- (5-Formylpyridin-2-yloxy) phenyl] -1- (hydroxymethyl) ethyl } carbamic acid tert-butyl ester
NMR (CDCI3, δ) : 1.43 (9H, s), 2.88 (2H, d, J=7.1Hz), 3.5-4.0 (3H, m) , 7.01-7.13 (3H, m) , 7.30 (2H, d, J=8.5Hz), 8.19 (1H, dd, J=2.3, 8.6Hz), 8.62 (1H, d,
J=2.2Hz), 9.98 (1H, s)
(3) (S)-{2-[4-(3, 5-Dichloropyridin-4-yloxy) phenyl] -1- (hydroxymethyl) ethyl } carbamic acid tert-butyl ester NMR (CDCI3, δ) : 1.41 (9H, s), 2.81 (2H, d, J=7.1Hz), 3.5-3.9 (3H, m) , 6.78 (2H, d, J=8.7Hz) , 7.17 (2H, d, J=8.6Hz), 7.26 (1H, s), 8.56 (1H, s)
(4) (S)-{2-[4-(6-Fluoropyridin-2-yloxy)phenyl]-l-
(hydroxymethyl ) ethyl } carbamic acid tert-butyl ester NMR (CDC13, δ) : 1.43 (9H, s), 2.86 (2H, d, J=7.1Hz),
3.5-4.0 (3H, m) , 6.61 (1H, dd, J=2.4 , 7.6Hz), 6.71 (1H, dd, J=1.3, 7.9Hz), 7.05-7.10 (2H, m) , 7.25- 7.30 (2H, m) , 7.74 (1H, q, J=8.0Hz)
Preparation 7
To a mixture of (S) - { 2- [4- (3-formylpyridin-2-yloxy) - phenyl] -1- (hydroxymethyl ) ethyl }carbamic acid tert-butyl ester (5.2 g) , 35% hydrogen peroxide (2.5 ml) and potassium dihydrogen phosphate (7.5 g) in a mixture of acetonitrile (60 ml) and water (15 ml) was dropwise added sodium chlorite (80% purity, 4.7 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. While cooling in ice-water bath, to the mixture was added sodium sulfite (3.5 g) . After removal of the bath, to this was added aqueous 1M citric acid to make it acidic, and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over sodium sulfate, and evaporated in vacuo. The crude product was triturated with diisopropyl ether to give (S) -2- [4- (2-tert-butoxycarbonylamino-3- hydroxypropyl) phenoxy] nicotinic acid (4.8 g) .
NMR (DMSO-d6, δ) : 1.34 (9H, s), 2.5-2.65 (1H, m) , 2.83 (1H, dd, J=5.2, 13.8Hz), 3.2-3.5 (2H, m) , 3.5-3.7 (1H, m) , 4.71 (1H, br s), 6.62 (1H, d, J=8.3Hz), 7.01 (2H, d, J=8.5Hz), 7.17-7.23 (3H, m) , 8.2-8.3
(2H, m) , 13.18 (1H, br s)
Preparation 8
The following compound was obtained according to a similar manner to that of Preparation 7. (S) -6- [4- (2-tert-Butoxycarbonylamino-3-hydroxypropyl) - phenoxy] nicotinic acid
NMR (DMSO-d6, δ) : 1.33 (9H, s), 2.5-2.7 (1H, m) , 2.86
(1H, dd, J=5.0, 13.8Hz), 3.2-3.5 (3H, m) , 6.65 (1H, d, J=8.4Hz), 7.08 (2H, d, J=8.3Hz), 7.26 (2H, d,
J=8.5Hz), 8.26 (1H, dd, J=2. , 8.5Hz), 8.66 (1H, d, J=2.1Hz)
Preparation 9 Under nitrogen, a suspension of (S) -2- [4- (2-tert- butoxycarbonylamino-3-hydroxypropyl ) phenoxy] nicotinic acid (5.7 g) , methyl iodide (1.0 ml), potassium carbonate (2.4 g) in N, N-dimethylformamide (28 ml) was stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 1:1) to give (S)-2-[4-(2- tert-butoxycarbonylamino-3-hydroxypropyl) phenoxy] nicotinic acid methyl ester (5.7 g) .
NMR (CDC13, δ) : 1.43 (9H, s) , 2.3-2.5 (1H, br s), 2.86 (2H, d, J=7.1Hz), 3.5-4.0 (3H, m) , 3.94 (3H, s), 4.76 (1H, d, J=7.5Hz), 7.02-7.12 (3H, m) , 7.23-7.27
(2H, m) , 8.24-8.29 (2H, m)
Preparation 10
The following compound was obtained according to a similar manner to that of Preparation 9.
(S) -6- [4- (2-tert-Butoxycarbonylamino-3-hydroxypropyl) - phenoxy] nicotinic acid methyl ester
NMR (CDCI3, δ) : 1.43 (9H, s), 2.87 (2H, d, J=7.2Hz), 3.5-4.0 (3H, m) , 3.92 (3H, s), 6.93 (1H, d, J=9.2Hz), 7.09 (2H, d, J=8.5Hz) , 7.28 (2H, d, J=8.5Hz), 8.27 (1H, dd, J=2.4, 8.6Hz) , 8.82 (1H, d, J=1.8Hz)
Preparation 11
To a solution of (S) -2- [4- (2-tert-butoxycarbonylamino-3- hydroxypropyl) phenoxy] nicotinic acid methyl ester (5.6 g) in methanol (56 ml) was added 4N hydrogen chloride in ethyl acetate (35 ml) at room temperature, and the solution was stirred at the same temperature overnight. The mixture was evaporated in vacuo, and the residue was triturated with ethyl acetate to give (S) -2- [ 4- (2-amino-3-hydroxypropyl) - phenoxy] nicotinic acid methyl ester dihydrochloride (5.0 g) . NMR (DMSO-d6, δ): 2.8-3.0 (2H, m) , 3.3-3.6 (3H, m) , 3.85 (3H, s), 7.08 (2H, d, J=8.4Hz), 7.23-7.33 (3H, m) , 8.26-8.31 (2H, m)
Preparation 12
The following compounds were obtained according to a similar manner to that of Preparation 11.
(1) (S) -2- [4- (2-Amino-3-hydroxypropyl) phenoxy] - nicotinonitrile hydrochloride
NMR (DMSO-d6, δ): 2.85-3.05 (2H, m) , 3.3-3.7 (3H, m) , 7.21 (2H, d, J=8.5Hz), 7.29-7.38 (3H, m) , 8.37-8.45
(2H, m)
(2) (S) -6- [4- (2-Amino-3-hydroxypropyl) phenoxy] nicotinic acid methyl ester dihydrochloride NMR (DMSO-d6, δ): 2.75-3.05 (2H, m) , 3.30-3.60 (3H, m) , 3.86 (3H, s), 7.11-7.20 (3H, m) , 7.35 (2H, d, J=8.5Hz), 8.32 (1H, dd, J=2.4 , 8.6Hz), 8.69 (1H, d, J=1.8Hz)
(3) (S) -2-Amino-3- [4- (3, 5-dichloropyridin-4-yloxy) phenyl] - propan-1-ol hydrochloride
NMR (DMSO-dg, δ) : 2.7-2.95 (2H, m) , 3.25-3.60 (3H, m) , 6.90 (2H, d, J=8.6Hz), 7.27 (2H, d, J=8.7Hz), 8.79 (2H, s)
(4) (S) -2-Amino-3- [4- ( 6-fluoropyridin-2-yloxy) phenyl] - propan-1-ol hydrochloride NMR (DMSO-d6, δ): 2.75-3.05 (2H, m) , 3.30-3.65 (3H, m) , 6.85-6.95 (2H, m) , 7.15 (2H, d, J=8.5Hz), 7.35 (2H, d, J=8.5Hz), 8.03 (1H, q, J=8.0Hz)
Preparation 13
Under nitrogen, a mixture of ( 6-chloropyridin-3- yl)methanol (1.2 g) and manganese (IV) oxide (6.0 g) in N, N-dimethylformamide (12 ml) was stirred at room temperature for 6 days. The mixture was diluted with ethyl acetate and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed successively with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane) to give 6-chloropyridine-3-carbaldehyde (0.58 g) .
NMR (CDC13, δ) : 7.52 (1H, d, J=8.2Hz), 8.15 (1H, dd, J=2.4, 8.3Hz), 8.88 (1H, d, J=2.3Hz), 10.10 (1H, s)
Preparation 14
Under nitrogen, a mixture of (S) - [ l-hydroxymethyl-2- ( 4- hydroxyphenyl) ethyl] carbamic acid tert-butyl ester (10 g) , 2, 6-dibromopyridine (18 g) and potassium carbonate (10 g) in N, N-dimethylformamide (100 ml) was stirred at 120°C for 3 days. The mixture was diluted with ethyl acetate, and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed successively with aqueous saturated sodium bicarbonate (twice) and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 100:1), followed by trituration with diisopropyl ether to give (S) -4- [ 4- ( 6-bromopyridin-2-yloxy) benzyl] oxazolidin-2-one (6.6 g) .
NMR (DMSO-d6, δ) : 2.75-2.85 (2H, m) , 3.95-4.15 (2H, m) , 4.25-4.40 (1H, m) , 6.99 (1H, d, J=8.1Hz), 7.11 (2H, d, J=8.4Hz), 7.25-7.40 (3H, m) , 7.79 (1H, t, J=7.7Hz)
Preparation 15
The following compound was obtained according to a similar manner to that of Preparation 14.
(S) -4- [4- ( 6-Chloropyridin-2-yloxy) benzyl] oxazolidin-2-one NMR (CDC13, δ) : 2.7-3.1 (2H, m) , 4.0-4.3 (2H, m) , 4.4- 4.6 (1H, m) , 6.80 (1H, d, J=8.1Hz), 7.0-7.3 (5H, m) , 7.64 (1H, t, J=7.9Hz)
Preparation 16
Under nitrogen, to a solution of butyllithium (1.6M in hexane, 14 ml) in tetrahydrofuran (20 ml) was added a solution of (S) -4- [ 4- ( 6-bromopyridin-2-yloxy) enzyl] - oxazolidin-2-one (3.5 g) in tetrahydrofuran (15 ml) at -78°C, and the mixture was stirred at the same temperature for 15 minutes. To it was added N, N-dimethylformamide (1.7 ml), the dry ice bath was removed to allow to come to room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was dissolved in ethanol, and treated with aqueous sodium hydrogen sulfite for 10 minutes. After evaporation in vacuo and partition between ethyl acetate and water, the aqueous layer was made basic with aqueous sodium carbonate and extracted with ethyl acetate twice. The organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 50:1), followed by crystallization from ethyl acetate to give (S) -6- [4- (2-oxo-oxazolidin-4-ylmethyl) phenoxy] pyridine-2- carbaldehyde (0.64 g) .
NMR (DMSO-d6, δ) : 2.7-2.95 (2H, m) , 3.95-4.15 (2H, m) ,
4.25-4.40 (1H, m) , 7.16 (2H, d, J=8.4Hz), 7.25-7.40 (3H, m) , 7.70 (1H, d, J=7.3Hz), 8.09 (1H, t,
J=7.5Hz), 9.73 (1H, s)
Preparation 17
Under nitrogen, to a suspension of (S) -6- [ - (2-oxo- oxazolidin-4-ylmethyl ) phenoxy] pyridine-2-carbaldehyde (0.43 g) in methanol (14 ml) was added sodium borohydride (54 mg) at 5°C, and the mixture was stirred at the same temperature for 5 minutes. The mixture was evaporated in vacuo. To the residue were added water and ethyl acetate. After separation, the organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo to give (S) -4- [4- ( 6-hydroxymethylpyridin-2-yloxy) benzyl ] oxazolidin-2- one (0.43 g) .
NMR (DMSO-d6, δ): 2.7-2.9 (2H, m) , 3.95-4.15 (2H, m) , 4.25-4.40 (1H, m) , 4.39 (2H, d, J=5.8Hz), 6.77 (1H, d, J=8.lHz), 7.04 (2H, d, J=8.5Hz), 7.15-7.30 (3H, m) , 7.84 (1H, t, J=7.8Hz) .
Preparation 18 The following compound was obtained according to a similar manner to that of Preparation 17.
(S) -4- [4- (5-Hydroxymethylpyridin-2-yloxy) benzyl] - oxazolidin-2-one NMR (CDC13, δ) : 2.8-3.0 (2H, m) , 4.0-4.25 (2H, m) , 4.50-4.60 (1H, m) , 4.67 (2H, d, J=5.7Hz) , 6.95 (1H, d, J=8.5Hz) , 7.11 (2H, d, J=8.6Hz), 7.22 (2H, d, J=8.6Hz), 7.77 (1H, dd, J=2.4 , 8.4Hz), 8.13 (1H, d, J=1.9Hz)
Preparation 19
Under nitrogen, a solution of (S)-4-[4-(6- hydroxymethylpyridin-2-yloxy) benzyl] oxazolidin-2-one (0.46 g) , (R) -3-chlorostyrene oxide (0.46 g) and potassium carbonate (0.41 g) in N, N-dimethylformamide (4.6 ml) was stirred at 80°C for 72 hours. The mixture was diluted with ethyl acetate and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed successively with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 50:1) to give ( 4S) -3- [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] -4- [4- ( 6-hydroxymethylpyridin-2-yloxy) benzyl] - oxazolidin-2-one (0.39 g) and (5R) -5- (3-chlorophenyl) -3-
( (IS) -2-hydroxy-1- [4- ( 6-hydroxymethylpyridin-2-yloxy) benzyl] - ethyl }oxazolidin-2-one (76 mg) .
(1) (4S)-3-[ ( 2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] -4 -[4- (6- hydroxymethylpyridin-2-yloxy) benzyl] oxazolidin-2-one
NMR (DMSO-d6, δ) : 2.68 (1H, dd, J=7.9, 13.4Hz), 3.05- 3.15 (1H, m) , 3.2-3.35 (1H, m) , 3.47 (1H, dd, J=4.4, 14.2Hz), 3.95-4.10 (1H, m) , 4.1-4.4 (2H, m) , 4.38 (2H, d, J=5.8Hz), 4.75-4.90 (1H, m) , 6.77 (1H, d, J=7.8Hz), 7.07 (2H, d, J=8.5Hz), 7.20-7.50 (8H, m) , 7.82 (1H, t, J=7.8Hz)
(2) (5R)-5- (3-Chlorophenyl)-3{ ( IS) -2-hydroxy-l- [4- ( 6- hydroxymethylpyridin-2-yloxy) benzyl] ethyl} oxazolidin-2- one NMR (DMSO-dg, δ) : 2.6-2.9 (2H, m) , 3.3-3.4 (1H, m) , 3.5-3.6 (2H, m) , 3.9-4.15 (2H, m) , 4.38 (2H, d, J=5.8Hz), 5.53 (1H, d, J=5.5, 8.8Hz), 6.76 (1H, d, J=8.1Hz), 6.96 (2H d, J=8.3Hz) , 7.0-7.5 (7H, m) , 7.83 (1H, t, J=7.8Hz)
Preparation 20
The following compounds were obtained according to a similar manner to that of Preparation 19.
(1) (4S)-3-[ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] -4- [4- (5- hydroxymethylpyridin-2-yloxy) benzyl] oxazolidin-2-one NMR (CDC13, δ) : 1.90-2.05 (1H, m) , 2.55-2.75 (1H, m) ,
3.14 (1H, dd, J=4.0, 13.6Hz), 3.2-3.4 (1H, m) , 3.28 (1H, dd, J=8.1, 14.8Hz), 3.67 (1H, dd, J=2.8,
14.8Hz), 4.05-4.30 (3H, m) , 4.66 (2H, d, J=5.6Hz), 4.95-5.05 (1H, m) , 6.92 (1H, d, J=8.4Hz), 7.08 (2H, d, J=8.8Hz), 7.15 (2H, d, J=8.8Hz), 7.2-7.4 (3H, m) , 7.41 (1H, s), 7.75 (1H, dd, J=2.4 , 8.4Hz), 8.12 (1H, d, J=2.1Hz)
(2) (5R) -5- (3-Chloroρhenyl) -3-{ (IS) -2-hydroxy-l- [4- (5- hydroxymethylpyridin-2-yloxy) benzyl] ethyl }oxazolidin-2- one NMR (DMSO-d6, δ) : 2.6-2.9 (2H, m) , 3.3-3.45 (1H, m) ,
3.5-3.6 (2H, m) , 3.9-4.15 (2H, m) , 4.47 (2H, d, J=5.6Hz), 5.5-5.6 (1H, m) , 6.9-7.2 (6H, m) , 7.27 (1H, s), 7.3-7.45 (2H, m) , 7.79 (1H, dd, J=2.4, 8.4Hz), 8.05-8.1 (1H, m)
Preparation 21
The following compounds were obtained according to a similar manner to that of Preparation 19.
(1) (4S) -3- [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] -4- [4- (pyridin-2-yloxy) benzyl ] oxazolidin-2-one NMR (DMSO-d6, δ) : 2.55-2.8 (1H, m) , 3.05-3.15 (1H, m) ,
3.2-3.6 (2H, m) , 3.95-4.1 (1H, m) , 4.1-4.4 (2H, m) , 4.8-4.9 (1H, m) , 6.9-7.5 (10H, m) , 7.8-7.9 (1H, m) , 8.1-8.2 (1H, m)
(2) (5R) -5- (3-Chlorophenyl) -3-{ ( IS) -2-hydroxy-l- [4- (pyridin-2-yloxy) benzyl] ethyl } oxazolidin-2-one NMR (DMSO-d6, δ) : 2.65-2.9 (2H, ) , 3.3-3.4 (1H, m) , 3.5-3.6 (2H, m) , 3.9-4.15 (2H, ) , 5.5-5.6 (1H, m) ,
6.95-7.3 (8H, m) , 7.35-7.4 (2H, m) , 7.8-7.9 (1H, m) , 8.15-8.2 (1H, m)
Preparation 22 A mixture of (S) -4- [4- ( 6-chloropyridin-2-yloxy) benzyl] - oxazolidin-2-one (4.1 g) , 10% palladium on activated carbon (50% wet, 0.82 g) and N, N-diisopropylethylamine (2.3 ml) in ethanol (41 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 2 hours, and filtered. The filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed successively with water and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 25:1) to give (S) -4- [4- (pyridin-2-yloxy) benzyl] oxazolidin-2- one (2.8 g) .
NMR (CDC13, δ) : 2.8-2.95 (2H, m) , 4.0-4.25 (2H, m) ,
4.45-4.55 (1H, m) , 6.9-7.3 (6H, m) , 7.65-7.75 (1H, m) , 8.15-8.20 (1H, m)
Preparation 23
Under nitrogen, to a solution of (S) - ( 2- [ 4- (5- formylpyridin-2-yloxy) phenyl] -1-hydroxymethylethyl } carbamic acid tert-butyl ester (1.4 g) in dichloromethane (37 ml) was added thionyl chloride (0.30 ml) at 5°C, and the mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo, and the residue was vigorously stirred in a mixture of ethyl acetate and aqueous saturated sodium bicarbonate at 50°C for 30 minutes. After separation, the organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane : ethyl acetate = 3:2), followed by trituration with ethyl acetate to give (S)-6-[4- (2-oxo-oxazolidin-4-ylmethyl) phenoxy] pyridine- 3-carbaldehyde (0.52 g) .
NMR (CDC13, δ) : 2.80-3.05 (2H, m) , 4.05-4.25 (2H, m) ,
4.45-4.60 (1H, m) , 7.05-7.35 (5H, m) , 8.21 (1H, d, J=2.3, 8.6Hz), 8.62 (1H, d, J=2.2Hz), 9.99 (1H, s)
Preparation 24
Under nitrogen, to a solution of m-fluorophenol (1.74 ml) and sodium hydride (772 mg) in dimethylformamide (25 ml) was added (2S) - (+) -glycidyl nosylate (5.0 g) at 0°C and the mixtue was stirred at the same temperature for 0.5 hour. The mixture was allowed to warm to room temperature and stirred for 2.5 hours at this temperature. The resulting mixture was poured into 10% aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford (2S) -3- (3-fluorophenoxy) - 1, 2-epoxypropane (2.82 g) as a colorless powder.
NMR (CDCI3, δ) : 2.75 (1H, dd, J=3.0, 4.8Hz) 2.90 (1H, t, J=4.8Hz), 3.35 (1H, m) , 3.90 (1H, dd, J=5.7, 11Hz) , 4.20 (1H, dd, J=3.0, 11Hz), 6.50-6.70 (3H, m) ,
7.20-7.25 (1H, m) MS (m/z) : 169 (M+l)
Preparation 25 The following compounds were synthesized according to a similar manner to that of Preparation 24.
(1) (2S) -3- ( 4-Chlorophenoxy) -1, 2-epoxypropane (2.79 g) as a colorless powder NMR (DMSO-d6, δ) : 2.70 (1H, dd, J=2.6, 6Hz), 2.85 (1H, t, J=4.3Hz), 3.28-3.36 (1H, m) , 3.80 (1H, dd, J=6, 11Hz), 4.30 (1H, dd, J=2.6, 11Hz) , 6.70-6.80 ('2H, m) , 7.30-7.40 (2H, m)
(2) (2S) -3- (2-Chlorophenoxy) -1, 2-epoxypropane (1.6 g) as a colorless powder
NMR (CDC13, δ) : 2.80-3.00 (2H, m) , 3.35-3.40 (1H, m) , 4.05 (1H, dd, J=5.2, 11Hz), 4.30 (1H, dd, J=3.1, 11Hz), 6.80-7.00 (2H, m) , 7.10-7.20 (1H, m) , 7.30- 7.40 (1H, m)
Preparation 26
Under nitrogen, a mixture of (S) -2- [4- (2-tert- butoxycarbonylamino-3-hydroxy-propyl) phenoxy] nicotinic acid (1.0 g) , ethyl iodide (0.2 ml), potassium carbonate (425 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 1:1) to give (S)-2-[4-(2- tert-butoxycarbonylamino-3-hydroxypropyl) phenoxy] nicotinic acid ethyl ester (1.01 g) as a colorless form. MALDI-MS (m/z) : 439 (M+Na)
Preparation 27
The following compound was synthesized according to a similar manner to that of Preparation 32.
(S) -2- [4- (2-Amino-3-hydroxypropyl) phenoxy] nicotinic acid ethyl ester hydrochloride (5.06 g) as a colorless powder MS (m/z) : 317 (M+l)
Preparation 28
Thionyl chloride (30.2 ml) was added dropwise to a solution of (R) -2-amino-3- (4-hydroxyphenyl) propionic acid hydrochloride (25.0 g) in methanol (250 ml) under ice water cooling over 10 minutes and the mixture was stirred at room temperature for 3 hours. The mixture was evaporated in vacuo and the residue was triturated with diisopropyl ether to give (R) -2-amino-3- ( 4-hydroxyphenyl) propionic acid methyl ester hydrochloride (33.9 g) .
NMR (DMSO-d6, δ) : 2.90-3.10 (2H, m) , 3.66 (3H, s), 4.17 (1H, t, J=6.1Hz), 6.70 (2H, d, J=9Hz) , 7.02 (2H, d, J=9Hz) , 9.47 (1H, br s)
Preparation 29
A solution of (S) -2-amino-3- (4-hydroxyphenyl) propionic acid methyl ester hydrochloride (33.9 g) , di-tert-butyl dicarbonate (30.5 g) and triethylamine (50.9 ml) in tetrahydrofuran (500 ml) was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate, and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated in vacuo to give (S) -2-tert-butoxycarbonylamino-3- (4- hydroxyphenyl) propionic acid methyl ester (42.28 g) as a colorless powder.
NMR (DMSO-d6, δ) : 1.30 (9H, s), 2.70-2.80 (2H, m) , 3.58 (3H, s), 4.10-4.20 (1H, m) , 6.60 (2H, d, J=8.3Hz), 7.20 (2H, d, J=8.3Hz), 9.21 (1H, br s) Preparation 30
Under nitrogen, to a solution of (R)-2-tert- butoxycarbonylamino-3- (4-hydroxyphenyl) propionic acid methyl ester (42.28 g) in tetrahydrofuran (400 ml) was added lithium borohydride (7.16 g) at 5°C, and the mixture was stirred at the same temperature for 5 hours. The mixture was evaporated in vacuo. To the residue was added water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give (R)-[l- (4-hydroxybenzyl) -2-hydroxyethyl] carbamic acid tert-butyl ester (4.63 g) as a colorless powder.
NMR (DMSO-dg, δ) : 1.32 (9H, s), 2.30-2.70 (2H, m) , 3.20- 3.50 (3H, m) , 6.60 (2H, d, J=8.3Hz), 7.00 (2H, d,
J=8.3Hz) , 9.10 (1H, br s) MS (m/z) : 290 (M+l)
Preparation 31 Under nitrogen, a mixture of (R) - [l-hydroxymethyl-2- (4- hydroxyphenyl) ethyl] carbamic acid tert-butyl ester (9.75 g) , 2-chloro-3-cyanopyridine (5.06 g) and potassium carbonate (6.04 g) in N, N-dimethylformamide (100 ml) was stirred at 60°C for 72 hours. The mixture was diluted with ethyl acetate, and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give (R) - { 2- [ 4- (3-cyanopyridin-2- yloxy) phenyl] -1-hydroxymethylethyl Jcarbamic acid tert-butyl ester (9.13 g) as a colorless powder. MALDI-MS (m/z) : 392 (M+Na)
Preparation 32 To a solution of (R) - { 2- [4- (3-cyanopyridin-2-yloxy) - phenyl] -1-hydroxymethylethyl } carbamic acid tert-butyl ester (9.13 g) in dioxane (20 ml) was added 4N hydrogen chloride in dioxane (10 ml) at room temperature, and the solution was stirred at the same temperature overnight. The mixture was evaporated in vacuo, and the residue was triturated with ethyl acetate to give (2R) -2-amino-3- [ 4- (3-cyanopyridin-2- yloxy) phenyl] propanol dihydrochloride (7.69 g) .
MS (m/z) : 392 (M+l)
Preparation 33
Thionyl chloride (32.2 ml) was added dropwise to a solution of (R, S) -2-amino-3- (3-hydroxyphenyl) propionic acid hydrochloride (20.0 g) in methanol (200 ml) under ice water cooling over 10 minutes and the mixture was stirred at room temperature for 3 hours. The mixture was evaporated in vacuo and the residue was triturated with diisopropyl ether to give (R, S) -2-amino-3- (3-hydroxyphenyl) propionic acid methyl ester hydrochloride (25.57 g) . NMR (DMSO-d6, δ) : 2.90-3.15 (2H, m) , 3.68 (3H, s) , 4.18
(1H, t, J=6Hz), 6.60-6.70 (3H, m) , 7.10 (1H, t, J=8Hz), 8.60-8.70 (1H, br s) , 9.50-9.60 (1H, br s) MS (m/z) : 196 (M+l)
Preparation 34
A solution of (R, S) -2-amino-3- (3-hydroxyphenyl) propionic acid methyl ester hydrochloride (25.57 g) , di-tert-butyl dicarbonate (21.15 g) and triethylamine (50.9 ml) in dioxane (500 ml) was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate, and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated in vacuo to give (R, S) -2-tert-butoxycarbonylamino-3- (3-hydroxyphenyl) propionic acid methyl ester (28.14 g) as a colorless powder.
NMR (DMSO-dβ, δ): 1.33 (9H, s), 2.70-2.95 (2H, m) , 3.60 (3H, s), 3.97-4.17 (1H, m) , 6.60-6.70 (3H, m) , 7.05-7.33 (1H, m) , 9.28 (1H, br s)
Preparation 35
Under nitrogen, to a solution of (R, S) -2-tert- butoxycarbonylamino-3- (4-hydroxyphenyl) propionic acid methyl ester (28.14 g) in tetrahydrofuran (300 ml) was added lithium borohydride (5.19 g) at 5°C, and the mixture was stirred at the same temperature for 5 hours. The mixture was evaporated in vacuo. To the residue was added water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give (R,S)- [ 1- ( 4-hydroxybenzyl ) -2-hydroxyethyl] carbamic acid tert-butyl ester (26.73 g) as a colorless powder.
NMR (CD3C1, δ) : 1.41 (9H, s), 2.70-2.80 (2H, d, J=7Hz), 3.50-3.80 (3H, ) , 6.60-6.75 (3H, m) , 7.05-7.23 (1H, m)
Preparation 36
The following compound was synthesized according to a similar manner to that of Preparation 31.
(R, S) -{2- [3- (3-Cyanopyridin-2-yloxy) phenyl] -1- hydroxymethylethyl } carbamic acid tert-butyl ester as a colorless form
NMR (DMSO-d6, δ): 2.50-2.60 (1H, m) , 2.80-3.00 (1H, m) , 3.30-3.40 (1H, m) , 3.50-3.60 (1H, m) , 4.60-4.70
(1H, m) , 7.00-7.15 (3H, m) , 7.30-7.40 (2H, m) , 8.30-8.40 (2H, )
Preparation 37 Under nitrogen, a mixture of (S) - [l-hydroxymethyl-2- (4- hydroxyphenyl) ethyl] carbamic acid tert-butyl ester (5.0 g) , 2-chloro-3-nitropyridine (1.52 g) , potassium carbonate (1.56 g) and N, N-dimethylformamide (50 ml) was stirred at 60°C for 72 hours. The mixture was diluted with ethyl acetate, and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give (S) -{ 2- [ 4- (3-nitropyridin-2-yloxy) phenyl] -1-hydroxymethylethyl } carbamic acid tert-butyl ester (4.11 g) as a yellow form.
MS (m/z) :389 (M+l)
Preparation 38
To a solution of ( IS) - { l-hydroxymethyl-2- [4- (3- nitropyridin-2-yloxy) phenyl] ethyl } carbamic acid tert-butyl ester (4.11 g) in methanol (20 ml) was added 4N hydrogen chloride in dioxane (20 ml) at room temperature, and the solution was stirred at the same temperature overnight. The mixture was evaporated in vacuo, and the residue was triturated with diisopropyl ether to give (2S) -2-amino-3- [4- (3-nitropyridin-2-yloxy) phenyl] propanol hydrochloride (3.2 g) as a yellow powder. MS (m/z) : 290 (M+l)
Preparation 39
Under nitrogen, a solution of (2S) -2- ( (2S) -2-hydroxy-3- phenoxypropylamino) -3- [4- (3-nitropyridin-2-yloxy) phenyl] - propanol (1.18 g) and di-tert-butyl dicarbonate (0.52 g) in
N, N-dimethylformamide (10 ml) was stirred at room temperature for 9 hours. The mixture was diluted with ethyl acetate and poured into water. The organic layer was washed with aqueous 10% potassium hydrogensulfate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 3:2) to give { ( IS) -l-hydroxymethyl-2- [ 4- (3-nitropyridin-2- yloxy) phenyl] ethyl } - (2S) - (2-hydroxy-3-phenoxypropyl) carbamic acid tert-butyl ester (1.34 g) . MALDI-MS (m/z) : 562 (M+Na)
Preparation 40
Under nitrogen, to a suspension of (S) - { 2- [4- (3- formylpyridin-2-yloxy) phenyl] -1-hydroxymethylethyl } carbamic acid tert-butyl ester (11.32 g) in methanol (100 ml) was added sodium borohydride (1.15 g) at 5°C, and the mixture was stirred at the same temperature for 1 hour. The mixture was evaporated in vacuo. To the residue were added water and ethyl acetate. After separation, the organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo to give (S) - { 2- [4- (3-hydroxymethylpyridin-2-yloxy) - phenyl] -1-hydroxymethylethyl } carbamic acid tert-butyl ester (9.88 g) as a colorless powder. MS (m/z) : 375 (M+l)
Preparation 41
The following compounds were synthesized according to a similar manner to that of Preparation 32.
(1) (2S)-2-Amino-3-[4- ( 3-hydroxymethylpyridin-2-yloxy) - phenyl] propanol hydrochloride (6.88 g) as a colorless powder
MS (m/z) : 275 (M+l)
(2) 2- [4- (2-Amino-3-hydroxypropyl) phenoxy] nicotinamide dihydrochloride (13.37 g) as a colorless powder NMR (CD3OD, δ) : 2.80-3.10 (2H, m) , 3.50-3.80 (3H, m) , 7.10-7.42 (5H, m) , 8.10-8.20 (1H, m) , 8.30-8.40 (1H, m) MS (m/z) : 288 (M+l) Preparation 42
A solution of (S) - { 2- [4- (3-cyanopyridin-2-yloxy) phenyl ] - 1-hydroxymethylethyl } carbamic acid tert-butyl ester in methyl sulfoxide (540 ml) was added dropwise 30% hydrogen peroxide (54 ml) under ice cooling, and the solution was stirred at the same temperature for 30 minutes. The mixture was added 5N sodium hydroxide- (54 ml) and stirred at room temperature for 1 hour. The resulting mixture was acidified with hydrochloric acid to pH 3 and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give (S)-2- [4- (2-tert-butoxycarbonylamino-3-hydroxypropyl ) phenoxy] - nicotinamide (17.99 g) as a colorless powder. NMR (CDC13, δ) : 1.50 (9H, s) , 2.90 (2H, d, J=7Hz) , 3.50-
3.90 (3H, m) , 7.00-7.32 (5H, m) , 8.20-8.30 (1H, m) , 8.50-8.60 (1H, m)
Preparation 43 To a solution of (S) - { l-hydroxymethyl-2- [ 4- ( 3-hydroxy- methylpyridin-2-yloxy) phenyl] ethyl } carbamic acid tert-butyl ester (3.4 g) in a mixture of 1,4-dioxane (4 ml) and tetrahydrofuran (6 ml) was added 4N hydrogen chloride in 1,4- dioxane (10 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. After evaporation in vacuo, the residue was triturated with hexane and dried in vacuo to give (S) -2-amino-3- [4- (3-hydroxymethylpyridin-2- yloxy) phenyl] propan-1-ol dihydrochloride (4.1 g) .
NMR (DMSO-d6, δ): 2.6-3.05 (2H, m) , 3.1-3.8 (3H, m) , 4.62 (2H, s), 7.05 (2H, d, J=8.5Hz), 7.15 (1H, ABq,
J=4.9, 7.3Hz), 7.30 (2H, d, J=8.5Hz), 7.8-8.1 (2H, m)
Preparation 44 Under nitrogen, powdered potassium hydroxide (74 g) was added to dimethylsulfoxide (5 ml) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. To this one were added (S) -[ l-hydroxymethyl-2- (4- hydroxyphenyl) ethyl] carbamic acid tert-butyl ester (300 mg) and 2-chloropyrimidine (129 mg) , and the mixture was stirred at room temperature for 24 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 1:1 to 1:2) to give (S) -{ l-hydroxymethyl-2- [4- (pyrimidin-2-yloxy) phenyl ] ethyl } carbamic acid tert-butyl ester ( 300 mg) .
NMR (CDC13, δ) : 1.42 (9H, s), 2.87 (2H, d, J=7.1Hz),
3.5-4.0 (3H, m) , 7.04 (1H, t, J=4.8Hz), 7.13 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.5Hz), 8.56 (2H, d, J=4.8Hz)
Preparation 45
The following compounds were obtained according to a similar manner to that of Preparation 43.
(1) (S) -2- [4- (2-Amino-3-hydroxypropyl) phenoxy] nicotinic acid ethyl ester dihydrochloride (460 mg)
NMR (DMSO-d6, δ) : 1.3 (3H, t, J=7.1Hz), 2.75-3.15 (2H, m) , 3.25-3.85 (2H, m) , 4.1-4.5 (3H, m) , 6.77 (1H, d, J=8.4Hz), 7.05-7.4 (4H, m) , 8.2-8.4 (2H, m)
(2 ) (S) -2-Amino-3- [ 4- (pyrimidin-2-yloxy) phenyl] propan-1- ol dihydrochloride (230 mg)
NMR (DMSO-d6, δ) : 2.75-3.05 (2H, m) , 3.25-3.65 (3H, m) , 7.16 (2H, d, J=8.5Hz), 7.27 (1H, t, J=4.8Hz), 7.34 (2H, d, J=8.5Hz), 8.65 (2H, d, J=4.8Hz) (3) (S) -2-Amino-3- [4- (pyrazin-2-yloxy) phenyl] propan-1-ol dihydrochloride (190 mg)
NMR (DMSO-d6, δ) : 2.75-3.1 (2H, m) , 3.2-3.7 (3H, m) , 7.17 (2H, d, J=8.5Hz), 7.36 (2H, d, J=8.5Hz), 8.1-
8.3 (1H, m) , 8.38 (1H, d, J=2.7Hz), 8.53 (1H, m)
Preparation 46
The following compound was obtained according to a similar manner to that of Preparation 44.
(S) - { 1-Hydroxymethyl-2- [4- (pyrazin-2-yloxy) phenyl] ethyl } carbamic acid tert-butyl ester (190 mg)
NMR (CDC13, δ) : 1.43 (9H, s), 3.5-3.75 (2H, m) , 3.8-3.95 (1H, m) , 7.05-7.15 (2H, m) , 7.2-7.35 (2H, m) , 8.08-
8.10 (1H, m) , 8.26 (1H, d, J=2.7Hz), 8.14 (1H, m)
Preparation 47
Under nitrogen, to a solution of (S) - [ l-hydroxymethyl-2- (4-hydroxyphenyl) ethyl] carbamic acid tert-butyl ester (24 g) in dichloromethane (500 ml) were added 2, 2-dimethoxypropane (34 ml) and p-toluenesulfonic acid monohydrate (1.7 g) at room temperature, and the mixture was stirred at the same temperature for 60 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to get a solid. To the solid was added hexane so as to triturate and then the slurry was stirred for 12 hours, followed by filtration and dryness in vacuo to give (S) -4- (4-hydroxybenzyl) -2, 2- dimethyloxazolidine-3-carboxylic acid tert-butyl ester (22 g).
NMR (DMSO-d6, δ) : 1.3-1.55 (15H, m) , 2.4-2.6 (1H, m) , 2.8-2.95 (1H, m) , 3.6-4.0 (3H, m) , 6.69 (2H, d, J=8 . 2Hz ) , 6 . 98 ( 2H , d, J=8 . 4Hz )
Preparation 48
Under nitrogen, to a suspension of 2-chloroisonicotinic acid (2.0 g) in methanol (50 ml) was added a catalytic amount of concentrated sulfuric acid at room temperature, and the mixture was refluxed for 11 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give methyl 2- chloroisonicotinate (2.0 g) .
NMR (CDC13, δ) : 3.98 (3H, s), 7.75-7.8 (1H, m) , 7.89 (1H, m) , 8.55 (1H, d, J=5.1Hz)
Preparation 49
A solution of methyl 2-chloroisonicotinate (1.9 g) and 28% ammonium hydroxide in water (4 ml) in methanol (20 ml) was sealed with stirring for 24 hours to result in the formation of precipitates. They were collected by filtration and dried in vacuo to give 2-chloroisonicotinamide (1.1 g) . NMR (DMSO-d6, δ) : 7.75-7.85 (1H, m) , 7.87 (1H, s), 8.56 (1H, d, J=5.1Hz)
Preparation 50
Under nitrogen, powdered potassium hydroxide (210 mg) was added to dimethylsulfoxide (20 ml) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To this one were added (S) -4- (4-hydroxybenzyl) -2, 2- dimethyloxazolidine-3-carboxylic acid tert-butyl ester (980 mg) and 2-chloroisonicotinamide (500 mg) , and the mixture was stirred at 100°C for 17 hours. The resulting mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 100:1 to 50:1) to give (S)- 4- [4- (4-carbamoylpyridin-2-yloxy) benzyl] -2, 2-dimethy1- oxazolidine-3-carboxylic acid tert-butyl ester (1.0 g) . NMR (CDC13, δ) : 1.5-1.7 (15H, m) , 2.65-2.75 (1H, m) ,
3.05-3.3 (1H, m) , 3.75-3.85 (2H, m) , 3.95-4.2 (1H, m) , 7.0-7.15 (2H, m) , 7.2-7.35 (4H, m) , 8.28 (1H, d, J=5.2Hz)
Preparation 51
To a solution of (S) -4- [4- ( 4-carbamoylpyridin-2-yloxy) - benzyl] -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (1.0 g) in a mixture of 1,4-dioxane (2.5 ml) and methanol (2.5 ml) was added 4N hydrogen chloride in 1,4- dioxane (5 ml) at room temperature, and the mixture was stirred at room temperature for 6 hours. After evaporation in vacuo, the residue was triturated with hexane and dried in vacuo to give (S) -2- [4- (2-amino-3-hydroxypropyl) phenoxy] - isonicotinamide hydrochloride (800 mg) . NMR (DMSO-d6, δ): 2.8-3.1 (2H, m) , 3.3-3.65 (3H, m) ,
7.12 (2H, d, J=8.4Hz), 7.3-7.45 (3H, m) , 7.5-7.6 (1H, m) , 8.27 (1H, d, J=5.2Hz)
Preparation 52 The following compounds were obtained according to a similar manner to that of Preparation 50.
(1) (S)-4-[4- (5-Carbamoylpyridin-2-yloxy) benzyl] -2,2- dimethyloxazolidine-3-carboxylic acid tert-butyl ester (1.4 g)
NMR (CDCI3, δ) : 1.3-1.7 (15H, m) , 2.65-2.8 (1H, m) ,
3.05-3.3 (1H, m) , 3.7-4.2 (3H, m) , 6.9-7.35 (5H, m) , 8.18 (1H, ABq, J=2.5, 8.6Hz), 8.60 (1H, d, J=2.4Hz) (2) (S)-4-[4- (6-Carbamoylpyridin-2-yloxy)benzyl]-2,2- dimethyloxazolidine-3-carboxylic acid tert-butyl ester (930 mg) NMR (CDC13, δ) : 1.4-1.7 (15H, m) , 2.55-2.85 (1H, m) ,
3.1-3.3 (1H, m) , 3.75-4.2 (3H, m) , 7.05-7.15 (3H, m) , 7.2-7.4 (2H, m) , 7.8-7.95 (2H, m)
(3) (S)-4-[4- (2-Carbamoylpyridin-4-yloxy) benzyl] -2,2- dimethyloxazolidine-3-carboxylic acid tert-butyl ester (1.4 g) NMR (CDCI3, δ) : 1.45-1.7 (15H, m), 2.65-2.8 (1H, m) ,
3.05-3.3 (1H, m) , 3.75-4.2 (3H, m) , 6.95-7.1 (3H, m) , 7.2-7.4 (2H, m) , 7.8-7.9 (1H, m) , 8.4-8.45 (1H, )
(4) (S) -2,2-Dimethyl-4- [4- (3-methylcarbamoylpyridin-2- yloxy) benzyl] oxazolidine-3-carboxylic acid tert-butyl ester (970 mg)
NMR (CDCI3, δ) : 1.45-1.75 (15H, m) , 2.65-2.8 (1H, m) , 3.0-3.3 (4H, m) , 3.75-3.9 (2H, m) , 3.95-4.2 (1H, m) , 7.05-7.4 (5H, m) , 8.20 (1H, ABq, J=2.0, 4.8Hz),
8.64 (1H, ABq, J=1.9, 7.6Hz)
(5) (S) -2,2-Dimethyl-4- [4- (quinolin-2-yloxy) benzyl ] - oxazolidine-3-carboxylic acid tert-butyl ester (650 mg) NMR (CDCI3, δ) : 1.5-1.7 (15H, m) , 2.65-2.8 (1H, m) ,
3.1-3.3 (1H, m) , 3.8-4.25 (3H, m) , 7.08 (1H, d, J=8.8Hz), 7.15-7.5 (5H, m) , 7.55-7.7 (1H, m) , 7.75- 7.85 (2H, m) , 8.12 (1H, d, J=8.8Hz)
Preparation 53
The following compound was obtained according to a similar manner to that of Preparation 48.
The obtained crude methyl 6-bromopicolinate was used successively in next step. Preparation 54
A solution of methyl 6-bromopicolinate obtained the previous step, and 28% ammonium hydroxide in water (6 ml) in methanol (40 ml) was sealed with stirring for 12 hours. The resulting mixture was evaporated in vacuo and dried to give 6-bromopicolinamide (2.8 g) .
(+) APCI-MS (m/z): 201, 203 (M+l) +
Preparation 55
The following compounds were obtained according to a similar manner to that of Preparation 51.
(1) (S)-6-[4- (2-Amino-3-hydroxypropyl) phenoxy] nicotinamide hydrochloride (1.1 g)
NMR (DMSO-d6, δ) : 2.8-3.05 (2H, m) , 3.3-3.7 (3H, m) , 7.05-7.2 (2H, d, J=8.5Hz), 8.28 (1H, ABq, J=2.5, 8.6Hz), 8.63 (1H, d, J=2.4Hz)
(2) (S) -6- [4- (2-Amino-3-hydroxypropyl) phenoxy] pyridine-2- carboxylic acid amide hydrochloride (690 mg) NMR (DMSO-d6, δ) : 2.8-3.1 (2H, m) , 3.3-3.7 (3H, m) ,
7.1-7.55 (5H, m) , 7.7-7.9 (1H, m) , 8.0-8.15 (1H, )
(3) (S) -4- [4- (2-Amino-3-hydroxypropyl) phenoxy] pyridine-2- carboxylic acid amide hydrochloride (1.1 g) NMR (DMSO-d6, δ): 2.85-3.15 (2H, m) , 3.3-3.8 (4H, m) , 7.25 (2H, d, J=8.4Hz), 7.36 (1H, ABq, J=2.6, 6.0Hz), 7.48 (2H, d, J=8.4Hz), 7.87 (1H, d, J=2.3Hz), 8.64 (1H, d, J=6.2Hz)
(4) (S) -2- [4- (2-Amino-3-hydroxypropyl) phenoxy] -N- methylnicotinamide hydrochloride (730 mg) NMR (DMSO-d6, δ): 2.7-3.0 (5H, m) , 3.3-3.7 (3H, m) , 7.05-7.4 (5H, m) , 8.1-8.2 (2H, m) (5) (S) -2-Amino-3- (4-phenoxyphenyl) propan-1-ol hydrochloride (730 mg)
NMR (DMSO-d6, δ) : 2.75-3.0 (2H, m) , 3.25-3.7 (3H, m) , 6.9-7.1 (4H, m) , 7.14 (1H, t, J=7.2Hz), 7.25-7.5 (4H, m)
(6) (S) -2-Amino-3- [4- (4-chlorophenoxy) phenyl] propan-1-ol hydrochloride (980 mg)
NMR (DMSO-d6, δ): 2.75-3.05 (2H, m) , 3.2-3.75 (3H, m) , 6.95-7.1 (4H, m) , 7.25-7.5 (4H, m)
(7 ) (S) -2-Amino-3- [4- (naphthalen-1-yloxy) phenyl ] propan-1-ol hydrochloride (630 mg)
NMR (DMSO-d6, δ) : 2.75-3.0 (2H, m) , 3.2-3.7 (3H, ) , 6.9-7.1 (3H, m) , 7.30 (2H, d, J=8.5Hz), 7.45-7.65
(3H, m) , 7.74 (1H, d, J=8.2Hz), 7.9-8.3 (2H, m)
(8) (S) -2-Amino-3- [4- (quinolin-2-yloxy) phenyl ] propan-1-ol dihydrochloride (550 mg) NMR (DMS0-d6, δ) : 2.8-3.1 (2H, m) , 3.3-3.7 (3H, m) ,
7.2-7.55 (6H, m) , 7.6-7.7 (1H, m) , 7.97 (1H, d, J=7.9Hz), 8.43 (1H, d, J=8.8Hz)
(9) (S) -2-Amino-3- [4- (quinolin-3-yloxy) phenyl] propan-1-ol dihydrochloride (1.3 g)
NMR (DMS0-d6, δ): 2.8-3.15 (2H, m) , 3.25-3.7 (3H, m) ,
7.18 (2H, d, J=8.4Hz), 7.40 (2H, d, J=8.5Hz), 7.65- 8.5 (5H, m) , 8.9-9.0 (1H, m)
(10) (S) -2-Amino-3- (4-phenylsulfanylphenyl) propan-1-ol hydrochloride (560 mg)
NMR (DMSO-d5, δ): 2.75-3.0 (2H, m) , 3.25-3.6 (3H, m) , 7.25-7.5 (9H, m)
Preparation 56 Under nitrogen, a mixture of picolinic acid (5 g) and thionyl chloride (12.5 ml) was refluxed for 180 hours. The reaction mixture was diluted with chloroform, and cooled in an ice bath. To this one was added methanol (30 ml) dropwise and the mixture was stirred at the same temperature for 1 hour, followed by evaporation in vacuo. The residue was dissolved in a mixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (toluene : chloroform = 5:1 to 1:5) to give methyl 4- chloropicolinate (3.3 g) .
NMR (CDC13, δ) : 4.03 (3H, s), 7.52 (1H, ABq, J=2.0, 5.2Hz), 8.15 (1H, d, J=2.0Hz), 8.66 (1H, d,
J=5.2Hz)
Preparation 57
The following compound was obtained according to a similar manner to that of Preparation 49.
4-Chloropicolinamide (2.4 g)
NMR (DMSO-d6, δ) : 7.77 (1H, ABq, J=2.1, 5.3Hz), 8.04 (1H, d, J=2.1Hz), 8.63 (1H, d, J=5.3Hz)
Preparation 58
Under nitrogen, a solution of 2-chloronicotinic acid (4.0 g) in N, N-dimethylformamide (40 ml) were added methylamine hydrochloride (1.9 g) , 1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide (5.1 ml) and 1-hydroxybenzotriazole (3.8 g) at 5°C, and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into IN aqueous sodium hydroxide and the aqueous mixture was extracted with ethyl acetate 7 times. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatograpy on silica gel (chloroform:methanol = 50:1) to give N-methyl-2- chloronicotinamide (2.9 g) .
NMR (CDC13, δ) : 2.95-3.05 (3H, m) , 7.32 (1H, ABq, J=7.7Hz), 8.00 (1H, ABq, J=2.0, 7.6Hz), 8.41 (1H,
ABq, J=2.0, 4.8Hz)
Preparation 59
To a mixture of (S) -4- (4-hydroxybenzyl ) -2, 2- dimethyloxazolidine-3-carboxylic acid tert-butyl ester (1.0 g) , phenylboronic acid (790 mg) , copper(II) acetate (590 mg) and powdered molecular sieves 4A (1.0 g) were added dichloromethane (33 ml) and pyridine (1.3 ml) at room temperature, and the mixture was stirred at the same temperature for 48 hours. After removal of insoluble materials by filtration, the filtrate was poured into 0. IN hydrochloric acid and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane : chloroform = 1:1 to only chloroform) to give (S) -2, 2-dimethyl-4- (4-phenoxybenzyl) oxazolidine-3- carboxylic acid tert-butyl ester (1.0 g) . NMR (CDCI3, δ) : 1.4-1.75 (15H, m) , 2.6-2.75 (1H, m) ,
3.0-3.3 (1H, m) , 3.7-4.2 (4H, m) , 6.9-7.4 (9H, m)
Preparation 60
The following compound was obtained according to a similar manner to that of Preparation 59.
(1) (S) -4- [4- (4-Chlorophenoxy) enzyl] -2, 2-dimethyl- oxazolidine-3-carboxylic acid tert-butyl ester (1.4 g) . NMR (CDCI3, δ) : 1.45-1.7 (15H, m) , 2.6-2.75 (1H, m) , 3.05-3.25 (1H, m) , 3.7-4.2 (3H, m) 6.9-7.0 (4H, m) , 7 . 1 -7 . 3 ( 4H , m)
(2) (S) -2, 2-Dimethyl-4- [4- (naphthalen-1-yloxy) benzyl] - oxazolidine-3-carboxylic acid tert-butyl ester (870 mg) NMR (CDC13, δ) : 1.45-1.7 (15H, m) , 2.6-2.75 (1H, m) ,
3.0-3.25 (1H, m) , 3.75-4.2 (3H, m) , 6.85-7.05 (3H, m) , 7.1-7.65 (6H, m) , 7.85-7.9 (1H, m) , 8.15-8.25 (1H, m)
(3) (S)-2,2-Dimethyl-4-[4-(quinolin-3-yloxy)benzyl]- oxazolidine-3-carboxylic acid tert-butyl ester (1.6 g) NMR (CDCI3, δ) : 1.45-1.7 (15H, m) , 2.65-2.8 (1H, m) , 3.05-3.3 (1H, m) , 3.75-4.2 (3H, m) , 7.04 (2H, d, J=7.9Hz), 7.15-7.35 (2H, m) , 7.5-7.8 (4H, m) , 8.1- 8.2 (1H, m) , 8.80 (1H, d, J=2.8Hz)
Preparation 61
Under nitrogen, to a solution of 3-bromoquinoline (3.3 ml) and triisopropyl borate (7.8 ml) in tetrahydrofuran (50 ml) was added n-butyl lithium (1.52M in hexane, 22 ml) dropwise in acetone-dry ice bath, and the mixture was stirred at the same temperature for 1 hour and then allowed to warm to room temperature by removal of the bath. The mixture was poured into 2N hydrochloric acid and adjusted to pH 5 with 5N aqueous sodium hydroxide. After separation, the organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with hexane and dried in vacuo to give 3-quinolinylboronic acid (4.4 g) . NMR (CDCI3, δ) : 7.55-7.7 (1H, m) , 7.75-7.85 (1H, m) ,
8.00 (2H, t, J=7.3Hz), 8.73 (1H, s), 9.19 (1H, d, J=1.6Hz)
Preparation 62 To a solution of 4-chloroquinoline-7-carboxylic acid (2.6 g) was added potassium hydroxide (870 mg) at room temperature, and the mixture was stirred at the same temperature for 12 hours. The mixture was evaporated and dried in vacuo. Under nitrogen, to a solution of the potassium salts in N, N-dimethylformamide (60 ml) was added iodoethane (1.0 ml) at room temperature, and the mixture was stirred at 80°C for 1.5 hours. The mixture was poured into ice-cold water with stirring to generate a precipitate. After stirred for 20 minutes, the precipitate was collected by filtration and immediately the filter cake was dissolved in ethyl acetate. The solution was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (toluene : ethyl acetate = 20:1 to 5:1) to give ethyl 4- chloroquinoline-7-carboxylate (2.3 g) .
NMR (CDC13, δ) : 1.46 (3H, t, J=7.1Hz), 4.48 (2H, q,
J=7.1Hz), 7.59 (1H, d, J=4.7Hz), 8.2-8.35 (2H, m) , 8.85-8.9 (2H, m)
Preparation 63
A mixture of ethyl 4-chloroquinoline-7-carboxylate (470 mg) and 2M ammonium hydroxide in methanol (30 ml) was sealed with stirring at 100°C for 60 hours. The reaction mixture was evaporated and dried in vacuo to give 4-chloroquinoline- 7-carboxylic acid amide (420 mg) .
NMR (DMSO-d6, δ): 7.86 (1H, d, J=4.7Hz), 8.15-8.45 (2H, m) , 8.65 (1H, d, J=1.3Hz), 8.94 (1H, d, J=4.7Hz)
Preparation 64 Under nitrogen, to a solution of (S)-4-(4- hydroxybenzyl ) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (10 g) in dichloromethane (100 ml) were added 2,6-lutidine (4.2 ml) and trifluoromethanesulfonic anhydride (6.0 ml) at 5°C, and the mixture was stirred at the same temperature for 80 minutes. The reaction mixture was poured into ice-cold 0. IN hydrochloric acid and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 10:1) to give trifluoromethanesulfonic acid (S)-4- (3-benzyl-2, 2-dimethyloxazolidin-4-ylmethyl) phenyl ester (13 g) • NMR (CDC13, δ) : 1.35-1.7 (15H, m) , 2.65-2.85 (1H, m) ,
3.05-3.3 (1H, m) , 3.7-4.2 (3H, m) , 7.15-7.4 (4H, m)
Preparation 65
Under nitrogen, to a solution of benzenethiol (0.94 ml) in tetrahydrofuran (30 ml) was added dropwise n-butyl lithium (1.52M in hexane, 6.0 ml) in acetone-dry ice bath, and the mixture was stirred at the same temperature for 20 minutes. Under nitrogen, to a solution of trifluoromethanesulfonic acid (S) -4- (3-benzyl-2, 2-dimethyloxazolidin-4-ylmethyl) phenyl ester (3.6 g) , lithium chloride (770 mg) and tetrakis (triphenylphosphine) palladium (0) (1.9 g) in tetrahydrofuran (40 ml) was added the above prepared solution at room temperature, and the mixture was refluxed for 40 minutes. The mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 20:1 to 10:1) to give (S) -2, 2-dimethyl-4- (4-phenylsulfanyl- benzyl) oxazolidine-3-carboxylic acid tert-butyl ester (1.8 g).
NMR (CDCI3, δ) : 1.4-1.7 (15H, m) , 2.55-2.75 (1H, m) ,
3.0-3.25 (1H, m) , 3.7-4.2 (3H, m) , 7.1-7.4 (9H, m)
Preparation 66 Under nitrogen, to a solution of (S) -4- (2-amino-3- hydroxypropyl) phenol hydrochloride (5.0 g) in methanol (50 ml) was added 28% sodium methoxide in methanol (4.7 ml) at 5°C, and the mixture was stirred at the same temperature for 10 minutes. After removal of insoluble materials by filtration, the filtrate was evaporated and dried in vacuo. A mixture of the residue and benzaldehyde (2.5 ml) in toluene (50 ml) in the presence of a catalytic amount of p- toluenesulfonic acid monohydrate was refluxed for 2 hours to remove water as the toluene azeotrope, and then the mixture was evaporated in vacuo. To a solution of the residue in methanol (50 ml) was added sodium borohydrite (930 mg) under nitrogen at 5°C, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into ice-cold water with stirring. After 20 minutes, ethyl acetate and brine were added, followed by separation. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 20:1 to 10:1) to give (S)-4-(2- benzylamino-3-hydroxypropyl) phenol (6.3 g) .
NMR (DMSO-d6, δ): 2.45-2.75 (3H, ) , 3.15-3.45 (2H, m) , 3.73 (2H, s), 6.6-6.7 (2H, m) , 6.9-7.0 (2H, m) , 7.15-7.35 (5H, m)
Preparation 67
The following compounds were obtained according to a similar manner to that of Example 57.
(1) 4- ( (2S)-2-{Benzyl [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino} -3-hydroxypropyl) phenol (4.3 g) NMR (CDC13, δ) : 2.4-2.95 (4H, m) , 3.0-3.2 (1H, m) ,
3.45-3.9 (4H, m) , 4.3-4.45 (1H, m) , 6.66 (2H, d, J=8.4Hz), 6.85 (2H, d, J=8.4Hz), 6.95-7.4 (9H, m) (2) 4- ( (2S) -2-{Benzyl [ (2R) -2- (4-benzyloxy-3-nitroρhenyl) -2- hydroxyethyl] amino} -3-hydroxypropyl) phenol (1.4 g) NMR (CDC13, δ) : 2.5-2.95 (4H, m) , 3.1-3.25 (1H, m) , 3.5- 3.9 (4H, m) , 4.3-4.4 (1H, m) , 5.16 (2H, s) , 6.71 (2H, d, J=8.4Hz), 6.9-7.0 (3H, m) , 7.1-7.5 (11H, m) , 7.62 (1H, d, J=2.1Hz)-
Preparation 68
Potassium hydroxide powder (85% purity, 236 mg, 3.58 mmol) was added to 10 ml of dimethyl sulfoxide and the mixture was stirred at room temperature for 20 minutes. To the resulting solution was added (S) -4- ( 4-hydroxybenzyl) -2 , 2- dimethyloxazolidine-3-carboxylic acid tert-butyl ester (1.00 g, 3.25 mmol) and the whole was stirred for additional 10 minutes. Then a solution of 4-chloroquinoline (585 mg, 3.58 mmol) in dimethyl sulfoxide (1 ml) was added and the whole was heated to 100°C, stirred for 5 hours. After cooling to room temperature, the mixture was quenched by the addition of water (20 ml) and extracted with ethyl acetate (20 ml x 1 ) . The extract was washed with water (20 ml x 1) and brine (20 ml x 1), dried (magnesium sulfate), and then evaporated to give a yellow solid (1.38 g) . The crude solid was chromatographed on a 40 g of silica gel (eluent: hexane/ethyl acetate = 4/1 to 2/1) to give (S) -2, 2-dimethyl-4- [4- (quinolin-4-yloxy) benzyl] oxazolidin-3-carboxylic acid tert- butyl ester (1.29 g, 92%) as a white solid.
NMR (CDCI3, δ) : 1.49-1.65 (15H, m) , 2.70-2.81 (1H, m) , 3.11-3.19 (1H, m) , 3.78-3.91 (2H, m) , 3.99-4.13 (1H, ) , 6.55 (1H, d, J=5.2Hz), 7.11-7.15 (2H, m) , 7.54-7.62 (1H, m) , 7.73-7.80 (1H, m) , 8.10 (1H, d,
J=8.4Hz), 8.36 (1H, d, J=7.2Hz), 8.67 (1H, d, J=5.2Hz) MS: 435 (M+l)
Preparation 69 To a solution of (S) -2, 2-dimethyl-4- [4- (quinolin-4- yloxy) benzyl] oxazolidin-3-carboxylic acid tert-butyl ester (679 mg, 1.56 mmol) in dioxane (6.0 ml) was added 4N hydrogen chloride in dioxane (6.0 ml, 24 mmol) at room temperature and the mixture was stirred at the same temperature for 90 minutes. The solvent was removed by evaporation to give (S)- 2-amino-3- [4- (quinolin-4-yloxy) phenyl] propan-1-ol dihydrochloride (920 mg, 161 mmol) as a pale yellow solid.
MS: 295 (M-HC1-C1")
Preparation 70
Potassium hydroxide powder (85% purity, 236 mg, 3.58 mmol) was added to 10 ml of dimethyl sulfoxide and the mixture was stirred at room temperature for 1 hour. To the resulting solution was added (S) -4- (4-hydroxybenzyl ) -2 , 2- dimethyloxazolidine-3-carboxylic acid tert-butyl ester (1.00 g, 3.25 mmol) and the whole was stirred for additional 10 minutes. A solution of 5-chloro-imidazo [1 , 2-α] pyridine (546 mg, 3.58 mmol) in dimethyl sulfoxide (1 ml) was added and the whole was warmed to 100°C then stirred at the same temperature for 2 hours. After cooling to room temperature, the mixture was quenched by the addition of water (20 ml) and extracted with ethyl acetate (20 ml x 1) . The extract was washed with water (20 ml x 2) brine (20 ml x 1), dried (MgSO^), and evaporated to give a crude oil (1.32 g) . The crude oil was chromatographed on a 26 g of silica gel (eluent: hexane/ethyl acetate = 1/1) to give 4- [4- (imidazo [1, 2-α] pyridine-5-yloxy) benzyl] -2, 2-dimethy1- oxazolidine-3-carboxylic acid tert-butyl ester (1.05 g, 76%) as a yellow paste. MS: 446 (M+l)
Preparation 71
To a solution of 4- [4- (imidazo [ 1, 2-α] pyridine-5-yloxy) - benzyl ] -2, 2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (994 mg, 2.35 mmol) in dioxane (10 ml) was added 4N hydrogen chloride in dioxane (10 ml) at room temperature and the solution was stirred at the same temperature for 1 hour. The solvent was removed under reduced pressure to give a pale yellow solid. The solid was dissolved in saturated aqueous solution of sodium hydrogencarbonate (15 ml) was extracted with dichloromethane (15 ml x 5) . The extracts were combined and dried (magnesium sulfate), then evaporated to give (S)-2- amino-3- [4- (imidazo [ 1, 2-α] pyridine-5-yloxy) phenyl] propan-1- ol (589 mg, 88%) as a pale yellow paste. MS: 284 (M+l)
Preparation 72
To a solution of (S) -2-amino-3- [ 4- (imidazo [1, 2-a] - pyridin-5-yloxy) phenyl] propan-1-ol (208 mg, 0.734 mmol) in 1, 3-dimethyl-2-imidazolidinone (2.0 ml) were successively added (S) -N- [2-benzyloxy-5- [2-iodo-l- ( triethylsilyloxy) - ethyl] phenyl] methanesulfonamide (495 mg, 0.881 mmol) and diisopropylethylamine (192 μl, 1.10 mmol). The solution was warmed to 100°C and stirred for 5 hours. After cooling to room temperature, 10 ml of water was added and the mixture was extracted with ethyl acetate (100 ml x 1) . The extract was washed with water (10 ml x 2 ) , brine (10 ml x 1), dried (magnesium sulfate), and evaporated to give a crude oil (545 mg) . The oil was chromatographed on a 50 g of silica gel
(eluent: chloroform/methanol = 95/5) to give N- [2-benzyloxy- 5-[ (IR) -2-[ (lS)-2-hydroxy-l-[4- (imidazo [ 1 , 2-a] pyridin-5- yloxy) benzyl] ethylamino] -1- (triethylsilyloxy) ethyl] phenyl] - methanesulfonamide (160 mg, 30%) as a colorless oil. NMR (CDC13, δ) : 0.53 (6H, q, J=7.7Hz), 0.88 (9H, t,
J=7.7Hz), 1.65 (2H, br s), 2.69-2.85 (5H, m) , 2.89 (3H, s), 3.21-3.27 (1H, m) , 3.53 (1H, dd, J=3.5, 10.7Hz), 4.74 (1H, t, J=5.0Hz), 5.08 (2H, s), 5.96 (1H, d, J=7.4Hz), 6.78 (1H, br s), 6.89-7.78 (16H, m, ArH) MS : 717 (M+l )
Preparation 73
Potassium hydroxide powder (85% purity, 236 mg, 3.58 mmol) was added to 10 ml of dimethyl sulfoxide and the mixture was stirred at the room temperature for 45 minutes. To the mixture was added (S) -4- (4-hydroxybenzyl ) -2, 2- dimethyloxazolidine-3-carboxylic acid tert-butyl ester (1.00 g, 3.25 mmol) and the whole was stirred for additional 5 minutes. Further, a solution of 2-chloro-N, N- dimethylnicotinamide (546 mg, 3.58 mmol) in dimethyl sulfoxide (1 ml) was added and the whole was warmed to 100°C. The mixture was stirred at the same temperature for 3 hours then at 120°C for 8 hours. After cooling to room temperature, the reaction mixture was quenched by the addition of water (20 ml) and extracted with ethyl acetate (20 ml x 1) . The extract was washed with water (20 ml x 2 ) , brine (20 ml x 1), dried (magnesium sulfate), then evaporated to give a pale yellow foam (1.34 g) . The crude product was chromatographed on a 40 g of silica gel (eluent: hexane/ethyl acetate = 2/1 to 1/1, then 1/2) to give (S) -4- [4- [3- (dimethyl carbamoyl) pyridin-2-yloxy] benzyl] -2,2- dimethyloxazolidine-3-carboxylic acid tert-butyl ester (878 mg, 59%) as a white foam. IR (KBr) : 1695, 1643, 1419 1390 crn-1
NMR (CDC13, δ) : 1.48-1.57 (15H, m) , 2.61-2.72 (1H, m) ,
3.03 (3H, s), 3.06-3.29 (1H, m) , 3.14 (3H, s), 3.79 (2H, d, J=3.1Hz), 3.89-4.18 (1H, m) , 7.05-7.09 (3H, m) , 7.21-7.27 (2H, m) , 7.75 (1H, dd, J=1.9, 7.3Hz), 8.17 (1H, dd, J=1.9, 5.0Hz)
MS: 478 (M+Na+)
Preparation 74
To a solution of (S) -4- [ 4- [3- (dimethylcarbamoyl) pyridin- 2-yloxy] benzyl] -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (866 mg, 1.90 mmol) in a mixed solvent of dioxane (4.0 ml) and methanol (4.0 ml) was added 4N hydrogen chloride in dioxane (8.0 ml) at room temperature. After stirring for 4 hours, the solvent was removed by evaporation to give (S) -2- [4- (2-amino-3-hydroxypropyl ) phenoxy] -N, N- dimethylnicotinamide hydrochloride (809 mg, 110%) as a pale yellow solid.
NMR (DMSO-d6, δ): 2.77-2.89 (2H, m) , 2.92 (3H, s), 3.01 (3H, s), 3.23-3.70 (3H, m) , 4.77 (1H, br) , 7.09 (2H, d, J=8.4Hz), 7.21 (1H, dd, J=4.9, 7.3Hz), 7.31
(2H, d, J=8.4Hz), 7.83 (1H, dd, J=1.8, 7.3Hz), 8.16 (1H, dd, J=1.8, 4.8Hz), 8.17 (3H, br) MS: 316 (M-Cl-)
Preparation 75
To a suspension of (S)-tyrosine methyl ester hydrochloride (20.0 g, 86.3 mmol) in acetonitrile (200 ml) was added dropwise triethylamine (48.1 ml, 345 mmol) at room temperature. After the addition, to the mixture was added dropwise benzyl bromide (30.8 ml, 259 mmol) over 10 minutes at room temperature. The mixture was warmed to 60°C and stirred for 20 hours. Then, additional benzyl bromide (10.3 ml, 86.6 mmol) was added and the mixture was stirred at 60°C for 12 hours. After cooling to room temperature, the mixture was quenched by the addition of water (400 ml) and extracted with ethyl acetate (400 ml) . The extract was washed with water (400 ml x 2), brine (400 ml x 1), dried (magnesium sulfate), and evaporated to give an orange oil (21.3 g) . The crude oil was chromatographed on a 500 g of silica gel (eluent: hexane/ethyl acetate = 9/1 to 7/1) to give (S)-2- dibenzylamino-3- ( 4-hydroxyphenyl) propionic acid methyl ester (15.9 g, 49.1%) as a colorless oil.
NMR (CDC13, δ) : 2.91 (1H, dd, J=8.2, 14.0Hz), 3.05 (1H, dd, J=7.3, 14.0Hz), 3.53 (2H, d, J=14.0Hz), 3.63 (1H, d, J=7.7Hz), 3.72 (3H, s, OMe) , 3.95 (2H, d, J=14.0Hz), 4.86 (1H, br s) , 6.69 (2H, d, J=8.5Hz), 6.87 (2H, d, J=8.5Hz) , 7.21-7.31 (10H, m, ArH) MS: 376 (M+l)
Preparation 76
To a solution of (S) -2-dibenzylamino-3- ( 4- hydroxyphenyl) propionic acid methyl ester (15.9 g, 42.3 mmol) in acetonitrile (160 ml) was added portionwise potassium carbonate (23.4 g, 169 mmol) at room temperature. To the mixture was added chloromethyl methyl ether (12.9 ml, 170 mmol) and the whole was stirred at room temperature for 5 •days. The mixture was quenched by the addition of water (160 ml) and the organic solvent was removed by evaporation. The residue was extracted with ethyl acetate (160 ml x 1) and washed with water (160 ml x 2), brine (160 ml x 1), dried (magnesium sulfate), and evaporated to give (S)-2- dibenzylamino-3- [4- (methoxymethoxy) phenyl] propionic acid methyl ester (17.0 g, 96%) as a colorless oil.
IR (Neat) : 2951, 1730, 1512, 1232, 1155, 1009 cm-1 NMR (CDC13, δ) : 2.92 (1H, dd, J=8.0, 14.0Hz), 3.07 (1H, dd, J=7.4, 14.0Hz), 3.41 (3H, s) , 3.52 (2H, d, J=14.0Hz), 3.63 (1H, d, J=7.7Hz), 3.73 (3H, s), 3.94 (2H, d, J=14.0Hz), 5.17 (2H, s) , 6.91 (4H, s) , 7.21-7.29 (10H, m) MS: 420 (M+l)
Preparation 77
To a solution of (S) -2-dibenzylamino-3- [4- (methoxymethoxy) phenyl] propionic acid methyl ester (591 mg, 1.41 mmol) in tetrahydrofuran (6.0 ml) were successively added sodium borohydride (53.3 mg, 1.41 mmol) and lithium iodide (189 mg, 1.41 mmol) at room temperature. After stirring for 1 hour, the reaction mixture was warmed to 60°C and stirred for 3 hours. Furthermore, additional sodium borohydride (53.3 mg, 1.41 mmol) and lithium iodide (189 mg, 1.41 mmol) were added and the mixture was refluxed for 9 hours. After cooling to room temperature, the mixture was quenched by the addition of aqueous saturated ammonium chloride solution (20 ml) . The mixture was extracted with ethyl acetate (20 ml x 2), brine (20 ml x 1), dried
(magnesium sulfate) , and evaporated to give a colorless oil (568 mg) . The crude oil was chromatographed on a 50 g of silica gel (eluent: hexane/ethyl acetate = 9/1 to 7/1) to give (S) -2-dibenzylamino-3- [4- (methoxymethoxy) phenyl] propan- l-ol (366 mg, 66%) as a white solid.
IR (KBr) : 3423 (br) , 2925, 1510, 1234, 1153, 1074,
1005 cm"1 NMR (CDC13, δ) : 2.32-2.44 (1H, m) , 2.90-3.11 (3H, ) , 3.35-3.55 (2H, m) , 3.47 (3H, s) , 3.48 (2H, d, J=13.3Hz), 3.93 (2H, d, J=13.3Hz), 5.15 (2H, s) ,
6.94 (2H, d, J=8.8Hz), 7.01 (2H, d, J=8.8Hz), 7.21- 7.37 (10H, m) MS: 392 (M+l)
Preparation 78
To a solution of (S) -2-dibenzylamino-3- [ 4- (methoxymethoxy) phenyl] propan-1-ol (319 mg, 0.815 mmol) in dimethylformamide (3.0 ml) was added sodium hydride (60% dispersion in oil, 48.9 mg, 1.22 mmol) at room temperature and the mixture was stirred at the same temperature for 80 minutes. To the mixture was added methyl iodide (76 μl, 1.22 mmol) and the mixture was stirred at room temperature for 24 hours. The mixture was quenched by the addition of water (10 ml) and extracted with ethyl acetate (10 ml x 1) . The extract was washed with brine (10 ml x 1), dried (magnesium sulfate), and evaporated to give a pale yellow oil (360 mg) . The crude oil was chromatographed on a 30 g of silica gel (eluent : hexane/ethyl acetate = 4/1) to give (S) -dibenzyl- [2- [4- (methoxymethoxy) phenyl] -1- (methoxymethyl) ethyl] amine (257 mg, 78%) as a colorless oil. IR (Neat) : 2925, 1612, 1510, 1495, 1454, 1232, 1176 cm-1 NMR (CDC13, δ) : 2.73 (1H, dd, J=7.8, 13.6Hz), 2.84 (1H, dd, J=6.7, 13.6Hz), 3.00-3.05 (1H, m) , 3.28 (3H, s), 3.38-3.56 (2H, m) , 3.49 (3H, s, OMe) , 3.75 (3H, s, OMe), 5.17 (2H, s), 6.90 (2H, d, J=8.8Hz), 6.97
(2H, d, J=8.8Hz), 7.17-7.25 (10H, m) MS: 406 (M+l)
Preparation 79 A mixture of (S) -dibenzyl [2- [ 4- (methoxymethoxy) phenyl ] -
1- (metnoxymetnyl) ethyl] amme (214 mg, 0.510 mmol), palladium (10% on activated carbon, 50% wet, 100 mg) and methanol (2.0 ml) was hydrogenated (1 atm) for 2 hours. The catalyst was removeα by filtration using Celite and washed with methanol. The filtrate was concentrated in vacuo to give (S)-2-[4-
(methoxymethoxy) phenyl] -1- (methoxymethyl ) ethylamme (113 mg, 98%) as a colorless oil.
NMR (CDCI3, δ) : 1.88 (2H, br s), 2.54 (1H, dd, J=7.5, 13.5Hz), 2.74 (1H, dd, J=4.9, 13.5Hz), 3.21-3.40 (3H, m) , 3.37 (3H, s, OMe), 3.48 (3H, s, OMe), 5.16
(2H, s), 6.98 (2H, d, J=8.6Hz), 7.12 (2H, d, J=8.6Hz) MS: 226 (M+l)
Preparation 80
To a solution of (S) -2-dιbenzylammo-3- [ 4- (methoxymethoxy) phenyl] propionic acid methyl ester (5.00 g, 11.9 mmol) in tetrahydrofuran (50 ml) was added methylmagnesium bromide (2.0M in ether, 18.0 ml, 36.0 mmol) at room temperature and the mixture was stirred for 20 minutes. The mixture was poured into a saturated aqueous solution of ammonium chloride (100 ml) and extracted with ethyl acetate (100 ml x 1 ) . The extract was washed with water (100 ml x 2), brine (100 ml x 1), dried (magnesium sulfate), and evaporated to give (S) -3-dιbenzylamιno-4- [ - (methoxymethoxy) phenyl] -2-methyl-butan-2-ol (5.03 g, 101%) as a yellow oil.
IR (Neat) : 2968, 1608, 1510, 1234, 1153, 1005 cm-1 NMR (CDC13, δ) : 1.00 (3H, s), 1.26 (3H, s), 2.79-3.13 (3H, m) , 3.34 (2H, br) , 3.51 (3H, s), 3.91 (2H, br), 4.20 (1H, br) , 5.20 (2H, s), 7.03-7.08 (2H, m) , 7.22-7.36 (12H, m) MS(m/z) : 420 (M+l)
Preparation 81
To a solution of (S) -3-dιbenzylammo-4- [ 4- (methoxymethoxy) phenyl] -2-methyl-butan-2-ol (1.00 g, 2.38 mmol) in methanol (10 ml) was added palladium (10% on activated carbon, 50%wet, 500 mg) and the mixture was hydrogenated (1 atm) for 6 hours. The catalyst was removed by filtration using Celite and washed with methanol. The filtrate was concentrated in vacuo to give (S) -3-amιno-4- [4- (methoxymethoxy) phenyl ] -2-methyl-butan-2-ol (555 mg, 97%) as a yellow solid. MS (m/z) : 240 (M+l)
Preparation 82
Potassium powder (85% purity, 236 mg, 3.58 mmoi) was added to dimethyl sulfoxide (10 ml) at room temperature and the mixture was stirred for 1 hour. To the mixture was added (S) -4- (4-hydroxybenzyl) -2, 2-dιmethyloxazolιdme-3-carboxylιc acid tert-butyl ester (1.00 g, 3.25 mmol) and stirred for 10 minutes. Further, 4 , 7-dιchloroquιnolιne (708 mg, 3.57 mmol) was added and the mixture was stirred at 100°C for 5.5 hours. After cooling to room temperature, the mixture was quenched by the addition of water (20 ml) and extracted with ethyl acetate (20 ml x 2 ) . The combined extracts were washed with water (40 ml x 2), brine (40 ml x 1), dried (magnesium sulfate), and evaporated to give crude paste (1.44 g) as a yellow paste. The paste was purified by a recycling preparative HPLC equipped with a GPC column (eluent: chloroform) to give (S) -4- [4- (7-chloroquιnolιn-4-yloxy) - benzyl ] -2 , 2-dιmethyloxazolιdme-3-carboxylιc acid tert-butyl ester (1.42 g, 93%) as a pale yellow solid. IR (KBr) : 2978, 1697 (C=0) , 1566, 1389, 1211 cm"1
NMR (CDC13, δ) : 1.49-1.67 (15H, m) , 2.70-2.82 (1H, m) , 3.11-3.28 (1H, ) , 3.78-4.13 (3H, m) , 6.54 (1H, d, J=5.2Hz), 7.10-7.14 (2H, m) , 7.33-7.38 (2H, m) , 7.53 (1H, dd, J=2.0, 8.9Hz), 8.08 (1H, d, J=2.0Hz), 8.30 (1H, d, J=8.9Hz), 8.66 (1H, d, J=5.2Hz)
MS (m/z) : 469 (M+l)
Preparation 83
To a solution of (S) -4- [4- (7-chloroαuιnolιn-d-yloxy) - benzyl ] -2, 2-dιmethyloxazolιdme-3-carboxylιc acid tert-outyl ester (1.31 g, 2.79 mmol) in a mixed solvent of dioxane (6.5 ml) and methanol (6.5 ml) was added 4N hydrogen chloride in dioxane (13 ml) at room temperature and the solution was stirred at the same temperature for 3 hours. The solvent was removed by evaporation to give (S) -2-ammo-3- [ 4- (7- chloroquιnolιn-4-yloxy) phenyl] propan-1-ol hydrochloride (1.47 g, 144%) as a pale yellow solid.
NMR (DMSO-d6, δ): 2.95-2.99 (2H, m) , 3.43-3.63 (3H, m) , 4.77 (1H, br), 6.94 (1H, d, J=6.1Hz), 7.37 (2H, d, J=8.5Hz), 7.52 (2H, d, J=8.5Hz), 7.93 (1H, dd, J=1.9,
9.0Hz), 8.18 (3H, br s), 8.39 (1H, d, J=1.9Hz), 8.53 (1H, d, J=9.0Hz), 9.00 (1H, d, J=6.1Hz) MS (m/z) : 329 (M-Cl-)
Preparation 84
To a solution of (S) -4- (2-benzylamιno-3-hydroxypropyl) - phenol (4.00 g, 15.5 mmol) m ethanol (80 ml) was added (S)- 3-phenoxy-l , 2-epoxypropane (2.56 g, 17.0 mmol) and the solution was refluxed for 7 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was chromatographed on a 350 g of silica gel (eluent: chloroform/methanol = 9/1) to give 4- [ (2S) -2- [benzyl [ (2S) -2- hydroxy-3-phenoxypropyl] ammo] -3-hydroxypropyl ] phenol (4.89 g, 77%) as a white foam. NMR (CDC13, δ) : 1.67 (2H, br) , 2.46 (1H, dd, J=8.9,
13.7Hz), 2.75-2.97 (4H, m) , 3.04-3.16 (1H, m) , 3.45-3.57 (2H, m) , 3.66 (1H, d, J=13.5Hz), 3.74- 3.90 (3H, m) , 3.92 (1H, d, J=13.5Hz), 6.68 (2H, d, J=8.4Hz), 6.81 (2H, d, J=7.8Hz), 6.92-6.98 (1H, m) , 6.94 (2H, d, J=8.4Hz), 7.20-7.3d (7H, m)
MS (m/z) : 408 (M+l)
Preparation 85
A mixture of (S) -[ l-hydroxymethyl-2- ( 4-hydroxyphenyl ) - ethyl] carbamic acid tert-butyl ester (1078 mg), 2,6- dibromopyridme (1110 mg), sodium tert-butoxide (0.7 g) and N,N-dιmethylformamide (10 ml) was heated at 120°C for 2 hours. To the reaction mixture, water (50 ml) and ethyl acetate (50 ml) was added. The organic layer was washed with water (50 ml x 2 times) followed by brme (50 ml x 1 time), dried over magnesium sulfate and evaporated to give (S)-4-[4- ( 6-bromo-2-pyrιdιnyloxy) enzyl] -2-oxazolιdmone as a crude product. To the product, methanol (10 ml), ammonium formate (4 g) and palladium on charcoal (0.2 g) were added, then tne resulting mixture was heated under reflux for 30 minutes, filtered and evaporated to afford (S) -4- [ - (2-pyrιdmyloxy) - benzyl ] -2-oxazolιdmone as a crude product. The mixture of the product, ethanol (10 ml) and aqueous sodium hydroxide solution (3N, 7 ml) was heated at 90°C for 1.5 hours, cooled to room temperature, added to hyαrochloric acid solution (3N, 6 ml), and followed by the addition of ethyl acetate (50 ml). The organic layer was separated, washed with water (50 ml x 2 times) followed by washing with brme (50 ml x 1), dried over sodium sulfate and evaporated. The crude residue was purified by column chromatography (silica gel, dichloromethane :methanol : concentrated ammonia solution = 7:1:0.1) to afford (S) -2-ammo-3- [ 4- (2-pyrιdmyloxy) phenyl] - propanol (471 mg) .
MS (m/z) : 245 (M++l)
Preparation 86
To a mixture of (S) -2-ammo-3- [4- (2-pyrιdmyloxy) - phenyl ] propanol (227 mg) , dichloromethane (5 ml), benzaldehyde (108 mg) and acetic acid (0.11 ml), sodium tπacetoxyborohydride (300 mg) was added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (30 ml) , and extracted with ethyl acetate (20 ml x 2 times) . The organic layer was washed with water (20 ml x 2 times) followed by washing with brme (20 ml x 1 time) , dried over sodium sulfate and evaporated to afford (S) -2-benzylammo-3- [ 4- (2-pyrιdιnyloxy) phenyl ] propanol (320 mg) .
MS (m/z) : 335 (M++l)
Preparation 87
(S) -2-Amιno-3- [4- ( 3-hydroxymethyl-2-pyrιdmyloxy) - pnenyl ] propanol dihydrochloride (350 mg) was hydrogenated by a similar manner to that described m Example 92 followed by free basing to afford (S) -2-amιno-3- [ 4- (3-methyl-2- pyπdinyloxy) phenyl ] propanol (187 mg) . MS (m/z) : 259 (M++l)
Preparation 88
The following compound was synthesized according to a similar manner to that of Preparation 31.
(S) -(2- [4- (3-Formylquιnolιn-2-yloxy) phenyl] -1- hydroxymethylethyl } carbamic acid tert-butyl ester (11.74 g) as a colorless form
MALDI-MS (m/z) : 425 (M+Na) Preparation 89
To a mixture of (S) - { 2- [ 4- ( 3-formylqumolm-2- yloxy) phenyl] -1-hydroxymethylethyl } carbamic acid tert-butyl ester (10.7 g) , 35% hydrogen peroxide (5.5 ml) and potassium dihydrogenphosphate (13.85 g) in a mixture of acetonitrile
(120 ml) and water (30 ml) was dropwise added sodium chlorite (80% purity, 8.63 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. While cooling in ice-water bath, to the mixture was added sodium sulfite (3.5 q , . After removal of the bath, to this was added aqueous 1M citric acid to make it acidic, and extracted with ethyl acetate. The organic layer was washed with water and brme, αried over sodium sulfate, and evaporated in vacuo. The crude product was triturated with αnsopropyl ether to give (S) -2- [4- (2-tert-butoxycarbonylammo-3-hydroxypropyl) - pnenoxy] qumolme-3-carboxylιc acid (4.8 g) as a colorless form.
MS (m/z) : 439 (M+l)
Preparation 90
The following compound was synthesized according to a similar manner to that of Preparation 26.
(S) -2- [4- (2-tert-Butoxycarbonylamιno-3-hydro ypropyl ) - pnenoxy] qumolme-3-carboxylιc aciα methyl ester (10.25 g) as a colorless form
MS (m/z) : 453 (M+l)
Preparation 91 The following compound was synthesized according to a similar manner to that of Preparation 32.
(S) -2- [4- (2-Ammo-3-hydroxypropyl) phenoxy] quιnolme-3- carboxylic acid methyl ester hydrocnloride (13.37 g) as a colorless powder MS (m/ z ) : 353 ( M+ l )
Preparation 92
The following compound was synthesized accordmg to a similar manner to that of Example 41.
2-{ 4- [ (2S) -3-hydroxy-2- ( (2S) -2-hydroxy-3-phenoxy- propylamino) propyl] phenoxy } qumolme-3-carboxylιc acid methyl ester (500 mg) as a colorless powder MS (m/z) : 503 (M+l)
Preparation 93
A mixture of {( IS) -l-hydroxymethyl-2- [ 4- ( 3-nιtropyrιdιn- 2-yloxy) phenyl] ethyl } - (2S) - (2-hydroxy-3-phenoxypropyl ) - carbamic acid tert-butyl ester (100 mg) , 10% palladium on activated carbon (50% wet, 20 mg) and methanol (2.0 ml) was stirred at room temperature m the presence of hydrogen at an atmospheric pressure for 1 hour, and filtered. The filtrate was evaporated in vacuo to give (( IS) -l-hydroxymethyl-2- [ 4- ( 3-ammopyrιdm-2-yloxy) phenyl]ethyl}- (2S) - (2-hydroxy-3- phenoxypropyl ) carbamic acid tert-butyl ester (1.1 g) as a brown oil.
MS (m/z) : 510 (M+l)
Example 1
Under nitrogen, a solution of (S) -2- [ 4- (2-ammo-3- hydroxypropyl) phenoxy] nicotinic acid methyl ester dihydrochloride (4.9 g) , (R) -3-chlorostyrene oxide (5.0 g) and N, N-diisopropylethylamme (4.5 ml) in a mixture of methanol (10 ml) and 1,4-dioxane (10 ml) was refluxed for 28 hours. The mixture was evaporated m vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 20:1), followed by treatment with oxalic acid in methanol and crystallization from methanol- ethyl acetate to give 2- [4- [ (2S) -2- [ (2R) -2- (3-chlorophenyl) - 2-hydroxyethylammo] -3-hydroxypropyl ] phenoxy] nicotinic acid methyl ester oxalate (1:1) (1.5 g) .
NMR (DMS0-d6, δ): 2.75-2.95 (1H, m) , 3.05-3.20 (2H, m) , 3.25-3.53 (3H, m) , 3.55-3.70 (1H, m) , 3.85 (3H, s), 4.95-5.05 (1H, m) , 7.08 (2H, d, J=8.5Hz), 7.20-
7.50 (7H, m) , 8.25-8.32 (2H, m)
Example 2
A mixture of 2- [4- [ (2S) -2- [ (2R) -2- ( 3-chlorophenyl ) -2- hydroxyethylamino] -3-hydroxypropyl ] phenoxy] nicotinic acid methyl ester oxalate (1:1) (0.65 g) and aqueous 28% ammonium hydroxide (26 ml) in 1,4-dioxane (13 ml) was stirred at room temperature for 2 days. The mixture was evaporated in vacuo, followed by partition between ethyl acetate and water. The organic layer was washed with brme, dried over sodium sulfate and evaporated m vacuo. The residue was treated with oxalic acid in ethanol followed by crystallization from methanol-ethyl acetate to give 2- [4- [ (2S) -2- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethylamino] -3-hydroxypropyl] phenoxy] - nicotmamide oxalate (1:1) (0.41 g).
NMR (DMSO-d6, δ): 2.75-2.95 (1H, m) , 3.05-3.55 (5H, m) , 3.55-3.70 (1H, m) , 4.95-5.05 (1H, m) , 7.1-7.6 (9H, m) , 8.1-8.2 (2H, m)
Example 3
To a solution of 2- [4- [ (2S) -2- [ (2R) -2- (3-chlorophenyl) - 2-hydroxyethylamino] -3-hydroxypropyl ] phenoxy] nicotinic acid methyl ester oxalate (1:1) (0.71 g) in methanol (7.1 ml) was added with aqueous IN sodium hydroxide (5.2 ml), and the mixture was stirred at room temperature for 2.5 hours. The mixture was evaporated in vacuo. The residue was dissolved in water followed by making acid at about pH 4 with aqueous IN hydrogen chloride. After stirred for 8 hours, the precipitate was collected and recrystallized from ethyl acetate-methanol to give 2- [4- [ (2S) -2- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethylammo] -3-hydroxypropyl] phenoxy] - nicotinic acid (0.52 g) .
NMR (DMSO-d6, δ): 2.55-2.75 (1H, m) , 2.80-3.15 (4H, m) , 3.20-3.35 (1H, m) , 3.45-3.55 (1H, m) , 4.85-4.95 (1H, m) , 6.90 (2H, d, J=8.5Hz), 7.10-7.20 (3H, m) ,
7.30-7.50 (4H, m) , 8.05-8.20 (2H, m)
Example 4
Under nitrogen, a solution of (S) -2- [ 4- (2-ammo-3- hydroxypropyl ) phenoxy] nicotmonitrile hydrochloride (1.5 g) , (R) -3-chlorostyrene oxide (1.5 g) and N,N- dnsopropylethylamine (1.6 ml) in ethanol (9.6 ml) was refluxed for 4 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 25:1), followed by treatment with 4N hydrogen chloride in ethyl acetate and tπturation with ethyl acetate to give 2- [ 4- [ (2S) -2- [ (2R) -2- (3- chlorophenyl ) -2-hydroxyethylammo] -3-hydroxypropyl ] phenoxy] - nicotmitπle hydrochloride (0.96 g) . NMR (DMSO-d6, δ): 2.8-3.8 (7H, m) , 5.05-5.15 (1H, m) ,
7.22 (2H, d, J=8.4Hz), 7.25-7.50 (7H, m) , 8.36-8.45 (2H, m)
Example 5 Under nitrogen, a solution of 2- [4- [ (2S) -2- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethylammo] -3-hydroxypropyl ] phenoxy] - nicotmonitrile hydrochloride (1.0 g) , di-tert-butyl dicarbonate (0.69 g) and triethylamine (0.89 ml) m N,N- dimethylformamide (10 ml) was stirred at room temperature for 9 hours. The mixture was diluted with ethyl acetate and poured into water. The organic layer was washed successively with aqueous 10% potassium hydrogen sulfate and brme, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 3:2) to give [ (2R) -2- ( 3-chlorophenyl) -2- hydroxyethyl] [ (IS) -1- [4- ( 3-cyanopyπdm-2-yloxy) benzyl] -2- hydroxyethyl ] carbamic acid tert-butyl ester (1.1 g) .
NMR (DMSO-d6, δ) : 1.3-1.5 (9H, m) , 2.5-3.1 (3H, m) , 3.2-3.9 (4H, m) , 4.6-4.9 (1H, m) , 7.13 (2H, d, J=8.5Hz), 7.15-7.20 (7H, m) , 8.3-8.35 (1H, m) , 8.40
(1H, dd, J=1.6, 7.6Hz)
Example 6
Under nitrogen, to a solution of a [(2R)-2-(3- chlorophenyl ) -2-hydroxyethyl ] [ (IS) -1- [4- (3-cyanopyndιn-2- yloxy) benzyl ] -2-hydroxyethyl ] carbamic acid tert-butyl ester (0.50 g) in toluene (5 ml) was added dnsopropylaluminum hydride (IM in hexane, 3.0 ml) at -78°C, and the mixture was stirred at the same temperature for 20 minutes. After quenched with aqueous IM Rochelle salt, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo. Because of the occurrence of an unfavorable deprotection in most of the obtained products, the residue was treated with di-tert-butyl dicarbonate (0.61 g) and triethylamine (0.39 ml) in N, N-dimethylformamide (6 ml). After stirred at room temperature for 3 hours, the mixture was poured into aqueous 10% potassium hydrogen sulfate and extracted with ethyl acetate. The organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 3:2) to give [(2R)-2-(3- chlorop enyl) -2-hydroxyethyl] [ ( IS) -1- [ 4- ( 3-formyIpyrιdm-2- yloxy) benzyl] -2-hydroxyethyl ] carbamic acid tert-butyl ester (0.26 g) .
NMR (CDC13, δ) : 1.54 (9H, s), 2.3-3.1 (3H, m) , 3.1-3.9 (4H, m) , 4.6-4.9 (1H, m) , 6.9-7.4 (9H, m) , 8.19- 8.23 (2H, m) , 10.53 (1H, s)
Example 7 Under nitrogen, to a solution of [(2R)-2-(3- chlorophenyl) -2-hydroxyethyl] [ ( IS) -1- [ 4- ( 3-formylpyrιdm-2- yloxy) benzyl] -2-hydroxyethyl ] carbamic acid tert-butyl ester (0.24 g) in methanol (4.5 ml) was added sodium borohydride (17 mg) at 5°C, and the mixture was stirred at the same temperature for 10 minutes. The mixture was evaporated in vacuo. To the residue was added water and extracted with ethyl acetate. The organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 3:2) to give [(2R)-2-(3- chlorophenyl) -2-hydroxyethyl] [ (IS) -2-hydroxy-l- [4- (3- hydroxymethylpyrιdm-2-yloxy) benzyl] ethyl ] carbamic acid tert- butyl ester (0.15 g) . NMR (CDC13, δ) : 1.53 (9H, s), 2.3-3.05 (3H, m) ,
3.2-3.9 (4H, m) , 4.75-4.90 (3H, m) , 6.94-7.25 (9H, m) , 7.70-7.80 (1H, m) , 7.90-7.95 (1H, m)
Example 8 To a solution of [ (2R) -2- ( 3-chlorophenyl ) -2- hydroxyethyl] [ (IS) -2-hydroxy-l- [4- ( 3-hydroxymethylpyπdm-2- yloxy) benzyl] ethyl] carbamic acid tert-butyl ester (0.14 g) in ethyl acetate (5.2 ml) was added 4N hydrogen chloride in ethyl acetate (1.3 ml) and the resulting mixture was allowed to stand at room temperature for 2 hours. The mixture was evaporated in vacuo. To the residue was added aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel
(dichloromethane :methanol = 10:1), followed by treatment with oxalic acid in ethanol and trituration with ethyl acetate to give (2S) -2- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethylammo] -3- [4- (3-hydroxymethylpyπdm-2-yloxy) phenyl] propan-1-ol oxalate (1:1) (83 mg) . NMR (DMSO-d6, δ): 2.75-2.90 (1H, m) , 3.0-3.5 (5H, m) ,
3.55-3.70 (1H, m) , 4.62 (2H, s), 4.90-5.05 (1H, m) , 7.04-7.17 (3H, m) , 7.27-7.48 (6H, m) , 7.87-7.98 (2H, m)
Example 9
Under nitrogen, a solution of (S) -6- [4- (2-ammo-3- hydroxypropyl) phenoxy] nicotinic acid methyl ester dihydrochloride (1.3 g) , (R) -3-chlorostyrene oxide (1.7 g) and N, N-diisopropylethylamme (1.2 ml) in a mixture of methanol (2.7 ml) and 1,4-dioxane (2.7 ml) was refluxed for 16 hours. The mixture was evaporated m vacuo. The residue was dissolved in ethyl acetate, washed successively with water and brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 25:1) to give 6- [4- [ (2S) -2- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethylammo] -3- hydroxypropyl ] phenoxy] nicotinic acid methyl ester (0.83 g) . The crude product was used m the next step.
Example 10
A solution of 6- [4- [ (2S) -2- [ (2R) -2- (3-chlorophenyl) -2- hydroxyethylammo] -3-hydroxypropyl ] phenoxy] nicotinic acid methyl ester (0.60 g) m metnanol (6 ml) was treated with 4N hydrogen chloride m 1,4-dioxane (1 ml), and evaporated in vacuo. The crude product was crystallized from methanol- ethyl acetate and collected to give 6- [ 4- [ (2S) -2- [ (2R) -2- (3- chlorophenyl ) -2-hydroxyethylammo] -3-hydroxypropyl] phenoxy] - nicotinic acid methyl ester dihydrochloride (0.33 g) . NMR (DMSO-d6, δ): 2.8-3.0 (1H, m) , 3.1-3.75 (6H, m) ,
3.86 (3H, s), 5.05-5.1 (1H, m) , 7.1-7.2 (3H, m) , 7.35-7.55 (6H, m) , 8.32 (1H, dd, J=2.4, 8.7Hz), 8.69 (1H, d, J=1.9Hz)
Example 11 A mixture of 6- [ 4- [ (2S) -2- [ (2R) -2- ( 3-chlorophenyl ) -2- hydroxyethylammo] -3-hydroxypropyl] phenoxy] nicotinic acid methyl ester dihydrochloride (0.26 g) and aqueous 28% ammonium hydroxide (26 ml) in 1,4-dioxane (5.2 ml) was stirred at room temperature for 1 day. The mixture was evaporated in vacuo, followed by partition between ethyl acetate and water. The organic layer was washed with brme, dried over sodium sulfate and evaporated in vacuo to give 6- [4- [ (2S) -2- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethylammo] -3- hydroxypropyl ] phenoxy] nicotmamide (0.21 g) .
NMR (DMSO-d6, δ): 2.5-2.9 (5H, m) , 3.1-3.4 (2H, m) , 4.55-4.65 (1H, m) , 7.00-7.06 (3H, m) , 7.20-7.50 (6H, m) , 8.25 (1H, dd, J=2.5, 8.6Hz), 8.62 (1H, d, J=2.2Hz)
Example 12
Crude 6- [4- [ (2S) -2- [ (2R) -2- (3-chlorophenyl) -2- hydroxyethylammo] -3-hydroxypropyl] phenoxy] nicotmamide (0.31 g) was purified by column chromatography on silica gel (dichloromethane :methanol = 10:1), followed by crystallization from ethanol-ethyl acetate to pure 6- [4- [ (2S) -2- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethylammo] -3- hydroxypropyl ] phenoxy] nicotmamide (90 mg) . 6- [4- [ (2S) -2- [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethylammo] -3- hydroxypropyl ] phenoxy] nicotmamide was treated with 4N hydrogen chloride in ethyl acetate, followed by crystallization from methanol-ethyl acetate to give 6- [4- [ (2S) -2- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethylammo] -3- hydroxypropyl ] phenoxy] nicotmamide dihydrochloride (57 mg) . NMR (DMSO-d6, δ): 2.8-3.7 (7H, m) , 5.0-5.1 (1H, m) ,
7.06-7.20 (3H, m) , 7.30-7.50 (6H, m) , 8.27 (1H, dd, J=2.5, 8.6Hz), 8.61 (1H, d, J=2.4Hz)
Example 13 To a solution of 6- [ 4- [ (2S) -2- [ (2R) -2- ( 3-chlorophenyl ) - 2-hydroxyethylammo] -3-hydroxypropyl] phenoxy] nicotmic acid methyl ester dihydrochloride (0.18 g) in methanol (3.6 ml) was added with aqueous IN sodium hydroxide (1.4 ml), and the mixture was stirred at room temperature for 4.5 hours. To the mixture was added aqueous IN hydrogen chloride (1.2 ml) and evaporated m vacuo. After partition between water and ethyl acetate contained a little amount of methanol, the organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. The residue was treated with 4N hydrogen chloride in 1,4-dioxane, followed by evaporation and trituration with ethyl acetate to give 6- [4- [ (2S) -2- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethylammo] -3- hydroxypropyl ] phenoxy] nicotinic acid dihydrochloride (0.13 g) • NMR (DMSO-d6, δ): 2.8-3.8 (7H, m) , 5.05-5.15 (1H, m) ,
7.08-7.20 (3H, m) , 7.35-7.50 (6H, m) , 8.29 (1H, dd, J=2.1, 8.5Hz), 8.66 (1H, d, J=2.3Hz)
Example 14 Under nitrogen, a solution of (S) -2-amιno-3- [4- (3, 5- dιchloropyrιdm-4-yloxy) phenyl] propan-1-ol hydrochloride (0.39 g) , (R) -3-chlorostyrene oxide (0.50 g) and N,N- dnsopropylethylamme (0.19 ml) in a mixture of methanol (1 ml) and 1,4-dioxane (1 ml) was refluxed for 14.5 nours . The mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed successively with water and brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 15:1), followed by treatment with 4N hydrogen chloride in ethyl acetate and crystallization from methanol-ethyl acetate to give (2S) -2- [ (2R) -2- ( 3- chlorophenyl) -2-hydroxyethylammo] -3- [4- (3, 5-dιchloropyrιdm- 4-yloxy) phenyl] propan-1-ol dihydrochloride (0.13 g) .
NMR (DMSO-d6, δ) : 2.75-2.9 (1H, m) , 2.9-3.5 (5H, ) , 3.5-3.7 (1H, m) , 5.0-5.1 (1H, m) , 6.91 (2H, d, J=8.6Hz) , 7.3-7.5 (6H, m) , 8.79 (2H, s)
Example 15
The following compound was obtained according to a similar manner to that of Example 1.
(2S) -2- [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethylammo] -3- [4- ( 6-f luoropyrιdm-2-yloxy) phenyl] propan-1-ol oxalate (1:1) NMR (DMSO-d6, δ) : 2.75-2.95 (1H, m) , 3.0-3.5 (5H, m) , 3.55-3.70 (1H, m) , 4.9-5.1 (1H, m) , 6.85-6.95 (2H, m) , 7.15 (2H, d, J=8.5Hz) , 7.3-7.5 (6H, m) , 8.02 (1H, q, J=8.0Hz)
Example 16 Under nitrogen, a suspension of (S)-4-[4-(6- chloropyπdm-2-yloxy) benzyl ] oxazolιdm-2-one (0.49 g) , (R)- 3-chlorostyrene oxide (0.49 g) and potassium carbonate (0.44 g) in N, N-dimethylformamide (4.9 ml) was stirred at 80°C for 96 hours. The mixture was diluted with ethyl acetate and insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved in a mixture of ethanol (8 ml) and water (7 ml) . To it was aqueous 4N sodium hydroxide (5.6 ml), and the mixture was refluxed for 3 hours. After evaporation in vacuo and partition between ethyl acetate and water, the organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 25:1), followed by treatment with oxalic acid in ethanol and trituration with ethyl acetate to give (2S) -2- [ (2R) -2- ( 3-chlorophenyl ) -2- hydroxyethylammo] -3- [4- ( 6-chloropyrιdm-2-yloxy) phenyl] - propan-1-ol oxalate (2:1) (62 mg).
NMR (DMSO-d6, δ): 2.7-3.6 (7H, m) , 4.8-4.9 (1H, m) ,
6.98 (1H, d, J=8.1Hz), 7.11 (2H, d, J=8.4Hz), 7.2- 7.5 (7H, m) , 7.90 (1H, t, J=8.0Hz) Example 17
To a solution of (5R) -5- ( 3-chlorophenyl ) -3- {( IS) -2- hydroxy-1- [4- (pyπdm-2-yloxy) benzyl] ethyl } oxazolιdm-2-one (0.22 g) in ethanol (5.1 ml) was added aqueous 4N sodium hydroxide (1.5 ml), and the mixture was refluxed for 2 hours. The mixture was evaporated in vacuo. After partition between ethyl acetate and water, the organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 25:1), followed by treatment with 4N hyαrogen chloride in ethyl acetate and trituration with ethyl acetate to give (2S) -2- [( 2R) -2- ( 3-chlorophenyl ) -2- hydroxyethylamino] -3- [4- (pyrιdm-2-yloxy) phenyl ] propan-1-ol dihydrochloride (0.15 g). NMR (DMSO-d6, δ): 2.75-3.0 (1H, m) , 3.05-3.7 (6H, m) ,
5.0-5.2 (1H, m) , 7.0-7.2 (4H, m) , 7.25-7.55 (6H, m) , 7.8-7.9 (1H, m) , 8.1-8.2 (1H, m)
Example 18 To a solution of ( 4S) -3- [ (2R) -2- ( 3-chlorophenyl) -2- hydroxyethyl]-4-[4-(pyπdm-2-yloxy)benzyl]oxazolιdm-2-one (0.67 g) in ethanol (6.7 ml) was added aqueous 4N sodium hydroxide (4 ml), and the mixture was refluxed for 2 hours. After evaporation in vacuo and partition between water and ethyl acetate, the organic layer was washed with brme, dried over sodium sulfate, and evaporated m vacuo. The residue was dissolved in N, -dimethylformamide (9 ml), and to it were added triethylamine (0.48 ml)) and a solution of di-tert- butyl dicarbonate (0.63 g) in N, N-dimethylformamide (3 ml). After stirred for 5 hours, the mixture was poured into aqueous 10% potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dιchloromethane:methanol = 50:1) to give [(2R)-2-(3- chlorophenyl) -2-hydroxyethyl] [ (2S) -2-hydroxy-l- [4- (pyrιdm-2- yloxy) benzyl] ethyl] carbamic acid tert-butyl ester (0.85 g) . NMR (CDC13, δ) : 1.53 (9H, s), 2.3-4.5 (7H, m) , 4.8-4.9 (1H, m) , 6.83 (1H, d, J=8.2Hz), 6.9-7.5 (8H, m) , 7.55-7.7 (1H, m) , 8.01 (1H, s), 8.05-8.15 (1H, m)
Example 19
Under nitrogen, to a solution of [(2R)-2- ( 3-chlorophenyl) -2-hydroxyethyl] [ (2S) -2-hydroxy-l- [ 4- (pyrιdm-2-yloxy) benzyl] ethyl] carbamic acid tert-butyl ester (0.82 g) m dichlorometnane (8.2 ml) was added 3-chloroperbenzoιc acid (1.0 g), and the mixture was stirred at room temperature for 1 day. The mixture was dilutee with ethyl acetate, washed with aqueous IN sodium hydroxide and brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 25:1) to give [(2R)-2-(3- chlorophenyl) -2-hydroxyethyl] [ (2S) -2-hydroxy-l- [4- (1- oxypyrιαm-2-yloxy) benzyl] ethyl ] carbamic acid tert-butyl ester (0.64 g) .
NMR (CDCI3, δ) : 1.53 (9H, s), 2.1-4.6 (7H, m) , 4.8-5.2
(1H, m) , 6.65-6.8 (1H, m) , 6.95-7.4 (10H, m) , 8.25- 8.35 (1H, m)
Example 20
The following compound was obtained according to a similar manner to that of Example 8.
(2R) -2- [ (2S) -2- (3-Chlorophenyl) -2-hydroxyethylammo] -3- [4- ( l-oxypyrιdιn-2-yloxy) phenyl ] propan-1-ol oxalate (1:1)
NMR (DMSO-d6, δ) : 2.8-3.7 (7H, m) , 4.9-5.1 (1H, m) ,
6.94 (2H, d, J=8.3Hz) , 7.15-7.55 (9H, m) , 8.30-8.40 (1H, m)
Example 21 To a solution of (4S) -3- [ (2R) -2- ( 3-cnlorophenyl ) -2- hydroxyethyl] -4- [4- ( 6-hydroxymethylpyrιdm-2-yloxy) benzyl] - oxazolιdm-2-one (0.37 g) and ( 5R) -5- ( 3-chlorophenyl ) -3- { ( IS) -2-hydroxy-l- [4- ( 6-hydroxymethylpyrιdm-2-yloxy) benzyl] - ethyl } oxazolιdm-2-one (62 mg) in ethanol (2.8 ml) was added aqueous 2N sodium hydroxide (5.6 ml), and the mixture was refluxed for 3 hours. The mixture was evaporated m vacuo. After partition between ethyl acetate and water, the organic -.ayer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column cnromatography on silica gel (dichloromethane :methanol = 10:1), followed by treatment with oxalic acid in ethanol and trituration with hexane to give (2S) -2- [ (2R) -2- ( 3- cnlorophenyl ) -2-hydroxyethylammo] -3- [ - ( 6-hydroxymethyl- pyrιdm-2-yioxy) phenyl ] propan-1-ol oxalate (1:1) (0.38 g) . NMR (DMSO-d6, δ): 2.7-2.95 (1H, m) , 3.0-3.7 (6H, m) ,
4.38 (2H, s), 5.01 (1H, d, J=8.0Hz), 6.80 (1H, d, J=8.1Hz), 7.08 (2H, d, J=8.4Hz), 7.2-7.5 (7H, m) , 7.84 (1H, t, J=7.6Hz)
Example 22
The following compound was obtained according to a similar manner to that of Example 21 starting from (^S)-3- r (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] -4- [4- (5- hydroxymethylpyrιdm-2-yloxy) benzyl ] oxazolιdm-2-one .
(2S) -2- [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethylammo] -3- [ 4- ( 5-hydroxymethylpyπdm-2-yloxy) phenyl ] propan-1-ol oxalate
(1:1) NMR (DMSO-d6, δ): 2.75-2.90 (1H, m) , 3.0-3.55 (5H, m) ,
3.55-3.70 (1H, m) , 4.48 (2H, s), 4.9-5.1 (1H, m) , 6.98 (1H, d, J=8.4Hz), 7.07 (2H, d, J=8.5Hz), 7.31 (2H, d, J=8.5Hz), 7.3-7.5 (4H, m) , 7.80 (1H, dd, J=2.4, 8.4Hz), 8.07 (1H, d, J=2.2Hz) Example 23
Under nitrogen, a solution of (S) -2- [ 4- (2-ammo-3- hydroxypropyl ) phenoxy] nicotmonitrile hydrochloride (5.0 g) , (2S) -1, 2-epoxy-3-phenoxypropane (2.45 g) and N,N- dnsopropylethylamme (5.5 ml) in ethanol (50 ml) was refluxed for 7 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 100:1) to give 2- [4- [ (2S) -2- [ (2S) - 2-hydroxy-3-phenoxypropylamιno] -3-hydroxypropyl] pnenoxy] - nicotmonitrile (4.92 g) .
IR (NaCl) : 3380, 2240, 1590, 1427 cm-1
NMR (CDC13, δ) : 2.60-3.14 (7H, m) , 3.50-3.80 (3H, m) ,
3.95 (2H, d, J=4.9Hz), 4.00-4.17 (1H, m) , 6.80-7.32 (10H, m) , 8.00 (1H, dd, J=2.0, 7.6Hz), 8.07 (1H, dd, J=2.0, 5.0Hz)
Example 24
2- [4- [ (2S) -2- [ (2S) -2-Hydroxy-3-phenoxypropylammo] -3- hydroxypropyl] phenoxy] nicotmonitrile (73 mg) was treated with 4N hydrogen chloride in ethyl acetate (3 ml) and triturated with diisopropyl ether to give 2- [ 4- [ (2S) -2- [ (2S) - 2-hydroxy-3-phenoxypropylammo] -3-hydroxypropyl ] phenoxy] - nicotmonitrile hydrochloride (70 mg) .
NMR (DMSO-d6, δ): 2.60-3.14 (7H, m) , 3.50-3.80 (3H, ) , 3.95 (2H, d, J=4.9Hz), 4.00-4.17 (1H, m) , 6.80-
7.32 (10H, m) , 8.00 (1H, dd, J=2.0, 7.6Hz), 8.07 (1H, dd, J=2.0, 5. Hz)
Example 25 Under nitrogen, a solution of 2- [4- [ (2S) -2- [ (2S) -2- hydroxy-3-phenoxypropylammo] -3-hydroxypropyl ] phenoxy] - nicotmonitrile (3.0 g) , di-tert-butyl dicarbonate (1.8 g) in tetrahydrofuran (20 ml) was stirred at room temperature for 9 hours. The mixture was evaporated in vacuo to give [(1S)-1- [4- (3-cyanopyrιdm-2-yloxy) benzyl] -2-hydroxyethyl] [(2S)-2- hydroxy-3-phenoxypropyl ] carbamic acid tert-butyl ester (3.0 g) •
NMR (CDC13, δ) : 1.46 (9H, s), 2.40-3.95 (7H, m) , 4.00- 4.40 (3H, m) , 6.80-7.40 (10H, m) , 8.00 (1H, dd, J=2.0, 7.5Hz), 8.20 (1H, dd, J=2.0, 5.0Hz)
Example 26
Under nitrogen, to a solution of a [ ( IS) -1- [4- ( 3- cyanopyπdm-2-yloxy) benzyl ] -2-hydroxyethyl ] [ (2S) -2-hydroxy- 3-phenoxypropyl ] carbamic acid tert-butyl ester (1.50 g) m toluene (20 mi) was added diisopropylalummum hydride ( IM in hexane, 17.3 ml) at -78°C, and the mixture was stirred at the same temperature for 20 minutes. After quenched with aqueous IM Rocnelle salt, the mixture was extracted with ethyl acetate. The organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. Because of the occurrence of an unfavorable deprotection m most of the obtained products, the residue was treated with di-tert-butyl dicarbonate (0.6 g) and triethylamine (0.39 ml) in N,N- dimethylformamide (6 ml). After stirred at room temperature for 3 hours, the mixture was poured into aqueous 10% potassium hydrogen sulfate and extracted with ethyl acetate. The organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 1:2) to give [ ( IS) -2- [ 4- ( 3-formylpyrιdιn-2-yloxy) benzyl] -2- hydroxyethyl] [ (2S) -2-hydroxy-3-phenoxypropyl ] carbamic acid tert-butyl ester (0.80 g).
NMR (CDCI3, δ) : 1.46 (9H s), 2.70-3.90 (7H, m) , 4.05- 4.40 (3H, m) , 6.80-7.40 (10H, m) , 8.16-8.32 (2H, m) , 10.54 (1H, s)
Example 27
Under nitrogen, a solution of [ ( IS) -1- [ 4- ( 3- cyanopyπdm-2-yloxy) benzyl] -2-hydroxyethyl] [ (2S) -2-hydroxy- 3-phenoxypropyl] carbamic acid tert-butyl ester (150 mg) in dimethyl sulfoxide (7.2 ml) was added 30% hydrogen peroxide (0.72 ml) and aqueous 5N sodium hydroxide (0.72 ml) at 0°C, and the mixture was stirred at the same temperature for 1 hour. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated m vacuo to give [ ( IS) -1- [ 4- (3- carbamoylpyridin-2-yloxy) benzyl] -2-hydroxyethyl ] [ (2S) -2- hydroxy-3-phenoxypropyl ] carbamic acid tert-butyl ester (150 mg) .
NMR (CDC13, δ) : 1.42 (9H, s), 2.50-4.00 (7H, m) , 4.05- 4.40 (3H, m) , 5.90 (1H, br s), 6.85-7.35 (10H, m) , 7.73 (1H, br s), 8.18 (1H, dd, J=2.0, 4.8Hz), 8.61 (1H, dd, J=2.0, 7.6Hz)
Example 28
Under nitrogen, to a solution of [ ( IS) -1- [ 4- (3- formylpyridin-2-yloxy) benzyl] -1-hydroxyethyl ] [ (2S) -2- hydroxy-3-phenoxypropyl ] carbamic acid tert-butyl ester (273 mg) m methanol (5 ml) was added sodium borohydride (20 mg) at 5°C, and the mixture was stirred at the same temperature for 30 minutes. The mixture was evapoated in vacuo. To the residue was added water and extracted with ethyl aceate. The organic layer was washed with brme, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 100:1) to give [ ( IS) -1- [ - ( 3-hydroxymethylpyπdin-2-yloxy) - benzyl] -2-hydroxyethyl] [ (2S) -2-hydroxy-3-phenoxypropyl ] - carbamic acid tert-butyl ester (260 mg) . NMR (DMSO-d6, δ): 1.43 (9H, s), 2.60-3.05 (4H, m) ,
3.40-4.05 (6H, m) , 4.60 (1H, d, J=5.5Hz), 5.0 (1H, br s), 5.2 (1H, br s), 5.33 (1H, t, J=5.5Hz), 6.86- 7.01 (5H, m) , 7.11-7.32 (5H, m) , 7.87 (1H, dd, J=1.0, 7.3Hz), 7.94 (1H, dd, J=1.9, 4.9Hz) Exampl e 29
To a solution of [ ( IS) -1- [ 4- ( 3-carbamoylpyrιdm-2- yloxy) benzyl] -2-hydroxyethyl] [ (2R) -2-hydroxy-3-phenoxy- propyl ] carbamic acid tert-butyl ester (150 mg) in ethyl acetate (5 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) at room temperature, and the solution was stirred at the same temperature for 4 hours. The mixture was evaporated m vacuo, and the residue was triturated with diisopropyl ether to give 2- [ 4- [ (2S) -2- [ (2R) -2-hydroxy-3- phenoxypropylammo] -3-hydroxypropyl] phenoxy] nicotmamide hydrochloride (130 mg) .
NMR (DMSO-d6, δ): 2.80-3.80 (7H, m) , 3.90-4.10 (2H, m) , 4.20-4.30 (1H, m) , 6.91-7.00 (3H, m) , 7.18-7.40 (7H, m) , 7.78 (2H, or s), 8.14-8.18 (2H, m) , 8.53 (1H, br s) , 9.15 (1H, br s)
Example 30
To a solution of [ (IS) -1- [4- (3-hydroxymethylpyndιn-2- yloxy) benzyl] -2-hydroxyethyl ] [ (2S) -2-hydroxy-3- phenoxypropyl ] carbamic acid tert-butyl ester (260 mg) in ethyl acetate (5 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) at room temperature, and the solution was stirred at the same temperature for 4 hours. The mixture was evaporated in vacuo, and the residue was triturated with diisopropyl ether to give (2S) -3- [4- (3-hydroxymethylpyndm- 2-yloxy) phenyl] -2- [ (2S) -2 -hydroxy-3-phenoxypropylamino] - propan-1-ol hydrochloride (130 mg) .
NMR (DMSO-d6, δ): 2.85-3.85 (7H, m) , 4.00 (2H, d,
J=4.6Hz), 4.20-4.35 (1H, m) , 4.62 (2H, s), 6.90- 7.20 (6H, m) , 7.23-7.42 (4H, m) , 7.90 (1H, d,
J=7.5Hz), 7.97 (1H, d, J=4.7Hz), 8.51 (1H, br s), 9.10 (1H, br s)
Example 31 Under nitrogen, a solution of 2- [ 4- (2S) - (2-ammo-3- hydroxypropyl ) phenoxy] nicotmamide dihydrochloride (200 mg) , (2S) -1, 2-epoxy-3- ( 3-fluorophenoxy) propane (93 mg) and N,N- diisopropylethylamme (0.29 ml) ethanol (10 ml) was refluxed for 7 hours. The mixture was evaporated m vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 100:1), followed by treatment with 4N hydrogen chloride in dioxane to give 2- ( 4- { 3-hydroxy- (2S) - 2- [ (2S) -2-hydroxy- 3- (3-fluoro) phenoxypropylammo] propyl } - phenoxy) nicotmamide dihydrochloride (40 mg) as a colorless powder.
NMR (DMSO-d6, δ): 2.80-2.95 (1H, m) , 3.10-3.70 (6H, m) , 4.03 (2H, d, J=4.9Hz), 4.20-4.30 (1H, m) , 6.70-6.90 (3H, m) , 7.10-7.40 (6H, m) , 7.78 (1H, br s), 8.10- 8.20 (2H, m) , 8.52 (1H, br s), 9.08 (1H, br s)
Figure imgf000081_0001
Example 32
The following compounds were synthesized according to a similar manner to that of Example 31.
(1) 2- (4-{3-Hydroxy- (2S) -2-[ (2S) -2-hydroxy-3- (4-chloro) - phenoxypropylammo] propyl (phenoxy) nicotmamide dihydrochloride as a colorless powder
IR (KBr) : 3560-3300, 1695, 1668, 1652, 1419, 1241 cm-1 NMR (DMSO-d6, δ): 2.80-3.00 (1H, m) , 3.10-3.80 (6H, m) ,
4.00 (2H, d, J=5.0Hz), 4.20-4.30 (1H, m) , 6.90-7.40 (9H, m) , 7.78 (1H, br s), 8.10-8.20 (2H, m) , 8.52 (1H, br s) , 9.08 (1H, br s) MS (m/z) : 472 (M+l)
(2) 2- (4-(3-Hydroxy- (2S) -2-[ (2S) -2-hydroxy-3- (2-fluoro) - phenoxypropylammo] propyl }phenoxy) nicotmamide dihydrochloride as a colorless powder
IR (KBr) : 3760-3330, 1670, 1652, 1590, 1508, 1419 cm-1 NMR (DMSO-d6, δ) : 2.90-3.05 (1H, m) , 3.10-3.90 (7H, m) , 4.05 (IH, d, J=4.9Hz) , 4.20-4.30 (IH, m) , 6.90- 7.07(3H, m) , 7.10-7.40 (6H, m) , 7.78 (IH, br s) , 8.10-8.20 (2H, m) , 8.53 (IH, br s) , 9.10 (IH, br s) MS (m/z) : 472 (M+l)
(3) (2S) -2-(4-{3-Hydroxy-2-[ (2S) -2-hydroxy-3- (4-fluoro)- phenoxypropylammo] propyl }phenoxy) nicotinamide dihydrochloride (40 mg) as a colorless powder
IR (KBr) : 3360-3050, 1683, 1650, 1650, 1508, 1419 cm-1 NMR (DMSO-d6, δ) : 2.80-3.00 (IH, m) , 3.10-3.80 (6H, m) ,
4.00 (2H, d, J=4.9Hz), 4.20-4.40 (IH, m) , 6.90-7.10 (2H, m) , 7.15-7.30 (5H, m) , 7.35-7.40 (2H, ) , 7.78 (IH, br s), 8.10-8.20 (2H, m) , 8.50-8.55 (2H, m) , 8.78 (IH, br s) , 9.07 (IH, br s) MS (m/z) : 456 (M+l)
(4) (2S)-3-[4- (3-Chloroquinoxalin-2-yloxy) phenyl] -2- ( (2S) -2- hydroxy-3-phenoxypropylamino) propan-1-ol (60 mg)
NMR (DMSO-d6, δ): 2.55-2.85 (5H, m) , 3.2-3.5 (2H, m) , 3.75-4.0 (3H, m) , 6.85-6.95 (3H, m) , 7.2-7.4 (6H, m) , 7.65-7.8 (3H, m) , 7.95-8.05 (IH, m)
(5) (2S) -3- [4- (Benzothιazol-2 -yloxy) phenyl] -2-((2S)-2- hydroxy-3-phenoxypropylamιno) propan-1-ol (90 mg) NMR (DMSO-d6, δ): 2.55-2.9 (5H, m) , 3.15-3.45 (2H, m) ,
3.75-4.0 (3H, m) , 6.85-7.0 (3H, m) , 7.2-7.5 (8H, m) , 7.65-7.7 (IH, m) , 7.85-7.95 (IH, m)
(6) (2S)-2-( (2S) -2 -Hydroxy- 3 -phenoxypropylammo) -3-[4- ( [ 1, 7] naphthyridin-8-yloxy) phenyl] propan-1-ol (57 mg)
NMR (DMSO-d6, δ) : 2.5-2.9 (5H, m) , 3.15-3.6 (2H, m) , 3.8-4.05 (3H, m) , 6.85-7.0 (3H, m) , 7.12 (2H, d, J=8.5Hz) , 7.2-7.35 (4H, m) , 7.57 (IH, d, J=5.7Hz) , 7.85 (IH, ABq, J=4.2, 8.3Hz) , 8.00 (IH, d, J=5.6Hz) , 8.44 (IH, ABq, J=1.7, 8.4Hz) , 9.05 (IH, ABq , J=1 . 7 , 4 . 2Hz )
(7) (2S)-2-((2S) -2-hydroxy-3-phenoxypropylamino) -3- [4- (6-nit roquinolin-4-yloxy) phenyl ] propan-1-ol (80 mg) . NMR (DMSO-d6, δ): 2.55-2.85 (5H, m) , 3.2-3.5 (2H, m) ,
3.7-4.0 (3H, m) , 6.71 (IH, d, J=5.3Hz), 6.85-7.0 (3H, m) , 7.2-7.35 (4H, m) , 7.40 (2H, d, J=8.5Hz), 8.25 (IH, d, J=9.3Hz), 8.55 (IH, ABq, J=2.6, 9.3Hz), 8.85 (IH, d, J=5.3Hz), 9.15 (IH, d, J=2.6Hz)
(8) 2 (S) -2-[ (2S) -2-hydroxy-3- (phenoxy) propylamino] -3- [ 4- (iso quinolin-1-yloxy) phenyl ] propan-1-ol (67.2 mg, 49%) as a yellow crystalline solid. IR (KBr) : 3408, 1628, 1597, 1570, 1496, 1375, 1246,
1221 cm-1 NMR (CDC13, δ) : 2.17, 2.70-2.89 (5H, m) , 3.48 (IH, dd,
J=4.2, 10.8Hz), 3.70 (IH, dd, J=3.5, 10.8Hz), 3.82-
3.92 (3H, m) , 6.84-6.94 (3H, m) , 7.16-7.32 (7H, m) , 7.61-7.86 (3H, m) , 7.91 (IH, d, J=5.9Hz), 8.43-8.48
(IH, m) MS (m/z) : 445 (M+l)
(9) 2 (S) -3- [ 4- ( 6-c loro-2-methoxyacridin-9-yloxy) phenyl] -2- [ (2S) -2-hydroxy-3- (phenoxy) propylamino] propan-1-ol (51.6 mg, 29%) as a yellow solid.
IR (KBr) : 3413, 1631, 1502, 1471, 1417, 1232 cm-1
NMR (CDCI3, δ) : 1.98 (3H, br) , 2.75-2.98 (5H, m) ,
3.40-3.65 (2H, m) , 3.81 (3H, s), 3.97 (3H, m) , 6.77 (IH, d, J-8.5HZ), 6.86-6.98 (3H, m) , 7.10 (IH, d,
J=8.5Hz), 7.16 (IH, d, J=2.7Hz), 7.22-7.30 (2H, m) , 7.36 (IH, dd, J=1.9, 9.2Hz), 7.47 (IH, dd, J=2.7, 9.5Hz), 7.96 (IH, d, J=9.2Hz), 8.12 (IH, d, J=9.5Hz), 8.22 (IH, d, J=1.9Hz) MS (m/z) : 559 (M+l) (10) 2 (S) -3- [4-(5-bromoisoquinolin-l-yloxy) -phenyl] -2- [ (2S) - 2-hydroxy-3- (phenoxy) propylamino] propan-1-ol (26.0 mg, 24%) as a yellow solid.
IR (KBr) : 3419, 1620, 1595, 1585, 1500, 1481, 1358, 1244, 1217 cm-1
MS (m/z) : 523, 525 (M+l)
(11) (3S)-3-[(2S) -2-hydroxy-3- (phenoxy) propylamino] -2-methyl- 4- [4- (quinolin-4-yloxy) phenyl ] utan-2-ol (26.7 mg, 43.1%) as a white solid.
IR (KBr): 3423, 1595, 1498, 1248, 1211 cm-1 NMR (CDC13, δ) : 1.23 (3H, s), 1.32 (3H, s), 1.73 (3H, br) , 2.44-3.11 (5H, m) , 3.83-3.93 (3H, m) , 6.53 (IH, d, J=5.2Hz), 6.87 (2H, d, J=7.8Hz), 6.96 (IH, t-like, J=7.4Hz), 7.15 (2H, d, J=8.4Hz), 7.23-7.31
(2H, m) , 7.36 (2H, d, J=8.4Hz), 7.55-7.62 (IH, m) , 7.73-7.80 (IH, m) , 8.10 (IH, d, J=8.4Hz), 8.37 (IH, d, J=8.3Hz), 8.61 (IH, d, J=5.2Hz) MS (m/z) : 473 (M+l)
(12) (3S) -4-[4- (3-carbamoylpyridin-2-yloxy) phenyl] -3- [ (2S)-2- hydroxy-3- (phenoxy) propylamino] -2- (methyl )butan-2-ol (109 mg, 67%) as a white solid.
IR (KBr): 3469, 1670 (C=0), 1587, 1419, 1242 cm-1 NMR (CDCI3, δ) : 1.24 (3H, s), 1.30 (3H, s), 1.73 (3H, br) , 2.37-12.61 (4H, m) , 3.04-3.11 (IH, m) , 3.50 (IH, m) , 3.73-3.76 (2H, m) , 6.00 (IH, br) , 6.73 (2H, d, J=7.8Hz), 6.93 (IH, t-like, J=7.4Hz), 7.10 (2H, d, J=8.5Hz), 7.19-7.26 (2H, m) , 7.35 (2H, d, J=8.5Hz), 7.76 (IH, br), 8.13 (IH, dd, J=2.0,
4.9Hz), 8.63 (IH, dd, J=2.0, 7.6Hz) MS (m/z) : 466 (M+l)
(13) (2S)-1-[(1S) -2-methoxy-l- [4- (quinolin-4 -yloxy) benzyl ] eth ylamino] -3-phenoxypropan-2-ol (46.5 mg, 47%) as a yellow sol id .
IR (KBr): 3408, 1593, 1579, 1510, 1311, 1244, 1123 cm-1
NMR (CDC13, δ) : 2.48-2.77 (2H, m) , 2.93-3.00 (IH, m) ,
3.20 (2H, d, J=5.3Hz), 3.31-3.35 (2H, m) , 3.33 (3H, s, OMe), 4.25 (2H, d, J=5.1Hz), 4.92-4.97 (IH, m) , 6.54 (IH, d, J=8.4Hz), 6.80-6.99 (6H, m) , 7.23-7.31 (2H, m) , 7.45-7.52 (IH, m) , 7.64-7.72 (IH, m) , 8.01-8.08 (2H, m) , 8.69 (IH, d, J=5.3Hz)
MS (m/z) : 459 (M+l)
Example 33
Under nitrogen, a solution of 2- [ 4- (2S) - (2-ammo-3- hydroxypropyl ) phenoxy] nicotmamide dihydrochloride (350 mg), (2S) -1 , 2-epoxy-3- (2-chlorophenoxy) propane (132 mg) and N,N- diisopropylethylamme (0.17 ml) in ethanol (10 ml) was refluxed for 7 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 100:1) to give 2- ( 4- { 3-hydroxy- (2S) -2- [ (2S) -2-hydroxy-3- (2-chlorophenoxy) propylamino] - propyl }phenoxy) nicotmamide as a colorless powder.
IR (KBr): 3760-3330, 1747, 1698, 1652, 1540, 1511,
1421 cm"1 NMR (DMSO-d6, δ): 2.60-3.30 (7H, m) , 3.80-3.90 (IH, br s), 3.90-4.00 (2H, m) , 4.50-4.60 (IH, m) , 4.50-4.60 (IH, m) , 5.05-5.10 (IH, br s) , 6.80-7.40 (9H, m) ,
7.70-7.85 (2H, br s), 8.10-8.15 (2H, m) MS (m/z) : 472 (M+l)
Example 34 The following compound was synthesized according to a similar manner to that of Example 33.
2- (4-{ (2S) -2-[ (2S)-3-(3-chlorophenoxy) -2-hydroxy- propylammo] -3-hydroxypropyl }phenoxy) nicotmic acid ethyl ester (450 mg) as a colorless form NMR (CDCI3, δ) : 1.40 (3H, t, J=7Hz), 2.60-2.90 (5H, m) , 3.45 (IH, dd, J=4.5, 11Hz), 3.70 (IH, dd, J=3.5, 11Hz), 3.80-3.90 (3H, m) , 4.40 (2H, t, J=7Hz), 6.70-7.27 (9H, m) , 8.10-8.28 (2H, m) MALDI-MS (m/z) : 501 (M+l)
Example 35
To a solution of 2- ( 4- { (2S) -2- [ (2S) -3- ( 3-chlorophenoxy) - 2-hyoroxypropylammo] -3-hydroxypropyl }phenoxy) nicotinic acid ethyl ester (32.3 mg) m methanol (1.0 ml) was added with aqueous IN sodium hydroxide (0.064 ml), and the mixture was stirred at room temperature for 2.5 hours. The mixture was evaporated in vacuo and the residue was triturated with diisopropyl ether to give sodium 2- ( 4- { (2S) -2- [ (2S) -3- ( 3- chlorophenoxy) -2-hydroxypropylammo] -3-hydroxypropyl } - phenoxy) nicotmic acid (0.52 g) as a colorless powder. IR (KBr) : 3360-3380, 1690, 1619, 1380 cm-1 NMR (D20, δ) : 2.60-3.00 (5H, m) , 3.45-3.60 (2H, m) , 3.80-4.10 (3H, m) , 6.80-6.92 (IH, m) , 7.00-7.09 (4H, m) , 7.10-7.40 (4H, m) , 7.90-8.05 (2H, m)
MS (m/z) : 473 (M+l)
Example 36
Under nitrogen, a solution of (2R) -2-amιno-3- [4- (3- cyanopyπdm-2-yloxy) phenyl ] propanol dihydrochloride (4.9 g) , (2S) -3-phenoxy-l, 2-epoxypropane (5.0 g) and N,N- diisopropylethylamme (4.5 ml) m a mixture of methanol (10 ml) and 1,4-dioxane (10 ml) was refluxed for 28 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 20:1), followed by treatment with 4N hydrogen chloride in dioxane to give (2R) -3- [ 4- ( 3-cyanopyπdm-2-yloxy) phenyl ] -2- ( (2S) -2-hydroxy-3-phenoxypropylammo) propanol hydrochloride (1-5 g) . IR (KBr) : 3560-3330, 2240, 1648, 1592, 1492 cm-1 NMR (DMSO-d6, δ): 2.90-3.00 (IH, m) , 3.05-3.80 (6H, m) , 4.00 (IH, d, J=5.0Hz), 4.20-4.30 (IH, m) , 5.48 (IH, br s), 5.90 (IH, d, J=5.0Hz), 6.90-7.05 (3H, m) , 7.10-7.50 (7H, m) , 8.30-8.45 (2H, m) , 8.70-8.80 (IH, br s)
MS (m/z) : 420 (M+l)
Example 37
To a solution of (R, S) - { 2- [ 3- ( 3-cyanopyridin-2-yloxy) - phenyl ] -1-hydroxymethylethyl } carbamic acid tert-butyl ester
(500 mg) in dioxane (10 ml) was added 4N hydrogen chloride in dioxane (10 ml) at room temperature, and the solution was stirred at the same temperature for 3 hours. The mixture was evaporated in vacuo, and the residue was triturated with ethyl acetate to give (R, S) -2-ammo-3- [ 3- ( 3-cyanopyridin-2- yloxy) phenyl ] propanol dihydrochloride (415 mg) . Under nitrogen, a solution of (R, S) -2-ammo-3- [3- (3-cyanopyridin-2- yloxy) phenyl ] propanol dihydrochloride (415 mg) , (2S)-3- phenoxy-1 , 2-epoxypropane (192 mg) and N, N-diisopropyl- ethylamme (0.43 ml) in ethanol (10 ml) was refluxed for 7 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 100:1), followed by treatment with 4N hydrogen chloride in dioxane to give (R, S) -3- [ 3- ( 3- cyanopyridin-2-yloxy) phenyl] -2- ( 2-hydroxy-3-phenoxypropyl- amino) propanol hydrochloride (174.7 mg) as a colorless powder.
IR (KBr): 3360-3330, 2227, 1690, 1590, 1425, 1240 cm-1 NMR (DMSO-d6, δ) : 2.80-3.80 (7H, m) , 4.00 (IH, d, J=5.2Hz), 4.20-4.30 (IH, m) , 5.44 (IH, br s), 6.90-
7.00 (3H, m) , 7.10-7.45 (7H, m) , 8.30-8.46 (2H, m) , 8.70-8.80 (IH, br s) MS (m/z) : 420 (M+l)
Example 38 Under nitrogen, a solution of (2S) -2-amιno-3- [4- ( 3- nιtropyrιdm-2-yloxy) phenyl ] propanol hydrochloride (3.1 g) , (2S) -1, 2-epoxy-3-phenoxypropane (1.43 g) and N,N- diisopropylethylamme (3.2 ml) in ethanol (30 ml) was refluxed for 4 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane :methanol = 25:1), followed by treatment with 4N hydrogen chloride in ethyl acetate and trituration with ethyl acetate to give (2S) -2- ( (2Ξ) -2-hydroxy-3- phenoxypropylammo) -3- [4- (3-nιtropyrιdm-2-yloxy) phenyl] - propanol (0.96 g) .
MS (m/z) : 440 (M+l)
Example 39 To a solution of (2S) -2- ( (2S) -2-hydroxy-3-pnenoxypropyl- amino) -3- [4- ( 3-nιtropyπdm-2-yloxy) phenyl] propanol (100 mg) in dioxane (3 ml) was added 4N hydrogen chloride in dioxane (3 ml) at room temperature, and the solution was stirred at the same temperature for 3 hours. The mixture was evaporated in vacuo, and the residue was triturated with diisopropyl ether to give (2S) -2- ( (2S) -2-hydroxy-3-phenoxypropylammo) -3- [ 4- ( 3-nιtropyrιdm-2-yloxy) phenyl ] propanol hydrochloride (80 mg) .
NMR (DMSO-d6, δ) : 2.70-3.70 (7H, m) , 4.00-4.10 (2H, m) , 4.20-4.30 (IH, m) , 5.50 (IH, br s), 5.80 (IH, br s), 6.90-7.00 (6H, m) , 7.10-7.40 (8H, m) , 8.50-8.70 (2H, m) MS (m/z) : 440 (M+l)
Example 40
A mixture of {( IS) -l-hydroxymethyl-2- [ 4- ( 3-nιtropyrιdm- 2-yloxy) phenyl ] ethyl}- (2S) - (2-hydroxy-3-phenoxypropyl) - carbamic acid tert-butyl ester (100 mg) , 10% palladium on activated carbon (50% wet, 20 mg) and methanol (2.0 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 1 hour, and filtered. The filtrate was evaporated in vacuo. To a solution of the residue in dioxane (3 ml) was added 4N hydrogen chloride in dioxane (3 ml) at room temperature, and the solution was stirred at the same temperature for 3 hours. The mixture was evaporated in vacuo, and the residue was triturated with diisopropyl ether to give 3-[4-(3-ammopyrιdm-2-yloxy)phenyl]-(2S)-2- ( (2S)-2- hydroxy-3-phenoxypropylammo) propanol dihydrochloride (85 mg) as a pale yellow powder. NMR (DMSO-d6, δ): 2.80-2.90 (IH, m) , 3.10-3.80 (6H, m) ,
3.90-4.00 (2H, m) , 4.25-4.30 (IH, m) , 5.10-5.20 (3H, br s), 6.90-7.10 (6H, m) , 7.20-7.40 (5H, m) , 7.60-7.70 (IH, m) , 8.55-8.75 (IH, br s), 9.23-9.50 (IH, br s) MS (m/z) : 410 (M+l)
Example 41
Under nitrogen, a solution of 2- [4- ( (2S) -2-ammo-3- hydroxypropyl) phenoxy] nicotmamide dihydrochloride (400 mg) , (2S) -1, 2-epoxy-3- (4-benzyloxyphenoxy) propane (284 mg) and
N,N-dnsopropylethylamme (0.57 ml) in ethanol (10 ml) was refluxed for 7 hours. The mixture was evaporated in vacuo.
The residue was purified by column chromatography on silica gel (chloroform: methanol = 100:1) to give 2- (4- ( 3-hydroxy- (2S) -2- [ (2S) -2-hydroxy-3- (4-benzyloxyphenoxy) propylamino] - propyl }phenoxy) nicotmamide (200 mg) as a colorless form. MS (m/z) : 544 (M+l)
Example 42 A mixture of 2- (4- { 3-hydroxy- (2S) -2- [ (2S) -2-hydroxy-3- ( 4-benzyloxyphenoxy) propylamino] propyl } phenoxy) nicotmamide (150 mg) , 10% palladium on activated carbon (50% wet, 50 mg) and methanol (10.0 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 1 hour, and filtered. The filtrate was evaporated m vacuo. The residue was chromatographed (chloroform-methanol ) over silica gel to afford 2- ( 4- { 3-hydroxy- (2S) -2- [ (2S) -2-hydroxy-3- ( 4- hydroxyphenoxy) propylamino] propyl Jphenoxy) nicotmamide. To a solution of 2- ( 4- { 3-hydroxy- (2S) -2-[ (2S) -2-hydroxy-3- (4- hydroxyphenoxy) propylamino] propyl }phenoxy) nicotmamide in dioxane (20 ml) was added 4N hydrogen chloride in dioxane (10 ml) at room temperature, and the solution was stirred at the same temperature for 3 hours. The mixture was evaporated in vacuo, and the residue was triturated with diisopropyl ether to give 2- (4- { 3-hydroxy- (2S) -2- [ (2S) -2-hydroxy-3- ( 4- hydroxyphenoxy) propylamino] propyl }phenoxy) nicotmamide dihydrochloride (7.69 g) as a colorless powder.
IR (KBr): 3760-3330, 1747, 1698, 1650, 1540, 1513, 1456 cm"1 NMR (DMSO-d6, δ): 2.70-2.95 (IH, m) , 3.10-3.90 (8H, m) ,
4.20-4.30 (IH, m) , 6.67-6.82 (4H, m) , 7.10-7.40 (5H, m) , 7.78 (IH, br s), 8.10-8.20 (2H, m) , 8.50 (IH, br s) , 9.10 (IH, br s) MS (m/z) : 454 (M+l)
Example 43
Under nitrogen, to a solution of (S) -2-ammo-3- [ 4- ( 3- hydroxymethylpyrιdm-2-yloxy) phenyl] propan-1-ol dihydrochloride (200 mg) in methanol (5 ml) were added N,N- dnsopropylethylamme (0.25 ml) and (S) -N- (2-benzyloxy-5- oxiranylmethoxyphenyl) methanesulfonamide (199 mg) at room temperature, and the mixture was refluxed for 19 hours. After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel (chloroform:methanol : 28% ammonium hydroxide in water =
80:8:1 to 20:2:1) to give N- [2-benzyloxy-5- ( (2S) -2-hydroxy-3- { (IS) -l-hydroxymethyl-2- [4- ( 3-hydroxymethylpyπdm-2-yloxy) - phenyl] ethylammo }propoxy) phenyl ] methanesulfonamide (22 mg) . NMR (CDC13, δ) : 2.6-2.9 (8H, m) , 3.3-4.1 (5H, m) , 4.79 (2H, s), 5.02 (2H, s), 6.5-6.75 (2H, m) , 6.85-7.45 ( 11H , m) , 7 . 75-7 . 90 ( IH , ) , 7 . 95- 8 . 00 ( IH , m)
Example 4 4
A mixture of N- [2-benzyloxy-5- ( (2S) -2-hydroxy-3- { ( IS) -1- hydroxymethyl-2- [4- ( 3-hydroxymethylpyrιdm-2- yloxy) phenyl] ethylammo} propoxy) phenyl] methanesulfonamide (20 mg) and 10% palladium on activated carbon (50% wet, 10 mg) in methanol (3 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 2 hours. After filtration, the filtrate was evaporated in vacuo, followed by treatment with 4N hydrogen chloride in 1,4- dioxane and trituration with hexane to give N- [2-hydroxy-5- ( (2S) -2-hydroxy-3-{ ( IS) -l-hydroxymethyl-2- [ 4- ( 3- hydroxymethylpyrιdιn-2-yloxy) phenyl ] ethylammo } propoxy) - phenyl ] methanesulfonamide dihydrochloride (6 mg) .
NMR (DMSO-d6, δ): 2.3-4.0 (12H, m) , 4.1-4.3 (IH, m) , 4.62 (IH, s), 6.6-7.4 (8H, m) , 7.8-8.0 (2H, m)
Example 45 Under nitrogen, to a solution of (S) -2-amιno-3- [4- (3- hydroxymethylpyrιdm-2-yloxy) phenyl ] propan-1-ol dihydrochloride (300 mg) in methanol (15 ml) were added N,N- diisopropylethylamme (0.38 ml) and (S) - [ 5- (oxiranyl ) - methoxypyπdm-2-yl ] carbamic acid oenzyl ester (260 mg) at room temperature, and the mixture was refluxed for 20 hours. After removal of the solvent in vacuo, the residue was dissolved in a mixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate. After separation, the organic layer was washed with brme, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 5:1) to give [ 5- ( (2S) -2-hydroxy-3- { (2S) -l-hydroxymethyl-2- [4- ( 3-hydroxymethylpyπdm-2-yloxy) - phenyl] ethylammo }propoxy) pyrιdm-2-yl ] carbamic acid benzyl ester (56 mg). NMR (CDCI3, δ) : 2.6-2.95 (5H, m) , 3.4-3.9 (5H, m) , 4.84 (2H, s), 5.21 (2H, s), 6.9-7.45 (10H, m) , 7.57 (IH s), 7.7-7.8 (2H, m) , 7.87 (IH, d, J=9.1Hz), 7.9-8.1 (IH, m)
Example 46
The following compounds were obtained according to a similar manner to that of Example 44.
(1) (2S)-2-[ (2Ξ) -3- ( 6-Ammopyrιdin-3-yloxy) -2-hydroxy- propylamino] -3- [4- (3-hydroxymethylpyπdιn-2- yloxy) phenyl ] propan-1-ol tetrahydrochloride (26 mg) NMR (DMSO-d6, δ) : 2.8-3.75 (7H, m) , 3.95-4.05 (2H, m) , 4.15-4.3 (IH, m) , 4.61 (2H, s) , 7.0-7.2 (4H, m) , 7.33 (2H, d, J=8.5Hz) , 7.68 (IH, d, J=2.6Hz) , 7.7-
8.0 (3H, m)
(2) N- (2-Hydroxy-5-{ (IR) -l-hydroxy-2- [ (IS) -1-hydroxymethyl- 2- ( 4-phenoxyphenyl) ethylamino] ethyl} phenyl) - methanesulfonamide hydrochloride (70 mg)
NMR (DMSO-d6, δ): 2.7-4.1 (10H, m) , 4.6-4.9 (IH, m) , 6.9-7.5 (12H, m)
(3) N- [5-( (IR) -2-{ (IS) -2- [4- ( 4-Chlorophenoxy ) phenyl ] -1- hydroxymethylethylamino} -1-hydroxyethyl ) -2- hydroxyphenyl] methanesulfonamide hydrochloride (130 mg) . NMR (DMS06, δ) : 2.8-4.1 (10H, m) , 4.55-4.9 (IH, m) , 6.9-7.5 (11H, m)
(4) N-[2-Hydroxy-5- ( ( IR) -l-hydroxy-2- { (IS) -1-hydroxymethyl- 2- [4- (naphthalen-1 -yloxy) phenyl ] ethylamino } ethyl ) - phenyl] methanesulfonamide hydrochloride (53 mg) NMR (DMSO-d6, δ): 2.7-4.1 (10H, m) , 4.55-4.9 (IH, m) , 6.9-7.7 (11H, m) , 7.76 (IH, d, J=8.2Hz), 7.9-8.15 (2H, m) Example 47
The following compounds were obtained according to a similar manner to that of Example 45.
(1) 2-(4-[ (2S) -3-Hydroxy-2- ( (2S) -2-hydroxy-3-phenoxypropyl- ammo) propyl] phenoxy [nicotinic acid ethyl ester (90 mg) NMR (CDC13, δ) : 1.40 (3H, t, J=7.1Hz), 2.65-2.95 (5H, m) , 3.4-3.5 (IH, m) , 3.65-3.75 (IH, m) , 3.8-4.0 (3H, m) , 4.42 (2H, q, J=7.1Hz), 6.8-7.35 (12H, m) , 8.15-8.3 (2H, m)
(2) 4-(4-[(2S) -3-Hydroxy-2- ( (2S) -2 -hydroxy- 3-phenoxypropylammo) propyl] phenoxy ) pyrιdme-2-carboxylιc acid amide (21 mg) NMR (DMSO-d6, δ): 2.5-2.9 (4H, m) , 3.25-3.5 (3H, m) ,
3.7-4.0 (3H, m) , 6.85-7.45 (11H, m) , 8.51 (IH, d, J=5.6Hz)
(3) 4- (4-{ (2S) -2- [ (2S) -3- (3-Chlorophenoxy) -2-hydroxypropyl- ammo] -3-hydroxypropyl [phenoxy) pyrιdme-2-carboxylιc acid amide (97 mg)
NMR (DMSO-d6, δ) : 2.55-2.8 (5H, m) , 3.15-3.5 (2H, m) ,
3.75-4.0 (3H, m) , 7.85-7.4 (10H, m) , 8.50 (IH, d,
J=5.6Hz)
(4) (2S) -2- ( (2S) -2-Hydroxy-3-phenoxypropylammo) -3- (4- phenoxyphenyl) propan-1-ol (80 mg)
NMR (DMSO-d6, δ) : 2.5-2.8 (5H, m) , 3.2-3.45 (2H, m) ,
3.75-3.95 (3H, m) , 6.85-7.0 (7H, m) , 7.1-^.45 (7H, m)
(5) (2S) -3- [4- (4-Chlorophenoxy) phenyl] -2- ( (2S) -2 -hydroxy-3- phenoxypropylammo) propan-1-ol hydrochloride (110 mg) NMR (DMSO-d6, δ): 2.5-2.85 (5H, m) , 3.15-3.45 (2H, m) , 3.75-3.95 (2H, m) , 4.5-4.65 (IH, m) , 6.85-7.0 (7H, m) , 7 . 15 -7 . 4 5 ( 6H , m)
(6) (2S) -2- ( (2S) -2-Hydroxy-3-phenoxypropylamino) -3- [4- (quinolin-2-yloxy) phenyl] propan-1-ol (60 mg) NMR (DMSO-d6, δ) : 2.5-2.9 (5H, m) , 3.2-3.5 (2H, m) ,
3.8-4.0 (3H, m) , 6.85-7.0 (3H, m) , 7.1-7.35 (7H, m) , 7.45-7.55 (IH, m) , 7.6-7.65 (2H, m) , 7.94 (IH, d, J=7.9Hz), 8.39 (IH, d, J=8.8Hz)
(7) (2S) -2-( (2S)-2-Hydroxy-3-phenoxypropylamino) -3-(4- phenylsulfanylphenyl) propan-1-ol (110 mg) NMR (DMSO-d6, δ): 2.5-2.8 (5H, m) , 3.15-3.4 (2H, m) ,
3.75-3.95 (3H, m) , 6.85-7.0 (3H, m) , 7.2-7.4 (11H, m)
Example 48
To a solution of 2- { 4- [ (2S) -3-hydroxy-2- ( (2S) -2-hydroxy- 3-phenoxypropylamino) propyl ] phenoxy [nicotinic acid ethyl ester (40 mg) in ethanol (3 ml) was added aqueous IN sodium hydroxide (86 μl) at 5°C, and the mixture was stirred at room temperature for 12 hours. After evaporation in vacuo, the residue was triturated with hexane and dried in vacuo to give sodium 2-{4-[ (2S) -3-hydroxy-2- ( (2S) -2-hydroxy-3- phenoxypropylammo) propyl ] phenoxy } nicotmate (32 mg) . NMR (D20, δ) : 2.6-3.1 (5H, m) , 3.5-3.75 (2H, m) , 3.9-4.2
(3H, m) , 6.9-7.5 (10H, m) , 7.9-8.1 (2H, m)
Example 49
Under nitrogen, to a solution of (S) -2-amino-3- [ 4- (pyrimidin-2-yloxy) phenyl ] propan-1-ol dihydrochloride (230 mg) in ethanol (5 ml) were added N, N-diisopropylethylamine (0.62 ml) and (S) -3-phenoxy-l , 2-epoxypropane (110 mg) at room temperature, and the mixture was refluxed for 6 hours. After removal of the solvent in vacuo, the residue was dissolved in a mixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate. After separation, the organic layer was washed with brme, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 10:1 to 5:1), followed by treatment with 4N hydrogen chloride m 1,4- dioxane, trituration with hexane and dryness in vacuo to give (2S) -2- ( (2S) -2-hydroxy-3-phenoxypropylammo) -3- [4- (pyrimidm- 2-yloxy) phenyl ] propan-1-ol dihydrochloride (65 mg) .
NMR (DMSO-d6, δ): 2.85-3.0 (IH, m) , 3.1-3.75 (6H, m) , 3.9-4.05 (2H, m) , 4.2-4.35 (IH, m) , 6.9-7.05 (3H, m) , 7.1-7.45 (7H, m) , 8.64 (2H, d, J=4.8Hz)
Example 50
The following compounds were obtained according to a similar manner to that of Example 49.
(1) (2S) -2- ( (2S) -2-Hydroxy-3-phenoxypropylammo) -3- [4- (pyrazm-2-yloxy) phenyl] propan-1-ol dihydrochloride (36 mg) NMR (DMSO-d6, δ): 2.8-3.0 (IH, m) , 3.05-3.7 (4H, m) ,
3.95-4.05 (2H, m) , 4.150-4.35 (IH, m) , 6.9-7.0 (3H, m) , 7.19 (2H, d, J=8.5Hz), 7.25-7.45 (4H, m) , 8.19- 8.21 (IH, m) , 8.38 (IH, d, J=2.7Hz), 8.53-8.54 (IH, m)
(2) 2-{4-[ (2S)-3-Hydroxy-2- ( (2S) -2-hydroxy-3-phenoxy- propylammo) propyl] phenoxy} lsonicotmamide dihydrochloride (30 mg)
NMR (DMSO-d6, δ) : 2.8-3.8 (7H, m) , 3.95-4.1 (2H, m) , 4.15-4.3 (IH, m) , 6.9-7.05 (3H, m) , 7.13 (2H, d,
J=8.4Hz), 7.25-7.4 (5H, m) , 7.5-7.55 (IH, m) , 8.26 (IH, d, J=5.2Hz)
(3) 6-{4- [ (2S) -3-Hydroxy-2- ( (2S) -2-hydroxy-3-phenoxy- propylamino) propyl ] phenoxy } nicotmamide dihydrochloride (17 mg) NMR (DMSO-d6, δ) : 2.9-3.9 (7H, m) , 4.0-4.35 (3H, m) ,
6.9-7.25 (6H, m) , 7.25-7.5 (4H, m) , 8.2-8.35 (IH, m) , 8.55-8.65 (IH, m)
(4) 6-{4-[ (2S)-3-Hydroxy-2-( (2S) -2-hydroxy-3-phenoxy- propylammo) propyl] phenoxy } pyridine-2-carboxylic acid amide hydrochloride (7 mg)
NMR (CD3OD, δ) : 2.95-4.2 (9H, m) , 4.25-4.4 (IH, m) , 6.9-8.2 (12H, m)
(5) 2-(4-((2S)-2-[(2S)-3- (3-Chlorophenoxy) -2-hydroxy- propylam o] -3-hydroxypropyl [phenoxy) lsonicotmamide dihydrochloride (100 mg) NMR (DMSO-d6, δ): 2.8-3.75 (7H, m) , 4.0-4.1 (2H, m) ,
4.15-4.3 (IH, m) , 6.95-7.2 (5H, m) , 7.3-7.4 (4H, m) , 7.5-7.55 (IH, m) , 8.26 (IH, d, J=5.2Hz)
(6) 6-(4-{ (2S)-2-[ (2S) -3- (3-Chlorophenoxy) -2-hydroxy- propylamino] -3-hydroxypropyl } phenoxy) nicotmamide dihydrochloride (30 mg)
NMR (DMSO-d6, δ): 2.8-3.8 (7H, m) , 4.0-4.1 (2H, m) ,
4.15-4.3 (IH, m) , 6.9-7.2 (7H, m) , 7.3-7.45 (3H, m) , 8.25-8.35 (IH, m) , 8.16 (IH, d, J=2.4Hz)
(7) 6- (4-{ (2S)-2-[ (2S)-3- (3-Chlorophenoxy) -2-hydroxy- propylammo] -3-hydroxypropyl } phenoxy) pyπdme-2- carboxylic acid amide hydrochloride (35 mg)
NMR (DMSO-d6, δ): 2.8-3.75 (7H, m) , 4.0-4.1 (2H, m) , 4.15-4.35 (IH, m) , 6.9-7.5 (10H, m) , 7.77 (IH, d,
J=7.3Hz), 8.02 (IH, d, J=7.7Hz)
(8) 2- (4-{ (2S) -2- [ (2S) -3- (3-Chlorophenoxy) -2-hydroxypropyl- ammo] -3-hydroxypropyl [phenoxy) -N-methylnicotmamide hydrochloride (70 mg) NMR (DMSO-dg, δ) : 2.75-3.75 (10H, m) , 4.0-4.1 (2H, m) , 4.15-4.3 (IH, m) , 6.9-7.4 (9H, m) , 8.1-8.2 (2H, m)
(9) (2S) -2- ( (2S) -2-Hydroxy-3-phenoxypropylammo) -3- [4-
(naphthalen-1-yloxy) phenyl] propan-1-ol hydrochloride
(140 mg)
NMR (DMSO-d6, δ) : 2.75-3.75 (7H, m) , 3.9-4.05 (2H, m) ,
4.15-4.35 (IH, m) , 6.85-7.1 (6H, m) , 7.25-7.65 (7H, m) , 7.74 (IH, d, J=8.3Hz), 7.95-8.15 (2H, m)
Example 51
Under nitrogen, a solution of (S) -2-ammo-3- ( 4- phenoxyphenyl ) propan-1-ol hydrochloride (300 mg) , (R)-N-{2- benzyloxy-5-[2-ιodo-l- (triethylsilyloxy) etyhyl] phenyl } - methanesulfonamide (600 mg) and N, N-dnsopropylethylamine (0.75 ml) in 1, 3-dιmethyl-2-ιmιdazolιdmone (5 ml) was stirred at 120°C for 60 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brme, dried over anhydrous magnesium sulfate, and evaporated in vacuo. To a mixture of the residue in 1,4-dioxane (4 ml) was added 4N hydrogen chloride in 1,4-dioxane (1 ml), and the mixture was stirred at room temperature for 1.5 hours. After evaporation in vacuo, the residue was dissolved in a mixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate, followed by separation. The organic layer was washed with brme, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 20:1 to 10:l)to give N-(2- benzyloxy-5- { (IR) -l-hydroxy-2- [ (IS) -l-hydroxymethyl-2- (4- phenoxyphenyl ) ethylammo] ethyl} phenyl) methanesulfonamide (170 mg) .
NMR (CDC13, δ) : 2.6-3.1 (8H, m) , 3.35-3.5 (IH, m) , 3.55- 3.7 (IH, m) , 4.55-4.7 (IH, m) , 5.09 (2H, s), 6.9- 7 . 2 ( 9H , m) , 7 . 25- 7 . 5 ( 8H , m )
Example 52
The following compounds were obtained according to a similar manner to that of Example 51.
(1) N-[2-Benzyloxy-5- ( ( IR) -2- ( ( IS) -2- [ 4- (4-chlorophenoxy) - phenyl] -1-hydroxymethylethylamino } -1- hydroxyethyl ) phenyl] methanesulfonamide (160 mg) NMR (DMSO-d6, δ): 2.45-2.8 (5H, m) , 2.88 (3H, s), 3.15-
3.45 (2H, m) , 4.45-4.55 (IH, m) , 5.14 (2H, s), 6.85-7.6 (16H, m)
(2) N- [2-Benzyloxy-5- ( (IR) -l-hydroxy-2- { (IS) -1-hydroxy- methyl -2- [4- ( naphthalen-1-yloxy) phenyl] ethylamino} - ethyl ) phenyl ] methanesulfonamide (99 mg)
NMR (DMSO-d6, δ): 2.5-2.8 (5H, m) , 2.89 (3H, s), 3.2-3.5
(2H, m) , 4.5-4.6 (IH, m) , 5.13 (2H, s), 6.9-7.85
(17H, m) , 7.95-8.15 (2H, m)
(3) N-[2-Benzyloxy-5- ( (IR) -l-hydroxy-2- { ( IS) -l-hydroxymethyl-2- [4- (quinolin-2-yloxy) phenyl] ethylammo [ethyl ) - phenyl ] methanesulfonamide (28 mg)
NMR (DMSO-d6, δ): 2.5-2.95 (8H, m) , 3.15-3.55 (2H, m) , 4.45-4.6 (IH, m) , 5.13 (2H, s), 7.0-7.75 (14H, m) ,
7.85-8.0 (2H, m) , 8.3-8.45 (2H, m)
(4) N-[2-Benzyloxy-5- ( (IR) -l-hydroxy-2- { ( IS) -l-hydroxymethyl-2- [4- (quinolin-3-yloxy) phenyl ] ethylammo [ethyl ) - phenyl ] methanesulfonamide (23 mg)
NMR (CDC13, δ) : 2.7-3.05 (8H, m) , 3.4-3.5 (IH, m) ,
3.65-3.75 (IH, m) , 4.55-4.7 (IH, m) , 5.09 (2H, s), 6.95-7.7 (16H, m) , 8.14 (IH, d, J=9.5Hz), 8.78 (IH, d, J=2.8Hz) (5) N- (2-Benzyloxy-5-{ (IR) -l-hydroxy-2- [ ( IS) -l-hydroxymethyl-2- ( 4-phenylsulfanylphenyl ) ethylammo] ethyl } - phenyl) methanesulfonamide (96 mg)
NMR (CDC13, δ) : 2.65-3.05 (8H, m) , 3.3-3.5 (IH, m) , 3.55-3.7 (IH, m) , 4.55-4.7 (IH, m) , 5.10 (2H, s) ,
6.97 (IH, d, J=8.4Hz), 7.1-7.5 (16H, m)
Example 53
A mixture of N- [2-benzyloxy-5- (( IR) -l-hydroxy-2- {( IS) -1- hydroxymethyl-2- [4- (qumolm-2-yloxy) phenyl] ethylammo} - ethyl) phenyl]methanesulfonamide (25 mg) and 10% palladium on activated carbon (50% wet, 10 mg) in methanol (3 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 3.5 hours. After filtration, the filtrate was evaporated m vacuo, and the residue was purified by preparative thin layer chromatography (silica gel, chloroform:methanol = 5:1) to give N- [2-hydroxy-5- ( (IR) - l-hydroxy-2-{ (IS) -l-hydroxymethyl-2- [4- (qumolm-2-yloxy) - phenyl ] ethylamino } ethyl ) phenyl] methanesulfonamide (7 mg) . NMR (DMSO-d6, δ): 2.5-2.95 (5H, m) , 2.93 (3H, s), 3.15-
3.6 (2H, m) , 4.45-4.6 (IH, m) , 6.85 (IH, d, J=8.2Hz), 6.95-7.35 (7H, m) , 7.45-7.55 (IH, m) , 7.6-7.75 (2H, m) , 7.94 (IH, d, J=7.8Hz), 8.39 (IH, d, J=8.8Hz)
Example 54
Under nitrogen, to a stirred solution of ( S) -2-ammo-3- [4- (qumolm-3-yloxy) phenyl] propan-1-ol dihydrochloride (200 mg) in ethanol (5 ml) was added sodium methoxide (28% in methanol, 0.21 ml) at 5°C. After 15 minutes, a solution of (S) -3-phenoxy-l , 2-epoxypropane (82 mg) in ethanol (1 ml) was added and the mixture was refluxed for 7.5 hours. The reaction mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 20:1 to 10:1) to give (2S) -2- ( (2S) -2- hydroxy-3-phenoxypropylamino) -3- [4- (qumolm-3-yloxy) phenyl ] - propan-1-ol (110 mg) .
NMR (DMSO-d6, δ): 2.55-2.85 (5H, m) , 3.2-3.5 (2H, m) , 3.75-4.0 (3H, m) , 6.85-6.95 (3H, m) , 7.05 (2H, d, J=8.4Hz), 7.2-7.35 (4H, m) , 7.5-7.75 (3H, m) , 7.85-
7.9 (IH, m) , 8.02 (IH, d, J=8.3Hz), 8.79 (IH, d, J=2.8Hz)
Example 55 A mixture of N- [2-benzyloxy-5- (( IR) -l-hydroxy-2- IS) -1- nydroxymethyl-2- [ 4- (qumolm-3-yloxy) phenyl] ethylammo} - ethyl) phenyl ] methanesulfonamide (20 mg) and 10% palladium on activated carbon (50% wet, 10 mg) in methanol (3 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 2 hours. After filtration, the filtrate was evaporated in vacuo and dried in vacuo to give N-[2-hydroxy-5- ( ( IR) -l-hydroxy-2- ( ( IS ) -l-hydroxymethyl-2- [4- (qumolm-3-yloxy) phenyl ] ethylamino } ethyl) phenyl] methane- sulfonamide (11 mg) . NMR (DMSO-d6, δ): 2.6-3.85 (10H, m) , 4.85-4.9 (IH, m) ,
6.85-7.3 (6H, m) , 7.36 (2H, d, J=8.5Hz), 7.55-7.75 (2H, m) , 7.80 (IH, d, J=2.7Hz), 7.91 (IH, d, J=7.1Hz), 8.04 (IH, d, J=8.2Hz), 8.78 (IH, d, J=2.8Hz)
Example 56
The following compound was obtained according to a similar manner to that of Preparation 50.
4- (4-{ (2S) -2- [Benzyl- ( (2S) -2-hydroxy-3-phenoxypropyl ) - ammo] -3-hydroxypropyl }phenoxy) qumolme-7-carboxylιc acid ethyl ester (39 mg)
NMR (CDC13, δ) : 1.46 (3H, t, J=7.1Hz), 2.6-3.3 (5H, m) , 3.55-4.0 (7H, m) , 4.48 (2H, q, J=7.1Hz) , 6.59 (IH, d, J=5.2Hz) , 6.84 (2H, d, J=7.8Hz) , 6.96 (IH, t, J=7.4Hz), 7.11 (2H, d, J=8.5Hz) , 7.2-7.4 (9H, m) , 8.18 (IH, ABq, J=1.6, 8.7Hz) , 8.42 (IH, d, J=8.7Hz), 8.72 (IH, d, J=5.2Hz) , 8.82 (IH, d, J=1.4Hz)
Example 57
Under nitrogen, a solution of (2S) -2- (benzyl [ (2R) -2- (4- benzyloxy-3-nitrophenyl) -2-hydroxyethyl] amino} -3- [4- (pyridin- 2-yloxy) phenyl] propan-1-ol (210 mg) and (R) -2- ( -benzyloxy-3- nitrophenyl ) oxirane (170 mg) in ethanol (5 ml) was refluxed for 15 hours. After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel (chloroform: ethyl acetate = 20:1 to 5:1) to give (2S)-2- { benzyl [ (2R) -2- ( 4 -benzyloxy-3-nitrophenyl ) -2-hydroxyethyl ] - amino} -3- [4- (pyridin-2-yloxy) phenyl] propan-1-ol (190 mg) .
NMR (CDC13, δ) : 2.55-3.0 (4H, m) , 3.1-3.3 (IH, m) , 3.55- 3.95 (4H, m) , 4.35-4.5 (IH, m) , 5.20 (2H, s), 6.85- 7.5 (18H, m) , 7.65-7.75 (2H, m) , 8.15-8.2 (IH, m)
Example 58
To a solution of (2S) -2- { benzyl [ (2R) -2- ( 4-benzyloxy-3- nitrophenyl) -2-hydroxyethyl] amino } -3- [4- (pyridin-2-yloxy) - phenyl ] propan-1-ol (170 mg) in a mixture of ethanol (3 ml) and water (1 ml) were added powdered iron (48 mg) and ammonium chloride (8 mg) at room temperature, and the mixture was refluxed for 80 minutes. Insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved into a mixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate. After separation, the organic layer was dried over anhydrous magnesium sulfate, evaporated in vacuo and dried in vacuo to give (2S) -2-{ [ (2R) -2- ( 3-amino-4-benzyloxyphenyl ) -2-hydroxyethyl] benzylamino } -3- [4- (pyridin-2-yloxy) phenyl] propan-1-ol (160 mg) . NMR (CDCI3, δ) : 2.5-2.65 (IH, m) , 2.7-3.0 (3H, m) , 3.05-3.25 (IH, m) , 3.5-4.0 (4H, m) , 4.4-4.5 (IH, m) , 5.06 (2H, s), 6.5-7.5 (19H, m) , 7.6-7.7 (IH, m) , 8.2-8.25 (IH, m)
Example 59
Under nitrogen, a solution of (2S) -2- { [ (2R) -2- (3-amιno- 4-benzyloxyphenyl) -2-hydroxyethyl] benzylammo} -3- [4- (pyπdin- 2-yloxy) phenyl] propan-1-ol (76 mg) , methanesulfonyl chloride (11 μl) and pyridine (16 μl) in dichloromethane (3 ml) was stirred at 5°C for 140 minutes. The resulting mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brme, dried over anhydrous magnesium sulfate and evaporated m vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 20:1) to give N- { 5- [ ( IR) -2- (benzyl- ( (IS) -l-hydroxymethyl-2- [4- (pyridm-2-yloxy) phenyl] - ethyl } ammo) -1-hydroxyethyl ] -2-benzyloxyphenyl } - methanesulfonamide (68 mg) .
NMR (CDC13, δ) : 2.5-3.15 (8H, m) , 3.4-3.5 (2H, m) , 3.7-3.95 (2H, m) , 4.52 (IH, d, J=6.6Hz), 5.09 (2H, s), 6.7-7.5 (19H, m) , 7.6-7.7 (IH, m) , 8.15-8.2 (IH, m)
Example 60 The following compound was obtained according to a similar manner to that of Example 55.
N- [2-Hydroxy-5- ( (IR) -l-hydroxy-2- { (IS) -1-hydroxymethyl- 2-[4-(pyπdιn-2-yloxy) phenyl] ethylammo }ethyl)phenyl]- methanesulfonamide (27 mg)
NMR (DMSO-d6, δ): 2.7-3.7 (10H, m) , 4.85-4.95 (IH, m) , 6.9-7.4 (9H, m) , 7.8-7.9 (IH, m) , 8.1-8.2 (IH, m)
Example 61 The following compounds were obtained according to a similar manner to that of Example 53.
(1) 4-{ 4- [ (2S) -3-Hydroxy-2- ( (2S) -2-hydroxy-3-phenoxypropyl- amino) propyl] phenoxy }quinoline-7-carboxylic acid ethyl ester (26 mg)
NMR (DMSO-d6, δ): 1.40 (3H, t, J=7.1Hz), 2.55-2.9 (5H, m) , 3.1-3.5 (2H, m) , 3.7-4.0 (3H, m) , 4.42 (2H, q, J=7.0Hz), 6.66 (IH, d, J=5.1Hz), 6.9-7.0 (3H, m) , 7.15-7.45 (6H, m) , 8.13 (IH, ABq, J=1.5, 8.7Hz), 8.44 (IH, d, J=8.7Hz), 8.60 (IH, m) , 8.76 (IH, d,
J=5.2Hz)
(2) 4-f 4- [ (2S) -3-Hydroxy-2- ( (2S) -2-hydroxy-3-phenoxypropyl- amino) propyl ] phenoxy } quinoline-7-carboxylic acid amide (15 mg)
NMR (DMSO-d6, δ): 2.55-2.85 (5H, m) , 3.15-3.5 (2H, m) , 3.75-4.0 (3H, m) , 6.61 (IH, d, J=5.1Hz), 6.9-7.0 (3H, m) , 7.15-7.4 (5H, m) , 8.09 (IH, ABq, J=1.6, 8.7Hz), 8.25-8.4 (2H, m) , 8.57 (IH, d, J=1.4Hz), 8.72 (IH, d, J=5.2Hz)
Example 62
To a solution of 4- { 4- [ (2S) -3-hydroxy-2- ( (2S) -2-hydroxy- 3-phenoxyp opylamino) propyl] phenoxy }quinoline-7-carboxylic acid ethyl ester (21 mg) in ethanol (3 ml) was added IN aqueous sodium hydroxide (41 μM) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was evaporated in vacuo. The residue was triturated with hexane and dried in vacuo to give sodium 4-( 4- [ (2S) -3-hydroxy-2- ( (2S) -2-hydroxy-3-phenoxypropylamino) - propyl ] phenoxy } quinoline-7-carboxylate (14 mg) .
NMR (DMSO-d6, δ): 2.55-2.9 (5H, m) , 3.1-3.5 (2H, m) ,
3.7-4.0 (3H, m) , 6.5-6.55 (IH, m) , 6.85-6.95 (3H, m) , 7.1-7.5 (6H, m) , 8.1-8.8 (4H, m) Example 63
Under nitrogen, to a solution of 4- { (2S) -2- [benzyl- ( (2S) -2-hydroxy-3-phenoxypropyl) ammo] -3-hydroxypropyl }- phenol (150 mg) dimethyl sulfoxide (5 ml) was added potassium tert-butoxide (41 mg) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To this one was added 4-chloroqumolme-7-carboxylιc acid amide (76 mg) , and the mixture was stirred at 100°C for 3.5 nours. The resulting mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brme, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel ichloroform:methanol = 100:3 to 20:1) to give 4- (4- { (2S) -2- [benzyl- ( (2S) -2-hydroxy-3-phenoxypropyl ) amino] -3-hydroxypropyl Jphenoxy) qumolme-7-carboxylιc acid amide (44 mg) .
NMR (CDC13, δ) : 2.6-3.35 (5H, m) , 3.5-4.1 (7H, m) , 6.60 (IH, d, J=5.2Hz), 6.8-6.9 (2H, m) , 6.96 (IH, d, J=7.3Hz), 7.10 (2H, d, J=8.5Hz), 7.2-7.4 (9H, m) , 8.09 (IH, ABq, J=1.6, 8.9Hz), 8.45-8.55 (2H, m) ,
8.71 (IH, d, J=5.2Hz)
Example 64
Under nitrogen, to a solution of N- (2-benzyloxy-5- ( ( IR) - l-hydroxy-2- [ (IS) -l-hydroxymethyl-2- ( 4-phenylsulfanylphenyl) - ethylammo] ethyl }phenyl) methanesulfonamide (90 mg) in dichloromethane (5 ml) was added dropwise boron tπbromide (IM in dichloromethane, 1.2 ml) at 5°C, and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was poured into ice-cold water, and the aqueous mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. To the residue was added 4N hydrogen chloride in 1,4- dioxane in order to decompose the boran complexes, followed by evaporation in vacuo. The residue was dissolved into a mixture of saturated aqueous sodium hydrogencarbonate and dichloromethane. After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (silica gel, chloroform:methanol = 5:1) to give N- (2-hydroxy-5- { (IR) -l-hydroxy-2- [ (IS) -1-hydroxymethyl- 2- (4-phenylsulfanylphenyl) ethylammo] ethyl } phenyl) methane- sulfonamide (4 mg) .
NMR (CD3OD, δ) : 1.9-2.1 (2H, m) , 2.65-3.1 (6H, m) , 3.3-3.7 (2H, m) , 4.55-4.75 (IH, m) , 6.86 (IH, d,
J=8.2Hz) , 7.05-7.4 (11H, m)
Example 65
To a solution of (S) -2-amιno-3- [4- (quιnolιn-4-yιoxy) - phenyl] propan-1-ol dihydrochloride (916 mg, 2.49 mmol) m ethanol (18 ml) was successively added (S) -3-phenoxy-l , 2- epoxypropane (374 mg, 2.49 mmol) and dnsopropylethylamme (2.17 ml, 12.5 mmol) at room temperature and the whole was refluxed for 11 hours. After cooling to room temperature, the solvent was evaporated and the residue was dissolved in ethyl acetate (20 ml) . The solution was washed with water (20 ml x 2), brme (20 ml x 1), dried (magnesium sulfate), and evaporated to give a crude oil (995 mg) . The crude oil was chromatographed on a 50 g of silica gel (eluent: chloroform/methanol = 9/1) to give (2S) -2- [ (2S) -2-hydroxy-3- phenoxypropylammo] -3- [4- ( qumolm-4-yloxy) phenyl] propan-1-ol (306 mg, 28%) as a white solid.
IR (KBr): 3421 (br, OH, NH) , 1500, 1250, 1213 cm-1 NMR (CDCI3, δ) : 2.02 (3H, br) , 2.80-3.06 (5H, m) , 3.47 (IH, dd, J=5.1, 11.0Hz), 3.71 (IH, dd, J=3.7,
11.0Hz), 4.01 (3H, m) , 6.54 (IH, d, J=5.2Hz), 6.89- 7.00 (3H, m) , 7.13 (2H, d, J=8.4Hz), 7.26-7.33 (4H, m) , 7.55-7.81 (2H, m) , 8.10 (IH, d, J=8.4Hz), 8.36 (IH, d, J=7.5Hz), 8.65 (IH, d, J=5.2Hz) MS: 445 (M+l) Example 66
A solution of (S) -2-ammo-3- [4- ( imidazo [ 1, 2-a] pyπdm-5- yloxy) phenyl] propan-1-ol (313 mg, 1.10 mmol) and (S)-3- phenoxy-1, 2-epoxypropane (198 mg, 1.32 mmol) in ethanol (6.0 ml) was refluxed for 4 hours. After cooling to room temperature, the solvent was evaporated and the residue was dissolved in ethyl acetate (20 ml) . The solution was washed with water (20 ml x 2), brme (20 ml x 1), dried (magnesium sulfate), and evaporated to give an orange oil. The oil was chromatographed on a 50 g of silica gel (eluent: chloroform/methanol = 95/5) to give a pale yellow oil (134 mg) . Further purification was performed by a recycling preparative HPLC equipped with a GPC column (eluent: chloroform) to give 2 (S) -2- [ (2S ) -2-hydroxy-3-pnenoxypropyl- ammo ] -3- [ 4 - ( imidazo [ 1 , 2-a ] pyrιdm-5-yloxy) phenyl ] propan-1 -ol
( 67 . 5 mg , 14 % ) as a pale yellow oi l . MS : 434 ( M+l )
Example 67 To a solution of 2 (S) -2- [ (2S) -2-hydroxy-3-phenoxypropyl- amino] -3- [4- (imidazo [1, 2-a] pyridm-5-yloxy) phenyl] propan-1-ol (63.6 mg, 0.147 mmol) in dioxane (1 ml) was added 4N hydrogen chloride in dioxane (1 ml) and the solution was stirred at room temperature for 1 hour. The solvent was removed by evaporation and the residue was dissolved in water (10 ml) . The aqueous solution was lyophilized to give 2 (S) -2- [ (2S) -2- hydroxy-3-phenoxypropylammo] -3- [4- (imidazo [1, 2-a]pyrιdm-5- yloxy) phenyl] propan-1-ol dihydrochloride (50.4 mg, 68%) as a pale yellow solid. MS: 434 (M-CH1-C1+)
Example 68
To a solution of N- [2-benzyloxy-5- [ ( IR) -2- [ (IS) -2- hydroxy-1- [4- (imidazo [ 1, 2-a] pyridm-5-yloxy) benzyl ] ethyl- ammo] -1- (triethylsilyloxy) ethyl] phenyl] methanesulfonamide (137 mg, 0.191 mmol) in tetrahydrofuran (1.4 ml) was added a solution of tetrabutylammonium fluoride m tetrahydrofuran
(l.OM solution, 0.2 ml, 0.2 mmol) at room temperature and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml x 1 ) , br e (10 ml x 1 ) , dried
(magnesium sulfate) , and evaporated to give a yellow paste
(119 mg) . The crude oil was chromatographed on a 50 g of silica gel (eluent: chloroform/methanol = 98/2 to 95/5) to give N- [2-benzyloxy-5- [ (IR) -l-hydroxy-2- [ (IS) -2-hydroxy-l- [ 4-
( imidazo [1, 2-a] pyπdιn-5-yloxy) benzyl] ethylammo] ethyl ] - phenyl ] methanesulfonamide (74.0 mg, 64%) as a pale yellow paste. The product was used immediately in the next step.
Example 69
A mixture of N- [2-benzyloxy-5- [( IR) -l-hydroxy-2- [( IS) -2- hydroxy-1- [4- (imidazo [ 1, 2-a] pyrid -5-yloxy) benzyl] - ethylammo] ethyl] phenyl ]methanesulfonamide (74.0 mg, 0.124 mmol), palladium (10% on activated carbon, 50% wet, 50 mg) and methanol (4.0 ml) was hydrogenated (1 atm) for 90 minutes. The catalyst was removed by filtration using Celite and washed with methanol. The filtrate was concentrated in vacuo to give N- [2-hydroxy-5- [( IR) -l-hydroxy-2- [( IS) -2- hydroxy-1- [ 4- ( imidazo [ 1, 2-a ]pyπdm-5-yloxy) benzyl] - ethylammo] ethyl] phenyl] methanesulfonamide (50.8 mg, 81%) as a white solid.
IR (KBr) 3423, 1502, 1153 cm-1 MS: 513 (M+l)
Example 70
To a solution of (S) -2- [ 4- ( 2-ammo-3-hydroxypropyl ) - phenoxy] -N, N-dimethylnicotmamide hydrochloride (439 mg, 1.13 mmol) in ethanol (8.0 ml) were successively added diisopropylethylamme (492 μl, 2.82 mmol) and (S)-2-(3- chlorophenoxymethyl) oxirane (250 mg, 1.35 mmol) at room temperature. The solution was refluxed for 2 hours. After cooling to room temperature, the solvent was evaporated and the residue was dissolved in ethyl acetate (20 ml) . The solution was washed with water (20 ml x 2) , brme (20 ml x 1), dried (magnesium sulfate), and evaporated to give a yellow oil (460 mg) . The crude oil was chromatographed on a 14 g of silica gel (eluent: chloroform/methanol = 95/5 to 9/1) to give 2- [4- [2- [ (2S) -3- (3-chlorophenoxy) -2- (hydroxy) - propylamino] -3-hydroxypropyl ] phenoxy] -N, N- dimethylnicotmamide (160 mg, 26%) as a white foam. IR (KBr) : 3425, 1626, 1593, 1419 cm-1
NMR (CDC13, δ) : 2.06 (3H, br) , 2.64-2.86 (5H, m) , 3.04 (3H, s), 3.15 (3H, s), 3.46 (IH, dd, J=4.3, 10.7Hz), 3.68 (IH, dd, J=3.5, 10.7Hz), 3.72-3.88 (3H, m) , 6.74 (IH, dd, J=2.3, 8.3Hz), 6.85-7.26
(8H, m) , 7.75 (IH, dd, J=1.8, 7.4Hz, ArH) , 8.12 (IH, dd, J=1.8, 5.0Hz) MS: 500 (M+l)
Example 71
To a solution of (S) -2-amιno-3- [ 4- (qumolm-4-yloxy) - phenyl] propan-1-ol dihydrochloride (441 mg, 1.20 mmol) m 1 , 3-dιmethyl-2-ιmιdazolιdmone (4.5 ml) were successively added (R) -N- [2-benzyloxy-5- [2-ιodo-l- ( triethylsilyloxy) - ethyl] phenyl] methanesulfonamide (809 mg, 1.44 mmol) and diisopropylethylamme (836 μl, 4.80 mmol) and the mixture was stirred at 100°C for 28 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml x 2), brme (20 ml x 1), dried (magnesium sulfate), and evaporated to give a yellow oil (736 mg) . The oil was dissolved in tetrahydrofuran (7.0 ml) , and a solution of tetrabutylammonium fluoride in tetrahydrofuran (l.OM, 1.44 ml) was added dropwise to this solution at room temperature. After stirring for 1 hour, the mixture was diluted with ethyl acetate (20 ml), washed with water (20 ml x 2), brme (20 ml x 1), dried (magnesium sulfate) and evaporated to give a yellow oil (636 mg) . The crude oil was chromatographed on a 50 g of silica gel (eluent: chloroform/methanol = 97/3 to 95/5 then 9/1) to give N-[2-benzyloxy-5-[ ( IR) -l-hydroxy-2- [ (IS) -2-hydroxy-l- [ 4- (qumolm-4-yloxy) benzyl] ethylamino] ethyl] phenyl ] methane- sulfonamide (24.3 mg, 3.3%) as a pale yellow paste. The product was immediately used in the next step.
Example 72
A mixture of N- [2-benzyloxy-5- [( IR) -l-hydroxy-2- [( IS) -2- hydroxy-1- [4-(quιnolιn-4-yloxy) benzyl] ethylammo] ethyl ] - phenyl] methanesulfonamide (24.3 mg, 0.0396 mmol), palladium (10% on activated carbon, 50% wet, 20 mg) and methanol (2.0 ml) was hydrogenated (1 atm) at room temperature for 2 hours. The catalyst was removed by filtration using Celite and washed with methanol. The filtrate was concentrated in vacuo to give N- [2-hydroxy-5- [ (IR) -l-hydroxy-2- [ (IS) -2-hydroxy-l- [4- (qumolm-4-yloxy) benzyl] ethylamino] ethyl ] phenyl] methane- sulfonamide (20.0 mg, 97%) as a colorless paste.
IR (KBr): 3423, 1618, 1591, 1504, 1306, 1151 cm-1 MS: 524 (M+l)
Example 73 To a suspension of (S) -2-amιno-3- [4- ( 7-cnloroqumolm-4- yloxy) phenyl] propan-1-ol hydrochloride (480 mg, 1.19 mmol) in ethanol (10 ml) were successively added dnsopropylamine (0.518 ml, 2.97 mmol) and (S) -3-phenoxy-l , 2-epoxypropane (197 mg, 1.31 mmol) at room temperature and the solution was refluxed for 2.5 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was suspended m ethyl acetate (50 ml). The mixture was washed with water (50 ml x 1), brme (50 ml x 1), dried (magnesium sulfate), and evaporated to give a yellow oil (480 mg) . The crude oil was chromatographed on a 50 g of silica gel (eluent: chloroform/methanol = 95/5) to give 2 (S) -3- [ 4- (7- chloroquinolm-4-yloxy) phenyl]-2-[ (2S) -2-hydroxy-3- (phenoxy) - propylamino] propan-1-ol (176 mg, 31%) as a white solid.
IR (KBr) : 3381, 1612, 1587, 1570, 1495, 1246, 1211 cm-1 NMR (CDC13, δ) : 2.02 (3H, br s), 2.78-3.02 (5H, m) , 3.47
(IH, dd, J=5.0, 10.8Hz), 3.71 (IH, dd, J=3.3, 10.8Hz), 4.01-4.05 (3H, m) , 6.52 (IH, d, J=5.2Hz), 6.89-7.00 (3H, m) , 7.25-7.33 (4H, m) , 7.53 (IH, dd, J=2.0, 8.9Hz), 8.09 (IH, d, J=2.0Hz), 8.30 (IH, d, J=8.9Hz), 8.64 (IH, d, J=5.2Hz)
MS (m/z) : 479 (M+l)
Example 74
To a suspension of (S) -2-ammo-3- [ - ( 7-chloroquιnolιn-4- yloxy) phenyl] propan-1-ol hydrochloride (400 mg, 1.10 mmol) in ethanol (10 ml) was added successively diisopropylethylamme (0.433 ml, 2.49 mmol) and (R) -2- ( 3-chlorophenyl) oxirane (154 mg, 0.996 mmol) and the mixture was refluxed for 9 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was suspended in ethyl acetate (20 ml). The suspension was washed with water (20 ml x 2), brine (20 ml x 1), dried (magnesium sulfate), and evaporated to give a yellow oil (658 mg) . The crude oil was purified by a recycling preparative HPLC equipped with a GPC column (eluent: chloroform/methanol = 99.5/0.5) to give (2S)-2- [ (2R) -2- (3-chlorophenyl) -2- (hydroxy) ethylamino] -3- [4- (7- chloroquinolin-4-yloxy) phenyl] propan-1-ol (50.6 mg, 10%) as a white foam.
IR (KBr): 3421, 2929, 1614, 1570, 1421,' 1209 cm"1 NMR (CDCI3, δ) : 1.78 (3H, br), 2.45 (IH, dd, J=10.7,
12.9Hz), 2.83 (IH, dd, J=3.0, 12.9Hz), 2.88-2.95 (2H, m) , 3.23 (IH, m) , 3.71-3.92 (2H, m) , 4.17-4.27 (IH, m) , 6.56 (IH, d, J=5.2Hz), 7.14-7.38 (8H, m) , 7.51 (IH, dd, J=2.1Hz), 8.06 (IH, d, J=2.1Hz), 8.30 (IH, d, J=8.9Hz), 8.47 (IH, d, J=5.2Hz) MS (m/z) : 483, 485 (M+l)
Example 75
Potassium hydroxide powder (85% purity, 35.3 mg, 0.535 mmol) was added to dimethyl sulfoxide (5.0 ml) at room temperature and the mixture was stirred at the same temperature for 1 hour. To the mixture was added 4-[(2S)-2- [benzyl [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] ammo] -3- hydroxypropyl ] phenol (200 mg, 0.486 mmol) and stirred for 30 minutes. Further, a solution of 4-chloroquιnolme (103 mg, 0.203 mmol) in dimethyl sulfoxide (0.5 ml) was added and the mixture was stirred at 100°C for 5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml x 2), orme (20 ml x 1), dried (magnesium sulfate), then evaporated to give a yellow solid (292 mg) . The crude solid was purified by a recycling preparative HPLC equipped with a GPC column (eluent: chloroform/triethylam e = 99.5/0.5) to give (2S) -2- [benzyl- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] ammo] -3- [4- (qumolm-4-yloxy) phenyl] propan-1-ol (155 mg, 59%) as a white solid.
MS (m/z) : 539 (M+l)
Example 76 To a solution of (2S) -2- [benzyl [ (2R) -2- ( 3-chlorophenyl) - 2-hydroxyethyl ] ammo] -3- [4- ( quinolm-4-yloxy) phenyl] propan-1- ol (148 mg, 0.275 mmol) in a mixed solvent of methanol (3.0 ml) and chlorobenzene (3.0 ml) was added palladium (10% on activated carbon, 50% wet, 70 mg) and the mixture was hydrogenated (1 atm) for 90 minutes. The catalyst was filtered off using Celite and washed with methanol. The filtrate was concentrated in vacuo to give 2- [ (2R) -2- (3- chlorophenyl ) -2-hydroxyethylammo] -3- [4- (quιnolιn-4-yloxy) - phenyl ] propan-1-ol (134 mg, 109%) as a pale yellow solid. MS (m/z) : 449 (M+l) Example 77
Potassium hydroxide powder (85% purity, 53.4 mg, 0.809 mmol) was added to dimethyl sulfoxide ( 6.0 ml ) at room temperature and the mixture was stirred at the same temperature for 80 minutes. To the mixture was added 4- [ (2S) -2- [benzyl [ (2S) -2-hydroxy-3-phenoxypropyl ] ammo] -3- hydroxypropyl] phenol (300 mg, 0.736 mmol) and stirred for 30 minutes. Further, 4-chloro-7-methoxyqumolme (171 mg, 0.883 mmol) was added and the mixture was stirred at 100°C for 3.5 hours. After cooling to room temperature, the mixture was quenched by the addition of water (30 ml) and extracted with ethyl acetate (30 ml x 1 ) . The organic layer was separated and washed with water (30 ml x 2), brme (30 ml x 1), dried (magnesium sulfate), then evaporated to give a brown paste (437 mg) . The crude paste was chromatographed on a 50 g of silica gel (eluent: hexane/ethyl acetate = 1/1 to 1/2) to give (2S)-2- [benzyl [ (2S) -2-hydroxy-3-phenoxypropyl ] ammo] -3- [4- (7-methoxyqumolιn-4-yloxy) phenyl] propan-1-ol (195 mg, 47%) as a white foam. NMR (CDC13, δ) : 1.82 (2H, br), 2.62 (IH, dd, J=8.5,
13.6Hz), 2.79-3.21 (4H, m) , 3.53-4.00 (8H, m) , 6.41 (IH, d, J=5.3Hz), 6.82-7.42 (16H, m) , 8.24 (IH, d, J=9.2Hz), 8.57 (IH, d, J=5.3Hz) MS (m/z) : 565 (M+l)
Example 78
To a solution of (2S) -2- [benzyl [ (2S) -2-hydroxy-3- phenoxypropyl] ammo] -3- [4- (7-methoxyqumolm-4-yloxy) phenyl] - propan-1-ol (184 mg, 0.326 mmol) in methanol (4.0 ml)) was added palladium (10% on activated carbon, 50% wet, 184 mg) and the mixture was hydrogenated (1 atm) for 2.5 hours. The catalyst was removed by filtration using Celite and washed with methanol. The filtrate was concentrated to give 2(S)-2- [ (2S) -2-hydroxy-3- (phenoxy) propylamino] -3- [4- (7-methoxy- quιnolιn-4-yloxy) phenyl] proρan-1-ol (135 mg, 87%) as a white solid .
IR (KBr): 3421, 1623, 1583, 1500, 1429, 1311, 1228 cm-1 NMR (CDC13, δ) : 2.78 (3H, br) , 2.89-3.18 (5H, m) , 3.57 (IH, dd, J=5.6, 11.4Hz), 3.78 (IH, dd, J=3.4, 11.4Hz), 3.97 (3H, s), 4.01 (2H, d, J=5.2Hz), 4.56
(IH, m) , 6.41 (IH, d, J=5.3Hz), 6.91-6.99 (3H, m) , 7.10 (2H, d, J=8.4Hz), 7.23-7.32 (5H, m) , 7.41 (IH, d, J=2.4Hz), 8.21 (IH, d, J=9.2Hz), 8.56 (IH, d, J=5.3Hz) MS (m/z) : 475 (M+l)
Example 79
Potassium hydroxide powder (85% purity, 53.4 mg, 0.809 mmol) was added to dimethyl sulfoxide (6.0 ml) at room temperature and the mixture was stirred at the same temperature for 1 hour. To the mixture was added 4-[(2S)-2- [benzyl [ (2S) -2-hydroxy-3-phenoxypropyl ] ammo] -3-hydroxypropyl] phenol (300 mg, 0.736 mmol) and stirred for 40 minutes. Further, 4-chloro-6-fluoroqumolme (160 mg, 0.881 mmol) was added and the mixture was stirred at 100°C for 24 hours. After cooling to room temperature, the mixture was quenched by the addition of water (20 ml) and extracted with ethyl acetate (20 ml x 1 ) . The organic layer was separated and washed with water (20 ml x 2), brme (20 ml x 1), dried (magnesium sulfate), then evaporated to give a pale brown paste (424 mg) . The crude paste was chromatographed on a 20 g of silica gel (eluent: hexane/ethyl acetate = 2/1 to 1/1) to give (2S) -2- [benzyl [ (2S) -2-hydroxy-3-phenoxypropyl] ammo] - 3- [4- (6-fluoroqumolm-4-yloxy) phenyl] propan-1-ol (195 mg, 48%) as a white foam.
NMR (CDCI3, δ) : 1.62 (2H, br), 2.58-3.22 (5H, m) ,
3.54-4.00 (5H, m) , 6.54 (IH, d, J=5.2Hz), 6.82-7.30 (14H, m) , 7.47-7.57 (IH, m) , 7.96 (IH, dd, J=2.9, 9.4Hz), 8.09 (IH, dd, J=5.3, 9.4Hz), 8.62 (IH, d, J=5.2Hz) MS (m/z) : 553 (M+l)
Example 80
To a solution of (2S) -2- [benzyl [ (2S) -2-hydroxy-3- phenoxypropyl] ammo] -3- [4- ( 6-fluoroqumolm-4-yloxy) phenyl] - propan-1-ol (182 mg, 0.329 mmol) methanol (4.0 ml) was added palladium (10% on activated carbon, 50% wet, 182 mg) and the mixture was hydrogenated (1 atm) for 6 hours. The catalyst was removed by filtration using Celite and washed with methanol. The filtrate was concentrated to give 2(S)-3- [4- (6-fluoroqumolm-4-yloxy) pnenyl] -2- [ (2S) -2-hydroxy-3- (phenoxy) propylamino] propan-1-ol (145 mg, 95%) as a white solid.
IR (KBr): 3381, 1599, 1502, 1466, 1296, 1215 cm-1 NMR (CDC13, δ) : 2.91-3.26 (8H, m) , 3.63 (IH, dd, J=5.6,
11.6Hz), 3.73 (IH, dd, J=3.0, 11.6Hz), 4.03 (IH, d, J=4.9Hz), 4.35 (IH, m) , 6.53 (IH, d, J=5.2Hz), 6.86-6.99 (3H, m) , 7.09 (2H, d, J=8.3Hz), 7.22-7.31 (2H, m) , 7.33 (2H, d, J=8.3Hz), 7.51 (IH, dt, J=2.8, 8.7Hz), 7.92 (IH, dd, J=2.9, 9.3Hz), 8.09
(IH, dd, J=5.3, 9.3Hz), 8.59 (IH, d, J=5.2Hz) MS (m/z) : 463 (M+l)
Example 81 Potassium hydroxide powder (85% purity, 55.0 mg, 0.833 mmol) was added to dimethyl sulfoxide ( 8.0 ml ) at room temperature and the mixture was stirred at the same temperature for 1 hour. To the mixture was added 4-[(2S)-2- [benzyl [ (2R) -2- ( 4-benzyloxy-3-nιtrophenyl ) -2-hydroxyethyl] - ammo] -3-hydroxypropyl] phenol (400 mg, 0.757 mmol) and stirred for 40 minutes. Further, 4-chloro-6-fluoroquinol e (179 mg, 0.986 mmol) was added and the mixture was stirred at 100°C for 96 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml x 3), brme (20 ml x 1), dried (magnesium sulfate), then evaporated to give a brown foam (468 mg) . The crude product was chromatographed on a 25 g of silica gel (eluent: hexane/ethyl acetate = 1/1, then chloroform/methanol = 9/1) to give (2S) -2- [benzyl [ (2R) -2- ( 4-benzyloxy-3- nitrophenyl ) -2-hydroxyethyl] ammo] -3- [ 4- ( 6-fluoroquιnolm-4- yloxy) phenyl] propan-1-ol (90.7 mg, 18%) as an orange foam. The product was immediately used in the next step.
Example 82 To a solution of (2S) -2- [benzyl [ (2R) -2- ( 4-benzyloxy-3- mtrophenyl ) -2-hydroxyethyl] ammo] -3- [4- (6-fluoroqumolm-4-y loxy) phenyl] propan-1-ol (90.7 mg, 0.135 mmol) in a mixed solvent of ethanol (6.0 ml) and water (2.0 ml) were successively added iron powder (22.6 mg, 0.405 mmol) and ammonium chloride (3.6 mg, 0.067 mmol) . The mixture was refluxed for 1 hour, with vigorous stirring. After cooling to room temperature, the metal was removed by filtration using Celite, and washed with ethanol. The filtrate was concentrated in vacuo to give a pale brown solid. To the solid were added aqueous saturated sodium hydrogencarbonate solution (20 ml) and ethyl acetate (20 ml), and the whole was stirred vigorously. The organic layer was separated and washed with water (20 ml x 2), brine (20 ml x 1), dried (magnesium sulfate), and evaporated to give (2S) -2- [ [ (2R) -2- (3-ammo-4-benzyloxyphenyl) -2-hydroxyethyl] benzylammo] -3- [4- ( 6-fluoroqumolm-4-yloxy) phenyl] propan-1-ol (89.1 mg, 103%) as a yellow foam. The product was immediately used in the next step.
Example 83
To a solution of (2S) -2- [ [ (2R) -2- ( 3-ammo-4-benzyloxy- phenyl) -2-hydroxyethyl] benzylamino] -3- [4- ( 6-fluoroqumolm-4- yloxy) phenyl] propan-1-ol (89.1 mg, 0.138 mmol) in dichloromethane (2.0 ml) was added pyridine (33.4 μl, 0.412 mmol) and the solution was cooled to 0°C. To the solution was added methanesulfonyl chloride (25.6 μl , 0.330 mmol) at 0°C and stirred at the same temperature for 1 hour. The reaction mixture was warmed to room temperature and stirred for 15 minutes. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml x 2), brme (10 ml x 1), dried over magnesium sulfate. Evaporation of the solvent gave an orange foam (97.6 mg) . The crude product was chromatographed on a 25 g of silica gel (eluent: cnloroform/methanol = 98/2) to give N- [5- [ ( IR) -2- [benzyl- [ (IS) -1- [4- (6-fluoroqumolm-4-yloxy) benzyl] -2-hydroxyethyl] - ammo] -1-hydroxyethyl] -2-benzyloxyphenyl ] methanesulfonamide (30.0 mg, 30%) as a pale yellow foam. The product was immediately used in the next step.
Example 84
To a solution of N- [5- [ ( IR) -2- [benzyl [ ( IS) -1- [ 4- ( 6- fluoroqumolm-4-yloxy) benzyl] -2-hydroxyethyl] ammo] -1- hydroxyethyl] -2-benzyloxyphenyl] methanesulfonamide (30.0 mg, 0.0416 mmol) in methanol (1.0 ml) was added palladium (10% on activated carbon, 50% wet, 30 mg) and the mixture was hydrogenated (1 atm) for 1 hour. The catalyst was removed by filtration using Celite and washed with methanol. The filtrate was concentrated to give N- [2-hydroxy-5- [ ( IR) -1- hydroxy-2- [ (IS) -1- [4- ( 6-fluoroqumolm-4-yloxy) benzyl] -2- hydroxyethylamino] ethyl] phenyl] methanesulfonamide (15.2 mg, 68%) as a pale yellow solid.
IR (KBr) : 3419, 1599, 1510, 1468, 1294, 1151 cm-1 MS (m/z) : 542 (M+l)
Example 85
The following compound was obtained by a similar manner to that of Example 94 followed by a reduction of the nitro group as described in Example 88.
(S) -1- ( 3-Ammo-4-benzyloxyphenoxy) -3- ( (S) -N-benzyl- [1- hydroxy-3- [ 4- (2-pyπdmyloxy) phenyl ] -2-propyl] ammo] -2- propanol
MS (m/z) : 606 (M+l)
Example 86
The following compound was obtained by a similar manner as described m Example 89.
(S) -1- ( 4-Hydroxy-3-methanesulfonylammophenoxy) -3- [ (S) - [ 1-hydroxy-3- [4- (pyrιdm-2-yloxy) phenyl] -2-propyl] ammo] -2- propanol
IR (KBr): 1649 (m) , 1512 (s), 1468 (m) , 1429 (m) cm-1 NMR (CD3OD, δ) : 2.6-2.9 (5H, m) , 2.90 (3H, s), 3.3-3.6 (2H, m) , 3.8-3.9 (2H, m) , 3.9-4.0 (IH, m) , 6.61 (IH, d, J=11.5Hz), 6.76 (IH, d, J=11.7Hz), 6.88
(IH, d, J=8.1Hz), 6.9-7.2 (3H, m) , 7.2-7.3 (3H, m) , 7.79 (IH, t, J=7.4Hz), 8.12 (IH, d, J=6Hz) MS (m/z) : 504 (M+l)
Example 87
A mixture of (S) -2- [( 4-benzyloxy-3-nιtrophenoxy) methyl ] - oxirane (123 mg) , (S) -2-amιno-3- [ 4- ( 3-methyl-2-pyπdmyloxy) - phenyl] propanol (96 mg) and methanol (2 ml) was heated under reflux for 3 hours and evaporated. The residue was purified by a column chromatography (silica gel, dichloromethane :methanol : concentrated ammonia solution = 20:1:0.1) to afford (S) -1- (4-benzyloxy-3-nιtrophenoxy) -3- [ (S) -l-hydroxy-3- [4- (3-methyl-2-pyridmyloxy) phenyl] -2- propylamino] -2-propanol (91.2 mg) . MS (m/z) : 560 (M+l)
Example 88
To a mixture of ( S ) - 1 - ( 4 -benzyloxy-3-nιtrophenoxy) -3- [ ( S ) - l-hydroxy-3- [ 4 - ( 3-methyl-2-pyπdmyloxy) phenyl ] -2- propylamino ] -2 -propanol ( 86 mg ) , tetrahydrofuran ( 5 ml ) and saturated aqueous sodium bicarbonate solution (5 ml), benzyloxycarbonyl chloride (26 μl ) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate (5 ml x 2) . The extract was washed with water (5 ml x 2) and evaporated to afford (S) -1- ( 4-benzyloxy-3-nιtrophenoxy) -3- [N- benzyloxycarbonyl- [ (S) -l-hydroxy-3- [4- ( 3-methyl-2-pyndmyl- oxy) phenyl] -2-propylammo] -2-propanol as a crude residue. The crude residue was dissolved m ethanol (3 ml) and heated with water (0.3 ml), iron powder (about 50 mg) and ammonium chloride (about 10 mg) under reflux for 1 hour. The reaction mixture was filtered and worked up by a similar manner to that described above to afford (S) -1- ( 3-ammo-4- benzyloxyphenoxy) -3- [N-benzyloxycarbonyl- [ (S) -l-hydroxy-3- [4- ( 3-methyl-2-pyπdmyloxy) phenyl ] -2-propylammo] -2-propanol (136 mg) as a crude product, which was used without any further purification.
MS (m/z) : 664 (M+l)
Example 89
To a mixture of (S) -1- ( 3-ammo-4-benzyloxyphenoxy) -3- [N- benzyloxycarbonyl- [ (S) -l-hydroxy-3- [4- ( 3-methyl-2-pyrιdmyl- oxy) phenyl ] -2-propylammo] -2-propanol (43.6 mg) , pyridine (0.03 ml) and dichloromethane (1 ml), methanesulfonyl chloride (7 μl) was added at 0°C. After 40 minutes, additional methanesulfonyl chloride (7 μl) was added. After 1 hour, saturated aqueous sodium bicarbonate solution (5 ml) and ethyl acetate (5 ml) were added therein and the resulting mixture was stirred at room temperature for 1 hour. The organic layer was separated, washed successively with water
(5 ml x 2) and brme (5 ml x 1), dried over magnesium sulfate and evaporated to afford (S) -1- ( 4-benzyloxy-3- methanesulfonylaminophenoxy) -3- [N-benzyloxycarbonyl- [ (S) -1- hydroxy-3- [4- ( 3-methyl-2-pyπdmyloxy) phenyl] -2-propylammo] - 2-propanol, which was converted to (S) -1- ( 4-hydroxy-3- methanesulfonylaminophenoxy) -3- [ (S)-l-hydroxy-3-[4-( 3-methy1- 2-pyrιdmyloxy) phenyl] -2-propylammo] -2-propanol (19.2 mg) by catalytic hydrogenation on palladium charcoal in a usual manner followed by preparative thin-layer chromatograpny (dichloromethane :methanol : concentrated ammonia solution = 7:1:0.1) .
IR (KBr): 3420 (broad s), 1510 (m) , 1415 (m) ,
1213 (m) cm"1 NMR (CD3OD, δ) : 2.32 (3H, s), 2.6-3.0 (5H, m) , 2.91 (3H, s), 3.3-3.7 (2H, m) , 3.8-4.0 (3H, m) , 6.64 (IH, d,
J=8.6Hz), 6.78 (IH, d, J=8.6Hz), 6.9-7.1 (4H, m)_, 7.25 (2H, d, J=8.4Hz), 7.67 (IH, d, J=6Hz), 7.89 (IH, d, J=4Hz) MS (m/z) : 518 (M+l)
Example 90
To a solution of (S) -2-ammo-3- [ 4- ( 3-hydroxymethyl-2- pyπdmyloxy) phenyl ] propanol dihydrochloride (112 mg) m methanol, 28% sodium methoxide-methanol solution (126 mg) was added and evaporated to afford the corresponding free base.
A mixture of the free base, (R) -3-pyrιdylox rane (117 mg) and isopropanol (4 ml) was heated under reflux for 6 hours, evaporated and purified by preparative thin-layer chromatography (dichloromethane :methanol : concentrated ammonia solution = 5:1:0.1) to afford (R) -1- (3-pyπdyl) -2- [ (S) -1- hydroxy-3- [ 4- ( 3-hydroxymethyl-2-pyπdmyloxy) phenyl] -2- propylammo] ethanol (16.1 mg) .
IR (KBr): 1585 (m) , 1425 (m) , 1240 (s), 1045 (s) cm"1 NMR (CD3OD, δ) : 2.7-3.2 (5H, m) , 3.4-3.7 (2H, m) , 4.73 (2H, s), 4.7-4.8 (IH, m) , 7.00 (2H, d, J=8.1Hz),
7.11 (IH, t, J=5.6Hz), 7.25 (2H, d, J=8.1Hz), 7.43 (IH, dd, J=5.6, 10.4Hz), 7.85 (IH, d, J=7.8Hz), 7.92 (2H, d, J=6.4Hz), 8.44 (IH, d, J=3.7Hz), 8.55 (IH, s) MS (m/z) : 396 (M+l) Example 91
The following compound was obtained by a similar manner to that of Example 87.
(S)-l-(3-Pyπdyloxy)-3-[ (S) -l-hydroxy-3- [4- (3- hydroxymethyl-2-pyrιdmyloxy) phenyl] -2-propylammo] -2- propanol
IR (KBr): 1579 (m) , 1427 (s), 1240 (s) cm-1 NMR (CD3OD, δ) : 2.6-3.1 (5H, m) , 3.4-3.7 (2H, m) , 3.9-4.3 (3H, m) , 4.73 (2H, s), 7.00 (2H, d,
J=8.4Hz), 7.11 (IH, t, J=6.6Hz), 7.27 (2H, d, J=8.5Hz), 7.3-7.5 (3H, m) , 7.93 (IH, d, J=5.9Hz), 8.12 (IH, d, J=3.3Hz), 8.24 (IH, s) MS (m/z) :426 (M+l)
Example 92
A mixture of (S) -l-phenoxy-3- [ (S) -l-hydroxy-3- [4- ( 3- hydroxymethyl-2-pyπdmyloxy) phenyl] -2-propylammo] -2- propanol dihydrochloride (29 mg) , palladium hydroxide on charcoal (5 mg) and methanol (2 ml) was stirred in the presence of hydrogen (1 atm) at room temperature for 2 hours The reaction mixture was filtered and evaporated to afford (S) -l-phenoxy-3- [ (S) -l-hydroxy-3- [4- ( 3-methyl-2-pyrιdmyl- oxy) phenyl ] -2-propylammo] -2-propanol dihydrochloride (19.7 mg)
IR (KBr): 1598 (m) , 1502 (m) , 1244 (s), 1049 (m) cm-1 NMR (CD3OD, δ) : 2.35 (3H, s), 3.0-3.2 (2H, m) , 3.4-3.9 (5H, m) , 4.0-4.1 (2H, m) , 4.2-4.4 (IH, m) , 6.9-7.4 (10H, m) , 7.84 (IH, d, J=7.1Hz), 7.95 (IH, d, J=5.3Hz)
MS (m/z) : 409 (M+l, free)
Example 93
The following compound was obtained by a similar manner to that of Example 90. (R) -1- (3-Pyrιdyl) -2- [ (S) -l-hydroxy-3- [ 4- ( 3-methyl-2- pyridinyloxy) phenyl] -2-propylammo] ethanol
IR (KBr): 2924 (m) , 1579 (s), 1415 (m) cm-1 NMR (CDC13, δ) : 2.31 (3H, s), 2.7-3.0 (5H, m) , 3.4-3.7 (2H, m) , 4.8-4.9 (IH, m) , 6.9-7.0 (3H, m) , 7.23 (2H, d, J=8.5Hz), 7.4-7.5 (IH, m) , 7.68 (IH, d, J=7.8Hz), 7.8-7.9 (2H, m) , 8.44 (IH, s), 8.54 (IH, s) MS (m/z) : 380 (M+l)
Example 94
The following compound was obtained in a similar manner to that of Example 87.
(S) -l-Phenoxy-3- [ (S) -l-hydroxy-3- [4- (2-pyrιdmyloxy) - phenyl] -2-propylammo] -2-propanol
IR (KBr): 1593 (m) , 1429 (m) , 1244 (s), 1043 (s) cm-1 NMR (CD3OD, δ) : 2.7-2.9 (3H, m) , 2.9-3.1 (2H, m) , 3.4-
3.7 (2H, m) , 3.9-4.0 (2H, m) , 4.0-4.2 (IH, m) , 6.9- 7.1 (7H, m) , 7.2-7.4 (4H, m) , 7.79 (IH, t,
J=7.1Hz), 8.10 (IH, d, J=7Hz) MS (m/z) : 395 (M+l)
Example 95 A mixture of 2- { 4- [ (2S) -3-hydroxy-2- ( (2S) -2-hydroxy-3- phenoxypropylammo) propyl] phenoxy} qumolme-3-carboxylic acid methyl ester (270 mg) and aqueous 28% ammonium hydroxide (5.0 ml) m 1,4-dioxane (5.0 ml) was stirred at room temperature for 2 days. The mixture was evaporated in vacuo, followed by partition between ethyl acetate and water. The organic layer was washed with brme, dried over sodium sulfate and evaporated in vacuo. To a solution of the residue in dioxane (3 ml) was added 4N hydrogen chloride in dioxane (3 ml) at room temperature, and the solution was stirred at the same temperature for 3 hours. The mixture was evaporated in vacuo, and the residue was triturated with diisopropyl ether to give 2- { 4- [ (2S) -3-hydroxy-2- ( (2S) -2-hydroxy-3-phenoxy- propylammo) propyl ] phenoxy } qumolme-3-carboxylιc acid amide (0.41 g) as a colorless powder. NMR (DMSO-d6, δ) : 2.80-3.73 (7H, m) , 3.99-4.05 (2H, m) ,
4.20-4.30 (IH, m) , 6.95-7.10 (3H, m) , 7.05-8.10 (10H, m) , 8.79 (IH, s) MS (m/z) : 488 (M+l)
Example 96
The following compound was synthesized according to a similar manner to that of Example 97.
N- (2-(4- [ (2S) -3-Hydroxy-2- ( (2S) -2-hydroxy-3-phenoxy- propylamino) propyl] phenoxy } pyridm-3-yl ) methanesulfonamide as a brown powder
NMR (DMSO-d6, δ): 2.90-3.60 (10H, m) , 4.00-4.10 (2H, m) , 4.20-4.30 (IH, m) , 6.90-7.17 (6H, m) , 7.25-7.40 (4H, m) , 7.75-7.95 (2H, m) , 9.60 (IH, br s) MS (m/z) : 488 (M+l)
Example 97
{ ( IS ) -1 -Hydroxymethyl -2- [ 4 - ( 3-ammopyπdm-2 -yloxy ) - phenyl ] ethyl } - ( 2S ) - ( 2 -hydroxy- 3 -phenoxypropyl ) carbamic acid tert-butyl ester (110 mg) and pyridine (0.1 ml) in dichloromethane (6 ml) under ice water cooling over 10 minutes and the mixture was stirred at room temperature for a further 1 hour. To this one was added aqueous saturated solution of sodium bicarbonate (5.0 ml). The mixture was stirred at the same temperature for 18 hours, and which was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo. To a solution of the residue in dioxane (3 ml) was added 4N hydrogen chloride in dioxane (3 ml) at room temperature, and the solution was stirred at the same temperature for 3 hours. The mixture was evaporated in vacuo, and the residue was triturated with diisopropyl ether to give N- (2- { 4- [ (2S) -3-hydroxy-2- ( (2S) -2- hydroxy-3-phenoxypropylammo) propyl] phenoxy }pyrιdm-3- yl) benzenesulfonamide as a brown powder.
NMR (DMSO-d6, δ): 2.90-3.60 (7H, m) , 4.50-4.10 (2H, m) , 4.20-4.30 (IH, m) , 6.90-7.17 (11H, m) , 7.24-7.40 (4H, m) , 7.75-7.95 (2H, m) MALDI-MS (m/z) : 549 (M+Na)

Claims

C L A I M S
1. A compound of the formula [I] :
Figure imgf000124_0001
wherem
Figure imgf000124_0002
X2 is -(CH2)n~, in which n is 1, 2 or 3; X3 is bond, -0-, -S- -OCH or -NH-
R ,1 is phenyl or pyridyl, each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, halogen, ammo, [( lower ) alkylsulfonyl] ammo, nitro, benzyloxycarbonylamino and benzyloxy;
R is hydrogen, (lower ) alkoxycarbonyl , benzyl or benzyloxycarbonyl ;
R^ is hydroxy ( lower) alkyl, ( lower ) alkoxy (lower ) alkyl or halo (lower ) alkyl ; and
R is aryl or an unsaturated heterocyclic group containing nitrogen, each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, halo ( lower) alkyl, halogen, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, cyano, carboxy, ( lower ) alkoxycarbonyl , lower alkanoyl, carbamoyl, (mono or di) (lower) - alkylcarbamoyl, [ (lower ) alkylsulfonyl ] carbamoyl, ammo, nitro, ureido, [ (lower ) alkylcarbonyl] ammo, [ (lower ) alkylsulfonyl ] ammo and (arylsulfonyl) ammo, and a salt thereof.
2. A compound of claim 1, wherem
Figure imgf000125_0001
X2 is -(CH2)n~, m which n is 1, 2 or 3; X3 is bond, -0-, -S-, -OCH2~ or -NH; R1 is phenyl or pyridyl, each of which may be substituted with one or two substituent ( s) selected from the group consisting of hydroxy, halogen, ammo, [( lower ) alkylsulfonyl ] ammo, nitro, benzyloxycarbonylamino and benzyloxy; R^ is hydrogen, ( lower ) alkoxycarbonyl, benzyl or benzyloxycarbonyl ;
3 R is hydroxy ( lower) alkyl, (lower ) alkoxy (lower) alkyl or halo (lower) alkyl ; and
R is phenyl, naphthyl or an unsaturated 5 or 6 membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) or an unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, halo (lower) alkyl, halogen, hydroxy ( lower) alkyl, (lower) alkoxy (lower ) alkyl, cyano, carboxy, (lower) alkoxycarbonyl, lower alkanoyl, carbamoyl, (mono or di) ( lower ) alkylcarbamoyl, [ (lower ) alkylsulfonyl] carbamoyl , ammo, nitro, ureido, [ (lower) alkylcarbonyl] ammo, [ (lower ) alkylsulfonyl] ammo and (arylsulfonyl ) ammo.
3. A compound of claim 2, wherem
Figure imgf000125_0002
X2 is _(CH2)n- in which n is 1;
X3 is bond, -0- or -S-;
R is phenyl which may be substituted with one or two substituent (s) selected from the group consisting of halogen, nitro, ammo, benzyloxy, benzyloxycarbonylamino, hydroxy and
[ (lower) alkylsulfonyl] ammo; or pyridyl which may be substituted with ammo R^ is hydrogen or (lower) alkoxycarbonyl; R is hydroxy (lower) alkyl ; and
R4 is phenyl, naphthyl, pyridyl, pyridyl N-oxide, pyrrolyl, pyrazmyl , qumolyl, isoquinolyl, lmidazopyridyl, benzothiazolyl , qumoxalmyl, acπdmyl, pyrimidmyl or naphthyridmyl , each of which may be substituted with one or two substituent (s) selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, halo (lower ) alkyl , halogen, hydroxy (lower ) alkyl, (lower) alkoxy ( lower) alkyl, cyano, carboxy,
(lower) alkoxycarbonyl , lower alkanoyl, carbamoyl,
(mono or di) (lower ) alkylcarbamoyl,
[ (lower) alkylsulfonyl] carbamoyl, ammo, nitro, ureido, [ (lower) alkylcarbonyl] ammo, [ (lower) alkylsulfonyl] ammo and
(arylsulfonyl) ammo .
4. A compound of claim 3, wherem
Figure imgf000126_0001
X2 is ~(CH2)n- ιn which n is 1;
Figure imgf000126_0002
R-^ is phenyl which may be substituted with one or two substituent ( s ) selected from the group consisting of halogen, nitro, ammo, benzyloxy, benzyloxycarbonylamino, hydroxy and
[ (lower) alkylsulfonyl] ammo; or pyridyl which may have amino. R2 is hydrogen.
R3 is hydroxy (lower ) alkyl ; and R is pyridyl which may be substituted with carbamoyl, lower alkoxycarbonyl, carboxy, cyano, nitro, ammo, hydroxy (lower) alkyl, monojor dι) (lower)- alkylcarbamoyl, lower alkyl, halogen, lower alkylsulfonylammo, phenylsulfonylamino or lower alkanoyl; phenyl which may be substituted with halogen; qumolyl which may be substituted with lower alkoxycarbonyl, nitro, carbamoyl, carboxy, halogen or lower alkoxy; naphthyl; benzothiazolyl; pyridyl N-oxide; pyrimidmyl; naphthyridinyl; pyrazmyl; imidazo [ 1, 2-a] pyridyl ; qumoxalmyl which may be substituted with halogen; acridmyl which may be substituted with halogen and lower alkoxy; or isoquinolyl which may be substituted with halogen;
5. A compound of claim 4, wherem
R is phenyl which may be substituted with one or two substituent (s) selected from th group consisting of halogen, nitro, ammo, benzyloxy, benzyloxycarbonylamino, hydroxy and lower alkylsulfonylamino . R4 is pyridyl which may be substituted with carbamoyl, lower alkoxycarbonyl, carboxy, cyano, nitro, ammo, hydroxy (lower) alkyl, mono (or di) (lower) - alkylcarbamoyl, lower alkyl, halogen, lower alkylsulfonylammo, phenylsulfonylamino or loweralkanoyl; phenyl which may be substituted with halogen; qumolyl which may be substituted with lower alkoxycarbonyl, nitro, carbamoyl, carboxy, halogen or lower alkoxy; naphthyl; benzothiazolyl; pyridyl N-oxide; pyrimidmyl; naphthyridinyl ; pyrazmyl; imidazo [ 1 , 2-a ] pyridyl ; qumoxalmyl which may be substituted with halogen; acridmyl which may be substituted with halogen and lower alkoxy; or isoquinolyl which may be substituted with halogen;
A compound of claim 4, wherein R-|_ is pyridyl which may have amino; and R is pyridyl which may have hydroxy (lower ) alkyl
A process for preparing a compound of claim 1, or a salt thereof, which comprises,
reacting a compound [II] of the formula :
R1-X -χι--CC ΛHH--CC.H2 [II
wherein X-^ and R are each as defined in claim 1, with a compound [III] of the formula :
Figure imgf000128_0001
wherein X2, X3, R ? , R ~ and R4 are each as defined in claim 1, or a salt thereof, to give a compound [I] of the formula :
Figure imgf000128_0002
wherein X^, ^2 ' x3' R ' R ' R and R are eacn as defined in claim 1, or a salt thereof, (11) subjecting a compound [la] of the formula
Rx
Figure imgf000129_0001
wherem X-j_, X2. X3, R , and R4 are each as defined in claim 1, and
2 Rg is ammo protective group, or a salt thereof, to elimination reaction of the ammo protective group, to give a compound [lb] of the formula :
Figure imgf000129_0002
wherem X-j_, X . X3, R , and R are each as defined in claim 1, or a salt thereof,
(111) reacting a compound [III] of the formula:
H
Figure imgf000129_0003
wherem X2, X3, R and R are each as defined in claim 1, or a salt thereof with a compound [IV] of the formula
Figure imgf000129_0004
wherem R is as defined in claim 1, Q is protected hydroxy and X is halogen, to give a compound [Ic] of the formula:
Figure imgf000130_0001
wherem X , X3, R , R and R4 are each as defined 11 claim 1, or a salt thereof, or
(iv) reacting a compound [V] of the formula:
Figure imgf000130_0002
wherem X-^, X . R 1 , and R ' are each as defined in claim 1, and R is benzyl with a compound [VI] of the formula:
MO "VI
wherem is aryl or an unsaturated heterocyclic
Figure imgf000130_0003
group containing nitrogen, each of which may be substituted with one or two substituent ( s ) selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, halo ( lower ) alkyl , halogen, hydroxy (lower) alkyl, ( lower ) alkoxycarbonyl, lower alkanoyl, carbamoyl, (mono or di) (lower) alkylcarbamoyl, [ (lower) alkylsulfonyl] carbamoyl, ammo, nitro, ureido,
[ (lower ) alkylcarbamoyl] ammo, [ (lower ) alkylsulfonyl] ammo and (arylsulfonyl) ammo, and X is as defined above, to give a compound [Id] of the formula:
Figure imgf000131_0001
1 wherem X-j_ , X2 , R , R and R are each as defined in claim 1 , and
A ) IS as defined above, or a salt thereof.
8. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof m admixture with pharmaceutically acceptable carriers or excipients
9. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament .
10. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.
11. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as selective 3 adrenergic receptor agonists .
2. A method for the prophylactic and/or the therapeutic treatment of pollakiuria or urinary incontinence which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.
PCT/JP1999/007203 1998-12-30 1999-12-22 Aminoalcohol derivatives and their use as beta 3 adrenergic agonists WO2000040560A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP99961305A EP1140849A1 (en) 1998-12-30 1999-12-22 Aminoalcohol derivatives and their use as beta 3 adrenergic agonists
JP2000592269A JP2002534415A (en) 1998-12-30 1999-12-22 New compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPP7967A AUPP796798A0 (en) 1998-12-30 1998-12-30 New compound
AUPP7967 1998-12-30

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09868615 A-371-Of-International 2001-06-22
US10/118,929 Continuation US20020143034A1 (en) 1998-12-20 2002-04-10 Aminoalcohol derivatives and their use as beta 3 adrenergic agonists

Publications (1)

Publication Number Publication Date
WO2000040560A1 true WO2000040560A1 (en) 2000-07-13

Family

ID=3812174

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/007203 WO2000040560A1 (en) 1998-12-30 1999-12-22 Aminoalcohol derivatives and their use as beta 3 adrenergic agonists

Country Status (4)

Country Link
EP (1) EP1140849A1 (en)
JP (1) JP2002534415A (en)
AU (1) AUPP796798A0 (en)
WO (1) WO2000040560A1 (en)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001035947A2 (en) * 1999-11-15 2001-05-25 Eli Lilly And Company Treating wasting syndromes with aryloxy propanolamines
WO2002000622A2 (en) * 2000-06-27 2002-01-03 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives
WO2002024635A2 (en) * 2000-09-25 2002-03-28 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives
EP1292564A2 (en) * 2000-02-28 2003-03-19 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives
US6653323B2 (en) * 2001-11-13 2003-11-25 Theravance, Inc. Aryl aniline β2 adrenergic receptor agonists
US6670376B1 (en) 2001-11-13 2003-12-30 Theravance, Inc. Aryl aniline β2 adrenergic receptor agonists
US6689800B2 (en) 2002-02-27 2004-02-10 Pfizer Inc. β3-adrenergic receptor agonist crystal forms, processes for the production thereof, and uses thereof
US6689888B2 (en) 2002-02-27 2004-02-10 Pfizer Inc. Processes and intermediates useful in preparing β3-adrenergic receptor agonists
WO2004026305A1 (en) * 2002-09-19 2004-04-01 Eli Lilly And Company Diaryl ethers as opioid receptor antagonist
WO2004026817A1 (en) * 2002-09-19 2004-04-01 Kyorin Pharmaceutical Co., Ltd. Amino alcohol derivative, addition salt thereof, and immunosuppressant
US6730792B2 (en) 2000-07-13 2004-05-04 Eli Lilly And Company β3 adrenergic agonists
WO2004080996A1 (en) * 2003-03-07 2004-09-23 Eli Lilly And Company Opioid receptor antagonists
US6825220B2 (en) 2000-11-10 2004-11-30 Eli Lilly And Company 3-Substituted oxindole β 3 agonists
US6864268B2 (en) 2002-02-27 2005-03-08 Pfizer Inc. β3 adrenergic receptor agonists
US6911463B2 (en) 2001-08-14 2005-06-28 Eli Lilly And Company 3-substituted oxindole β-3 agonists
WO2005066164A1 (en) * 2003-12-22 2005-07-21 Eli Lilly And Company Opioid receptor antagonists
US7009060B2 (en) 2002-01-11 2006-03-07 Eli Lilly And Company 2-oxo-benzimidazolyl substituted ethanolamine derivatives and their use as β3 agonists
DE102004050952A1 (en) * 2004-10-18 2006-04-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of a beta-3-adrenoreceptor-agonist for the prophylaxis and/or treatment of e.g. benign prostata hyperplasia and/or its associated symptoms and chronic pelvic base pain syndrome, pelvic myoneuropathy, prostatodynia or prostatopathy
US7071208B2 (en) 2001-11-20 2006-07-04 Eli Lilly And Company β3 Adrenergic agonists
US7205407B2 (en) 2001-11-20 2007-04-17 Eli Lilly And Company 3-Substituted oxindole β3 agonists
US7208505B2 (en) 2001-08-14 2007-04-24 Eli Lilly And Company β3 adrenergic agonists
WO2007078523A2 (en) * 2005-12-15 2007-07-12 Astrazeneca Ab 5-phenyl-3-benzyl-0xaz0lidin-2-0ne derivatives and related compounds as metabotropic glutamate receptor potentiators for the treatment of neurological and psychiatric disorders
US7317023B2 (en) 2004-07-21 2008-01-08 Theravance, Inc. Diaryl ether β2 adrenergic receptor agonists
US7622583B2 (en) 2005-01-14 2009-11-24 Chemocentryx, Inc. Heteroaryl sulfonamides and CCR2
US7884110B2 (en) 2007-07-12 2011-02-08 Chemocentryx, Inc. Fused heteroaryl pyridyl and phenyl benzenesuflonamides as CCR2 modulators for the treatment of inflammation
US7977334B2 (en) 2004-04-30 2011-07-12 Boehringer Ingelheim International Gmbh Beta-agonists, methods for the preparation thereof and their use as pharmaceutical compositions
US8519135B2 (en) 2006-07-14 2013-08-27 Chemocentryx, Inc. Heteroaryl sulfonamides and CCR2/CCR9
US10758540B2 (en) 2017-10-11 2020-09-01 Chemocentryx, Inc. Treatment of focal segmental glomerulosclerosis with CCR2 antagonists
US10973809B2 (en) 2016-11-23 2021-04-13 Chemocentryx, Inc. Method of treating focal segmental glomerulosclerosis

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL373429A1 (en) * 2002-07-17 2005-08-22 Lek Pharmaceuticals D.D. Novel derivatives of pyridylethanol (phenylethyl) amines as inhibitors of cholesterol biosynthesis, processes for their preparation, and pharmaceutical compositions containing them
JPWO2006041015A1 (en) * 2004-10-12 2008-05-15 杏林製薬株式会社 Amino alcohol derivatives and their addition salts and immunosuppressants
US8476305B2 (en) 2008-02-07 2013-07-02 Kyorin Pharmaceutical Co., Ltd. Therapeutic agent or prophylactic agent for inflammatory bowel disease comprising amino alcohol derivative as active ingredient
CN102863345A (en) * 2011-07-06 2013-01-09 中国医学科学院药物研究所 Amino propylene glycol derivative, preparation method of amino propylene glycol derivative, medicine composition of amino propylene glycol derivative and application of amino propylene glycol derivative

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0318092A2 (en) * 1987-11-27 1989-05-31 Merck & Co. Inc. Novel beta-adrenergic agonists
EP0659737A2 (en) * 1993-12-21 1995-06-28 Bristol-Myers Squibb Company Catecholamine surrogates useful as B3 agonists
EP0714883A1 (en) * 1994-12-02 1996-06-05 Bristol-Myers Squibb Company Aryloxypropanolamine beta 3 adrenergic agonists
EP0764640A1 (en) * 1995-09-21 1997-03-26 Eli Lilly And Company Selective beta3 adrenergic agonists
EP0764632A2 (en) * 1995-09-21 1997-03-26 Eli Lilly And Company Selective beta3 adrenergic agonists
EP0801060A1 (en) * 1996-04-09 1997-10-15 Pfizer Inc. Heterocyclic Beta-3 Adrenergenic Agonists

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0318092A2 (en) * 1987-11-27 1989-05-31 Merck & Co. Inc. Novel beta-adrenergic agonists
EP0659737A2 (en) * 1993-12-21 1995-06-28 Bristol-Myers Squibb Company Catecholamine surrogates useful as B3 agonists
EP0714883A1 (en) * 1994-12-02 1996-06-05 Bristol-Myers Squibb Company Aryloxypropanolamine beta 3 adrenergic agonists
EP0764640A1 (en) * 1995-09-21 1997-03-26 Eli Lilly And Company Selective beta3 adrenergic agonists
EP0764632A2 (en) * 1995-09-21 1997-03-26 Eli Lilly And Company Selective beta3 adrenergic agonists
EP0801060A1 (en) * 1996-04-09 1997-10-15 Pfizer Inc. Heterocyclic Beta-3 Adrenergenic Agonists

Cited By (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001035947A2 (en) * 1999-11-15 2001-05-25 Eli Lilly And Company Treating wasting syndromes with aryloxy propanolamines
WO2001035947A3 (en) * 1999-11-15 2001-11-22 Lilly Co Eli Treating wasting syndromes with aryloxy propanolamines
EP1292564A2 (en) * 2000-02-28 2003-03-19 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives
WO2002000622A2 (en) * 2000-06-27 2002-01-03 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives
WO2002000622A3 (en) * 2000-06-27 2002-08-29 Fujisawa Pharmaceutical Co Aminoalcohol derivatives
US6730792B2 (en) 2000-07-13 2004-05-04 Eli Lilly And Company β3 adrenergic agonists
WO2002024635A2 (en) * 2000-09-25 2002-03-28 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives
WO2002024635A3 (en) * 2000-09-25 2003-02-20 Fujisawa Pharmaceutical Co Aminoalcohol derivatives
US6826033B2 (en) 2000-09-25 2004-11-30 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives
US6825220B2 (en) 2000-11-10 2004-11-30 Eli Lilly And Company 3-Substituted oxindole β 3 agonists
US7122680B2 (en) 2000-11-10 2006-10-17 Eli Lilly And Company 3-Substituted oxindole β3 agonsists
US7208505B2 (en) 2001-08-14 2007-04-24 Eli Lilly And Company β3 adrenergic agonists
US6911463B2 (en) 2001-08-14 2005-06-28 Eli Lilly And Company 3-substituted oxindole β-3 agonists
US7087635B2 (en) 2001-08-14 2006-08-08 Eli Lilly And Company 3-substituted oxindole β3 agonists
US7452995B2 (en) 2001-11-13 2008-11-18 Theravance, Inc. Aryl aniline β2 adrenergic receptor agonists
US7553971B2 (en) 2001-11-13 2009-06-30 Theravance, Inc. Aryl aniline β2 adrenergic receptor agonists
US6670376B1 (en) 2001-11-13 2003-12-30 Theravance, Inc. Aryl aniline β2 adrenergic receptor agonists
US6653323B2 (en) * 2001-11-13 2003-11-25 Theravance, Inc. Aryl aniline β2 adrenergic receptor agonists
US7265127B2 (en) 2001-11-20 2007-09-04 Eli Lilly And Company β3 adrenergic agonists
US7071208B2 (en) 2001-11-20 2006-07-04 Eli Lilly And Company β3 Adrenergic agonists
US7253181B2 (en) 2001-11-20 2007-08-07 Eli Lilly And Company β3 adrenergic agonists
US7205407B2 (en) 2001-11-20 2007-04-17 Eli Lilly And Company 3-Substituted oxindole β3 agonists
US7241772B2 (en) 2001-11-20 2007-07-10 Eli Lilly And Company β3 adrenergic agonists
US7214697B2 (en) 2002-01-11 2007-05-08 Eli Lilly And Company 2-Oxo-benzimidazolyl substituted ethanolamine derivatives and their use as β3 agonists
US7009060B2 (en) 2002-01-11 2006-03-07 Eli Lilly And Company 2-oxo-benzimidazolyl substituted ethanolamine derivatives and their use as β3 agonists
US6689800B2 (en) 2002-02-27 2004-02-10 Pfizer Inc. β3-adrenergic receptor agonist crystal forms, processes for the production thereof, and uses thereof
US6919460B2 (en) 2002-02-27 2005-07-19 Pfizer Inc, Processes and intermediates useful in preparing β3-adrenergic receptor agonists
US6689888B2 (en) 2002-02-27 2004-02-10 Pfizer Inc. Processes and intermediates useful in preparing β3-adrenergic receptor agonists
US6864268B2 (en) 2002-02-27 2005-03-08 Pfizer Inc. β3 adrenergic receptor agonists
US7482491B2 (en) 2002-09-19 2009-01-27 Kyorin Pharmaceutical Co., Ltd. Amino alcohol derivative, addition salt thereof, and immunosuppressant
HRP20050253B1 (en) * 2002-09-19 2013-11-08 Eli Lilly And Company Diaryl ethers as opioid receptor antagonists
WO2004026817A1 (en) * 2002-09-19 2004-04-01 Kyorin Pharmaceutical Co., Ltd. Amino alcohol derivative, addition salt thereof, and immunosuppressant
CN1312125C (en) * 2002-09-19 2007-04-25 杏林制药株式会社 Amino alcohol derivative, addition salt thereof, and immunosuppressant
JP4646628B2 (en) * 2002-09-19 2011-03-09 イーライ リリー アンド カンパニー Diaryl ethers as opioid receptor antagonists
EA008861B1 (en) * 2002-09-19 2007-08-31 Эли Лилли Энд Компани Diaryl ethers as opioid antagonists
WO2004026305A1 (en) * 2002-09-19 2004-04-01 Eli Lilly And Company Diaryl ethers as opioid receptor antagonist
US7763752B2 (en) 2002-09-19 2010-07-27 Kyorin Pharmaceutical Co., Ltd. Amino alcohol derivatives, salts thereof and immunosuppresive agents
EP2208727A1 (en) * 2002-09-19 2010-07-21 Eli Lilly &amp; Company Diaryl ethers as opioid receptor antagonist
US7381719B2 (en) 2002-09-19 2008-06-03 Eli Lilly And Company Diaryl ethers as opioid receptor antagonist
US7560463B2 (en) 2002-09-19 2009-07-14 Eli Lilly And Company Diaryl ethers as opioid receptor antagonists
US7531557B2 (en) 2002-09-19 2009-05-12 Eli Lilly And Company Diaryl ethers as opioid receptor antagonists
JP2006511474A (en) * 2002-09-19 2006-04-06 イーライ・リリー・アンド・カンパニー Diaryl ethers as opioid receptor antagonists
WO2004080996A1 (en) * 2003-03-07 2004-09-23 Eli Lilly And Company Opioid receptor antagonists
US7396943B2 (en) 2003-03-07 2008-07-08 Eli Lilly And Company Opioid receptor antagonists
US7414132B2 (en) 2003-12-22 2008-08-19 Eli Lilly And Company Opioid receptor antagonists
WO2005066164A1 (en) * 2003-12-22 2005-07-21 Eli Lilly And Company Opioid receptor antagonists
US7977334B2 (en) 2004-04-30 2011-07-12 Boehringer Ingelheim International Gmbh Beta-agonists, methods for the preparation thereof and their use as pharmaceutical compositions
US7662815B2 (en) 2004-07-21 2010-02-16 Theravance, Inc. Diaryl ether β2 adrenergic receptor agonists
US7317023B2 (en) 2004-07-21 2008-01-08 Theravance, Inc. Diaryl ether β2 adrenergic receptor agonists
DE102004050952A1 (en) * 2004-10-18 2006-04-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of a beta-3-adrenoreceptor-agonist for the prophylaxis and/or treatment of e.g. benign prostata hyperplasia and/or its associated symptoms and chronic pelvic base pain syndrome, pelvic myoneuropathy, prostatodynia or prostatopathy
US8093247B2 (en) 2005-01-14 2012-01-10 Chemocentryx, Inc. Heteroaryl sulfonamides and CCR2
US7622583B2 (en) 2005-01-14 2009-11-24 Chemocentryx, Inc. Heteroaryl sulfonamides and CCR2
US7816354B2 (en) 2005-12-15 2010-10-19 Astrazeneca Ab Oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators
WO2007078523A3 (en) * 2005-12-15 2007-11-15 Astrazeneca Ab 5-phenyl-3-benzyl-0xaz0lidin-2-0ne derivatives and related compounds as metabotropic glutamate receptor potentiators for the treatment of neurological and psychiatric disorders
WO2007078523A2 (en) * 2005-12-15 2007-07-12 Astrazeneca Ab 5-phenyl-3-benzyl-0xaz0lidin-2-0ne derivatives and related compounds as metabotropic glutamate receptor potentiators for the treatment of neurological and psychiatric disorders
US10206912B2 (en) 2006-07-14 2019-02-19 Chemocentryx, Inc. Heteroaryl sulfonamides and CCR2/CCR9
US8519135B2 (en) 2006-07-14 2013-08-27 Chemocentryx, Inc. Heteroaryl sulfonamides and CCR2/CCR9
US11433061B2 (en) 2006-07-14 2022-09-06 Chemocentryx, Inc. Heteroaryl sulfonamides and CCR2/CCR9
US10532044B2 (en) 2006-07-14 2020-01-14 Chemocentryx, Inc. Heteroaryl sulfonamides and CCR2/CCR9
US9745312B2 (en) 2007-07-12 2017-08-29 Chemocentryx, Inc. Fused heteroaryl pyridyl and phenyl benzenesuflonamides as CCR2 modulators for the treatment of inflammation
US7884110B2 (en) 2007-07-12 2011-02-08 Chemocentryx, Inc. Fused heteroaryl pyridyl and phenyl benzenesuflonamides as CCR2 modulators for the treatment of inflammation
US10208050B2 (en) 2007-07-12 2019-02-19 Chemocentryx, Inc. Fused heteroaryl pyridyl and phenyl benzenesuflonamides as CCR2 modulators for the treatment of inflammation
US9394307B2 (en) 2007-07-12 2016-07-19 Chemocentryx, Inc. Fused heteroaryl pyridyl and phenyl benzenesuflonamides as CCR2 modulators for the treatment of inflammation
US10899765B2 (en) 2007-07-12 2021-01-26 Chemocentryx, Inc. Fused heteroaryl pyridyl and phenyl benzenesuflonamides as CCR2 modulators for the treatment of inflammation
US8546408B2 (en) 2007-07-12 2013-10-01 Chemocentryx, Inc. Fused heteroaryl pyridyl and phenyl benzenesuflonamides as CCR2 modulators for the treatment of inflammation
US10973809B2 (en) 2016-11-23 2021-04-13 Chemocentryx, Inc. Method of treating focal segmental glomerulosclerosis
US11324736B2 (en) 2016-11-23 2022-05-10 Chemocentryx, Inc. Method of Treating Focal Segmental Glomerulosclerosis
US10758540B2 (en) 2017-10-11 2020-09-01 Chemocentryx, Inc. Treatment of focal segmental glomerulosclerosis with CCR2 antagonists
US11382915B2 (en) 2017-10-11 2022-07-12 Chemocentryx, Inc. Treatment of focal segmental glomerulosclerosis with CCR2 antagonists

Also Published As

Publication number Publication date
AUPP796798A0 (en) 1999-01-28
JP2002534415A (en) 2002-10-15
EP1140849A1 (en) 2001-10-10

Similar Documents

Publication Publication Date Title
EP1140849A1 (en) Aminoalcohol derivatives and their use as beta 3 adrenergic agonists
US6017919A (en) Compounds and pharmaceutical use thereof
CN108884029B (en) LSD1 inhibitors
US20020143034A1 (en) Aminoalcohol derivatives and their use as beta 3 adrenergic agonists
AU702832B2 (en) Substituted aryl piperazines as neurokinin antagonists
JP3507494B2 (en) Tachykinin antagonist
KR100231089B1 (en) Heterocyclic derivatives as platelet aggregation inhibitors
CN101701006B (en) Phenethanolamine derivatives for treatment of respiratory diseases
RU2283835C2 (en) Heterocyclic compound derivatives and pharmaceutical agents
CA2200981A1 (en) Urea derivatives and their use as acat-inhibitors
WO2002000622A2 (en) Aminoalcohol derivatives
US20100179137A1 (en) Pyridone compound
US20080312237A1 (en) Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
KR20050071472A (en) Process for preparing quinolin antibiotic intermediates
JP2002512636A (en) Urokinase inhibitors
US4505910A (en) Amino-pyrimidine derivatives, compositions and use
IL265790B2 (en) 2-amino-n-(arylsulfinyl)-acetamide compounds as inhibitors of bacterial aminoacyl-trna synthetase
EP0130735B1 (en) Amino-pyrimidine derivatives
WO2002094770A2 (en) Aminoalcohol derivatives
US20040138462A1 (en) Aminoalcohol derivatives
US6812237B2 (en) N-substituted peptidyl nitriles as cysteine cathepsin inhibitors
KR101071748B1 (en) Aminoalcohol derivatives
JPH10114744A (en) Aminoguanidinehydrazone derivative, and its production and pharmaceutical preparation
AU764031B2 (en) Cinnamamide derivatives and drug compositions containing the same
US20230131180A1 (en) Processes for producing amide compounds, and their crystalline and salt form

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 592269

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1999961305

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 09868615

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1999961305

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1999961305

Country of ref document: EP