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WO2009009278A1 - Urées à fluoroéthyle substitué en tant qu'agents adrénergiques alpha 2 - Google Patents

Urées à fluoroéthyle substitué en tant qu'agents adrénergiques alpha 2 Download PDF

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Publication number
WO2009009278A1
WO2009009278A1 PCT/US2008/067748 US2008067748W WO2009009278A1 WO 2009009278 A1 WO2009009278 A1 WO 2009009278A1 US 2008067748 W US2008067748 W US 2008067748W WO 2009009278 A1 WO2009009278 A1 WO 2009009278A1
Authority
WO
WIPO (PCT)
Prior art keywords
pain
compound
atoms
disease
substituents
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2008/067748
Other languages
English (en)
Inventor
Wenkui K. Fang
Ken Chow
Evelyn G. Corpuz
Daniel W. Gil
Michael E. Garst
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Allergan Inc
Original Assignee
Allergan Inc
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 Allergan Inc filed Critical Allergan Inc
Priority to US12/667,970 priority Critical patent/US20110028559A1/en
Priority to EP08771647A priority patent/EP2175844A1/fr
Publication of WO2009009278A1 publication Critical patent/WO2009009278A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • n 0 or 1
  • A is cyclohexyl having 0, 1, 2, 3, or 4 substituents wherein the substituents each independently consist of: a moiety consisting of from 0 to 8 carbon atoms, 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms, 0 or 1 sulfur atoms, 0 to 3 fluorine atoms, and from 0 to 17 hydrogen atoms; F; Cl; Br; or I.
  • substituents each independently consist of: a moiety consisting of from 0 to 8 carbon atoms, 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms, 0 or 1 sulfur atoms, 0 to 3 fluorine atoms, and from 0 to 17 hydrogen atoms; F; Cl; Br; or I.
  • Another embodiment is use of a compound disclosed herein in the manufacture of a medicament for the treatment of pain.
  • the pain is chronic pain. "Chronic pain is pain that persists or recurs for [greater than] 3 months, persists [for greater than] 1 month after resolution of an acute tissue injury, or accompanies a nonhealing lesion.” (Online Merck Manual, Eighteenth Edition.) [7] In another embodiment the pain is neuropathic pain. "Neuropathic pain results from damage to or dysfunction of the peripheral or central nervous system.” (Online Merck Manual, Eighteenth Edition.)
  • the pain is visceral pain.
  • “Visceral pain comes from the abdominal viscera, which are innervated by autonomic nerve fibers and respond mainly to the sensations of distention and muscular contraction.” (Online Merck Manual, Eighteenth Edition.)
  • the pain is allodynia. Allodynia is "pain due to a nonnoxious stimulus.” (Online Merck Manual, Eighteenth Edition.) [10] In another embodiment the pain is associated with muscle spasticity. [11] In another embodiment the pain is associated with diarrhea. [12] For the purposes of this disclosure, “treat,” “treating,” or “treatment” refers to the diagnosis, cure, mitigation, treatment, or prevention of disease or other undesirable condition.
  • the compounds can be used to treat include hypertension, congestive heart failure, asthma, depression, glaucoma, elevated intraocular pressure, ischemic neuropathies, optic neuropathy, corneal pain, headache pain, migraine, cancer pain, back pain, irritable bowel syndrome pain, muscle pain, pain associated with diabetic neuropathy, the treatment of diabetic retinopathy, stroke, drug dependence, withdrawal symptoms, obsessive compulsive disorder, obesity, insulin resistance, diarrhea, diuresis, nasal congestions, spasticity, attention deficit disorder, psychoses, Crohn's disease, gastritis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and combinations thereof.
  • reference to a compound should be construed broadly to include pharmaceutically acceptable salts, prodrugs, tautomers, alternate solid forms, and non-covalent complexes of a chemical entity of the depicted structure or chemical name.
  • a pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human.
  • a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
  • a salt is a chemical species having an ionic form of the compound, such as a conjugate acid or base, associated with a corresponding amount of counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).
  • a prodrug is a compound which is converted to a therapeutically active compound after administration to an animal or human. For example, conversion may occur by hydrolysis of an ester group or some other biologically labile group.
  • Prodrug preparation is well known in the art. For example, "Prodrugs and Drug Delivery Systems,” which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496- 557, provides further detail on the subject.
  • Tautomers are isomers that are in rapid equilibrium with one another. For example, they may include a transfer of a proton, hydrogen atom, or hydride ion.
  • the structures herein are intended to include, but are not limited to, the tautomeric forms shown below.
  • Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein.
  • alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.
  • Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.
  • n is 0 or 1
  • the following compounds are possible.
  • the substituents each independently consist of: a moiety consisting of from 0 to 8 carbon atoms, 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms, 0 or 1 sulfur atoms, 0 to 3 fluorine atoms, and from 0 to 17 hydrogen atoms; F; Cl; Br; or I.
  • substituents include, but are not limited to:
  • Hydrocarbyl meaning a moiety consisting of carbon and hydrogen only, including, but not limited to:
  • alkyl meaning hydrocarbyl having no double or triple bonds, including, but not limited to:
  • linear alkyl e.g. methyl, ethyl, w-propyl, w-butyl, w-pentyl, w-hexyl, etc.
  • branched alkyl e.g. ⁇ o-propyl, ?-butyl and other branched butyl isomers, branched pentyl isomers, etc.
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • combinations of linear, branched, and/or cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • alkenyl e.g. hydrocarbyl having 1 or more double bonds, including linear, branched, or cycloalkenyl
  • alkynyl e.g. hydrocarbyl having 1 or more triple bonds, including linear, branched, or cycloalkenyl
  • alkyl-CN such as -CH 2 -CN, -(CH 2 ) 2 -CN; -(CH 2 ) 3 -CN, and the like; [33] hydroxyalkyl, i.e. alkyl-OH, such as hydroxymethyl, hydroxyethyl, and the like; [34] ether substituents, including -O-alkyl, alkyl-O-alkyl, and the like; [35] thioether substituents, including -S-alkyl, alkyl-S-alkyl, and the like; [36] amine substituents, including -NH 2 , -NH-alkyl j -N-alky ⁇ alkyl 2 (i.e., alkyl 1 and alkyl 2 are the same or different, and both are attached to N), alkyl-NH 2 , alkyl-NH-alkyl, alkyl-N-alkyl 1 alkyl 2 , and the like;
  • aminoalkyl meaning alkyl-amine, such as aminomethyl (-CH 2 -amine), aminoethyl, and the like; [38] ester substituents, including -CO 2 -alkyl, -CO 2 _phenyl, etc.; [39] other carbonyl substituents, including aldehydes; ketones, such as acyl (i.e. o
  • hydrocarbyi an( j ⁇ jjj ⁇ g. m particular, acetyl, propionyl, and benzoyl substituents are contemplated;
  • fluorocarbons or hydroflourocarbons such as -CF 3 , _CH 2 CF 3 , etc.; and [42] -CN;
  • a substituent may be -F, -Cl, -Br, or -I.
  • alkyl having from 1 to 8 carbon atoms is contemplated as a substituent.
  • alkyl having from 1 to 4 carbon atoms is contemplated; [47] Substituents must be sufficiently stable to be stored in a bottle at room temperature under a normal atmosphere for at least 12 hours, or stable enough to be useful for any purpose disclosed herein.
  • a substituent is a salt, for example of a carboxylic acid or an amine
  • the counter-ion of said salt i.e. the ion that is not covalently bonded to the remainder of the molecule is not counted for the purposes of determining the number of atoms in a substituent.
  • the salt -CO 2 Na + is a stable substituent consisting of 1 carbon atom and 2 oxygen atoms, i.e. sodium is not counted.
  • the salt -NH(Me) 2 + Cl " is a stable substituent consisting of 1 nitrogen atom, 2 carbon atoms, and 7 hydrogen atoms, i.e. chlorine is not counted.
  • the substituents are independently C 1 - 4 alkyl, C 1 -3 alkoxy, F, Cl, Br, I, or NH 2 .
  • Ci_6 alkyl means alkyl having from 1 to 6 carbon atoms
  • Ci_6 hydrocarbyl means hydrocarbyl having from 1 to 6 carbon atoms.
  • Another embodiment is a compound having the formula
  • R 1 is alkyl having from 1 to 6 carbon atoms.
  • R 1 is w-propyl, i.e. -CH 2 CH 2 CH 3 .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne le traitement de la douleur chez les mammifères avec un composé de la formule (I).
PCT/US2008/067748 2007-07-06 2008-06-20 Urées à fluoroéthyle substitué en tant qu'agents adrénergiques alpha 2 Ceased WO2009009278A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/667,970 US20110028559A1 (en) 2007-07-06 2008-06-20 Substituted fluoroethyl ureas as alpha 2 adrenergic agents
EP08771647A EP2175844A1 (fr) 2007-07-06 2008-06-20 Urées à fluoroéthyle substitué en tant qu'agents adrénergiques alpha 2

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US94838907P 2007-07-06 2007-07-06
US60/948,389 2007-07-06

Publications (1)

Publication Number Publication Date
WO2009009278A1 true WO2009009278A1 (fr) 2009-01-15

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/067748 Ceased WO2009009278A1 (fr) 2007-07-06 2008-06-20 Urées à fluoroéthyle substitué en tant qu'agents adrénergiques alpha 2

Country Status (2)

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EP (1) EP2175844A1 (fr)
WO (1) WO2009009278A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6178724A (ja) * 1984-09-25 1986-04-22 Tetsuo Suami 抗腫瘍剤
WO2001078702A2 (fr) * 2000-04-13 2001-10-25 Allergan, Inc. Procedes et compositions de modulation de l'activite des recepteurs adrenergiques alpha
WO2007137029A1 (fr) * 2006-05-17 2007-11-29 Allergan, Inc. Urées de fluoroéthyle thérapeutiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6178724A (ja) * 1984-09-25 1986-04-22 Tetsuo Suami 抗腫瘍剤
WO2001078702A2 (fr) * 2000-04-13 2001-10-25 Allergan, Inc. Procedes et compositions de modulation de l'activite des recepteurs adrenergiques alpha
WO2007137029A1 (fr) * 2006-05-17 2007-11-29 Allergan, Inc. Urées de fluoroéthyle thérapeutiques

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JOHNSON T P ET AL: "THE SYNTHESIS OF POTENTIAL ANTICANCER AGENTS. XXXVI. N-NITROSOUREAS. II. HALOALKYL DERIVATIVES", JOURNAL OF MEDICINAL CHEMISTRY, US AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 9, no. 6, 1 January 1966 (1966-01-01), pages 892 - 910, XP000929924, ISSN: 0022-2623 *
JOHNSTON ET AL: "Synthesis of analogues of N-(2-chloroethyl)-N'-(trans-4-methylcyclohe xyl)-N-nitrosourea for evaluation as anti cancer agents", J. MED.CHEM,, vol. 20, no. 2, 1 January 1977 (1977-01-01), pages 279 - 290, XP002480859 *
JOHNSTON T P ET AL: "SYNTHESIS OF POTENTIAL ANTICANCER AGENTS 38. N-NITROSOUREAS FURTHER SYNTHESIS AND EVALUATION OF HALOETHYL DERIVATIVES", JOURNAL OF MEDICINAL CHEMISTRY, US AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 14, no. 7, 1 January 1971 (1971-01-01), pages 600 - 614, XP001053530, ISSN: 0022-2623 *
NG E W ET AL: "Unique Analogs of Anandamide: Arachidonyl Ethers and Carbamates and Norarachidonyl Carbamates and Ureas", JOURNAL OF MEDICINAL CHEMISTRY, US AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 42, no. 11, 1 January 1999 (1999-01-01), pages 1975 - 1981, XP002351602, ISSN: 0022-2623 *

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