WO2004048317A1 - Substituted amides active at the cannabinoid-1 receptor - Google Patents

Substituted amides active at the cannabinoid-1 receptor Download PDF

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Publication number
WO2004048317A1
WO2004048317A1 PCT/US2003/007039 US0307039W WO2004048317A1 WO 2004048317 A1 WO2004048317 A1 WO 2004048317A1 US 0307039 W US0307039 W US 0307039W WO 2004048317 A1 WO2004048317 A1 WO 2004048317A1
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WO
WIPO (PCT)
Prior art keywords
trifluoromethyl
methylpropanamide
pyridyloxy
chlorophenyl
methyl
Prior art date
Application number
PCT/US2003/007039
Other languages
French (fr)
Inventor
William K. Hagmann
Linus S. Lin
Shrenik K. Shah
Ravindra N. Guthikonda
Hongbo Qi
Linda L. Chang
Ping Liu
Helen M. Armstrong
James P. Jewell
Thomas J. Lanza, Jr.
Original Assignee
Merck & Co., 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.)
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=32393400&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2004048317(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to IL16382403A priority Critical patent/IL163824A0/en
Priority to BR0308349-7A priority patent/BR0308349A/en
Priority to EA200401066A priority patent/EA007747B1/en
Priority to AU2003218005A priority patent/AU2003218005A1/en
Priority to MXPA04008748A priority patent/MXPA04008748A/en
Priority to KR1020047014299A priority patent/KR100748380B1/en
Priority to YUP-791/04A priority patent/RS79104A/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CNA03805678XA priority patent/CN1639112A/en
Priority to UA20040907424A priority patent/UA76590C2/en
Publication of WO2004048317A1 publication Critical patent/WO2004048317A1/en
Priority to IS7411A priority patent/IS7411A/en
Priority to TNP2004000176A priority patent/TNSN04176A1/en
Priority to NO20043803A priority patent/NO20043803L/en
Priority to HR20040823A priority patent/HRP20040823A2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
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    • 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
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • 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
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    • 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
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07C2601/14—The ring being saturated

Definitions

  • Marijuana (Cannabis sativa L.) and its derivatives have been used for centuries for medicinal and recreational purposes.
  • a major active ingredient in marijuana and hashish has been determined to be ⁇ 9-tetrahydrocannabinol ( ⁇ 9-THC).
  • ⁇ 9-THC ⁇ 9-tetrahydrocannabinol
  • CBl and CB2 G-protein coupled receptors
  • the CBl receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs.
  • the CB2 receptor is found primarily in lymphoid tissues and cells.
  • mice The genes for the respective cannabinoid receptors have each been disrupted in mice.
  • the CBl-/- receptor knockout mice appeared normal and fertile. They were resistant to the effects of ⁇ 9-THC and demonstrated a strong reduction in the reinforcing properties of morphine and the severity of withdrawal syndrome. They also demonstrated reduced motor activity and hypoalgesia. Excessive exposure to ⁇ 9-THC can lead to overeating, psychosis, hypothermia, memory loss, and sedation.
  • CBl modulator characterized as an inverse agonist or an antagonist, N-(l ⁇ piperidinyl)-5 ⁇ (4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methylpyrazole-3-carboxamide (SR141716A), in clinical trials for treatment of eating disorders at this time.
  • CBl modulator characterized as an inverse agonist or an antagonist, N-(l ⁇ piperidinyl)-5 ⁇ (4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methylpyrazole-3-carboxamide (SR141716A)
  • CBl modulators that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.
  • CBl receptor modulators such as CBl inverse agonists
  • CBl inverse agonists presynaptic cannabinoid CBl receptors mediate the inhibition of noradrenaline release (in the guinea pig lung) (Europ. J. of Pharmacology, 2001, 431 (2), 237-244).
  • CBl receptor modulators Treatment of cirrhosis of the liver with CBl receptor modulators is supported by the finding that a CBl receptor modulator will reverse the low blood pressure observed in rats with carbon tetrachloride-induced liver cirrhosis and will lower the elevated mesenteric blood flow and portal vein pressure (Nature Medicine, 2001, 7 (7), 827-832).
  • PCT Application Nos. WO98/37061, WO00/10967, and WO00/10968 disclose diaryl ether sulfonamides having activity against the cannabinoid receptors.
  • PCT Application Nos. WO97/29079 and WO99/02499 disclose alkoxy-isoindolones and alkoxy-quinolones as having activity against the cannabinoid receptors.
  • US Patent US 5,532,237 discloses N-benzoyl-indole derivatives having activity against the cannabinoid receptors.
  • PCT publication WO 01/58869 discloses pyrazoles, pyrroles and imidazole cannabinoid receptor modulatorsuseful for treating respiratory and non- respiratory leukocyte activation-associated disorders.
  • PCT publications WO 01/64632, 01/64633, and 01/64634 assigned to Aventis are directed to azetidine derivatives as cannabinoid antagonists.
  • the compounds of the present invention are modulators of the Cannabinoid-1 (CBl) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the Cannabinoid-1 (CBl) receptor.
  • compounds of the present invention are antagonists or inverse agonists of the CBl receptor.
  • the invention is concerned with the use of these compounds to modulate the Cannabinoid-1 (CBl) receptor.
  • compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia.
  • the compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine.
  • the compounds are also useful for the treatment of eating disorders by inhibiting excessive food intake and the resulting obesity and complications associated therewith.
  • the compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction, as well as for the treatment of asthma, and ci ⁇ hosis of the liver.
  • the present invention is concerned with novel substituted amides of the general Formula I :
  • (I) and pharmaceutically acceptable salts thereof which are antagonists and/or inverse agonists of the Cannabinoid-1 (CBl) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the Cannabinoid-1 (CBl) receptor.
  • the invention is concerned with the use of these novel compounds to selectively antagonize the Cannabinoid-1 (CBl) receptor.
  • compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Ba ⁇ e syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia.
  • the compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine, including smoking cessation.
  • the compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith.
  • the compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction.
  • the compounds are also useful for the treatment of cirrhosis of the liver.
  • the compounds are also useful for the treatment of asthma.
  • the present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions.
  • the present invention is also concerned with treatment of these conditions through a combination of compounds of formula I and other currently available pharmaceuticals.
  • the invention is also concerned with novel compounds of structural formula I.
  • the invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient.
  • the invention is further concerned with processes for preparing the compounds of this invention.
  • R2 is selected from:
  • each cycloalkyl, aryl and heteroaryl is optionally substituted with one to three substituents independently selected from Rb; each R a is independently selected from:
  • each R D is independently selected from: (1) halogen,
  • R c is independently selected from:
  • each R c may be unsubstituted or substituted with one to three substituents selected from Rh;
  • Rd is independently selected from:
  • each Rd may be unsubstituted or substituted with one to three substituents selected from R n ; each R n is independently selected from: (1) halogen, (2) Ci- 3 alkyl,
  • Rl is selected from:
  • each aryl and heteroaryl is optionally substituted with one or two substitutents independently selected from Rb, and each pyridyl is optionally present as the N-oxide.
  • Rl is selected from:
  • Rl is 5-cyano-3- pyridyl.
  • R2 is selected from: (1) Ci-6alkyl,
  • R is selected from:
  • R2 is selected from: (1) 2-methylpropyl,
  • each R a is independently selected from:
  • each R a is independently selected from:
  • each Rb is independently selected from: (1) halogen,
  • each Rb is independently selected from:
  • each Rb is independently selected from: (1) fluoro, (2) chloro,
  • each R c is independently selected from: (1) hydrogen,
  • each R c may be unsubstituted or substituted with a substituent selected from Rh.
  • R c is phenyl.
  • Rd is selected from: (1) C4_6cycloalkyl
  • Rd may be unsubstituted or substituted with one or two substituents selected from Rh.
  • Rd is selected from:
  • Rd is selected from:
  • Rd is 5-trifluoromethyl-2-pyridyl.
  • each Rh is independently selected from:
  • each Rh is independently selected from:
  • novel compounds which may be employed in the methods, uses and compositions of the present invention, include:
  • Alkyl as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
  • Cycloalkyl means mono- or bicyclic or bridged saturated carbocyclic rings, each of which having from 3 to 10 carbon atoms
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Aryl means mono- or bicyclic aromatic rings containing only carbon atoms. Examples of aryl include phenyl, naphthyl, and the like.
  • Heteroaryl means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms.
  • heteroaryl include py ⁇ olyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, imidazothiazolyl, and the like.
  • Cycloheteroalkyl means mono- or bicyclic or bridged saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
  • the term also includes monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion.
  • Examples of “cycloheteroalkyl” include indolyl, azaindolyl and the like. The cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • substituted shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
  • Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
  • Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
  • Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or EtOAc or a mixture thereof.
  • a suitable solvent for example MeOH or EtOAc or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.
  • any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.
  • crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occu ⁇ ing substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • pharmaceutically acceptable salt further includes all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollyl
  • Compounds of the present invention are modulators of the CBl receptor.
  • the compounds of structural formula I are antagonists or inverse agonists of the CBl receptor.
  • An "agonist” is a compound (hormone, neurotransmitter or synthetic compound) which binds to a receptor, inducing a conformational change in the receptor which, in turn, produces a response such as contraction, relaxation, secretion, change in enzyme activity, etc. similar to that elicited by the physiologically relevant agonist ligand(s) for that receptor.
  • An "antagonist” is a compound which attenuates the effect of an agonist.
  • An “inverse agonist” is a compound which acts on a receptor but produces the opposite effect produced by the agonist of the particular receptor.
  • Compounds of this invention are modulators of the CBl receptor and as such are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia.
  • the compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine.
  • the compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith.
  • the compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction.
  • the compounds are also useful for the treatment of cirrhosis of the liver.
  • the compounds are also useful for the treatment of asthma.
  • administering should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
  • the administration of the compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the patient in need of such treatment or prophylaxis.
  • the need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors.
  • the effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.
  • the utilities of the present compounds in these diseases or disorders may be demonstrated in animal disease models that have been reported in the literature.
  • mice The following are examples of such animal disease models: a) suppression of food intake and resultant weight loss in rats (Life Sciences 1998, 63, 113-117); b) reduction of sweet food intake in marmosets (Behavioural Pharm. 1998, 9, 179-181); c) reduction of sucrose and ethanol intake in mice (Psychopharm. 1997, 132, 104- 106); d) increased motor activity and place conditioning in rats (Psychopharm. 1998, 135, 324-332; Psychopharmacol 2000, 151: 25-30); e) spontaneous locomotor activity in mice (J. Pharm. Exp. Ther. 1996, 277, 586-594); f) reduction in opiate self- administration in mice (Sci.
  • prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • a suitable dosage range is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of Foimula I per kg of body weight per day and for preventive use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of Formula I per kg of body weight per day.
  • a suitable dosage range is, e.g. from about 0.01 mg to about 1000 mg of a compound of Formula I per day, preferably from about 0.1 mg to about 10 mg per day.
  • the compositions are preferably provided in the form of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
  • the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers.
  • the compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device.
  • the preferred delivery systems for inhalation are metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol, which may be formulated as a dry powder of a compound of Formula I with or without additional excipients.
  • MDI metered dose inhalation
  • DPI dry powder inhalation
  • Suitable topical formulations of a compound of fo ⁇ nula I include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders, and the like.
  • the topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle.
  • Transdermal skin patches useful for administering the compounds of the present inveniton include those well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being prefe ⁇ ed over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules (including timed release and sustained release formulations), pills, cachets, powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion, incluidng elixirs, tinctures, solutions, suspensions, syrups and emulsions.
  • Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated
  • each cachet or capsule contains from about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • Additional suitable means of administration of the compounds of the present invention include injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular and topical, with or without occlusion.
  • Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also exemplifying the invention is a phannaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier.
  • An illustration of the invention is a process for malting a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
  • the dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration, the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage will, of course, be co ⁇ espondingly larger for the less frequent administration.
  • Compound of Formula I 25 Microcrystalline Cellulose 415 Povidone 14.0
  • Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is prefe ⁇ ed.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I.
  • Examples of other active ingredients that may be combined with a compound of Formula I include, but are not limited to: antipsychotic agents, cognition enhancing agents, anti-migraine agents, anti-asthmatic agents, antiinflammatory agents, axiolytics, anti-Parkinson's agents, anti-epileptics, anorectic agents, and serotonin reuptake inhibitors, and other anti-obesity agents which may be administered separately or in the same pharmaceutical compositions. It will be appreciated that for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents.
  • the present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anorectic agent, such that together they give effective relief.
  • "Obesity” is a condition in which there is an excess of body fat. The operational definition of obesity is based on the Body Mass Index (BMI), which is calculated as body weight per height in meters squared (kg/m2).
  • BMI Body Mass Index
  • “Obesity” refers to a condition whereby an otherwise healthy subject has a Body Mass Index (BMI) greater than or equal to 30 kg/m2, or a condition whereby a subject with at least one co- morbidity has a BMI greater than or equal to 27 kg/m2.
  • An “obese subject” is an otherwise healthy subject with a Body Mass Index (BMI) greater than or equal to 30 kg/m2 or a subject with at least one co-morbidity with a BMI greater than or equal to 27 kg/m2.
  • BMI Body Mass Index
  • a “subject at risk for obesity” is an otherwise healthy subject with a BMI of 25 kg/m2 to less than 30 kg/m2 or a subject with at least one co-morbidity with a BMI of 25 kg/m2 to less than 27 kg/m2.
  • BMI Body Mass Index
  • “obesity” refers to a condition whereby a subject with at least one obesity-induced or obesity-related co- morbidity that requires weight reduction or that would be improved by weight reduction, has a BMI greater than or equal to 25 kg/m2.
  • an “obese subject” refers to a subject with at least one obesity-induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, with a BMI greater than or equal to 25 kg/m2.
  • a "subject at risk for obesity” is a subject with a BMI of greater than 23 kg/m2 to less than 25 kg/m.2.
  • obesity is meant to encompass all of the above definitions of obesity.
  • Obesity-induced or obesity-related co-morbidities include, but are not limited to, diabetes, non-insulin dependent diabetes mellitus - type 2, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, and infertility.
  • co-morbidities include: hypertension, hyperlipidemia, dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea, diabetes mellitus, and other obesity-related conditions.
  • Treatment refers to the administration of the compounds or compositions of the present invention to reduce or maintain the body weight of an obese subject.
  • One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds or compositions of the present invention.
  • Another outcome of treatment may be preventing regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy.
  • Another outcome of treatment may be decreasing the occurrence of and or the severity of obesity-related diseases.
  • the treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof.
  • the treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.
  • "Prevention” refers to the administration of the compounds or compositions of the present invention to reduce or maintain the body weight of a subject at risk for obesity.
  • One outcome of prevention may be reducing the body weight of a subject at risk for obesity relative to that subject's body weight immediately before the administration of the compounds or compositions of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk for obesity. Another outcome of prevention may be decreasing the occu ⁇ ence and/or severity of_obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk for obesity.
  • such treatment may prevent the occu ⁇ ence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
  • Obesity-related disorders are associated with, caused by, or result from obesity.
  • obesity-related disorders include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia.
  • obesity-related disorders are metabolic syndrome, also known as syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer.
  • the compositions of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.
  • diabetes includes both insulin- dependent diabetes mellitus (i.e., LDDM, also known as type I diabetes) and non- insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type II diabetes.
  • Type I diabetes, or insulin-dependent diabetes is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization.
  • Type II diabetes, or insulin-independent diabetes i.e., non-insulin-dependent diabetes mellitus
  • Most of the Type II diabetics are also obese.
  • the compounds and compositions of the present invention are useful for treating both Type I and Type II diabetes.
  • the compounds and compositions are especially effective for treating Type II diabetes.
  • the compounds and compositions of the present invention are also useful for treating and/or preventing gestational diabetes mellitus.
  • substance abuse disorders includes substance dependence or abuse with or without physiological dependence.
  • the substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all of the above.
  • the term "substance abuse disorders” includes drug withdrawal disorders such as alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances. It will be appreciated that reference to treatment of nicotine withdrawal includes the treatment of symptoms associated with smoking cessation.
  • substance abuse disorders include substance-induced anxiety disorder with onset during withdrawal; substance-induced mood disorder with onset during withdrawal; and substance-induced sleep disorder with onset during withdrawal.
  • a combination of a conventional antipsychotic drug with a CBl receptor modulator may provide an enhanced effect in the treatment of mania. Such a combination would be expected to provide for a rapid onset of action to treat a manic episode thereby enabling prescription on an "as needed basis”. Furthermore, such a combination may enable a lower dose of the antispychotic agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side-effects.
  • a yet further advantage of such a combination is that, due to the action of the CB 1 receptor modulator, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.
  • the present invention also provides a method for the treatment or prevention of mania, which method comprises administration to a patient in need of such treatment or at risk of developing mania of an amount of a CBl receptor modulator and an amount of an antipsychotic agent, such that together they give effective relief. It will be appreciated that the CB 1 receptor modulator and the antipsychotic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of mania.
  • the CBl receptor modulator and the antipsychotic agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously.
  • the term “combination” also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the antipsychotic agent may be administered as a tablet and then, within a reasonable period of time, the CBl receptor modulator may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form.
  • a fast-dissolving oral formulation is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
  • a combination of a conventional antipsychotic drug with a CBl receptor modulator may provide an enhanced effect in the treatment of schizophrenic disorders. Such a combination would be expected to provide for a rapid onset of action to treat schizophrenic symptoms thereby enabling prescription on an "as needed basis". Furthermore, such a combination may enable a lower dose of the CNS agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side-effects.
  • a yet further advantage of such a combination is that, due to the action of the CB 1 receptor modulator, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.
  • a combination of a conventional anti- asthmatic drug with a CBl receptor modulator may provide an enhanced effect in the treatment of asthma.
  • the present invention also provides a method for the treatment or prevention of asthma, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-asthmatic agent, such that together they give effective relief.
  • the method of treatment of this invention comprises a method of modulating the CBl receptor and treating CBl receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the CBl receptor in preference to the other CB or G-protein coupled receptors.
  • terapéuticaally effective amount means the amount the compound of structural formula I that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated.
  • the novel methods of treatment of this invention are for disorders known to those skilled in the art.
  • the term “mammal” includes humans.
  • Step A 3-(4-Chlorophenyl)-2-phenylpropanoic acid, methyl ester.
  • methyl phenylacetate (12 g, 80 mmol) and 4-chlorobenzyl bromide (16 g, 80 mmol) in 250 mLanhydrous THF at -78°C was added sodium hexamethyldisilazide (1 M in THF, 80 mL, 80 mmol) (potassium hexamethyldisilazide in toluene may be used with similar results).
  • the reaction was allowed to warm to room temperature overnight.
  • Step B 3-(4-Chlorophenyl)-2-phenylpropanoic acid.
  • Step A To a mixture of methyl 3-(4-chlorophenyl)-2-phenylpropionate (Step A, 20 g, 74 mmol) in acetonitrile (100 mL) and water (100 mL) was added lithium hydroxide monohydrate (8.8 g, 0.21 mol). After stirring at room temperature for 3 days, the volatile materials were removed by concentrating on a rotary evaporator and the residue was partitioned between water (300 mL) and hexane/ether (1:1, 200 mL).
  • Step E 4-(4-Chlorophenyl)-3-phenyl-2-butanol.
  • Step D To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanone (Step D, 13 g, 50 mmol) in MeOH (100 mL) at 0 °C was added sodium borohydride (3.8 g, 100 mmol). After stirring at 0°C for 30 min, the reaction was quenched by addition of 2 M hydrochloric acid (50 mL). The volatile materials were removed by concentrating on a rotary evaporator and the residue partitioned between water (100 mL) and EtOAc (200 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 200 mL).
  • Step F 4-(4-Chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane.
  • 4-(4-chlorophenyl)-3-phenyl-2-butanol (Step E, faster eluting isomer, 9.0 g, 34 mmol) in EtOAc (100 mL) at 0°C was added triethyl amine (dried over activated molecular sieves, 5.8 mL. 42 mmol) and methanesulfonyl chloride (3.0 mL, 38 mmol).
  • Step F To a solution of 4-(4-chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane (Step F, 12 g, 34 mmol) in DMF (50 mL) was added sodium azide (11 g, 0.17 mol). After stirring at 120°C for 1 h, the reaction mixture was poured into water (200 mL), and the product was extracted with ether (2 x 100 mL). The combined organic extracts were washed with water, dried over MgSO4, filtered and concentrated to dryness, and the residue was purified on a silica gel column eluting with hexane to give the title compound.
  • Step H 2-(N-tert-Butoxycarbonyl)amino-4-(4-chlorophenyl)-3-phenylbutane
  • 2-azido-4-(4-chlorophenyl)-3-phenylbutane (Step G, 7.0 g, 24 mmol) in EtOAc (150 mL) was added di (tert-butyl) dicarbonate (8.0 g, 37 mmol) and platinum dioxide (0.50 g, 2.2 mmol).
  • the mixture was degassed and filled with hydrogen with a balloon.
  • Step I ⁇ -r3-(4-Chlorophenyl)-2-phenyl-l-methylpropy ⁇ -amine hydrochloride (Diastereomer ). 2-(N-tert-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-phenylbutane (Step H, 7.0 g, 24 mmol) was treated with a saturated solution of hydrogen chloride in EtOAc (100 mL) at room temperature for 30 min (4 M hydrogen chloride in dioxane may be used with similar results). The mixture was concentrated to dryness to give the title compound.
  • Step A The product of Step A (4-(4-chlorophenyl)-3(S)-phenyl-2(R)-butanol, 1.8 g, 7.0 mmol) was converted to the title compound following the steps described in Reference Example 3, Steps F-I, except hydrogen chloride in dioxane (4 M) was used in place of hydrogen chloride in EtOAc.
  • Steps F-I except hydrogen chloride in dioxane (4 M) was used in place of hydrogen chloride in EtOAc.
  • !H ⁇ MR 500 MHz, CD3OD): ⁇ 7.35-6.98 (m, 9H), 3.62 (m, IH), 3.20 (dd, IH), 3.05 (m, IH), 2.98 (dd, IH), 1.19 (d, 3H).
  • LCMS m/e 260 (M + H) + (2.3 min).
  • Step A 4-(4-Chlorophenyl)-3-pyridyl-2-butanone.
  • Step B N-r3-(4-chlorophenyl)-2-(3-pyridyl)-l-methylpropyn-amine, hydrochloride (mixture of diastereomers ⁇ / ⁇ 10:1).
  • the product of Step A (4-(4-chlorophenyl)-3-pyridyl-2-butanone) (14 g, 57 mmol) was converted to the title compound following the procedure described in Reference Example 3, Steps E-I.
  • Step B Benzyl 2-(2-Pyridyloxy -2-methylbutanoate.
  • Step B N- 1 " 3 -(4-Chlorophenyl)-2-(3 -c yanophenyl)- 1 -methylprop yll amine hydrochloride (Diastereomer ⁇ )
  • Oxalyl chloride (0.95 mL, 11 mmol) was added dropwise to a suspension of 2-(l- l,2,3-triazolyl))acetic acid (Step B, 1.27 g, 10 mmol) in 10 mL CH2CI2 containing 0.05 mL DMF. Vigorous effervescence was observed. This mixture was sti ⁇ ed at room temperature for 4 h and cooled to -78°C. A solution of N.O- dimethylhydroxylamine hydrochloride (1.2 g, 13 mmol) and diisopropylethyl amine (6.0 mL, 35 mmol) in 10 mL CH2CI2 was added slowly over 3 min.
  • Step D N-Methoxy-N-methyl-3-(4-chlorophenyl)-2-(l-(l,2,3-triazolyl)) propionamide
  • Lithium hexamethyldisilazide (lmolar in THF, 8.4 mL, 8.4 mmol) was added dropwise to a solution of N-methoxy-N-methyl-2-(l-(l,2,3-triazolyl))acetamide (Step C, 1.19 g, 7 mmol) in 15 mL THF at -78°C. After additional 30 min stirring, a solution of 4-chlorobenzyl bromide (1.65 g, 8 mmol) in 5 mL THF was added dropwise.
  • Step D N-methoxy-N-methyl-3-(4-chlorophenyl)-2-(l -(1,2,3- triazolyl)propionamide was converted to the title compound following the procedures described in Reference Example 3, Step D-G.
  • lH NMR 400 MHz, CDCI3: ⁇ 1.219-1.246 (d's 3H), 3.253-4.754 (m, 4H0, 6.866-7.299 (d's, 4H), 7.313, 7.618, 7.63, & 7.706 (s's, 2H).
  • Step B N-r3-(4-Chlorophenyl)-2-(3-methylphenyl)-l-methylpropyllamine hydrochloride (Diastereomer )
  • Step B 4-(5-Chloro-2-pyridyl)-3(S)-phenyl-2(R)-butanol.
  • Step A To a solution of 5-chloro-2-methylpyridine (Step A, 1.1 g, 8.7 mmol) in 15 mL anhydrous ether was added phenyl lithium (1.8 M in cyclohexane/ether, 7.2 mL, 13 mmol) at 0°C, and the reaction was sti ⁇ ed at room temperature for 30 min. The resulting mixture was cooled back to 0°C, and was added (lR,2R)-l-phenylpropylene oxide (2.3 g, 17 mmol), and the reaction was allowed to warm to room temperature overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL).
  • Step D N-r3-(5-Chloro-2-pyridyl)-2(Sl-phenyl-l(S)-methylpropyllamine, hydrochloride
  • the product of Step C (0.20 g, 0.70 mmol) was converted to the title compound following the procedure described in Reference Example 3, Steps H-I, except hydrogen chloride in dioxane (4 M) was used in place of hydrogen chloride in EtOAc.
  • iH ⁇ MR 500 MHz, CD3OD: ⁇ 8.75 (d, IH), 8.19 (dd, IH), 7.55 (d, IH), 7.4-7.2
  • Step C 3-(3-Bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanol
  • 3-(3-bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone (Step B, 6.7 g, 20 mmol) in 50 mL anhydrous THF at -78°C was added lithium tri(sec- butyl)borohydride (1.0 M in THF, 30 mL, 30 mmol), and the reaction was allowed to warm to room temperature overnight.
  • the reaction was cooled to 0°C, and was carefully added 2 M hydrochloric acid (50 mL), and the resulting mixture was partitioned between hexane (200 mL) and water (200 mL). The aqueous layer was separated and the organic layer extracted with 2 M hydrochloric acid (2 x 100 mL). The combined aqueous extracts were neutralized with 5 N aqueous sodium hydroxide (pH > 12), and was extracted with EtOAc (2x200 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the title compound.
  • Step D N-r2-(3-Bromophenyl)-3-(5-chloro-2-pyridyl)-l-methylpropyl1amine, hydrochloride
  • the product of Step C (5.9 g, 17 mmol) was converted to the title compound following the procedure described in Reference Example 18, Steps C-D.
  • Step C N-r2-(5-Bromo-3-pyridyl)-3-(4-chlorophenyl)-l-methylpropyllamine hydrochloride (Diastereomer ) The title compound was prepared following the procedure described for Reference Example 4, Step B. LC-MS: m/e 339 (M + H) + (2.5 min).
  • Step B N-r3-(4-ChloiOphenyl)-2-(5-cvano-2-pyridyl)-l-methylpropyllamine hydrochloride (Diastereomer / ⁇ 5:1)
  • the title compound was prepared following the procedure described for Reference Example 5 substituting 3-pyridylacetone with 5-cyano-3-pyridylacetone (Step A).
  • Step B N-r3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-l-methylpropyllamine hydrochloride (Diastereomer )
  • the title compound was prepared following the procedure described for Reference Example 20, Step B-C substituting 5-bromo-3-pyridylacetone with 5-chloro-3- pyridylacetone at Step B.
  • LC-MS m/e 295 (M + H) + (1.9 min).
  • Step A Ethyl 3-(4-chlorophenyl)-2-indolin-N-ylpropanoate.
  • l.lg LiOH H2 ⁇ 26.25 mmol
  • DMF 20 mL
  • 4 angstrom molecular sieves 4 angstrom molecular sieves.
  • room temperature 2.8 mL (25mmol) indoline was added dropwise.
  • room temperature 2.9 mL (26.25 mmol) ethyl bromoacetate was added dropwise.
  • the solid material was filtered and the residue was washed with copious amounts of EtOAc.
  • Step B N,O-dimethyl-3-(4-chlorophenyl)-2-indolin-N-ylpropanamide.
  • Step C 4-(4-chlorophenyl)-3-indolin-N-ylbutan-2-one.
  • a 1-M solution of CH3MgBr in THF was added dropwise to a stirring solution of N,O-dimethyl-3-(4- chlorophenyl)-2-indolinylpropanamide (from Step B, 965 mg) in 25 mL anhydrous THF.
  • the solution was sti ⁇ ed for 4 h while being allowed to warm to room temperature. Then approximately 20 mL water were added.
  • the mixture was extract three times with 50 mL ether.
  • the combined extracts were dried over MgSO4.
  • Step D 4-(4-chlorophenyl)-3-indolin-N-ylbutan-2-one methoxime.
  • This compound was prepared in an analogous manner to Reference Example 28.
  • the aqueous layer was separated and neutralized to pH 7 with 2N hydrochloric acid and extracted again into CH2CI2.
  • the combined organic washes were dried with MgSO4 and concentrated.
  • the crude material was purified by column chromatography on silica gel eluting from 0-10% EtOAc/hexane to give the title compound.
  • Step C 4-(4-Methylphenyl)-3-phenylbutan-2-amine
  • a solution of the 4-(4-methylphenyl)-3-phenylbutan-2-one (308 mg, 1.29 mmol) in 7M ammonia in MeOH (5 mL) and acetic acid (3 mL) was added sodium cyanoborohydride (130 mg, 2.06 mmol) and the reaction sti ⁇ ed at room temperature overnight.
  • the reaction was quenched by pouring into 2M sodium carbonate solution and extracted into EtOAc.
  • the aqueous layer was salted and re-extracted.
  • the combined organic extracts were dried over MgSO4 and concentrated to give the title compound as a mixture of 4 isomers which was used without further purification.
  • LCMS m/e 240 (M + H) + (2.22 min).
  • Step B 2-(lH-l,2,3-Benzotriazol-l-yl)-3-(4-chlorophenyl)-N-methoxy-N- methyl-propanamide.
  • 2-(lH-.l,2,3-benzotriazol-l-yl)-N-methoxy-N- methylacetamide in 15 mL anhydrous THF at -78 °C, 10 mL (10 mmol) of IM lithium bis(trimethylsilyl)amide was added dropwise. After stirring for 25 min, a solution of 2.06 g (10 mmol) of 4-chlorobenzyl bromide in 2 mL anhydrous THF was added.
  • Step D 2-(lH-l,2,3-Benzotriazol-l-yl)-3-(4-chlorophenyl)-l-methyl propylamine
  • 2-(lH-l,2,3-benzotriazol-l-yl)-3-(4- chlorophenyl)-butan-2-one in 8.5 mL (60 mmol) of 7N ammonia in MeOH at 0 °C, 4 mL (964 mmol) of glacial acetic acid was added followed by 410 mg (6.5 mmol) of sodium cyanoborohydride.
  • Example 34 substituting thiophene-3-acetic acid for 2-(lH-l,2,3-benzotriazol-l- yl)acetic acid in Step A.
  • Step B 3-(3-Cyanophenyl)-4-cvclobutyl-butan-2-one
  • a solution of 1.45 g (9.07 mmol) of l-(3-cyanophenyl)acetone in 18 mL acetonitrile 1.1 mL (9.5 mmol) cyclobutyl bromide and 5.91 g (18.1 mmol) cesium carbonate were added.
  • the filtrate was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc.
  • the combined organic layer was washed with brine, dried and concentrated.
  • Diastereomer ⁇ lH ⁇ MR (500 MHz, CD3OD): ⁇ 7.16 (d, 2H), 7.14 (d, 2H), 7.09 (d, 2H), 6.99 (d, 2H), 6.88 (d, 2H), 6.64 (d, 2H), 4.33 (m, IH), 3.12 (dd, IH), 3.03 (ddd, IH), 2.74 (dd, IH), 1.36 (s, 3H), 1.30 (d, 3H), 1.30 (s, 3H).
  • LC-MS m/e 490(M + H) + (4.7 min).
  • Examples 4-7 (Table 2) were prepared following the procedures described in Examples 2 and 3 substituting 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt with the appropriate amines from the Reference Examples and 2- (4-chlorophenyloxy)-2-methylpropionic acid with the appropriate acids from the Reference Examples.
  • commercial acids or acyl chlorides were employed, and N-diisopropyl-ethylamine may be used in place of N- methylmorpholine with similar results.
  • the diastereomer designations ( ⁇ or ⁇ ) co ⁇ espond to designations of the starting amines.
  • N-r2,3-Bis(4-Chlorophenyl)-l-methylpropyn-2-(4-chlorophenyloxy)-2- methylpropanamide (Diastereomer , Enantiomers A and B).
  • Example 60 1.0 g in hexane (3 mL)/ethanol (7 mL) was loaded onto a Chiralpak AD column (2 cm x 25 cm), which was eluted with 5% ethanol in hexane (flow rate 9 mL/min, 500 ⁇ L per injection) to give the two pure enantiomers.
  • Example 18 (Table 4) was prepared following the procedures described in Examples 2-3 employing N-[3-(4-chlorophenyl)-2(S)-phenyl-l(S)- methylpropyl] -amine, hydrochloride from Reference Example 4 coupled to the appropriate carboxylic acid. Table 4. Single enantiomeric compounds prepared with N-[3-(4-chloro ⁇ henyl)-2(S)- phenyl-l(S)-methylpropyl]-amine, hydrochloride from Reference Example 4.
  • N-r2,3-Bis(4-chlorophenyl)-l-methylpropyl1-2-(4-chlorophenylamino)-2- methylpropanamide N-r2,3-Bis(4-chlorophenyl)-l-methylpropyl1-2-(4-chlorophenylamino)-2- methylpropanamide.
  • 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt Diastereomer ⁇ , Section I, Reference Example 1, 0.31 g, 0.94 mmol
  • 2-(4- chlorophenylamino)-2-methylpropionic acid (0.20 g, 0.94 mmol) in 5 mL CH2CI2 was added N-methylmorpholine (0.41 mL, 3.5 mmol) and tris(pyrrolindinyl)phosphonium hexafluorophosphate (0.73 g, 1.4 mmol).
  • Examples 30-33 were prepared from N-[3-(4-chlorophenyl)- 2(S)-phenyl-l(S)-methylpropyl]amine, hydrochloride (Reference Example 4) or N-[3- (5-chloro-2-pyridyl)-2(S)-phenyl-l(S)-methylpropyl]amine, hydrochloride (Reference Example 18) and the appropriate carboxylic acid following the procedures described in Examples 2-3 (via an acyl chloride intermediate) or Example 19 (with a coupling reagent),
  • Examples 34-39 were prepared from the appropriate amine and acid of Reference Examples following the procedures described in Examples 2-3 (via an acyl chloride intermediate) or Example 19 (with a coupling reagent).
  • Examples 41-52 (Table 11) were isolated as single enantiomers from the co ⁇ esponding racemic material (Table 10) following the procedures described in Examples 8-9 with appropriate modifications of (1) the eluent composition (4-15% ethanol/hexane), (2) flow rate (6-9 mL/min) and (3) injection volume (200 to 2000 ⁇ L).
  • Examples 53-56 (Table 12) were isolated as diastereomers as indicated (Isomer A or B) on silica gel chromatography columns. The single enantiomers noted were separated on the chiral AD column noted above.
  • Example 57 Prepared as in Example 57 only using 3-[2-amino-l-(4- fluorobenzyl)propyl]benzonitrile (Reference example 33) as the amine component to give the title compound as a mixture of 4 isomers.
  • the diastereomers were separated by HPLC on a Zorbax RxSi column eluting 96% hexane: 4% ethanol at 20 mL/min with retention times of: less polar diastereomer eluted at 11.75 minutes;
  • Binding affinity determination is based on recombinant human CBl receptor expressed in Chinese Hamster Ovary (CHO) cells (Felder et al, Mol.
  • Binding buffer contains 50mM Tris-HCl, pH7.4, 2.5 mM EDTA, 5mM MgCl2, 0.5mg/mL fatty acid free bovine serum albumin and protease inhibitors (Cat#P8340, from Sigma). To initiate the binding reaction, 5 ⁇ l of radioligand solution is added, the mixture is incubated with gentle shaking on a shaker for 1.5 h at 30°C.
  • binding is terminated by using 96-well harvester and filtering through GF/C filter presoaked in 0.05% polyethylenimine.
  • the bound radiolabel is quantitated using scintillation counter. Apparent binding affinities for various compounds are calculated from IC50 values (DeBlasi et al., Trends Pharmacol Sci 10: 227-229, 1989).
  • the binding assay for CB2 receptor is done similarly with recombinant human CB2 receptor expressed in CHO cells.
  • CBl receptor The functional activation of CBl receptor is based on recombinant human CBl receptor expressed in CHO cells (Felder et al, Mol. Pharmacol. 48: 443- 450, 1995).
  • 50 ul of CB1-CHO cell suspension are mixed with test compound and 70 ul assay buffer containing 0.34 mM 3-isobutyl-l-methylxanthine and 5.1 uM of forskolin in 96-well plates.
  • the assay buffer is comprised of Earle's Balanced Salt Solution supplemented with 5 mM MgCl2, 1 mM glutamine, 10 mM HEPES, and 1 mg/mL bovine serum albumin.
  • the mixture is incubated at room temperature for 30 minutes, and terminated by adding 30uL/well of 0.5M HCl.
  • the total intracellular cAMP level is quantitated using the New England Nuclear Flashplate and cAMP radioimmunoassay kit.
  • the reaction mixture also contains 0.5 nM of the agonist CP55940, and the reversal of the
  • CP55940 effect is quantitated.
  • a series of dose response curves for CP55940 is perfoimed with increasing concentration of the test compound in each of the dose response curves.
  • the functional assay for the CB2 receptor is done similarly with recombinant human CB2 receptor expressed in CHO cells.

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Abstract

Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson s disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.

Description

SUBSTITUTED AMIDES ACTIVE AT THE CANNABINOID-1
RECEPTOR
CROSS-REFERENCE TO RELATED APPLICATIONS Not applicable.
BACKGROUND OF THE INVENTION
Marijuana (Cannabis sativa L.) and its derivatives have been used for centuries for medicinal and recreational purposes. A major active ingredient in marijuana and hashish has been determined to be Δ9-tetrahydrocannabinol (Δ9-THC). Detailed research has revealed that the biological action of Δ9-THC and other members of the cannabinoid family occurs through two G-protein coupled receptors termed CBl and CB2. The CBl receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs. The CB2 receptor is found primarily in lymphoid tissues and cells. Three endogenous ligands for the cannabinoid receptors derived from arachidonic acid have been identified (anandamide, 2-arachidonoyl glycerol, and 2-arachidonyl glycerol ether). Each is an agonist with activities similar to Δ9-THC, including sedation, hypothermia, intestinal immobility, antinociception, analgesia, catalepsy, anti-emesis, and appetite stimulation.
The genes for the respective cannabinoid receptors have each been disrupted in mice. The CBl-/- receptor knockout mice appeared normal and fertile. They were resistant to the effects of Δ9-THC and demonstrated a strong reduction in the reinforcing properties of morphine and the severity of withdrawal syndrome. They also demonstrated reduced motor activity and hypoalgesia. Excessive exposure to Δ9-THC can lead to overeating, psychosis, hypothermia, memory loss, and sedation. There is at least one CBl modulator characterized as an inverse agonist or an antagonist, N-(l~piperidinyl)-5~(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methylpyrazole-3-carboxamide (SR141716A), in clinical trials for treatment of eating disorders at this time. There still remains a need for potent low molecular weight
CBl modulators that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.
Treatment of asthma with CBl receptor modulators (such as CBl inverse agonists) is supported by the finding that presynaptic cannabinoid CBl receptors mediate the inhibition of noradrenaline release (in the guinea pig lung) (Europ. J. of Pharmacology, 2001, 431 (2), 237-244).
Treatment of cirrhosis of the liver with CBl receptor modulators is supported by the finding that a CBl receptor modulator will reverse the low blood pressure observed in rats with carbon tetrachloride-induced liver cirrhosis and will lower the elevated mesenteric blood flow and portal vein pressure (Nature Medicine, 2001, 7 (7), 827-832).
US Patents US 5,624,941 and US 6,028,084, PCT Application Nos. WO98/43636 and WO98/43635, and EPO Application No. EP-658546 disclose substituted pyrazoles having activity against the cannabinoid receptors.
PCT Application Nos. WO98/31227 and WO98/41519 also disclose substituted pyrazoles having activity against the cannabinoid receptors.
PCT Application Nos. WO98/37061, WO00/10967, and WO00/10968 disclose diaryl ether sulfonamides having activity against the cannabinoid receptors. PCT Application Nos. WO97/29079 and WO99/02499 disclose alkoxy-isoindolones and alkoxy-quinolones as having activity against the cannabinoid receptors.
US Patent US 5,532,237 discloses N-benzoyl-indole derivatives having activity against the cannabinoid receptors. US Patents US 4,973,587, US 5,013,837, US 5,081,122, and US
5,112,820, US 5,292,736 disclose aminoalkylindole derivatives as having activity against the cannabinoid receptors.
PCT publication WO 01/58869 discloses pyrazoles, pyrroles and imidazole cannabinoid receptor modulatorsuseful for treating respiratory and non- respiratory leukocyte activation-associated disorders.
PCT publications WO 01/64632, 01/64633, and 01/64634 assigned to Aventis are directed to azetidine derivatives as cannabinoid antagonists.
Schultz, E.M, et al. J. Med Chem. 1967, 10, 111 and Pines, S. H. et al. J. Med. Chem. 1967, 10, 725 disclose maleamic acids affecting plasma chloesterol and penicillin excretion.
The compounds of the present invention are modulators of the Cannabinoid-1 (CBl) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the Cannabinoid-1 (CBl) receptor. In particular, compounds of the present invention are antagonists or inverse agonists of the CBl receptor. The invention is concerned with the use of these compounds to modulate the Cannabinoid-1 (CBl) receptor. As such, compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine. The compounds are also useful for the treatment of eating disorders by inhibiting excessive food intake and the resulting obesity and complications associated therewith. The compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction, as well as for the treatment of asthma, and ciπhosis of the liver.
SUMMARY OF THE INVENTION
The present invention is concerned with novel substituted amides of the general Formula I :
Figure imgf000004_0001
(I) and pharmaceutically acceptable salts thereof which are antagonists and/or inverse agonists of the Cannabinoid-1 (CBl) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the Cannabinoid-1 (CBl) receptor. The invention is concerned with the use of these novel compounds to selectively antagonize the Cannabinoid-1 (CBl) receptor. As such, compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Baπe syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine, including smoking cessation. The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith. The compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction. The compounds are also useful for the treatment of cirrhosis of the liver. The compounds are also useful for the treatment of asthma.
The present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions. The present invention is also concerned with treatment of these conditions through a combination of compounds of formula I and other currently available pharmaceuticals.
The invention is also concerned with novel compounds of structural formula I.
The invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient.
The invention is further concerned with processes for preparing the compounds of this invention.
DETAILED DESCRIPTION OF THE INVENTION
The compounds used in the methods of the present invention are represented by the compound of structural formula I:
Figure imgf000005_0001
(I) or a pharmaceutically acceptable salt thereof, wherein; Rl is selected from:
(1) cycloheteroalkyl, (2) aryl, (3) heteroaryl, and
(4) -NRaRC; wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from Rb; R2 is selected from:
(1) CMoalkyl,
(2) C3_ιocycloalkyl-Ci-4alkyl,
(3) aryl-Ci_4alkyl, and
(4) heteroaryl-Cι_4alkyl; wherein each cycloalkyl, aryl and heteroaryl is optionally substituted with one to three substituents independently selected from Rb; each Ra is independently selected from:
(1) hydrogen,
(2) methyl, and (3) -CF3 ; each RD is independently selected from: (1) halogen,
(2) cyano,
(3) trifluoromethyl,
(4) trifluoromethoxy,
(5) Cι_3alkyloxy, and
(6) Ci-3alkyl;
Rc is independently selected from:
(1) hydrogen,
(2) Cι_6alkyl,
(3) aryl,
(4) heteroaryl,
(5) aryl-methyl, and
(6) heteroaryl-mefhyl, each Rc may be unsubstituted or substituted with one to three substituents selected from Rh;
Rd is independently selected from:
(1) cycloalkyl,
(2) aryl, and
(3) heteroaryl, each Rd may be unsubstituted or substituted with one to three substituents selected from Rn; each Rn is independently selected from: (1) halogen, (2) Ci-3alkyl,
(3) -CN, and
(4) -CF3, wherein when pyridyl groups are unsubstituted on the nitrogen, they are optionally present as the N-oxide. In one embodiment of the present invention, Rl is selected from:
(1) phenyl,
(2) pyridyl,
(3) indolyl,
(4) 7-aza-indolyl, (5) thiophenyl, and
Figure imgf000007_0001
wherein each aryl and heteroaryl is optionally substituted with one or two substitutents independently selected from Rb, and each pyridyl is optionally present as the N-oxide.
In one class of this embodiment of the present invention, Rl is selected from:
(1) phenyl,
(2) 3-cyanophenyl,
(3) 3-methylphenyl,
(4) 3,5-difluorophenyl,
(5) 3-pyridyl,
(6) 5 -chloro-3 -pyridyl ,
(7) 5-mefhyl-3-pyridyl,
(8) 5-cyano-3-pyridyl,
(9) l-oxido-5-cyano-3-pyridyl,
(10) 1 -indolyl, (11) 7-aza-indol-N-yl,
(12) 2-thiophenyl, and (13)
Figure imgf000008_0001
In a subclass of this class of the present invention, Rl is 5-cyano-3- pyridyl.
In another embodiment of the present invention, R2 is selected from: (1) Ci-6alkyl,
(2) C3_6cycloalkylmethyl,
(3) phenylmethyl,
(4) heteroarylmethyl, wherein each cycloalkyl, phenyl and heteroaryl is optionally substituted with one to three substituents independently selected from Rb.
In one class of this embodiment of the present invention, R is selected from:
(1) Cι_6alkyl,
(2) C4_6cycloalkylmethyl, (3) phenylmethyl,
(4) pyridyl, wherein each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or two substituents independently selected from Rb.
In a subclass of this class of the present invention, R2 is selected from: (1) 2-methylpropyl,
(2) n-pentyl,
(3) cyclobutylmethyl,
(4) cyclopentylmethyl,
(5) cyclohexylmethyl, (6) benzyl,
(7) 4-chlorobenzyl,
(8) 4-methylbenzyl, (9) 4-fluorobenzyl,
(10) 4-methoxybenzyl, and
(11) (5-chloro-2-pyridyl)methyl.
In one embodiment of the present invention, each Ra is independently selected from:
(1) hydrogen,
(2) methyl, and
(3) -CF3.
In one class of this embodiment of the present invention, each Ra is independently selected from:
(1) hydrogen, and
(2) methyl.
In one embodiment of the present invention, each Rb is independently selected from: (1) halogen,
(2) cyano,
(3) Cι_3alkyloxy and
(4) Cι_3alkyl.
In one class of this embodiment of the present invention, each Rb is independently selected from:
(1) fluoro,
(2) chloro,
(3) bromo,
(4) iodo, (5) cyano,
(6) methoxy, and
(7) methyl.
In one subclass of this class, each Rb is independently selected from: (1) fluoro, (2) chloro,
(3) cyano,
(4) methoxy, and
(5) methyl.
In one embodiment of the present invention, each Rc is independently selected from: (1) hydrogen,
(2) Ci-6alkyl,
(3) phenyl,
(4) pyridyl, (5) benzyl, and
(6) pyridyl-methyl; each Rc may be unsubstituted or substituted with a substituent selected from Rh. In one class, Rc is phenyl.
In one embodiment of the present invention, Rd is selected from: (1) C4_6cycloalkyl„
(2) aryl, and
(3) heteroaryl, wherein Rd may be unsubstituted or substituted with one or two substituents selected from Rh. In one class of the present invention, Rd is selected from:
(1) phenyl,
(2) pyridyl, and
(3) pyrimidinyl, wherein Rd may be unsubstituted or substituted with one or two substituents selected from Rh.
In one subclass of the present invention, Rd is selected from:
(1) phenyl,
(2) 4-chlorophenyl,
(3) 3-chlorophenyl, (4) 3,5-difluorophenyl,
(5) 3,5-dichlorophenyl,
(6) 2-pyridyl,
(7) 5-chloro-2-pyridyl,
(8) 6-methyl-2-pyridyl, (9) 5-trifluoromethyl-2-pyridyl,
(10) 4-trifluoromethyl-2-pyridyl,
(11) 4-trifluoromethyl-2-pyrimidyl, and
(12) 6-trifluoromethyl-4-pyrimidyl.
In another subclass of the present invention, Rd is 5-trifluoromethyl-2-pyridyl. In one embodiment of the present invention, each Rh is independently selected from:
(1) halogen,
(2) Ci-3alkyl, (3) -CN, and
(4) -CF3.
In one class of this embodiment, each Rh is independently selected from:
(1) fluoro, (2) chloro,
(3) methyl,
(4) -CN, and
(5) -CF3.
Particular novel compounds which may be employed in the methods, uses and compositions of the present invention, include:
(1) N-[3-(4-chlorophenyl)-l-methyl-2-phenylpropyl]-2-(4-chlorophenyloxy)-2- methylpropan amide;
(2) N- [3-(4-chlorophenyl)- 1 -methyl-2-phenylpropyl] -2-(2-pyridyloxy)-2- methylpropanamide; (3) N-[3-(4-chlorophenyl)-l-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2- methylpropanamide;
(4) N-[3-(4-chlorophenyl)-l-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2- methylpropanamide ;
(5) N-[3-(4-chlorophenyl)-2-phenyl-l-methylpropyl]-2-(3,5-dichlorophenyloxy)-2- methylpropanamide;
(6) N-[3-(4-chlorophenyl)-l-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2- methylpropanamide;
(7) N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-l-methylpropyl]-2-(2- pyridyloxy)-2-methylpropanamide; (8) N-[3-(4-chlorophenyl)-l-methyl-2-phenyl-propyl]-2-(5-chloro-2-pyridyloxy)-2- methylpropan amide; (9) N- [3-(4-chlorophenyl)-l -methyl-2-phenylpropyl]-2-(6-methyl-pyridyloxy)-2- methylpropan amide ; (10) N-[3-(4-chlorophenyl)-l-methyl-2-phenylpropyl]-2-(phenyloxy)-2- methylpropan amide;
(11) N-[(3-(4-chlorophenyl)-l-methyl-2-phenylpropyl]-2-(5- trifluoromethylpyridyloxy)-2-methylpropan amide; (12) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-l-methylpropyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide;
(13) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-l-methylproρyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(14) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(15) N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(16) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; (17) N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(18) N-[3-(4-chlorophenyl)-2-phenyl-l-methylpropyl]-2-(4-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide;
(19) N- [3-(4-chlorophenyl)-2-phenyl- 1 -methylpropyl]-2-(4-trifluoromethyl-2- pyrimidyloxy)-2-methylpropanamide;
(20) Ν-[3-(4-chlorophenyl)-l-methyl-2-(thiophen-3-yl)propyl]-2-(5-chloro-2- pyridyloxy)-2-methylpropan amide;
(21) N-[3-(5-chloro-2-pyridyl)-2-phenyl-l-methylpropyl']-2-(5-trifluoiOmethyl-2- pyridyloxy)-2-methylpropanamide; (22) N-[3-(4-methyl-phenyl)-l-methyl-2-phenylpropyl]-2-(4-trifluoromethyl- phenyloxy)-2-methylpropanamide;
(23) N-[3-(4-fluoro-phenyl)-2-(3-cyano-phenyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(24) Ν-[3-(4-chlorophenyl)-2-(l-indolyl)-l-methyl)propyl]-2-(5-trifluoromethyl-2- oxypyridine-2-yl)-2-methylpropanamide;
(25) N-[3-(4-chlorophenyl)-2-(7-azaindol-N-yl)-l-methyl)propyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropan amide;
(26) N-[3-(4-chloro-phenyl)-2-(l-indolinyl)-l-methylpropyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropan amide; (27) N-[3-(4-chloro-phenyl)-2-(N-methyl-anilino)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(28) N-[3-(4-methoxy-phenyl)-2-(3-cyano-phenyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; (29) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-l-methylpropyl]-2-(6- trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(30) Ν-[2-(3-cyanophenyl)-l,4-dimethylpentyl]-2-(5-trifluoromethyl-2-pyridyloxy)- 2-methylpropanamide;
(31) N-[3-(4-chlorophenyl)-2-(l-oxido-5-cyano-3-pyridyl]-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(32) N-[2-(3-cyanophenyl)-3-cyclobutyl-l-methylpropyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide;
(33) N-[2-(3-cyanophenyl)-l-methyl-heptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2- methylpropanamide; (34) N-[2-(3-cyanophenyl)-3-cyclopentyl-l-methylpropyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide; (35) N-[2-(3-cyanophenyl)-3-cyclohexyl-l-methylpropyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide; and pharmaceutically acceptable salts thereof. "Alkyl", as well as other groups having the prefix "alk", such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
"Cycloalkyl" means mono- or bicyclic or bridged saturated carbocyclic rings, each of which having from 3 to 10 carbon atomsExamples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
"Aryl" means mono- or bicyclic aromatic rings containing only carbon atoms. Examples of aryl include phenyl, naphthyl, and the like.
"Heteroaryl" means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms. Examples of heteroaryl include pyπolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, imidazothiazolyl, and the like. In particular, "heteroaryl" includes pyridyl, pyrimidyl, and thiophenyl, The heteroaryl ring may be substituted on one or more carbon or nitrogen atoms
"Cycloheteroalkyl" means mono- or bicyclic or bridged saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. The term also includes monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of "cycloheteroalkyl" include indolyl, azaindolyl and the like. The cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens. "Halogen" includes fluorine, chlorine, bromine and iodine.
When any variable (e.g., Rl, Rd, etc.) occurs more than one time in any constituent or in formula I, its definition on each occuπence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a Ci-5 alkylcarbonylamino Cχ_6 alkyl substituent is equivalent to
O
II
Chalky! - C-NH-C-,.6alkyl-
In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability.
The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or EtOAc or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.
Alternatively, any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
It is generally preferable to administer compounds of the present invention as enantiomerically pure formulations. Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.
Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occuπing substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. The term "pharmaceutically acceptable salt" further includes all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations.
It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
Compounds of the present invention are modulators of the CBl receptor. In particular, the compounds of structural formula I are antagonists or inverse agonists of the CBl receptor.
An "agonist" is a compound (hormone, neurotransmitter or synthetic compound) which binds to a receptor, inducing a conformational change in the receptor which, in turn, produces a response such as contraction, relaxation, secretion, change in enzyme activity, etc. similar to that elicited by the physiologically relevant agonist ligand(s) for that receptor. An "antagonist" is a compound which attenuates the effect of an agonist. An "inverse agonist" is a compound which acts on a receptor but produces the opposite effect produced by the agonist of the particular receptor.
Compounds of this invention are modulators of the CBl receptor and as such are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine. The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith. The compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction. The compounds are also useful for the treatment of cirrhosis of the liver. The compounds are also useful for the treatment of asthma.
The terms "administration of" and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
The administration of the compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the patient in need of such treatment or prophylaxis. The need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors. The effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment. The utilities of the present compounds in these diseases or disorders may be demonstrated in animal disease models that have been reported in the literature. The following are examples of such animal disease models: a) suppression of food intake and resultant weight loss in rats (Life Sciences 1998, 63, 113-117); b) reduction of sweet food intake in marmosets (Behavioural Pharm. 1998, 9, 179-181); c) reduction of sucrose and ethanol intake in mice (Psychopharm. 1997, 132, 104- 106); d) increased motor activity and place conditioning in rats (Psychopharm. 1998, 135, 324-332; Psychopharmacol 2000, 151: 25-30); e) spontaneous locomotor activity in mice (J. Pharm. Exp. Ther. 1996, 277, 586-594); f) reduction in opiate self- administration in mice (Sci. 1999, 283, 401-404); g) bronchial hyperresponsiveness in sheep and guinea pigs as models for the various phases of asthma (for example, see W. M. Abraham et al., "04-Integrins mediate antigen-induced late bronchial responses and prolonged airway hypeπesponsiveness in sheep." J. Clin. Invest. 93, 776 (1993) and A. A. Y. Milne and P. P. Piper, "Role of NLA-4 integrin in leucocyte recruitment and bronchial hyperresponsiveness in the gunea-pig." Eur. J. Pharmacol., 282, 243 (1995)); h) mediation of the vasodilated state in advanced liver cirrhosis induced by carbon tetrachloride (Nature Medicine, 2001, 7 (7), 827-832); i) amitriptyline-induced constipation in cynomolgus monkeys is beneficial for the evaluation of laxatives (Biol. Pharm. Bulletin (Japan), 2000, 23(5), 657-9); j) neuropathology of paediatric chronic intestinal pseudo-obstruction and animal models related to the neuropathology of paediatric chronic intestinal pseudo-obstruction (Journal of Pathology (England), 2001, 194 (3), 277-88).
The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases. For use where a composition for intravenous administration is employed, a suitable dosage range is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of Foimula I per kg of body weight per day and for preventive use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of Formula I per kg of body weight per day.
In the case where an oral composition is employed, a suitable dosage range is, e.g. from about 0.01 mg to about 1000 mg of a compound of Formula I per day, preferably from about 0.1 mg to about 10 mg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
Another aspect of the present invention provides pharmaceutical compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In particular, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well- known in the art of pharmacy.
For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers. The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery systems for inhalation are metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol, which may be formulated as a dry powder of a compound of Formula I with or without additional excipients.
Suitable topical formulations of a compound of foπnula I include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders, and the like. The topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle. Transdermal skin patches useful for administering the compounds of the present inveniton include those well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being prefeπed over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules (including timed release and sustained release formulations), pills, cachets, powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion, incluidng elixirs, tinctures, solutions, suspensions, syrups and emulsions. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated, and each cachet or capsule contains from about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
Additional suitable means of administration of the compounds of the present invention include injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular and topical, with or without occlusion.
Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also exemplifying the invention is a phannaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for malting a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier. The dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration, the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage will, of course, be coπespondingly larger for the less frequent administration.
When administered via intranasal routes, transdermal routes, by rectal or vaginal suppositories, or through a continual intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. The following are examples of representative pharmaceutical dosage forms for the compounds of Formula I:
Injectable Suspension (IM.) mg/mL
Compound of Formula I 10
Methylcellulose 5.0
Tween 80 0.5
Benzyl alcohol 9.0
Benzalkonium chloride 1.0
Water for injection to a total volume of 1 mL
Tablet mg/tablet
Compound of Formula I 25 Microcrystalline Cellulose 415 Povidone 14.0
Pregelatinized Starch 43.5 Magnesium Stearate 2.5
500
Capsule mg capsule Compound of Formula I 25 Lactose Powder 573.5
Magnesium Stearate 1.5 600
Aerosol Per canister
Compound of Formula I 24 mg
Lecithin, NF Liq. Cone. 1.2 mg
Trichlorofluoromethane, NF 4.025 g
Dichlorodifluoromethane, NF 12.15 g
Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is prefeπed. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be combined with a compound of Formula I include, but are not limited to: antipsychotic agents, cognition enhancing agents, anti-migraine agents, anti-asthmatic agents, antiinflammatory agents, axiolytics, anti-Parkinson's agents, anti-epileptics, anorectic agents, and serotonin reuptake inhibitors, and other anti-obesity agents which may be administered separately or in the same pharmaceutical compositions. It will be appreciated that for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents. The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anorectic agent, such that together they give effective relief. "Obesity" is a condition in which there is an excess of body fat. The operational definition of obesity is based on the Body Mass Index (BMI), which is calculated as body weight per height in meters squared (kg/m2). "Obesity" refers to a condition whereby an otherwise healthy subject has a Body Mass Index (BMI) greater than or equal to 30 kg/m2, or a condition whereby a subject with at least one co- morbidity has a BMI greater than or equal to 27 kg/m2. An "obese subject" is an otherwise healthy subject with a Body Mass Index (BMI) greater than or equal to 30 kg/m2 or a subject with at least one co-morbidity with a BMI greater than or equal to 27 kg/m2. A "subject at risk for obesity" is an otherwise healthy subject with a BMI of 25 kg/m2 to less than 30 kg/m2 or a subject with at least one co-morbidity with a BMI of 25 kg/m2 to less than 27 kg/m2.
The increased risks associated with obesity occur at a lower Body Mass Index (BMI) in Asians. In Asian countries, including Japan, "obesity" refers to a condition whereby a subject with at least one obesity-induced or obesity-related co- morbidity that requires weight reduction or that would be improved by weight reduction, has a BMI greater than or equal to 25 kg/m2. In Asian countries, including Japan, an "obese subject" refers to a subject with at least one obesity-induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, with a BMI greater than or equal to 25 kg/m2. In Asian countries, a "subject at risk for obesity" is a subject with a BMI of greater than 23 kg/m2 to less than 25 kg/m.2.
As used herein, the term "obesity" is meant to encompass all of the above definitions of obesity.
Obesity-induced or obesity-related co-morbidities include, but are not limited to, diabetes, non-insulin dependent diabetes mellitus - type 2, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, and infertility. In particular, co-morbidities include: hypertension, hyperlipidemia, dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea, diabetes mellitus, and other obesity-related conditions.
"Treatment" (of obesity and obesity-related disorders) refers to the administration of the compounds or compositions of the present invention to reduce or maintain the body weight of an obese subject. One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds or compositions of the present invention. Another outcome of treatment may be preventing regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of treatment may be decreasing the occurrence of and or the severity of obesity-related diseases. The treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof. The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss. "Prevention" (of obesity and obesity-related disorders) refers to the administration of the compounds or compositions of the present invention to reduce or maintain the body weight of a subject at risk for obesity. One outcome of prevention may be reducing the body weight of a subject at risk for obesity relative to that subject's body weight immediately before the administration of the compounds or compositions of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk for obesity. Another outcome of prevention may be decreasing the occuπence and/or severity of_obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk for obesity. Moreover, if treatment is commenced in already obese subjects, such treatment may prevent the occuπence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
Obesity-related disorders are associated with, caused by, or result from obesity. Examples of obesity-related disorders include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia. Further examples of obesity-related disorders are metabolic syndrome, also known as syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer. The compositions of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.
The term "diabetes," as used herein, includes both insulin- dependent diabetes mellitus (i.e., LDDM, also known as type I diabetes) and non- insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type II diabetes. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type II diabetes, or insulin-independent diabetes (i.e., non-insulin-dependent diabetes mellitus), often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese. The compounds and compositions of the present invention are useful for treating both Type I and Type II diabetes. The compounds and compositions are especially effective for treating Type II diabetes. The compounds and compositions of the present invention are also useful for treating and/or preventing gestational diabetes mellitus.
As used herein, the term "substance abuse disorders" includes substance dependence or abuse with or without physiological dependence. The substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all of the above.
In particular, the term "substance abuse disorders" includes drug withdrawal disorders such as alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances. It will be appreciated that reference to treatment of nicotine withdrawal includes the treatment of symptoms associated with smoking cessation.
Other "substance abuse disorders" include substance-induced anxiety disorder with onset during withdrawal; substance-induced mood disorder with onset during withdrawal; and substance-induced sleep disorder with onset during withdrawal. It will be appreciated that a combination of a conventional antipsychotic drug with a CBl receptor modulator may provide an enhanced effect in the treatment of mania. Such a combination would be expected to provide for a rapid onset of action to treat a manic episode thereby enabling prescription on an "as needed basis". Furthermore, such a combination may enable a lower dose of the antispychotic agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side-effects. A yet further advantage of such a combination is that, due to the action of the CB 1 receptor modulator, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented. The present invention also provides a method for the treatment or prevention of mania, which method comprises administration to a patient in need of such treatment or at risk of developing mania of an amount of a CBl receptor modulator and an amount of an antipsychotic agent, such that together they give effective relief. It will be appreciated that the CB 1 receptor modulator and the antipsychotic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of mania.
It will be appreciated that when using a combination of the present invention, the CBl receptor modulator and the antipsychotic agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term "combination" also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the antipsychotic agent may be administered as a tablet and then, within a reasonable period of time, the CBl receptor modulator may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a "fast-dissolving oral formulation" is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
It will be appreciated that a combination of a conventional antipsychotic drug with a CBl receptor modulator may provide an enhanced effect in the treatment of schizophrenic disorders. Such a combination would be expected to provide for a rapid onset of action to treat schizophrenic symptoms thereby enabling prescription on an "as needed basis". Furthermore, such a combination may enable a lower dose of the CNS agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side-effects. A yet further advantage of such a combination is that, due to the action of the CB 1 receptor modulator, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.
It will be appreciated that a combination of a conventional anti- asthmatic drug with a CBl receptor modulator may provide an enhanced effect in the treatment of asthma.
Thus, according to a further aspect of the present invention there is provided the use of a CBl receptor modulator and an anti-asthmatic agent for the manufacture of a medicament for the treatment or prevention of asthma.
The present invention also provides a method for the treatment or prevention of asthma, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-asthmatic agent, such that together they give effective relief.
The method of treatment of this invention comprises a method of modulating the CBl receptor and treating CBl receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the CBl receptor in preference to the other CB or G-protein coupled receptors.
The term "therapeutically effective amount" means the amount the compound of structural formula I that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated. The novel methods of treatment of this invention are for disorders known to those skilled in the art. The term "mammal" includes humans. Abbreviations used in the following Schemes and Examples: aq.: aqueous; API-ES: atmospheric pressure ionization-electrospray (mass spectrum term); DMF: dimethylformamide; DMSO: dimethylsulfoxide; EDC: l-ethyl-3-(3- dimethylaminopropyl)-carbodiimide hydrochloride; EPA: ethylene polyacrylamide (a plastic); EtOAc: ethyl acetate; h: hours; Hex: hexane; HOBt: 1-hydroxybenzo- triazole; HPLC: high pressure liquid chromatography; HPLC/MS: high pressure liquid chromatography/mass spectrum; in vacuo: rotoevaporation; IPAC: isopropyl acetate; KHMDS: potassium hexamethyldisilazide; LC: Liquid chromatography; LC/MS, LC-MS: liquid chromatography-mass spectrum; M: molar; Me: methyl; MeOH: methanol; mmol: millimole; MS or ms: mass spectrum; N: normal; NaHMDS: sodium hexamethyldisilazide; NMR: nuclear magnetic resonance; PyBOP: (benzotriazol-l-yloxy)tripyπolidinophosphonium hexafluorophosphate; R^: retention time; rt or RT: room temperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin layer chromatography. ι
Compounds of the present invention may be prepared by procedures illustrated in the accompanying scheme and examples. Scheme 1.
Figure imgf000029_0001
In Scheme 1, an appropriately substituted amine A is reacted with a carboxylic acid B under standard amide bond forming conditions to afford the arylamide C. In order to illustrate the invention, the following examples are included. These examples do not limit the invention. They are only meant to suggest a method of reducing the invention to practice. Those skilled in the art may find other methods of practicing the invention which are readily apparent to them. However, those methods are also deemed to be within the scope of this invention.
General Procedures. The LC/MS analyses were preformed using a MICROMASS
ZMD mass spectrometer coupled to an AGILENT 1100 Series HPLC utilizing a
YMC ODS-A 4.6 x 50 mm column eluting at 2.5 mL/min with a solvent gradient of
10 to 95% B over 4.5 min, followed by 0.5 min at 95% B: solvent A = 0.06% TFA in water; solvent B = 0.05% TFA in acetonitrile. iH-NMR spectra were obtained on a 500 MHz NARIAN Spectrometer in CDCI3 or CD3OD as indicated and chemical shifts are reported as δ using the solvent peak as reference and coupling constants are reported in hertz (Hz).
REFERENCE EXAMPLE 1
Figure imgf000030_0001
N-r2,3-Bis(4-chlorophenyl)-l-methylpropyn-amine hydrochloride
The preparation of the two diastereomers (alpha and beta) of N-[2,3- bis(4-chlorophenyl)-l-methylpropyl]-amine hydrochloride salt has been disclosed (Schultz, E.M, et al. J. Med Chem. 1967, 10, 111). Diastereomer α: LC-MS: calculated for C 6H 7CI2Ν 293, observed m/e 294 (M + H)+ (retention time 2.5 min). Diastereomer β: LC-MS: calculated for C 6H17CI2N 293, observed m/e 294 (M + H)+ (retention time 2.2 min). REFERENCE EXAMPLE 2
Figure imgf000031_0001
2-Amino-4-(4-chlorophenyl)-3-phenylbutane hydrochloride salt
The titled compound was prepared by the procedure described in Reference Example
1.
Diastereomer :
LC-MS: calculated for Cχ6H 8ClN 259, observed m/e 260 (M + H)+ (2.3 min).
Diastereomer β:
LC-MS: calculated for Cχ6Hχ8ClN 259, observed m/e 260 (M + H)+ (2.2 min).
REFERENCE EXAMPLE 3
Figure imgf000031_0002
N-[3-(4-Chlorophenyl)-2-phenyl-l-methylpropyn-amine hydrochloride (Diastereomer )
Step A 3-(4-Chlorophenyl)-2-phenylpropanoic acid, methyl ester. To a solution of methyl phenylacetate (12 g, 80 mmol) and 4-chlorobenzyl bromide (16 g, 80 mmol) in 250 mLanhydrous THF at -78°C was added sodium hexamethyldisilazide (1 M in THF, 80 mL, 80 mmol) (potassium hexamethyldisilazide in toluene may be used with similar results). The reaction was allowed to warm to room temperature overnight. The volatile materials were removed on a rotary evaporator, and the resulting mixture was partitioned between saturated ammonium chloride (200 mL) and EtOAc (200 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound iH NMR (500 MHz, CD3OD): δ 7.36-7.10 (m, 9H), 3.81 (dd, IH), 3.52 (s, 3H), 3.36
(dd, IH), 3.02 (dd, IH).
Step B 3-(4-Chlorophenyl)-2-phenylpropanoic acid.
To a mixture of methyl 3-(4-chlorophenyl)-2-phenylpropionate (Step A, 20 g, 74 mmol) in acetonitrile (100 mL) and water (100 mL) was added lithium hydroxide monohydrate (8.8 g, 0.21 mol). After stirring at room temperature for 3 days, the volatile materials were removed by concentrating on a rotary evaporator and the residue was partitioned between water (300 mL) and hexane/ether (1:1, 200 mL). The water layer was separated, acidified to pH = 2-3, and extracted with EtOAc (2 x 200 mL) The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. ^H NMR (500 MHz, CD3OD): δ 7.34-7.10 (m, 9H), 3.82 (dd, IH), 3.36 (dd, IH) , 2.98 (dd, IH).
Step C N-Methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropanamide.
To a solution of 3-(4-chlorophenyl)-2-phenylpropionic acid (Step B, 14 g, 55 mmol) in CH2CI2 (125 mL) at 0°C was added dimethyl formamide (50 μL) and oxalyl chloride (14 g, 0.11 mol) dropwise. The reaction was allowed to warm to room temperature overnight and concentrated to dryness to give the crude acyl chloride, which was used without further purification. Thus, to a solution of the acyl chloride in CH2CI2 (250 mL) was added N-methoxy-N-methylamine hydrochloride (11 g, 0.11 mol) and triethyl amine (dried over activated molecular sieves, 30 mL, 0.22 mol) at 0°C. After stirring at room temperature for 4 h, the reaction mixture was diluted with ether (500 mL) and successively washed with water, dilute aqueous sodium hydrogen sulfate and brine, dried over anhydrous MgSO4, filtered and concentrated to dryness to give the crude product, which was used without further purification. ^H ΝMR (500 MHz, CD3OD): δ 7.4-7.1 (m, 9H), 4.38 (br, IH), 3.48 (s, 3H), 3.35 (dd, IH), 3.10 (s,
3H), 2.92 (dd, IH); LC-MS: m/e 304 (3.6 min). Step D 4-(4-Chlorophenyl)-3-phenyl-2-butanone.
To a solution of N-methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropanamide (Step C, 16 g, 53 mmol, dried by azeotroping with toluene) in anhydrous THF (200 mL) at 0°C was added methylmagnesium bromide (3 M in ether, 35 mL, 0.11 mol). After stirring at 0°C for 2 h, the reaction was quenched with MeOH (5 mL) and 2 M hydrochloric acid (50 mL). The volatile materials were removed by concentrating on a rotary evaporator and the residue partitioned between saturated ammonium chloride (200 mL) and ether (200 mL). The organic layer was separated, and the aqueous layer was extracted with ether (2 x 200 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness to give the title compound, which was used without further purification. H NMR (500 MHz, CD3OD): δ 7.45-7.02 (m, 9H), 4.08 (dd, IH), 3.34 (dd, IH), 2.90 (dd, IH), 2.03 (s,
3H). Step E 4-(4-Chlorophenyl)-3-phenyl-2-butanol.
To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanone (Step D, 13 g, 50 mmol) in MeOH (100 mL) at 0 °C was added sodium borohydride (3.8 g, 100 mmol). After stirring at 0°C for 30 min, the reaction was quenched by addition of 2 M hydrochloric acid (50 mL). The volatile materials were removed by concentrating on a rotary evaporator and the residue partitioned between water (100 mL) and EtOAc (200 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the crude product, which was purified by flash column chromatography on silica gel eluted with 10% EtOAc in hexane to afford the pure faster eluting isomer and a mixture containing both the faster eluting isomer and the slower eluting isomer. Faster eluting isomer: 1H NMR (500 MHz, CD3OD): δ 7.25-7.00 (m, 9H), 4.00 (m,
IH), 3.15 (m, IH), 2.97 (m, IH), 2.85 (m, IH), 1.10 (d, 3H).
Step F 4-(4-Chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane. To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanol (Step E, faster eluting isomer, 9.0 g, 34 mmol) in EtOAc (100 mL) at 0°C was added triethyl amine (dried over activated molecular sieves, 5.8 mL. 42 mmol) and methanesulfonyl chloride (3.0 mL, 38 mmol). After stiπing at 0°C for 30 min, the reaction was quenched by addition of saturated aqueous sodium bicarbonate (100 mL). After stirring at room temperature for 1 h, the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound, which was used without further purification. ΪH NMR (500 MHz, CD3OD): δ 7.3-7.0 (m, 9H), 5.05 (m, IH),
3.2-3.0 (m, 3H), 2.80 (s, 3H), 1.40 (d, 3H). Step G 2-Azido-4-(4-chlorophenyl)-3-phenylbutane.
To a solution of 4-(4-chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane (Step F, 12 g, 34 mmol) in DMF (50 mL) was added sodium azide (11 g, 0.17 mol). After stirring at 120°C for 1 h, the reaction mixture was poured into water (200 mL), and the product was extracted with ether (2 x 100 mL). The combined organic extracts were washed with water, dried over MgSO4, filtered and concentrated to dryness, and the residue was purified on a silica gel column eluting with hexane to give the title compound.
Step H 2-(N-tert-Butoxycarbonyl)amino-4-(4-chlorophenyl)-3-phenylbutane To a solution of 2-azido-4-(4-chlorophenyl)-3-phenylbutane (Step G, 7.0 g, 24 mmol) in EtOAc (150 mL) was added di (tert-butyl) dicarbonate (8.0 g, 37 mmol) and platinum dioxide (0.50 g, 2.2 mmol). The mixture was degassed and filled with hydrogen with a balloon. After stirring for 1 day, the reaction mixture was filtered through CELITE diatomaceous earth, and the filtrate was concentrated to give the crude product, which was contaminated with some unreacted di (tert-butyl) dicarbonate. *H ΝMR (500 MHz, CD3OD): δ 7.25-6.88 (m, 9H), 3.89 (m, IH), 3.20
(m, IH), 2.86-2.77 (m, 2H), 1.54 (s, 9H), 0.92 (d, 3H). Step I Ν-r3-(4-Chlorophenyl)-2-phenyl-l-methylpropyπ-amine hydrochloride (Diastereomer ). 2-(N-tert-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-phenylbutane (Step H, 7.0 g, 24 mmol) was treated with a saturated solution of hydrogen chloride in EtOAc (100 mL) at room temperature for 30 min (4 M hydrogen chloride in dioxane may be used with similar results). The mixture was concentrated to dryness to give the title compound. !H ΝMR (500 MHz, CD3OD): δ 7.35-6.98 (m, 9H), 3.62 (m, IH), 3.20 (dd, IH), 3.05 (m, IH), 2.98 (dd, IH), 1.19 (d, 3H). LC-MS: m/e 260 (M + H)+ (2.3 min).
REFERENCE EXAMPLE 4
Figure imgf000035_0001
N-r3-(4-Chlorophenyl)-2fS)-phenyl-l(S)-methylpropyn-amine hydrochloride Step A 4-(4-Chlorophenyl)-3(S)-phenyl-2(R)-butanol.
A sample of magnesium (20 g, 0.82 mol) was activated by stirring under nitrogen for 12 h, and anhydrous ether (100 mL) was added to cover the solid material. The mixture was cooled to 0°C, and was added 4-chlorobenzyl chloride (40 g, 0.25 mmol) in 400 mL anhydrous ether dropwise. After stirring at room temperature for 1 h, a sample of the above solution (32 mL) was added to (lR,2R)-l-phenylpropylene oxide (1.0 g, 7.5 mmol) in 100 mL ether at 0°C via syringe. After stirring at 0°C for 2 h, the reaction was quenched by addition of saturated aqueous ammonium chloride (100 mL). The organic layer was separated and the aqueous layer extracted with ether (2 x 100 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with hexane to 15% EtOAc in hexane to afford the title compound. 1H ΝMR (500 MHz, CD3OD): δ 7.28-7.02 (m,
9H), 4.01 (m, IH), 3.14 (dd, IH), 2.97 (dd, IH), 2.85 (m, IH), 1.12 (d, 3H). Step B N-r3-(4-chlorophenyl)-2(S)-phenyl-l(S)-methylpropyll-amine, hydrochloride
The product of Step A (4-(4-chlorophenyl)-3(S)-phenyl-2(R)-butanol, 1.8 g, 7.0 mmol) was converted to the title compound following the steps described in Reference Example 3, Steps F-I, except hydrogen chloride in dioxane (4 M) was used in place of hydrogen chloride in EtOAc. !H ΝMR (500 MHz, CD3OD): δ 7.35-6.98 (m, 9H), 3.62 (m, IH), 3.20 (dd, IH), 3.05 (m, IH), 2.98 (dd, IH), 1.19 (d, 3H). LCMS: m/e 260 (M + H)+ (2.3 min). REFERENCE EXAMPLE 5
Figure imgf000036_0001
N-rS-^-chlorophenvD-Σ-fS-pyridyD-l-methylpropyll-amine, hydrochloride (mixture of diastereomers oc/β 10:1)
Step A 4-(4-Chlorophenyl)-3-pyridyl-2-butanone.
To a solution of 3-pyridylacetone hydrochloride (Wibaud, van der V. Reel. Trav. Chim. Pays-Bas. 1952, 71, 798) (10 g, 58 mmol) and 4-chlorobenzyl chloride (9.1 g, 58 mmol) in 100 mL CH2CI2 at -78°C was added cesium hydroxide monohydrate (39 g, 0.23 mol) and tetiabutyl ammonium iodide (1 g). The reaction was allowed to warm to room temperature overnight, and the resulting mixture was partitioned between brine (100 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound. 1H ΝMR (500 MHz, CD3OD): δ 8.42 (d, IH), 8.34 (d, IH), 7.72 (d, IH), 7.40 (dd, IH), 7.18 (d, 2H), 7.06 (d, IH), 4.23 (dd, IH), 3.38 (dd, IH), 2.95 (dd, IH), 2.10 (s, 3H). LC-MS: m/e 260 (M + H)+ (1.9 min). Step B N-r3-(4-chlorophenyl)-2-(3-pyridyl)-l-methylpropyn-amine, hydrochloride (mixture of diastereomers α/β 10:1). The product of Step A (4-(4-chlorophenyl)-3-pyridyl-2-butanone) (14 g, 57 mmol) was converted to the title compound following the procedure described in Reference Example 3, Steps E-I. LC-MS: m/e 261 (M + H)+ (1.2 min).
REFERENCE EXAMPLE 6
Figure imgf000036_0002
2-(2-FluorophenyloxyV2-methylpropionic acid Step A 2-(2-Fluorophenyloxy)-2-methylpropionic acid
To a solution of 2-fluorophenol (2.0 g, 18 mmol) and l,l,l-trichloro-2-methyl-2- propanol (7.9 g, 45 mmol) in acetone (100 mL) was added sodium hydroxide (7.1 g, 0.18 mol), and an ice-water bath was periodically applied to maintain a gentle reflux. After the reflux subsided, the reaction was stiπed for one additional hour. The volatile materials were removed on a rotary evaporator, and the residue partitioned between ether (100 mL), hexane (lOOmL) and water (200 mL). The aqueous layer was separated and acidified with concentrated hydrochloric acid (pH = 2), and extracted with ether (3 x 100 mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.15-7.05 (m, 4H), 1.56 (s, 6H). LC-MS: m/e 199 (M + 1)+ (2.3 min).
The acids of Reference Examples 7 and 8 were prepared following the procedures described for Reference Example 6 substituting 2-fluorophenol with appropriately substituted phenols.
REFERENCE EXAMPLE 7
Figure imgf000037_0001
2-(3-Chlorophenyloxy)-2-methylpropionic acid
XH NMR (500 MHz, CD3OD): δ 7.23 (t, IH), 7.00 (dd, IH), 6.93 (t, IH), 6.84 (dd,
IH), 1.59 (s, 6H). LC-MS: m/e 215 (M + 1)+, (2.7 min). REFERENCE EXAMPLE 8
Figure imgf000038_0001
2-(3,5-Dichlorophenyloxy)-2-methylpropionic acid
1H NMR (500 MHz, CD3OD): δ 7.05 (t, IH), 6.84 (d, 2H), 1.60 (s, 6H).
REFERENCE EXAMPLE 9
Figure imgf000038_0002
2-(2-Pyridyloxy)-2-methylbutanoic acid.
Step A Benzyl 2-(2-Pyridyloxy)propionate
To a mixture of 2-hydroxypyridine (2.9 g, 30 mmol), benzyl lactate (5.0 g, 21 mmol) and triphenylphosphine (12 g, 47 mmol) in 100 mL CH2CI2 was added diethylazodicarboxylate (7.8 mL, 45 mmol) at 0°C. The reaction was allowed to warm to room temperature for 4 h. The resulting mixture was diluted with hexane
(100 mL) and concentrated with 20 g silica gel. The material was loaded onto a silica gel column, which was eluted with 10% EtOAc in hexane to give the title compound. !H NMR (500 MHz, CD3OD): δ 8.00 (dd, IH), 7.68 (ddd, IH), 7.36-7.28 (m, 5 H),
6.94 (dd, IH), 6.84 (dd, IH), 5.30 (q, IH), 5.18 (s, 2H), 1.59 (d, 3H). LC-MS: m/e 258 (M + H)+ (3.3 min).
Step B Benzyl 2-(2-Pyridyloxy -2-methylbutanoate.
To a solution of benzyl 2-(2-pyridyloxy)propionate (1.6 g, 6.2 mmol) and ethyl iodide (1.5 mL, 25 mmol) in 10 mLanhydrous THF at -78°C was added sodium hexamethyldisilazide (1 M in THF, 9.3 mL, 9.3 mmol) (potassium hexamethyldisilazide in toluene may be used with similar results). The reaction was allowed to warm to room temperature over 2 h and was partitioned between saturated ammonium chloride (100 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10% EtOAc in hexane to give the title compound. *H NMR (500 MHz, CD3OD): δ 7.87 (dd, IH), 7.63 (ddd, IH), 7.27 (m, 3H), 7.18. (m, 2H), 6.85 (dd,
IH), 6.74 (dd, IH), 5.08 (ABq, 2H), 2.13 (m, IH), 1.94 (m, IH), 1.65 (s, 3H), 0.95 (t, 3H). LC-MS: m/e 286 (M + H)+ (3.8 min). Step C 2-(2-Pyridyloxy)-2-methylbutanoic Acid
A mixture of benzyl 2-(2-pyridyloxy)-2-methylbutanoate (1.6 g, 5.5 mmol) and 10% palladium on carbon (50 mg) in 50 mL MeOH was degassed and filled with hydrogen using a balloon. After stirring at room temperature overnight, the reaction mixture was filtered through CELITE diatomaceous earth and washed with MeOH (20 mL), and the filtrate was concentrated to dryness to give the title compound. ^H NMR (500 MHz, CD3OD): δ 8.03 (dd, IH), 7.64 (ddd, IH), 6.89 (dd, IH), 6.76 (dd, IH), 2.14 (m, IH), 1.94 (m, IH), 1.64 (s, 3H), 0.99 (t, 3H). LC-MS: m/e 196 (M + H)+ (1.8 min).
REFERENCE EXAMPLE 10
Figure imgf000039_0001
2-(2-Pyridyloxy)-2-methylpropionic Acid
The title compound was prepared following the procedures described for Reference Example 9 substituting ethyl iodide and sodium hexamethyldisilazide with methyl iodide and potassium hexamethyldisilazide respectively at Step B. !H NMR (500 MHz, CD3OD): δ 8.04 (dd, IH), 7.64 (ddd, IH), 6.89 (dd, IH), 6.76
(dd, IH), 1.66 (s, 6H). LC-MS: m/e 182 (M + H)+ (1.5 min).
REFERENCE EXAMPLE 11
Figure imgf000040_0001
N-r3-(4-Chlorophenyl)-2-(3,5-difluorophenyl)-l-methylpropyllamine hydrochloride (Diastereomer α)
The title compounds was prepared following the procedures described for Reference Example 3 substituting methyl phenylacetate with methyl 3,5-difluorophenylacetate (prepared from 3,5-difluorophenylacetic acid and trimethylsilyldiazomethane) at Step A and sodium borohydride in MeOH with lithium
Figure imgf000040_0002
in THF at Step E. LC-MS: m/e 296 (M + H)+ (2.39 min).
REFERENCE EXAMPLE 12
Figure imgf000040_0003
N-[3-(4-Chlorophenyl)-2-(3-cvanophenyl)-l-methylpropyllamine hydrochloride (Diastereomer ) Step A 2-(N-tert-Butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3- cyanophenypbutane To a solution of 2-(N-tert-butoxycarbonyl)amino-3-bromophenyl-4-(4- chlorophenyl)butane (prepared according to the procedure of Reference Example 3, Step H, 1.0 g, 2.3 mmol) in 5 mL DMF was added zinc cyanide (0.16 g, 1.4 mmol), tris(dibenzylidene-acetone)dipalladium chloroform complex (3.0 mg, 2.8 μmol), 1,1'- bis(diphenylp-hosphino)ferrocene (5.0 mg, 9.0 μmol) and water (0.1 mL). After heating at 120°C for 6 h under nitrogen, another batch of zinc cyanide (0.16 g, 1.4 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (5.0 mg, 4.8 μmol), l,l'-bis(diphenylphosphino)ferrocene (5.0 mg, 9.0 μmol) and water (0.05 mL) was added, and heating was continued for another 18 h. After cooling to room temperature, the resulting mixture was partitioned between water (50 mL) and ether (50 mL). The organic layer was separated and the aqueous layer extracted with ether (2 x 50 mL). The combined extracts were dried over anhydrous MgSO4, filtered and concentrated, and the residue was purified by flash column chromatography on silica gel eluted with 20% EtOAc in hexane to afford the title compound. *H NMR (400 MHz, CD3OD): δ 7.6-7.3 (m, 4H), 7.10 (d, 2H), 6.92 (d, 2H), 3.88 (m, IH), 3.20 (m,
IH), 2.97 (m, IH), 1.82 (m, IH), 1.45 (s, 9H), 0.94 (d, 3H). LC-MS: m/e 385 (M + H)+ (3.9 min).
Step B N- 1"3 -(4-Chlorophenyl)-2-(3 -c yanophenyl)- 1 -methylprop yll amine hydrochloride (Diastereomer α)
The title compound was prepared following the procedure described for Reference Example 3, Step I. LC-MS: m/e 285 (M + H)+ (2.2 min).
REFERENCE EXAMPLE 13
Figure imgf000041_0001
2-Methyl-2-(5-chloro-2-pyridyloxy)propionic acid Step A Ethyl 2-Methyl-2-(5-chloro-2-pyridyloxy)propionate
A mixture of 5-chloro-2-hydroxypyridine (5.0 g, 39 mmol), ethyl 2-bromoisobutyrate (5.7 mL, 39 mmol) and cesium carbonate (25 g, 77 mmol) in 50 mL acetonitrile was heated at 50°C overnight. The volatile materials were removed by concentrating on a rotary evaporator, and the residue was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5% EtOAc in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.99 (d, IH), 7.67 (dd, IH), 6.68 (d, IH), 4.13 (q, 2H), 1.64 (s, 6H), 1.14 (t, 3H). LC-MS: m/e 244 (M + H)+ (3.41 min).
Step B 2-Methyl-2-(5-chloro-2-pyridyloxy)propionic Acid
A mixture of ethyl 2-methγl-2-(5-chloro-2-pyridyloxy)propionate and sodium hydroxide (0.85 g, 21 mmol) in 15 mL acetonitrile and 15 mL water was heated at 50°C overnight. The volatile materials were removed by concentrating on a rotary evaporator, and the residue was partitioned between 2 M hydrochloric acid (100 mL) and ether (100 mL). The organic layer was separated and washed with water (2 x 50 mL), dried over anhydrous MgSO4, filtered and concentrated to dryness to give the title compound. !H NMR (500 MHz, CD3OD): δ 8.02 (d, IH), 7.65 (dd, IH), 6.77 (d, IH), 1.62 (s, 6H). LC-MS: m/e 216 (M + H)+ (2.33 min).
REFERENCE EXAMPLE 14
Figure imgf000042_0001
2-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propionic Acid The title compound was prepared following the procedures described for Reference Example 13 substituting 5-chloro-2-hydroxpyridine with 5-trifluoromethyl-2- hydroxpyridine at Step A. !H NMR (500 MHz, CD3OD): δ 8.38 (br s, IH), 7.93 (dd,
IH), 7.13 (d, IH), 1.70 (s, 6H). LC-MS: m/e 250 (M + H)+ (2.6 min).
REFERENCE EXAMPLE 15
Figure imgf000042_0002
2-Methyl-2-(6-methyl-2-pyridyloxy)propionic Acid The title compound was prepared following the procedures described for Reference Example 13 substituting 5-chloro-2-hydroxpyridine with 6-methyl-2- hydroxpyridine at Step A. *H NMR (500 MHz, CD3OD): δ 7.51 (t, IH), 6.74 (d,
IH), 6.53 (d, IH), 2.34 (s, 3H), 1.64 (s, 6H). LC-MS: m/e 196 (M + H)+ (1.3 min).
REFERENCE EXAMPLE 16
Figure imgf000043_0001
2-Amino-3-(l-(l,2,3-triazolyl))-4-(4-chlorophenyl)butane: Step A Benzyl 2-(l-(1.2,3-triazolyl))acetate:
A mixture of 1,2,3-triazole (2.07 g, 30 mmol), phenyl bromoacetate (6.9 g, 30 mmol), and diisopropylethylamine (5,1 mL, 30 mmol) in 40 mL CH2CI2 was stiπed overnight at room temperature. This mixture was then diluted with ether until no further precipitate formed. The solid was filtered and washed with ether. The filtrate was concentrated and the residue was purified on silica gel using 10% hexane in CH2CI2 to give the title compound's isomer, benzyl 2-(2-(l,2,3-triazolyl)acetate as amorphous solid. Further elution with a solvent mixture containing equal amounts of ether and CH2CI2 gave the title compound as amorphous solid. lH NMR (400 MHz, CDCl3):5 2.251(s, 2H0, 7.267-7.390(m, 5H), 7.723(s, IH), 7.785(s,lH) Step B 2-(l-(l,2,3-triazolyl))acetic acid:
Palladium hydroxide (20% on carbon, 800 mg) was added to a solution of benzyl 2- (l-(l,2,3-triazolyl))acetate (Step A, 8.68 g, 39.9 mmol) in 150 mL MeOH and the mixture was hydrogenated overnight on a Pan shaker under an atmosphere of hydrogen at room temperature and 45 psi. The catalyst was filtered through a bed of CELITE diatomaceous earth and washed with MeOH. The filtrate was concentrated to give a solid, which was dried in vacuo at 50°C for 36 h resulting in the title compound. lH NMR (400 MHz, CD3θD):δ 5.3 (s, 2H), 7,75 (s, 1H0, 8.016 (s, IH).
Step C N-Methoxy-N-methyl-2-(l-(l,2,3-triazolyl))acetamide:
Oxalyl chloride (0.95 mL, 11 mmol) was added dropwise to a suspension of 2-(l- l,2,3-triazolyl))acetic acid (Step B, 1.27 g, 10 mmol) in 10 mL CH2CI2 containing 0.05 mL DMF. Vigorous effervescence was observed. This mixture was stiπed at room temperature for 4 h and cooled to -78°C. A solution of N.O- dimethylhydroxylamine hydrochloride (1.2 g, 13 mmol) and diisopropylethyl amine (6.0 mL, 35 mmol) in 10 mL CH2CI2 was added slowly over 3 min. The mixture was then allowed to warm to room temperature and stiπed overnight . The reaction mixture was then diluted with ether until no additional precipitate appeared. The solid was filtered and washed with ether. The filtrate was concentrated and the residue was purified on silica gel using EtOAc as solvent to provide the title compound as amorphous solid. lH NMR (400 MHz, CDCl3):δ 3.252 (s, 3H0, 3.812 (s, 3H), 5.379 (s, 2H), 7.753 & 7.761 (s's, 2H).
Step D N-Methoxy-N-methyl-3-(4-chlorophenyl)-2-(l-(l,2,3-triazolyl)) propionamide Lithium hexamethyldisilazide (lmolar in THF, 8.4 mL, 8.4 mmol) was added dropwise to a solution of N-methoxy-N-methyl-2-(l-(l,2,3-triazolyl))acetamide (Step C, 1.19 g, 7 mmol) in 15 mL THF at -78°C. After additional 30 min stirring, a solution of 4-chlorobenzyl bromide (1.65 g, 8 mmol) in 5 mL THF was added dropwise. The mixture was allowed to warm to room temperature and stiπed 5.5 h. This mixture was purified on silica gel using 40% EtOAc in hexane to give the title compound. lH NMR (400 MHz, CDCI3.): δ 3.186 (s, 3H), 3.234-3,267 (m, IH), 3,453-3.506 (m, IH), 3.582 (s, 3H), 6.145-6.188 (m, IH), 7.048-7.279 (m, 4H), 7.726 (s, IH), 7.954 (s, IH).
Step E 2-Azido-3-(l-(l,2,3-triazolyl))-4-(4-chlorophenyl)butane:
The product of Step D, N-methoxy-N-methyl-3-(4-chlorophenyl)-2-(l -(1,2,3- triazolyl)propionamide was converted to the title compound following the procedures described in Reference Example 3, Step D-G. lH NMR (400 MHz, CDCI3): δ 1.219-1.246 (d's 3H), 3.253-4.754 (m, 4H0, 6.866-7.299 (d's, 4H), 7.313, 7.618, 7.63, & 7.706 (s's, 2H).
Step F 2-Amino-3-(l-(l,2,3-triazolyl))-4-(4-chlorophenyl)butane:
Platinum oxide (14 mg) was added to a solution of 2-azido-3-(l-(l,2,3-triazolyl))-4- (4-chlorophenyl)butane (Step E, 138 mg, 0.5 mmol) in 4 mL MeOH. This mixture was hydrogenated in an atmosphere of hydrogen using a hydrogen filled balloon for 3 h at room temperature. The catalyst was filtered through a bed of CELITE diatomaceous earth and washed with MeOH. The filtrate was concentrated to give the title compound as oil. lH NMR (400 MHz, CDCl3):δ 1.085-1.174 (d's 3H), 3.220- 3.361 (m, 2H), 3.517-3.563 (m, IH), 4.379-4.431 (m, IH), 6.679-7.179 (d's, 4H), 7.297, 7.40, 7.592 & 7.607 (s's, 2H).
REFERENCE EXAMPLE 17
Figure imgf000045_0001
N-r3-(4-Chlorophenyl)-2-(3-methylphenyl)-l-methylpropynamine hydrochloride
(Diastereomer )
Step A 2-(N-tert-Butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3- methylphenypbutane
A mixture of 2-(N-tert-butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4- chlorophenyl)butane (Reference Example 3, Step H, 0.50 g, 1.1 mmol), tetramethyltin (0.41 g, 2.3 mmol), triphenylphosphine (0.12 g, 0.46 mmol), lithium chloride (0.38 g, 9.1 mmol) and dichlorobis(triphenylphosphine)palladium (0.12 g, 0.17 mmol) in 20 mL anhydrous DMF was heated at 100°C under nitrogen for 18 h. The reaction mixture was cooled to room temperature, and was partitioned between water (100 mL) and ether (100 mL). The organic layer was separated and the aqueous layer was extracted with ether (100 mL). The combined extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10% EtOAc in hexane to afford the title compound. lH ΝMR (400 MHz, CD3OD): δ 7.2-6.8 (m, 8H), 3.84 (m, IH), 3.16
(m, IH), 2.80-2.68 (m, 2H), 2.24 (s, 3H), 1.45 (s, 9H), 0.86 (d, 3H). LC-MS: m/e 396 (M + Νa)+ (4.4 min).
Step B N-r3-(4-Chlorophenyl)-2-(3-methylphenyl)-l-methylpropyllamine hydrochloride (Diastereomer )
The title compound was prepared following the procedure described for Reference Example 3, Step I. LC-MS: m/e 274 (M + H)+ (2.5 min). REFERENCE EXAMPLE 18
Figure imgf000046_0001
N-r3-(5-Chloro-2-pyridyl)-2(S)-phenyl-l(S)-methylpropyllamine hydrochloride (Diastereomer )
Step A 5-Chloro-2-methylpyridine
A mixture of 2,5-dichloropyridine (15 g, 0.10 mol), tetramethyltin (15 mL, 0.11 mol), and dichlorobis(triphenylphosphine)palladium (2.0 g, 2.8 mmol) in 200 mL anhydrous DMF was heated at 110°C under nitrogen for 72 h. The reaction mixture was cooled to room temperature, and was poured into a saturated solution of potassium fluoride (200 mL). The resulting mixture was partitioned between water (500 mL) and ether (500 mL). The organic layer was separated and the aqueous layer was extracted with ether (200 mL). The combined extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 2 to 10% ether in hexane to afford the title compound. ±H ΝMR (500 MHz, CD3OD): δ 8.41 (d, IH), 7.75 (dd, IH),
7.30 (d, IH), 2.53 (s, 3H).
Step B 4-(5-Chloro-2-pyridyl)-3(S)-phenyl-2(R)-butanol.
To a solution of 5-chloro-2-methylpyridine (Step A, 1.1 g, 8.7 mmol) in 15 mL anhydrous ether was added phenyl lithium (1.8 M in cyclohexane/ether, 7.2 mL, 13 mmol) at 0°C, and the reaction was stiπed at room temperature for 30 min. The resulting mixture was cooled back to 0°C, and was added (lR,2R)-l-phenylpropylene oxide (2.3 g, 17 mmol), and the reaction was allowed to warm to room temperature overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10 to 40% EtOAc in hexane to afford the title compound. *H ΝMR (500 MHz, CD3OD): δ 8.28 (d, IH), 7.59 (dd, IH), 7.25-7.12 (m, 5H), 7.05 (d, IH), 4.03 (m, IH), 3.29 (dd, IH), 3.19 (dd, IH), 3.12
(m, IH), 1.12 (d, 3H).
Step C 2(S)-Azido-4-(5-chloro-2-PyridylV3(S)-phenylbutane
To a mixture of 4-(5-chloro-2-pyridyl)-3-phenyl-2-butanol (Step B, 0.24 g, 0.92 mmol), triphenylphosphine (1.5 g, 1.4 mmol) and diphenylphosphoryl azide (0.30 mL, 1.4 mmol) in 5 mL anhydrous THF was added diethylazodicarboxylate (0.24 mL,
1.4 mmol). After stirring at room temperature overnight, the resulting mixture was concentrated with silica gel (10 g) and the residue was loaded onto a silica gel column. Elution with 5 to 15% EtOAc in hexane afforded the title compound. H
NMR (500 MHz, CD3OD): δ 8.35 (d, IH), 7.52 (dd, IH), 7.25-7.05 (m, 5H), 6.95 (d,
IH), 3.81 (m, IH), 3.48 (m, IH), 3.15-3.05 (m, 2H), 1.14 (d, 3H).
Step D N-r3-(5-Chloro-2-pyridyl)-2(Sl-phenyl-l(S)-methylpropyllamine, hydrochloride The product of Step C (0.20 g, 0.70 mmol) was converted to the title compound following the procedure described in Reference Example 3, Steps H-I, except hydrogen chloride in dioxane (4 M) was used in place of hydrogen chloride in EtOAc. iH ΝMR (500 MHz, CD3OD): δ 8.75 (d, IH), 8.19 (dd, IH), 7.55 (d, IH), 7.4-7.2
(m, 5H), 3.78 (m, IH), 3.62 (dd, IH), 3.48 (m, IH), 3.43 (dd, IH), 1.22 (d, 3H). LCMS: m/e 261 (M + H)+ (2.2 min).
REFERENCE EXAMPLE 19
Figure imgf000047_0001
N-r2-(3-Bromophenyl)-3-(5-chloro-2-pyridyl)-l-methylpropynamine hydrochloride (Diastereomer α)
Step A 3-Bromophenylacetone
To a solution of Ν-methoxy-Ν-methylacetamide (10 g, 100 mmol) in 100 mL anhydrous ether at 0°C was added 3-bromobenzylmagnesium bromide (0.25 M in ether, 200 mL, 50 mmol). The reaction was allowed to warm to room temperature overnight and was quenched by the addition of saturated ammonium chloride (100 mL). The organic layer was separated and the aqueous layer was extracted with hexane (100 mL). The combined extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness to afford the title compound. ^H NMR (500 MHz, CD3OD): δ 7.45-7.40 (m, 2H), 7.26 (t, IH), 7.19 (d, IH), 2.20 (s, 3H).
Step B 3-(3-Bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone
A suspension of 5-chloro-2-methylpyridine (Reference Example 18, Step A, 6.4 g, 50 mmol) and N-bromosuccinimide (12.5 g, 70 mmol) in 100 mL carbon tetrachloride was heated to gentle reflux (bath temperature 90°C), and 2,2' -azobisisobutyronitrile (0.74 g) was added in several portions over 30 min. After stirring at this temperature for 5 h, the reaction mixture was concentrated. The resulting sluπy was diluted with EtOAc (100 mL) and was washed with water (100 mL), saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate, and brine. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 2 to 15% ether/CH2Cl2 (1:1) in hexane to afford 2-bromomethyl-5-chloropyridine (6.0 g, 60%), which was used immediately for the ensuing reaction. Thus, to a vigorously stiπed solution of 2-bromomethyl-5-chloropyridine (6.0 g, 29 mmol) and 3- bromophenyl acetone (Step A, 6.0 g, 28 mmol) and tetrabutylammonium iodide (20 mg) in 30 mL CH2CI2 at -78°C was added cesium hydroxide monohydrate (10 g, 60 mmol), and the reaction was allowed to slowly warm to room temperate overnight.. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5 to 40% EtOAc in hexane to afford the title compound. lH NMR (500 MHz, CD3OD): δ 8.44 (d, IH), 7.66 (dd, IH), 7.46-7.41
(m, 2H), 7.24 (t, IH), 7.22 (d, IH), 7.15 (d, lh), 4.42 (dd, IH), 3.54 (dd, IH), 3.07 (dd, IH), 2.12 (s, 3H). LC-MS: m/e 338 (M + H)+ (3.0 min).
Step C 3-(3-Bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanol To a solution of 3-(3-bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone (Step B, 6.7 g, 20 mmol) in 50 mL anhydrous THF at -78°C was added lithium tri(sec- butyl)borohydride (1.0 M in THF, 30 mL, 30 mmol), and the reaction was allowed to warm to room temperature overnight. The reaction was cooled to 0°C, and was carefully added 2 M hydrochloric acid (50 mL), and the resulting mixture was partitioned between hexane (200 mL) and water (200 mL). The aqueous layer was separated and the organic layer extracted with 2 M hydrochloric acid (2 x 100 mL). The combined aqueous extracts were neutralized with 5 N aqueous sodium hydroxide (pH > 12), and was extracted with EtOAc (2x200 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the title compound. Step D N-r2-(3-Bromophenyl)-3-(5-chloro-2-pyridyl)-l-methylpropyl1amine, hydrochloride The product of Step C (5.9 g, 17 mmol) was converted to the title compound following the procedure described in Reference Example 18, Steps C-D. LC-MS: m/e 338 (M + H)+ (2.3 min).
REFERENCE EXAMPLE 20
Figure imgf000049_0001
N-r2-(5-Bromo-2-pyridyl)-3-(4-chlorophenyl)-l-methylpropyl]amine hydrochloride
(Diastereomer α)
Step A 5-Bromo-3-pyridylacetone
A mixture of 3,5-dibromopyridine (50 g, 0.21 mol), isopropenyl acetate (26 mL, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (1.0 g, 1.1 mmol) and 2-
(diphenylphosphino)-2'(Ν,Ν-dimethylamino)biphenyl (1.6 g, 4.2 mmol) in 400 mL toluene was heated at 100°C under nitrogen for 2 h. The reaction mixture was cooled to room temperature, and was concentrated to about 100 mL. The resulting mixture was loaded onto a silica gel column, which was eluted with 0 to 60% EtOAc in hexane to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.54 (br s,
IH), 8.33 (br s, IH), 7.88 (br s, IH), 3.90 (s, 2H), 2.25 (s, 3H). Step B 3-(5-Bromo-3-pyridyl)-4-(4-chlorophenyl)-2-butanol
The title compound was prepared following the procedure described in Reference Example 19, Step B-C, substituting 2-bromomethyl-5-chloropyridine with 4- chlorobenzyl chloride and 3-bromophenylaceatone with 5-bromo-3-pyridylacetone (Step A). lH NMR (500 MHz, CD3OD): δ 8.43 (d, IH), 8.24 (d, IH), 7.98 (dd, IH),
7.17 (d, 2H), 7.07 (d, 2H), 4.04 (m, IH), 3.16 (dd, IH), 3.0-2.9 (m, 2H), 1.04 (d, 3H). Step C N-r2-(5-Bromo-3-pyridyl)-3-(4-chlorophenyl)-l-methylpropyllamine hydrochloride (Diastereomer ) The title compound was prepared following the procedure described for Reference Example 4, Step B. LC-MS: m/e 339 (M + H)+ (2.5 min).
REFERENCE EXAMPLE 21
Figure imgf000050_0001
N-r3-(4-Chlorophenyl)-2-(5-cyano-3-pyridyl)-l-methylpropyllamine hydrochloride
(Diastereomer )
Step A 5 -Cyano-3 -pyridyl acetone
The title compound was prepared following the procedure described for Reference
Example 20 substituting 3,5-dibromopyridine with 5-bromonicotinonitrile (5-bromo- 3-cyanopyridine) at Step A. *H ΝMR (400 MHz, CD3OD): δ 8.89 (d, IH), 8.60 (d,
IH), 8.02 (t, IH), 3.98 (s, 2H), 2.24 (s, 3H).
Step B N-r3-(4-ChloiOphenyl)-2-(5-cvano-2-pyridyl)-l-methylpropyllamine hydrochloride (Diastereomer /β 5:1) The title compound was prepared following the procedure described for Reference Example 5 substituting 3-pyridylacetone with 5-cyano-3-pyridylacetone (Step A). LC-MS: m/e 286 (M + H)+ (1.9 min). REFERENCE EXAMPLE 22
Figure imgf000051_0001
N-r3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-l-methylpropyl1amine hydrochloride (Diastereomer )
Step A 5-Chloro-3-pyridylacetone
The title compound was prepared following the procedure described for Reference Example 20 substituting 3,5-dibromopyridine with 3,5-dichloropyrdine and 2- (diphenylphosphino)-2' (Ν,Ν-dimethylamino)biphenyl with 2-(di-t-butylphosphino) biphenyl at Step A. lH NMR (500 MHz, CD3OD): δ 8.42 (d, IH), 8.27 (d, IH), 7.73
(dd, IH), 3.90 (s, 2H), 2.25 (s, 3H).
Step B N-r3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-l-methylpropyllamine hydrochloride (Diastereomer ) The title compound was prepared following the procedure described for Reference Example 20, Step B-C substituting 5-bromo-3-pyridylacetone with 5-chloro-3- pyridylacetone at Step B. LC-MS: m/e 295 (M + H)+ (1.9 min).
REFERENCE EXAMPLE 23
Figure imgf000051_0002
N-r3-(4-Chlorophenyl)-2-(5-methyl-3-pyridyl)-l-methylpropyllamine hvdrochloride(Diastereomer α) The title compound was prepared following the procedure described for Reference Example 17 substituting 2-(N-tert-butoxycarbonyl)amino-3-(3- bromophenyl)-4-(4-chlorophenyl)butane with 2-(N-tert-butoxycarbonyl)amino-3-(5- bromo-3-pyridyl)-4-(4-chlorophenyl)butane (intermediate of Reference Example 20, Step B) at Step A. LC-MS: m/e 275 (M + H)+ (1.3 min).
REFERENCE EXAMPLE 24
Figure imgf000052_0001
2-Methyl-2-(2-pyrimidyloxy)propionic Acid
The title compound was prepared following the procedures described for Reference Example 13 substituting 5-chloro-2-hydroxpyridine with 2- hydroxpyrimidine at Step A. 1H NMR (500 MHz, CD3OD): δ 8.53 (d, 2H), 7.09 (t,
IH), 1.74 (s, 6H).
REFERENCE EXAMPLE 25
Figure imgf000052_0002
2-Methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionic Acid The title compound was prepared following the procedures described for Reference Example 13 substituting 5-chloro-2-hydroxpyridine with 4- trifluoromethyl-2-hydroxpyridine at Step A. ±H NMR (500 MHz, CD3OD): δ 8.30
(d, IH), 7.18 (d, IH), 7.05 (s, IH), 1.71 (s, 6H). REFERENCE EXAMPLE 26
Figure imgf000053_0001
2-Methyl-2-(6-trifluoromethyl-4-pyrimidyloxy)propionic Acid The title compound was prepared following the procedures described for Reference Example 13 substituting 5-chloro-2-hydroxpyridine with 6- trifluoromethyl-4-hydroxpyrimidine at Step A. 1H NMR (500 MHz, CD3OD): δ 8.81
(s, IH), 7.28 (s, IH), 1.75 (s, 6H). LC-MS: m/e 251 (M + H)+ (2.1 min).
REFERENCE EXAMPLE 27
2-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propionic Acid
Two nitrogen flushed, 12 L 3-necked round bottom flasks, each fitted with a thermometer and a reflux condenser were charged with KHMDS in THF (0.91 M, 3.52 L each, 3.205 mol, 1.5 eq). The solutions were cooled to -70°C and stiπed magnetically. Ethyl-2-hydroxyisobutyrate (98%) (463 mL, 447g, 3.38 mol) was added to each flask over 30 min, keeping the reaction temperature below -62°C. After 10 min 2-chloro-5-trifluormethylpyridine (388 g, 2.14 mol) was added to each flask in one portion. The cooling bath was removed and the reactions were allowed to warm to 20°C overnight (ca 16 hr.).The reactions were monitored by TLC (silica, 90/10 Hex/EtOAc) and HPLC:
Sodium hydroxide (1.36 L, 5N) was added to each reaction flask and the reactions were refluxed overnight (ca 22 hr). The reactions were concentrated together on a rotary evaporator to remove the THF. To the concentrate was added water (4L) and the solution extracted with n-heptane (2 x 4L). The aqueous layer was added over 10 min to 2N HCl (9L, 18 mol) with stirring. The resulting suspension was aged for 30 min (temperature 30°C) then filtered. The cake was washed with water (3 x 2L), and air-dried to a damp tan solid.
The material was dissolved in n-heptane (4 L) at 65°C. IP Ac (1 L) and DARCO KB (40 g, 100 mesh) were added. The mixture was stiπer for 15 min, filtered through CELITE diatomaceous earth, and the cake washed with 4:1 heptane/IP Ac (3 x 500 mL). The filtrate was concentrated to ca. 2 L affording a white suspension. The sluπy was flushed with heptane (2 x 3L) and concentrated to ca. 3L. The resulting white suspension was cooled to 0°C and aged 1 hr. The product was filtered and the cake washed with cold heptane (1 L) to provide the title compound as white crystalline material. HPLC Column: YMC Combiscreen Pro C18, 50 x 4.6mm; Mobile phase: A 0.1%TFA in H2O; B CH3CN. Gradient: 90/10 A/B to
10/90 A/B in 4 min. Flow rate: 4 mL/min. Detection: 254 nm. RT 2-chloro-5- trifluormethylpyridine 2.1 min. RT 2-ethoxy-5-trifluoromethylpyridine 2.9 min. RT Product Ester 3.1 min. RT Final Acid 2.05 min.
REFERENCE EXAMPLE 28
Figure imgf000054_0001
2-Amino-3-indolin-N-yl-4(4-chloro)phenylbutane
Step A. Ethyl 3-(4-chlorophenyl)-2-indolin-N-ylpropanoate. In an oven-dried flask under an atmosphere of nitrogen, l.lg LiOH H2θ (26.25 mmol) in DMF (20 mL) was added to a stirring suspension of 4 angstrom molecular sieves. After 30 minutes of stirring at room temperature 2.8 mL (25mmol) indoline was added dropwise. After one hour at room temperature 2.9 mL (26.25 mmol) ethyl bromoacetate was added dropwise. After 1.5 h the solid material was filtered and the residue was washed with copious amounts of EtOAc. The organics were washed 3 times with water and the organic material was dried over MgSO4. The solvents were evaporated under reduced pressure. The crude material was then dissolved in 75 mL anhydrous THF, charged into an oven dried round bottom flask under an atmosphere of nitrogen, cooled to -78°C, and then treated with 26.25 mL of a IM solution of NaHMDS. The solution was allowed to stir for 30 minutes at -78°C after which the enolate was alkylated with 5.4 g (26.25 mmol) of parachlorobenzyl bromide (solution in 25 mL anhydrous THF). The reaction was allowed to warm to room temperature overnight. The next day the reaction was quenched with water. The aqueous layer was extracted with 3 large portions of EtOAc. The combined organics were dried over MgSO4. The solvents were removed under reduced pressure and the residue was purified by flash chromatography which yielded the title compound as a yellow oil. LC/MS m/e=331 (M+l). TLC Rf=0.22 (20:1 hexanes : EtOAc). Hi NMR (500 MHz , CDCI3): δ 1.11 (t, J=3.55 Hz, 3H), 2.96 (m, 2H), 3.06 (m, IH), 3.25 (m, IH), 3.60 (t, 2H), 4.07 (m, 2H), 4.36 (t, J=3.75 Hz, IH).
Step B. N,O-dimethyl-3-(4-chlorophenyl)-2-indolin-N-ylpropanamide. In an oven-dried flask under an atmosphere of nitrogen, 11.75 mL of a 1-M solution of
(CH3)2A1C1 in CH2CI2 was added via addition funnel to a stirring suspension of 1.15 g (11.75 mmol) N,O-dimethylhydroxylamine hydrochloride at 0°C. After warming to room temperature a solution of 970 mg (2.94 mmol) of ethyl 3-(4-chlorophenyl)-2- indolinylpropanoate (obtained from Step A) in 10 mL was added via addition funnel. After stirring at room temperature for 5 h, 35 mL of a pH 8 phospate buffer solution was added and the resulting mixture was stiπed vigorously for 30 minutes. The phases were separated and the aqueous layer was extracted 2 times with chloroform. The combined organics were washed with water and then dried over MgSO4. A brown oil was collected. The crude material was carried on to the next step. TLC (10:1 hexanes : EtOAc). lH NMR (500 MHz, CDCI3): δ 2.83 (m, IH),
2.97(m, 2H), 3.13 (s, 3H), 3.34 (m, IH), 3.45 (s, 3H), 3.61 (m, 2H), 4.87 (b, IH), 6.54 >(d, IH), 6.66 (t, J=7.1 Hz, IH), 7.07 ( t, J=7.1 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H)
Step C. 4-(4-chlorophenyl)-3-indolin-N-ylbutan-2-one. In an oven dried flask under an atmosphere of nitrogen, 2.8 mL if a 1-M solution of CH3MgBr in THF was added dropwise to a stirring solution of N,O-dimethyl-3-(4- chlorophenyl)-2-indolinylpropanamide (from Step B, 965 mg) in 25 mL anhydrous THF. The solution was stiπed for 4 h while being allowed to warm to room temperature. Then approximately 20 mL water were added. The mixture was extract three times with 50 mL ether. The combined extracts were dried over MgSO4. The solvents were removed under reduced pressure yielding a brown oil which was carried on to the next step without purification. LC/MS m/e=301 (M+l). TLC Rf=0.5 (4:1 hexanes:EtOAc). lH NMR (500 MHz, CDCI3): δ 2.14 (s, 3H), 2.81 (dd, J=14.6, 6.6 Hz, IH), 2.97 (t, J=8.5 Hz, 2H), 3.26 (m, 2H), 3.5 (m, IH), 4.21 (dd, J=6.6, 6.6 Hz), 6.39 (d, J=8 Hz, IH), 6.66 (dd, J=7, 7 Hz, IH), 7.07 (m, 2H), 7.13 (d, J=8.5 Hz), 7.22 (d, J=8.3 Hz).
Step D. 4-(4-chlorophenyl)-3-indolin-N-ylbutan-2-one methoxime.
A solution of 472 mg (1.573 mmol) of the product of Step C and 263 mg (3.147 mmol) of methoxylamine hydrochloride in anhydrous ethanol was treated with 255 μL (3.147 mmol) of pyridine. The solution was stiπed for 2 h at room temperature. Solvent was removed under reduced pressure and the residue was partitioned between water and ether. The water was extracted with ether again. The extracts were then combined and dried over MgSO4, filtered and concentrate to obtain crude material. Both the E and Z isomers were carried onto the next step. LC/MS m/e=330 (M+l). TLC Rf=.77 and .65 (4:1 hexanes:EtOAc). lH NMR (500 MHz, CDCI3): δ 1.78 (2s,
IH), 2.88 (dd, J=6.2, 13.8 Hz, IH), 2.95 (m, 2H), 3.30 (m, 2H), 3.45 (m, IH), 3.75 and 3.89 (2s, 3H), 4.21 (dd, J=6.9, 7.8 Hz, IH), 6.28 and 6.47 (2d, J=8.1, IH), 6.61 (m, IH), 7.02 (m, 2H), 7.22 (m, 4H). Step E. 2-Amino-3-indolin-N-yl-4(4-chloro)phenylbutane
In an oven-dried flask equipped with a water condenser under an atmosphere of nitrogen, a solution of 301 mg (0.914 mmol) 4-(4-chlorophenyl)-3-indolinylbutan-2- one methoxime (obtained from Step D) in 1.5 mL anhydrous THF was treated with 3.7 mL (3.7 mmol) of IM BH3-THF at room temperature. The solution was then heated to 75°C for 2 days. The solution was then cooled to 0°C and treated with chips of ice until bubbling subsided. 500 μL of 20% KOH were then added and the solution was heated at 45°C for 2h. The solution was then cooled to room temperature and extracted with ether 3x. The combined extracts were dried over MgSO4, filtered, and concentrated to afford crude amine which was used in the next experiment without further purification. LC/MS m/e=302 (M+l). lH NMR (500 MHz, CDCI3): δ 1.13,
1.14 (2d, J=6.5 Hz, IH), 1.55-1.60 (m, 2H), 2.80-3.10 (m, 4H), 3.30-3.60 (m, 2H), 6.348 and 6.38 (2d, J=7.9 Hz, IH), 6.50-6.78 (m, 2H), 6.95-7.24 (m, 5H)
REFERENCE EXAMPLE 29
Figure imgf000057_0001
2-Amino-3-indol-N-yl-4(4-chloro)phenylbutane
This compound was prepared in an analogous manner to Reference Example 28 except that during Step A, sodium hydride was used as the base instead of the lithium hydroxide monohydrate/molecular sieves combination. LC/MS: calculated for C 8Hi9CL 2299, observed m/e 300 (M + H)+ (2.4 min).
REFERENCE EXAMPLE 30
Figure imgf000057_0002
2-Amino-3-(N-methyl, N-phenyl)amino-4(4-chloro)phenylbutane This compound was prepared in an analogous manner to Reference Example 28. LC/MS: calculated for C17H21CIN2289, observed m/e 290 (M + H)+ (2.4 min).
REFERENCE EXAMPLE 31
Figure imgf000057_0003
2-Amino-3-(7-azaindol-N-yl)-4(4-chloro)phenylbutane
This compound was prepared in an analogous manner to Reference Example 28.
LC/MS: calculated for C17H18CIN3 300, observed m/e 301 (M + H)+ (2.7 min).
REFERENCE EXAMPLE 32
Figure imgf000058_0001
4-(4-Methylphenyl)-3-phenylbutan-2-amine (mixture of 4 isomers) Step A 1-Phenylacetone
To a solution of N-methyl-N-methoxyacetamide (9.9mL. 97 mmol) in ether (300 mL) at 0°C was added benzylmagnesium chloride (97 mL a IM solution in ether). The cloudy, white reaction mixture was warmed to room temperature for 2 h and then quenched by careful addition of IN hydrochloric acid (100 mL). The organic phase was separated, washed with brine, dried over MgSO4 and concentrated. The crude material was purified by column chromatography on silica gel eluting from 0-10% EtOAc/hexane to give the title compound. !H NMR (500 MHz, CDCI3): δ 7.36 (t, J
= 7.1Hz, 2H), 7.30 (t, J = 7.3Hz, IH), 7.24 (d, J = 7.3Hz, 2H), 3.72 (s, 2H), 2.18 (s, 3H). LC-MS: m/e 135 (M + H)+ (1.95 min). Step B 4-(4-Methylphenyl)-3-phenylbutan-2-one
1-Phenylacetone (200 mg, 1.49 mmol) was mixed with powdered potassium hydroxide (167 mg, 2.98 mmol) and tetfa-n-butylammonium bromide (lmol %, 5 mg) in a flask without solvent. This mixture was stiπed at room temperature for 90 min. before the addition of l-(chloromethyl)-4-methylbenzene (198 μl, 1.49 mmol). The reaction mixture was then stiπed overnight before diluting with water and CH2CI2.
The aqueous layer was separated and neutralized to pH 7 with 2N hydrochloric acid and extracted again into CH2CI2. The combined organic washes were dried with MgSO4 and concentrated. The crude material was purified by column chromatography on silica gel eluting from 0-10% EtOAc/hexane to give the title compound. 1H NMR (500 MHz, CDCI3): δ 7.35 (t, J - 7.0 Hz, 2H), 7.29 (t, J = 7.4 Hz, IH), 7.23 (d, J = 7.1 Hz, 2H), 7.05 (d, 7.8 Hz, 2H), 6.98 (d, J = 7.8 Hz, 2H), 3.94 (t, J = 7.3 Hz, IH), 3.43 (dd, J = 13.9, 7.5 Hz, IH), 2.91 (dd, J = 14, 7.1 Hz, IH), 2.32 (s, 3H), 2.08 (s, 3H). LC-MS: m/e 239 (M + H)+ (3.61 min). Step C 4-(4-Methylphenyl)-3-phenylbutan-2-amine To a solution of the 4-(4-methylphenyl)-3-phenylbutan-2-one (308 mg, 1.29 mmol) in 7M ammonia in MeOH (5 mL) and acetic acid (3 mL) was added sodium cyanoborohydride (130 mg, 2.06 mmol) and the reaction stiπed at room temperature overnight. The reaction was quenched by pouring into 2M sodium carbonate solution and extracted into EtOAc. The aqueous layer was salted and re-extracted. The combined organic extracts were dried over MgSO4 and concentrated to give the title compound as a mixture of 4 isomers which was used without further purification. LCMS: m/e 240 (M + H)+ (2.22 min).
REFERENCE EXAMPLE 33
Figure imgf000059_0001
3-r2-Amino-l-(4-fluorobenzyl)propyllbenzonitrile
Prepared using the procedures described in Example 5, Steps B and C using 3- (2-oxopropyl)benzonitrile and l-(chloromethyl)-4-fluorobenzene as the reactants in Step B. LC-MS: m/e 269 (M + H)+ (2.87 min).
REFERENCE EXAMPLE 34
Figure imgf000059_0002
2-(lH-L2,3-Benzotriazol-l-yl)-3-(4-chlorophenyl)-l-methylpropylamine Step A 2-(lH-l,2,3-Benzotriazol-l-yl)-N-methoxy-N-methylacetamide
A mixture of 1.77 g (10 mmol) of 2-(lH-l,2,3-benzotriazol-l-yl)acetic acid, 1.07 g (11 mmoles) of N,O-dimethylhydroxylamine hydrochloride, 5.8 g (11 mmol) of PyBOP, and 3.4 mL (24.2 mmol) of diisopropylethylamine in 50 mL CH2CI2 was stiπed overnight at RT. This mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous MgSO4. Solvent removal afforded a crude product which was purified on silica gel using 60% EtOAC in hexane as solvent to give 2.01 g the desired amide as a solid. lH NMR: (CDCI3): δ 3.26 (s, 3H), 3.84 (s, 3H), 5.63 (s, 2H), 7.35-8.2 (m, 4H).
Step B 2-(lH-l,2,3-Benzotriazol-l-yl)-3-(4-chlorophenyl)-N-methoxy-N- methyl-propanamide. To a solution of 2.0 g (9 mmol) of 2-(lH-.l,2,3-benzotriazol-l-yl)-N-methoxy-N- methylacetamide in 15 mL anhydrous THF at -78 °C, 10 mL (10 mmol) of IM lithium bis(trimethylsilyl)amide was added dropwise. After stirring for 25 min, a solution of 2.06 g (10 mmol) of 4-chlorobenzyl bromide in 2 mL anhydrous THF was added. The resulting reaction mixture was allowed to warm to RT and stiπed for 6 h. This reaction was quenched, diluted with 75 mL EtOAc and washed 3 times with 10 mL each of brine, After drying the organic phase solvent removal afforded a crude product which was purified on silica gel using 40% EtOAc in hexane as solvent to afford the desired product as a solid. lH NMR: (CDCI3): δ 3.2 (s, 3H), 3.34 (s, 3H),
3.52 (m, IH), 3.7 (m, IH), 6.32 (t, IH), 6.9-8.2 (m, 8H).
Step C 2-(lH-l,2,3-Benzotriazol-l-yl)-3-(4-chlorophenyl)-butan-2-one. To a solution of 1.73 g (5 mmol) of 2-(lH-l,2,3-benzotriazol-l-yl)-3-(4- chlorophenyl)-N-methoxy-N-methyl-propanamide in 10 mL anhydrous THF at 0 °C, 4 mL (10 mmol) of 2.5M methyl magnesium bromide in ether was added. The reaction mixture was stiπed for 4 h as it warmed to RT. The reaction was quenched by adding 10 mL IN HCl and the resulting mixture was partitioned between EtOAc and water. The organic phase was washed with brine and dried over anhydrous
MgSO4. Solvent removal gave a crude ketone, which was purified on silica gel using
40% EtOAc in hexane to provide the desired ketone. Step D 2-(lH-l,2,3-Benzotriazol-l-yl)-3-(4-chlorophenyl)-l-methyl propylamine To a solution of 1.18 g (4 mmol) of 2-(lH-l,2,3-benzotriazol-l-yl)-3-(4- chlorophenyl)-butan-2-one in 8.5 mL (60 mmol) of 7N ammonia in MeOH at 0 °C, 4 mL (964 mmol) of glacial acetic acid was added followed by 410 mg (6.5 mmol) of sodium cyanoborohydride. The reaction mixture was allowed to warm to RT and stirred overnight. The reaction was partitioned between EtOAc and saturated NaHCO3 solution. The organic phase was dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified on silica gel using a mixture of 5% 2N methanolic ammonia solution and 95% CH2CI2 to give the desired amine as a mixture of diastereomers. LC-MS, RT = 2.0 min, m/e = 301.
REFERENCE EXAMPLE 35
Figure imgf000061_0001
3-(4-Chlorophenyl)-2-(thiophene-3-yl)- 1 -meth ylpropylamine The title amine was prepared by the method described in Reference
Example 34, substituting thiophene-3-acetic acid for 2-(lH-l,2,3-benzotriazol-l- yl)acetic acid in Step A. LC-MS, RT = 2.19 min, m/e = 266.
REFERENCE EXAMPLE 36
Figure imgf000061_0002
2-(3-Cyanophenyl)-3-cyclobutyl-l-methylpropylamine Step A 1 -(3-Cyanophenyl)acetone
The title compound was prepared from 3-bromobenzonitrile and isopropenyl acetate by the procedure of Reference Example 20, Step A.
Step B 3-(3-Cyanophenyl)-4-cvclobutyl-butan-2-one To a solution of 1.45 g (9.07 mmol) of l-(3-cyanophenyl)acetone in 18 mL acetonitrile, 1.1 mL (9.5 mmol) cyclobutyl bromide and 5.91 g (18.1 mmol) cesium carbonate were added. After heating the solution in a 60 °C bath overnight, it was cooled and filtered. The filtrate was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The residue was purified on a flash column using a gradient of 5-10% EtOAc/hexane to isolate the title compound. lH NMR: (500 MHz, CDCI3): δ 1.5-2.2 (m, 9H), 2.13 (s, 3H), 3.64 (m, IH), 7.4-7.7 (m, 4H).
Step C 2-(3-Cyanophenyl)-3-cvclobutyl-l-methylpropylamine This amine was prepared by following the method of Reference Example 3, Steps E-I. LC-MS, RT = 2.48 min, m/e = 229.
The compounds of Reference Examples 37 and 38 were obtained by procedures described in Reference Example 36.
REFERENCE EXAMPLE 37
Figure imgf000062_0001
2-(3 -Cy anophenyl)-3 -cyclopentyl- 1 -meth ylprop ylamine LC-MS, RT = 2.7 min, m/e = 243.
REFERENCE EXAMPLE 38
Figure imgf000062_0002
2-(3-Cyanophenyl)-3-cyclohexyl-l-methylpropylamine LC-MS, RT = 2.8 min, m/e = 257. EXAMPLE 1 Automated Synthesis of a One Dimensional Amide Library
The following synthesis of a 1 -dimensional, single, pure compound library was perfoimed on a MYRIAD CORE System. All reaction vessels were dried under a stream of nitrogen at 120°C for 12 h prior to use. All solvents were dried over sieves for at least 12 h prior to use. An appropriate stock solution of N-[2,3- bis(4-chlorophenyl)-l-methylpropyl]-amine hydrochloride (alpha isomer) was prepared immediately prior to use in pyridine with 0.05 equivalents (relative to N- [2,3-bis(4-chlorophenyl)-l-methylpropyl]-amine hydrochloride (alpha isomer)) of dimethylaminopyridine added; the diverse carboxylic acids available from commercial sources were dissolved immediately prior to use in DMSO. The relative amounts of reactants and coupling reagents are listed in Table 1. Table 1.
Figure imgf000063_0001
Procedure: To vessel one of a total of 192 dry, 10 mL fritted MYRIAD reaction vessels under nitrogen was added the appropriate diverse acid subunit (1.0 mL, 0.2 mmoles, 0.2 M in DMSO); this was repeated for the remaining 191 reactions until the diversity acids had been enumerated to all 192 reaction vessels. To each of 192 reaction vessels under nitrogen was then added the EDC/HOBt cocktail (0.8 mL, 0.2 mmoles, 0.25 M each in deuterated chloroform). Finally, to each of the 192 reaction vessels was added N-[2,3-bis(4-chlorophenyl)-l-methylpropyl]-amine hydrochloride (alpha isomer) (0.6 mL, 0.12 mmoles, 0.2M in pyridine). The reactions were then aged for 4 h at room temperature (20-25° C) followed by 16 h at 65°C with nitrogen sparging agitation (Is pulse of nitrogen every 30 minutes). The crude reactions were analyzed by HPLC-MS Method 1.
Analytical LC Method 1 Column: MetaChem Polaris C-18A, 30 mm X 4.6 mm, 5.0 μm Eluent A 0.1% TFA in Water Eluent B 0.1 % TFA in Acetonitrile Gradient 5% B to 95 % B in 3.3 minutes, ramp back to 5% B in
0.3 min
Flow: 2.5 mL/min.
Column Temp.: 50° C Injection amount: 5 uL of undiluted crude reaction mixture. Detection: UN at 220 and 254 nm. MS: API-ES ionization mode, mass scan range (100-700) ELSD: Light Scattering Detector
Crude reactions were purified by preparative HPLC using UN based detection (Preparative method 2). The collected fractions were then analyzed for purity by LCMS (Analytical method 3); fractions found to be greater than 90% purity were pooled into tared 40 mL EPA vials and lyophilized. Preparative LC Method 2:
Column: MetaChem Polaris C-18A, 100 mm X 21.2 mm, 10 μm Eluent A: 0.1% TFA in Water
Eluent B : 0.1% TFA in Acetonitrile
Pre-inject Equilibration: 1.0 min Post-Inject Hold: 0.0 min
Gradient: 10% B to 100 % B in 6.0 minutes, hold at 100% B for an additional 2.0 minutes, ramp back from 100% B to 10% B in 1.5 minutes.
Flow: 25 mL/min. Column Temp.: ambient Injection amount: 1.5 mL undiluted crude reaction mixture. Detection: UN at 220 and 254 nm.
Analytical LC Method 3:
Column: MetaChem Polaris C-18A, 30 mm X 2.0 mm, 3.0 μm
Eluent A: 0.1% TFA in Water
Eluent B : 0.1% TFA in Acetonitrile
Gradient: 5% B to 95 % B in 2.0 minutes, ramp back to 5% B in 0.1 min Flow: 1.75 mL/min.
Column Temp.: 60°C Injection amount: 5 uL of undiluted fraction. Detection: UN at 220 and 254 nm.
MS: API-ES ionization mode, mass scan range (100-700)
ELSD: Light Scattering Detector
Lyophilization Parameters
Initial Freeze Setpoint: 1 h at -70°C Drying Phase Condenser Setpoint: -50°C Dryin Phase Table:
Figure imgf000065_0002
EXAMPLES 2 and 3
Figure imgf000065_0001
N-r2,3-Bis(4-Chlorophenyl)-l-methylpropyn-2-(4-chlorophenyloxy)-2- methylpropanamide (Diastereomers and β).
To a solution of 2-(4-chlorophenyloxy)-2-methylpropionic acid (Aldrich, 0.22 g, 1.0 mmol) in CH2CI2 (2 mL) at 0°C was added a drop of DMF and oxalyl chloride (0.27 mL, 3.0 mmol). After stirring at room temperature for 1 h, the reaction mixture was concentrated on a rotary evaporator and dried under vacuum, and the resulting crude acyl chloride was used without further purification. Thus, the crude acyl chloride was dissolved in 1 mL CH2CI2 and was added to a suspension of 2-amino-
3,4-bis(4-chlorophenyl)butane hydrochloride salt (Reference Example 1) (diastereomer contaminated with some diastereomer β, 0.20 g, 0.60 mmol) and N- methylmorpholine (0.27 mL, 2.4 mmol) in 4 mL CH2CI2. After stirring at room temperature for 6 h, the reaction mixture was loaded onto a silica gel column, which was eluted with 10% EtOAc to give a pure faster eluting isomer (diastereomer α) and a slower eluting isomer (diastereomer β). Diastereomer α: !H ΝMR (500 MHz, CD3OD): δ 7.24 (d, 2H), 7.20 (d, 2H), 7.05 (d,
2H), 7.01 (d, 2H), 6.94 (d, 2H), 6.76 (d, 2H), 4.25 (m, IH), 3.03 (dd, IH), 2.88 (ddd, IH), 2.67 (dd, IH), 1.59 (s, 3H), 1.53 (s, 3H), 0.88 (d, 3H). LC-MS: m/e 490(M + H)+ (4.7 min). Diastereomer β: lH ΝMR (500 MHz, CD3OD): δ 7.16 (d, 2H), 7.14 (d, 2H), 7.09 (d, 2H), 6.99 (d, 2H), 6.88 (d, 2H), 6.64 (d, 2H), 4.33 (m, IH), 3.12 (dd, IH), 3.03 (ddd, IH), 2.74 (dd, IH), 1.36 (s, 3H), 1.30 (d, 3H), 1.30 (s, 3H). LC-MS: m/e 490(M + H)+ (4.7 min).
Examples 4-7 (Table 2) were prepared following the procedures described in Examples 2 and 3 substituting 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt with the appropriate amines from the Reference Examples and 2- (4-chlorophenyloxy)-2-methylpropionic acid with the appropriate acids from the Reference Examples. In some cases, commercial acids or acyl chlorides were employed, and N-diisopropyl-ethylamine may be used in place of N- methylmorpholine with similar results. The diastereomer designations (α or β) coπespond to designations of the starting amines.
Table 2. Compounds prepared according to the methods described in Examples 2-3.
Figure imgf000067_0001
EXAMPLES 8 and 9
Figure imgf000068_0001
N-r2,3-Bis(4-Chlorophenyl)-l-methylpropyn-2-(4-chlorophenyloxy)-2- methylpropanamide (Diastereomer , Enantiomers A and B).
Preparative HPLC was performed on a Gilson HPLC system for the separation of enantiomers. Thus, a solution of N-[2,3-bis(4-chlorophenyl)-l- methylpropyl] -2-(4-chlorophenyloxy)-2-methylpropanamide (Diastereomer α)
(Example 60, 1.0 g) in hexane (3 mL)/ethanol (7 mL) was loaded onto a Chiralpak AD column (2 cm x 25 cm), which was eluted with 5% ethanol in hexane (flow rate 9 mL/min, 500 μL per injection) to give the two pure enantiomers.
Faster eluting enantiomer (Enantiomer A): Analytical HPLC: retention time = 7.8 min (Chiralpak AD column, flow rate = 0.75 mL/min, 5% ethanol/hexane). LC-MS: m/e 490 (M + H)+ (4.7 min). Slower eluting enantiomer (Enantiomer B): Analytical HPLC: retention time = 9.6 min (Chiralpak AD column, flow rate = 0.75 mL/min, 5% ethanol/hexane). LC-MS: m/e 490 (M + H)+ (4.7 min).
Examples 10-17 (Table 3) were isolated as single enantiomers following the procedures described in Examples 8-9 from the coπesponding racemic material (Table 2) with appropriate modifications of (1) the eluent composition (4-
15% ethanol/hexane), (2) flow rate (6-9 mL/min) and (3) injection volume (200 to
2000 μL).
Table 3. Enantiomeric compounds isolated according to the methods described in Examples 8-9.
Figure imgf000069_0001
Figure imgf000070_0001
Example 18 (Table 4) was prepared following the procedures described in Examples 2-3 employing N-[3-(4-chlorophenyl)-2(S)-phenyl-l(S)- methylpropyl] -amine, hydrochloride from Reference Example 4 coupled to the appropriate carboxylic acid. Table 4. Single enantiomeric compounds prepared with N-[3-(4-chloroρhenyl)-2(S)- phenyl-l(S)-methylpropyl]-amine, hydrochloride from Reference Example 4.
Figure imgf000071_0002
EXAMPLE 19
Figure imgf000071_0001
N-r2,3-Bis(4-chlorophenyl)-l-methylpropyl1-2-(4-chlorophenylamino)-2- methylpropanamide. To a mixture of 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt (Diastereomer α, Section I, Reference Example 1, 0.31 g, 0.94 mmol) and 2-(4- chlorophenylamino)-2-methylpropionic acid (0.20 g, 0.94 mmol) in 5 mL CH2CI2 was added N-methylmorpholine (0.41 mL, 3.5 mmol) and tris(pyrrolindinyl)phosphonium hexafluorophosphate (0.73 g, 1.4 mmol). After stirring at room temperature overnight, the reaction mixture was loaded onto a silica gel column eluted with 30% EtOAc in hexane to give the title compound. H ΝMR (400 MHz, CD3OD): δ 7.18 (d, 2H), 7.04 (d, 2H), 7.02 (d, 2H), 6.97 (d, 2H), 6.70 (d,
2H), 6.56 (d, 2H), 4.20 (m, IH), 3.02 (dd, IH), 2.78 (ddd, IH), 2.64 (dd, IH), 1.52 (s, 3H), 1.45 (s, 3H), 0.82 (d, 3H). LC-MS: m/e 489 (M + H)+ (4.3 min). EXAMPLE 20
Figure imgf000072_0001
N-(2,3-Diphenyl-l-methylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide (Diastereomer β)
A solution of 2-(4-chlorophenoxy)-2-methylpropionic acid (20 mg, 0.095 mmol) in CH2CI2 (1 mL) and DMF (10 μL) was treated with oxalyl chloride
(11 μL). After 30 min the reaction was concentrated and the residue was dissolved in 1 mL CH2CI2. This solution was added to a mixture of 16 mg N-(2,3-diphenyl-l- methylpropylamine (β isomer from Reference Example 2) and 1 mL saturated NaHCO3. The reaction was stiπed overnight and the organic layer was removed with a pipet. Purification of this solution by preparative TLC eluted with 30% EtOAc/hexane afforded the title compound. lH NMR: (500 MHz, CDCI3): δ 1.17
(d, 3H), 1.36 (s, 3H), 1.46 (s, 3H), 2.85-3.05 (m, 3H), 4.44(m, IH), 6.37 (d, IH), 6.75- 7.4 (m, 14H). LC-MS: R = 4.4 min. m/e = 422.2 (M+l).
The following compounds in Table 5 were prepared following the procedures of Example 20 substituting an appropriate amine for N-(2,3-diphenyl-l- methylpropylamine and appropriate carboxylic acid for 2-(4-chlorophenoxy)-2- methyl-propionic acid.
Figure imgf000072_0002
Figure imgf000073_0001
The following compounds in Table 6 were prepared following the procedures of Examples 2-3 substituting an appropriate amine for N-(2,3-diphenyl-l- methylpropylamine and appropriate carboxylic acid for 2-(4-chlorophenoxy)-2- methyl-propionic acid.
Figure imgf000073_0002
The following compounds in Table 7 were isolated according to the procedures for separating enantiomers described in Examples 8-9.
Table 7. Enantiomeric compounds isolated according to the methods described in Examples 8-9.
Figure imgf000073_0003
Figure imgf000074_0002
The following compounds in Table 8 were prepared with N-[3-(4- chlorophenyl)-2(S)-phenyl-l(S)-methylpropyl]-amine, hydrochloride from Reference Example 4 and the appropriate acid to afford a single enantiomer.
Table 8. Single enantiomeric compounds prepared with N-[3-(4-chlorophenyl)-2(S)
Figure imgf000074_0001
Examples 30-33 (Table 9) were prepared from N-[3-(4-chlorophenyl)- 2(S)-phenyl-l(S)-methylpropyl]amine, hydrochloride (Reference Example 4) or N-[3- (5-chloro-2-pyridyl)-2(S)-phenyl-l(S)-methylpropyl]amine, hydrochloride (Reference Example 18) and the appropriate carboxylic acid following the procedures described in Examples 2-3 (via an acyl chloride intermediate) or Example 19 (with a coupling reagent),
Figure imgf000075_0001
Figure imgf000076_0001
Examples 34-39 (Table 10) were prepared from the appropriate amine and acid of Reference Examples following the procedures described in Examples 2-3 (via an acyl chloride intermediate) or Example 19 (with a coupling reagent).
Table 10.
Figure imgf000076_0002
Figure imgf000077_0001
Figure imgf000078_0001
Examples 41-52 (Table 11) were isolated as single enantiomers from the coπesponding racemic material (Table 10) following the procedures described in Examples 8-9 with appropriate modifications of (1) the eluent composition (4-15% ethanol/hexane), (2) flow rate (6-9 mL/min) and (3) injection volume (200 to 2000 μL).
Table 11. Enantiomeric compounds isolated according to the methods described in Examples 8-9.
Figure imgf000078_0002
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Examples 53-56 (Table 12) were isolated as diastereomers as indicated (Isomer A or B) on silica gel chromatography columns. The single enantiomers noted were separated on the chiral AD column noted above.
Table 12.
Figure imgf000082_0001
EXAMPLE 57
Figure imgf000083_0001
2-Methyl-N-n-methyl-3-(4-methylρhenyl)-2-phenylproρvn-2-i r5- (trifluoromethyl)pyridin-2-yπoxy}propanamide
To a solution of 2-methyl-2-{[5-(trifluoromethyl)pyridin-2- yl]oxy}propanoic acid (Reference example 14, 250 mg, 1.04 mmol) and 4-(4- methylphenyl)-3-phenylbutan-2-amine (Reference example 102, 260 mg, 1.04 mmol, mixture of 4 isomers) in CH2CI2 (5.5 mL) at RT was added diisopropylethylamine
(272 μl, 1.56 mmol) followed by PyBOP (649 mg, 1.25 mmol) and the reaction mixture stiπed overnight. The reaction was purified by loading the reaction mixture directly onto a silica gel column and eluting from 0-30% EtOAc/hexane to give the title compound as a mixture of 4 isomers. The diastereomers were separated by HPLC on a ZORBAX RxSi column eluting 97% hexane: 3% ethanol at 20 mL/min with retention times of :
-less polar diastereomer eluted at 4.73 minutes; more polar diasteromer eluted at 5.87 minutes. The more polar diastereomer was additionally separated into enantiomers on a ChiralPak AD column eluting with 95% hexane : 5% ethanol at 8 mL/min with retention times of: less polar enantiomer eluted at 6.84 minutes;more polar diastereomer eluted at 8.36 minutes.
Less polar diastereomer: !H ΝMR (500 MHz, CDCI3): δ 8.44 (s, IH), 7.86 (dd, J =
8.6, 2.5 Hz, IH), 7.19 (t, J = 3.2 Hz, 3H), 7.00 (dd, J = 21.3, 8.0 Hz, 4H), 6.91 (m, 2H), 6.83 (d, J = 8.7 Hz, IH), 5.70 (d, J = 9.4 Hz, IH), 4.43 (m, IH), 3.02 (dd, J = 13.3, 6.7 Hz, IH), 2.84 (dt, J = 7.3, 4.3 Hz, IH), 2.84 (dd, J = 13.2, 7.7 Hz, IH), 2.29 (s, 3H), 1.69 (s, 3H), 1.66 (s, 3H), 1.03 (d, J = 6.8 Hz, 3H). LC-MS: m/e 471 (M + H)+ (4.22 min) More polar diastereomer: lH ΝMR (500 MHz, CDCI3): δ 8.40 (s, IH), 7.83 (dd, J = 8.7, 2.6 Hz, IH), 7.21 (m, 3H), 7.00 (dd, J = 30.4, 6.2 Hz, 4H), 6.82 (t, J = 9.2 Hz, 3H), 5.84 (d, J = 9.2 Hz, IH), 4.36 (ddt, J = 9.1, 6.7, 6.6 Hz, IH), 3.06 (dd, J = 12.8, 4.1 Hz, IH), 2.88 (m, IH), 2.26 (s, 3H), 1.78 (s, 3H), 1.73 (s, 3H), 0.92 (d, J = 6.6 Hz, 3H). LC-MS: m/e 471 (M + H)+ (4.17 min).
EXAMPLE 58
Figure imgf000084_0001
N-r2-(3-Cyanophenyl)-3-(4-fluorophenyl)-l-methylpropyn-2-methyl-2-{ r5- (trifluoromethyl)pyridin-2-vπoxy)propan amide
Prepared as in Example 57 only using 3-[2-amino-l-(4- fluorobenzyl)propyl]benzonitrile (Reference example 33) as the amine component to give the title compound as a mixture of 4 isomers. The diastereomers were separated by HPLC on a Zorbax RxSi column eluting 96% hexane: 4% ethanol at 20 mL/min with retention times of: less polar diastereomer eluted at 11.75 minutes;
-more polar diasteromer eluted at 15.17 minutes. The more polar diastereomer was additionally separated into enantiomers on a ChiralPak AD column eluting with 92% hexane : 8% ethanol at 8 mL/min with retention times of: less polar enantiomer eluted at 9.65 minutes; more polar diastereomer eluted at 11.78 minutes. Less polar diastereomer: ^ ΝMR (500 MHz, CD3OD): δ 8.29 (s, IH), 7.93 (dd, J =
8.7, 2.5 Hz, IH), 7.50 (m, IH), 7.42 (m, IH), 7.27 (m, 2H), 6.96-6.78 (m, 5H 5.70 (d, J = 9.6 Hz, IH), 4.33 (m, IH), 3.18-3.04 (m, 2H), 2.7 (dd, J = 13.5, 6.6 Hz, IH), 1.52 (s, 3H), 1.35 (s, 3H), 1.17 (d, J = 6.6 Hz, 3H). LC-MS: m/e 500 (M + H)+ (4.33 min) More polar diastereomer: *H ΝMR (500 MHz, CD3OD): δ 8.28 (s, IH), 7.95 (dd, J = 8.7, 2.5 Hz, IH), 7.50 (d, J = 7.5 Hz, IH), 7.36 (m, 3H), 7.05 (d, J = 8.9 Hz, 3H), 6.78 (m, 2H), 6.72 (m, 2H) 4.26 (dq, J = 10, 6.6 Hz, IH), 3.04 (dd, J = 13.7, 3.4 Hz, IH), 2.85 (ddt J = 11.2, 3.7 Hz, IH), 2.63 (dd, J = 13.7, 11.4 Hz, IH), 1.77 (s, 3H), 1.74 (s, 3H), 0.81 (d, J = 6.8 Hz, 3H). LC-MS: m/e 500 (M + H)+ (4.25 min). The compound of Table 13 was prepared from the appropriate amine and acid of the Reference Examples following the procedures described in Examples 2-3 (via an acyl chloride intermediate) or Examples 19 (with a coupling reagent.) Table 13.
Figure imgf000085_0001
The compounds in Table 14 were isolated according to the procedure for separating enantiomers described in Examples 8-9.
Table 14. Enantiomeric compounds isolated according to the methods described in
Figure imgf000085_0002
Figure imgf000086_0001
EXAMPLE 64
Figure imgf000087_0001
Pyridine N-Oxide of N-r3-(4-Chlorophenyl)-2-(5-cyano-3-pyridyl)-l-methylpropyl1- 2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpiOpanamide (Enantiomer B) A mixture of N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-l-methylpropyl]-2-(5- trifluoiOmethyl-2-pyridyloxy)-2-methylpropanamide (Enantiomer B, Example 50, 0.10 g, 0.19 mmol) and m-chloroperbenzoic acid (77%, 0.15 g, 0.67 mmol) in 2 mL of methylene chloride was stiπed at room temperature for 14 h. The reaction mixture was concentrated and the residue was purified by HPLC eluting on a reverse phase C18 column with 30 to 100% acetonitrile in water (contains 0.1% trifluoroacetic acid) to give the title compound. !H ΝMR (500 MHz, CD3OD): δ 8.58 (s, IH), 8.32 (br s,
IH), 8.17 (s, IH), 7.99 (br d, IH), 7.97 (dd, IH), 7.81 (s, IH), 7.16 (d, 2H), 7.06 (d, IH), 6.87 (d, 2H), 4.28 (m, IH), 3.11 (dd, IH), 3.01 (m, IH), 2.71 (dd, IH), 1.75 (s, 3H), 1.74 (s, 3H), 0.94 (d, 3H). LC-MS: m/e 533 (M + H)+ (4.1 min).
EXAMPLE 65 Cannabinoid Receptor-1 (CBl) Binding Assay.
Binding affinity determination is based on recombinant human CBl receptor expressed in Chinese Hamster Ovary (CHO) cells (Felder et al, Mol.
Pharmacol. 48: 443-450, 1995). Total assay volume is 250 μl (240 μl CBl receptor membrane solution plus 5 μl test compound solution plus 5 μl [3H]CP-55940 solution). Final concentration of [3H]CP-55940 is 0.6 nM. Binding buffer contains 50mM Tris-HCl, pH7.4, 2.5 mM EDTA, 5mM MgCl2, 0.5mg/mL fatty acid free bovine serum albumin and protease inhibitors (Cat#P8340, from Sigma). To initiate the binding reaction, 5 μl of radioligand solution is added, the mixture is incubated with gentle shaking on a shaker for 1.5 h at 30°C. The binding is terminated by using 96-well harvester and filtering through GF/C filter presoaked in 0.05% polyethylenimine. The bound radiolabel is quantitated using scintillation counter. Apparent binding affinities for various compounds are calculated from IC50 values (DeBlasi et al., Trends Pharmacol Sci 10: 227-229, 1989).
The binding assay for CB2 receptor is done similarly with recombinant human CB2 receptor expressed in CHO cells.
EXAMPLE 66 Cannabinoid Receptor- 1 (CBl) Functional Activity Assay.
The functional activation of CBl receptor is based on recombinant human CBl receptor expressed in CHO cells (Felder et al, Mol. Pharmacol. 48: 443- 450, 1995). To determine the agonist activity or inverse agonist activity of any test compound, 50 ul of CB1-CHO cell suspension are mixed with test compound and 70 ul assay buffer containing 0.34 mM 3-isobutyl-l-methylxanthine and 5.1 uM of forskolin in 96-well plates. The assay buffer is comprised of Earle's Balanced Salt Solution supplemented with 5 mM MgCl2, 1 mM glutamine, 10 mM HEPES, and 1 mg/mL bovine serum albumin. The mixture is incubated at room temperature for 30 minutes, and terminated by adding 30uL/well of 0.5M HCl. The total intracellular cAMP level is quantitated using the New England Nuclear Flashplate and cAMP radioimmunoassay kit.
To determine the antagonist activity of test compound, the reaction mixture also contains 0.5 nM of the agonist CP55940, and the reversal of the
CP55940 effect is quantitated. Alternatively, a series of dose response curves for CP55940 is perfoimed with increasing concentration of the test compound in each of the dose response curves.
The functional assay for the CB2 receptor is done similarly with recombinant human CB2 receptor expressed in CHO cells.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:
1. A compound of structural formula I:
Figure imgf000089_0001
(I) or a pharmaceutically acceptable salt thereof, wherein: Rl is selected from:
(1) cycloheteroalkyl,
(2) aryl, (3) heteroaryl, and
(4) -NRaRC; wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from Rb; R2 is selected from: (1) Cι_i0alkyl,
(2) C3_iocycloalkyl-Ci-4alkyl,
(3) aryl-Ci-4alkyl,
(4) heteroaryl-Cι_4alkyl, wherein each cycloalkyl, aryl and heteroaryl is optionally substituted with one to three substituents independently selected from Rb; each Ra is independently selected from:
(1) hydrogen,
(2) methyl, and
(3) -CF3; each RD is independently selected from:
(1) halogen,
(2) cyano,
(3) trifluoromethyl,
(4) trifluoromethoxy, (5) Cl-3alkyloxy, and
(6) Ci-3alkyl; Rc is independently selected from:
(1) hydrogen,
(2) Cι_6alkyl,
(3) aryl, (4) heteroaryl,
(5) aryl-methyl, and
(6) heteroaryl-methyl, each Rc may be unsubstituted or substituted with one to three substituents selected from Rh; Rd is independently selected from:
(1) cycloalkyl,
(2) aryl,
(3) heteroaryl, each Rd may be unsubstituted or substituted with one to three substituents selected from Rh; each Rh is independently selected from:
(1) halogen,
(2) Cι_3alkyl,
(3) -CN, and (4) -CF3; wherein when pyridyl groups are unsubstituted on nitrogen, they may optionally be present as the N-oxide.
2. The compound according to Claim 1, wherein Rl is selected from:
(1) phenyl,
(2) pyridyl,
(3) indolyl,
(4) 7-aza-indolyl,
(5) thiophenyl, and
Figure imgf000090_0001
wherein each aryl and heteroaryl is optionally substituted with one or two substitutents independently selected from Rb, and each pyridyl may be optionally present as the N-oxide; and pharmaceutically acceptable salts thereof.
The compound according to Claim 2, wherein Rl is selected from:
(1) phenyl,
(2) 3-cyanophenyl,
(3) 3-methylphenyl,
(4) 3 ,5-difluorophenyl,
(5) 3-pyridyl,
(6) 5-chloro-3-pyridyl,
(7) 5-methyl-3 -pyridyl ,
(8) 5-cyano-3-pyridyl,
(9) 1 -oxido-5-cyano-3 -pyridyl ,
(10) 1 -indolyl,
(11) 7-aza-indol-N-yl,
(12) 2-thiophenyl, and
Figure imgf000091_0001
and pharmaceutically acceptable salts thereof.
4. The compound according to Claim 3, wherein Rl is 5-cyano-3- pyridyl; and pharmaceutically acceptable salts thereof.
5. The compound according to Claim 2, wherein R is selected from:
(1) Ci_6alkyl, (2) C3_6cycloalkylmethyl,
(3) phenylmethyl,
(4) heteroarylmethyl, wherein each cycloalkyl, aryl and heteroaryl is optionally substituted with one to three substituents independently selected from Rb, and pharmaceutically acceptable salts thereof.
6. The compound according to Claim 5, wherein R2 is selected from:
(1) 2-methylpropyl,
(2) n-pentyl,
(3) cyclobutylmethyl,
(4) cyclopentylmethyl, (5) cyclohexylmethyl,
(6) benzyl,
(7) 4-chlorobenzyl,
(8) 4-methylbenzyl,
(9) 4-fluorobenzyl, (10) 4-methoxybenzyl, and
(11) (5-chloro-2-pyridyl)methyl; and phaπnaceutically acceptable salts thereof.
7. The compound according to Claim 2, wherein Rd is selected from:
(1) C4-6cycloalkyl,
(2) aryl,
(3) heteroaryl, wherein Rd may be unsubstituted or substituted with one or two substituents selected from Rh, and pharmaceutically acceptable salts thereof.
8. The compound according to Claim 7, wherein Rd is selected from: (1) phenyl,
(2) pyridyl, and
(3) pyrimidinyl, wherein Rd may be unsubstituted or substituted with one or two substituents selected from Rh; and pharmaceutically acceptable salts thereof.
9. The compound according to Claim 8, wherein Rd is selected from:
(I) phenyl, (2) 4-chlorophenyl,
(3) 3-chlorophenyl,
(4) 3,5-difluorophenyl,
(5) 3,5-dichlorophenyl,
(6) 2-pyridyl, (7) 5-chloro-2-pyridyl,
(8) 6-methyl-2-pyridyl,
(9) 5-trifluoromethyl-2-pyridyl,
(10) 4-trifluoromethyl-2-pyridyl,
(II) 4-trifluoromethyl-2-pyrimidyl, and (12) 6-trifluoromethyl-4-pyrimidyl; and pharmaceutically acceptable salts thereof.
10. The compound according to Claim 1, selected from:
(1) N-[3-(4-chlorophenyl)-l-methyl-2-phenylpropyl]-2-(4-chlorophenyloxy)-2- methylpropanamide;
(2) N-[3-(4-chlorophenyl)-l-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2- methylpropanamide;
(3) N-[3-(4-chlorophenyl)-l-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2- methylpropanamide; (4) N-[3-(4-chlorophenyl)-l-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2- methylpropanamide;
(5) N-[3-(4-chlorophenyl)-2-phenyl-l-methylpropyl]-2-(3,5-dichlorophenyloxy)-2- methylpropanamide;
(6) N-[3-(4-chlorophenyl)-l-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2- methylpropanamide;
(7) N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-l-methylpropyl]-2-(2- pyridyloxy)-2-methylpropanamide;
(8) N-[3-(4-chlorophenyl)-l-methyl-2-phenyl-propyl]-2-(5-chloro-2-pyridyloxy)-2- methylpropanamide; (9) N-[3-(4-chlorophenyl)-l-methyl-2-phenylpropyl]-2-(6-methyl-pyridyloxy)-2- methylpropanamide ;
(10) N-[3-(4-chlorophenyl)-l-methyl-2-phenylpropyl]-2-(phenyloxy)-2- methylpropanamide; (11) N-[(3-(4-chlorophenyl)-l-methyl-2-phenylproρyl]-2-(5- trifluoiOmethylpyridyloxy)-2-methylpropanamide;
(12) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-l-methylρropyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide;
(13) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(14) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-l-methylρropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(15) N-[3-(4-chloroρhenyl)-2-(5-methyl-3-pyridyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; (16) N-[3-(4-chloroρhenyl)-2-(5-cyano-3-pyridyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(17) N-[3-(4-chloroρhenyl)-2-(3-methylphenyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(18) N-[3-(4-chlorophenyl)-2-phenyl-l-methylpropyl]-2-(4-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide;
(19) N-[3-(4-chlorophenyl)-2-phenyl-l-methylpropyl]-2-(4-trifluoromethyl-2- pyrimidyloxy)-2-methylpropanamide;
(20) Ν-[3-(4-chloroρhenyl)-l-methyl-2-(thiophen-3-yl)propyl]-2-(5-chloro-2- pyridyloxy)-2-methylpropan amide; (21) N-[3-(5-chloro-2-pyridyl)-2-ρhenyl-l-methylproρyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropan amide;
(22) N-[3-(4-methyl-phenyl)-l-methyl-2-phenylproρyl]-2-(4-trifluoromethyl- phenyloxy)-2-methylpropanamide;
(23) N-[3-(4-fluoro-ρhenyl)-2-(3-cyano-phenyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(24) Ν-[3-(4-chlorophenyl)-2-(l-indolyl)-l-methyl)ρropyl]-2-(5-trifluoromethyl-2- oxypyridine-2-yl)-2-methylpropanamide;
(25) N-[3-(4-chlorophenyl)-2-(7-azaindol-N-yl)-l-methyl)propyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpiOpanamide; (26) N-[3-(4-chloro-phenyl)-2-(l-indolinyl)-l-methylproρyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide;
(27) N-[3-(4-chloro-phenyl)-2-(Ν-methyl-anilino)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; (28) N-[3-(4-methoxy-phenyl)-2-(3-cyano-phenyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(29) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-l-methylpropyl]-2-(6- trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(30) Ν-[2-(3-cyanophenyl)-l,4-dimethylρentyl]-2-(5-trifluoromethyl-2-pyridyloxy)- 2-methylpropanamide;
(31) N-[3-(4-chlorophenyl)-2-(l-oxido-5-cyano-3-pyridyl]-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(32) N- [2-(3-cyanophenyl)-3-cyclobutyl- 1 -methylpropyl] -2-(5 -trifluoromethyl-2- pyridyloxy)-2-methylpropan amide; (33) N-[2-(3-cyanophenyl)-l-methyl-heptyl]-2-(5-trifluoiOmethyl-2-pyridyloxy)-2- methylpropanamide;
(34) N-[2-(3-cyanophenyl)-3-cyclopentyl-l-methylpropyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropan amide;
(35) N-[2-(3-cyanophenyl)-3-cyclohexyl-l-methylpropyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide; and pharmaceutically acceptable salts thereof.
11. The compound according to Claim 9, wherein Rd is 5- trifluoromethyl-2-pyridyl ; and pharmaceutically acceptable salts thereof.
12. The compound according to Claim 11 selected from: ( 1 ) N- [(3-(4-chlorophenyl)- 1 -methyl-2-phenylpropyl] -2-(5- trifluoromethylpyridyloxy)-2-methylpropanamide; (2) N-[3-(4-chlorophenyl)-2-(3-ρyridyl)-l-methylproρyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpiOpanamide;
(3) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(4) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; (5) N-[3-(4-chlorophenyl)-2-(5-methyl-3-ρyridyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(6) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; (7) N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(8) N-[3-(5-chloro-2-ρyridyl)-2-phenyl-l-methylpropyl]-2-(5-trifluoromethyl-2- ρyridyloxy)-2-methylpropan amide;
(9) N-[3-(4-fluoro-ρhenyl)-2-(3-cyano-phenyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(10) Ν-[3-(4-chlorophenyl)-2-(l-indolyl)-l-methyl)proρyl]-2-(5-trifluoromethyl-2- oxypyridine-2-yl)-2-methylpropanamide;
(11) N-[3-(4-chlorophenyl)-2-(7-azaindol-N-yl)-l-methyl)propyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpiOpanamide; (12) N-[3-(4-chloro-ρhenyl)-2-(l-indolinyl)-l-methylpropyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide;
(13) N-[3-(4-chloro-phenyl)-2-(Ν-methyl-anilino)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(14) N-[3-(4-methoxy-phenyl)-2-(3-cyano-phenyl)-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(15) Ν-[2-(3-cyanophenyl)-l,4-dimethylpentyl]-2-(5-trifluoromethyl-2-pyridyloxy)- 2-methylpropanamide;
(16) N-[3-(4-chlorophenyl)-2-(l-oxido-5-cyano-3-pyridyl]-l-methylpropyl]-2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; (17) N-[2-(3-cyanophenyl)-3-cyclobutyl-l-methylpropyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide;
(18) N-[2-(3-cyanophenyl)-l-methyl-heptyl]-2-(5-trifluoiOmethyl-2-pyridyloxy)-2- methylpropanamide;
(19) N-[2-(3-cyanophenyl)-3-cyclopentyl-l-methylpropyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropanamide;
(20) N-[2-(3-cyanophenyl)-3-cyclohexyl-l-methylpropyl]-2-(5-trifluoromethyl-2- pyridyloxy)-2-methylpropan amide; and pharmaceutically acceptable salts thereof.
13. A composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier.
14. The use of a compound according to Claim 1, for the manufacture of a medicament useful for the treatment of a disease mediated by the Cannabinoid-1 receptor in a human patient in need of such treatment.
15. The use according to Claim 14 wherein the disease mediated by the Cannabinoid-1 receptor is an eating disorder associated with excessive food intake.
16. The use according to Claim 15 wherein the eating disorder associated with excessive food intake is obesity.
17. The use of a compound according to Claim 1 for the manufacture of a medicament for the prevention of obesity in a person at risk therefor.
PCT/US2003/007039 2002-11-22 2003-03-07 Substituted amides active at the cannabinoid-1 receptor WO2004048317A1 (en)

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BR0308349-7A BR0308349A (en) 2002-11-22 2003-03-07 Compound, composition, and use of a compound
YUP-791/04A RS79104A (en) 2002-11-22 2003-03-07 Substituted amides active at the cannabinoid-1 receptor
EA200401066A EA007747B1 (en) 2002-11-22 2003-03-07 Submitted amides active at the cannabinoid-1 receptor
AU2003218005A AU2003218005A1 (en) 2002-11-22 2003-03-07 Substituted amides active at the cannabinoid-1 receptor
MXPA04008748A MXPA04008748A (en) 2002-11-22 2003-03-07 Substituted amides active at the cannabinoid-1 receptor.
KR1020047014299A KR100748380B1 (en) 2002-11-22 2003-03-07 Substituted amides active at the cannabinoid-1 receptor
CNA03805678XA CN1639112A (en) 2002-11-22 2003-03-07 Substituted amides active at the cannabinoid-1 receptor
IL16382403A IL163824A0 (en) 2002-11-22 2003-03-07 Substituted amides active at the cannabinoid-1 receptor
UA20040907424A UA76590C2 (en) 2002-11-22 2003-07-03 Substituted amides acting on receptor of cannabinoid-1
IS7411A IS7411A (en) 2002-11-22 2004-08-19 Substituted amides active at the cannabinoid-1 receptor
TNP2004000176A TNSN04176A1 (en) 2002-11-22 2004-09-10 Substituted amides active at the cannabinoid-1 receptor
NO20043803A NO20043803L (en) 2002-11-22 2004-09-10 Substituted amides active in the cannabinoid 1 receptor
HR20040823A HRP20040823A2 (en) 2002-11-22 2004-09-10 Substituted amides active at the cannabinoid-1 receptor

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EA (1) EA007747B1 (en)
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HR (1) HRP20040823A2 (en)
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Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1623741A2 (en) 2004-07-22 2006-02-08 Cadila Healthcare Ltd. Cannabinoid receptor ligands for hair growth modulation
EP1641493A1 (en) * 2003-06-30 2006-04-05 Merck & Co., Inc. Radiolabeled cannabinoid-1 receptor modulators
WO2006035760A1 (en) * 2004-09-27 2006-04-06 Santen Pharmaceutical Co., Ltd. Drug for treating skin disease
WO2006035759A1 (en) * 2004-09-27 2006-04-06 Santen Pharmaceutical Co., Ltd. Drug for treating respiratory disease
WO2006043518A1 (en) * 2004-10-18 2006-04-27 Santen Pharmaceutical Co., Ltd. Drug for treating neurological disease
EP1682494A1 (en) * 2003-10-30 2006-07-26 Merck & Co., Inc. Aralkyl amines as cannabinoid receptor modulators
US7091216B2 (en) 2002-08-02 2006-08-15 Merck & Co., Inc. Substituted furo[2,3-b]pyridine derivatives
EP1765771A2 (en) * 2004-07-08 2007-03-28 Merck & Co., Inc. Formation of tetra-substituted enamides and stereoselective reduction thereof
WO2007041052A2 (en) 2005-09-29 2007-04-12 Merck & Co., Inc. Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
WO2007062314A2 (en) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Heterocyclic cetp inhibitors
WO2008017381A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
WO2006119260A3 (en) * 2005-05-02 2008-02-28 Merck & Co Inc Combination of dipeptidyl peptidase-iv inhibitor and a cannabinoid cb1 receptor antagonist for the treatment of diabetes and obesity
US7348456B2 (en) 2002-12-19 2008-03-25 Merck & Co., Inc. Substituted amides
WO2008059335A1 (en) 2006-11-13 2008-05-22 Pfizer Products Inc. Diaryl, dipyridinyl and aryl-pyridinyl derivatives and uses thereof
WO2008070496A2 (en) 2006-12-01 2008-06-12 Bristol-Myers Squibb Company N- ( (3-benzyl) -2, 2- (bis-phenyl) -propan-1-amine derivatives as cetp inhibitors for the treatment of atherosclerosis and cardiovascular diseases
WO2008120653A1 (en) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Indoledione derivative
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
EP2078729A1 (en) 2005-02-04 2009-07-15 Pfizer Products Inc. PPY agonists and uses thereof
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
US7649002B2 (en) 2004-02-04 2010-01-19 Pfizer Inc (3,5-dimethylpiperidin-1yl)(4-phenylpyrrolidin-3-yl)methanone derivatives as MCR4 agonists
WO2010051236A1 (en) 2008-10-30 2010-05-06 Merck Sharp & Dohme Corp. Isonicotinamide orexin receptor antagonists
WO2010056717A1 (en) 2008-11-17 2010-05-20 Merck Sharp & Dohme Corp. Substituted bicyclic amines for the treatment of diabetes
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
US7816534B2 (en) 2002-03-12 2010-10-19 Merck Sharp & Dohme Corp. Substituted amides
WO2011011508A1 (en) 2009-07-23 2011-01-27 Schering Corporation Benzo-fused oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors
WO2011011506A1 (en) 2009-07-23 2011-01-27 Schering Corporation Spirocyclic oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
WO2011137024A1 (en) 2010-04-26 2011-11-03 Merck Sharp & Dohme Corp. Novel spiropiperidine prolylcarboxypeptidase inhibitors
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EP2392567A1 (en) 2005-10-21 2011-12-07 Bristol-Myers Squibb Company Benzothiazine derivatives and their use as lxr modulators
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US8138188B2 (en) 2006-02-23 2012-03-20 Pfizer Inc. Melanocortin type 4 receptor agonist piperidinoylpyrrolidines
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WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
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US8592403B2 (en) 2008-08-06 2013-11-26 Pfizer Limited Diazepine and diazocane compounds as MC4 agonists
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998041519A1 (en) * 1997-03-18 1998-09-24 Smithkline Beecham Corporation Novel cannabinoid receptor agonists
WO2002068388A2 (en) * 2001-02-28 2002-09-06 Merck & Co., Inc. Acylated piperidine derivatives as melanocortin-4 receptor agonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998041519A1 (en) * 1997-03-18 1998-09-24 Smithkline Beecham Corporation Novel cannabinoid receptor agonists
WO2002068388A2 (en) * 2001-02-28 2002-09-06 Merck & Co., Inc. Acylated piperidine derivatives as melanocortin-4 receptor agonists

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7816534B2 (en) 2002-03-12 2010-10-19 Merck Sharp & Dohme Corp. Substituted amides
US7091216B2 (en) 2002-08-02 2006-08-15 Merck & Co., Inc. Substituted furo[2,3-b]pyridine derivatives
US7576239B2 (en) 2002-12-19 2009-08-18 Merck & Co., Inc. Substituted amides
US7348456B2 (en) 2002-12-19 2008-03-25 Merck & Co., Inc. Substituted amides
EP1641493A1 (en) * 2003-06-30 2006-04-05 Merck & Co., Inc. Radiolabeled cannabinoid-1 receptor modulators
EP1641493A4 (en) * 2003-06-30 2007-10-31 Merck & Co Inc Radiolabeled cannabinoid-1 receptor modulators
US7390835B2 (en) 2003-10-30 2008-06-24 Merck & Co., Inc. Aralkyl amines as cannabinoid receptor modulators
EP1682494A1 (en) * 2003-10-30 2006-07-26 Merck & Co., Inc. Aralkyl amines as cannabinoid receptor modulators
EP1682494A4 (en) * 2003-10-30 2006-11-08 Merck & Co Inc Aralkyl amines as cannabinoid receptor modulators
US7649002B2 (en) 2004-02-04 2010-01-19 Pfizer Inc (3,5-dimethylpiperidin-1yl)(4-phenylpyrrolidin-3-yl)methanone derivatives as MCR4 agonists
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US7629470B2 (en) 2004-07-08 2009-12-08 Merck & Co., Inc. Formation of tetra-substituted enamides and stereoselective reduction thereof
EP1623741A2 (en) 2004-07-22 2006-02-08 Cadila Healthcare Ltd. Cannabinoid receptor ligands for hair growth modulation
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AR038948A1 (en) 2005-02-02
CN1639112A (en) 2005-07-13
EA007747B1 (en) 2006-12-29
MA27185A1 (en) 2005-01-03
KR20050083563A (en) 2005-08-26
TW200408620A (en) 2004-06-01
EA200401066A1 (en) 2005-04-28
HRP20040823A2 (en) 2005-06-30
TNSN04176A1 (en) 2007-03-12
DOP2003000609A (en) 2004-06-15
RS79104A (en) 2007-02-05
UA76590C2 (en) 2006-08-15
GEP20074208B (en) 2007-10-10
KR100748380B1 (en) 2007-08-10
ECSP045289A (en) 2004-10-26
PL373656A1 (en) 2005-09-05
BR0308349A (en) 2005-01-25
MXPA04008748A (en) 2004-12-06
NO20043803L (en) 2005-05-24
IL163824A0 (en) 2005-12-18
AU2003218005A1 (en) 2004-06-18
PL200328B1 (en) 2008-12-31
MY134457A (en) 2007-12-31
JO2482B1 (en) 2009-01-20
CR7432A (en) 2005-10-05
IS7411A (en) 2004-08-19
PE20040599A1 (en) 2004-09-08

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